Summary: development and regulatory status as of September 2026

The FDA approved tiratricol (Emcitate) tablets for oral suspension on 28 September 2026 for the treatment of peripheral thyrotoxicosis in adults and pediatric patients with MCT8 deficiency (Allan-Herndon-Dudley syndrome), with a limitation of use stating that it is not recommended for the treatment of primary hypothyroidism. The approval was granted to Egetis Therapeutics US Inc., and it is the first FDA-approved treatment for MCT8 deficiency. Egetis completed a rolling NDA submission on 29 January 2026, and on 27 March 2026 announced that the FDA had accepted the application with priority review and a PDUFA target action date of 28 September 2026. Tiratricol received orphan drug designation in January 2019, rare pediatric disease designation in November 2020, fast track designation in 2021, and breakthrough therapy designation in 2025, and the FDA granted Egetis a rare pediatric disease priority review voucher in connection with the approval. The prescribing information states that efficacy was evaluated in two studies (NCT05579327 and NCT02060474); Egetis states that the approval was also supported by Triac Trial II, the EMC Cohort Study, the EMC Survival Study, and the U.S. Expanded Access Program. Egetis expects commercial availability in the United States eight to ten weeks after approval. In the European Union, tiratricol was authorised on 12 February 2025 as a hybrid medicine whose reference product is Téatrois, a 0.35 mg tablet authorised in France in 1974, and it was launched in Germany on 1 May 2025. A U.S. composition patent was granted on 5 May 2026, and Egetis expects it to expire in 2045. In Japan, the licensee Fujimoto Pharmaceuticals expects to submit an NDA at the beginning of 2027.

Regulatory submission: NDA submitted January 2026 and approved September 2026

“Stockholm, Sweden, January 29, 2026.” (opens the source at this quote in a new tab)
“Egetis Therapeutics AB (publ) (“Egetis” or the “Company”) (NASDAQ Stockholm: EGTX), today announced that the Company has completed the rolling New Drug Application (NDA) submission to the U.S. Food and Drug Administration (FDA) for Emcitate® (tiratricol) for treatment of patients with MCT8 deficiency.” (opens the source at this quote in a new tab)

“Egetis completed the rolling NDA in January 2026.” (opens the source at this quote in a new tab)

“For Immediate Release: September 28, 2026” (opens the source at this quote in a new tab)
“The U.S. Food and Drug Administration today approved Emcitate (tiratricol) tablets for oral suspension to treat peripheral thyrotoxicosis (excess thyroid hormone levels in the blood that causes symptoms, such as rapid heart rate, increased blood pressure and adverse effects on metabolism) in patients with MCT8 deficiency, also known as Allan-Herndon-Dudley syndrome.” (opens the source at this quote in a new tab)

Launch: Anticipated eight to ten weeks after the September 2026 approval

“STOCKHOLM, SWEDEN, September 28, 2026.” (opens the source at this quote in a new tab)
“The Company expects EMCITATE to be commercially available in the United States in eight to ten weeks post approval.” (opens the source at this quote in a new tab)

FDA approval on 28 September 2026

“Emcitate is the first therapy approved by the FDA to treat symptoms of this very rare, devastating genetic disease.” (opens the source at this quote in a new tab)
“The approval of Emcitate was granted to Egetis Therapeutics US Inc.” (opens the source at this quote in a new tab)

Drug name	Active ingredient	Approval date	FDA-approved use on approval date
“Emcitate”	“tiratricol”	“9/28/2026”	“To treat peripheral thyrotoxicosis in patients with MCT8 deficiency”

“Initial U.S. Approval: 2026” (opens the prescribing information at this quote)
“EMCITATE is indicated for the treatment of peripheral thyrotoxicosis in adults and pediatric patients with monocarboxylate transporter 8 (MCT8) deficiency (Allan-Herndon-Dudley syndrome).” (opens the prescribing information at this quote)

Evidence supporting approval

“The efficacy of EMCITATE in patients with MCT8 deficiency was evaluated in two studies; Study 1 (NCT05579327) and Study 2 (NCT02060474).” (opens the prescribing information at this quote)

“The FDA approval of EMCITATE was supported by a comprehensive clinical development program evaluating EMCITATE in patients with MCT8 deficiency, including ReTRIACt, Triac Trial I, Triac Trial II, Erasmus Medical Center (EMC) Cohort Study, EMC Survival Study and the U.S. Expanded Access Program.” (opens the source at this quote in a new tab)

“The effectiveness of Emcitate was evaluated in two clinical studies in patients ranging in age from infants to adults, including an international, multi-center, randomized, placebo-controlled trial (NCT05579327) and a longer-term open-label study.” (opens the source at this quote in a new tab)
“Across both studies, patients treated with Emcitate had reductions in excess thyroid hormone levels in the bloodstream and improvements in cardiovascular and metabolic symptoms impacted by thyroid levels, such as systolic blood pressure and heart rate.” (opens the source at this quote in a new tab)

Expedited programs: priority review and special FDA designations

“Emcitate was granted Orphan Drug, Rare Pediatric Disease, Fast Track and Breakthrough Therapy designations as well as Priority Review.” (opens the source at this quote in a new tab)

“The application has been granted Priority Review and assigned a Prescription Drug User Fee Act (PDUFA) target action date, or FDA decision date, of September 28, 2026.” (opens the source at this quote in a new tab)

Rare pediatric disease priority review voucher

“In connection with the approval of EMCITATE, the FDA granted Egetis a Rare Pediatric Disease Priority Review Voucher (PRV).” (opens the source at this quote in a new tab)
“The Company currently expects to explore monetization of the PRV, which could potentially occur in the fourth quarter of 2026, subject to market conditions.” (opens the source at this quote in a new tab)

“Egetis is entitled to 50 percent of net proceeds from any Emcitate-related PRV sale, with the rest paid as earnout to Rare Thyroid Therapeutics International AB sellers following acquisition of Emcitate in 2020.” (opens the source at this quote in a new tab)

Advisory committee

“Thus far, the review has been constructive, and the mid-cycle as well as the late-cycle meetings have been held with the agency, which has confirmed that FDA expects to finish its review by the PDUFA date of September 28, 2026 and does not plan to hold an advisory committee meeting.” (opens the source at this quote in a new tab)

Special FDA designations: orphan drug designation

Field	Quoted record
Generic name	“tiratricol”
Date designated	“01/16/2019”
Orphan designation	“Treatment of Monocarboxylate 8 Transporter (MCT8) Deficiency (Allan-Herndon-Dudley-Syndrome)”
FDA orphan approval status	“Not FDA Approved for Orphan Indication”
Sponsor	“Rare Thyroid Therapeutics”

Special FDA designations: Fast Track

“October 8, 2021” (opens the source at this quote in a new tab)
“Egetis Therapeutics AB (publ) (ticker: EGTX) today announced that the U.S. Food and Drug Administration (FDA) has granted the company’s lead candidate drug Emcitate®, currently in a pivotal study, Fast Track Designation for the treatment of the rare genetic disease MCT8 deficiency.” (opens the source at this quote in a new tab)

Special FDA designations: Breakthrough Therapy

“Stockholm, Sweden, July 15, 2025.” (opens the source at this quote in a new tab)
“Egetis Therapeutics AB (publ) (“Egetis” or the “Company”) (NASDAQ Stockholm: EGTX), today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for tiratricol, as a treatment for monocarboxylate transporter 8 (MCT8) deficiency.” (opens the source at this quote in a new tab)

Special FDA designations: Rare Pediatric Disease

“Emcitate holds Orphan Drug Designation (ODD) in both EU and the US and was granted US Rare Pediatric Disease Designation (RPD) in November 2020 and in October 2021 the product received Fast Track status from the FDA.” (opens the source at this quote in a new tab)

Patent protection: U.S. composition patent

“On May 5, 2026, the United States Patent and Trademark Office (USPTO) granted Patent No. US 12611383B1 for the Company’s patent application No. 19/261,360 entitled “Pharmaceutical Compositions for Treating MCT8 Deficiency”.” (opens the source at this quote in a new tab)
“The claims cover, among other things, a method of treating MCT8 deficiency with the claimed pharmaceutical composition that encompasses tiratricol, dosing regimens, and tiratricol compositions with specific excipients.” (opens the source at this quote in a new tab)
“Egetis expects the granted patent will be Orange Book-listable, with a patent expiration date in 2045.” (opens the source at this quote in a new tab)

Approval and launch outside the United States: European Union authorisation

“Emcitate received a marketing authorisation valid throughout the EU on 12/02/2025.” (opens the source at this quote in a new tab)
“Emcitate contains the active substance tiratricol and is a hybrid medicine.” (opens the source at this quote in a new tab)
“The reference medicine for Emcitate is Téatrois, which was marketed in France for the treatment of thyroid hormone resistance syndrome.” (opens the source at this quote in a new tab)
“MCT8 deficiency is rare, and Emcitate was designated an ‘orphan medicine’ (a medicine used in rare diseases) on 8 November 2017.” (opens the source at this quote in a new tab)
“A study involving patients with MCT8 deficiency has shown that Emcitate reduces the average levels of the thyroid hormone T3 and leads to small improvements in signs of peripheral thyrotoxicosis.” (opens the source at this quote in a new tab)

“EMA has recommended granting a marketing authorisation in the European Union (EU) for Emcitate (tiratricol), an oral treatment for peripheral thyrotoxicosis (inappropriately high levels of circulating thyroid hormones) in patients with monocarboxylate transporter 8 (MCT8) deficiency.” (opens the source at this quote in a new tab)

Approval and launch outside the United States: European Union application and legal basis

“The applicant Rare Thyroid Therapeutics International AB submitted on 6 October 2023 an application for marketing authorisation to the European Medicines Agency (EMA) for Emcitate, through the centralised procedure under Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004.” (opens the source at this quote in a new tab)
“The applicant initially applied for the following indication:” (opens the source at this quote in a new tab)
“Emcitate is indicated for the treatment of monocarboxylate transporter 8 (MCT8) deficiency in all age groups.” (opens the source at this quote in a new tab)
“The final applied indication was as follows:” (opens the source at this quote in a new tab)
“Emcitate is indicated for the treatment of peripheral thyrotoxicosis in patients with monocarboxylate transporter 8 (MCT8) deficiency (Allan-Herndon-Dudley Syndrome), from birth.” (opens the source at this quote in a new tab)

Field	Quoted record
Legal basis	“Hybrid application (Article 10(3) of Directive No 2001/83/EC).”
Reference product	“Téatrois 0.35 mg tablet”
Reference product date of authorisation	“25-06-1974”
Reference product Member State	“France”

Approval and launch outside the United States: launch in Germany

“Egetis initiated the launch of Emcitate® in Germany on May 1, 2025.” (opens the source at this quote in a new tab)

“We initiated the launch of Emcitate in the first country, Germany, in May 2025, and in October 2025 we started price negotiations with the German national statutory health insurers, GKV-Spitzenverband.” (opens the source at this quote in a new tab)

Approval and launch outside the United States: other European countries and Japan

“In Spain we have recently submitted a national pricing and reimbursement dossier for Emcitate.” (opens the source at this quote in a new tab)
“In Italy and France, we plan to strengthen our value dossiers with survival data for Emcitate, once it has been published in a peer-reviewed journal by Erasmus Medical Center.” (opens the source at this quote in a new tab)
“Our Japanese partner Fujimoto Pharmaceuticals, who has an exclusive license for the development and commercialization of Emcitate for MCT8 deficiency in Japan, continues to prepare the Japanese NDA submission dossier, utilizing existing data generated from the global clinical development program.” (opens the source at this quote in a new tab)
“The NDA submission in Japan for Emcitate is expected to be submitted in the beginning of 2027.” (opens the source at this quote in a new tab)

Tiratricol development and approval review

“Tiratricol received its first approval on 12 February 2025 in the European Union, for the treatment of peripheral thyrotoxicosis in patients with MCT8 deficiency (Allan-Herndon-Dudley Syndrome), from birth.” (opens the source at this quote in a new tab)
“This article summarizes the milestones in the development of tiratricol leading to this first approval for MCT8 deficiency.” (opens the source at this quote in a new tab)

Generic name

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

Brand name

“Tiratricol (Emcitate®) is an orally bioavailable small molecule being developed by Egetis Therapeutics for the treatment of monocarboxylate transporter 8 (MCT8) deficiency.” (opens the source at this quote in a new tab)

“EMCITATE® is a registered trademark of Rare Thyroid Therapeutics International AB” (opens the prescribing information at this quote)

Manufacturer: Egetis Therapeutics

“The approval of Emcitate was granted to Egetis Therapeutics US Inc.” (opens the source at this quote in a new tab)

“Manufactured for: Rare Thyroid Therapeutics International AB” (opens the prescribing information at this quote)
“Distributed by Egetis Therapeutics US Inc., Cambridge, MA 02142, USA.” (opens the prescribing information at this quote)

“Rare Thyroid Therapeutics International is a wholly owned subsidiary of Egetis Therapeutics” (opens the source at this quote in a new tab)

Therapeutic class: thyroid hormone receptor agonist

“EMCITATE tablets for oral suspension contain tiratricol, a thyroid hormone receptor agonist.” (opens the prescribing information at this quote)

“The active substance of Emcitate is tiratricol, an analogue of the thyroid hormone T3, the most important active thyroid hormone.” (opens the source at this quote in a new tab)

Chemical description

“The chemical name for tiratricol is 2-[4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl]acetic acid.” (opens the prescribing information at this quote)
“The molecular formula of tiratricol is C14H9I3O4, its molecular weight is 621.93 g/mol and its chemical structure is depicted below.” (opens the prescribing information at this quote)
“Tiratricol is a white to off-white solid powder, with a pH-dependent solubility in water.” (opens the prescribing information at this quote)

Tablet for oral suspension: strength and appearance

“Tablets for oral suspension: 350 mcg. White oblong tablet with functional scoring on both sides.” (opens the prescribing information at this quote)
“EMCITATE (tiratricol) tablets for oral suspension, 350 mcg, are white, oblong tablets (size: 10 mm long, 5 mm wide) with functional score lines on both sides of the tablet and debossed with “E” on one side of the tablet, mirrored on both halves.” (opens the prescribing information at this quote)

Inactive ingredients

“Each tablet contains tiratricol as the active ingredient and the following inactive ingredients: anhydrous dibasic calcium phosphate, corn starch, lactose monohydrate, and magnesium stearate.” (opens the prescribing information at this quote)

Package and national drug code

Package	Contents	NDC
Carton	“PVC/Aluminum blisters, 60 tablets for oral suspension. Each outer carton contains 6 blister cards of 10 tablets each.”	“87216-0100-1”

Storage

“Store refrigerated at 2°C to 8°C (36°F to 46°F), and keep protected from light.” (opens the prescribing information at this quote)
“If dosing requires half a tablet, store the unused half in the original blister pack and outer carton (or in the light-protective packaging from the pharmacy) to protect from light and refrigerate at 2°C to 8°C (36°F to 46°F).” (opens the prescribing information at this quote)

European Union presentation: dispersible tablet strength

“Tiratricol will be available as 350 µg dispersible tablets.” (opens the source at this quote in a new tab)

“Emcitate is available as dispersible tablets (to be mixed with water before being taken), while the reference medicine was available as tablets to be taken by mouth.” (opens the source at this quote in a new tab)

European Union presentation: composition, storage, and pack size

“Each tablet contains 350 micrograms tiratricol.” (opens the source at this quote in a new tab)
“Each tablet contains 19 mg of lactose (corresponding to 20 mg of lactose monohydrate).” (opens the source at this quote in a new tab)
“White, oblong tablet (size: 10 mm long, 5 mm wide) with score lines on both sides.” (opens the source at this quote in a new tab)
“Store in a refrigerator (2 °C – 8 °C).” (opens the source at this quote in a new tab)
“Store in the original package in order to protect from light.” (opens the source at this quote in a new tab)
“Pack size of 60 dispersible tablets.” (opens the source at this quote in a new tab)

Material safety data sheet

No evidence found.

U.S. average sales price and wholesale acquisition cost

No evidence found.

Product pricing, Germany: pharmacy sales price and statutory rebates

Packaging size	Costs (pharmacy sales price)	Rebate Section 130 SGB V	Rebate Section 130a SGB V	Costs after deduction of statutory rebates	Price list revision
“60 TOS”	“€ 15,415.68”	“€ 1.77”	“€ 877.10”	“€ 14,536.81”	“15 August 2025”

Product pricing, Germany: dose range used for annual treatment costs

“Adjustment of the maintenance dose of tiratricol is patient-individual, depending on the thyroid levels in the serum and body weight. Against this background, the decision is based on a cost range.” (opens the source at this quote in a new tab)
“The starting dose of 175μg/day for children weighing less than 10 kg is used as the lower limit.” (opens the source at this quote in a new tab)
“The product information specifies a maximum dosage of 50 μg/day/kg body weight (BW) for subjects weighing more than 60 kg.” (opens the source at this quote in a new tab)

Limit of cost range	Dose per treatment day	Consumption by potency per treatment day	Treatment days per patient per year	Average annual consumption by potency
Lower limit	“175 μg”	“0.5 x 350 μg”	“365.0”	“182.5 x 350 μg”
Upper limit	“3850 μg”	“11 x 350 μg”	“365.0”	“4015 x 350 μg”

German reimbursement negotiations: subsequent price agreement

“The Emcitate price negotiations within the German reimbursement process (AMNOG) concluded in Q2 2026 and are valid from August 1” (opens the source at this quote in a new tab)

ATC classification

Field	Quoted record
Anatomical therapeutic chemical (ATC) code	“H03AA04”
Pharmacotherapeutic group	“Thyroid therapy”

U.S. indication and limitation of use

“EMCITATE is indicated for the treatment of peripheral thyrotoxicosis in adults and pediatric patients with monocarboxylate transporter 8 (MCT8) deficiency (Allan-Herndon-Dudley syndrome).” (opens the prescribing information at this quote)
“EMCITATE is not recommended for the treatment of primary hypothyroidism.” (opens the prescribing information at this quote)

European Union therapeutic indication

“Emcitate is indicated for the treatment of peripheral thyrotoxicosis in patients with monocarboxylate transporter 8 (MCT8) deficiency (Allan-Herndon-Dudley Syndrome), from birth.” (opens the source at this quote in a new tab)

Thyroid hormone receptor agonism independent of MCT8

“Tiratricol is a thyroid hormone receptor (THR) agonist which, unlike triiodothyronine (T3) and thyroxine (T4), can enter cells independent of the transmembrane transporter protein MCT8.” (opens the prescribing information at this quote)
“In patients with MCT8 deficiency, X-linked loss-of-function mutations in the SLC16A2 gene encoding MCT8 impair T3 entry into target tissues.” (opens the prescribing information at this quote)
“This results in insufficient T3 activity in the brain concurrent with persistent peripheral thyrotoxicosis from accumulation of circulating T3.” (opens the prescribing information at this quote)
“Intracellular tiratricol activity at THR-independent of MCT8-mediated membrane transport, can modulate hypothalamic-pituitary-thyroid axis signaling and reduce circulating T3 in patients with MCT8 deficiency.” (opens the prescribing information at this quote)

MCT8-independent cellular entry

“Tiratricol, an analogue and metabolite of the thyroid hormone triiodothyronine (T3), has thyromimetic effects but differs from T3 in that it can enter cells independent of MCT8.” (opens the source at this quote in a new tab)

“The active substance in Emcitate, tiratricol, is very similar to T3 but it does not need MCT8 to move in and out of cells.” (opens the source at this quote in a new tab)

MCT8-independent uptake in patient fibroblasts and neural cells

“Fibroblasts from MCT8 patients showed an impaired T3 uptake compared with controls, whereas TA3 uptake was similar in patient and control fibroblasts.” (opens the source at this quote in a new tab)
“In transfected cells, TA3 did not show significant transport by MCT8.” (opens the source at this quote in a new tab)
“Most importantly, treatment of athyroid Pax8-knockout mice and Mct8/Oatp1c1-double knockout mice between postnatal days 1 and 12 with TA3 restored T3-dependent neural differentiation in the cerebral and cerebellar cortex, indicating that TA3 can replace T3 in promoting brain development.” (opens the source at this quote in a new tab)

“In vitro studies have clearly shown that Triac acts similarly in MCT8-deficient and control cells, indicating that MCT8 is not involved in cellular entry of Triac.” (opens the source at this quote in a new tab)

Thyroid receptor binding

“Tiratricol binds with high affinity to thyroid receptors and does not require MCT8 to enter cells.” (opens the source at this quote in a new tab)
“It exerts similar biologic effects to T3 and can restore normal thyroid hormone activity in MCT8-dependent tissues.” (opens the source at this quote in a new tab)

Tiratricol cellular transport

“The aim of the study was to identify transporters that facilitate TRIAC uptake into cells.” (opens the source at this quote in a new tab)
“We identified SLC22A9 and SLC29A2 as transporters mediating cellular uptake of TRIAC.” (opens the source at this quote in a new tab)
“SLC22A9 encodes the organic anion transporter 7 (OAT7), a sodium-independent organic anion transporter expressed in the plasma membrane in brain, pituitary, liver, and other organs.” (opens the source at this quote in a new tab)
“SLC29A2 encodes the equilibrative nucleoside transporter 2 (ENT2), which is ubiquitously expressed, including pituitary and brain.” (opens the source at this quote in a new tab)
“Knowledge of TRIAC transporter expression patterns, also during brain development, may thus in the future help to interpret observations on TRIAC effects, as well as understand why TRIAC may not show a desirable effect on cells or organs not expressing appropriate transporters.” (opens the source at this quote in a new tab)

Concentration-dependent T3 lowering

“Tiratricol reduces elevated T3 concentrations in patients with MCT8 deficiency in a concentration-dependent manner, with greater T3-lowering effect at higher tiratricol exposures; however, this effect plateaus at or above mean tiratricol concentrations of approximately 746 ng/dL in patients 5 years and older.” (opens the prescribing information at this quote)
“Following discontinuation of EMCITATE, total T3 concentrations increased toward pretreatment levels within one week.” (opens the prescribing information at this quote)

Exposure-response relationship and TSH suppression

“This suggests that dosing tiratricol higher than a mean concentration of 15 nmol/L (corresponding to an AUC of 360 nmol*24h/L and a daily dose of ~ 80 µg / kg) has a limited additional effect on serum T3.” (opens the source at this quote in a new tab)
“The study of Everts and colleagues (Everts et al., 1994) shows that Triac uptake into anterior pituitary cells isolated from adult WT rats is higher compared to uptake of T3. Moreover, Triac was shown to be more potent to suppress TSH secretion compared to T3.” (opens the source at this quote in a new tab)

Cardiac electrophysiology

“There is insufficient information to characterize the effect of tiratricol on the QTc interval.” (opens the prescribing information at this quote)

“Tiratricol produced a concentration-dependent inhibition of hERG tail current amplitude by 5.0 ± 1.4%, 12.2 ± 2.1%, 16.8 ± 1.3% and 23.0 ± 2.0% in the presence of TIRATRICOL at 0.1, 1, 10 and 30 µmol/L, respectively. This inhibition was statistically significant (p<0.01).” (opens the source at this quote in a new tab)

Human cerebral organoid study

“Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human induced pluripotent stem cells (iPSCs) from MCT8-deficient patients.” (opens the source at this quote in a new tab)
“We next treated for 24 hours control and MCT8-deficient COs with 10 nM T3 and equivalent doses of DITPA (3.5 μM) or TRIAC (10 nM) and measured T3-responsive genes.” (opens the source at this quote in a new tab)
“Overall, these results indicate that the T3 signaling in the MCT8-deficient COs might be compromised and represent a proof of concept that the thyromimetic molecules TRIAC and DITPA can act in human neural cells despite a nonfunctional MCT8.” (opens the source at this quote in a new tab)
“In contrast, the TH analogs 3,5-diiodothyropropionic acid and 3,3′,5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting proof of concept that lack of T3 transport underlies the pathophysiology of AHDS and demonstrating the clinical potential for TH analogs to be used in treating patients with AHDS.” (opens the source at this quote in a new tab)

Preclinical findings in Mct8/Oatp1c1 double knockout mice

“Here, we directly compared their thyromimetic potential in Mct8/Oatp1c1 double knock-out mice (Dko) modeling human MCT8 deficiency.” (opens the source at this quote in a new tab)
“Dko mice received either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) daily during the first three postnatal weeks.” (opens the source at this quote in a new tab)
“Triac treatment (400 ng/g) induced normalized myelination, cortical GABAergic interneuron differentiation, electrophysiological parameters, and locomotor performance only when administered during the first three postnatal weeks.” (opens the source at this quote in a new tab)
“Together, Triac is highly-effective and more efficient than Ditpa in promoting CNS maturation and function in Dko mice yet needs to be initiated directly after birth for the most beneficial effects.” (opens the source at this quote in a new tab)

Preclinical findings concerning T4 suppression

“The aim of this study was to evaluate the effects and efficacy of therapeutic doses of TRIAC on Mct8-deficient mice (Mct8KO).” (opens the source at this quote in a new tab)
“Wild-type (Wt) and Mct8KO mice were treated with 30 ng TRIAC/g of body weight/day, given in drinking water, from postnatal day 21 to 30.” (opens the source at this quote in a new tab)
“TRIAC treatment greatly decreased plasma T4 in Wt and Mct8KO mice, and reduced T3 to normal levels in the Mct8KO mice.” (opens the source at this quote in a new tab)
“Therapeutic doses of TRIAC in Mct8KO mice restored plasma T3 levels but severely decreased T4 levels.” (opens the source at this quote in a new tab)
“The increase in the plasma TRIAC levels after treatment is not sufficient to increase TRIAC levels in the brain and to promote the expression of T3-dependent genes in brain cells. Instead, it leads to a state of brain hypothyroidism with reduced T3 content.” (opens the source at this quote in a new tab)

Commentary on the preclinical T4 findings

“The study by Bárez-López et al. is important as it shows that Triac can attenuate the thyrotoxicosis of Mct8 KO mice.” (opens the source at this quote in a new tab)
“However, the results based on studies performed on Mct8 KO mouse brains should be interpreted in the context of the model used and the safety profile obtained in humans.” (opens the source at this quote in a new tab)
“First, as Mct8 KO mice lack any overt neurological deficit, they do not provide an optimal model for the neurocognitive phenotype of AHDS.” (opens the source at this quote in a new tab)
“As in other clinical settings (TH resistance, thyroid cancer), the beneficial peripheral effects of Triac are mediated by potent suppression of TSH secretion with consequent decreases in serum TH levels.” (opens the source at this quote in a new tab)

Pharmacokinetic parameters: prescribing information

Parameter	Prescribing information
Dose proportionality	“The area under the plasma concentration-time curve (AUC) and maximal plasma concentration (Cmax) of tiratricol increased dose proportionally over the dose range studied (175 mcg to 1050 mcg) after oral administration.”
Enteral tube administration	“Administration of EMCITATE via an enteral tube compared to standard oral administration did not affect tiratricol pharmacokinetics.”
Absorption	“The absorption of tiratricol is rapid with a median time to maximum plasma concentration (Tmax) of 0.5 hours (range 0.25 to 1 hour).”
Plasma protein binding	“Tiratricol plasma protein binding is 99%.”
Apparent volume of distribution	“The apparent volume of distribution is 364 L for a 70 kg patient and 130 L for a 25 kg patient.”
Apparent clearance	“The apparent clearance of tiratricol is 21 L/hr for a 70 kg patient and 10 L/hr for a 25 kg patient.”
Steady-state half-life	“The steady state half-life is approximately 12 hours for a 70 kg patient and 9.4 hours for a 25 kg patient.”
Metabolism	“Tiratricol is metabolized by stepwise deiodination, sulfation and glucuronidation, mainly in the liver.”
Excretion	“Tiratricol and its metabolites are predominantly eliminated in urine as inorganic iodine and in bile.”

Effect of food: prescribing information

“Administration of EMCITATE in healthy volunteers at doses of 175 mcg and 1050 mcg with a high-fat high-calorie meal (956 kcal energy, 35 g protein, 65 g carbohydrate and 61 g fat (with 57% energy from fat)) resulted in a delayed Tmax (1 hour), reduced Cmax (67%-70%), and unchanged AUC, compared to fasted conditions.” (opens the prescribing information at this quote)
“These changes are not clinically significant” (opens the prescribing information at this quote)

Healthy-volunteer bioequivalence, food-effect, and dose-proportionality study

“This study investigates the pharmacokinetics (PK) of tiratricol.” (opens the source at this quote in a new tab)
“This novel Phase 1, randomized, five-period cross-over study was a hybrid combination of a two-period cross-over and a three-period balanced incomplete block design in healthy adult male subjects (n = 30) with a washout of ≥3 days between periods.” (opens the source at this quote in a new tab)
“Bioequivalence was established between 350μg tiratricol oblong and 350μg tiratricol round tablets in terms of AUC and Cmax with a serum half-life of approximately 13h for both administrations.” (opens the source at this quote in a new tab)
“Overall exposure (AUC) was comparable between the fasted and fed state.” (opens the source at this quote in a new tab)
“Absorption was rapid in the fasted state (median Tmax 0.5 hr) but slower in the fed state (median Tmax approximately 1.5 hr), with Cmax 67–70% lower.” (opens the source at this quote in a new tab)
“Cmax following treatment with the 175μg, 350μg, and 1050μg oblong tablet doses increased proportionally with increasing dose, whereas AUC increased in a slightly greater than proportional manner with increasing dose.” (opens the source at this quote in a new tab)
“Tiratricol was well tolerated in all doses and fasting states, with no serious adverse events recorded.” (opens the source at this quote in a new tab)

Population pharmacokinetics in patients and accumulation

“The applicant analysed PK measurements from 10 patients from the ReTRIACt study with the Population PK modelling. The Population PK modelling of the ReTRIACt data supports that in patients tiratricol PK is similar to healthy volunteer PK.” (opens the source at this quote in a new tab)
“The Population PK model predicts some accumulation of AUC and Cmax when comparing a single administration versus steady state. However, accumulation ratios based on the same dose frequency on day 1 to steady state are modest (≤1.5) regardless of dose frequency, dose and body weight, consistent with the relative short half-life of tiratricol.” (opens the source at this quote in a new tab)
“No formal clinical study to investigate the impact of special populations on tiratricol PK has been conducted.” (opens the source at this quote in a new tab)
“The available data indicate a weight dependence of PK.” (opens the source at this quote in a new tab)

Pharmacokinetics: European summary of product characteristics

“The in vitro plasma protein binding of tiratricol is high, with protein binding of > 99% in human plasma. The bioavailability of tiratricol (F) was 67 ± 6% suggesting tiratricol is well absorbed from the gastrointestinal (GI) tract.” (opens the source at this quote in a new tab)
“The geometric mean t½ was between 13.3 – 14.0 hours for the 350 microgram and 1 050 microgram doses, respectively. Tiratricol is eliminated through bile and urine.” (opens the source at this quote in a new tab)

Boxed warning: not for treatment of obesity or for weight loss

“WARNING: NOT FOR TREATMENT OF OBESITY OR FOR WEIGHT LOSS” (opens the prescribing information at this quote)
“Thyroid hormones, including EMCITATE, either alone or with other therapeutic agents, should not be used for the treatment of obesity or for weight loss” (opens the prescribing information at this quote)
“EMCITATE should not be taken for weight reduction as it may cause symptoms of thyrotoxicosis that could be serious or life-threatening.” (opens the prescribing information at this quote)

Contraindication: primary hyperthyroidism

“EMCITATE is contraindicated in patients with primary hyperthyroidism” (opens the prescribing information at this quote)

Warning: new onset or worsening of thyrotoxicosis

“Signs and symptoms of thyrotoxicosis, such as increased heart rate, elevated blood pressure, diarrhea, hyperhidrosis, irritability, insomnia, and nightmares, have occurred in patients receiving EMCITATE” (opens the prescribing information at this quote)
“These symptoms may occur if the EMCITATE dose is further increased despite T3 normalization, due to a drug-induced thyromimetic effect” (opens the prescribing information at this quote)
“Signs and symptoms of thyrotoxicosis may also occur during the dose titration period due to a combined thyromimetic effect from endogenous T3 levels that have not yet declined and EMCITATE.” (opens the prescribing information at this quote)
“If signs and symptoms of thyrotoxicosis occur despite T3 level normalization, decrease the EMCITATE dose according to the dose titration schedule” (opens the prescribing information at this quote)

Warning: laboratory test interference for T3 measurement

“Tiratricol can cross-react with T3 immunoassays leading to unreliable T3 results. When present, such cross-reactivity causes an overestimation of T3. Cross-reactivity of tiratricol is not expected to impact measurement of T3 by LC-MS/MS. An FDA-authorized LC-MS/MS test for the measurement of total T3 is not currently available.” (opens the prescribing information at this quote)

Interference with thyroid hormone laboratory measurements

“Varying concentrations (50-1,000 ng/dL) of TRIAC (Sigma Aldrich) were added to pooled serum and assayed for total T3 (TT3) and free T3 (FT3) on the following platforms: e602 (Roche Diagnostics), Architect (Abbott Diagnostics), Centaur (Siemens Healthcare Diagnostics), IMMULITE (Siemens Healthcare Diagnostics), DxI (Beckman Coulter), and Vitros (Ortho Clinical Diagnostics).” (opens the source at this quote in a new tab)
“Significant overestimation of TT3 and FT3 assays were observed across all platforms corresponding to increasing concentrations of TRIAC. The TRIAC effect at 250 ng/dL showed a constant interference of approximately 190 ng/dL TT3.” (opens the source at this quote in a new tab)
“All commercial TT3 and FT3 assays tested in this work cross-react significantly with TRIAC. Therefore, patients undergoing TRIAC therapy should have T3 hormone response monitored using alternative nonimmunoassay-based methods to avoid misinterpretation of thyroid function profiles.” (opens the source at this quote in a new tab)

“However, in many commercial total and FT3 assays, TRIAC has been shown to cross-react with T3 in a dose-dependent manner, likely due to a shared antibody-binding epitope.” (opens the source at this quote in a new tab)
“This cross-reactivity can lead to overestimation of T3 levels in patients receiving TRIAC treatment” (opens the source at this quote in a new tab)
“In patients receiving TH analogues, particularly TRIAC, T3 levels should be measured using LC-MS whenever available.” (opens the source at this quote in a new tab)
“If LC-MS assays are unavailable, some specific immunoassays may show lower cross-reactivity between T3 and TRIAC.” (opens the source at this quote in a new tab)

Adverse reactions in more than 5% of participants in Study 1 and Study 2

“Study 1 enrolled 20 male patients with MCT8 deficiency.” (opens the prescribing information at this quote)
“Adverse reactions reported in > 5% of patients treated with EMCITATE are summarized in Table 1.” (opens the prescribing information at this quote)

Adverse reaction	Study 1, EMCITATE, N = 20, n (%)	Study 2, EMCITATE, N = 46, n (%)
Diarrhea	“0”	“6 (13)”
Vomiting	“2 (10)”	“5 (11)”
Rash	“2 (10)”	“4 (9)”
Hyperhidrosis	“1 (5)”	“3 (7)”

Common adverse effects in the European regulatory overview

“The most common side effects with Emcitate (which may affect up to 1 in 10 people) include hyperhidrosis (excessive sweating), diarrhoea, irritability, anxiety and nightmares.” (opens the source at this quote in a new tab)
“These side effects usually happen at the start of treatment, or when the dose is increased, and tend to get better within a few days.” (opens the source at this quote in a new tab)

Adverse reactions in the European summary of product characteristics

“The most commonly reported adverse reactions associated with the use of tiratricol treatment were hyperhidrosis (7%), diarrhoea (6%), irritability (2%), anxiety (2%), and nightmares (2%). These reactions usually occurred at the start of treatment and/or when the dose was increased, and generally resolved within a few days.” (opens the source at this quote in a new tab)
“In clinical trials in patients with MCT8 deficiency, the onset of the observed adverse reactions hyperhidrosis, irritability, anxiety, and nightmares coincided with treatment initiation or dose modification. In all cases, these reactions were mild and resolved spontaneously.” (opens the source at this quote in a new tab)
“Signs and symptoms of a hypermetabolic state may appear in cases of overdose. Decreasing the dose of Emcitate or temporarily discontinuing treatment alleviates these symptoms.” (opens the source at this quote in a new tab)

European Union contraindications and precautions

“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)
“Hyperthyroidism for other reasons than MCT8 deficiency (e.g. Grave’s Disease).” (opens the source at this quote in a new tab)
“Caution should be used during dose titration in patients with cardiac disease, as they may be at increased risk of adverse reactions associated with a hypermetabolic state (see section 4.8).” (opens the source at this quote in a new tab)
“Tiratricol should not be taken for weight reduction. It may cause serious or life-threatening undesirable effects, particularly in combination with orlistat (see section 4.5 under “Orlistat”).” (opens the source at this quote in a new tab)
“Emcitate tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.” (opens the source at this quote in a new tab)

Nonclinical ophthalmologic findings

“Beagle dogs treated orally for 13 weeks with 0, 0.15, 0.5, or 5 mg/kg/day tiratricol had lens opacities and lens fiber degeneration in all animals treated at the highest dose (approximately 24-fold clinical exposures based on AUC estimates).” (opens the prescribing information at this quote)
“The risk of ocular toxicity from tiratricol use in humans is unknown, but is considered low based on the absence of findings in dogs at clinically relevant exposures.” (opens the prescribing information at this quote)

Nonclinical toxicology: carcinogenicity, genotoxicity, and fertility

“Tiratricol was not carcinogenic in Tg-RasH2 mouse carcinogenicity studies up to the highest tolerable dose tested of 15 mg/kg/day.” (opens the prescribing information at this quote)
“Tiratricol was not genotoxic in a bacterial reverse mutation assay, an in vitro micronucleus assay in human lymphoblastoid cells, and in an in vivo rat bone marrow micronucleus assay.” (opens the prescribing information at this quote)
“Dedicated fertility studies have not been conducted with tiratricol.” (opens the prescribing information at this quote)

“Embryofetal development studies showed embryolethality in rabbits and embryolethality and structural myocardial damage in rats.” (opens the source at this quote in a new tab)
“No effects on mating ability or fertility were observed in a study in male and female rats administered high and otherwise toxic doses of tiratricol.” (opens the source at this quote in a new tab)

Pregnancy

“There are no available data on the use of tiratricol for the treatment of MCT8 deficiency during pregnancy to inform a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with tiratricol.” (opens the prescribing information at this quote)

Pregnancy restriction: European Union

“MCT8 deficiency is an X-linked disease that almost exclusively affects males.” (opens the source at this quote in a new tab)
“Tiratricol crosses the placenta. There are no or limited amount of data from the use of tiratricol in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).” (opens the source at this quote in a new tab)
“Emcitate is contraindicated during pregnancy (see section 4.3).” (opens the source at this quote in a new tab)
“Women of childbearing potential have to use effective contraception during treatment.” (opens the source at this quote in a new tab)

Lactation

“There are no data regarding the presence of tiratricol in human or animal milk, the effects on the breastfed infant, or the effects on milk production.” (opens the prescribing information at this quote)

Pediatric use

“The safety and effectiveness of EMCITATE for the treatment of peripheral thyrotoxicosis have been established in pediatric patients with MCT8 deficiency.” (opens the prescribing information at this quote)
“Use of EMCITATE in pediatric patients is supported by a single-arm trial and a double-blind, placebo-controlled, randomized withdrawal trial that included pediatric patients with MCT8 deficiency ages 10 months to less than 2 years (n=5), ages 2 years to less than 12 years (n=38), and ages 12 years to less than 17 years (n=12)” (opens the prescribing information at this quote)
“Pediatric patients (5 to 16 years of age) with a lower body weight had a lower clearance and volume of distribution as compared to adult patients.” (opens the prescribing information at this quote)

“Safety data were evaluated in 63 patients between 0 and 17 years of age, in Triac Trial I and Triac Trial II combined. Thirty (30) patients were below 2 years of age at start of treatment, 25 patients were between 2 and 11 years of age and 8 patients were between 12 and 17 years of age. There is no indication from clinical trial data that the safety profile in any subset of the paediatric population is different from the safety profile in adult patients.” (opens the source at this quote in a new tab)

Geriatric use

“MCT8 deficiency is largely a disease of children and young adults; therefore, there are insufficient data on the use of EMCITATE in patients aged 65 years and older to determine whether they respond differently from younger patients.” (opens the prescribing information at this quote)

Renal and hepatic impairment

“No clinical studies have been performed in subjects with renal and hepatic impairment.” (opens the prescribing information at this quote)

“No specific studies have been performed in patients with hepatic impairment. In these patients, careful dose titration and regular monitoring of serum concentrations of T3 are recommended” (opens the source at this quote in a new tab)
“No specific studies have been performed in patients with renal impairment. In these patients, careful dose titration and regular monitoring of serum concentrations of T3 are recommended” (opens the source at this quote in a new tab)

Clinical drug interaction studies

“Many drugs can exert effects on thyroid hormone pharmacokinetics and may alter the therapeutic response. No clinical drug interaction studies have been conducted with EMCITATE.” (opens the prescribing information at this quote)

Drugs that may affect tiratricol absorption

Drug or drug class	Effect	Clinical recommendation
Bile acid sequestrants and ion exchange resins	“Bile acid sequestrants and ion exchange resins decrease thyroid hormone exposure by binding and delaying or preventing absorption.”	“Avoid concomitant use of bile acid sequestrants and ion exchange resins with EMCITATE.”
Iron and calcium supplements	“Iron and calcium may interfere with the absorption of tiratricol.”	“If concomitant use of iron or calcium supplements is necessary, administer iron or calcium supplements consistently at the same time each day relative to EMCITATE dosing.”
Proton pump inhibitors	“Changes in gastric pH associated with PPI therapy may increase the absorption of tiratricol.”	“Serum concentrations of T3 should be monitored and dose adjustments of EMCITATE considered when initiating, modifying or discontinuing PPI treatment.”

Drugs that may alter plasma binding of T3

Drug or drug class	Effect	Clinical recommendation
Oral estrogen-containing products	“These drugs may increase serum thyroxine-binding globulin (TBG) concentration and increase total T3 serum levels.”	“Monitor clinical symptoms and evaluate free T3 levels.”
Anabolic steroids and glucocorticoids	“These drugs may decrease serum TBG concentration and decrease total T3 serum levels.”	“Monitor clinical symptoms and evaluate free T3 levels.”
Salicylates, more than 2 g/day	“Salicylates inhibit binding of T3 to TBG and transthyretin and may inhibit binding of tiratricol to transthyretin.”	“Monitor clinical symptoms and evaluate free T3 levels.”

Drugs that may increase hepatic metabolism of tiratricol

Drug or drug class	Effect	Clinical recommendation
Drugs that increase hepatic drug-metabolizing enzyme activity	“Administration of drugs that increase hepatic drug-metabolizing enzyme activity may increase the hepatic degradation of thyroid hormones and tiratricol.”	“Serum concentrations of thyroid hormones should be monitored and dose adjustments of EMCITATE considered when initiating, titrating or discontinuing treatment with enzyme inducing agents.”

In vitro transporter substrate studies

“Tiratricol is not a substrate for P-gp, BCRP, OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1 or MATE2-K.” (opens the prescribing information at this quote)

Drugs that may affect tiratricol: European summary of product characteristics

Drug or drug class	Statement in the summary of product characteristics
Antacids, charcoal, calcium, cationic resins, iron, and sucralfate	“Antacids, charcoal, calcium, cationic resins (e.g. cholestyramine), iron, sucralphate, and other gastrointestinal agents may interfere with the gastrointestinal absorption of tiratricol. These treatments should be taken before or after tiratricol (more than 2 hours before or after if possible). In the case of cholestyramine, tiratricol should be taken 1 hour before or 4 hours after the resin dose.”
Proton pump inhibitors	“Co-administration with PPIs may cause a decrease in the absorption of the thyroid hormones, due to the increase of the intragastric pH caused by PPIs such as omeprazole, esomeprazole, pantoprazole, rabeprazole and lansoprazole. Serum concentrations of T3 should be monitored and dose adjustment of tiratricol considered when initiating, changing or discontinuing PPI treatment.”
Sevelamer	“Sevelamer may decrease the concentration of thyroid hormones and result in reduced efficacy of tiratricol. Sevelamer should be taken more than 2 hours before or after administration of tiratricol.”
Enzyme inducers, including antiepileptics	“Medicinal products that can induce the enzyme system in the liver, such as barbiturates, phenytoin carbamazepine, rifabutin, rifampicin or products containing St. John’s wort (Hypericum perforatum) may increase the hepatic clearance of tiratricol.”
Antimalarials	“Concomitant use of tiratricol and antimalarial medicinal products (chloroquine, proguanil) may cause clinical hypothyroidism.”
Non-contraceptive oestrogens	“Non-contraceptive oestrogen and oestrogen containing products (including hormone replacement therapy) may increase the requirement of tiratricol treatment dose.”
Orlistat	“Orlistat may decrease tiratricol absorption which may result in hypothyroidism (changes in thyroid function should be monitored).”

Proton pump inhibitors: published management recommendations

“Patients should be monitored for signs of gastroesophageal reflux disease and may benefit from treatment with proton pump inhibitors (PPIs).” (opens the source at this quote in a new tab)
“While this finding is debated and has not been replicated upon coadministration of PPIs and TRIAC, additional monitoring of TH levels is recommended when the dose of either is initiated, adjusted, or discontinued.” (opens the source at this quote in a new tab)

Oral anticoagulants

“EMCITATE may increase the response to oral anticoagulant therapy, which may increase the risk of hemorrhage. Therefore, a reduction in the dose of anticoagulant may be warranted if administered concomitantly with EMCITATE. Closely monitor coagulation tests to permit appropriate and timely dosage adjustments of the anticoagulant.” (opens the prescribing information at this quote)

Psychostimulants

“Administration of psychostimulants (e.g., caffeine, norepinephrine–dopamine reuptake inhibitors (NDRIs), and amphetamines) in combination with high doses of EMCITATE may lead to increased heart rate and blood pressure. Concomitant use of psychostimulants and EMCITATE is not recommended.” (opens the prescribing information at this quote)

In vitro enzyme and transporter inhibition and induction

“CYP450 Enzymes: Tiratricol is unlikely to inhibit or induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 at clinically relevant doses.” (opens the prescribing information at this quote)
“UGT Enzymes: Tiratricol is unlikely to inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15 and UGT2B17 at clinically relevant doses.” (opens the prescribing information at this quote)
“Tiratricol is unlikely to inhibit BCRP, OAT1, OAT3, OATP1B1 transporters at clinically relevant doses.” (opens the prescribing information at this quote)

Effects of tiratricol on other drugs: European summary of product characteristics

Drug or drug class	Statement in the summary of product characteristics
CYP3A4 substrates with narrow therapeutic indices	“Based on in vitro data there is an indication that tiratricol may induce CYP3A4 at a gut level and therefore medicinal products with narrow therapeutic indices that are dependent on CYP3A4, including but not limited to: alfentanil, cisapride, cyclosporine, ergot derivatives, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, atorvastatin, lovastatin, and simvastatin should be used with caution.”
P-gp and BCRP substrates with narrow therapeutic indices	“Medicinal products that are substrates of P-glycoprotein (P-gp) or Breast Cancer Resistance Protein (BCRP) efflux transporters with narrow therapeutic indices should also be used with caution.”
Anti-diabetic agents	“Tiratricol may reduce blood glucose levels. The dose of anti-diabetic agents may need to be adjusted if administered concomitantly with tiratricol. Periodic monitoring of blood glucose is necessary (see section 4.4).”
Oral anticoagulants	“The effect of anti-coagulant therapy may be increased during treatment with tiratricol. This may increase the risk of haemorrhage. The dose of anti-coagulant therapy may have to be adjusted if administered concomitantly with tiratricol.”

Drug-laboratory interference

“An LC-MS/MS method should be used for total T3 measurement due to interference of EMCITATE with T3 immunoassays.” (opens the prescribing information at this quote)

Individualized dosage

“EMCITATE dosage is individualized based on weight, total T3 levels, and signs and symptoms of thyrotoxicosis” (opens the prescribing information at this quote)
“Assess total T3 levels by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method” (opens the prescribing information at this quote)

Starting dosage, titration increment, and dosage reduction by body weight

Body weight	Recommended starting dosage	Titration increment	Dosage reduction for new or worsening thyrotoxicosis	Discontinuation taper
10 kg or less	“175 mcg/day”	“175 mcg/day.”	“175 mcg”	“reduce EMCITATE by 175 mcg/day once every two weeks.”
Greater than 10 kg	“350 mcg/day”	“350 mcg/day.”	“350 mcg”	“reduce EMCITATE by 350 mcg/day once every two weeks.”

Maximum recommended dosage by body weight

Body weight	Maximum recommended dosage
Less than 10 kg	“100 mcg/kg/day”
10 kg to less than 40 kg	“80 mcg/kg/day”
40 kg to less than 60 kg	“60 mcg/kg/day”
60 kg and above	“50 mcg/kg/day”

Dose titration to total T3

“Measure individual total T3 levels using an LC-MS/MS method.” (opens the prescribing information at this quote)
“Based on total T3 levels, increase the dosage approximately every two weeks in the following increments for patients weighing:” (opens the prescribing information at this quote)
“Increase the dosage until a total T3 level below the midpoint of the normal range for age has been achieved (the maintenance dose) or until the maximum recommended dosage based on weight is achieved” (opens the prescribing information at this quote)
“If total T3 is within the normal range, the dosage may be further adjusted up to the maximum recommended dosage based on the patient’s heart rate and blood pressure.” (opens the prescribing information at this quote)
“Once on a stable dose of EMCITATE, reassess total T3 levels once every 6 months and modify the dosage as clinically required.” (opens the prescribing information at this quote)

Dosage reduction for new or worsening thyrotoxicosis

“If signs or symptoms of thyrotoxicosis either occur for the first time or worsen, and do not resolve within two weeks, reduce the EMCITATE dosage by 175 mcg for patients with a body weight equal to or less than 10 kg or by 350 mcg for patients with a body weight greater than 10 kg” (opens the prescribing information at this quote)
“Continue to reduce the dosage by these amounts every two weeks, if needed, until the signs or symptoms of thyrotoxicosis have resolved.” (opens the prescribing information at this quote)

Missed dose or vomiting

“If a dose is missed and there are more than 4 hours to the next scheduled dose, the missed dose should be taken as soon as possible. If a dose is missed and the next dose is scheduled within 4 hours, the dose should be skipped and the next dose taken according to the regular schedule. Doses should not be doubled.” (opens the prescribing information at this quote)
“If vomiting occurs within 30 minutes after administration, administer a new dose.” (opens the prescribing information at this quote)

Discontinuation

“Do not abruptly stop EMCITATE treatment in order to avoid occurrence or worsening of symptoms of thyrotoxicosis” (opens the prescribing information at this quote)
“If discontinuing EMCITATE, reduce the dosage approximately every two weeks as follows:” (opens the prescribing information at this quote)

Starting dose by body weight: published management recommendations

Body weight	Starting dose
Less than 10 kg	“175 µg once daily”
10 kg or greater	“350 µg once daily”

Maximum daily dose by body weight: published management recommendations

Body weight	Maximum daily dose
Less than 10 kg	“100 µg/kg/day”
10–40 kg	“80 µg/kg/day”
40–60 kg	“60 µg/kg/day”
More than 60 kg	“50 µg/kg/day”

Origin of the dosing regimen

“No distinct dose-finding was performed in the development program of tiratricol for use in MCT8-deficiency and the dose had been adopted from the reference medicinal product Téatrois.” (opens the source at this quote in a new tab)

Dose escalation in Triac Trial I

“Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 μg Triac, the daily dose was increased progressively in 350 μg increments, with the goal of attaining serum total T3 concentrations within the target range of 1·4-2·5 nmol/L.” (opens the source at this quote in a new tab)

Maintenance dose in a real-life cohort

“The daily starting dose was based on body weight (175 µg Triac < 10 kg; 350 µg Triac ≥ 10 kg). The daily dose was increased with increments of 175 µg or 350 µg with a goal of attaining serum total T3 concentrations within the target range of 1.4 to 2.5 nmol/L.” (opens the source at this quote in a new tab)
“The mean time to reach the maintenance dose was 5.0 (SD 4.7) months, with a mean of 2.7 (SD 1.1) dose increments. The median maintenance dose was 38 µg/kg/day (interquartile range, 31-61 µg/kg/day; range, 15-105 µg/kg/day).” (opens the source at this quote in a new tab)

Daily dosing schedule

“Administer the EMCITATE total daily dosage orally or by enteral feeding tube once daily or in two to three divided doses spread throughout the day.” (opens the prescribing information at this quote)
“The prepared EMCITATE suspension may be administered with or without food” (opens the prescribing information at this quote)

Preparation of the oral suspension

“Do not swallow, chew, or crush the tablets.” (opens the prescribing information at this quote)
“EMCITATE tablets for oral suspension must be dispersed in room temperature drinking water directly in a 10-12 mL syringe and given as a suspension only. Do not prepare with other liquids, food vehicles or enteral nutrition formulas.” (opens the prescribing information at this quote)
“If more than 3 tablets are needed for a single dose, divide the dose into multiple, separate preparations not to exceed 3 tablets per preparation.” (opens the prescribing information at this quote)
“Discard the suspension 30 minutes after preparation if not used.” (opens the prescribing information at this quote)
“EMCITATE tablets for oral suspension have a functional score line and can be split into equal halves.” (opens the prescribing information at this quote)

Enteral feeding tube administration

“Prepared EMCITATE suspension can be administered through an enteral feeding tube directly into the stomach. Either nasogastric (NG) tubes (6 French and above) or gastrostomy (G) tubes (12 French and above) can be used.” (opens the prescribing information at this quote)
“For enteral feeding tube administration, prepare the oral suspension based on tube size.” (opens the prescribing information at this quote)

Divided dosing: published management recommendations

“The total daily dose may be administered in one to three divided doses, and dose escalation should not exceed 80 µg/kg/day in patients weighing 10–40 kg, 60 µg/kg/day in those weighing 40–60 kg, and 50 µg/kg/day in patients weighing >60 kg” (opens the source at this quote in a new tab)

European Union administration: dispersion volume and feeding tubes

“The dispersion should be prepared in a dedicated small glass, by dispersing the tablet(s) (maximum 4 tablets at each dosing occasion) in 30 mL of drinking water, by stirring with a teaspoon for 1 minute.” (opens the source at this quote in a new tab)
“The contents of the syringe should be administered immediately into the gastroenteral feeding tube (30 mL + 10 mL for all age groups).” (opens the source at this quote in a new tab)
“The product has been tested using a percutaneous endoscopic gastrostomy (PEG) silicone tube (lumen 12 French, maximum length 34 cm), and nasogastric (NG) polyurethane tubes (lumen 6 French and 8 French, maximum length 56 cm). This product has not been tested with other types of tubes or tube materials.” (opens the source at this quote in a new tab)

U.S. commercial availability

“The Company expects EMCITATE to be commercially available in the United States in eight to ten weeks post approval.” (opens the source at this quote in a new tab)

Specialty pharmacy: PANTHERx Rare

“As part of its U.S. commercialization strategy, Egetis has partnered with PANTHERx® Rare to support medication access, education, care coordination and ongoing treatment services.” (opens the source at this quote in a new tab)

“I authorize the forwarding of this start form (and the information included herein) to PANTHERx Rare Pharmacy.” (opens the source at this quote in a new tab)

Patient support program: Egetis RareLink

“Egetis launches Egetis RareLink™, the EMCITATE patient support program, in partnership with PANTHERx® Rare” (opens the source at this quote in a new tab)

“Such services include: disease state and product education (including starter kit), medication and adherence communications, insurance coverage and financial assistance support, product administration training support, free drug (if eligible), coordination of medication delivery” (opens the source at this quote in a new tab)

QuickStart, Bridge, patient assistance, and copay programs

“FOR INSURED PATIENTS ONLY: An optional program available to eligible patients at no cost if coverage approval is delayed.” (opens the source at this quote in a new tab)
“I authorize Egetis RareLink to forward this prescription to the pharmacy dispensing the QuickStart, Bridge, and PAP product to the patient named herein, if eligible.” (opens the source at this quote in a new tab)
“I also understand any products distributed under the patient support program are provided free of charge, and may not be submitted for reimbursement to any payer, including a federal healthcare program, and may not be sold, traded, distributed for sale or returned for credit; nor may I bill for administration of such product.” (opens the source at this quote in a new tab)
“I understand that copay card details (such as card identification number and processing information) will be sent to my specialty pharmacy so the copay benefit can be applied when my prescription is filled, and any assistance with my cost-sharing or co-payment for EMCITATE will be made in accordance with the Egetis RareLink Copay Card Program’s Terms and Conditions.” (opens the source at this quote in a new tab)

Prior authorization support

“I authorize PANTHERx and Egetis RareLink™ to prepare and submit prior authorization requests, appeal requests, and other administrative tasks on my behalf and to receive notices in connection with requests which may include faxes, phone calls, mail, email, or any other form of communication.” (opens the source at this quote in a new tab)

Prescription requirements

Form item	Form text
Prescriber attestation	“Prescriber Attestation: I confirm that the patient has been diagnosed with MCT8 deficiency.”
Genetic confirmation	“Genetic test result for a mutation in SLC16A2”
Copy of genetic test	“Copy of genetic test result included”
Baseline thyroid function	“Baseline serum T3 (include units of measurement and date of result)”
Prior thyromimetic therapy	“Has the patient ever received DITPA (3,5-diiodothyropropionic acid)?”
Prior tiratricol exposure	“Did the patient take EMCITATE® as part of the EAP or clinical trial?”
Body weight	“Weight (kg)”

Distribution and expanded access: U.S. distribution

“During the period we have contracted a specialty pharmacy and a distributor to assist us in providing Emcitate to patients with MCT8 deficiency after approval.” (opens the source at this quote in a new tab)

Distribution and expanded access: U.S. Expanded Access Program

“At FDA’s request, Egetis has implemented an Expanded Access Program (EAP) in the U.S. Currently, 17 hospitals are included and approximately 60 patients are receiving tiratricol in the EAP. The EAP allows physicians to access tiratricol for patients not eligible for clinical trials prior to marketing approval, as well as for continued treatment of patients who completed the ReTRIACt and Triac Trial II studies.” (opens the source at this quote in a new tab)

Distribution and expanded access: managed access policy

“In exceptional circumstances and where permitted by local laws and regulations, Egetis may consider providing access to investigational medicines through Managed Access programs.” (opens the source at this quote in a new tab)
“Managed Access programs are governed by local laws, regulations and company policies. Availability may differ between countries and programs.” (opens the source at this quote in a new tab)

Other thyroid medications

“Taking EMCITATE in combination with thyromimetic products or products used to treat thyroid conditions (e.g., levothyroxine, propylthiouracil, and carbimazole) may increase the risk of thyrotoxicosis or hypothyroidism and should be avoided.” (opens the prescribing information at this quote)

“Patients taking another thyroid medication should talk to their healthcare provider before starting Emcitate, as the two should not be used together.” (opens the source at this quote in a new tab)

“Conventional antithyroid drugs such as carbimazole or methimazole are not recommended in MCT8 deficiency, as the thyrotoxic state is not driven by primary TH overproduction, and their use may exacerbate central hypothyroidism.” (opens the source at this quote in a new tab)

Concomitant hepatotoxic medications

“These patients often receive concomitant medications, some of which have known hepatotoxic side effects. In an open-label clinical trial, 25 of 46 patients (54%) treated with TRIAC showed mild increases in ALT, aspartate aminotransferase, or γ-glutamyl transferase at baseline, attributed to concurrent use of hepatotoxic medications. Therefore, liver function assessment is an important parameter to evaluate before and during therapy initiation, particularly when patients receive potentially hepatotoxic medications, such as anticonvulsants” (opens the source at this quote in a new tab)

Comparison with diiodothyropropionic acid: published management recommendations

“TRIAC and DITPA are TH analogues that bypass MCT8-dependent transport and activate thyroid hormone receptors (THRs). TRIAC has a high affinity for THR β, reduces serum T3 levels, and ameliorates peripheral thyrotoxic manifestations, with the strongest clinical evidence supporting its use. DITPA similarly lowers serum T3 levels but is supported by less consistent clinical data. For both agents, the extent of improvement in neurological outcomes remains uncertain” (opens the source at this quote in a new tab)
“TRIAC is associated with substantially higher costs than conventional TH preparations, requiring individualized cost-benefit evaluation within different healthcare systems.” (opens the source at this quote in a new tab)

Comparison with the reference product Téatrois

“The main body of efficacy evidence is acquired in the TRIAC I in which the reference product “Téatrois, 0.350 mg IR tablet” approved in France during the period from 1974 to 2020 was used. This formulation is now discontinued.” (opens the source at this quote in a new tab)
“Reportedly, the only difference between Téatrois /Emcitate-DEV and Emcitate FCP with regards to excipients is the tablet filler, where calcium hydrogen phosphate dihydrate is replaced by calcium hydrogen phosphate to improve tablet properties.” (opens the source at this quote in a new tab)
“The MCT8-2023-5 study established bioequivalence between the two formulations Emcitate-DEV and Emcitate FCP for both Cmax and the various measures of AUC considered, with all 95% confidence intervals within the acceptance region of [0.80, 1.25].” (opens the source at this quote in a new tab)

Genetic etiology

“MCT8 deficiency is an X-linked disorder caused by pathogenic variants in the SLC16A2 gene. It results in a state of T3 deprivation in the brain from early development, leading to severe psychomotor impairment and peripheral hyperthyroidism.” (opens the source at this quote in a new tab)

Transporter function and loss-of-function mechanism

“Monocarboxylate transporter 8 (MCT8), the protein product of SLC16A2, is thought to play a crucial role in neuronal T3 uptake and in endothelial cells allowing partial entry of thyroid hormone through the blood-brain barrier. MCT8 deficiency results in an insufficient supply of T3 to nuclear T3 receptors.” (opens the source at this quote in a new tab)
“AHDS results from a loss of function of the MCT8 protein.” (opens the source at this quote in a new tab)

X-linked inheritance and recurrence risk

“AHDS is inherited in an X-linked manner. If the mother of a proband has an SLC16A2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the variant will be heterozygotes (carriers) and usually will not be clinically affected but may have minor thyroid test abnormalities.” (opens the source at this quote in a new tab)
“In a study of 24 affected individuals, 17 males had inherited the SLC16A2 pathogenic variant from their mother” (opens the source at this quote in a new tab)
“In a study of 24 affected individuals, seven had a de novo SLC16A2 pathogenic variant” (opens the source at this quote in a new tab)

Affected females with skewed X-chromosome inactivation

“MCT8 deficiency typically affects males due to its X-linked inheritance.” (opens the source at this quote in a new tab)
“Female patients with heterozygous pathogenic variants in SLC16A2 and skewed X-chromosome inactivation may present with variable neuro(psycho)logical, behavioral, and thyroid function test abnormalities.” (opens the source at this quote in a new tab)

Nationwide Japanese epidemiology: incidence

Measure	Estimate
Incidence per million births in Japan, with 95% confidence interval	“2.12 (95 % CI: 0.99–3.25)”

Nationwide Japanese epidemiology: survey method and response rate

“In the primary survey, the response rate was 694/1027 (67.6 %), and 31 hospitals had experience in treating patients with MCT8 deficiency. Forty-five patients were genetically diagnosed as MCT8 deficient, and eight were strongly suspected based on the clinical course.” (opens the source at this quote in a new tab)

Estimated birth frequency

“The frequency of MCT8 deficiency among people with intellectual disability is not known, though estimated to occur in 1 in 70,000 newborns.” (opens the source at this quote in a new tab)

Prevalence uncertainty

“Prevalence of Allan-Herndon-Dudley syndrome (AHDS) is unknown; however, the identification of more than 160 affected individuals in approximately 15 years suggests that the syndrome is more common than previously thought.” (opens the source at this quote in a new tab)

Published prevalence estimates

“Prevalence estimates range from fewer than one in one million to one in seventy thousand males” (opens the source at this quote in a new tab)

“The estimated prevalence based on diagnosed cases to date is fewer than one in a million” (opens the source at this quote in a new tab)

Number of identified patients and families worldwide

“More than 300 families have been identified with 210 different MCT8 gene variants.” (opens the source at this quote in a new tab)

“However, a substantial proportion of patients is included, with approximately 350 patients reported worldwide” (opens the source at this quote in a new tab)

Nationwide Japanese epidemiology: prevalence

Measure	Estimate
Estimated prevalence in Japan	“1 in 1,890,000”

Nationwide Japanese epidemiology: prevalence calculation

“To estimate the minimum number of patients with MCT8 deficiency patients in Japan, we divided the number of genetically confirmed patients (n = 45) by the questionnaire response rate of the primary survey (67.6 %). Thus, there are approximately 67 MCT8 deficiency patients in Japan.” (opens the source at this quote in a new tab)

Stated limitation of the Japanese prevalence estimate

“There is a need for caution regarding the present results. This survey mainly asked questions to pediatric facilities and did not survey adult departments.” (opens the source at this quote in a new tab)
“number of adult patients with MCT8 deficiency who are followed by general practitioners may be underestimated.” (opens the source at this quote in a new tab)
“Therefore, the present results should be regarded as minimum estimates.” (opens the source at this quote in a new tab)

International natural-history cohort: design, objective, and population

“We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death.” (opens the source at this quote in a new tab)
“Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations.” (opens the source at this quote in a new tab)

International natural-history cohort: mortality, causes of death, and overall survival

“32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]).” (opens the source at this quote in a new tab)
“Median overall survival was 35·0 years (95% CI 8·3–61·7).” (opens the source at this quote in a new tab)

International natural-history cohort: prognostic factors for death

“Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76–8·34; log-rank test p=0·0041).” (opens the source at this quote in a new tab)
“Patients who were underweight during age 1–3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26–17·58, p=0·021).” (opens the source at this quote in a new tab)

International natural-history cohort: motor and cognitive abilities with age

“The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III.” (opens the source at this quote in a new tab)

Childhood mortality

“Outcomes for individuals with MCT8 deficiency remain poor, with an estimated one in three affected individuals dying during childhood.” (opens the source at this quote in a new tab)

Causes of early death and survival into late adulthood

“Early death has occurred in some individuals, usually caused by recurrent infections and/or aspiration pneumonia. In a few instances survival beyond age 70 years has been reported.” (opens the source at this quote in a new tab)

Japanese nationwide survey: functional status and deaths

“All patients showed severe psychomotor retardation, and none were able to walk or speak.” (opens the source at this quote in a new tab)
“Subsequently, 29 surviving and three deceased patients were identified (Fig. 1). The cause and age of death in the three patients were sudden death (4 years), cardiopulmonary arrest after vomiting (35 years), and pneumonia (24 years).” (opens the source at this quote in a new tab)
“The mean age of the surviving 29 patients was 12.0 years (range 2.3–31.4) with a median of 9.7 years (three patients over 20 years of age).” (opens the source at this quote in a new tab)

Japanese nationwide survey: imaging and neurophysiology over time

“Initial white matter signal abnormalities on head MRI showed recovery, but somatosensory evoked potentials (SEP) showed no improvement, suggesting that the patient remained dysfunctional.” (opens the source at this quote in a new tab)

Central hypothyroidism and chronic peripheral thyrotoxicosis

“Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis.” (opens the source at this quote in a new tab)

Tissue-specific thyroid hormone transport and elevated serum T3

“Tri-iodothyronine (T3) transport across the blood-brain barrier is highly MCT8-dependent; therefore, individuals with MCT8 deficiency exhibit markedly low levels of T3 in the central nervous system. In contrast, T3 can enter peripheral tissues outside the central nervous system through alternative transporters, albeit with lower specificity.” (opens the source at this quote in a new tab)
“However, peripheral thyrotoxicosis in MCT8 deficiency is directly related to consistently elevated serum T3 levels, while thyroid-stimulating hormone (TSH) and free (F)T4 may be normal or only mildly altered” (opens the source at this quote in a new tab)
“It should be noted that the exact mechanisms underlying the distinctive TH profile in MCT8 deficiency have not yet been conclusively defined, and further research is needed to clarify the precise drivers of T3 elevation in these patients.” (opens the source at this quote in a new tab)

Peripheral manifestations and serum markers of thyroid hormone excess

“At the peripheral level, T3 may enter the tissues by alternative transporters and cause peripheral hyperthyroidism, manifested by warm skin, tachycardia, arterial hypertension (HTN), and poor height and weight growth. The synthesis of sex hormone binding globulin (SHBG) increases and cholesterol and creatinine levels decrease; muscle hypoplasia and low creatinine kinase (CPK) levels also occur.” (opens the source at this quote in a new tab)

Guideline recommendations for diagnostic evaluation and SLC16A2 sequencing

“When considering a diagnosis of MCT8 deficiency, we recommend a full clinical assessment to determine whether the patient exhibits any recognized clinical phenotypes and a physical examination, including neurological assessment” (opens the source at this quote in a new tab)
“If MCT8 deficiency is suspected, we recommend additional investigations including (but not limited to) serum (free) T3, (free) T4, reverse T3 (rT3) and TSH concentrations (interpreting results in the context of age-specific reference intervals)” (opens the source at this quote in a new tab)
“We recommend that SLC16A2 sequencing be performed in any male patient with: the following ‘major criteria’; typical biochemical profile (TSH within normal range or mildly raised, low or low-normal (F)T4, raised (F)T3, low reverse T3, and/or elevated (F)T3/(F)T4 or T3/rT3 ratio) in combination with either global developmental delay, hypomyelination on MRI, clinical signs of movement disorder (e.g. dystonia, bradykinesia), persistent primitive reflexes, or a positive family history for MCT8 deficiency” (opens the source at this quote in a new tab)
“Definitive diagnosis of MCT8 deficiency requires identification of a known pathogenic mutation, either by reliable in silico prediction and/or functional studies of novel variants in transfected cells or patient-derived cells.” (opens the source at this quote in a new tab)

Diagnostic and genetic criteria

“The diagnosis of AHDS is established in a male proband with suggestive findings and a hemizygous SLC16A2 pathogenic variant identified by molecular genetic testing, and in a female proband by identification of a heterozygous pathogenic variant in SLC16A2.” (opens the source at this quote in a new tab)
“All males with SLC16A2 pathogenic variants had high serum T3 concentration and, when obtained, low serum rT3 concentration.” (opens the source at this quote in a new tab)

Free T3 to free T4 ratio as a screening biomarker: Japanese nationwide survey

“The significantly higher value of the free T3/free T4 (fT3/fT4) ratio found in our study can be a simple and useful diagnostic biomarker (Our value 11.60 ± 4.14 vs control 3.03 ± 0.38).” (opens the source at this quote in a new tab)
“We created a receiver operating characteristic (ROC) curve from our data (27 genetically diagnosed cases) and Oto et al.’s data (129 controls) and confirmed that the sensitivity was 96.2 % and the false positive rate was 0 at cutoff values of 4, 4.5 and 5.” (opens the source at this quote in a new tab)

Free T3 to free T4 ratio as a screening biomarker: Turkish multicentre cohort

“In this multicenter, retrospective, cross-sectional study, the genetic characteristics and clinical data of twenty-one cases of genetically confirmed MCT8 deficiency were evaluated. The median age at the diagnosis was 2.4 (1.29; 5.9) years, which ranged from 0.5 to 14.0 years.” (opens the source at this quote in a new tab)
“In this study, with the exception of three cases with fT3/fT4 ratios of 4.95, 3.58, and 4.52, all cases exhibited fT3/fT4 ratios higher than five (9.9 (7.9; 12.0)).” (opens the source at this quote in a new tab)

Free T3 to free T4 ratio threshold in a monitoring guideline

“Calculating the free (F)T3/FT4 ratio is a readily accessible, cost-effective, and rapid test; a value exceeding 0.75 or above the 97th percentile strongly suggests MCT8 deficiency” (opens the source at this quote in a new tab)

Newborn screening and neonatal biomarkers

“Newborn screening, which is established to detect congenital hypothyroidism, is typically based on TSH concentration and does not currently include measurement of FT3. However, TSH is often within the reference range in newborns with MCT8 deficiency.” (opens the source at this quote in a new tab)
“Low reverse T3 (rT3) and a high T3/rT3 ratio have been identified in newborns with MCT8 deficiency, but this test is neither routinely offered in clinical practice nor regularly performed” (opens the source at this quote in a new tab)

Dried blood spot reverse T3 at birth

“Contrary to characteristic iodothyronine abnormalities of MCT8 deficiency during later life, T3 and T4 values were not discriminatory from those of other study groups. In contrast, rT3 was significantly lower.” (opens the source at this quote in a new tab)
“rT3 and T3/rT3 ratio in DBS samples obtained from neonates can serve as biomarkers to detect MCT8 deficiency at birth.” (opens the source at this quote in a new tab)

Diagnostic delay: international natural-history cohort

“Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0).” (opens the source at this quote in a new tab)

Diagnostic delay and alternative diagnoses: international parent registry

“The median reported age of onset of symptoms was 4 months (range, 1-13 months; Supplementary Fig. S5) (11), whereas the median age of diagnosis was 18 months (range, 4-312 months), indicating a median diagnostic delay of 14 months (range, 0-311 months).” (opens the source at this quote in a new tab)
“Median diagnostic delay was significantly shorter in patients born in or after 2017 vs before 2017 (8 vs 19 months, P < .0001).” (opens the source at this quote in a new tab)
“Reported alternative diagnoses (total n = 6) were cerebral palsy (n = 4), Pelizaeus-Merzbacher (like) disease (n = 1) and mitochondrial disease (not otherwise specified, n = 1).” (opens the source at this quote in a new tab)

Onset and early presentation

“Individuals with MCT8 deficiency are typically born following an uneventful pregnancy and have normal weight and length for gestational age. In many cases, the first presentation to a healthcare professional occurs around 4 months of age, with signs of gross developmental delay, general failure to thrive, and severe muscular hypotonia” (opens the source at this quote in a new tab)

Cognitive and developmental symptoms: intellectual disability, walking, and speech

“Most affected males have profound-to-severe intellectual disability with no acquisition of walking; most affected males never speak or may develop only garbled sounds secondary to severely dysarthric speech. Less frequently, affected males have mild-to-moderate intellectual disability, and develop the ability to walk (with or without aid) and use of language allowing academic learning with aid.” (opens the source at this quote in a new tab)

Developmental milestones: Japanese nationwide survey

Finding	Participants with finding (evaluable denominator in label)
Completion of head control, n = 28	“7 (25 %)”
Able to keep sitting, n = 28	“0 (0 %)”
Able to speak a word, n = 27	“0 (0 %)”
Abnormal sleep rhythm, n = 27	“9 (33 %)”
Feeding difficulty, n = 26	“4 (15 %)”

Motor symptoms: hypotonia, dystonia, and bradykinesia

“All three patients exhibit profound psychomotor delay, with axial hypotonia, limb dystonia, and bradykinesia as consistent features.” (opens the source at this quote in a new tab)

Motor symptoms: truncal hypotonia and paroxysmal dyskinesias

“Truncal hypotonia, a main feature of AHDS, persists into adulthood.” (opens the source at this quote in a new tab)
“It is common for affected males to experience purposeless movements described as dystonic and/or athetoid and characteristic paroxysms or kinesigenic dyskinesias” (opens the source at this quote in a new tab)
“These can be triggered by somatosensory stimuli, including changing clothes or diaper, or lifting the affected child.” (opens the source at this quote in a new tab)

Seizures

“Patients with MCT8 deficiency may be predisposed to seizures, which predominantly manifest as generalized, absence-like episodes without an overt motor component.” (opens the source at this quote in a new tab)
“Seizures in patients with MCT8 deficiency are often reported to be refractory or poorly controlled” (opens the source at this quote in a new tab)

Peripheral thyrotoxic symptoms

“Peripheral dysthyroidism can be expressed as cold intolerance, sweating, intestinal transit disorders, tachycardia, high blood pressure, and sleep disorders.” (opens the source at this quote in a new tab)

Cardiovascular and nutritional manifestations: international natural-history cohort

Manifestation	Affected participants and evaluable denominator
Elevated systolic blood pressure above the 90th percentile	“25 (53%) of 47”
Premature atrial contractions	“34 (76%) of 45”
Resting tachycardia	“20 (31%) of 64”
Underweight	“59 (71%) of 83”

Biochemical and neuroimaging findings: international natural-history cohort

“Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients.” (opens the source at this quote in a new tab)
“The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients.” (opens the source at this quote in a new tab)

Phenotypic spectrum in an exome-sequenced United States cohort

“In a cohort of 122 individuals with SLC16A2 variants, we identified 68 cases with likely pathogenic/pathogenic (L/PATH) variants and 54 individuals with variants of uncertain significance (VUSs).” (opens the source at this quote in a new tab)
“Common HPO terms included global developmental delay (79/108, 73.1%), generalized hypotonia (40/108, 37.0%), and delayed speech and language development (29/108, 26.9%).” (opens the source at this quote in a new tab)
“HPO terms related to thyroid function and/or hormone levels were not commonly reported, with hypothyroidism the most frequently reported term, seen in six individuals.” (opens the source at this quote in a new tab)

Progressive motor complications

“Progressive hypertonicity of the limbs with brisk reflexes, ankle clonus, and extensor plantar responses (Babinski sign) leads to spastic quadriplegia and joint contractures. Overall muscle mass (particularly proximally) is reduced and associated with generalized muscle weakness.” (opens the source at this quote in a new tab)
“Pectus excavatum and kyphoscoliosis are most likely the result of hypotonia and reduced muscle mass.” (opens the source at this quote in a new tab)

Cardiovascular morbidity and sudden death

“Sudden death is one of the leading causes of mortality in individuals with MCT8 deficiency and may be linked to cardiac events. In a large retrospective cohort study, a wide spectrum of cardiac abnormalities was observed in these individuals, including premature atrial contractions, elevated blood pressure, and resting tachycardia.” (opens the source at this quote in a new tab)

Feeding difficulties, undernutrition, and respiratory infection

“Feeding difficulties are among the most frequent and functionally limiting complications in patients with MCT8 deficiency.” (opens the source at this quote in a new tab)
“Low body weight is frequently observed in individuals with MCT8 deficiency and likely reflects the combined effects of increased basal metabolic rate and dysphagia secondary to axial hypotonia and progressive muscle wasting.” (opens the source at this quote in a new tab)
“Furthermore, respiratory infections, a leading cause of mortality in this population, are more frequent in undernourished patients, suggesting a link between impaired nutritional status and increased susceptibility to infection” (opens the source at this quote in a new tab)

Bone health and fracture risk

“Elevated TH levels in adulthood have been associated with accelerated bone turnover, reduced bone mineral density, increased fracture risk, and osteoporosis. Individuals with MCT8 deficiency are typically immobile, which may further contribute to their elevated risk of fractures” (opens the source at this quote in a new tab)

Liver function abnormalities

“Some individuals with MCT8 deficiency exhibit abnormal liver function markers, such as elevated SHBG or transaminase levels.” (opens the source at this quote in a new tab)

International parent registry: objective and population

“The primary objective was to document the complex needs and daily care challenges encountered in care for patients with MCT8 deficiency and to what extent these are met by supportive measures and specialist care.” (opens the source at this quote in a new tab)
“Of the 46 registered patients with full informed consent, data of 40 patients (40 males, 100%) with a median age of 3.0 years (range, 0.5-31.6 years), from 18 countries in 5 different continents” (opens the source at this quote in a new tab)

International parent registry: difficulties in daily care

Parent-reported difficulty	Participants
Feeding	“17 of 33 patients”
Limited motor skills	“12 of 33 patients”
Sleeping problems	“11 of 33 patients”
Mobility	“10 of 33 patients”
Communication	“8 of 33 patients”

International parent registry: use of supportive and specialist care

“Despite feeding problems being the most commonly reported difficulty in daily life, only 11 of 36 patients received advice from a professional dietician or nutrologist” (opens the source at this quote in a new tab)
“Of those with reported feeding problems, only 2 of 16 patients had a feeding tube (data on feeding tube missing for 1 patient).” (opens the source at this quote in a new tab)
“Two of 32 patients were under care of a cardiologist.” (opens the source at this quote in a new tab)
“The majority of parents (18 of 31 patients) deemed knowledge about MCT8 deficiency among medical professionals as bad or very bad” (opens the source at this quote in a new tab)

International parent registry: limitations stated by the authors

“First, it is unclear to which extent the patients in this study represent the entire population of patients with MCT8 deficiency.” (opens the source at this quote in a new tab)
“Second, patients deceased before the initiation of the registry were not included.” (opens the source at this quote in a new tab)

Caregiver-reported patient functioning and health-related quality of life

“As assessing HRQoL directly from patients with MCT8 deficiency can be challenging, caregivers completed the EQ-5D-5L proxy version 1 to rate their care recipient’s HRQoL.” (opens the source at this quote in a new tab)
“Twenty-two caregivers residing in the United Kingdom, United States, Canada, France, Netherlands, Italy, and Germany participated in the study. The mean age of the patients with MCT8 deficiency was 8.8 years, ranging from 0.8 to 30.4 years. Over half (54.5%) had no head control and none could sit or walk without support.” (opens the source at this quote in a new tab)
“The majority of patients with MCT8 deficiency were unable to walk (72.7%), wash or dress themselves (77.3%) or carry out their usual activities (68.2%). Over half (54.5%) had slight pain or discomfort and over one-third felt slightly anxious or depressed (36.4%).” (opens the source at this quote in a new tab)
“No disease-specific instrument exists for MCT8 deficiency and the EQ-5D-5L has limitations as a generic instrument.” (opens the source at this quote in a new tab)

Dependence on caregivers for activities of daily living

“All the patients in this study presented with severe psychomotor retardation. Most were bedridden (a few held their head up) and had no speech. All patients required assistance in all aspects of daily living, including eating and toileting.” (opens the source at this quote in a new tab)

United States real-world cost study: objective, data sources, and population

“Evaluate the healthcare resource utilization and cost of care.” (opens the source at this quote in a new tab)
“The lack of a dedicated ICD-10 code for MCT8 deficiency contributes to the challenge of conducting analysis utilizing real-world data.” (opens the source at this quote in a new tab)
“In total, 44 unique patients with a confirmed MCT8 deficiency diagnosis were analyzed.” (opens the source at this quote in a new tab)
“The mean (SD) age of the patients was 5.9 (6.9) years, with a mean follow-up of 72.4 (20.8) months.” (opens the source at this quote in a new tab)
“This research was conducted in collaboration with Inizio Ignite Putnam and was funded by Egetis Therapeutics.” (opens the source at this quote in a new tab)

United States real-world cost study: all-cause costs and utilization

Measure	Value
All-cause cost per patient per year	“$245,393 PPPY”

“Patients experienced nearly 7 inpatient visits per year, corresponding to approximately $327,000 PPPY in hospital-based costs, indicating substantial acute care utilization.” (opens the source at this quote in a new tab)
“Outpatient visits occurred more than twice per month, highlighting the high burden of care.” (opens the source at this quote in a new tab)
“Inpatient care was the largest contributor to healthcare costs, despite outpatient visits representing the highest-utilization setting on a PPPY basis (>2 visits per month).” (opens the source at this quote in a new tab)

United States real-world cost study: clinical drivers of cost

“Cardiovascular-related and infection-related encounters were key cost drivers; cardiovascular events contributed substantially to costs despite representing fewer visits, suggesting that each cardiovascular-related episode is associated with high costs.” (opens the source at this quote in a new tab)
“Nearly all patients had weight-related claims, primarily characterized by underweight/malnutrition and failure to thrive.” (opens the source at this quote in a new tab)
“Cardiovascular claims affected approximately 64% of patients, with over 33% of patients experiencing tachycardia.” (opens the source at this quote in a new tab)
“Infection-related events were common, with 16% of patients experiencing sepsis.” (opens the source at this quote in a new tab)

United States real-world cost study: limitations stated by the authors

“Consistent with rare diseases, the relatively smaller sample size, may make the generalizability of the findings limited.” (opens the source at this quote in a new tab)
“Claims and EHR data were combined for this study; however, this integration may have introduced the potential for underestimation of cost due to differences in data capture across data sources.” (opens the source at this quote in a new tab)
“Cost estimates for infection-related, sepsis-related, cardiac-related, and weight-related categories may be subject to overestimation, as these categories were not mutually exclusive, potentially resulting in overlapping attribution of costs.” (opens the source at this quote in a new tab)

Access to genetic diagnostics by health system and payer

“For example, while genetic panels are partially standardized in some countries, access to molecular genetic diagnostics in other countries may depend on the health care system or insurance companies.” (opens the source at this quote in a new tab)

Financial means as a condition of carrier, prenatal, and preimplantation testing

“As MCT8 deficiency is an inherited condition, carrier testing of at-risk female relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible, but this is only practicable in families where an affected child has already been born and there are the financial means to pursue this approach” (opens the source at this quote in a new tab)

Guideline recommendations for thyroid hormone analogues

“We recommend treatment with TRIAC (Recommendation: S, Quality of evidence: ØØØO) or DITPA (Recommendation: W, Quality of evidence: ØØOO).” (opens the source at this quote in a new tab)
“We recommend titrating the dosage of TRIAC (or DITPA), aiming to reduce serum T3 concentrations to a target range between 1.4 and 2.5 nmol/L to alleviate the peripheral thyrotoxic state, unless limited by the occurrence of dose-related side effects” (opens the source at this quote in a new tab)
“We recommend long-term therapy with TRIAC (or DITPA) in all patients unless concerns about drug side effects or tolerability arise” (opens the source at this quote in a new tab)

Evidence base for thyroid hormone analogues

“Knowledge of response to thyroxine (alone, or in combination with PTU) and DITPA is limited to case reports and case series, whereas the effects of TRIAC have been studied in a phase 2 clinical trial and a prospective cohort study.” (opens the source at this quote in a new tab)
“Treatment with DITPA (dose range: 2.1–2.5 mg/kg/day) normalized serum T3 and TSH without reduction of T4 concentrations (4/4 cases) and had mixed effects on peripheral symptoms, including a reduction in heart rate (3/4 cases) and improvement in body weight (2/4 cases). Commencement of treatment between 8.5 and 25 months did not improve neurocognitive development” (opens the source at this quote in a new tab)

Mechanism and relative evidence for TRIAC and DITPA

“TRIAC and DITPA are TH analogues that bypass MCT8-dependent transport and activate thyroid hormone receptors (THRs). TRIAC has a high affinity for THR β, reduces serum T3 levels, and ameliorates peripheral thyrotoxic manifestations, with the strongest clinical evidence supporting its use. DITPA similarly lowers serum T3 levels but is supported by less consistent clinical data.” (opens the source at this quote in a new tab)

Guideline position on levothyroxine monotherapy and on combined levothyroxine and propylthiouracil

“Post-natal treatment with levothyroxine monotherapy is not recommended” (opens the source at this quote in a new tab)
“If thyroid hormone analogs are unavailable, we suggest that a combination of levothyroxine and PTU treatment could be considered” (opens the source at this quote in a new tab)
“Given the rare but potentially severe and life-threatening side effects of PTU and the unknown long-term effects of thyroid hormone analogs, we acknowledge that the risks versus benefits of such therapies should be considered carefully, particularly in patients whose baseline liver function is already deranged” (opens the source at this quote in a new tab)

Published outcomes of levothyroxine alone and with propylthiouracil

“Treatment with levothyroxine in a wide dose range (2.5–15 mcg/kg/day), commenced at the age of 0.5 to 36 months, did not improve neurodevelopment and, in some cases even aggravated the hyperthyroid state in peripheral tissues” (opens the source at this quote in a new tab)
“Combination therapy with propylthiouracil (PTU− given to block T4 to T3 conversion) and levothyroxine reduced signs of hyperthyroidism in peripheral tissues in some patients, increasing body weight, reducing heart rate, and serum sex hormone-binding globulin (SHBG) concentrations, but had no beneficial effects on neurocognitive development” (opens the source at this quote in a new tab)

Conventional antithyroid drugs

“Conventional antithyroid drugs such as carbimazole or methimazole are not recommended in MCT8 deficiency, as the thyrotoxic state is not driven by primary TH overproduction, and their use may exacerbate central hypothyroidism.” (opens the source at this quote in a new tab)

Combined treatment case series: objective and population

“To evaluate the combined administration of propylthiouracil (PTU) and levothyroxine (LT4) in managing monocarboxylate transporter 8 (MCT8) deficiency and identify optimal therapeutic dosages.” (opens the source at this quote in a new tab)
“This multicenter case series involved 12 male patients with MCT8 deficiency whose parents/guardians consented to PTU and LT4 treatment. Data were collected from January 2008 to June 24, 2024.” (opens the source at this quote in a new tab)
“At the beginning of treatment, the median age was 18 months (IQR: 9–28 months), and a median of 40 months (IQR: 25–88 months) at the last encounter.” (opens the source at this quote in a new tab)

Combined treatment case series: biochemical outcomes

“Patients showed a significant reduction in serum total triiodothyronine (TT3) concentration and TT3/TT4 ratio, with increased serum TT4 and free T4 (fT4) concentrations. The use of PTU effectively reduced TT3 concentration by 25% at an average dose of 6.8 mg/kg/day, while LT4 increased fT4 concentration by 40% from baseline at an average dose of 4.3 µg/kg/day.” (opens the source at this quote in a new tab)
“Combined treatment with PTU and LT4 normalized serum T3, fT4, and TT4 in patients with MCT8 deficiency.” (opens the source at this quote in a new tab)

Combined treatment case series: baseline and last-encounter values

Parameter	Baseline	Last encounter	p value
Total T3, ng/dL	“337.7 ± 66”	“237 ± 91”	“<0.001”
Free T4, pmol/L	“8.9 ± 2.8”	“27.7 ± 15.3”	“0.003”
SHBG, nM/L	“242 ± 64.9”	“212.1 ± 73.4”	“0.170”
Heart rate, bpm	“102.7 ± 14.6”	“108.7 ± 21.13”	“0.433”

Combined treatment case series: metabolic and physical outcomes

“No statistical differences were observed in metabolic and physical parameters between baseline and last encounter overall for the group, but six of eight patients for whom these data were available had an increase in weight (z-score).” (opens the source at this quote in a new tab)

Combined treatment case series: hepatic and hematologic safety

“There were no adverse effects on liver function or granulocyte numbers noted throughout the period of observation.” (opens the source at this quote in a new tab)
“In our limited study, we did not find any evidence of liver toxicity; however, close monitoring of liver function tests is indicated given the concern and the relatively high doses of PTU used.” (opens the source at this quote in a new tab)

Combined treatment case series: limitations stated by the authors

“The number of patients in this study is not sufficiently powered to detect significant differences in peripheral tissue markers of TH action due to the variable baseline. Furthermore, the length of treatment was variable. Direct comparisons to other treatments such as DITPA and TRIAC are not possible in this report.” (opens the source at this quote in a new tab)

Guideline recommendations on nutrition and enteral tube feeding

“We recommend careful evaluation of dietary intake to maintain body weight that is adequate for age, and addressing feeding problems to prevent undernutrition. We suggest initiating percutaneous enteral tube feeding and the input of a dietitian to ensure adequate caloric intake at an early stage to prevent malnutrition” (opens the source at this quote in a new tab)
“Being underweight in early childhood is associated with higher mortality (104), while caloric intake is frequently inadequate due to impaired swallowing function and increased catabolism due to peripheral tissue thyrotoxicosis.” (opens the source at this quote in a new tab)

Gastrostomy placement and underuse of enteral nutrition

“Despite a high prevalence of feeding problems, enteral nutrition remains underutilized in this patient population.” (opens the source at this quote in a new tab)
“Placement of a percutaneous endoscopic gastrostomy/jejunostomy tube should be considered. The decision to place a percutaneous endoscopic gastrostomy/jejunostomy tube should be made jointly with parents and caregivers.” (opens the source at this quote in a new tab)

Feeding therapy and tube feeding in severe dysfunction

“Assuming that the child is safe to eat by mouth, feeding therapy (typically by an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.” (opens the source at this quote in a new tab)

Guideline recommendation for symptomatic neurological treatment

“We suggest that all patients should be offered empirical symptomatic treatment for neurological symptoms, including dystonia/hypertonia (spasmolytic drugs), drooling (e.g. anticholinergic drugs), and true epilepsy (carefully distinguished from a paroxysmal movement disorder); and should be referred to rehabilitation physicians/orthopedic surgeons/physiotherapists for measures anticipating contractures, scoliosis, a hip subluxation” (opens the source at this quote in a new tab)
“In the context of MCT8 deficiency, the effectiveness of such interventions has not been evaluated.” (opens the source at this quote in a new tab)

Symptomatic treatments by manifestation

Manifestation	Treatment	Considerations
Dystonia	“Medications such as anticholinergics, L-DOPA, carbamazepine, or lioresal”	“These therapies have shown no or mild efficacy.”
Drooling	“Glycopyrolate or scopolamine”	“Consider the ↑ risk for hyposalivation assoc w/↑ risk for dental caries”
Epilepsy	“Standardized treatment w/ASM by experienced neurologist”	“Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.”

Levodopa for dystonia

“Although dystonia is a prominent feature in MCT8 deficiency, current evidence does not support a dopaminergic mechanism underlying the motor symptoms. Consequently, levodopa is not considered a disease-modifying or standard treatment.” (opens the source at this quote in a new tab)

Guideline recommendations for specialist and multidisciplinary care

“We recommend all patients with MCT8 deficiency remain under the care of a (pediatric) endocrinologist and a (pediatric) neurologist” (opens the source at this quote in a new tab)
“We recommend the discussion of cases by a multidisciplinary team, comprising (pediatric) endocrinologists, neurologists, cardiologists, dietitians, occupational, speech and physiotherapists, physicians in rehabilitation medicine (physiatrists), orthopedic surgeons, and medical daycare centers” (opens the source at this quote in a new tab)

Supportive treatment and physical therapy

“Multidisciplinary team to provide standard care for hypotonia, poor feeding, DD/ID, spasticity, and extrapyramidal movement disorders.” (opens the source at this quote in a new tab)
“Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).” (opens the source at this quote in a new tab)

Use of rehabilitation services in an international parent registry

“In line with mobility being an important difficulty in daily life, a majority of 29 of 36 patients received supportive care from a physical therapist” (opens the source at this quote in a new tab)
“Further, 18 of 36 patients received therapy on speech and feeding techniques, and 7 of 38 patients used devices to enhance communication (eg, eye tracking devices).” (opens the source at this quote in a new tab)

Summary

Available therapies address peripheral thyrotoxicosis and individual symptoms; none has been shown to restore neurodevelopment. The 2024 European Thyroid Association guideline states that no available treatment regimen has rescued the neurocognitive phenotype and that the effectiveness of supportive neurological and gastrointestinal interventions has not been evaluated in MCT8 deficiency. Levothyroxine monotherapy did not improve neurodevelopment and in some cases aggravated peripheral thyrotoxicosis. In Triac Trial II, in participants younger than 30 months at enrollment, tiratricol reduced total serum T3 but did not meet its co-primary GMFM-88 and BSID-III gross motor endpoints compared with natural history scores from Triac Trial I. In a case series of 12 participants receiving combined levothyroxine and propylthiouracil, serum thyroid hormone concentrations normalized, but metabolic and physical parameters did not differ significantly between baseline and the last encounter, and the guideline advises weighing the risk of severe propylthiouracil adverse effects. Supportive care is inconsistently delivered: in an international parent registry, 11 of 36 participants received professional dietary advice and 2 of 16 participants with feeding problems had a feeding tube.

Guideline statement on neurocognitive outcomes and supportive care

“No available treatment regimen has proven to rescue the neurocognitive phenotype in humans with MCT8 deficiency. Patients require supportive/symptomatic treatment of neurological sequelae (i.e. dystonia, spasticity, drooling, scoliosis, feeding problems, epilepsy) and frequently occurring gastrointestinal symptoms (i.e. gastro-esophageal reflux disease, gastroparesis, constipation) according to common practice.” (opens the source at this quote in a new tab)

Summary

Tiratricol is approved in the United States (September 2026) for peripheral thyrotoxicosis in adults and pediatric patients with MCT8 deficiency and in the EU (February 2025) for peripheral thyrotoxicosis in MCT8 deficiency from birth; it is the first FDA-approved treatment for the disease. The 2024 European Thyroid Association guideline recommends TRIAC (strong recommendation) or DITPA (weak recommendation) with long-term therapy, and suggests combined levothyroxine and propylthiouracil only when thyroid hormone analogues are unavailable. The label advises against combining tiratricol with other thyroid medications such as levothyroxine and propylthiouracil. Dosing is individualized by body weight, total T3 measured by LC-MS/MS, and signs and symptoms of thyrotoxicosis, and the suspension can be given by mouth or through a feeding tube. A 2026 monitoring guideline notes that TRIAC costs substantially more than conventional thyroid hormone preparations and that treatment may be deferred in individual cases, such as patients without biochemical or cardiovascular evidence of thyrotoxicosis. Tiratricol does not replace supportive management of feeding difficulties, developmental disability, spasticity, or movement disorders. In the United States it is dispensed through PANTHERx Rare with the Egetis RareLink support program; before approval, the U.S. Expanded Access Program included 17 hospitals and approximately 60 treated individuals.

Use with other thyroid medications

“Taking EMCITATE in combination with thyromimetic products or products used to treat thyroid conditions (e.g., levothyroxine, propylthiouracil, and carbimazole) may increase the risk of thyrotoxicosis or hypothyroidism and should be avoided.” (opens the prescribing information at this quote)

Cost relative to conventional thyroid hormone preparations

“TRIAC is associated with substantially higher costs than conventional TH preparations, requiring individualized cost-benefit evaluation within different healthcare systems.” (opens the source at this quote in a new tab)

Circumstances in which treatment may be deferred

“Although treatment to reduce peripheral thyrotoxicosis is generally recommended in MCT8 deficiency, therapy may occasionally be deferred in individual cases, for example, in the absence of biochemical or cardiovascular evidence of thyrotoxicosis (which may occur in patients with milder phenotypes), intolerance to treatment, limited access to therapy, or following individualized clinical assessment.” (opens the source at this quote in a new tab)

Treatment effect by functional impact of the SLC16A2 variant

“In these patients, Triac treatment according a predefined protocol with a median duration of 22.4 (IQR:12.9–42.4) months and a median dose of 40.5 (IQR:28.9–58.0) μg/kg was equally effective in reducing serum T3 concentrations, as well as improving clinical and biochemical outcomes irrespective of the functional impact of the underlying variant, leveraging the potential impact of treatment on thyrotoxic features to all patients” (opens the source at this quote in a new tab)
“We also showed equal effectiveness of the MCT8-independent T3 analogue Triac treatment on different thyrotoxic features across different LoF classifications.” (opens the source at this quote in a new tab)

Treatment targets by age

“Appropriate treatment targets may vary with age. For example, improved neurodevelopmental outcomes may be the most important goal in neonates but not adults; however, gaining body weight is beneficial to patients of all ages. Attaining these treatment targets may require different therapeutic strategies.” (opens the source at this quote in a new tab)

Phenotypic severity and residual transporter function

“It has been repeatedly reported that the severity of the clinical phenotype is related to the residual transport capacity of the mutated MCT8 protein.” (opens the source at this quote in a new tab)

Monitoring guideline: development process and evidence basis

“The recommendations presented in this manuscript were developed during a virtual advisory board meeting on 26 November 2024, facilitated by Egetis Therapeutics.” (opens the source at this quote in a new tab)
“MCT8 deficiency is a rare disease, and the available evidence supporting these recommendations is limited and has not been assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.” (opens the source at this quote in a new tab)

Clinical lead and multidisciplinary coordination

“Patients require lifelong, coordinated, and cohesive multidisciplinary care tailored to their specific clinical presentation.” (opens the source at this quote in a new tab)
“A clinical lead should be assigned for each patient who is newly diagnosed with MCT8 deficiency. The appointment of this lead will depend on local circumstances and, in most cases, will be an endocrinologist or neurologist.” (opens the source at this quote in a new tab)
“Family members and caregivers should be referred for support with social pediatric issues: psychological counseling for parents or siblings may also be warranted, depending on individual needs.” (opens the source at this quote in a new tab)

Family support, care coordination, and palliative care

“Ensure appropriate social work involvement to connect families w/local resources, respite, & support.” (opens the source at this quote in a new tab)
“Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.” (opens the source at this quote in a new tab)
“Ongoing assessment of need for palliative care involvement &/or home nursing” (opens the source at this quote in a new tab)

Patient and caregiver counseling on thyrotoxicosis and abrupt discontinuation

“Advise patients to report signs and symptoms of thyrotoxicosis (such as hyperhidrosis, irritability, insomnia, nightmares, increases in heart rate and elevations in systolic blood pressure, or diarrhea) that occur for the first time or worsen during treatment” (opens the prescribing information at this quote)
“Inform patients and/or caregivers not to stop taking EMCITATE abruptly or without first checking with their healthcare providers as there will be a need for gradual dose reductions to decrease the risk of thyrotoxic symptoms and signs.” (opens the prescribing information at this quote)

Pre-approval expanded access requested by the FDA

“At FDA’s request, Egetis has implemented an Expanded Access Program (EAP) in the U.S. Currently, 17 hospitals are included and approximately 60 patients are receiving tiratricol in the EAP. The EAP allows physicians to access tiratricol for patients not eligible for clinical trials prior to marketing approval, as well as for continued treatment of patients who completed the ReTRIACt and Triac Trial II studies.” (opens the source at this quote in a new tab)

FDA post-marketing obligations

No evidence found.

Total T3 monitoring during maintenance treatment

“Once on a stable dose of EMCITATE, reassess total T3 levels once every 6 months and modify the dosage as clinically required.” (opens the prescribing information at this quote)
“An FDA-authorized LC-MS/MS test for the measurement of total T3 is not currently available. Currently available LC-MS/MS tests used to measure total T3 may vary in accuracy” (opens the prescribing information at this quote)

Vision assessment in children younger than 8 years

“For pediatric patients less than 8 years of age, consider periodic vision assessment during treatment with EMCITATE to rule out lens abnormalities (e.g., cataract formation)” (opens the prescribing information at this quote)

Serum T3 measurement: recommended analytical method

“In patients receiving TH analogues, particularly TRIAC, T3 levels should be measured using LC-MS whenever available.” (opens the source at this quote in a new tab)
“If LC-MS assays are unavailable, some specific immunoassays may show lower cross-reactivity between T3 and TRIAC.” (opens the source at this quote in a new tab)

Laboratory monitoring frequency

“Laboratory tests, including thyroid function diagnostics, should be performed at baseline and repeated at least annually, with frequency adapted to the clinical context and individual patient needs, including the emergence of new symptoms of hypothyroidism or thyrotoxicosis. In our clinical experience, this often corresponds to monitoring approximately twice per year.” (opens the source at this quote in a new tab)
“Liver function should be monitored more frequently in patients receiving medications with known hepatotoxic side effects.” (opens the source at this quote in a new tab)

Cardiac and bone monitoring

“Echocardiograms and ECGs should be performed at baseline and as clinically indicated.” (opens the source at this quote in a new tab)
“Bone mineral density assessment by dual-energy X-ray absorptiometry (DEXA) should be performed at baseline from puberty onward. Follow-up DEXA measurements should be guided by baseline findings and clinical context and may be repeated approximately every 3–5 years, where clinically indicated.” (opens the source at this quote in a new tab)

Thyroid hormone and cardiovascular outcomes across the two studies supporting approval

“The effectiveness of Emcitate was evaluated in two clinical studies in patients ranging in age from infants to adults, including an international, multi-center, randomized, placebo-controlled trial (NCT05579327) and a longer-term open-label study. Across both studies, patients treated with Emcitate had reductions in excess thyroid hormone levels in the bloodstream and improvements in cardiovascular and metabolic symptoms impacted by thyroid levels, such as systolic blood pressure and heart rate.” (opens the source at this quote in a new tab)

Biochemical response: Triac Trial II

“Among key secondary endpoints, total serum thyroid hormone T3 concentrations were reduced significantly and durably in all patients, thereby verifying tiratricol’s ability to alleviate thyrotoxicosis in MCT8 deficiency patients.” (opens the source at this quote in a new tab)

Neurodevelopmental outcomes: Triac Trial II

“The numerical improvements versus baseline observed on the primary endpoints of neurocognitive development assessed by the GMFM-88 and BSID-III scales did not show a statistically significant improvement versus historical controls.” (opens the source at this quote in a new tab)
“The co-primary endpoints were assessed by changes in the Gross Motor Function Measure (GMFM)-88 total score and the Bayley Scales for Infant and toddler Development (BSID)-III Gross Motor Skill domain, compared to natural history scores from the Triac Trial I.” (opens the source at this quote in a new tab)
“Patients were initially treated for 96 weeks with tiratricol, and the treatment effect was evaluated after 96 weeks.” (opens the source at this quote in a new tab)
“Unfortunately, the study didn’t show a clinically relevant and statistically significant improvement on the primary neurocognitive endpoints, but the study confirmed the effects of tiratricol on reducing T3 concentrations, which are relevant to alleviate features of thyrotoxicosis in patients with MCT8 deficiency, regardless of age.” (opens the source at this quote in a new tab)