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Aqneursa (levacetylleucine)

Ataxia-telangiectasia

Also known as IB1001
Manufacturer
IntraBio
Last updated
206 sources

Product information and disease descriptionProduct descriptionProduct information

Product comparison

12 evidence topics · 19 sources

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
AttributePrescribing 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
AttributePublished 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
AttributeCompany 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)