Summary: development and regulatory status as of October 2026

The FDA approved a supplemental new drug application (NDA 219132, supplement 2) for levacetylleucine (Aqneursa) for oral suspension on 18 September 2026 for the treatment of ataxia in adults and pediatric patients with ataxia-telangiectasia (A-T) weighing at least 15 kg. The approval was granted to IntraBio Inc., and the FDA describes Aqneursa as the first treatment approved for ataxia in patients with A-T. The supplement was dated and received on 19 March 2026. IntraBio announced in May 2026 that the FDA had accepted it with priority review and a PDUFA target action date of 19 September 2026. Levacetylleucine has held orphan drug designation for A-T since 2 October 2018, and the FDA orphan drug record lists the exclusivity end date for the A-T approval as "TBD". Efficacy was evaluated in one randomized, double-blind, placebo-controlled, two-period crossover study of 73 participants (Trial 2, NCT06673056). IntraBio stated in its approval announcement that the product was commercially available. Levacetylleucine was first approved on 24 September 2024 for neurological manifestations of Niemann-Pick disease type C (NPC) with priority review, fast track, orphan drug, and rare pediatric disease designations, and a rare pediatric disease priority review voucher was granted with that approval. The Orange Book lists new chemical entity exclusivity through 24 September 2029, orphan drug exclusivity for the NPC indication through 24 September 2031, and four patents expiring 19 April 2037, one of which (patent 12144792, use code U-4603, submitted 23 September 2026) carries a use code for A-T. In the European Union, Aqneursa was authorised for NPC on 19 January 2026. IntraBio announced a variation application for A-T in June 2026, and the draft agenda of the CHMP meeting of 14 to 17 September 2026 lists the extension of indication for adoption. Acetylleucine has held European Union orphan designation for A-T since 11 January 2019.

Regulatory submission: sNDA submitted March 2026 and approved September 2026

“Please refer to your supplemental new drug application (sNDA) dated March 19, 2026, received March 19, 2026, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for Aqneursa (levacetylleucine), for oral suspension.” (opens the source at this quote in a new tab)
“This Prior Approval sNDA provides for use of Aqneursa as a treatment of ataxia in adults and pediatric patients with ataxia-telangiectasia weighing ≥ 15 kg.” (opens the source at this quote in a new tab)
“We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling.” (opens the source at this quote in a new tab)

“IntraBio Inc. today announced the submission of a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for levacetylleucine for the treatment of Ataxia-Telangiectasia (A-T), a rare, progressive, inherited neurodegenerative disorder.” (opens the source at this quote in a new tab)

Action date	Submission	Supplement categories or approval type
“09/18/2026”	“SUPPL-2”	“Efficacy-New Indication”

Launch: Commercially available at approval in September 2026

“AQNEURSA is commercially available now” (opens the source at this quote in a new tab)
“Second FDA-approved indication for AQNEURSA, following previous approval for Niemann-Pick disease type C (NPC)” (opens the source at this quote in a new tab)

Field	Quoted record
Marketing approval date	“09/18/2026”
Approved labeled indication	“treatment of ataxia in adults and pediatric patients with ataxia-telangiectasia (A-T) weighing > or = 15 kg”

FDA approval on 18 September 2026

“The U.S. Food and Drug Administration has approved Aqneursa (levacetylleucine) for oral suspension to treat ataxia in adults and pediatric patients with ataxia-telangiectasia weighing at least 15 kg (about 33 pounds).” (opens the source at this quote in a new tab)
“Aqneursa was previously approved in 2024 to treat the neurological manifestations of Niemann-Pick disease type C.” (opens the source at this quote in a new tab)
“Today’s approval makes Aqneursa the first treatment approved for ataxia in patients with ataxia-telangiectasia.” (opens the source at this quote in a new tab)
“Approval was granted to IntraBio Inc.” (opens the source at this quote in a new tab)

“IntraBio Inc., a leader in the discovery, development, and commercialization of novel therapies for rare and common neurodegenerative diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved AQNEURSA® (levacetylleucine) for the treatment of ataxia in adult and pediatric patients with ataxia-telangiectasia (A-T) weighing ≥15 kg.” (opens the source at this quote in a new tab)
“AQNEURSA is the first and only drug approved for the treatment of A-T anywhere in the world.” (opens the source at this quote in a new tab)

“Initial U.S. Approval: 2024” (opens the prescribing information at this quote)
“Indications and Usage (1.2) 9/2026” (opens the prescribing information at this quote)
“Revised: 9/2026” (opens the prescribing information at this quote)

Evidence supporting approval

“The safety and efficacy of AQNEURSA for the treatment of ataxia in patients with A-T were evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study that evaluated the efficacy of AQNEURSA in 73 patients (Trial 2; NCT06673056).” (opens the prescribing information at this quote)

“The effectiveness of Aqneursa was evaluated in a randomized, double-blind, placebo-controlled, two-period crossover study (NCT06673056) of 73 patients aged 4 years or older with a confirmed diagnosis of ataxia-telangiectasia.” (opens the source at this quote in a new tab)

“The approval is supported by the pivotal IB1001-303 study (NCT06673056), a randomized, double-blind, placebo-controlled, crossover trial that enrolled 73 patients aged 4 to 50 years with genetically confirmed A-T across 10 clinical trial sites in Germany, Slovakia, Spain, Switzerland, the United Kingdom, and the United States.” (opens the source at this quote in a new tab)
“These findings were published in the July 2026 issue of The Lancet Neurology.” (opens the source at this quote in a new tab)

Supplemental application timeline: topline results and planned submissions

“Based on these results, IntraBio plans to immediately advance regulatory submissions to the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and additional global regulatory authorities.” (opens the source at this quote in a new tab)
“Levacetylleucine is an investigational drug for A-T and has not yet been approved by the FDA or any other regulatory authority for this indication.” (opens the source at this quote in a new tab)

“Based on the robust findings from the study, IntraBio is proceeding immediately with regulatory submissions to the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), and additional global regulatory authorities, to support the label expansion of levacetylleucine for A-T.” (opens the source at this quote in a new tab)

Supplemental application timeline: sNDA submission

“This submission represents the first regulatory application submitted to the U.S. Food and Drug Administration seeking approval of a therapy for the treatment of Ataxia-Telangiectasia.” (opens the source at this quote in a new tab)
“The sNDA seeks to expand the label of levacetylleucine, marketed as AQNEURSA®, to include A-T.” (opens the source at this quote in a new tab)
“The submission is supported by data from a pivotal Phase III clinical trial evaluating levacetylleucine in adult and pediatric patients with A-T.” (opens the source at this quote in a new tab)

Supplemental application timeline: FDA acceptance and priority review

“IntraBio Inc., a global biopharmaceutical company focused on developing and commercializing therapies for neurological diseases, today announced that the U.S. Food and Drug Administration (FDA) has accepted for review its supplemental New Drug Application (sNDA) for AQNEURSA® (levacetylleucine) for the treatment of Ataxia-Telangiectasia (A-T) in adults and pediatric patients.” (opens the source at this quote in a new tab)
“The FDA simultaneously granted Priority Review and assigned a PDUFA target action date of 19 September 2026.” (opens the source at this quote in a new tab)

Expedited programs: priority review and orphan drug designation for A-T

“Aqneursa received Orphan Drug designation and Priority Review for the ataxia-telangiectasia indication.” (opens the source at this quote in a new tab)

Special FDA designations: orphan drug designation for A-T

Field	Quoted record
Generic name	“levacetylleucine”
Trade name	“Aqneursa”
Date designated	“10/02/2018”
Orphan designation	“Treatment of Ataxia Telangiectasia”
Orphan designation status	“Designated/Approved”
Sponsor	“IntraBio Inc.”
Marketing approval date	“09/18/2026”
Exclusivity end date	“TBD”

Exclusivity listed in the Orange Book

Exclusivity code	Exclusivity expiration
“NCE”	“09/24/2029”
“ODE-498”	“09/24/2031”

Patents listed in the Orange Book

Patent number	Patent expiration	Patent use code	Submission date
“11400067”	“04/19/2037”	“U-4170”	“04/22/2025”
“12144792”	“04/19/2037”	“U-4603”	“09/23/2026”
“12433862”	“04/19/2037”	“U-4284”	“10/22/2025”
“12433863”	“04/19/2037”	“U-4285”	“10/22/2025”

Patent listing requirement for the supplement

“You must submit the patent information required by 21 CFR 314.53(d)(2)(i)(A) through (C) and 314.53(d)(2)(ii)(A) and (C), as applicable, to FDA on Form FDA 3542 within 30 days after the date of approval of the supplement for the patent information to be timely filed (see 21 CFR 314.53(c)(2)(ii)).” (opens the source at this quote in a new tab)

U.S. patents marked by the manufacturer

“The following U.S. patents apply to IntraBio Inc’s product, AQNEURSA®:” (opens the source at this quote in a new tab)
“and other pending patent applications.” (opens the source at this quote in a new tab)

Product history: first FDA approval for Niemann-Pick disease type C in 2024

“Today, the U.S. Food and Drug Administration approved Aqneursa (levacetylleucine) for the treatment of neurological symptoms associated with Niemann-Pick disease type C (NPC) in adults and pediatric patients weighing at least 15 kilograms.” (opens the source at this quote in a new tab)
“The FDA granted Aqneursa Priority Review, Fast Track, Orphan Drug and Rare Pediatric Disease designations for this application.” (opens the source at this quote in a new tab)

Action date	Submission	Action type	Submission classification	Review priority; orphan status
“09/24/2024”	“ORIG-1”	“Approval”	“Type 1 - New Molecular Entity”	“PRIORITY; Orphan”

“Please refer to your new drug application (NDA), dated and received January 24, 2024, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA), for Aqneursa (levacetylleucine) for oral suspension.” (opens the source at this quote in a new tab)

Product history: rare pediatric disease priority review voucher granted with the 2024 approval

“We also inform you that you have been granted a rare pediatric disease priority review voucher, as provided under section 529 of the FDCA.” (opens the source at this quote in a new tab)
“This priority review voucher (PRV) has been assigned a tracking number, PRV NDA 219132.” (opens the source at this quote in a new tab)

“FDA has determined that AQNEURSA (levacetylleucine), approved on September 24, 2024, manufactured by IntraBio Inc., meets the criteria for a priority review voucher.” (opens the source at this quote in a new tab)

Product history: advisory committee for the original application

“Your application for Aqneursa was not referred to an FDA advisory committee because the application did not raise significant public health questions on the role of the drug in the diagnosis, cure, mitigation, treatment, or prevention of a disease.” (opens the source at this quote in a new tab)

Pivotal trial enrollment milestone

“IntraBio’s Phase III Pivotal trial investigating N-Acetyl-L-Leucine (levacetylleucine) for Ataxia-Telangiectasia has completed recruitment in under two months, ultimately over-enrolling the trial by over 167%. Data readout is expected in Q1 of 2026.” (opens the source at this quote in a new tab)

Regulatory status outside the United States: European Union authorisation for Niemann-Pick disease type C

“Aqneursa received a marketing authorisation valid throughout the EU on 19 January 2026.” (opens the source at this quote in a new tab)
“Aqneursa is a medicine used to treat neurological symptoms (symptoms affecting the brain and nerves) of Niemann-Pick type C (NPC) disease in adults and children aged 6 years and older who weigh at least 20 kg.” (opens the source at this quote in a new tab)

Field	Quoted record
EMA product number	“EMEA/H/C/006327”
Marketing authorisation holder	“Intrabio Ireland Limited”
Opinion adopted	“13/11/2025”
Marketing authorisation issued	“19/01/2026”

Regulatory status outside the United States: European Union orphan designation for A-T

“On 11 January 2019, orphan designation (EU/3/18/2124) was granted by the European Commission to IntraBio Limited, United Kingdom, for acetylleucine for treatment of ataxia telangiectasia.” (opens the source at this quote in a new tab)
“The sponsorship was transferred to IntraBio Ireland Ltd, Ireland, in April 2019.” (opens the source at this quote in a new tab)

Regulatory status outside the United States: variation application to the EMA for A-T

“IntraBio Inc. today announced the submission of a variation application to the European Medicines Agency (EMA) to expand the approved Marketing Authorization Application (MAA) for AQNEURSA® (levacetylleucine) to include the treatment of Ataxia-Telangiectasia (A-T).” (opens the source at this quote in a new tab)
“This submission represents the first regulatory application submitted to the EMA seeking approval of a therapy for the treatment of A-T, a rare, progressive, inherited neurodegenerative disorder.” (opens the source at this quote in a new tab)
“The variation application is subject to EMA validation before the start of formal scientific review.” (opens the source at this quote in a new tab)

Regulatory status outside the United States: scope of the European Union variation under CHMP review

“AQNEURSA - Levacetylleucine - ORPHAN - EMA/VR/0000354947” (opens the source at this quote in a new tab)
“C.6: Extension of indication to include treatment of Ataxia-telangiectasia for AQNEURSA based on results from study IB1001-303.” (opens the source at this quote in a new tab)
“As a consequence, sections 4.1, 4.2, 4.8 and 5.1 of the SmPC are updated.” (opens the source at this quote in a new tab)
“Version 2.0 of the RMP has also been submitted.” (opens the source at this quote in a new tab)
“C.6: Modification of the approved indication for Niemann-Pick type C disease to include treatment of the neurological manifestations in patients aged 4 years and older and weighing at least 15 kg based on results from study IB1001-301.” (opens the source at this quote in a new tab)
“Action: For adoption” (opens the source at this quote in a new tab)

Regulatory status outside the United States: extensions of indication recommended at the September 2026 CHMP meeting

“The committee recommended extensions of indication for another 10 medicines that are already authorised in the European Union (EU): Abiraterone Mylan, Cosentyx, Enhertu, Jyseleca, Keytruda, Ocrevus, Padcev, Pepaxti, Sogroya, and Tecvayli.” (opens the source at this quote in a new tab)

Generic name

“AQNEURSA® (levacetylleucine) for oral suspension” (opens the prescribing information at this quote)

Drug name	Active ingredients	Strength	Dosage form/route	Marketing status
“AQNEURSA”	“LEVACETYLLEUCINE”	“1GM/PACKET”	“FOR SUSPENSION;ORAL”	“Prescription”

Brand name

“AQNEURSA® is a registered trademark of IntraBio.” (opens the prescribing information at this quote)

Manufacturer: IntraBio

“Approval was granted to IntraBio Inc.” (opens the source at this quote in a new tab)

“Distributed by: IntraBio Inc., Austin TX 78701” (opens the prescribing information at this quote)

“IntraBio Inc. is a global biopharmaceutical company headquartered in Austin, Texas, focused on developing and commercializing targeted therapies for rare and common neurological, neurodevelopmental, and mitochondrial diseases.” (opens the source at this quote in a new tab)

Development code and synonyms

“The objective of this study is to evaluate the safety, tolerability and efficacy of N-acetyl-L-leucine (IB1001) compared to standard of care.” (opens the source at this quote in a new tab)

“We evaluated the safety and efficacy of N-acetyl-l-leucine (NALL), an agent that potentially ameliorates lysosomal and metabolic dysfunction, for the treatment of Niemann-Pick disease type C.” (opens the source at this quote in a new tab)

Field	Quoted record
Name of medicine	“Aqneursa”
Active substance	“L-acetylleucine”
International non-proprietary name (INN) or common name	“L-acetylleucine”

“Aqneursa contains the active substance levacetylleucine.” (opens the source at this quote in a new tab)

Therapeutic class: modified amino acid

“AQNEURSA (levacetylleucine) for oral suspension contains the drug substance levacetylleucine, a modified amino acid.” (opens the prescribing information at this quote)

“AQNEURSA® (levacetylleucine) is a first-in-class, chemically modified amino acid approved by the FDA for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adults and pediatric patients weighing ≥15 kg and for ataxia in in adults and pediatric patients with ataxia-telangiectasia (A-T) weighing ≥15 kg.” (opens the source at this quote in a new tab)
“It is taken orally as a suspension.” (opens the source at this quote in a new tab)

Chemical description

“Levacetylleucine is slightly soluble in aqueous solutions.” (opens the prescribing information at this quote)
“The chemical name is 2-acetamido-4-methylpentanoic acid.” (opens the prescribing information at this quote)
“The empirical formula is C8H15NO3 and the molecular weight is 173.21.” (opens the prescribing information at this quote)

Enantiomer: distinction from N-acetyl-DL-leucine and N-acetyl-D-leucine

“Avoid concomitant use of AQNEURSA with N-acetyl-DL-leucine and N-acetyl-D-leucine.” (opens the prescribing information at this quote)
“The D-enantiomer, N-acetyl-D-leucine, competes with levacetylleucine for monocarboxylate transporter uptake, which may reduce the levacetylleucine efficacy.” (opens the prescribing information at this quote)

Granules for oral suspension: strength and appearance

“For oral suspension: 1 gram levacetylleucine in a unit-dose packet.” (opens the prescribing information at this quote)
“For oral suspension: 1 gram levacetylleucine as white to off-white strawberry flavored granules in a unit-dose packet.” (opens the prescribing information at this quote)
“One AQNEURSA packet contains 1 gram levacetylleucine.” (opens the prescribing information at this quote)

Packet contents and inactive ingredients

“Each packet of AQNEURSA granules contains 1 gram levacetylleucine and the inactive ingredients hypromellose, isomalt and strawberry flavor.” (opens the prescribing information at this quote)
“Each packet contains 1.7 gram white to off-white granules, equivalent to 1 gram levacetylleucine.” (opens the prescribing information at this quote)

Package and national drug code

Package	Contents	NDC
Carton	“Carton containing 28 unit-dose packets”	“83853-101-01”

Storage

“Store AQNEURSA at room temperature between 20°C to 25°C (68°F to 77°F); excursion permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].” (opens the prescribing information at this quote)

Expiry dating period

“Based on the stability data submitted to date, the expiry dating period for Aqneursa (levacetylleucine) for oral suspension shall be 24 months from the date of manufacture when stored at 20°C to 25°C (68°F to 77°F).” (opens the source at this quote in a new tab)

European Union presentation

“Aqneursa 1 g granules for oral suspension in sachet” (opens the source at this quote in a new tab)
“Each sachet contains 1 g levacetylleucine.” (opens the source at this quote in a new tab)
“Each sachet contains 642.2 mg isomalt and 0.153 mg propylene glycol.” (opens the source at this quote in a new tab)

Material safety data sheet

No evidence found.

Wholesale acquisition cost at U.S. introduction: manufacturer filing with the California Department of Health Care Access and Information

Field	Quoted record
Manufacturer name	“Intrabio Inc.”
National drug code	“83853010101”
Drug product description	“Aqneursa (levacetylleucine) 1 gram sachet, carton of 28”
Date introduced to market	“2024-09-24”
Wholesale acquisition cost at introduction (USD)	“13450.0000”

Cost per packet and cost at the maximum labeled dose: Oklahoma Medicaid review, February 2025

Product	Cost per unit	Cost per 30 days	Cost per year
Aqneursa (levacetylleucine) 1 g packet	“$480.36”	“$57,643.20”	“$691,718.40”

“Cost per 30 days based on the FDA approved max dose of 4g per day.” (opens the source at this quote in a new tab)
“Unit = each capsule or packet” (opens the source at this quote in a new tab)
“Costs do not reflect rebated prices or net costs. Costs based on National Average Drug Acquisition Costs (NADAC), Wholesale Acquisition Costs (WAC), or State Maximum Allowable Costs (SMAC).” (opens the source at this quote in a new tab)

Estimated wholesale acquisition cost per 28 days: pharmacy benefit manager summary, fourth quarter 2024

Product	Estimated wholesale acquisition cost (WAC)
Aqneursa (levacetylleucine)	“$40K per 28 days”

Company price disclosure at the 2024 launch

“IntraBio has not released the cost of its medication and did not answer questions about pricing but said it has an access program that will help cover the cost of the medication while working with insurance to pay for it.” (opens the source at this quote in a new tab)

Federal Supply Schedule and Big Four prices per carton of 28 packets

Price type	Quoted trade name	Quoted package	Quoted price (USD)	Quoted price start date	Quoted price stop date
Federal Supply Schedule	“AQNEURSA 1GM/PKT GRANULES”	“28”	“13339.54”	“01/01/2026”	“06/30/2030”
Big Four	“AQNEURSA 1GM/PKT GRANULES”	“28”	“10206.02”	“01/01/2026”	“06/30/2030”

New York Medicaid maximum reimbursable amount per packet: list effective 29 September 2026

Field	Quoted record
Description	“AQNEURSA 1 GRAM GRANULE PACKET”
National drug code	“83853-0101-01”
Maximum reimbursable amount cost	“555.7142800”
Basis of maximum reimbursable amount	“EA”
Effective date	“09/29/2026”
Maximum quantity	“112.000”

“Displays the maximum total reimbursement per drug unit.” (opens the source at this quote in a new tab)

Reported cost at the time of the ataxia-telangiectasia approval: Fierce Pharma, September 2026

“The drugmaker manages a financial support program to help families offset the out-of-pocket costs of Agneursa, which can cost $15,000 every one to two weeks.” (opens the source at this quote in a new tab)

Pharmacy cash price per carton of 28 packets

“The cost for Aqneursa 1 g oral granule for reconstitution is around $15,207 for a supply of 28 granule for reconstitution, depending on the pharmacy you visit. Quoted prices are for cash-paying customers and are not valid with insurance plans.” (opens the source at this quote in a new tab)

Wholesale acquisition cost announced with the ataxia-telangiectasia approval

No evidence found.

Annual cost by body weight band

No evidence found.

National Average Drug Acquisition Cost

No evidence found.

Average sales price

Not applicable.

AHFS classification

“Drug class: Other Miscellaneous Therapeutic Agents” (opens the source at this quote in a new tab)

ATC classification: WHO index

ATC level	Code	Name
Anatomical main group	“N”	“NERVOUS SYSTEM”
Therapeutic subgroup	“N07”	“OTHER NERVOUS SYSTEM DRUGS”
Chemical subgroup	“N07XX”	“Other nervous system drugs”
Chemical substance	“N07XX27”	“levacetylleucine”

ATC classification: European Medicines Agency record

Field	Quoted record
Anatomical therapeutic chemical (ATC) code	“N07XX27”
Pharmacotherapeutic group	“Other nervous system drugs”

FDA pharmacologic class indexing

Field	Quoted record
Product NDC	“83853-101”
Pharmacologic class	“Bile Salt Export Pump Inhibitors [MoA]”
Pharmacologic class	“Breast Cancer Resistance Protein Inhibitors [MoA]”
Pharmacologic class	“Organic Anion Transporter 1 Inhibitors [MoA]”
Pharmacologic class	“Organic Anion Transporter 3 Inhibitors [MoA]”
Pharmacologic class	“P-Glycoprotein Inhibitors [MoA]”

U.S. indication: ataxia in ataxia-telangiectasia

“AQNEURSA is indicated for the treatment of ataxia in adults and pediatric patients with ataxia-telangiectasia (A-T) weighing ≥15 kg.” (opens the prescribing information at this quote)

“This Prior Approval sNDA provides for use of Aqneursa as a treatment of ataxia in adults and pediatric patients with ataxia-telangiectasia weighing ≥ 15 kg.” (opens the source at this quote in a new tab)

U.S. indication: signs and symptoms that ataxia comprises

“Ataxia may be comprised of multiple signs and symptoms, including gait ataxia, truncal ataxia, oculomotor ataxia, and difficulties with balance, speech, and hand coordination.” (opens the prescribing information at this quote)

U.S. indication: Niemann-Pick disease type C

“AQNEURSA® is indicated for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adults and pediatric patients weighing ≥15 kg.” (opens the prescribing information at this quote)

European Union therapeutic indication and status of the A-T extension

“Aqneursa is indicated for the treatment of neurological manifestations of Niemann-Pick type C (NPC) disease, in combination with miglustat, or as a monotherapy in patients where miglustat is not tolerated, in adults and children aged 6 years and older and weighing at least 20 kg.” (opens the source at this quote in a new tab)

“C.6: Extension of indication to include treatment of Ataxia-telangiectasia for AQNEURSA based on results from study IB1001-303.” (opens the source at this quote in a new tab)

Molecular target: prescribing information

“The distinct molecular target for levacetylleucine in the treatment of NPC or A-T is unknown.” (opens the prescribing information at this quote)

Mechanism as described by the European regulator

“The exact way the active substance in Aqneursa, levacetylleucine, works is not known. However, studies in animals suggest that it may help correct the cells’ ability to generate energy. This includes the cells’ ability to make adenosine triphosphate, the main source of energy for cells in the brain that control movement and balance.” (opens the source at this quote in a new tab)

“Aqneursa contains levacetylleucine that targets underlying processes of neurological dysfunction. Nonclinical studies demonstrated that levacetylleucine corrects energy metabolism, including improving adenosine triphosphate production.” (opens the source at this quote in a new tab)

“No studies researched the mechanism of action on the target.” (opens the source at this quote in a new tab)
“The mode of action of levacetylleucine in NPC disease is unclear.” (opens the source at this quote in a new tab)
“Mechanism of action is described very generally. Symptomatic, neuroprotective and disease-modifying effect is claimed. Based on results from period of 12 weeks of treatment, improvements have been observed, which may indicate symptomatic treatment rather than a disease modifying effect.” (opens the source at this quote in a new tab)

Proposed mechanism stated by the investigators of the A-T phase 3 trial

“Levacetylleucine (N-acetyl-L-leucine) is a modified amino acid that enters enzyme-controlled pathways to correct metabolic dysfunction, improve function of the lysosomal-mitochondrial axis, and restore membrane potential and cellular signaling.” (opens the source at this quote in a new tab)

Rationale in A-T: mitochondrial and metabolic function

“The increasingly recognized role of ATM in oxidative stress was also considered and how it was pertinent to mitochondrial dysfunction, metabolic abnormalities and energy metabolism in A-T.” (opens the source at this quote in a new tab)
“An important contribution to the meeting was the description of pathways /mechanisms that have led to the development of therapeutic approaches for A-T including the use of specific antisense oligonucleotides to restore ATM function in patients; delivery of full-length ATM cDNA to A-T cells; eDSP (formerly EryDex) that encapsulates dexamethasone sodium phosphate in a patient's own red blood cells and the use of small molecules (triheptanoin, nicotinamide riboside and N-acetyl leucine) to correct mitochondrial and metabolic function.” (opens the source at this quote in a new tab)

Shared neurological manifestations as the basis for one development protocol across NPC, GM2 gangliosidoses, and A-T

“Despite their different etiologies, NPC, GM2, and A-T are all characterized by progressive neurodegeneration of the cerebellum and cerebrum, resulting in physical and cognitive decline, and premature death.” (opens the source at this quote in a new tab)
“Owing to their common neurological manifestations, and the mechanism of action of the investigational product N-acetyl-l-leucine, a single master protocol has been developed for the three disorders.” (opens the source at this quote in a new tab)

Cellular uptake: acetylation switches transport from LAT1 to MCT1 and organic anion transporters

“Here we show that acetylation of leucine switches its uptake into cells from the l-type amino acid transporter (LAT1) used by leucine to organic anion transporters (OAT1 and OAT3) and the monocarboxylate transporter type 1 (MCT1).” (opens the source at this quote in a new tab)
“Both the kinetics of MCT1 (lower affinity compared to LAT1) and the ubiquitous tissue expression of MCT1 make it well suited for uptake and distribution of N-acetyl-l-leucine.” (opens the source at this quote in a new tab)
“MCT1-mediated uptake of a N-acetyl-l-leucine as a prodrug of leucine bypasses LAT1, the rate-limiting step in activation of leucine-mediated signalling and metabolic process inside cells such as mTOR.” (opens the source at this quote in a new tab)
“Our calculations show that at physiological pH, l-leucine is a zwitterion, whereas N-acetyl-l-leucine is present as mainly an anion.” (opens the source at this quote in a new tab)
“We found that N-acetyl-l-leucine was a substrate of MCT1 with a Km of 3.0 mM (Fig. 4a) and an inhibitor of MCT1 (Fig. 4c) with an IC50 of 15 mM.” (opens the source at this quote in a new tab)

Transport of the D-enantiomer by the same carrier

“N-acetyl-D-leucine was also a substrate, with Km of 1.0 mM (Fig. 4b), and an inhibitor of MCT1 with an IC50 of 11 mM (Fig. 4d).” (opens the source at this quote in a new tab)
“which yielded an affinity (Ki) of 4.3 mM for the l-enantiomer and 1.6 mM for the d-enantiomer, similar to the respective Km values.” (opens the source at this quote in a new tab)
“This enantiomeric selectivity during transport by MCT1 provides a mechanistic explanation for the lower bioavailability of the l-enantiomer when administered as a racemate which impacts its therapeutic efficacy” (opens the source at this quote in a new tab)

Prodrug hypothesis: intracellular deacetylation to L-leucine

“are consistent with N-acetyl-l-leucine acting as prodrug, such as l-dopa, in which both uptake and metabolism are crucial components of its mechanism of action” (opens the source at this quote in a new tab)
“MCT1 can deliver leucine via the prodrug form N-acetyl-l-leucine without interference from, and disruption to, the uptake of other essential amino acids.” (opens the source at this quote in a new tab)

“Taken together, these data showing low amounts of N-acetyl-leucine in the brain and muscle suggest that the mechanism of action of N-acetyl-L-leucine requires metabolism.” (opens the source at this quote in a new tab)

MCT1-dependent uptake in human induced neurons

“We demonstrated that NALL exhibits neuroprotective properties in MS- and HC-derived hiPNs subjected to acute damage induced by the microtubule-destabilizing agent nocodazole determined by neurite length. This effect can be blocked by inhibition of transporter-specific NALL uptake.” (opens the source at this quote in a new tab)
“The specific uptake of NALL via MCT1 as here firstly demonstrated in hiPNs suggests that the proposed transporter switch is functionally relevant in neurons.” (opens the source at this quote in a new tab)

Lysosomal regulation through transcription factor EB

“Here, we describe a direct effect of levacetylleucine on lysosomal regulation through modulation of TFEB, the master transcription factor for lysosomal and autophagy genes.” (opens the source at this quote in a new tab)
“In wild-type HeLa cells, levacetylleucine promotes TFEB activation and nuclear localisation. However, in NPC1 disease models, where we show that TFEB is over-activated and enriched in the nucleus due to lysosomal stress, levacetylleucine reduces nuclear TFEB and restores a more normal cytoplasmic-to-nuclear balance.” (opens the source at this quote in a new tab)
“The effects of the drug are stereospecific: while the L-enantiomer is active, the D-enantiomer and racemate show no effect, revealing the antagonistic properties of the D-enantiomer.” (opens the source at this quote in a new tab)

Mechanisms summarized in a published review

“Preclinical studies demonstrated that NALL enhances mitochondrial bioenergetics, reduces oxidative stress, restores lysosomal and autophagic function, and modulates neuroinflammation.” (opens the source at this quote in a new tab)

Clinical pharmacodynamics: prescribing information

“Clinical pharmacodynamic studies have not been conducted for levacetylleucine.” (opens the prescribing information at this quote)
“A relationship was not observed between increasing levacetylleucine exposure and clinical efficacy.” (opens the prescribing information at this quote)
“The time course of pharmacodynamic response is unknown.” (opens the prescribing information at this quote)

Clinical pharmacology and exposure-response: European assessment

“The Applicant did not conduct clinical primary or secondary pharmacology studies.” (opens the source at this quote in a new tab)
“No phase I study in healthy volunteers has been conducted, and the primary pharmacology is primarily based on the non-clinical studies.” (opens the source at this quote in a new tab)
“The paucity of both the PK and PD data from study IB1001-301 cannot allow reliable conclusions from these analyses.” (opens the source at this quote in a new tab)

Cardiac electrophysiology

“With regards to hERG assay, it is understood that a single concentration (i.e., 525 µM) was tested and as this concentration did not inhibit 30% of the hERG tail current amplitude no dose-response curve was generated and the IC50 value was not estimated.” (opens the source at this quote in a new tab)
“According to the submitted clinical data, there is no signal or trend of pattern related to any TQT prolongation that could be due to levacetylleucine. Therefore, the Applicant request for a waiver for a thorough QT/QTC study with levacetylleucine is accepted.” (opens the source at this quote in a new tab)

Respiratory and central nervous system safety pharmacology

“In female Sprague-Dawley rats, respiratory function was not modified by a single dose of levacetylleucine administered orally up to 2500 mg/kg (maximum feasible dose level).” (opens the source at this quote in a new tab)

Active enantiomer: postural compensation and cerebellar glucose metabolism in the rat

“A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-leucine (p < 0.03) and the N-acetyl-L-leucine groups (p < 0.01), compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group).” (opens the source at this quote in a new tab)
“The effect of N-acetyl-L-leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect.” (opens the source at this quote in a new tab)
“Measurements of the regional cerebral glucose metabolism (rCGM) by means of μPET revealed that only N-acetyl-L-leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7.” (opens the source at this quote in a new tab)

Active enantiomer: vestibular compensation in the cat

“Whatever the parameters tested, the behavioral recovery was strongly and significantly accelerated under pharmacological treatments with N-acetyl-dl-leucine and N-acetyl-L-leucine.” (opens the source at this quote in a new tab)
“In contrast, the N-acetyl-D-leucine isomer had no effect at all on the behavioral recovery, and animals of this group showed the same recovery profile as those receiving a placebo.” (opens the source at this quote in a new tab)

Neuronal membrane potential: central vestibular neurons of the guinea pig

“However, intracellular recordings from MVN neurons revealed that the nature of the response depended on the resting membrane potential.” (opens the source at this quote in a new tab)
“Altogether, our results suggest that acetyl-DL-leucine might act mainly on abnormally hyperpolarized and/or depolarized MVN neurons, by bringing back their membrane potential towards a mean value of -65 to -60 mV.” (opens the source at this quote in a new tab)

Disease progression, survival, and glucose metabolism in Npc1-deficient mice

“When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to Npc1−/− mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not.” (opens the source at this quote in a new tab)
“Relative to untreated Npc1−/− mice, the life span of animals treated from weaning was modestly but significantly increased by 8 days (9.1%) with ALL treatment (P = 0.0334), 4 days with ADLL (P = 0.0305) (4.5%) and was not changed with ADL (P = 0.6908) (Fig. 1G), therefore displaying l-enantiomer selectivity.” (opens the source at this quote in a new tab)
“Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in Npc1−/− mice.” (opens the source at this quote in a new tab)
“Individual enantiomers had distinct effects in NPC1 cerebellum; while ALL normalizes altered levels of PDH and LDH and mildly reduces SOD1 levels, ADL enhanced levels of the mitochondrial reactive oxygen species scavenger SOD2 (manganese dependent SOD2).” (opens the source at this quote in a new tab)

Regulatory appraisal of the nonclinical pharmacology package

“Most of the in vitro and in vivo primary pharmacological data came from publications by different authors.” (opens the source at this quote in a new tab)
“The Applicant affirms that levacetylleucine has been demonstrated to reduce lysosomal volume and glycosphingolipids levels (GSL) and normalize mitochondria numbers and mitochondrial superoxide levels.” (opens the source at this quote in a new tab)
“No data on secondary pharmacodynamics were performed.” (opens the source at this quote in a new tab)

Glucose and glutamate metabolism and autophagy in a Sandhoff disease mouse model

“ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2.” (opens the source at this quote in a new tab)
“ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1).” (opens the source at this quote in a new tab)

Autophagy flux and neuroinflammation after traumatic brain injury in mice

“We demonstrate that orally administered N-acetyl-l-leucine (NALL) significantly improved motor and cognitive outcomes in the injured mice, led to the attenuation of cell death, and reduced the expression of neuroinflammatory markers after controlled cortical impact (CCI) induced experimental TBI in mice.” (opens the source at this quote in a new tab)
“Our data indicate that partial restoration of autophagy flux mediated by NALL may account for the positive effect of treatment in the injured mouse brain.” (opens the source at this quote in a new tab)

Lysosomal, mitochondrial, and synaptic proteins in human dopaminergic neurons

“Discovery-based proteomic analysis revealed that NALL treatment upregulated lysosomal, mitochondrial, and synaptic proteins without inducing cytotoxicity.” (opens the source at this quote in a new tab)

Glutathione synthesis enzyme in human induced neurons

“HiPNs from MS donors treated with NALL expressed higher levels of glutamate cysteine ligase (GCL), the ratelimiting enzyme in glutathione synthesis.” (opens the source at this quote in a new tab)

Cerebral glucose metabolism in patients with cerebellar ataxia treated with the racemate

“Retrospective analyses of [18F]-FDG-PET data in 22 patients with CA (with vestibular and ocular motor disturbances) of different etiologies who were scanned before (PET A) and on AL treatment (PET B).” (opens the source at this quote in a new tab)
“With AL (PET B vs. A) cerebellar hypometabolism was deepened and sensorimotor hypermetabolism increased only in responders with clinical benefit, but not for the non-responders and the whole CA group.” (opens the source at this quote in a new tab)
“The enhanced divergence of cortical sensorimotor up- and cerebellar downregulation with AL in responders could reflect amplification of inhibitory cerebellar mechanisms.” (opens the source at this quote in a new tab)

Pharmacokinetic parameters at steady state: prescribing information

Parameter	Prescribing information
Presentation of values	“Levacetylleucine pharmacokinetic parameters at steady state are presented as mean (SD) unless otherwise specified.”
Maximum concentration and exposure	“Levacetylleucine maximum concentration (Cmax) and area under the curve from time 0 to 24 hours (AUC0-24hrs) were 8.3 (3.3) µg/mL and 33.2 (12.5) h*µg/mL.”
Accumulation	“No levacetylleucine accumulation occurs after repeated administration.”
Absorption	“Levacetylleucine time to Cmax (Tmax) is 1 hour (ranging from 0.5 to 2.5 hours).”
Distribution	“Levacetylleucine apparent (oral) volume of distribution (Vss/F) is 253 (125) L.”
Elimination	“Levacetylleucine estimated half-life is around 1 hour and the apparent (oral) clearance is 139 (59) L/h.”
Metabolism	“Levacetylleucine is metabolized into acetate and L-leucine by ubiquitously expressed enzymes, which are used endogenously in catabolic and metabolic pathways.”
Cytochrome P450 involvement	“Cytochrome P450 enzymes are not involved in the metabolism of levacetylleucine.”

Covariates: age, sex, race, and body weight

“No clinically significant differences in pharmacokinetics of levacetylleucine were observed based on age (range 4 to 67 years), gender (female 47%, male 53%), or race/ethnicity (White 92%, Asian 3%, Other or not specified 5%).” (opens the prescribing information at this quote)
“The volume of distribution and clearance of levacetylleucine increases with increasing body weight (21 kg to 109 kg), but these effects on pharmacokinetics are minimized by the recommended weight-based dosing.” (opens the prescribing information at this quote)

Pharmacokinetics: European summary of product characteristics

“After oral administration, levacetylleucine is rapidly absorbed.” (opens the source at this quote in a new tab)
“Mean, dose-normalised (per gram of levacetylleucine) Cmax and area under the curve from time 0 to 24 hours (AUC0-24hrs) were 4 mcg/mL/g and 9 h*mcg/mL/g. The absolute oral bioavailability is unknown.” (opens the source at this quote in a new tab)
“No studies on food effect on absorption have been conducted.” (opens the source at this quote in a new tab)
“Levacetylleucine is taken up by ubiquitously expressed monocarboxylate transporters, thereby delivering levacetylleucine to all tissues including the central nervous system.” (opens the source at this quote in a new tab)
“No or only minor accumulation was observed after repeat administration.” (opens the source at this quote in a new tab)

Clinical pharmacology program

“Another Phase II study IB1001-203 is ongoing but was not included as part of this application. No Phase I studies were performed.” (opens the source at this quote in a new tab)
“Only a single dose level was evaluated in humans and consequently the range of linear PK could not be determined.” (opens the source at this quote in a new tab)

Rich sampling in the phase 2 NPC study

“Following single dose of levacetylleucine (Commercial formulation, Visit 7B, n=14) in subjects from Study IB1001-201, absorption was reasonably rapid with a Cmax approximately achieved at a median (min-max) Tmax of 1h (0.5-2 h).” (opens the source at this quote in a new tab)
“Following multiple doses of levacetylleucine (Commercial formulation, Visit 9B, n=19) in subjects from Study IB1001-201, absorption was reasonably rapid with a Cmax approximately achieved at a median (min-max) Tmax of 1h (0.75-1.3 h).” (opens the source at this quote in a new tab)
“Based on study IB1001-201, after multiple doses, geometric mean Vss/F was 227 L.” (opens the source at this quote in a new tab)
“Based on study IB1001-201, after multiple doses, geometric mean CLss/F was 128 L/h.” (opens the source at this quote in a new tab)

Protein binding, bioavailability, metabolism, and excretion

“Based on in vitro investigation (Study ADM-20-2970b), levacetylleucine tested at a concentration of 1, 10 and 100 µg/mL has a protein binding near 0%.” (opens the source at this quote in a new tab)
“No information was provided with regards to levacetylleucine absolute bioavailability” (opens the source at this quote in a new tab)
“Interconversion between the L to the D enantiomer is unlikely.” (opens the source at this quote in a new tab)
“Only minor amounts of levacetylleucine are excreted via the urine.” (opens the source at this quote in a new tab)

Population pharmacokinetic analysis

“The PPK of levacetylleucine was based on PK results pooling 3 clinical studies from patients aged 4 years and over (IB1001-201/202/301).” (opens the source at this quote in a new tab)
“Overall, 185 subjects with 567 PK observations were included.” (opens the source at this quote in a new tab)
“The final PPK model consisted of a one compartment PK model parameterized with first order absorption and lag time and linear elimination, in terms of Ka, Tlag, CL/F and Vd/F.” (opens the source at this quote in a new tab)
“Body weight allometric scaling with fixed exponents to theoretical values was considered on both CL/F and Vd/F.” (opens the source at this quote in a new tab)
“Based on the PPK analysis IIV CL/F and Vd/F were 38.7% and 83%.” (opens the source at this quote in a new tab)

Variability and reliability of pharmacokinetic sampling

“The inter-subject variability in exposure of levacetylleucine in patients with NPC was moderate to high (from single to multiple dose) with range from 30% to 47 % for Cmax and 36% to 39 %for AUC0-24.” (opens the source at this quote in a new tab)
“Considering the findings related to findings for the PK sampling/bioanalysis observed during the GCP inspection for study IB1001-301, the reliability of the PK samples measurement could be questioned and the potential impact of endogenous PK levels cannot be fully excluded” (opens the source at this quote in a new tab)

Enantiomer pharmacokinetics after oral dosing in mice

“When administered as the racemate, both the maximum plasma concentration (Cmax) and the area under the plasma drug concentration over time curve (AUC) were much greater for the D-enantiomer relative to the L-enantiomer.” (opens the source at this quote in a new tab)
“When administered as the racemate, the ratio of D/L enantiomer was about 25 for both Cmax (Fig 5H; 26 versus 1, p = 0.014) and AUC (Fig 5I, 25 vs 1, p = 0.015).” (opens the source at this quote in a new tab)
“Elimination (ke and T1/2) was similar for both enantiomers.” (opens the source at this quote in a new tab)
“These results are most readily explained by inhibition of uptake at an intestinal carrier of the L-enantiomer by the D-enantiomer, and by first-pass metabolism of the L-, but not D-enantiomer, likely by deacetylation.” (opens the source at this quote in a new tab)
“In brain and muscle, N-acetyl-L-leucine levels were lower than N-acetyl-D-leucine, consistent with rapid conversion into L-leucine and utilization by normal leucine metabolism.” (opens the source at this quote in a new tab)

Deacetylation in human and mouse liver fractions

“The time course revealed that the disappearance of 1 µM N-acetyl-dl-[2H10]leucine asymptotically approached 50% of the initial concentration (i.e., 0.5 µM) and correlated well with the appearance of l-leucine for both human (Fig. 4f) and mouse (Fig. 4g) fractions.” (opens the source at this quote in a new tab)
“Kinetic data fit to the Michaelis–Menten equation yielded a Km values of 216 and 69 µM and Vmax values of 6.8 and 2.6 µmol/min/mg protein for human and mouse, respectively (Fig. 4h).” (opens the source at this quote in a new tab)

Brain distribution of the radiolabeled racemate in monkeys

“An important uptake of radioactivity is localized in the cortical structures and in several tisses such as nuclei of the vestibular system, including the inner ear.” (opens the source at this quote in a new tab)

Contraindications

“None.” (opens the prescribing information at this quote)

“There are no contraindications for Aqneursa, although this drug may cause fetal harm based on data from animal studies.” (opens the source at this quote in a new tab)

Warning: embryo-fetal toxicity

“Based on findings from animal reproduction studies, AQNEURSA may cause embryo-fetal harm when administered during pregnancy.” (opens the prescribing information at this quote)
“Administration of levacetylleucine to pregnant rats and rabbits during the period of organogenesis caused an increase in embryo-fetal death (post implantation loss/resorption) and skeletal malformations at a dose that was approximately 1.4-fold and 6-fold, respectively, the maximum recommended human dose (MRHD) of 4 g/day of levacetylleucine (based on body surface area).” (opens the prescribing information at this quote)
“The decision to continue or discontinue AQNEURSA treatment during pregnancy should consider the female’s need for AQNEURSA, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal disease.” (opens the prescribing information at this quote)
“For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment with AQNEURSA.” (opens the prescribing information at this quote)
“Advise females of reproductive potential to use effective contraception during treatment with AQNEURSA and for 7 days after the last dose if AQNEURSA is discontinued” (opens the prescribing information at this quote)

Interpretation of adverse reaction rates from clinical trials

“Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.” (opens the prescribing information at this quote)

Adverse reactions in A-T: safety population and exposure in Trial 2

“The safety of AQNEURSA was evaluated in Trial 2, which included a total of 73 patients with ataxia-telangiectasia (A-T) in a placebo-controlled, randomized, crossover trial” (opens the prescribing information at this quote)
“The mean (SD) treatment duration of AQNEURSA was 84.5 (11.2) days (9 min, 97 max); the mean (SD) treatment duration on placebo was 85.5 (3.6) days (77 min, 94 max).” (opens the prescribing information at this quote)
“Table 3 summarizes common adverse reactions that occurred in patients who were treated with AQNEURSA in Treatment Period I of Trial 2.” (opens the prescribing information at this quote)
“In A-T, the most common adverse reactions (incidence ≥5% and greater than placebo) are fall, skin laceration, and urinary tract infection.” (opens the prescribing information at this quote)

Adverse reactions in A-T at an incidence of 5% or more in Treatment Period I of Trial 2

Adverse reaction	AQNEURSA, N=36, n (%)	Placebo, N=37, n (%)
Fall	“2 (6)”	“1 (3)”
Skin laceration	“2 (6)”	“0 (0)”
Urinary tract infection	“2 (6)”	“1(3)”

Laboratory findings in A-T: thrombocytopenia in Trial 2

“Thrombocytopenia with platelets < 100 10^3 cells/µL was observed in one patient during Trial 2. The patient had thrombocytopenia at baseline, which decreased further during the trial while the patient was receiving placebo.” (opens the prescribing information at this quote)

Adverse reactions in NPC: safety population and exposure in Trial 1

“The safety of AQNEURSA was evaluated in Trial 1, which included a total of 60 patients with Niemann-Pick disease Type C (NPC), in a placebo-controlled, randomized, crossover trial” (opens the prescribing information at this quote)
“The mean (SD) treatment duration of AQNEURSA was 86.2 (4.7) days (69 min, 97 max); the mean (SD) treatment duration on placebo was 87.3 (4.8) days (78 min, 113 max).” (opens the prescribing information at this quote)
“In NPC, the most common adverse reactions (incidence ≥5% and greater than placebo) are abdominal pain, dysphagia, upper respiratory tract infections, and vomiting.” (opens the prescribing information at this quote)

Adverse reactions in NPC at an incidence of 5% or more in Treatment Period I of Trial 1

Adverse reaction	AQNEURSA, N=30, n (%)	Placebo, N=30, n (%)
Upper respiratory tract infection	“5 (17)”	“1 (3)”
Abdominal pain	“2 (7)”	“0 (0)”
Dysphagia	“2 (7)”	“0 (0)”
Vomiting	“2 (7)”	“0 (0)”

Rosacea and thrombocytopenia in NPC Trial 1

“One patient experienced an exacerbation of rosacea during Trial 1 that responded to treatment. AQNEURSA was not discontinued.” (opens the prescribing information at this quote)
“Thrombocytopenia with platelets < 100 10^3 cells/µL was observed in four patients during Treatment Period 1 of Trial 1, all of whom were receiving miglustat for 42 days or longer at the time of enrollment.” (opens the prescribing information at this quote)
“In two of these patients, the thrombocytopenia was present at baseline. In the other two patients, the thrombocytopenia developed during Trial 1.” (opens the prescribing information at this quote)

Safety information in the FDA approval announcement

“The most common adverse reactions in patients with ataxia-telangiectasia were fall, skin laceration, and urinary tract infection.” (opens the source at this quote in a new tab)

Adverse events in the published report of the A-T phase 3 trial

“54 adverse events occurred in 29 patients receiving levacetylleucine versus 75 events in 25 patients receiving placebo. No treatment-related serious adverse events or deaths occurred.” (opens the source at this quote in a new tab)

Patient counseling

“Advise the patient and/or caregiver to read the FDA-approved patient labeling (Instructions for Use).” (opens the prescribing information at this quote)
“Advise a female of reproductive potential and caregiver to inform their healthcare provider of a known or suspected pregnancy” (opens the prescribing information at this quote)

Nonclinical toxicology: carcinogenesis, mutagenesis, and impairment of fertility

“Animal studies to evaluate the carcinogenic potential of levacetylleucine have not been conducted.” (opens the prescribing information at this quote)
“Levacetylleucine was not mutagenic or clastogenic in a battery of in vitro and in vivo assays including bacterial reverse mutation (Ames), chromosomal aberration (in human lymphocytes) and mouse micronucleus assays.” (opens the prescribing information at this quote)
“Animal studies to evaluate effects of levacetylleucine on fertility have not been conducted.” (opens the prescribing information at this quote)

“No carcinogenicity studies have been conducted. The carcinogenic risk is unknown.” (opens the source at this quote in a new tab)
“No effect on fertility was seen in rats at doses up to 1 000 mg/kg/day (1.5- to 2.3-fold human exposure).” (opens the source at this quote in a new tab)

Carcinogenicity study commitment and repeat-dose toxicology: European assessment

“Consequently, the Applicant committed to realize the 26-week carcinogenicity study in rasH2 mice and submit the results when available. The submission of the final report for this study is due by 30 June 2027 (MEA).” (opens the source at this quote in a new tab)
“GI was the primary target organ identified for levacetylleucine.” (opens the source at this quote in a new tab)
“The renal toxicity found in male rats is specific to the species and is not relevant for the clinical aspect.” (opens the source at this quote in a new tab)

European Union contraindication and hypersensitivity warning

“Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.” (opens the source at this quote in a new tab)
“Although no patient experienced anaphylactic or hypersensitivity reaction during the clinical studies, anaphylactic and hypersensitivity reactions may occur after administration of levacetylleucine. Immediate discontinuation of Aqneursa and necessary emergency treatment is required if such reactions occur.” (opens the source at this quote in a new tab)

“No hypersensitivity reactions have been observed in clinical trials with levacetylleucine to date. Such reactions remain generally plausible also for levacetylleucine, given that NADLL is the racemic mixture of the enantiomer levacetylleucine and with NADLL events of hypersensitivity reactions have been observed in the clinical setting.” (opens the source at this quote in a new tab)

European Union excipient warning: isomalt and hereditary fructose intolerance

“Each sachet contains 642.2 mg isomalt. Patients with rare hereditary problems of fructose intolerance should not take this medicinal product.” (opens the source at this quote in a new tab)

European Union adverse reaction listing and overdose

“The most common adverse reaction, with a frequency of 1.2%, is flatulence.” (opens the source at this quote in a new tab)
“Adverse reactions observed during the placebo-controlled, randomised, crossover clinical study and the open-label, rater-blinded study, including extension phase, in patients with NPC are based on a total of 84 patients with a median treatment duration of 86 days.” (opens the source at this quote in a new tab)
“In case of overdose, symptomatic treatment is recommended.” (opens the source at this quote in a new tab)

Pooled NPC safety database: European assessment

“From the pooling data, the total observation duration was 52.98 patient-years for the levacetylleucine use group” (opens the source at this quote in a new tab)
“The mean levacetylleucine treatment duration was 229.3 days, with a maximum of 938 days.” (opens the source at this quote in a new tab)
“In the pooled safety data, two-third of patients who received levacetylleucine (65,5% n=55/84) experienced adverse events (AEs), corresponding to 241 events” (opens the source at this quote in a new tab)
“Overall, none of the reported SAEs was considered to be treatment-related by the Applicant, and none resulted in withdrawal of study drug treatment.” (opens the source at this quote in a new tab)
“No signs of withdrawal or rebound have been observed in nonclinical or clinical studies with levacetylleucine.” (opens the source at this quote in a new tab)

Liver enzymes and the European risk management plan

“Presently available data cannot allow any liver toxicity potential to be identified.” (opens the source at this quote in a new tab)
“Therefore, in respect to liver enzymes changes and the uncertainties on levacetylleucine causality, the risk of hepatotoxicity has been added as an important potential risk in the list of safety concerns of the RMP.” (opens the source at this quote in a new tab)
“Hepatotoxicity; Carcinogenicity; Developmental toxicity” (opens the source at this quote in a new tab)

Pregnancy: risk summary

“There are no available data on AQNEURSA use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.” (opens the prescribing information at this quote)
“In animal reproduction studies, an increase in embryo-fetal death (post implantation loss/resorption), decrease in fetal body weight, and increase in external and skeletal malformations were observed in rats and rabbits when levacetylleucine was administered in pregnant rats and rabbits during the period of organogenesis.” (opens the prescribing information at this quote)
“These effects were observed in rats and rabbits at the doses that were approximately 1.4-fold and 6-fold, respectively, the maximum recommended human dose (MRHD) in patients taking 4 grams of AQNEURSA per day” (opens the prescribing information at this quote)
“The background risk of major birth defects and miscarriage for the indicated population is unknown.” (opens the prescribing information at this quote)
“In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.” (opens the prescribing information at this quote)

Pregnancy: animal data

“Increases in the mean number of resorptions, mean post-implantation losses and skeletal malformations (thoracic arch of the vertebra-fused thoracic arch, misaligned thoracic arch, hemicentric thoracic centrum, and misaligned thoracic centrum; vertebral column-scoliosis, and ribs-absent costal cartilage and short rib) were observed at a dose of 600 mg/kg/day, which is 1.4-fold the 4 g/day MRHD of levacetylleucine based on body surface area.” (opens the prescribing information at this quote)
“Increased embryo-fetal death (post-implantation loss/resorption), decreased fetal body weight, and increase in external (open or partially open eyes, hyperflexion of limbs) and skeletal malformations (misshapen maxillae and premaxillae, and small interparietal bones) were observed at the dose of 1250 mg/kg/day, which is 6-fold the MRHD of levacetylleucine based on body surface area.” (opens the prescribing information at this quote)

Pregnancy: European Union labeling

“There are no data on the use of levacetylleucine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).” (opens the source at this quote in a new tab)
“Aqneursa is not recommended during pregnancy and in women of childbearing potential not using contraception.” (opens the source at this quote in a new tab)
“In embryofoetal development studies, levacetylleucine did not induce adverse developmental effects at doses up to 1 000 mg/kg/day in rats (2.0-fold human exposure).” (opens the source at this quote in a new tab)
“external and skeletal malformations were observed at 1 250 mg/kg/day (7.1-fold of human exposure) with a no observed adverse effect level of 675 mg/kg/day (4.9-fold human exposure).” (opens the source at this quote in a new tab)

Lactation

“There are no data on the presence of levacetylleucine or its metabolites in either human or animal milk, the effects on the breastfed infant or the effects on milk production.” (opens the prescribing information at this quote)
“The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AQNEURSA and any potential adverse effects on the breastfed infant from levacetylleucine or from the underlying maternal condition.” (opens the prescribing information at this quote)

“A decision must be made as to whether to discontinue breast-feeding or to discontinue/abstain from Aqneursa therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.” (opens the source at this quote in a new tab)

Females and males of reproductive potential

“AQNEURSA may cause embryo-fetal harm when administered to a pregnant female” (opens the prescribing information at this quote)
“For a female of reproductive potential, verify that the patient is not pregnant prior to initiating treatment with AQNEURSA.” (opens the prescribing information at this quote)
“Advise a female of reproductive potential to use effective contraception during treatment and for 7 days after the last dose if AQNEURSA is discontinued.” (opens the prescribing information at this quote)

“No human data on the effect of levacetylleucine on fertility is available. Animal studies indicate no effects of levacetylleucine on male or female fertility (see section 5.3).” (opens the source at this quote in a new tab)

Pediatric use in A-T and the 15 kg weight limit

“The safety and effectiveness of AQNEURSA for the treatment of ataxia in patients with A-T have been established in 47 pediatric patients weighing ≥ 15 kg in Trial 2” (opens the prescribing information at this quote)
“The safety and effectiveness of AQNEURSA have not been established in pediatric patients weighing <15 kg.” (opens the prescribing information at this quote)

Pediatric use in NPC and supporting pharmacokinetic data

“The safety and effectiveness of AQNEURSA for the treatment of NPC have been established in 23 pediatric patients weighing ≥15 kg in Trial 1.” (opens the prescribing information at this quote)
“Use of AQNEURSA for this indication is supported by evidence from one adequate and well-controlled study in adults and pediatric patients weighing ≥15 kg with additional pharmacokinetic data from 40 adults and 17 pediatric patients who participated in two open-label studies” (opens the prescribing information at this quote)

Pediatric limits in the European Union: 6 years and 20 kg

“The safety and efficacy of Aqneursa in children aged less than 6 years or weighing under 20 kg have not yet been established. No data are available.” (opens the source at this quote in a new tab)

“For children weighing 15-20 kg, it is predicted a 24% higher exposure however no PK data are yet available.” (opens the source at this quote in a new tab)
“No PK data from children aged below 6 years have been submitted as part of this application, whereas children of at least 4 years were planned to be enrolled.” (opens the source at this quote in a new tab)
“A dose range-finding toxicity study in juvenile rats was already completed, and a final study report is not yet available for the definitive study.” (opens the source at this quote in a new tab)

Geriatric use

“NPC and A-T are largely diseases of pediatric and young adult patients.” (opens the prescribing information at this quote)
“Clinical studies of AQNEURSA did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.” (opens the prescribing information at this quote)

“Only two subjects from study IB1001-301 had an age over 65 years (66 and 67 years) and none were above 68 years.” (opens the source at this quote in a new tab)

Renal and hepatic impairment

“The effect of renal impairment, hepatic impairment, or pregnancy on levacetylleucine pharmacokinetics is unknown.” (opens the prescribing information at this quote)

“The effect of renal or hepatic impairment on the PK of levacetylleucine has not been studied.” (opens the source at this quote in a new tab)

“No formal PK study investigating the effect of renal impairment on levacetylleucine PK was performed, since the product is rapidly metabolized into L-leucine and acetate and both are used in further catabolic pathways.” (opens the source at this quote in a new tab)
“No impact of renal impairment is expected.” (opens the source at this quote in a new tab)
“No impact of hepatic impairment is expected.” (opens the source at this quote in a new tab)
“No studies were done in patients with renal impairment. Patients with moderate and severe hepatic insufficiency were excluded from levacetylleucine clinical studies.” (opens the source at this quote in a new tab)

Age and sex subgroups in the pooled NPC safety data

“There were no relevant differences in safety variables across age groups in the pooled studies.” (opens the source at this quote in a new tab)

N-acetyl-DL-leucine and N-acetyl-D-leucine

“Avoid concomitant use of AQNEURSA with N-acetyl-DL-leucine and N-acetyl-D-leucine.” (opens the prescribing information at this quote)
“The D-enantiomer, N-acetyl-D-leucine, competes with levacetylleucine for monocarboxylate transporter uptake, which may reduce the levacetylleucine efficacy.” (opens the prescribing information at this quote)

“Aqneursa interacts with N-acetyl-DL-leucine and simultaneous use should be avoided.” (opens the source at this quote in a new tab)

“Concomitant use of levacetylleucine with N-acetyl-DL-leucine and N-acetyl-D-leucine should be avoided.” (opens the source at this quote in a new tab)

Nonclinical basis of the enantiomer interaction

“Second, when administered as purified N-acetyl-L-leucine, both the Cmax and the AUC for N-acetyl-L-leucine were higher compared to administration as the racemate, even when scaled for the relative dose.” (opens the source at this quote in a new tab)

“It can be agreed that there are PK differences between the racemate and the L-enantiomer and that non-clinical PK data suggest that the D-enantiomer negatively impacts the uptake of the L-enantiomer.” (opens the source at this quote in a new tab)

Levacetylleucine as a transporter substrate

“Levacetylleucine is a substrate of organic anion transporter (OAT)1 and OAT3, but not organic cation transporter (OCT)2, breast cancer resistance protein (BCRP), or P-glycoprotein (P-gp).” (opens the prescribing information at this quote)

“It was shown in vitro that levacetylleucine is a substrate for OAT1/3. However, since the renal pathway is not the primary route of elimination, the clinical risk of drug-drug interactions with modulators of these transporters is likely minimal.” (opens the source at this quote in a new tab)
“Uptake could be abolished by addition of the inhibitor diclofenac.” (opens the source at this quote in a new tab)

Enzyme modulators and absence of clinical interaction studies

“No interaction studies have been performed.” (opens the source at this quote in a new tab)

“It was shown in vitro that levacetylleucine is metabolized without the involvement of the body's primary detoxification enzymes (CYP, UGT, SULT).” (opens the source at this quote in a new tab)
“This indicates that levacetylleucine is metabolized efficiently, without the risk of overloading the detoxification enzyme systems, the DDI risk with these enzyme modulators could be ruled out.” (opens the source at this quote in a new tab)

P-glycoprotein transporter substrates

“Monitor more frequently for P-gp substrate related adverse reactions when used concomitantly with AQNEURSA.” (opens the prescribing information at this quote)
“Levacetylleucine inhibits P-gp” (opens the prescribing information at this quote)
“However, the clinical significance of this finding has not been fully characterized.” (opens the prescribing information at this quote)

“Patients receiving P-glycoprotein (P-gp) substrates should be monitored more frequently for related adverse reactions when used with Aqneursa.” (opens the source at this quote in a new tab)

In vitro enzyme and transporter studies: prescribing information

Study	Prescribing information
Cytochrome P450 inhibition and induction	“Levacetylleucine does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 and does not induce CYP 1A2, 2B6, or 3A4.”
Transporter inhibition	“Levacetylleucine inhibits P-gp, BCRP, bile salt export pump (BSEP), OAT1 and OAT3, but does not inhibit organic anion transporting polypeptide (OATP)1B1 and OATP1B3.”

Substrates of P-gp, BCRP, BSEP, and MATE transporters: European Union labeling

“Levacetylleucine may be an inhibitor of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) or bile salt export pump (BSEP) (see section 5.2). The relevance to humans is uncertain.” (opens the source at this quote in a new tab)
“A potential interaction of levacetylleucine with other medicinal products that are substrates of P-gp (e.g. digoxin, dabigatran, loperamide, irinotecan, doxorubicin, vinblastine, paclitaxel, fexofenadine, seliciclib, quinidine, talinolol), BCRP (e.g. sulfasalazine, rosuvastatin) or BSEP cannot be excluded.” (opens the source at this quote in a new tab)
“Caution should be exercised when levacetylleucine is co-administered with BSEP substrates.” (opens the source at this quote in a new tab)
“The potential inhibitory effect of levacetylleucine on multidrug and toxin extrusion proteins (MATE) transporters is unknown; therefore, caution is advised when co-administering levacetylleucine with substrates of MATE transporters.” (opens the source at this quote in a new tab)
“Levacetylleucine is a substrate and an in vitro inhibitor of organic anion transporter (OAT)1 and OAT3. The likelihood of clinically meaningful drug interactions is considered low.” (opens the source at this quote in a new tab)

Inhibitory concentrations and the planned clinical interaction study

“Inhibition towards efflux transporters MDR1, BCRP and BSEP by levacetylleucine was observed and IC50 values were 227 (MDR1), 491 (BCRP) and 408 (BSEP) μg/mL equal to 1.31 (MDR1), 2.83 (BCRP) and 2.36 (BSEP) mM.” (opens the source at this quote in a new tab)
“Therefore, a clinical DDI study involving P-gp and BCRP substrates is warranted to evaluate the extent of levacetylleucine's inhibitory effect on these transporters.” (opens the source at this quote in a new tab)
“The Applicant committed to conduct a DDI study to evaluate P-gp and BCRP inhibition.” (opens the source at this quote in a new tab)

Cytochrome P450 substrates: European assessment

“These finding suggest that the DDI potential between levacetylleucine and the tested CYPs substrates could be ruled out at both systemic and intestinal level.” (opens the source at this quote in a new tab)
“From a clinical perspective, these findings suggest that there is no risk of CYP enzyme induction-related DDI.” (opens the source at this quote in a new tab)

Recommended dosage by body weight

Body weight	Morning dose	Afternoon dose	Evening dose
15 kg to less than 25 kg	“1 gram”	“No Dose”	“1 gram”
25 kg to less than 35 kg	“1 gram”	“1 gram”	“1 gram”
35 kg or more	“2 grams”	“1 gram”	“1 gram”

Basis of the dosage and packet strength

“The recommended dosage of AQNEURSA to be administered orally, with or without food, is based on the patient’s actual body weight (kg), as shown in Table 1” (opens the prescribing information at this quote)
“One AQNEURSA packet contains 1 gram levacetylleucine.” (opens the prescribing information at this quote)
“For AQNEURSA doses of 2 grams, prepare two packets individually” (opens the prescribing information at this quote)
“The approved dosage regimen is based on body weight and not age.” (opens the prescribing information at this quote)

Pregnancy status before treatment initiation

“For females of reproductive potential, verify that the patient is not pregnant” (opens the prescribing information at this quote)

Missed dose

“If a dose of AQNEURSA is missed, skip the missed dose and take the next dose at the scheduled time. Do not take 2 doses at the same time to make up for a missed dose.” (opens the prescribing information at this quote)

Dosage studied in the A-T trial

“Patients weighing ≥35 kg received 4 gram per day (as 2 gram morning dose, 1 gram afternoon dose, and 1 gram evening dose).” (opens the prescribing information at this quote)

Dose rationale: European assessment

“No dose-finding study has been performed by the Applicant. The selection of the dose was purely based on non-clinical data and experience gained from off-label use of racemate N-acetyl-DL-leucine.” (opens the source at this quote in a new tab)
“The Applicant justified the different morning dose of 2 g by the need for a loading dose after no dose overnight.” (opens the source at this quote in a new tab)
“Based on a simulation exercise for children aged 6-12 years and weighing 20-25 kg or 25 to 35 kg, the total daily dose of 2 g and 3 g respectively can be considered acceptable based on matching exposure (AUC24h).” (opens the source at this quote in a new tab)
“The CHMP agreed that the dose of 4 g/day for adults and children weighing at least 35 kg has been demonstrated in both non-clinical and clinical studies to be safe and well-tolerated.” (opens the source at this quote in a new tab)

Oral administration: preparation of the suspension

“Obtain the required number of AQNEURSA packets for the prescribed dose (one or two packets).” (opens the prescribing information at this quote)
“Open and empty the entire contents of one AQNEURSA packet into a container with 40 mL of water, orange juice, almond milk, or yogurt. Do not use hot liquid.” (opens the prescribing information at this quote)
“Stir to form a suspension.” (opens the prescribing information at this quote)
“Swallow the suspension immediately (within 30 minutes).” (opens the prescribing information at this quote)
“For doses requiring two AQNEURSA packets, repeat steps 2 to 4.” (opens the prescribing information at this quote)
“Discard unused AQNEURSA suspension if not administered within 30 minutes.” (opens the prescribing information at this quote)

Gastrostomy tube administration

“For patients who have a G-tube (French size 12 or larger) in place, administer AQNEURSA as follows:” (opens the prescribing information at this quote)
“Prepare AQNEURSA suspension immediately before administration via gastrostomy tube.” (opens the prescribing information at this quote)
“Open and empty the entire contents of one AQNEURSA packet into a container with 40 mL of water ONLY. Do not use hot liquid.” (opens the prescribing information at this quote)
“Draw up the suspension into a catheter tip syringe.” (opens the prescribing information at this quote)
“Administer the suspension immediately through the G-tube.” (opens the prescribing information at this quote)
“Flush any residual suspension in the catheter tip syringe with an additional 20 mL of water.” (opens the prescribing information at this quote)
“For doses requiring two AQNEURSA packets, repeat steps 3 to 8.” (opens the prescribing information at this quote)
“Discard unused AQNEURSA suspension if not administered immediately.” (opens the prescribing information at this quote)

Administration with respect to food: European Union labeling and planned food effect study

“Food and drink should be avoided 0.5 hours before and 2 hours after administration (see section 5.2).” (opens the source at this quote in a new tab)

“Although, no formal PK study was performed to investigate the effect of food on levacetylleucine PK, in both studies IB1001-201 and IB1001-301, levacetylleucine was advised to be taken 0.5 h before or 2 h after a meal.” (opens the source at this quote in a new tab)
“The Applicant committed to conduct and submit the results (when available) of a food effect PK study (planned in 2026) (REC) and drug-drug interaction study (REC).” (opens the source at this quote in a new tab)

European Union administration: dispersion in water and gastrostomy tube size

“The content of one sachet should be poured into 40 mL (3 tablespoons) of water and stirred until fully dispersed.” (opens the source at this quote in a new tab)
“Aqneursa may be administered via gastrostomy tube (French size 18 or larger).” (opens the source at this quote in a new tab)
“The enteral feeding should be stopped if the patient is on continuous feeding.” (opens the source at this quote in a new tab)

Dispersion of two packets at once: outstanding quality recommendation

“The applicant is recommended to conduct an experiment of dispersion of two sachets in 80 mL of liquid at the same time by September 2025 (REC2).” (opens the source at this quote in a new tab)

U.S. commercial availability

“AQNEURSA is commercially available now” (opens the source at this quote in a new tab)

“To access AQNEURSA, download and complete the Start AQNEURSA Prescription Form.” (opens the source at this quote in a new tab)

Specialty pharmacy: Curant Health

“Curant Health, a rare disease specialty pharmacy that improves health outcomes for rare and complex care patients, has been chosen by IntraBio as the exclusive specialty pharmacy for AQNEURSA™ (levacetylleucine).” (opens the source at this quote in a new tab)

“I may reply STOP to opt out of text messaging or by contacting Curant Health at 866-200-0419.” (opens the source at this quote in a new tab)

Home delivery and retail pharmacy availability

“The pharmacist will call prior to shipping the medicine to ensure that all mailing information is correct and that someone will be home to accept the delivery the next day.” (opens the source at this quote in a new tab)
“You will not be able to get or pick up AQNEURSA at a retail or neighborhood pharmacy.” (opens the source at this quote in a new tab)

“Levacetylleucine is available through the manufacturer.” (opens the source at this quote in a new tab)

Patient support program: AQNEURSA Cares

“IntraBio offers support programs to eligible patients through their Patient Support Service, AQNEURSA Cares®.” (opens the source at this quote in a new tab)
“This program includes financial support to reduce or eliminate out-of-pocket costs for qualifying patients and also connects patients with third-party resources.” (opens the source at this quote in a new tab)
“The team is available to help with individuals’ unique challenges including starting treatment, questions about taking the medication, and navigating insurance coverage.” (opens the source at this quote in a new tab)

“AQNEURSA Cares is the single point of contact for access to AQNEURSA and will work with you and your doctor to get you started on treatment.” (opens the source at this quote in a new tab)

AQNEURSA Cares services initiated by the enrollment packet

Service	Website text
Benefits verification	“Verification of insurance coverage for AQNEURSA”
Copay eligibility	“Determination of eligibility for co-pay assistance”
Prior authorization	“Support during the prior authorization process”
Shipment	“Patient outreach and scheduling of medication shipments directly to the patient/caregiver”

“The complete enrollment packet consists of the Start AQNEURSA Prescription Form and the clinical information listed in the Prior Authorization Checklist.” (opens the source at this quote in a new tab)
“Fax the completed and signed Start AQNEURSA Prescription Form, along with the clinical information, to AQNEURSA Cares at 470-751-8639.” (opens the source at this quote in a new tab)

Enrollment form: prescription fields and diagnosis codes

Form item	Form text
Prescription	“AQNEURSA Prescription (NDC: 83853-101-01)”
Supply	“Dose & Directions (28-Day Supply)”
Diagnosis code for A-T	“G11.3 Ataxia-telangiectasia”
Diagnosis code for NPC	“E75.242 Niemann-Pick Disease Type C”
Body weight	“Patient weight”
Eligible prescribers and patients	“FOR U.S. PATIENTS AND U.S.-LICENSED PRESCRIBERS ONLY”

“Clinical documentation for Prior Authorization (see Prior Authorization Checklist)” (opens the source at this quote in a new tab)
“Copy of the front and back side of patient’s insurance card” (opens the source at this quote in a new tab)

Benefits verification and prior authorization support

“AQNEURSA Cares will contact the insurance plan to determine the patient’s out-of-pocket costs and any prior authorization requirements” (opens the source at this quote in a new tab)
“The AQNEURSA Cares team can submit a PA request if allowed by the insurance plan” (opens the source at this quote in a new tab)
“Electronic prescriptions may be submitted for refills provided by AQNEURSA Cares” (opens the source at this quote in a new tab)

Copay assistance and financial assistance

“Co-pay assistance: Patients with commercial insurance may be eligible for assistance with their co-pay from IntraBio. Restrictions apply.” (opens the source at this quote in a new tab)
“Patients who participate in Medicaid, Medicare, or any other federal healthcare program are not eligible to receive co-pay assistance.” (opens the source at this quote in a new tab)
“Patients who are unable to afford their cost-share for AQNEURSA may be eligible for financial assistance” (opens the source at this quote in a new tab)

“Co-pay assistance may lower the amount you pay for your AQNEURSA prescription to as little as $0 a month, depending on eligibility restrictions and maximum benefits.” (opens the source at this quote in a new tab)

Prior authorization checklist: diagnosis code and diagnostic information for A-T

Checklist item	Checklist text
ICD-10-CM diagnosis code	“G11.3 Ataxia-Telangiectasia (A-T)”
Official descriptor of the code	“Cerebellar ataxia with defective DNA repair”
Genetic confirmation	“Confirmation of A-T diagnosis by genetic testing identifying biallelic pathogenic variants in the ATM gene”
Biomarker	“Elevated serum alpha-fetoprotein (AFP)”
Clinical features	“Observation of the clinical features of A-T”
Systemic features	“oculocutaneous telangiectasia, immunodeficiency, pulmonary disease, endocrine abnormalities”

Prior authorization checklist: patient condition and medical history

Checklist item	Checklist text
Growth	“Patient weight, growth, and development”
Testing	“Neurological and/or psychological testing results”
Symptoms	“Symptoms and quality of life (physician observation)”
Records	“Chart notes”
Laboratory	“Laboratory test results”
Pregnancy	“Verification that the patient is not pregnant”
Hospitalization	“Details on hospital admissions and discharges”

Prior authorization checklist: supporting materials and coverage disclaimer

“The following materials may help payors learn more about AQNEURSA and can be submitted with a PA or formulary exception request:” (opens the source at this quote in a new tab)
“IntraBio makes no representation or guarantee concerning coverage or reimbursement.” (opens the source at this quote in a new tab)
“Please check individual payor policies for plan-specific coverage information and requirements.” (opens the source at this quote in a new tab)

Sample letters of medical necessity and appeal for A-T

“Resources to help access an AQNEURSA prescription:” (opens the source at this quote in a new tab)
“A-T Sample Letter of Medical Necessity” (opens the source at this quote in a new tab)
“A-T Sample Letter of Appeal” (opens the source at this quote in a new tab)

Expanded access for A-T: manufacturer policy

“IntraBio currently operates an Expanded Access Program in the United States for levacetylleucine for people living with Ataxia-Telangiectasia who meet program eligibility criteria.” (opens the source at this quote in a new tab)
“Participation in the Expanded Access Program is subject to physician request, medical review, and applicable regulatory requirements and is evaluated on a case-by-case basis, as required by applicable law.” (opens the source at this quote in a new tab)

Expanded access for A-T: registry record

“This expanded access program provides investigational levacetylleucine to patients with Ataxia-Telangiectasia who are not eligible for clinical trials and have no satisfactory alternative therapies.” (opens the source at this quote in a new tab)
“Patient has a genetically confirmed diagnosis of Ataxia-Telangiectasia, a rare and serious disease with no alternative approved treatments.” (opens the source at this quote in a new tab)
“Patient weighs ≥15 kg.” (opens the source at this quote in a new tab)
“Patient resides in the United States at time of enrollment and throughout the duration of their participation in the EAP.” (opens the source at this quote in a new tab)

Published payer policies that predate the A-T approval: Cigna Healthcare

“Prior Authorization is required for benefit coverage of Aqneursa.” (opens the source at this quote in a new tab)
“Any other use is considered experimental, investigational, or unproven, including the following (this list may not be all inclusive; criteria will be updated as newly published data are available):” (opens the source at this quote in a new tab)
“A multinational, multicenter, open-label, rater-blinded prospective Phase II study is underway to assess the safety and efficacy of levacetylleucine for the treatment of Ataxia-Telangiectasia.” (opens the source at this quote in a new tab)

Policy item	Policy text
Coverage policy number	“IP0715”
Section heading	“Conditions Not Covered”
Listed condition	“Ataxia-Telangiectasia.”
Latest revision	“Annual Revision”
Summary of changes	“No criteria changes.”
Revision date	“12/15/2025”

Published payer policies that predate the A-T approval: Medical Mutual

Policy item	Policy text
Last revised date	“08/21/2025”
Section heading	“CONDITIONS NOT RECOMMENDED FOR APPROVAL”
Listed condition	“Ataxia-Telangiectasia.”
Stated basis	“Results are not yet available.”

Published payer policies that predate the A-T approval: UnitedHealthcare

Policy item	Policy text
Program number	“2026 P 2355-4”
Effective date	“4/1/2026”
Diagnosis criterion	“Diagnosis of Niemann-Pick disease type C (NPC)”
Authorization duration	“Authorization will be issued for 12 months.”

Payer coverage policies with criteria for the A-T indication

No evidence found.

N-acetyl-DL-leucine products

“N-acetyl-DL-leucine or N-acetyl-D-leucine: Avoid concomitant use with AQNEURSA.” (opens the prescribing information at this quote)

“Levacetylleucine is the L-enantiomer of N-acetyl-DL-leucine, a modified amino acid that has been available in France as a solution for injection and in tablet form since 1957, under the trade name Tanganil (Pierre Fabre Laboratories) as a treatment for acute vertigo.” (opens the source at this quote in a new tab)

Medications prohibited in the pivotal A-T trial

“Patients unwilling and/or not able to undergo a 42-day washout period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6.” (opens the source at this quote in a new tab)
“N-Acetyl-DL-Leucine (e.g. Tanganil®);” (opens the source at this quote in a new tab)
“N-Acetyl-L-Leucine (prohibited if not provided as IMP in the IB1001-303 trial);” (opens the source at this quote in a new tab)
“Sulfasalazine;” (opens the source at this quote in a new tab)
“Rosuvastatin.” (opens the source at this quote in a new tab)

Conditions for other concomitant therapies in the pivotal A-T trial

“Patients are willing to disclose their existing medications/therapies for (the symptoms) of A-T, including those on the prohibited medication list.” (opens the source at this quote in a new tab)
“The Investigator does not believe the medication/therapy will interfere with the study protocol/results” (opens the source at this quote in a new tab)
“Patients have been on a stable dose/duration and type of therapy for at least 42 days before Visit 1 (Baseline 1)” (opens the source at this quote in a new tab)
“Patients are willing to maintain a stable dose/do not change their therapy throughout the duration of the study.” (opens the source at this quote in a new tab)

Medications prohibited in the phase 2 master protocol that included A-T

Item	Protocol text
Washout requirement	“Patients unwilling and/or not able to undergo a 42-day washout period from any of the following prohibited medication prior to Visit 1 (Baseline 1) and remain without prohibited medication through Visit 6.”
a	“Aminopyridines (including sustained-release form);”
b	“N-Acetyl-DL-Leucine (e.g. Tanganil®) ;”
c	“N-Acetyl-L-Leucine (prohibited if not provided as IMP);”
d	“Riluzole;”
e	“Gabapentin;”
f	“Varenicline;”
g	“Chlorzoxazone;”
h	“Sulfasalazine;”
i	“Rosuvastatin.”

Standard-of-care and supportive-care medication in clinical trials

“No data on pharmacology drug interaction with levacetylleucine were provided. However, during Phase II and III clinical trials, levacetylleucine was combined with a broad spectrum of standard-of-care and supportive-care medication and no potential for respective pharmacodynamic drug-drug interactions was identified.” (opens the source at this quote in a new tab)

Summary: levacetylleucine, intra-erythrocyte dexamethasone, and the racemate

Levacetylleucine is supplied as an oral suspension in 1 gram packets and is given two or three times daily according to body weight. In Trial 2 of the prescribing information, 73 participants with A-T received levacetylleucine and placebo for 12 weeks each in a crossover design, and the least squares treatment effect on the functional SARA total score was -0.6 (95% CI -0.9 to -0.2). The FDA announcement describes Aqneursa as the first treatment approved for ataxia in A-T.
Intra-erythrocyte dexamethasone sodium phosphate (eDSP, formerly EryDex) is given by intravenous infusion: once a month for 6 months in ATTeST, and six infusions every 21 to 30 days in NEAT. In ATTeST, 175 participants received treatment and the least squares mean differences from placebo in mICARS change were -1.37 for the low-dose group and -1.40 for the high-dose group; the primary endpoint was not met. NEAT randomized 105 participants, its primary endpoint did not reach statistical significance (p=0.0851), and the sponsor announced that it would cease clinical development of eDSP.
N-acetyl-DL-leucine, the racemate marketed in France as Tanganil for acute vertigo, has been reported in A-T in a case series of 6 participants and in a single case report. In the ALCAT crossover trial of 108 participants with cerebellar ataxia of hereditary, nonhereditary, or unknown type, the mean treatment difference in SARA total score between the racemate and placebo was 0.23 points (95% CI -0.40 to 0.85).
No head-to-head clinical comparison of levacetylleucine with the racemate has been performed. The CHMP concluded that the data submitted for the European application did not allow the conclusion that the two differ significantly in efficacy or safety.

Approved treatments for A-T before and at the approval of levacetylleucine

“Today’s approval makes Aqneursa the first treatment approved for ataxia in patients with ataxia-telangiectasia.” (opens the source at this quote in a new tab)
“There is no cure for ataxia-telangiectasia, and treatment options for the neurological symptoms of the disease have been limited.” (opens the source at this quote in a new tab)

“There are currently no approved therapeutic treatments in any global market for A-T.” (opens the source at this quote in a new tab)

“There is currently no approved treatment in any jurisdiction for A-T.” (opens the source at this quote in a new tab)

Treatments under investigation for A-T: narrative review

“Currently, there are no curative therapies available for this disorder.” (opens the source at this quote in a new tab)
“This review provides an overview of the latest advances in treatment methods including 1- Acetyl-DL-leucine, 2- Bone Marrow Transplantation, 3- Gene Therapy, 4- Dexamethasone, and finally 5- Red Blood Cells (RBCs) as a carrier for dexamethasone (encapsulation of dexamethasone sodium phosphate into autologous erythrocytes, known as EryDex).” (opens the source at this quote in a new tab)
“Most of the treatments under investigation are in the early stages, except for the EryDex System.” (opens the source at this quote in a new tab)

Levacetylleucine: product profile from the prescribing information

Attribute	Prescribing information
Dosage form	“For oral suspension: 1 gram levacetylleucine in a unit-dose packet.”
Pivotal trial in A-T	“a randomized, double-blind, placebo-controlled, two-period crossover study that evaluated the efficacy of AQNEURSA in 73 patients (Trial 2; NCT06673056)”
Treatment duration per period	“AQNEURSA and placebo were administered orally with or without food for 12 weeks in each period.”
Efficacy result	“The Least Squares treatment effect for the fSARA total score was -0.6 (95% CI: -0.9, -0.2)”
Completion	“Seventy patients (96%) completed the study and received both placebo and AQNEURSA.”

Intra-erythrocyte dexamethasone sodium phosphate: product description

“eDSP is comprised of dexamethasone sodium phosphate (DSP) encapsulated in a patient’s own red blood cells (autologous erythrocytes).” (opens the source at this quote in a new tab)
“The eDSP System is designed to provide the efficacy of corticosteroids and to reduce or eliminate the significant adverse effects that accompany chronic use of corticosteroid treatment.” (opens the source at this quote in a new tab)

Intra-erythrocyte dexamethasone sodium phosphate: ATTeST phase 3 trial

Attribute	Published abstract
Design	“This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 22 centres in 12 countries (Australia, Belgium, Germany, India, Israel, Italy, Norway, Poland, Spain, Tunisia, the UK, and the USA).”
Population	“Eligible participants were children aged 6 years or older weighing more than 15 kg who met clinical criteria for ataxia telangiectasia but who had preserved autonomous gait.”
Regimen	“Intravenous intra-erythrocyte dexamethasone sodium phosphate was administered once a month for 6 months.”
Participants treated	“175 patients received at least one dose of treatment (59 patients received the low dose and 57 received the high dose of intra-erythrocyte dexamethasone sodium phosphate, and 59 received placebo).”
Primary endpoint	“Compared with the placebo group, no differences were identified with regard to change in mICARS score from baseline to 6 months in the low-dose group (least squares mean difference -1·37 [95% CI -2·932 to 0·190]) or the high-dose group (-1·40 [-2·957 to 0·152]; p=0·0765).”
Serious adverse events	“Serious adverse events were observed in six (10%) of 59 participants in the low-dose group, seven (12%) of 57 participants in the high-dose group, and seven (12%) of 59 participants in the placebo group.”
Corticosteroid adverse effects	“There were no reports of hyperglycaemia, hypertension, hirsutism, or Cushingoid appearance in any of the treatment groups, nor any treatment-related deaths.”
Interpretation	“Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age.”

Intra-erythrocyte dexamethasone sodium phosphate: NEAT phase 3 trial topline results

Attribute	Company release
Primary endpoint	“In the NEAT study, the company’s pivotal Phase 3 international, multicenter, randomized, double-blind, placebo-controlled study (n=105), the primary endpoint, which measured the change from baseline to last efficacy visit at month six using the Rescored modified International Cooperative Ataxia Rating Scale (RmICARS) compared to placebo, did not reach statistical significance.”
Primary endpoint values	“The mean change from baseline to month six was 0.94 in the active arm compared to 2.24 in the placebo arm (difference -1.30) with a p-value of 0.0851.”
Key secondary endpoint	“Furthermore, the study did not meet its key secondary endpoint of improvement in Clinical Global Impression of Severity (CGI-S) measured from baseline to month six with a p-value of 0.522.”
Regimen	“The study consisted of two cohorts randomized (1:1) between eDSP or placebo and the treatment included six infusions scheduled once every 21 to 30 days.”
Enrollment by age	“Quince enrolled a total of 105 participants in the NEAT study, including 83 participants in the six to nine year-old primary analysis population and 22 participants aged 10 years and older.”
Safety	“The most common adverse events reported in the eDSP arm included pruritis and pyrexia.”
Development status	“Company to cease clinical development of eDSP; Intends to preserve cash and explore available options”

Racemate N-acetyl-DL-leucine: marketed use

“N-acetyl-d,l-leucine is approved in France for vertigo and its l-enantiomer is being developed as a drug for rare and common neurological disorders.” (opens the source at this quote in a new tab)

“Up until 2018, no RCTs have been published on the efficacy of acetylleucine in vertigo/dizziness.” (opens the source at this quote in a new tab)

Racemate N-acetyl-DL-leucine in A-T: case series and case report

“There is no authorized treatment for ataxia telangiectasia (AT).” (opens the source at this quote in a new tab)
“Six patients were treated with ADLL 3 g/day for 1 week followed by 5g/day for 3 weeks to 1 year.” (opens the source at this quote in a new tab)
“The Scale for Assessment and Rating of Ataxia changed from the baseline, mean, (SD, min-max) of 22.1 (5.88, 11-28.5) to 18 points (5.39, 8.5-23.5) after 1 month on medication (P = .0028).” (opens the source at this quote in a new tab)

“This study assessed the effect of 16 weeks N-acetyl-DL-leucine supplementation on ataxia symptoms in a 9-year-old female with AT.” (opens the source at this quote in a new tab)
“The SARA score progressively improved, and by week 16 had improved by 11.0 points (48.88%).” (opens the source at this quote in a new tab)

Racemate N-acetyl-DL-leucine in cerebellar ataxia: ALCAT randomized crossover trial

“In this randomized clinical crossover trial including 108 patients with cerebellar ataxia, a 6-week treatment with acetyl-DL-leucine was not effective. Adverse events were mild.” (opens the source at this quote in a new tab)
“Patients were randomly assigned (1:1) to receive acetyl-DL-leucine orally (5 g per day after 2 weeks up-titration) followed by a matched placebo, each for 6 weeks, separated by a 4-week washout, or vice versa.” (opens the source at this quote in a new tab)
“There was no evidence of a difference in the mean absolute change from baseline to week 6 in SARA total scores between both treatments (mean treatment difference: 0.23 points [95% CI, −0.40 to 0.85 points]).” (opens the source at this quote in a new tab)

Levacetylleucine and the racemate: nonclinical differences

“Taken together, these results have clinical implications supporting the use of N-acetyl-L-leucine instead of the racemate or N-acetyl-D-leucine, and support the research and development of only N-acetyl-L-leucine.” (opens the source at this quote in a new tab)

“It is concluded that the N-acetyl-L-leucine isomer is the active part of the racemate component since it induces a significant acceleration of the vestibular compensation process similar (and even better) to that observed under treatment with the racemate component only.” (opens the source at this quote in a new tab)

“Remarkably, the racemate N-acetyl-D-L-leucine also failed to activate TFEB translocation, indicating that the presence of the D-enantiomer in the racemic mixture antagonises the effect of the pharmacologically active L-enantiomer, levacetylleucine.” (opens the source at this quote in a new tab)

Levacetylleucine and the racemate: European regulatory appraisal

“Of note, it should be kept in mind that insufficient evidence was provided in non-clinical studies that levacetylleucine is superior to the racemic NADLL, which is approved as Tanganil in France.” (opens the source at this quote in a new tab)
“A direct head-to-head comparison between NALL (N-acetyl-L-leucine, L-enantiomer) and the racemate, NADLL (N-acetyl-DL-leucine), to compare their efficacy and safety profiles has not been performed in patients with Niemann-Pick disease type C or any other similar indication, due to feasibility/ethical issues, which are acknowledged.” (opens the source at this quote in a new tab)
“Although PK studies demonstrated that administration of NADL as part of the racemate supresses exposure to NALL, pharmacological data do not suggest that efficacy of the racemate is reduced because of this.” (opens the source at this quote in a new tab)
“Formulations: powder for oral suspension (NALL) versus tablets (NADLL), which can influence PK and bioavailability and therefore pharmacological activity.” (opens the source at this quote in a new tab)
“In conclusion, on the basis of the totality of clinical data provided by the Applicant in this re-examination procedure, it is not possible to conclude that levacetylleucine (N-acetyl-L-leucine) differs significantly in properties with regard to safety and/or efficacy from N-acetyl-DL-leucine.” (opens the source at this quote in a new tab)

Regulatory description of the disease

“Ataxia-telangiectasia is a rare, inherited neurodegenerative disorder caused by mutations in the ATM gene. It primarily affects the nervous system, causing progressive loss of muscle control and coordination (ataxia) that typically begins in early childhood. The disease also causes small dilated blood vessels (telangiectasias), immune deficiencies, and an elevated risk of cancer.” (opens the source at this quote in a new tab)

Clinical definition

“Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome.” (opens the source at this quote in a new tab)
“A-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages.” (opens the source at this quote in a new tab)

ATM gene and protein

“The mode of inheritance for A-T is autosomal recessive. A-T is caused by mutations in the ATM (ataxia telangiectasia, mutated) gene which was cloned by Savitsky et al. in 1995” (opens the source at this quote in a new tab)
“ATM is located on human chromosome 11q22-q23” (opens the source at this quote in a new tab)
“The ATM gene encodes a large 3056 amino acid protein of the same name whose best known, and arguably most well understood, role is coordinating the cellular response to DNA DSBs.” (opens the source at this quote in a new tab)

Autosomal recessive inheritance and recurrence risk

“A-T is caused by biallelic pathogenic variants in ATM and inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ATM pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and having A-T, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial ATM pathogenic variants.” (opens the source at this quote in a new tab)

Classic and variant forms

“The phenotypic spectrum of ataxia-telangiectasia (A-T), a multisystem disorder, is a continuum ranging from classic A-T at the severe end and variant A-T at the milder end. Nonetheless, distinguishing between classic A-T and variant A-T on this spectrum helps understand differences in disease course, rate of progression, and life expectancy.” (opens the source at this quote in a new tab)

“People with mild A-T present with less severe, later onset manifestations associated with longer survival” (opens the source at this quote in a new tab)

Genotype and residual ATM kinase activity

“To study genotype-phenotype correlations, we evaluated the clinical and laboratory data of 51 genetically proven A-T patients, and additionally measured ATM protein expression and kinase activity. Patients without ATM kinase activity showed the classical phenotype.” (opens the source at this quote in a new tab)
“Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan.” (opens the source at this quote in a new tab)
“The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity.” (opens the source at this quote in a new tab)

“In general, nonsense and/or frameshift variants lead to the classic A-T phenotype, whereas missense and splice site variants are more typically associated with variant A-T.” (opens the source at this quote in a new tab)

Proportion of cases with a variant form

“It appears that approximately one case in three of A-T in the UK is of a mild-variant form (compared to an estimated one in five in other parts of the world).” (opens the source at this quote in a new tab)

Heterozygous carriers

“Although individuals heterozygous for an ATM pathogenic variant are not at risk for A-T, their risk of developing cancer is increased compared to that of the general population (in particular, heterozygous females have an increased risk of developing breast cancer).” (opens the source at this quote in a new tab)

United States birth incidence: nationwide case finding

Measure	Estimate
Cases identified in 1970 to 1972 and 1980 to 1984	“231 white, 29 black, and three Oriental A-T cases”
Birth rate of identified white patients, 1965 to 1969	“3.0 per million live births”
Highest observed state incidence (Michigan, 1965 to 1969)	“11.3 per million births”

United Kingdom birth frequency

“A prevalence study of ataxia telangiectasia was conducted in the West Midlands, with a population of over 5 million. The prevalence in those aged 50 or less was found to be 1 in 514,000 and the birth frequency to be about 1 in 300,000.” (opens the source at this quote in a new tab)

Range of reported incidence

“The reported incidence of A-T, a rare disorder, varies between 1:300,000 and 1:40,000.” (opens the source at this quote in a new tab)

“The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.” (opens the source at this quote in a new tab)
“With the exception of consanguineous populations, individuals of all races and ethnicities are affected equally by A-T.” (opens the source at this quote in a new tab)

United States estimate per live births

“In the United States, the prevalence of AT is approximately 1:40,000 to 1:100,000 live births. Males and females are affected in equal numbers. Certain ethnic groups may have a higher prevalence of AT due to a founder effect.” (opens the source at this quote in a new tab)

Estimated prevalence

“The estimated prevalence is 1-9:100,000” (opens the source at this quote in a new tab)

“Ataxia-telangiectasia occurs in 1 in 40,000 to 100,000 people worldwide.” (opens the source at this quote in a new tab)

Estimates stated by the manufacturer

“A-T is a rare, progressive, and prematurely fatal autosomal-recessive neurodegenerative disorder that affects an estimated 1 in 40,000 people.” (opens the source at this quote in a new tab)

“A-T is estimated to affect 1 in 40,000-100,000 people.” (opens the source at this quote in a new tab)

“Regulatory submissions planned in the US, Europe, and other jurisdictions for levacetylleucine in Ataxia-Telangiectasia, a neurodegenerative disease without any approved treatment and impacting approximately 1 in 70,000 people” (opens the source at this quote in a new tab)

Children known to the United States patient organization

“In the United States approximately 350 children with A-T are known to the patient organization A-T Children's Project” (opens the source at this quote in a new tab)

Participants in the Global A-T Family Data Platform

“Between 2016 and 2024, 624 participants with ataxia telangiectasia completed the questionnaire.” (opens the source at this quote in a new tab)
“Participant ages ranged from 0 to 64 years.” (opens the source at this quote in a new tab)

Europe: prevalence estimates and registry counts

“The Orphanet registry estimates the average prevalence of A-T at 1/100 000 children” (opens the source at this quote in a new tab)
“The prevalence of patients with A-T in Europe is estimated to be 1/150 000” (opens the source at this quote in a new tab)
“In Europe, 410 living A-T patients are currently listed on the European Society for Immunodeficiencies registry” (opens the source at this quote in a new tab)
“The most reliable estimates for the number of people with A-T, in the UK at least, are 3 per million” (opens the source at this quote in a new tab)

“Data of 659 A-T patients on age, gender, immunoglobulin levels IgA, IgG2, IgM, and lymphocyte counts, date of birth, and date of death (until 2014) were collected from the ESID registry and analyzed for mortality.” (opens the source at this quote in a new tab)

United Kingdom and Ireland: number of affected families and individuals

“Our estimate is that in the UK and Ireland there are currently approximately 150 families with approximately 170 cases of A-T, giving a prevalence of approximately 1 in 400,000.” (opens the source at this quote in a new tab)

Carrier frequency

“Given that complementation analysis has demonstrated the genetic heterogeneity of A-T, the A-T heterozygote frequency will probably fall between 0.68% and 7.7%, with 2.8% being the most likely estimate.” (opens the source at this quote in a new tab)

“About 1 percent of the United States population carries one altered copy and one normal copy of the ATM gene in each cell.” (opens the source at this quote in a new tab)

“Based on the incidence of A-T in the United States, the heterozygote frequency is estimated to be one in 200 persons” (opens the source at this quote in a new tab)

“The carrier frequency would therefore be of the order of 0.3% or approximately 1 in 300.” (opens the source at this quote in a new tab)

Founder populations with higher carrier frequency

Population	Heterozygote frequency
Druze population in northern Israel	“One in three to one in 15”
Moroccan and Tunisian Jewish population	“One in 81”
Romani population in Spain	“One in 36”

Rank among autosomal recessive hereditary cerebellar ataxias

“Friedreich ataxia was the most frequent AR-HCA, followed by ataxia with oculomotor apraxia or ataxia-telangiectasia.” (opens the source at this quote in a new tab)

Absence of population-based prevalence studies

“Despite our comprehensive literature search and review, we did not find population-based studies and were unable to determine the prevalence of A-T.” (opens the source at this quote in a new tab)
“Despite excluding duplicate cases, we found reports of 18247 cases. Most were classical A-T but 2.5% were reported as variants. The worldwide prevalence of variant A-T is not determined as yet.” (opens the source at this quote in a new tab)
“Although cases were reported from 74 countries, nearly a quarter of the cases were from the USA and another quarter from just four other countries (the UK, Italy, Germany, and Turkey).” (opens the source at this quote in a new tab)

Course of neurological decline in classic A-T

“In the classic presentation of the disease, ataxia first appears during the toddler stage when children begin to sit and walk.” (opens the source at this quote in a new tab)
“In primary school years, walking becomes more difficult, and children will use doorways and walls for support.” (opens the source at this quote in a new tab)
“Most of these neurologic problems stop progressing after the age of about 12–15 years.” (opens the source at this quote in a new tab)
“Neurological deficits are typically observed during the toddler years resulting in wheelchair dependency around the age of 10.” (opens the source at this quote in a new tab)

“After about age ten years most children with classic A-T require use a wheelchair to compensate for the cerebellar ataxia and extrapyramidal and peripheral nervous manifestations.” (opens the source at this quote in a new tab)

Age at symptom onset and at diagnosis

“Referral centers from 9 Latin American countries participated in this retrospective cohort study, and 218 patients were included. Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0) and 5.0 (3.0-8.0) years, respectively.” (opens the source at this quote in a new tab)

“The mean age at which the first neurological symptom was noted was 1.8 ± 1.0 years. The mean age at diagnosis of ataxia telangiectasia was 3.95 ± 2.56 years, and the mean age at the time of walking capacity reporting was 7.97 ± 4.60 years.” (opens the source at this quote in a new tab)

Loss of walking capacity: Global A-T Family Data Platform

“Children with ataxia telangiectasia who presented with neurological symptoms at 5 years of age or younger and were 18 years of age or younger at the time of walking capacity reporting were included.” (opens the source at this quote in a new tab)
“Mean walking capacity scores from 372 participants remained stable until age 5, followed by progressive worsening between ages 5 and 14, with persistently high scores thereafter.” (opens the source at this quote in a new tab)
“the majority of patients reported walking independently all or most of the time (225/372, 60.5%); 72/372 (19.3%) reported needing assistance for walking, while 75/372 (20.2%) used a wheelchair.” (opens the source at this quote in a new tab)
“The mean age at which wheelchair dependence developed was 13.5 years.” (opens the source at this quote in a new tab)
“We could not control for disease severity, as genetic confirmation and ATM kinase activity data were not available.” (opens the source at this quote in a new tab)

Mean age by walking capacity category: Global A-T Family Data Platform

Walking capacity category	Mean age and number of participants
Walks independently	“5.0 ± 2.7 years (N = 170)”
Walks independently most of the time	“6.6 ± 3.5 years (N = 55)”
Needs assistance for long trips	“10.3 ± 3.7 years (N = 62)”
Walks with bilateral support	“10.1 ± 2.7 years (N = 10)”
Uses wheelchair without assistance	“14.2 ± 2.5 (N = 9)”
Uses wheelchair with assistance	“13.4 ± 3.2 (N = 66)”

Age at wheelchair use in national and referral cohorts

“The mean age of loss of walking was 10 years and of writing 8 years.” (opens the source at this quote in a new tab)

“Thirty one patients (34.1%) became dependent on wheelchair at a mean age of 12.1±2.8 years. Eleven patients (12.1%) became bedridden by a mean age of 14.7±1.8 years.” (opens the source at this quote in a new tab)

“Most of the patients in this cohort were severely affected by ataxia and wheelchair use started at a median age of 9 years.” (opens the source at this quote in a new tab)

“In keeping with the existing view, we found that the median reported age of wheelchair requirement is 10 years. This requirement comes considerably later, by 26–27 years, in those with variant A-T.” (opens the source at this quote in a new tab)

Rate of change on the Scale for the Assessment and Rating of Ataxia in adults

“We analysed longitudinal Scale for the Assessment and Rating of Ataxia (SARA) data from the largest published adult AT cohort to date (n = 82, age > 16 years).” (opens the source at this quote in a new tab)
“Neurological impairment progressed with a mean SARA increase of 0.38 points/year. Adults with classic AT were more severely affected than those with variant AT, with SARA scores approximately 8-9 points higher at baseline. However, neurological progression in adulthood was similar between classic and variant AT (0.33 vs 0.41 points per year), which includes 15 individuals with the antisense oligonucleotide targetable c.5763-1050A>G variant.” (opens the source at this quote in a new tab)
“SARA remains a useful outcome measure but may underestimate progression in advanced disease and non-cerebellar domains.” (opens the source at this quote in a new tab)

SARA scores by disease form

“Ataxia was present in all patients except one (p13) and with increased severity in those with classical A-T as shown by a median SARA score of 30 for these 12 patients compared to a median score of nine for the two with vA-T.” (opens the source at this quote in a new tab)

SARA and A-T NEST score ranges by functional severity in variant A-T

Severity class	Functional definition and score ranges
Mild	“Individuals still ambulant with/without a walking aid and could use the upper limbs for most activities without help. A‐T NEST scores within this group were > 55, SARA scores <22.”
Moderate	“Individuals used a wheelchair frequently, but were able to transfer, walk a few steps with help, and use the upper limbs for most activities, such as feeding themselves. A‐T NEST scores within the moderate group were 42 to 75, SARA scores 15 to 33.”
Severe	“Individuals were permanently wheelchair bound, were unable to transfer unaided, and had significant limitation of upper limb function, requiring assistance with most activities of daily living. A‐T NEST scores within this group were < 46, SARA scores >30.”

Structure of SARA and its limitations in A-T

“It assesses 8 domains: gait, stance, sitting ability, speech disturbance, finger chase, nose-finger test, fast alternating hand movements and heel-shin slide. It carries a maximum score of 40 with higher scores indicating more severe ataxia symptoms” (opens the source at this quote in a new tab)
“However, the SARA score remains unvalidated specifically for use in A-T and is not without its limitations.” (opens the source at this quote in a new tab)
“Many classical A-T patients lose ambulation by their teenage years, and it is unclear how this influences the assessment of disease progression in non-ambulant patients who continue to report clinical deterioration” (opens the source at this quote in a new tab)
“The medical records of 55 individuals (males = 27, females = 28) with genetically confirmed diagnoses of A-T who attended the National Adult A-T Clinic at Royal Papworth Hospital over a 7-year period were retrospectively reviewed in a longitudinal manner.” (opens the source at this quote in a new tab)
“The A-T NEST correlates strongly with the SARA score at the single timepoint level and changes proportionally with the SARA score longitudinally which demonstrates its ability to track the severity of the disease over time.” (opens the source at this quote in a new tab)

“Even in advanced stages of A-T, the scores lose their value, since the course of the disease for patients who are already wheelchair-bound becomes gradually more difficult to quantify by an increase in points.” (opens the source at this quote in a new tab)
“The SARA score was available from 28 A-T patients and correlated significantly with NfL (r = 0.41, p ≤ 0.05)” (opens the source at this quote in a new tab)

A-T Index and A-T NEST: relation to age and individual progression

“The overall index was applied to 52 patients with A-T, 2 to 29 years of age.” (opens the source at this quote in a new tab)
“In a linear regression model of individuals under 19 years of age, controlled for correlation within sibships, age accounted for 87% of the variation in the A-T Index.” (opens the source at this quote in a new tab)

“Neurological assessments were performed using the A-T Index (Crawford Score) and the A-T Neurological Examination Scale Toolkit (A-T NEST).” (opens the source at this quote in a new tab)
“Unlike the per-genotype analysis, the individual progression of neurological scores in the 34 patients that attended on three or more occasions was not smooth and linear (and in some cases improved over time).” (opens the source at this quote in a new tab)
“Residual kinase activity confers a milder phenotype but there is no difference between kinase-dead and protein-null genotypes.” (opens the source at this quote in a new tab)

International Cooperative Ataxia Rating Scale scores in a pediatric cohort

“We recruited 63 patients with ataxia, aged 10.76 ± 3.2 years, followed at 6 international AT centers, 49 of them (77.8%) with classical AT.” (opens the source at this quote in a new tab)
“Mean ICARS score was 44.7 ± 20.52, and it's severity positively correlated with age (Spearman correlation, r = 0.46, p < 0.01).” (opens the source at this quote in a new tab)

Median survival: United States cohorts

“In the prospective ATCC cohort, median survival is calculated to be 25 years (fig 1). In the retrospective ATCP cohort, median survival is 19 years (fig 2).” (opens the source at this quote in a new tab)
“Mortality crossed the 25th and 75th centiles in the prospective ATCC cohort at ages 18 and 28, and at ages 14 and 28 in the retrospective ATCP cohort.” (opens the source at this quote in a new tab)
“The median date of death in the ATCP cohort was 1993, compared with the median date of death in the ATCC cohort of 2001.” (opens the source at this quote in a new tab)
“Life expectancy does not correlate well with severity of neurological impairment.” (opens the source at this quote in a new tab)

Causes of death: Johns Hopkins prospective cohort

“There were 24 deaths through the end of 2004.” (opens the source at this quote in a new tab)
“nine apparently died of complications of chemotherapy or cancer, seven of pneumonia, four had significant acute neurological deterioration associated with multiple CNS telangiectatic vascular abnormalities, two died from sudden unknown causes, and two died from complications of chronic lung disease.” (opens the source at this quote in a new tab)
“Hence most deaths should be considered to be the result of a complication of ataxia telangiectasia rather than an inevitable consequence of severe neurological debilitation.” (opens the source at this quote in a new tab)

Survival and risk factors for death: French national cohort

“We performed a retrospective cohort study in France of 240 patients with A-T born from 1954 to 2005 and analyzed ATM mutations in 184 patients, along with neurologic manifestations, infections, and cancers.” (opens the source at this quote in a new tab)
“Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954.” (opens the source at this quote in a new tab)
“Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality.” (opens the source at this quote in a new tab)
“Cancer (hazard ratio, 5.8; 95% CI, 2.9-11.6) was a major risk factor for mortality among patients with null mutations, whereas respiratory tract infections (hazard ratio, 4.1; 95% CI, 1.8-9.1) were the leading cause of death among patients with hypomorphic mutations.” (opens the source at this quote in a new tab)

Survival: Latin American multicenter cohort

“Mean survival was 24.2 years, and Kaplan-Meier 20-year-survival rate was 52.6%, with higher mortality associated with female gender and low IgG levels.” (opens the source at this quote in a new tab)

Survival: German single-center cohort

“Our study includes 69 A-T patients between 8 January 2002 and 1 December 2019.” (opens the source at this quote in a new tab)
“The 15-year OS of 82·5% (72-95%) was significantly decreased among A-T patients with malignancies, who had a median OS of 2·11 years, with a two-year-estimated OS of 50·7% (31-82%).” (opens the source at this quote in a new tab)

Survival by phenotype and immunological status: Dutch cohort

“This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy).” (opens the source at this quote in a new tab)
“Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG2 deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG2 levels (HR 7.8, 95%CI 1.7-36.2), respectively.” (opens the source at this quote in a new tab)

Survival, IgA deficiency, and causes of death: European Society for Immunodeficiencies registry

“As shown in Fig. 1, A-T patients with deficient IgA died significantly earlier than patients with no deficient IgA (p < 0.0001). The corresponding hazard ratio (HR) for patients with IgA deficiency compared to those with IgA-levels greater than 0.07 g/L was 1.9 (1.34–2.77).” (opens the source at this quote in a new tab)
“Data about the cause of death was available from 60 A-T patients with available IgA values in the ESID registry and the patients from the Frankfurt cohort (Fig. S2). Of these, 27 died from respiratory failure, 29 died from cancer, and 4 died for other reasons.” (opens the source at this quote in a new tab)

Deaths and causes of death: Italian Primary Immunodeficiency Network cohort

“Retrospective data of 69 AT patients diagnosed between December 1984 and November 2019 were collected from the database of the Italian Primary Immunodeficiency Network.” (opens the source at this quote in a new tab)
“At the end of the Fup, 11 patients were dead at a mean age ± SD of 22.4 ± 6.5 years. Causes of death were severe pneumonia (n = 6), pneumonia + malignancy (n = 2), and malignancy (n = 3).” (opens the source at this quote in a new tab)

Age at death and causes of death: systematic review of published cases

“687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months).” (opens the source at this quote in a new tab)
“As expected, median age of death was lower in classical cases (14 years 0 months) compared to variant cases (48 years 0 months), likely due to no ATM protein kinase activity resulting in a more severe phenotype in classical cases.” (opens the source at this quote in a new tab)
“Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T.” (opens the source at this quote in a new tab)

Excess mortality relative to the general population

“The standardized mortality ratio was 24.6 (95% CI, 21.1–28.4) overall and 232.9 (95% CI,178.1–299.2) among individuals with cancer.” (opens the source at this quote in a new tab)

“For white and black A-T patients, respectively, all-cause mortality was 50 and 147 times higher than expected based on U.S. mortality rates.” (opens the source at this quote in a new tab)

Life expectancy and leading causes of death

“The two most common causes of death are chronic lung disease (about one-third of cases) and cancer (about one-third of cases).” (opens the source at this quote in a new tab)

“Life expectancy in classic A-T is significantly reduced due to cancer, pulmonary disease, and infections. Most affected individuals do not live longer than age 30 years” (opens the source at this quote in a new tab)
“Individuals with the hyper IgM phenotype of classic A-T have a poorer prognosis than individuals with classic A-T, and most die before age 15 years due to respiratory failure” (opens the source at this quote in a new tab)

Survival after a cancer diagnosis

“Overall survival was shorter in patients with AT who developed cancer compared with those who did not develop cancer (15 v 24 years, respectively; P < .001).” (opens the source at this quote in a new tab)

Course of variant A-T

“The study includes 57 individuals. Mean age at assessment was 37.5 years. Most had their first symptoms by age 10 (81%).” (opens the source at this quote in a new tab)
“Disease severity was mild in one third of patients, and 43% were still ambulant 20 years after disease onset.” (opens the source at this quote in a new tab)
“Forty‐two individuals used a wheelchair and 15 were still ambulant. Median age at first getting a wheelchair was 20 years (range, 8–51; Fig 1C).” (opens the source at this quote in a new tab)

“The longer life expectancy in variant A-T than in classic A-T can be attributed to less progressive neurologic decline, typical absence of respiratory and immunologic features, and older age of occurrence of malignancies” (opens the source at this quote in a new tab)

Classic A-T beyond 30 years of age

“In the Dutch cohort, seven classic A–T patients survived beyond 30 years of age. Fourteen additional patients were retrieved by the literature search.” (opens the source at this quote in a new tab)
“Most patients had pulmonary, endocrine, cardiovascular, and gastro-intestinal problems. All patients had a tetraparesis with contractures. This led to immobilization and frequent hospital admissions.” (opens the source at this quote in a new tab)

“One patient died before the age of 30 years, but five patients had survived beyond this age.” (opens the source at this quote in a new tab)

Function of the ATM protein

“A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.” (opens the source at this quote in a new tab)

“The ATM protein assists cells in recognizing damaged or broken DNA strands and coordinates DNA repair by activating enzymes that fix the broken strands.” (opens the source at this quote in a new tab)
“Variants in the ATM gene reduce or eliminate the function of the ATM protein. Without this protein, cells become unstable and die. Cells in the part of the brain involved in coordinating movements (the cerebellum) are particularly affected by loss of the ATM protein.” (opens the source at this quote in a new tab)

Cerebellar degeneration and Purkinje cell loss

“The neuropathological hallmark of A-T is diffuse degeneration or atrophy of the cerebellar vermis and hemispheres, involving Purkinje cells (PCs) and, to a lesser extent, granule neurons.” (opens the source at this quote in a new tab)
“The cause of this cell death is not known, though many hypotheses have been proposed” (opens the source at this quote in a new tab)
“Much of the evidence in existence to date supports the idea that a defective response to genotoxic and/or oxidative stress contributes to the neuronal cell dysfunction and death in A-T.” (opens the source at this quote in a new tab)

“In parallel, ATM also functions in the maintenance of the cellular redox balance, mitochondrial function and turnover and many other metabolic circuits.” (opens the source at this quote in a new tab)
“This review suggests that it is the absence of a comprehensive role of ATM in responding to ongoing DNA damage induced mainly by endogenous agents. It is the ensuing deterioration and eventual loss of cerebellar Purkinje cells, which are very vulnerable to ATM absence due to a unique combination of physiological features, which kindles the cerebellar decay in A-T.” (opens the source at this quote in a new tab)

Proposed mechanisms of neurodegeneration

Mechanism	Hypothesis as listed
Oxidative stress	“Defective response to oxidative stress characterized by elevated ROS and altered cellular redox status”
Mitochondria	“Mitochondrial dysfunction”
Cell cycle	“Failed cell cycle regulation resulting in the re-entry of post-mitotic (mature) neurons into the cell cycle”
Synaptic function	“Synaptic/vesicular dysregulation”
Vasculature	“Defects in brain vasculature”
Protein homeostasis	“Altered protein turnover”

Neurological involvement outside the cerebellum

“Various neuropathological abnormalities (e.g. neuronal changes, gliosis and vascular changes) have also been observed in the cerebrum, brain stem and spinal cord.” (opens the source at this quote in a new tab)
“Importantly, the loss of cerebellar cells does not explain all of the neurologic abnormalities seen in people with A-T, and the effects of ATM deficiency on the other areas of the brain outside of the cerebellum are being actively investigated.” (opens the source at this quote in a new tab)

“In A-T, neurophysiological assessment revealed neuropathic changes as early as the first year of life.” (opens the source at this quote in a new tab)

Neuroimaging correlates of cerebellar degeneration

“For the majority of people with A-T, neuroimaging studies in the toddler years and early child years are normal” (opens the source at this quote in a new tab)
“As the disease progresses, MRI studies support the pathological finding of variable, progressive and diffuse cerebellar atrophy” (opens the source at this quote in a new tab)

Serum neurofilament light chain as a marker of neurodegeneration

“We found significantly increased levels of NfL in patients with A-T compared to healthy controls (21.5 ± 3.6 pg/mL vs. 9.3 ± 0.49 pg/mL, p ≤ 0.01). There was a significant correlation of NfL with age, AFP, and SARA.” (opens the source at this quote in a new tab)

ATM functions outside the DNA damage response

“The pathogenesis of A-T is not limited to the role of ATM in the DNA damage response (DDR) pathway, and it has other functions mainly in the hematopoietic cells and neurons. ATM adjusts the functions of organelles such as mitochondria and peroxisomes and also regulates angiogenesis and glucose metabolisms.” (opens the source at this quote in a new tab)

Cellular phenotype and radiosensitivity

“Cells derived from patients with A-T demonstrate sensitivity to ionizing irradiation, chromosomal instability, shortened telomeres, premature senescence and a defective response to DNA double strand breaks (DSBs)” (opens the source at this quote in a new tab)

“Due to impairment of repair of DNA double-strand breaks, individuals with A-T have an increased sensitivity to ionizing radiation (x-ray and gamma ray)” (opens the source at this quote in a new tab)

Mechanisms of lung disease

“Immune dysregulation in A-T can lead to recurrent pneumonia, bronchiectasis and ILD. Poor mucociliary clearance from an inadequate cough and chronic aspiration from impaired bulbar function can increase severity of chronic respiratory symptoms.” (opens the source at this quote in a new tab)

Unexplained alpha-fetoprotein elevation and telangiectasia

“Why the majority of individuals with A-T have elevated levels of AFP remains unknown.” (opens the source at this quote in a new tab)
“The cause of telangiectasia or dilated, enlarged blood vessels in the absence of the ATM protein is not yet known.” (opens the source at this quote in a new tab)

Diagnostic criteria and genetic confirmation

“No consensus clinical diagnostic criteria for ataxia-telangiectasia (A-T) have been published.” (opens the source at this quote in a new tab)
“The diagnosis of A-T is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in ATM identified by molecular genetic testing” (opens the source at this quote in a new tab)

“The diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels).” (opens the source at this quote in a new tab)
“A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene.” (opens the source at this quote in a new tab)

Yield of molecular genetic testing of ATM

Method	Proportion of pathogenic variants identified
Sequence analysis	“90%-95%”
Deletion/duplication analysis	“5%-10%”

Serum alpha-fetoprotein

“Serum concentration of alpha-fetoprotein (AFP) is the most important blood biomarker in individuals with classic A-T. In all individuals with classic A-T, serum AFP is elevated (>10 ng/mL, range: 200-1,000 ng/mL)” (opens the source at this quote in a new tab)
“Because serum AFP concentrations are high at birth in all persons and only reach normal values around age two years, it is unreliable as a diagnostic marker in young children” (opens the source at this quote in a new tab)

“We have followed 12 patients (five girls and seven boys) for 1-12 years (mean 5.5 years) measuring in each patient AFP 2-8 (mean 4) times. Serum AFP levels were increased in all patients, mean 168.7 (range 40-373) kU/L, and without significant differences between the patients.” (opens the source at this quote in a new tab)
“A positive linear relationship (r=0.61, p=0.04) could be found between AFP level and age.” (opens the source at this quote in a new tab)

“All 60 tested showed increased sensitivity to ionizing irradiation, 43 of 48 had an elevated alpha-fetoprotein level and 14 of 21 had an immunoglobulin deficiency.” (opens the source at this quote in a new tab)

Alpha-fetoprotein in variant A-T and its relation to severity

“Mean serum AFP was 176 μg/l (range, 2–600; SD, 146) in 45 individuals with a result available. Three (6.6%) had levels in the normal range” (opens the source at this quote in a new tab)

“Although AFP is considered a reliable diagnostic biomarker for the disease, in a small proportion of variant A-T patients, AFP can be normal” (opens the source at this quote in a new tab)
“Furthermore, there is no clear association of AFP levels with disease severity” (opens the source at this quote in a new tab)

Laboratory abnormalities supporting the diagnosis

Test category	Abnormality as listed
Alpha-fetoprotein	“Elevated and slowly increasing serum alpha-fetoprotein levels after two years of age”
Immunology	“Low serum levels of immunoglobulins (IgA, IgG, IgG subclasses, IgE) and lymphopenia (particularly affecting T-lymphocytes)”
Cytogenetics	“Spontaneous and X-ray induced chromosomal breaks and rearrangements in cultured lymphocytes and fibroblasts”
Radiosensitivity	“Reduced survival of cultured lymphocytes and fibroblasts after exposure to ionizing radiation”
Neuroimaging	“Cerebellar atrophy detected by MRI”

ATM protein and kinase activity assays

“The diagnosis of A-T can be confirmed by the absence or deficiency of ATM protein and/or ATM kinase activity in cultured cell lines established from lymphocytes or skin biopsies” (opens the source at this quote in a new tab)
“These more specialized tests are not always needed, but are particularly helpful if an individual’s symptoms are atypical.” (opens the source at this quote in a new tab)

“A lymphoblastoid cell line (LCL) is made from the blood sample and a western blot carried out to look for loss of ATM protein.” (opens the source at this quote in a new tab)
“There is a strong phenotype-genotype correlation in A-T and patients with some residual A-T kinase activity generally have a milder clinical course.” (opens the source at this quote in a new tab)

Brain magnetic resonance imaging at presentation

“Most children in whom there is a suspicion of cerebellar ataxia, dystonia, or chorea will have an MRI brain scan, and this will be grossly normal early on in A-T.” (opens the source at this quote in a new tab)

Newborn screening by T-cell receptor excision circles: proportion of classic A-T detected

“Newborn screening (NBS) for severe combined immunodeficiency (SCID), a severe but treatable immunologic disorder, relies on the identification of reduced T-cell receptor excision circle (TREC) levels in blood spots.” (opens the source at this quote in a new tab)
“NBS for SCID most likely identifies about 50% of children with classic A-T” (opens the source at this quote in a new tab)
“Since variant A-T is not associated with immunodeficiencies, NBS for SCID does not detect variant A-T.” (opens the source at this quote in a new tab)

“Of 13 older AT patients for whom newborn DBS had been stored, 7 samples tested positive for SCID under the criteria of California’s newborn screening program.” (opens the source at this quote in a new tab)

“Based on the fact that 24/31 (77.4%) of retrospectively analyzed newborn screening cards of patients with AT were below the cutoff values for an abnormal SCID screening result, we expect that the number of screening-identified AT cases will continue to increase as SCID newborn screening programs expand globally.” (opens the source at this quote in a new tab)
“To date, 15 newborns with an early diagnosis of AT identified after SCID newborn screening have been published” (opens the source at this quote in a new tab)
“AT is not a target disease in NBS programs. Additionally, since the screening is not designed to detect AT, not all patients with AT will be identified through NBS-SCID.” (opens the source at this quote in a new tab)

Newborn screening: cases identified in the Ontario program

“Four patients were diagnosed with AT as a result of low TRECs on NBS.” (opens the source at this quote in a new tab)
“One case was identified per year, while the total rate for SCID has been five new cases per year.” (opens the source at this quote in a new tab)

Parent views on diagnosis in the neonatal phase

“Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference.” (opens the source at this quote in a new tab)

Diagnostic delay and misdiagnosis: United States referral center

“In 48 patients with AT, who were the index cases in their respective families, the median age of diagnosis (78 months) occurred after the onset of gait abnormalities (15 months) and closely corresponded to the development of telangiectasia (72 months).” (opens the source at this quote in a new tab)
“The most common misdiagnosis was cerebral palsy (29/48 cases).” (opens the source at this quote in a new tab)
“We recommend the use of routine serum alpha-fetoprotein testing for all children with persistent ataxia.” (opens the source at this quote in a new tab)

Diagnostic delay: United Kingdom national pediatric clinic

“At presentation, 71 children (90%) had ataxia. The median presentation delay (from first parental concern to presentation) was 8 months (range 0-118 months), and the median diagnostic delay (genetic confirmation of diagnosis) was 12 months (range 1-109 months).” (opens the source at this quote in a new tab)

Age at diagnosis in published cases

Group	Median (IQR, range) age at diagnosis in months
All cases, 329 cases	“72.0 (36.0–120.0, 0.7–720.0)”
Variant cases only, 14 cases	“354.0 (231.0–456.0, 24.0–720.0)”
Classical cases only, 315 cases	“72.0 (36.0–108.0, 0.7–528.0)”

Diagnostic delay in variant A-T

“There was a diagnostic delay of more than 10 years in 68% and more than 20 years in one third of probands.” (opens the source at this quote in a new tab)
“our data suggest the condition may sometimes be mis‐ or underdiagnosed because of atypical features, including exclusive extrapyramidal symptoms, normal eye movements, and normal alpha‐fetoprotein levels in some individuals.” (opens the source at this quote in a new tab)

“Patients with variant A-T were only correctly diagnosed in adulthood.” (opens the source at this quote in a new tab)
“Measurement of serum alpha-fetoprotein and chromosomal instability precipitates the correct diagnosis.” (opens the source at this quote in a new tab)

Differential diagnosis in early childhood

“In early childhood A-T can mimic cerebral palsy, especially dyskinetic types, cerebellar ataxia from a number of other causes, and developmental co-ordination disorder or developmental dyspraxia.” (opens the source at this quote in a new tab)

Presenting symptoms

“1314 cases reported 2134 presenting symptoms. The most common presenting symptom was abnormal gait (1160 cases; 188 studies) followed by recurrent infections in classical ataxia-telangiectasia and movement disorders in variant ataxia-telangiectasia.” (opens the source at this quote in a new tab)
“As expected, cerebellar gait ataxia was the most reported first presenting symptom however over a quarter did not have ataxia as their first clinical presentation. Dysarthria was reported as the first presentation in 9% of cases.” (opens the source at this quote in a new tab)

“Initial manifestations of Ataxia-telangiectasia include cerebellar symptoms (67%), dystonia (18%), choreoathetosis (10%), and tremor (4%), with parkinsonism and myoclonus not reported as initial features.” (opens the source at this quote in a new tab)

Motor symptoms: cerebellar ataxia of gait, trunk, and limbs

“In most children with classic A-T, cerebellar ataxia is the presenting manifestation observed after the child starts to sit and walk” (opens the source at this quote in a new tab)
“Infants show postural instability when sitting or standing. Although children start to walk at a normal age, their gait does not improve and remains wobbly.” (opens the source at this quote in a new tab)

“Ataxia may be comprised of multiple signs and symptoms, including gait ataxia, truncal ataxia, oculomotor ataxia, and difficulties with balance, speech, and hand coordination.” (opens the prescribing information at this quote)

“Generally children learn to walk at the usual age (about 10-18 months of age), but remain a bit unsteady, like normal children who have only just learned to walk, then become more wobbly (ataxic) over 2-3 years with frequent falls, then actually cannot get about as well as they used to from 5-6 years.” (opens the source at this quote in a new tab)

Neurological signs in a British Isles cohort of 70 individuals

“The majority (43/68) presented by 3 years of age with truncal ataxia. All had progressive, handicapping neurological symptoms exhibiting ataxia (70/70), ocular motor apraxia (70/70), an impassive face (70/70), dysarthria (70/70), chorea (68/70), dystonia (55/70) and peripheral neuropathy (50/70).” (opens the source at this quote in a new tab)
“Clinical immune deficiency was present in 43 of 70 patients. Ocular telangiectasia were seen in all but one case and excessive thinness in 54 of 70.” (opens the source at this quote in a new tab)

Motor symptoms: extrapyramidal movement disorders

“The prevalence of movement disorders during the course of the disease includes cerebellar symptoms (96%), dystonia (89%), parkinsonism (41%), choreoathetosis (89%), myoclonus (92%), and tremor (74%).” (opens the source at this quote in a new tab)

“In addition, most children with classic A-T have extrapyramidal involvement such as dystonia, choreoathetosis, myoclonic jerks, and tremor. In the second or third decade, parkinsonism can occur” (opens the source at this quote in a new tab)

“Dystonia was present in 11/14 (79%) and chorea was present in 6/14 (43%).” (opens the source at this quote in a new tab)

Peripheral nervous system symptoms: sensorimotor neuropathy

“After about age eight years children begin to show clinical signs of peripheral neuropathy, manifesting as a progressive sensorimotor neuropathy, decreased or loss of deep tendon reflexes, distal muscle weakness and atrophy, and impaired vibration sense” (opens the source at this quote in a new tab)

“In this prospective study, 42 classical A-T patients were assessed.” (opens the source at this quote in a new tab)
“We found significant correlations between age and the development of motor and sensory polyneuropathy in A-T compared with healthy controls (p < 0.001).” (opens the source at this quote in a new tab)

Oculomotor symptoms: oculomotor apraxia, saccade abnormalities, and nystagmus

“Abnormal eye movements associated with A-T include: oculomotor apraxia, nystagmus (including horizontal nystagmus in primary gaze, nystagmus on lateral gaze, post-rotary nystagmus and periodic alternating nystagmus), hypometric saccades and saccadic intrusions, convergence/accommodation and VOR abnormalities” (opens the source at this quote in a new tab)

“Visual acuity was preserved in most patients, with 24 (79%) achieving 6/12 or better.” (opens the source at this quote in a new tab)
“Eye movement recordings revealed hypometric saccades, increased latency, impaired smooth pursuit (especially vertical) and frequent nystagmus.” (opens the source at this quote in a new tab)

Bulbar symptoms: dysarthria

“With disease progression, speech problems occur in all individuals. Despite dysarthria, oral communication generally remains possible” (opens the source at this quote in a new tab)

“Early language development is normal, but by school entry most children with typical A-T will have a quiet voice, with indistinct words, which gradually become harder for strangers to understand.” (opens the source at this quote in a new tab)

Bulbar symptoms: dysphagia and aspiration

“Seventy patients (mean age, 10.7 years; range, 1.8 to 30 years) had feeding/swallowing and nutritional evaluations.” (opens the source at this quote in a new tab)
“Fourteen of the 51 patients (27%) with histories suggestive of dysphagia demonstrated aspiration. Of these, silent aspiration (aspiration without a cough) occurred in 10 (71%) patients.” (opens the source at this quote in a new tab)
“Aspirators were significantly older than non-aspirators (mean age, 16.9 vs 10.8 years; P =.002).” (opens the source at this quote in a new tab)

“Dysphagia is common in A-T and typically appears during the second decade of life because of the neurological changes which interfere with the coordination of mouth and pharynx movements necessary for safe and efficient swallowing” (opens the source at this quote in a new tab)

Ocular and cutaneous signs: telangiectasia

“Telangiectasia within the bulbar conjunctiva over the exposed sclera of the eyes usually occur by the age of 5–8 years, but sometimes later or not at all” (opens the source at this quote in a new tab)
“The absence of telangiectasia does not exclude the diagnosis of A-T.” (opens the source at this quote in a new tab)

“Strabismus was identified in four (13%) and moderate to severe conjunctival telangiectasia was present in 20 (67%) patients.” (opens the source at this quote in a new tab)

Immunological symptoms: immunodeficiency and infections

“Immunoglobulin (Ig) deficiencies are common, affecting IgG4 in 65% of patients, IgA in 63%, IgG2 in 48%, IgE in 23%, and IgG in 18%. Lymphopenia affected 71% of patients, with reduced B-lymphocyte number in 75%, CD4 T lymphocytes in 69%, and CD8 T lymphocytes in 51%.” (opens the source at this quote in a new tab)
“Recurrent upper and lower respiratory tract infections were frequent: otitis media in 46% of patients, sinusitis in 27%, bronchitis in 19%, and pneumonia in 15%.” (opens the source at this quote in a new tab)
“In spite of the high prevalence of laboratory immunologic abnormalities, systemic bacterial, severe viral, and opportunistic infections are uncommon in A-T.” (opens the source at this quote in a new tab)

“IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%.” (opens the source at this quote in a new tab)

“Infections were reported in the majority of the cohort (88%; 61/69).” (opens the source at this quote in a new tab)

“In this study we analyse the clinical history and immunological data in 44 patients with A-T who attended the National Ataxia-Telangiectasia clinic in Nottingham between 2001 and 2011.” (opens the source at this quote in a new tab)
“However, in general, for the majority of patients the severity of immune deficiency (both clinically and in terms of immunological blood markers) does not seem to deteriorate significantly with time.” (opens the source at this quote in a new tab)

Respiratory symptoms: lung disease phenotypes

“There are three recognised major lung disease phenotypes. 1) Immune dysfunction leading to recurrent upper and lower respiratory tract infections (RTIs), which in turn can lead to bronchiectasis; 2) lung disease associated with dysfunctional swallow and inefficient cough due to neurodegenerative deficits, which increases the risk for aspiration and consequently may also cause or worsen bronchiectasis; and 3) ILD/pulmonary fibrosis.” (opens the source at this quote in a new tab)

“Lingering cough, chest congestion and/or wheeze may be early symptoms of underlying lung disease in a person with A-T.” (opens the source at this quote in a new tab)

“Patients with A-T showed significant differences compared to healthy controls in symptom score, daytime and nighttime cough, days with symptoms and missed days in kindergarten/school. Severe infections with hospitalization occurred rarely.” (opens the source at this quote in a new tab)

Malignancy: tumor types in children and adults

“Children are prone to developing lymphomas (B-cell non-Hodgkin lymphoma and Hodgkin lymphoma) and leukemias (most notably T-cell acute lymphoblastic leukemias and T-cell prolymphocytic leukemia)” (opens the source at this quote in a new tab)
“In addition to hematologic malignancies, adults are prone to developing solid tumors including breast cancer, ovarian cancer, gastric cancer, liver cancer, esophageal carcinomas, melanomas, leiomyomas, and sarcomas” (opens the source at this quote in a new tab)

Endocrine and growth abnormalities

“We found that classic A-T patients were smaller overall, and suffered from height and weight faltering that continued throughout childhood and adolescence. When compared to the CDC growth references, the median heights and weights for both male and female patients eventually fell to or below the 3rd centile on the CDC charts.” (opens the source at this quote in a new tab)

“Endocrine abnormalities include growth impairment, gonadal dysfunction, and insulin resistance” (opens the source at this quote in a new tab)
“Elevated LH and FSH levels are common in adolescent females with A-T, indicating ovarian failure.” (opens the source at this quote in a new tab)

“Short stature, here defined as more than 2 standard deviations below age-adjusted average height at latest assessment, was present in 6/13 (46%) patients” (opens the source at this quote in a new tab)

Cognitive symptoms

“Cognitive deficits in AT at a young age are mild and limited to visual-spatial functions. More widespread cognitive difficulties emerge with age and disease progression, impacting executive function, spatial skills, affect, and social cognition.” (opens the source at this quote in a new tab)

“Although it is generally accepted that intellectual disability is not common in A-T, disturbances in cerebellar as well as non-cerebellar brain areas and networks may result in cognitive deficits.” (opens the source at this quote in a new tab)

Radiosensitivity

“People with A-T have an increased sensitivity to ionizing radiation (X-rays and gamma rays), which can be cytotoxic. X-ray exposure should be limited to times when it is medically necessary for diagnostic purposes.” (opens the source at this quote in a new tab)

“Increased sensitivity to ionizing radiation (x-ray and gamma ray) can result in severe side effects from such treatments.” (opens the source at this quote in a new tab)

Presentation of variant A-T

“Only one third had predominant ataxia, and 18% had a pure extrapyramidal presentation.” (opens the source at this quote in a new tab)
“There were no significant respiratory or immunological complications, but 25% of individuals had a history of malignancy.” (opens the source at this quote in a new tab)

“They often presented with extrapyramidal symptoms in childhood, whereas cerebellar ataxia appeared later.” (opens the source at this quote in a new tab)

“Variant A-T has a significantly milder disease course. While cerebellar ataxia can be absent, extrapyramidal movement disorders are common (typically dystonia and dystonic tremor) and most individuals have manifestations of axonal sensorimotor polyneuropathy.” (opens the source at this quote in a new tab)

Cancer incidence: French national registry

“In this large retrospective cohort, 69 patients with cancers (24.5%) were identified among 279 patients with AT.” (opens the source at this quote in a new tab)
“Eight patients developed acute leukemias (including four T-cell acute lymphoblastic leukemias), 12 developed Hodgkin lymphoma (HL), 38 developed non-Hodgkin lymphoma (NHL), three developed T-cell prolymphocytic leukemia (T-PLL), and eight developed carcinoma at a median age of 8.3, 10.6, 9.7, 24.2, and 31.4 years, respectively (P < .001).” (opens the source at this quote in a new tab)
“Immunodeficiency was associated with increased risk of cancer.” (opens the source at this quote in a new tab)

Cancer incidence: Johns Hopkins Ataxia Telangiectasia Clinical Center cohort

“Eighty-four (16.5%) of 508 individuals were diagnosed with a primary cancer, of whom 62 (74%) were hematologic in origin and 22 (26%) were solid-organ cancers. The cumulative incidence of cancer was 29% by age 35 years.” (opens the source at this quote in a new tab)
“Non–Hodgkin lymphoma occurred most frequently (n = 39), whereas solid cancers disproportionately affected those 18 years and older (n = 22).” (opens the source at this quote in a new tab)

Childhood cancer risk: German register-based cohort

“Among the 160 patients with AT, we observed 19 cases of childhood cancer (15 cases of lymphoma, three cases of leukemia, and one case of medulloblastoma) versus 0.32 expected. This corresponds to a 56-fold increased risk (SIR = 56; 95% CI, 33 to 88).” (opens the source at this quote in a new tab)
“Approximately 11% of patients with FA and 14% of patients with AT develop cancer by age 18 years.” (opens the source at this quote in a new tab)

Tumor type, residual ATM kinase activity, and breast cancer risk

“From a total of 296 consecutive genetically confirmed A-T patients from the British Isles and the Netherlands, we identified 66 patients who developed a malignant tumour; 47 lymphoid tumours and 19 non-lymphoid tumours were diagnosed.” (opens the source at this quote in a new tab)
“In addition, the presence of eight breast cancers in A-T patients, a 30-fold increased risk, establishes breast cancer as part of the A-T phenotype.” (opens the source at this quote in a new tab)
“This gives a standardised mortality ratio of 31.1 (with a wide 95% CI=14.4–74.7) equivalent to a cumulative risk of breast cancer diagnosis by the age of 50 years of 45% (95% CI=24–76%)” (opens the source at this quote in a new tab)

Outcomes of hematological malignancies in children and young adults

“In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries.” (opens the source at this quote in a new tab)
“Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively.” (opens the source at this quote in a new tab)
“The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4).” (opens the source at this quote in a new tab)

Excess cancer incidence in a historical United States cohort

“There were 52 primary cancers, representing a 61-fold cancer excess for white probands and a 184-fold excess for black probands.” (opens the source at this quote in a new tab)

Cancer in variant A-T

“Fourteen patients have been diagnosed with a malignancy.” (opens the source at this quote in a new tab)
“Missense mutations were associated with milder neurological disease severity, but with a higher risk of malignancy, compared to leaky splice site mutations.” (opens the source at this quote in a new tab)

Chronic lung disease: bronchiectasis and interstitial lung disease

“The medical records of 97 patients with A-T and chronic lung disease were reviewed. Interstitial lung disease (ILD) was specifically diagnosed in 25 of 97 patients.” (opens the source at this quote in a new tab)
“Nineteen of these 25 patients with ILD died within 24 months of the onset of their ILD, and of 7 patients treated with corticosteroids, 5 are still alive.” (opens the source at this quote in a new tab)

“Occurrence of recurrent sinopulmonary infections (n=45) and bronchiectasis (n=22) were found to be more common in patients with impaired immunological parameters (P=0.029 and P=0.023, respectively).” (opens the source at this quote in a new tab)

“Lung disease is common in patients with A-T and often progresses with age and neurological decline. Diseases of the respiratory system cause significant morbidity and are a frequent cause of death in the A-T population.” (opens the source at this quote in a new tab)

Lung function

“The mean forced vital capacity % predicted (FVC %) in the population was 56.6 ± 20.0.” (opens the source at this quote in a new tab)
“No significant change in FVC % was found in a subset of subjects (n = 25) who underwent pulmonary function testing on two or more occasions over an average of 2 years.” (opens the source at this quote in a new tab)

“FVC declined from 67 ± 8 while walking to 19 ± 6 %predicted values.” (opens the source at this quote in a new tab)

Dysphagia, growth failure, and nutritional decline

“Oropharyngeal dysphagia is common and appears to be progressive in patients with ataxia-telangiectasia. Older patients also have a higher incidence of poorer nutritional status.” (opens the source at this quote in a new tab)

“101 children (51 girls) had 222 measurements (32 once, 32 twice, 24 thrice) between 2009 and 2016.” (opens the source at this quote in a new tab)
“35/101 children had weight Z-scores below -2 on at least one occasion. Weight, height and BMI Z-scores declined over time. Decline was most obvious after 8 years of age. 14/101 (14%) children had a PEG, with longitudinal data available for 12.” (opens the source at this quote in a new tab)

“The distribution of patients according to nutritional status by age group revealed an over-time increase in the proportion of patients with severe thinness (p = 0.016). High glucose and triglyceride levels were observed in 9.5% and 23.6% of patients, respectively.” (opens the source at this quote in a new tab)

Diabetes and insulin resistance

“Seven out of 39 (17.9%) patients suffered from diabetes.” (opens the source at this quote in a new tab)
“Diabetes is a common finding in older A-T patients and often starts in puberty.” (opens the source at this quote in a new tab)

“Three patients developed type 2 diabetes in young adulthood and nine patients (64%) had a history of elevated liver function tests.” (opens the source at this quote in a new tab)

Liver disease

“For analysis, patients were divided into two age groups (Group 1: <12 years; group 2: ≥12 years).” (opens the source at this quote in a new tab)
“Ultrasound revealed hepatic steatosis in 11/19 (57.9%) patients in group 2.” (opens the source at this quote in a new tab)
“Liver disease is present in the majority of older A-T patients.” (opens the source at this quote in a new tab)

Loss of ambulation, neuropathy, and immobility

“Polyneuropathy, determined by clinical examination was present in 9/13 (69%) and by neurophysiological studies in 3/5 (60%), cognitive impairment in 8/14 (53%), wheelchair use in 11/14 (79%), and cerebellar atrophy in 9/11 (82%) patients.” (opens the source at this quote in a new tab)

“All patients with classic A–T beyond the age of 30 years were wheelchair-bound and dependent on others in activities of daily living (ADL). As a result of immobilization most patients developed pressure sores and had constipation.” (opens the source at this quote in a new tab)

Orthopedic and age-related complications

“Acquired deformity of the feet is common in people with A-T (unpublished observations) and compounds the difficulty individuals have with walking due to impaired coordination.” (opens the source at this quote in a new tab)
“Certain problems occur with an unexpectedly high frequency in patients with A-T who survive into their twenties and beyond.” (opens the source at this quote in a new tab)

PedsQL study in children and young people: design and population

“24 children/young people with A-T (mean age 11.2 ± 3.5 years; 13 males) and 20 parents were recruited, and 58% were reassessed after an average interval of 3.4 years.” (opens the source at this quote in a new tab)
“Participants were children and young people with A-T and disorders closely related to A-T recruited to the Childhood Ataxia Telangiectasia Neuroimaging Assessment Project (CATNAP) [14] through the United Kingdom National Paediatric A-T clinic at the Nottingham University Hospitals NHS Trust.” (opens the source at this quote in a new tab)
“QoL data from 20 healthy controls and their parents was used for comparison.” (opens the source at this quote in a new tab)

PedsQL study in children and young people: total scores compared with healthy controls

Rater	Ataxia-telangiectasia	Healthy controls	p value
Child or young person, total QoL	“53.8 ± 12.6”	“81.8 ± 11.8”	“<.0005”
Parent proxy, total QoL	“43.2 ± 13.2”	“90.7 ± 8.7”	“<.0005”

PedsQL study in children and young people: self-report, parent proxy report, age, and neurological disability

“Children and young people with A-T rated total QoL statistically significantly higher than their parents at both timepoints” (opens the source at this quote in a new tab)
“For the pooled (T1 and T2) dataset, there was no significant relationship between child QoL rating and age (r = −0.16, p = .380) (Fig. 1a), but a significant negative correlation was identified between parent QoL rating and the child's age (r = −0.43, p = .008) (Fig. 1b).” (opens the source at this quote in a new tab)
“Speech and Neuropathy contributed significantly to the model predicting QoL, with higher neurological scores (i.e., less impairment) predicting greater QoL” (opens the source at this quote in a new tab)
“Neurological disability does not determine child/young person QoL ratings in A-T. While certain aspects of neurological disability predict parent-proxy ratings, there is no decline in QoL over time.” (opens the source at this quote in a new tab)

PedsQL study in children and young people: limitations stated by the authors

“It may have been difficult for the child or young person to give an honest verbal response in front of their parent resulting in reporting bias.” (opens the source at this quote in a new tab)
“Therefore, while the data provides novel insights, the findings are exploratory and limited in their generalisability.” (opens the source at this quote in a new tab)

PROMIS survey of adult and pediatric participants and caregivers

“PRO evaluations of 90 international adult and pediatric A-T patients and their caregivers were completed via secure online administration of Patient-Reported Outcomes Measurement Information System (PROMIS) short forms evaluating anger, cognition, mood, social health, fatigue, pain, anxiety, and upper extremity function.” (opens the source at this quote in a new tab)
“It was found that a diagnosis of A-T complexly impacts patient PROs, but such data offers the potential for preventative and therapeutic interventions to improve the care of such patients.” (opens the source at this quote in a new tab)
“While most A-T patients and their caregivers feel their primary A-T medical provider has expertise and compassion in addition to being accessible and trustworthy, a significant percentage of study subjects did not agree that their provider was an expert in A-T or overall trustworthy.” (opens the source at this quote in a new tab)

Interviews with young people aged 16 to 27 years: study population

“Eleven young people (aged 16 – 27 years) and ten parents of young people (aged 16-27 years) responded to the invitation to take part in the My Life project.” (opens the source at this quote in a new tab)
“This represents around a third of all young people in this age group with the condition in the UK.” (opens the source at this quote in a new tab)

Interviews with young people aged 16 to 27 years: loss of walking, tiredness, and speech

“The loss of the ability to walk, (increasing) physical tiredness, and difficulties with speech and communicating were identified as impacting on, among other things, the inter-related concepts of identity and emotional well-being.” (opens the source at this quote in a new tab)
“The young people described the consequences of this in lost friendships and contact with peers, and a ‘narrowing’ of their life-worlds.” (opens the source at this quote in a new tab)
“Those not independently mobile, inside and/or outside of their home, typically regarded this as a key priority for change in their lives.” (opens the source at this quote in a new tab)

Interviews with young people aged 16 to 27 years: mental health and sources of emotional support

“A minority of parents currently, or had previously, had significant concerns about their young person’s mental health.” (opens the source at this quote in a new tab)
“Indeed, most believed they were their children’s only source of emotional/mental health support.” (opens the source at this quote in a new tab)

Fatigue, social isolation, and mental health in older children and adolescents

“Children and adolescents with A-T often complain of progressive daily fatigue which can be exacerbated by physical activities.” (opens the source at this quote in a new tab)
“Quality of life may deteriorate in older children and adolescents due to their increasing disabilities, social isolation, and the development of depression and anxiety. Attention to mental health care needs should be given to all children and adults with A-T.” (opens the source at this quote in a new tab)

Dependence in activities of daily living among adults older than 30 years with classic disease

“All patients with classic A–T beyond the age of 30 years were wheelchair-bound and dependent on others in activities of daily living (ADL).” (opens the source at this quote in a new tab)
“All Dutch patients were unable to write, type, or use a phone. All patients needed help with feeding.” (opens the source at this quote in a new tab)
“Although validated questionnaires to assess quality of life were not used by us, nor was this explicitly scored in any of the patients from the literature, we believe this is poor in older patients with A–T.” (opens the source at this quote in a new tab)

Parents as long-term caregivers

“Regardless of their own age, parents continued to be the most prominent caregivers for their child with A–T.” (opens the source at this quote in a new tab)

Cost-of-illness and claims-based studies specific to ataxia-telangiectasia

No evidence found.

Cost of illness of inherited ataxia in Ireland: a cohort that included 4 participants with ataxia-telangiectasia

“One hundred twenty-nine respondents completed a cross-sectional study on healthcare resource utilisation for progressive ataxia in Ireland. Costs were calculated using a prevalence-based approach and bottom-up methodology.” (opens the source at this quote in a new tab)
“Of the remaining 129, 56 (43%) had FRDA and 18 (14%) had a different type of inherited ataxia (Non-FRDA): these included ataxia-telangiectasia (n = 4)” (opens the source at this quote in a new tab)
“The COI for inherited ataxia in 2016 was €59,993 per person per year. Results were similar between participants with Friedreich’s ataxia (FRDA, n = 56), non-FRDA (n = 18) and those with undetermined ataxia (n = 55).” (opens the source at this quote in a new tab)
“Indirect costs, based on productivity losses by participants or caregivers, accounted for 52% of the cost of illness.” (opens the source at this quote in a new tab)
“Over two thirds of participants required professional or informal homecare and used a wheelchair.” (opens the source at this quote in a new tab)

Intensive care admissions at one academic center, 1995 to 2009

“Seven consecutive patients with confirmed diagnosis of ataxia-telangiectasia had nine intensive care admissions between January 1995 and December 2009.” (opens the source at this quote in a new tab)
“Mean duration of intensive care unit stay was 17 days (median, 9 days; range, 2-39 days). The most common admitting diagnosis was respiratory distress (six of seven patients).” (opens the source at this quote in a new tab)
“Forty-three percent (three of seven patients) survived to intensive care unit discharge with a 3-yr survival that was 14% (one of seven patients).” (opens the source at this quote in a new tab)

Hospital visits and admissions as a disruption to schooling

“Repeated hospital visits or admissions and the resultant disruption to schooling and the child's social life could also be important factors that contribute to the unexplained variance in parental QoL scores.” (opens the source at this quote in a new tab)

Household income and parental employment

“It is important to note, however, that some parents were concerned about the household income. Instances of a drastic reduction in the overall family purse caused by changes to benefits at 18 years were reported.” (opens the source at this quote in a new tab)
“In some cases parents were reluctantly working although deeply concerned that this meant their son or daughter was spending a lot of time at home without company and unable to get out and about.” (opens the source at this quote in a new tab)

Cost of mobility equipment and other one-off purchases

“Accessing funding for wheelchairs/ mobility scooters was a significant issue for some families.” (opens the source at this quote in a new tab)
“Motorised wheelchairs or scooters were other high cost items which some reported being unable to afford.” (opens the source at this quote in a new tab)
“Whilst there was general satisfaction with the level of benefits and allowances, capacity to meet one-off, high cost items was limited.” (opens the source at this quote in a new tab)

Productivity losses and informal care in inherited ataxia: a cohort that included 4 participants with ataxia-telangiectasia

“Disability associated with inherited ataxia is incapacitating; almost half of participants reported being unable to work or retiring due to their illness.” (opens the source at this quote in a new tab)
“While various financial supports from the state subsidise the indirect costs from productivity losses, almost 75% of these societal costs still fall to patients and caregivers.” (opens the source at this quote in a new tab)

Cost of diagnostic testing specific to ataxia-telangiectasia

No evidence found.

Molecular genetic testing that establishes the diagnosis

“The diagnosis of A-T is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in ATM identified by molecular genetic testing” (opens the source at this quote in a new tab)

Method	Proportion of pathogenic variants identified
Sequence analysis	“90%-95%”
Deletion/duplication analysis	“5%-10%”

Diagnostic confirmation required for entry to the pivotal trial

“To be eligible for the study, patients had to be aged 4 years or older with a confirmed diagnosis of A-T.” (opens the prescribing information at this quote)

“Eligible patients were aged 4 years or older with a genetically confirmed diagnosis of ataxia-telangiectasia” (opens the source at this quote in a new tab)

Sequential genetic testing in inherited ataxia

“These investigations and the associated clinic visits incur substantial costs.” (opens the source at this quote in a new tab)
“For example, patients requiring genetic testing often undergo sequential testing for multiple genes or costly next-generation sequencing before a diagnosis is identified [9].” (opens the source at this quote in a new tab)

Delay between symptom onset and diagnosis

“All 13 AT patients initially presented with symptoms of ataxia and abnormal gait between ages 12 months and 8 years (median 17 months). Patients experienced a delay from 2 months to 10 years between onset of symptoms and AT diagnosis, which occurred between ages 1.5 and 12 years (median age 3 years 5 months).” (opens the source at this quote in a new tab)

“From the experience of our national reference center for A-T at the Radboud University Medical Center, we know that the diagnostic process for A-T may take a long time and may include many procedures, e.g., lumbar punctures, muscle biopsies, and diagnostic x-rays (which are potentially harmful in the context of a DNA-repair disorder).” (opens the source at this quote in a new tab)

Yield of newborn screening for severe combined immunodeficiency

“NBS for SCID most likely identifies about 50% of children with classic A-T” (opens the source at this quote in a new tab)
“Since variant A-T is not associated with immunodeficiencies, NBS for SCID does not detect variant A-T.” (opens the source at this quote in a new tab)

“Of 13 older AT patients for whom newborn DBS had been stored, 7 samples tested positive for SCID under the criteria of California’s newborn screening program.” (opens the source at this quote in a new tab)

“Four patients were diagnosed with AT as a result of low TRECs on NBS. In each case, whole exome sequencing was diagnostic.” (opens the source at this quote in a new tab)
“One case was identified per year, while the total rate for SCID has been five new cases per year.” (opens the source at this quote in a new tab)

Views of parents of healthy newborns on early detection, additional tests, hospital visits, and health costs

“A total of 664 of 4,000 parents sent back the questionnaire (response rate 16.6%). The vast majority of parents (81.9%) favored early diagnosis of A-T over late diagnosis.” (opens the source at this quote in a new tab)

Statement rated by parents	Agree (%)	Fully agree (%)	Rating mean (SD)
“Early detection of A-T prevents unnecessary additional tests”	“51.5”	“24.3”	“3.9 (0.93)”
“Early detection of A-T prevents multiple visits to the hospital”	“42.5”	“20.3”	“3.6 (1.05)”
“Early detection of A-T saves extra health costs”	“36.3”	“12.6”	“3.3 (1.10)”

Views of parents of affected children on early diagnosis

“Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference.” (opens the source at this quote in a new tab)
“The majority of parents of a child with A-T would have preferred an early diagnosis during the asymptomatic phase of the disease, because the uncertainty during the diagnostic process had had a major impact on their lives.” (opens the source at this quote in a new tab)

Antenatal diagnosis and carrier detection within affected families

“Antenatal diagnosis and carrier detection can be cost effectively performed in families if the ATM mutations in an affected child have been identified.” (opens the source at this quote in a new tab)

Guideline scope and recommendation for multidisciplinary symptomatic treatment

“This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition.” (opens the source at this quote in a new tab)
“No curative therapy is available for ataxia-telangiectasia.” (opens the source at this quote in a new tab)
“Given the complexity and severity of the disorder, patients should receive optimal symptomatic treatment in the setting of a dedicated and experienced multidisciplinary team of health care professionals.” (opens the source at this quote in a new tab)

Supportive care and the specialties involved

“There is no cure for ataxia-telangiectasia.” (opens the source at this quote in a new tab)
“Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in (pediatric) neurology, pulmonology, immunology, pediatrics (for children) and internal medicine (for adults), rehabilitation medicine, and professionals in physical therapy, speech-language therapy, occupational therapy, and nutrition.” (opens the source at this quote in a new tab)
“Most of the guidelines recommended for the management of health-related problems in individuals with ataxia-telangiectasia (A-T) are expert and evidence based, due to a lack of clinical trials” (opens the source at this quote in a new tab)

Manifestations that respond to treatment and those that do not

“The management and treatment of A-T is symptomatic and supportive.” (opens the source at this quote in a new tab)
“Treatment of the neurologic problems associated with A-T is symptomatic and supportive, as there are no treatments known to slow or stop the neurodegeneration. However, other manifestations of A-T, e.g. immunodeficiency, pulmonary disease, failure to thrive and diabetes can be treated effectively.” (opens the source at this quote in a new tab)

Status of the United Kingdom clinical guidance for children

“There are currently no fully-researched and evidence-based clinical guidelines on the treatment of people with A-T published anywhere.” (opens the source at this quote in a new tab)
“What this document does aim to do is to provide suggestions for care based on the experience and current state of knowledge of doctors and therapists with considerable experience of seeing patients with A-T at what is the world’s longest-established multi-disciplinary A-T clinic.” (opens the source at this quote in a new tab)

Effect of supportive and multidisciplinary care on survival and quality of life

“Earlier diagnosis, supportive care and a multidisciplinary approach to patient follow-up can improve survival and quality of life.” (opens the source at this quote in a new tab)

Guideline position on rehabilitation therapy

“Importantly, the treatment of motor problems should be multidisciplinary, foremost consisting of intensive support from a rehabilitation physician and allied health care professionals, only sometimes combined with drug therapy.” (opens the source at this quote in a new tab)
“Multidisciplinary rehabilitation therapy is the cornerstone in the treatment of motor disability in ataxia-telangiectasia” (opens the source at this quote in a new tab)
“Aids that may be valuable for patients include foot orthoses, wheelchairs, standing frames, and electronic communication aids and equipment. Speech–language therapy can alleviate speech problems and dysphagia.” (opens the source at this quote in a new tab)

Expected effect of therapy and exercise on function and on neurodegeneration

“Physical, occupational and speech therapies as well as exercise may help maintain function but will not slow the course of neurodegeneration. Therapeutic exercises should not be used to the point of fatigue and should not interfere with activities of daily life.” (opens the source at this quote in a new tab)

Roles of physical therapists and speech-language therapists

“Physical therapists can provide exercises to maintain muscle strength, overall condition, and activity and to prevent joint contractures.” (opens the source at this quote in a new tab)
“When dysarthria is severe, a speech-language therapist can suggest use of communication aids (e.g., augmentative and alternative communication [AAC]) and equipment.” (opens the source at this quote in a new tab)

Physiotherapy aims and postural management in children

“The key aims of physiotherapy for children with ataxia-telangiectasia are to optimise and maintain functional activity.” (opens the source at this quote in a new tab)
“From an early age a 24-hour postural management system should be the goal.” (opens the source at this quote in a new tab)

Scoping review of nursing and allied health interventions: strength of the evidence

“Although limited, some of the evidence included within this review was specific to A-T and may, therefore, hold direct relevance to our research question: most notably, therapeutic exercise, including coordinative training, IMT, and early nutritional intervention.” (opens the source at this quote in a new tab)
“However, this review makes evidence-guided rather than evidence-based recommendations for practice given the lack of rigorous research focused on children and young people with A-T.” (opens the source at this quote in a new tab)

Guideline position on drug treatment of ataxia, dystonia, and chorea

“Few small non-randomized studies have investigated the neurological treatment in ataxia-telangiectasia specifically.” (opens the source at this quote in a new tab)
“In general, treatment of ataxia is difficult owing to the lack of effective drugs.” (opens the source at this quote in a new tab)
“Botulinum neurotoxin A is the first-choice treatment for focal dystonia.” (opens the source at this quote in a new tab)
“No studies on the treatment of chorea in ataxia-telangiectasia have been conducted.” (opens the source at this quote in a new tab)

Effectiveness of pharmacotherapy for extrapyramidal movement disorders

“The effectiveness of pharmacotherapy in movement disorders in A-T is low to moderate.” (opens the source at this quote in a new tab)
“Dystonia, the most troublesome movement disorder in A-T, can vary in distribution and severity and varies among affected individuals.” (opens the source at this quote in a new tab)
“As in individuals with torticollis, botulinum toxin A is the treatment of first choice.” (opens the source at this quote in a new tab)
“Anticholinergic drugs and GABA mimetics can be helpful.” (opens the source at this quote in a new tab)

Drugs commonly prescribed for neurological symptoms

“Commonly prescribed drugs include trihexyphenidyl (Artane), amantadine [148], baclofen and BOTOX® injections.” (opens the source at this quote in a new tab)
“However, to date, their efficacy and the features of motor impairment that would best be targeted in A-T are not known. All drugs should be prescribed by a neurologist familiar with the assessment and treatment of individuals with movement disorders.” (opens the source at this quote in a new tab)

“Other medication will be useful from time to time for particular symptoms as part of the child’s care, for example muscle relaxants such as baclofen, diazepam, tizanidine, dantrolene are sometimes helpful for stiffness and spasms.” (opens the source at this quote in a new tab)

Amantadine: open-label study in 17 children

“We treated 17 children (aged 11.2 ± 3.9 years) for 8 weeks with the dopaminergic and anti-N-methyl-d-aspartate (NMDA) agent amantadine sulfate 6.3 ± 0.87 mg/kg/d.” (opens the source at this quote in a new tab)
“Overall, 76.5% of patients were responders, with a mean 29.3% improvement. Ataxia, involuntary movements, and parkinsonism improved significantly (25.3%, 32.5%, and 29.5%, respectively); (P < .001, t test).” (opens the source at this quote in a new tab)
“Side effects were mild and transient, and they did not lead to drug discontinuation.” (opens the source at this quote in a new tab)
“Assessment of long-term effects and a double-blind study should follow.” (opens the source at this quote in a new tab)

Amantadine: appraisal in a systematic review

“However, the composite AT score, aggregating ICARS, the Abnormal Involuntary Movement Scale, and the Unified Parkinson's Disease Rating Scale, may primarily reflect effects on parkinsonian symptoms rather than direct improvement in cerebellar ataxia, and the absence of a control group, small sample size (n = 17), and short follow‐up duration severely limit the interpretability of these findings [30].” (opens the source at this quote in a new tab)

4-Aminopyridine: eye movement and vestibular function in 4 participants

“The influence of 4-AP on disorders of eye movements and vestibular function was studied in four A-T patients.” (opens the source at this quote in a new tab)
“Among two A-T subjects who manifested PAN, 4-AP reduced the peak slow phase velocity of the more severely affected individual and abrogated the PAN in the other.” (opens the source at this quote in a new tab)

Nicotinamide riboside: guideline statement

“Nicotinamide riboside, a form of vitamin B3, at 25 mg/kg/day (maximum dose of 900 mg/day), has significantly reduced ataxia scores (i.e., improved the motor disorder) in a single trial with 24 individuals with both classic and variant A-T” (opens the source at this quote in a new tab)

Nicotinamide riboside: open-label study over 4 months

“In this open‐label, proof‐of‐concept study, 24 patients with A‐T were treated with NR during four consecutive months.” (opens the source at this quote in a new tab)
“During treatment, ataxia scores improved; mean total Scale for the Assessment and Rating of Ataxia and International Cooperative Ataxia Rating Scale scores decreased to 2.4 and 10.1 points, respectively. After NR withdrawal, ataxia scores worsened.” (opens the source at this quote in a new tab)
“Adverse effects did not occur.” (opens the source at this quote in a new tab)

Nicotinamide riboside: open-label study over 2 years

“A single-arm, open-label clinical trial was performed in individuals with A-T, receiving NR over a period of 2 years.” (opens the source at this quote in a new tab)
“The total scores in the neuromotor test panels, as evaluated at the 18-month time point, improved for all but one participant, primarily driven by improvements in coordination subscores and eye movements.” (opens the source at this quote in a new tab)

Triheptanoin: phase 2a/b placebo-controlled dose-escalation trial

“31 participants with A-T were enrolled aged from 4 to 37 years (median 16-years).” (opens the source at this quote in a new tab)
“The primary outcome was cell death in respiratory epithelial cells.” (opens the source at this quote in a new tab)
“Adverse events including abdominal pain, nausea, vomiting, and diarrhoea, requiring dose capping at 20%, were observed in 12 (38%) participants.” (opens the source at this quote in a new tab)

Guideline position on steroids for ataxia

“Steroids have been shown to temporarily improve ataxia in ataxia-telangiectasia” (opens the source at this quote in a new tab)
“but should be prescribed with great caution because of their side effects” (opens the source at this quote in a new tab)

“long-term use of steroids may potentially cause severe side effects” (opens the source at this quote in a new tab)

“Some specific treatments to slow the disease progression are being trialled, for example various steroid regimes and amantidine sulphate, but their place in treatment is not yet established.” (opens the source at this quote in a new tab)

Oral betamethasone: randomized crossover trial in 13 children

“In a multicenter, double-blind, randomized, placebo-controlled crossover trial, oral betamethasone (BETA) and placebo were compared in terms of their reduction of ataxia symptoms as assessed with the International Cooperative Ataxia Rating Scale (ICARS).” (opens the source at this quote in a new tab)
“In this study of 13 A-T children, betamethasone reduced the ICARS total score by a median of 13 points in the intent-to-treat population and 16 points in the per-protocol population (ie, median percent decreases of ataxia symptoms of 28% and 31%, respectively).” (opens the source at this quote in a new tab)
“In conclusion, Oral betamethasone could be a promising therapy to relieve ataxia symptoms in A-T patients; however, long-term effectiveness and safety must be established.” (opens the source at this quote in a new tab)

Oral betamethasone: minimum effective dose in 9 participants

“Nine A-T patients were enrolled to receive betamethasone at increasing dosages of 0.001, 0.005 and 0.01 mg/kg/day.” (opens the source at this quote in a new tab)
“Four of nine patients had a benefit at a dose of 0.005 mg/kg/day of oral betamethasone. Using the higher dosage, only one additional patient had a positive response. Conversely, a daily dose of 0.001 mg/kg was ineffective.” (opens the source at this quote in a new tab)

Oral betamethasone: two years of treatment in 6 participants

“Six patients with ataxia telangiectasia received betamethasone at 0.02 mg/kg/day for two years.” (opens the source at this quote in a new tab)
“Transient improvement of neurological symptom was observed in five of the six patients. However, after two years betamethasone treatment, only one of the six patients showed a slight improvement in the neurological score, one patient showed no change, and the neurological scores of the remaining four patients deteriorated.” (opens the source at this quote in a new tab)
“As an adverse effect of betamethasone, transient adrenal dysfunction was observed in all cases.” (opens the source at this quote in a new tab)

Intra-erythrocyte dexamethasone: phase 2 open-label trial

“Twenty two patients (F:M = 1; mean age 11.2 ± 3.5) with a confirmed diagnosis of AT and a preserved or partially supported gait were enrolled for the study. The subjects underwent for six months a monthly infusion of EryDex.” (opens the source at this quote in a new tab)
“An improvement in ICARS (reduction of the score) was detected in the intention-to-treat (ITT) population (n = 22; p = 0.02) as well as in patients completing the study (per protocol PP) (n = 18; p = 0.01), with a mean reduction of 4 points (ITT) or 5.2 points (PP).” (opens the source at this quote in a new tab)

Intra-erythrocyte dexamethasone: 24-month extension in 4 participants

“After the end of the first trial, 4 patients continued to be treated with monthly EryDex infusions for an additional 24 months, and their clinical outcome was compared with that of 7 age-matched patients who stopped the treatment after the first 6 infusions.” (opens the source at this quote in a new tab)
“These promising preliminary results call for a large-scale controlled study on protracted treatment of patients with AT with dexamethasone-loaded erythrocytes.” (opens the source at this quote in a new tab)

Intra-erythrocyte dexamethasone: ATTeST phase 3 trial design and population

“This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 22 centres in 12 countries (Australia, Belgium, Germany, India, Israel, Italy, Norway, Poland, Spain, Tunisia, the UK, and the USA).” (opens the source at this quote in a new tab)
“Eligible participants were children aged 6 years or older weighing more than 15 kg who met clinical criteria for ataxia telangiectasia but who had preserved autonomous gait.” (opens the source at this quote in a new tab)
“175 patients received at least one dose of treatment (59 patients received the low dose and 57 received the high dose of intra-erythrocyte dexamethasone sodium phosphate, and 59 received placebo).” (opens the source at this quote in a new tab)

Intra-erythrocyte dexamethasone: ATTeST phase 3 trial primary endpoint

“Compared with the placebo group, no differences were identified with regard to change in mICARS score from baseline to 6 months in the low-dose group (least squares mean difference -1·37 [95% CI -2·932 to 0·190]) or the high-dose group (-1·40 [-2·957 to 0·152]; p=0·0765).” (opens the source at this quote in a new tab)
“Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age.” (opens the source at this quote in a new tab)

Intra-erythrocyte dexamethasone: NEAT phase 3 trial design and population

“NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA).” (opens the source at this quote in a new tab)
“Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment.” (opens the source at this quote in a new tab)

Intra-erythrocyte dexamethasone: NEAT phase 3 trial primary endpoint

“Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1·30 (95% CI -2·77 to 0·18; p=0·085).” (opens the source at this quote in a new tab)
“The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance.” (opens the source at this quote in a new tab)

“Furthermore, the study did not meet its key secondary endpoint of improvement in Clinical Global Impression of Severity (CGI-S) measured from baseline to month six with a p-value of 0.522.” (opens the source at this quote in a new tab)

Intra-erythrocyte dexamethasone: development status

“Company to cease clinical development of eDSP; Intends to preserve cash and explore available options” (opens the source at this quote in a new tab)

Intra-erythrocyte dexamethasone: safety over at least 2 years of treatment

“Sixty-eight patients completed a minimum of 2 years of treatment with EryDex (mean treatment length 39 ± 11 months).” (opens the source at this quote in a new tab)
“Notable adverse events included transient pruritus reported in 23 (34%) patients and findings of low serum iron reported in 27 (40%) patients, while at baseline one fifth of patients had low serum iron.” (opens the source at this quote in a new tab)
“The mean bone mineral density (BMD) z-score showed a decline of 0.4 points over the 24 months of treatment.” (opens the source at this quote in a new tab)

Guideline indications for immunoglobulin replacement

“Immunoglobulin replacement therapy, aiming at a serum immunoglobulin-G >6g/L, is indicated in all patients with a severe immunoglobulin-G deficiency (serum immunoglobulin-G <4g/L)” (opens the source at this quote in a new tab)

“Immunoglobulin replacement therapy is indicated in individuals with severe IgG deficiency and in those with the hyper IgM phenotype.” (opens the source at this quote in a new tab)

“Immune replacement therapy is considered when hypogammaglobulinemia and/or specific antibody deficiency is present together with a history of recurrent respiratory infections or established bronchiectasis, or when other preventive measures such as vaccinations and prophylactic antibiotics do not result in clinical improvement of the RTI symptoms irrespective of the severity of the immunological abnormalities.” (opens the source at this quote in a new tab)

Proportion of patients who receive immunoglobulin replacement

“About 15% of individuals with A-T will require Immunoglobulin replacement.” (opens the source at this quote in a new tab)
“Subcutaneous administration has shown to be both efficacious and acceptable to patients on replacement therapy.” (opens the source at this quote in a new tab)

“Hence there is wide variation in the proportion of patients who are on replacement treatment (table 2).” (opens the source at this quote in a new tab)
“If Ig therapy is considered, most centres administer subcutaneous Ig, as is currently recommended for severe immundeficiencies [29–31].” (opens the source at this quote in a new tab)

Retrospective series	Receiving immunoglobulin therapy (%)
80 participants	“12.5”
100 participants	“13”
15 participants	“60”
240 participants	“34.8”
44 participants	“15.9”
100 participants	“18.8”

Evidence base for prophylactic antibiotics and immunoglobulin replacement

“No placebo-controlled trials have been performed with regards to prophylactic antibiotic therapy or immune replacement therapy.” (opens the source at this quote in a new tab)
“A high proportion (74%) of children with A-T are prescribed prophylactic antibiotics [24] on inconsistent and non-evidence-based criteria.” (opens the source at this quote in a new tab)

Guideline position on prophylactic antibiotics

“Antibiotic prophylaxis may be indicated in patients with frequent or severe infections, and should be advised in immunoglobulin-G deficiency or specific polysaccharide antibody deficiency.” (opens the source at this quote in a new tab)
“Antibiotic prophylaxis has not been studied in ataxia-telangiectasia” (opens the source at this quote in a new tab)

“Prophylactic antibiotic treatment is considered when the burden of respiratory infections is high, if there is associated specific polysaccharide antibody deficiency and when there is established bronchiectasis.” (opens the source at this quote in a new tab)

“There is no data to recommend, or otherwise, prophylactic antibiotics, but most children are recommended prophylactic azithromycin by the immunologists.” (opens the source at this quote in a new tab)

Evidence base for respiratory management

“There are no randomised controlled trials with respect to the treatment of the respiratory complications in A-T.” (opens the source at this quote in a new tab)
“Current approaches are based on minimal best available evidence in A-T, and extrapolation from other more common disorders such as cystic fibrosis.” (opens the source at this quote in a new tab)

Lung function monitoring

“Regular assessments at least twice a year provide an impression of the degree of lung decline and allows for proactive early intervention.” (opens the source at this quote in a new tab)

“Children with A-T should undergo annual lung function studies starting at 6 years of age.” (opens the source at this quote in a new tab)
“These interventions may include the initiation of a cough assist device and chest physiotherapy to help improve MCC and lung inflation.” (opens the source at this quote in a new tab)

Airway clearance and cough augmentation

“Regular airway clearance and measures to augment cough and mucociliary clearance is advised by most experts looking after children with A-T.” (opens the source at this quote in a new tab)

“Respiratory muscle strength training, chest physiotherapy, and cough-assist devices can be useful in improving pulmonary function and reducing aspiration.” (opens the source at this quote in a new tab)

Antibiotic treatment of respiratory symptoms

“Administration of antibiotics should be considered when children and adults have prolonged respiratory symptoms (greater than 7 days) following a respiratory illness, including those that begin with a viral illness.” (opens the source at this quote in a new tab)

Interstitial lung disease

“Progressive, diffuse lung disease that poorly responds to aggressive antibiotic therapy, physiotherapy and immunoglobulin replacement and to which aspiration does not seem to contribute should lead to consideration of noninfective causes of lung disease in A-T, including ILD and pulmonary fibrosis and early treatment with corticosteroids.” (opens the source at this quote in a new tab)

Inspiratory muscle training: study in 11 participants

“A longitudinal study was conducted with 11 AT patients and nine healthy volunteers.” (opens the source at this quote in a new tab)
“The health and vitality domains of the SF-36 also showed significant improvement (P = 0.009 and P = 0.014, respectively) post-IMT.” (opens the source at this quote in a new tab)

Guideline recommendations on feeding support and gastrostomy

“Speech–language therapists and dieticians can support families by giving practical advice about changes in feeding routines.” (opens the source at this quote in a new tab)
“Therefore, gastrostomy placement should be considered early.” (opens the source at this quote in a new tab)

“Assessment of the adequacy and safety of nutritional intake should be performed at least annually. Provision of supplemental calories by the oral or enteral route should be undertaken in those with worsening nutritional status. Early gastrostomy insertion is likely to be required in those with unsafe swallow or inadequate nutritional intake.” (opens the source at this quote in a new tab)

Indications for a gastrostomy tube

“A gastrostomy tube (G-tube or feeding tube) is recommended when any of the following occur: a child cannot eat enough to grow or a person of any age cannot eat enough to maintain weight; aspiration is problematic; mealtimes are stressful or too long, interfering with other activities” (opens the source at this quote in a new tab)

“If the child has an unsafe swallow, gastrostomy or jejunostomy feeding is advised.” (opens the source at this quote in a new tab)

Gastrostomy at the Johns Hopkins clinic: tolerance and caregiver satisfaction

“We completed a retrospective review of 175 patients who visited the A-T Children's Center at Johns Hopkins Hospital from 2001 through 2008, and identified 28 patients with A-T (19 males, 9 females) who underwent GT placement for non-palliative reasons.” (opens the source at this quote in a new tab)
“Twenty-five (89%) patients tolerated GT placement and were a median of 5.0 (0.4-12.6) years post GT placement at the time of this investigation. Three (11%) patients died within one month of GT placement.” (opens the source at this quote in a new tab)
“In comparison to patients who tolerated GT placement, patients with early mortality were older when GT's were placed (median 24.9 vs. 12.3 years, p = 0.006) and had developed a combination of dysphagia, nutritional, and respiratory problems.” (opens the source at this quote in a new tab)
“Caregivers of patients tolerating GT placement reported significant improvements in mealtime satisfaction and participation in daily activities.” (opens the source at this quote in a new tab)

Gastrostomy at the United Kingdom national pediatric clinic

“14/101 (14%) children had a PEG, with longitudinal data available for 12. In a nested case control study, there was a trend for improvement in weight in those with a PEG (p=0.10).” (opens the source at this quote in a new tab)
“We suggest early proactive consideration of PEG from age 8 years onwards to prevent progressive growth failure.” (opens the source at this quote in a new tab)

Gastrostomy in a single-center cohort followed from 1986 to 2015

“Gastrostomy tubes were inserted in 12 patients, leading to improvement in BMI-Z from -5.1 ± 2.4 to -4 ± 2.9 (P < 0.05).” (opens the source at this quote in a new tab)

Caregiver acceptance of gastrostomy

“We know how to manage the nutritional needs of people with A-T, but do not do an adequate job of communicating this to caregivers and convincing them to use gastrostomy tubes to deliver supplemental calories early enough in life to make a difference to their children.” (opens the source at this quote in a new tab)

“Most parents are understandably reluctant to consider a feeding tube or gastrostomy, however discussion with another family with first-hand experience of the benefits can help.” (opens the source at this quote in a new tab)

Summary

Before the approval of levacetylleucine in September 2026, no therapy was approved for ataxia-telangiectasia in any market, and no treatment was known to slow or stop the neurological decline. Published guidance rests on expert opinion and small non-randomized studies: the European Respiratory Society statement reports no randomized controlled trials of respiratory treatments and no placebo-controlled trials of prophylactic antibiotics or immunoglobulin replacement, and the United Kingdom guidance for children states that it is not an evidence-based guideline. Evidence for symptomatic drugs comes from open-label studies of amantadine (17 participants, 8 weeks), 4-aminopyridine (4 participants), and nicotinamide riboside (24 participants, 4 months). Oral betamethasone reduced the ICARS total score by a median of 13 points in a crossover trial of 13 participants; in a two-year study of 6 participants, the neurological scores of 4 participants deteriorated and all 6 had transient adrenal dysfunction. Intra-erythrocyte dexamethasone did not meet its primary endpoint in the ATTeST trial (175 participants treated) or in the NEAT trial (105 participants), and its sponsor ceased clinical development in January 2026. A 2026 systematic review of 13 studies with 314 participants concluded that no intervention had demonstrated sustained efficacy in adequately powered controlled trials. Physical, occupational, and speech therapies may maintain function and do not slow neurodegeneration.

Absence of a treatment that slows neurological decline

“There is no treatment known to slow or stop the progression of the neurologic deficits associated with A-T.” (opens the source at this quote in a new tab)

“Although physical and occupational therapies and exercise may help maintain overall physical well-being and quality of life, there are currently no treatments capable of slowing or halting the neurologic decline in A-T.” (opens the source at this quote in a new tab)

Systematic review of pharmacological treatment of ataxia in pediatric ataxia-telangiectasia

“Thirteen studies (3 RCTs, 10 single‐arm trials) involving 314 participants (mean age 10.87 years) were included.” (opens the source at this quote in a new tab)
“No intervention has demonstrated sustained efficacy in adequately powered controlled trials.” (opens the source at this quote in a new tab)
“The recurrent pattern of promising open‐label findings followed by negative phase 3 results highlights a translational gap attributable to methodological limitations, including small sample sizes, heterogeneous populations, and variable outcome measures.” (opens the source at this quote in a new tab)
“Current evidence remains insufficient to guide clinical practice.” (opens the source at this quote in a new tab)

Absence of an approved therapy before September 2026

“To date, there are no approved treatments for ataxia-telangiectasia anywhere.” (opens the source at this quote in a new tab)

“Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials.” (opens the source at this quote in a new tab)

“There is no cure for ataxia-telangiectasia, and treatment options for the neurological symptoms of the disease have been limited.” (opens the source at this quote in a new tab)

“Until today, there were no approved treatments for A-T anywhere in the world.” (opens the source at this quote in a new tab)

Summary

Levacetylleucine was approved in the United States in September 2026 for ataxia in adults and pediatric patients with ataxia-telangiectasia weighing at least 15 kg, and the FDA describes it as the first treatment approved for ataxia in this disease. The indication is defined by diagnosis and body weight, and the label lists no contraindications. The pivotal trial enrolled 73 participants aged 4 years or older with genetically confirmed disease and a SARA score of 7 to 34; participants younger than 4 years, asymptomatic participants, and participants with advanced disease who could not complete functional assessments were excluded. The trial authors propose levacetylleucine as a first-line, foundational therapy. Dosing follows body weight (2 g, 3 g, or 4 g per day in two or three doses) as an oral suspension taken with or without food or given through a gastrostomy tube, and the label directs patients and caregivers to the Instructions for Use. The approved indication covers ataxia; published guidance continues to recommend multidisciplinary supportive care for immunodeficiency, respiratory disease, nutrition, and malignancy surveillance. Pregnancy status is verified before initiation in females of reproductive potential, and concomitant N-acetyl-DL-leucine and N-acetyl-D-leucine are avoided. The 12-week controlled period measured a symptomatic effect that was lost during the subsequent placebo period, and long-term data depend on the ongoing open-label extension. The manufacturer stated that the product was commercially available at approval.

First treatment approved for ataxia in ataxia-telangiectasia

“Today’s approval makes Aqneursa the first treatment approved for ataxia in patients with ataxia-telangiectasia.” (opens the source at this quote in a new tab)

Position proposed by the pivotal trial investigators

“Given that ataxia-telangiectasia is a debilitating, prematurely fatal condition with no approved drug, if approved, levacetylleucine could be considered as the first-line, foundational therapy for the treatment of ataxia-telangiectasia.” (opens the source at this quote in a new tab)

Population studied and populations excluded from the pivotal trial

“Eligible patients were aged 4 years or older with a genetically confirmed diagnosis of ataxia-telangiectasia; had a SARA score of 7–34 and were either within the 2–7 range of the gait subtest of the SARA scale or were able to perform the 9-hole peg test with their dominant hand in a time of 20–150 sec; and weighed 15 kg or more at screening.” (opens the source at this quote in a new tab)
“Second, the focus on symptomatic endpoints excluded patients younger than 4 years, asymptomatic patients, or patients with advanced disease states who would not be reliably able to complete functional assessments.” (opens the source at this quote in a new tab)

Route of administration and care setting

“The recommended dosage of AQNEURSA to be administered orally, with or without food, is based on the patient’s actual body weight (kg), as shown in Table 1” (opens the prescribing information at this quote)
“For patients who have a G-tube (French size 12 or larger) in place, administer AQNEURSA as follows:” (opens the prescribing information at this quote)
“Advise the patient and/or caregiver to read the FDA-approved patient labeling (Instructions for Use).” (opens the prescribing information at this quote)

Use with racemic acetylleucine

“Avoid concomitant use of AQNEURSA with N-acetyl-DL-leucine and N-acetyl-D-leucine. The D-enantiomer, N-acetyl-D-leucine, competes with levacetylleucine for monocarboxylate transporter uptake, which may reduce the levacetylleucine efficacy.” (opens the prescribing information at this quote)

Commercial availability at approval

“AQNEURSA is commercially available now” (opens the source at this quote in a new tab)

Predefined subgroup analyses of the primary endpoint in IB1001-303

“For the primary and each secondary endpoint, there were separate evaluations within key subgroups predefined in the statistical analysis plan (the trial was not powered for conclusions in these subgroups).” (opens the source at this quote in a new tab)
“Figure 3B displays results for the primary SARA endpoint in the predefined subgroups showing 95% CIs. There is no evidence of heterogeneity in treatment effect across subgroups that would suggest a differential treatment effect across the population. Instead, across all subgroups, there were consistent improvements with levacetylleucine versus placebo.” (opens the source at this quote in a new tab)
“Subgroup analysis showed consistent benefit across all demographics of patients, irrespective of age (paediatric vs adult), age at disease onset, or gender.” (opens the source at this quote in a new tab)
“Subgroup analyses showed that the improvement in neurological status was observed across all demographics of patients (age of neurological disease onset, disease severity, and gender, etc), indicating that the treatment might be applicable for all patients with ataxia-telangiectasia.” (opens the source at this quote in a new tab)

Size of the age, age-at-diagnosis, and dose subgroups in IB1001-303

Subgroup	Participants (n=73)
Paediatric (<18 years)	“47 (64%)”
Adult (≥18 years)	“26 (36%)”
Age at diagnosis: early-infantile (<2 years)	“51 (70%)”
Age at diagnosis: late-infantile (2 to <6 years)	“16 (22%)”
Age at diagnosis: juvenile (6 to <15 years)	“3 (4%)”
Age at diagnosis: adolescent or adult (≥15 years)	“3 (4%)”
Weight 15 to <25 kg (2 g per day)	“18 (25%)”
Weight 25 to <35 kg (3 g per day)	“17 (23%)”
Weight ≥35 kg (4 g per day)	“38 (52%)”

Randomization without stratification by age

“As the trial was a crossover design, in which each patient received levacetylleucine and placebo and therefore served as their own control, no stratification by age was done.” (opens the source at this quote in a new tab)

Company statements on subgroup consistency

“Subgroup analysis of the primary and secondary endpoints demonstrated consistent clinical effects across all demographics (age, gender, disease severity, age of symptom onset, etc.).” (opens the source at this quote in a new tab)

“Improvement was consistent across secondary endpoints and prespecified subgroups, including pediatric and adult patients, with no evidence of heterogeneity in treatment effect across the population.” (opens the source at this quote in a new tab)

Classic versus variant ataxia-telangiectasia

No evidence found.

Pediatric, low body weight, and geriatric populations in the label

“The safety and effectiveness of AQNEURSA for the treatment of ataxia in patients with A-T have been established in 47 pediatric patients weighing ≥ 15 kg in Trial 2” (opens the prescribing information at this quote)
“The safety and effectiveness of AQNEURSA have not been established in pediatric patients weighing <15 kg.” (opens the prescribing information at this quote)
“Clinical studies of AQNEURSA did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.” (opens the prescribing information at this quote)

Exposure and response

“A relationship was not observed between increasing levacetylleucine exposure and clinical efficacy.” (opens the prescribing information at this quote)

Race and ethnicity of the trial population

“Fourth, most patients in this trial were White and of North American or European descent, and data on patients of other ethnicities were scarce or absent.” (opens the source at this quote in a new tab)

United Kingdom specialist center model for children

“Once a diagnosis of A-T has been made the patient should be referred to the appropriate national specialist centre for a detailed multi-disciplinary assessment.” (opens the source at this quote in a new tab)
“Clinics are held over two days (Thursday & Friday), six times a year. At each clinic, six children are seen on an outpatient basis.” (opens the source at this quote in a new tab)
“Patients are usually recalled to the clinic every two or three years.” (opens the source at this quote in a new tab)

Local care between specialist center visits

“We also recommend that each child has a local named key worker, and a local named lead professional” (opens the source at this quote in a new tab)
“Respiratory care: A respiratory review at least every three months, and more frequently if the child is unstable.” (opens the source at this quote in a new tab)
“Neurology: A paediatric neurodisability review at least every 6 months, and more frequently if the child is unstable.” (opens the source at this quote in a new tab)

National adult service specification in England

“offer a multi-disciplinary review for patients with AT on an annual basis which is individualised to their specific requirements” (opens the source at this quote in a new tab)
“minimise hospital admissions and the requirement for unplanned medical intervention” (opens the source at this quote in a new tab)
“Patients will generally stay under the care of Papworth for their whole lifetime.” (opens the source at this quote in a new tab)

Multidisciplinary clinics in other countries

“Several multidisciplinary clinics across Europe (the UK, Netherlands, Norway, France and Germany) and elsewhere (Israel, Baltimore (MD, USA) and Brisbane (Australia)) manage patients with A-T.” (opens the source at this quote in a new tab)

Recommended surveillance

System or concern	Evaluation	Frequency
Neurologic	“Eval by neurologist for response to therapy for existing findings & development of new findings”	“Annually”
Immunodeficiency	“By immunologist (immunoglobulin levels, white blood cell count)”	“Annually”
Pulmonary disease	“Lung function testing (by spirometry)”	“Annually for persons w/evidence of disease at time of initial diagnosis”
Malignancy, laboratory	“Blood count & smear, immunoglobulin levels, M protein, LDH, IgM”	“Annually”
Malignancy, abdomen	“Ultrasound exam of abdomen in adulthood”	“Annually”
Malignancy, breast	“Breast MRI in females”	“Annually starting at age 25 yrs”
Diabetes	“Diabetes screening: urinalysis, fasting blood glucose concentration, Hgb A1c”	“Annually in adults”
Feeding and nutrition	“By SLP/nutritionist”	“Annually”

Avoidance of ionizing radiation

“Ionizing radiation (x-ray and gamma ray) is contraindicated, due to increased sensitivity” (opens the source at this quote in a new tab)
“Radiation therapy is contraindicated because increased radiosensitivity may lead to very severe complications” (opens the source at this quote in a new tab)

“Radiotherapy is strongly discouraged.” (opens the source at this quote in a new tab)
“Diagnostic radiographic examinations should be avoided” (opens the source at this quote in a new tab)

“According to this approach, a single X-ray can be performed for diagnostic purposes such as diagnosis of a chest infection or scoliosis. However, repeated X-rays should be avoided.” (opens the source at this quote in a new tab)

Vaccination guidance

“Inactivated vaccines are safe in ataxia-telangiectasia and are recommended as part of routine childhood vaccination programmes, except for patients who are on immunoglobulin replacement therapy. Annual vaccination with inactivated influenza vaccine is recommended for all patients, including those receiving immunoglobulin replacement therapy.” (opens the source at this quote in a new tab)
“Live oral polio vaccine should not be administered.” (opens the source at this quote in a new tab)

“Flu vaccines, 13-valent pneumococcal conjugate, and 23-valent pneumococcal polysaccharide vaccines should be given to all individuals with A-T.” (opens the source at this quote in a new tab)
“Rubella vaccination should be avoided in individuals with severe immunodeficiency as it can possibly increase the risk for granulomas” (opens the source at this quote in a new tab)

“Yellow fever vaccine should not be used in any patients with A-T.” (opens the source at this quote in a new tab)

Surgery and anesthesia

“Patients who have to undergo surgery should preferably be prepared, monitored, and operated in a dedicated ataxia-telangiectasia clinic.” (opens the source at this quote in a new tab)

Pregnancy testing and contraception during levacetylleucine treatment

“For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment with AQNEURSA.” (opens the prescribing information at this quote)
“Advise females of reproductive potential to use effective contraception during treatment with AQNEURSA and for 7 days after the last dose if AQNEURSA is discontinued” (opens the prescribing information at this quote)
“The decision to continue or discontinue AQNEURSA treatment during pregnancy should consider the female’s need for AQNEURSA, the potential drug-related risks to the fetus, and the potential adverse outcomes from untreated maternal disease.” (opens the prescribing information at this quote)

Monitoring with concomitant P-glycoprotein substrates

“Monitor more frequently for P-gp substrate related adverse reactions when used concomitantly with AQNEURSA.” (opens the prescribing information at this quote)

Missed doses

“If a dose of AQNEURSA is missed, skip the missed dose and take the next dose at the scheduled time. Do not take 2 doses at the same time to make up for a missed dose.” (opens the prescribing information at this quote)

Clinical scales available to document neurological status in practice

“We found a strong correlation between A-T NEST and the established SARA score, validating the use of A-T NEST and SARA in capturing the natural history of A-T patients.” (opens the source at this quote in a new tab)

Summary: postmarketing obligations for levacetylleucine

The FDA approval letter for the A-T supplement (NDA 219132/S-002, 18 September 2026) lists no postmarketing requirement or postmarketing commitment and contains no pediatric assessment section. It requires submission of structured product labeling within 14 days, patent information within 30 days, and compliance with the reporting requirements for an approved NDA. The original approval letter of 24 September 2024 for the NPC indication set eight postmarketing requirements under section 505(o) (PMR 4683-1 to 4683-8), comprising seven nonclinical toxicology and carcinogenicity studies and one clinical drug-drug interaction trial with a P-gp probe substrate, and one postmarketing commitment (PMC 4683-9), a food effect trial. The agreed final report dates run from December 2024 to June 2029. That letter states that the application was exempt from the Pediatric Research Equity Act assessment requirement because the product has orphan drug designation for the indication. The prescribing information revised in September 2026 states that animal studies of carcinogenic potential and of fertility have not been conducted.

A-T supplement approval letter: labeling and reporting obligations

“As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at FDA.gov.” (opens the source at this quote in a new tab)
“All promotional materials that include representations about your drug product must be promptly revised to be consistent with the labeling changes approved in this supplement, including any new safety-related information [21 CFR 314.70(a)(4)].” (opens the source at this quote in a new tab)
“We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81).” (opens the source at this quote in a new tab)

Pediatric Research Equity Act status

“Because this drug product for this indication has an orphan drug designation, you are exempt from this requirement.” (opens the source at this quote in a new tab)

Postmarketing requirements from the 2024 approval: basis for the nonclinical studies

“of serious risks with levacetylleucine use related to embryofetal development, fertility, early embryonic development, pre- and postnatal development, and carcinogenicity.” (opens the source at this quote in a new tab)
“Furthermore, the active postmarket risk identification and analysis system as available under section 505(k)(3) of the FDCA will not be sufficient to assess these serious risks.” (opens the source at this quote in a new tab)
“Therefore, based on appropriate scientific data, FDA has determined that you are required to conduct the following studies:” (opens the source at this quote in a new tab)

Postmarketing requirements from the 2024 approval: nonclinical studies

Requirement	Study	Final report submission
PMR 4683-1	“Conduct an embryo-fetal development (EFD) toxicity and toxicokinetic study with levacetylleucine in the rodent.”	“12/2024”
PMR 4683-2	“Conduct an embryo-fetal development toxicity and toxicokinetic study with levacetylleucine in the non-rodent.”	“12/2024”
PMR 4683-3	“Conduct a juvenile toxicity and toxicokinetic study with levacetylleucine.”	“05/2025”
PMR 4683-4	“Conduct a fertility and early embryonic development (FEED) toxicity study with levacetylleucine.”	“12/2024”
PMR 4683-5	“Conduct a pre- and postnatal development (PPND) toxicity study with levacetylleucine.”	“01/2025”
PMR 4683-6	“Conduct a 26-week carcinogenicity study with levacetylleucine, administered by daily oral gavage, in an appropriate transgenic mouse model.”	“03/2027”
PMR 4683-7	“Conduct a long-term (2-year) GLP-complaint carcinogenicity study by oral gavage administration in rats.”	“06/2029”

Postmarketing requirements from the 2024 approval: clinical drug-drug interaction trial

“Finally, we have determined that only a clinical trial (rather than a nonclinical or observational study) will be sufficient to identify an unexpected serious risk of drug-drug interactions with P-gp substrates.” (opens the source at this quote in a new tab)

Requirement	Trial	Trial completion	Final report submission
PMR 4683-8	“Conduct a clinical drug-drug interaction (DDI) trial in healthy volunteers to evaluate the effect of levacetylleucine on a probe substrate of P-gp to thoroughly assess its inhibitory potential and its impact on patient safety.”	“09/2026”	“09/2027”

Postmarketing commitment from the 2024 approval: food effect trial

Commitment	Trial	Trial completion	Final report submission
PMC 4683-9	“Conduct a dedicated food effect trial to evaluate the impact of food on exposure of levacetylleucine granules for oral suspension”	“09/2025”	“03/2026”

Status of the required studies as reflected in the September 2026 prescribing information

“Animal studies to evaluate the carcinogenic potential of levacetylleucine have not been conducted.” (opens the prescribing information at this quote)
“Animal studies to evaluate effects of levacetylleucine on fertility have not been conducted.” (opens the prescribing information at this quote)
“Levacetylleucine inhibits P-gp [see Clinical Pharmacology (12.3)]. However, the clinical significance of this finding has not been fully characterized.” (opens the prescribing information at this quote)

Rare pediatric disease priority review voucher: sponsor obligations

“FDA may revoke the PRV if the rare pediatric disease product for which the PRV was awarded is not marketed in the U.S. within 1 year following the date of approval.” (opens the source at this quote in a new tab)
“The sponsor of an approved rare pediatric disease product application who is awarded a PRV must submit a report to FDA no later than 5 years after approval that addresses, for each of the first 4 post-approval years:” (opens the source at this quote in a new tab)
“the actual amount of product distributed in the U.S.” (opens the source at this quote in a new tab)

Other product development: phase 3 trial in CACNA1A-related disorders

“The Phase III study (IB1001-304) is a 12-week, randomized, double-blind, placebo-controlled crossover trial designed to assess the safety, tolerability, and efficacy of levacetylleucine in this population.” (opens the source at this quote in a new tab)
“Levacetylleucine is investigational for the treatment of CACNA1A-related disorders and has not been approved by the FDA, MHRA, EMA, Swissmedic, or any other regulatory authority for this indication.” (opens the source at this quote in a new tab)

“This is a multinational, randomized, placebo-controlled, double-blinded, cross-over Phase III study that will assess the safety and efficacy of N-Acetyl-L-Leucine (IB1001) versus Placebo for the treatment of CACNA1A Disorders.” (opens the source at this quote in a new tab)

Extension phase of the pivotal A-T trial

“Patients who have participated in the study may be offered the opportunity to roll over into an Extension Phase, which is planned to allow patients to have further access to IB1001.” (opens the source at this quote in a new tab)
“Randomized, placebo-controlled, double-blind, crossover, multi-center, study with 1:1 randomization of IB1001 plus SOC for 12-weeks versus placebo plus SOC for 12-weeks, followed by open-label extension study.” (opens the source at this quote in a new tab)

“The study includes a randomized, placebo-controlled, double-blind crossover phase, followed by a long-term open-label extension.” (opens the source at this quote in a new tab)
“It was designed in partnership with key opinion leaders and A-T patient organizations to evaluate both symptomatic effects and longer-term clinical outcomes.” (opens the source at this quote in a new tab)

Adverse reaction reporting

“To report SUSPECTED ADVERSE REACTIONS, contact IntraBio Inc. at 1-833-306-9677 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.” (opens the prescribing information at this quote)

Monitoring recommended in the prescribing information

“Monitor more frequently for P-gp substrate related adverse reactions when used concomitantly with AQNEURSA.” (opens the prescribing information at this quote)
“For females of reproductive potential, verify that the patient is not pregnant prior to initiating treatment with AQNEURSA.” (opens the prescribing information at this quote)

Periodic status reports on postmarketing studies

“Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any study or clinical trial required under this section.” (opens the source at this quote in a new tab)
“This section also requires you to periodically report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue.” (opens the source at this quote in a new tab)

European Union pharmacovigilance: additional monitoring

“This medicine is under additional monitoring, meaning that it is monitored even more intensively than other medicines.” (opens the source at this quote in a new tab)
“As for all medicines, data on the use of Aqneursa are continuously monitored.” (opens the source at this quote in a new tab)

Real-world evidence collection through the specialty pharmacy

“In collaboration with IntraBio, Curant Rare developed a first-of-its-kind real-world evidence (RWE) system that is delivering unprecedented NPC insights to the scientific community.” (opens the source at this quote in a new tab)

Product registry for ataxia-telangiectasia

No evidence found.

Functional SARA after 12 weeks: prescribing information

“Each domain was rescored from 0 to 4, where 0 is the best neurological status and 4 the worst, with a total score ranging from 0 to 16.” (opens the prescribing information at this quote)
“The Least Squares Mean fSARA total score was 7.2 when patients were treated with AQNEURSA and 7.8 when patients were treated with placebo. The Least Squares treatment effect for the fSARA total score was -0.6 (95% CI: -0.9, -0.2)” (opens the prescribing information at this quote)
“Patients who received AQNEURSA in Period I followed by placebo in Period II (Treatment Sequence 1) showed a greater improvement in the fSARA score while receiving AQNEURSA in Period I with a mean change from baseline of -0.7 (SD 1.0), compared to Period II with a mean change from baseline of -0.2 (1.1).” (opens the prescribing information at this quote)
“Results on the fSARA were supported by consistent results demonstrated on the original SARA.” (opens the prescribing information at this quote)

SARA total score after 12 weeks: trial publication

“The mean change in the SARA score following 12 weeks of treatment was –1·92 (SD 2·81) with levacetylleucine treatment and –0·14 (2·38) with placebo (linear mixed model treatment effect –1·88, SD 0·41; 95% CI –2·70 to –1·06; p<0·0001; table 2).” (opens the source at this quote in a new tab)

Change from baseline on each scale after 12 weeks: trial publication

Endpoint	Levacetylleucine, mean change (SD)	Placebo, mean change (SD)	Treatment effect (95% CI)
SARA	“−1·92 (2·81)”	“−0·14 (2·38)”	“−1·88 (−2·70 to −1·06)”
FDA functional SARA	“−0·65 (1·16)”	“−0·10 (1·02)”	“−0·57 (−0·92 to −0·23)”
SCAFI	“0·06 (0·28)”	“0·04 (0·24)”	“0·01 (−0·06 to 0·07)”
ICARS	“−4·22 (7·77)”	“−1·69 (6·09)”	“−2·84 (−4·87 to −0·81)”
Investigator's Clinical Global Impression of Improvement	“−0·6 (0·8)”	“−0·2 (0·6)”	“−0·4 (−0·7 to −0·02)”

Loss of effect after crossover to placebo

“By contrast, patients who received levacetylleucine followed by placebo (n=35) had an increase in SARA score of 1·81 (SD 3·12) during period 2 on placebo, which effectively served as a washout from levacetylleucine, reflecting a deterioration in neurological signs and symptoms when treatment with levacetylleucine was stopped.” (opens the source at this quote in a new tab)
“For patients randomly assigned to sequence 1 (levacetylleucine to placebo), the improvements of levacetylleucine treatment observed in period 1 were lost in period 2 (consistent with the drug's pharmacological and pharmacokinetic action), as patients worsened and returned to their baseline status.” (opens the source at this quote in a new tab)

Participant and caregiver exit interviews

“57 (81%) of 70 exit interviews completed by participants or caregivers reported improvement in patients’ neurological signs and symptoms during the study while on levacetylleucine.” (opens the source at this quote in a new tab)

Time to effect

“Results from the study showed AQNEURSA significantly improved signs and symptoms of ataxia and demonstrated functional benefits important to everyday life that were evident within 12 weeks.” (opens the source at this quote in a new tab)

“The time course of pharmacodynamic response is unknown.” (opens the prescribing information at this quote)

Minimal clinically important difference on SARA: thresholds cited in the trial publication

“for which a 1-point change has been validated as representing a clinically meaningful change in functioning (gain or loss of complex function which is relevant to the patient's everyday life)” (opens the source at this quote in a new tab)
“A sample size of 46 patients was estimated to provide 80% power, at a one-sided significance level of 5%, to detect a true mean difference between groups in the SARA scores of 1·0” (opens the source at this quote in a new tab)
“Multiple studies have investigated a minimally clinically important difference on the SARA scale, ranging from 1 to 1·5 points” (opens the source at this quote in a new tab)
“the mean change on levacetylleucine and the treatment effect with levacetylleucine versus placebo are larger than all reported thresholds” (opens the source at this quote in a new tab)

Minimal clinically important difference on SARA: lysosomal storage disorder trial cohorts

“We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, and IB1001-301) of patients with Niemann–Pick disease type C (NPC) and GM2 Gangliosidoses (Tay–Sachs and Sandhoff disease) comprising 122 patients and 703 visits.” (opens the source at this quote in a new tab)
“For the CGI-I responses and change in SARA scores, Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigator’s, Caregiver’s, and Patient’s CGI-I respectively, indicating strong agreement.” (opens the source at this quote in a new tab)
“A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function.” (opens the source at this quote in a new tab)

Minimal clinically important difference on SARA: cerebellar ataxia exercise trial

“Sixty‐two individuals with cerebellar ataxias participated in a home‐exercise clinical trial.” (opens the source at this quote in a new tab)
“The MCID for SARA using anchor‐based method was 1.75. The distribution‐based method and distribution‐based mapping identified a median MCID score of 1.23.” (opens the source at this quote in a new tab)
“Synthesizing the methods, we recommend an MCID of 1.5 for SARA, which is slightly higher that what is currently used in clinical trials.” (opens the source at this quote in a new tab)

Meaningful change on the functional SARA: clinician interviews in spinocerebellar ataxia

“For the total f-SARA score, all 8 HCPs regarded minimum meaningful improvements or worsening as a 1- to 2-point change” (opens the source at this quote in a new tab)

Minimal clinically important difference established in ataxia-telangiectasia

No evidence found.

Annual SARA progression in adults with ataxia-telangiectasia

“We analysed longitudinal Scale for the Assessment and Rating of Ataxia (SARA) data from the largest published adult AT cohort to date (n = 82, age > 16 years).” (opens the source at this quote in a new tab)
“Neurological impairment progressed with a mean SARA increase of 0.38 points/year.” (opens the source at this quote in a new tab)

Durability beyond 12 weeks and effects on other disease features

“First, the study was designed to investigate the symptomatic effects of levacetylleucine; data from the ongoing extension phase will provide further insights into its impact on ataxia-telangiectasia disease progression and continued data on the long-term safety of levacetylleucine for ataxia-telangiectasia.” (opens the source at this quote in a new tab)
“Finally, the study duration was not long enough to investigate the effects of levacetylleucine on other key features of ataxia-telangiectasia, such as immunological defects and oncological risks.” (opens the source at this quote in a new tab)
“An ongoing open-label extension phase of this trial will investigate potential long-term, neuroprotective and disease-modifying effects.” (opens the source at this quote in a new tab)

“Patients who have participated in the study may be offered the opportunity to roll over into an Extension Phase, which is planned to allow patients to have further access to IB1001.” (opens the source at this quote in a new tab)