Written and Reviewed by Team Pharmacally
Introduction
The European Medicines Agency (EMA) has recently approved Emcitate (tiratricol), a revolutionary treatment for peripheral thyrotoxicosis in patients with monocarboxylate transporter 8 (MCT8) deficiencies, known as Allan-Herndon-Dudley syndrome (AHDS). This milestone provides the first targeted treatment aimed at treating life-threatening metabolic complications for those suffering from this ultra-rare genetic disorder.
Understanding AHDS and MCT8 Deficiency
AHDS is a rare X-linked recessive condition caused by mutations in the SLC16A2 gene, which meets the genetic code for the Monocarboxylate Transporter 8 (MCT8) protein. This most commonly affects male individuals as the gene is found on the X chromosome; females are nearly always carriers. MCT8 conveys thyroid hormones (T3 and T4) into the cells. MCT8 deficiency impairs the transport of thyroid hormones (T3/T4) to neurons; hence the severe brain hypothyroidism, with peripheral thyrotoxicosis possible. In the AHDS, brain development and systemic metabolism are affected. The neurological symptoms include severe mental impairment, hypotonia (infancy), spasticity, dystonia, and quadriplegia and limited speech and motor skills (eg. unable to walk). Affected tissues are hormonally deficient, despite high serum hormone levels, with a systemic profile that includes Poor growth, muscle weakness, possible seizures, tachycardia, and weight loss.
How Emcitate Works
This is a synthetic analog of thyroid hormones, called Emcitate, acting on peripheral thyrotoxicosis in MCT8 deficiency (Allan-Herndon-Dudley Syndrome) through the following mechanisms:
1. TSH Suppression: Tiratricol will act directly on the thyroid hormone receptors in the pituitary, circumventing the dysfunctional MCT8 transporter by the usage of alternative transporters (e.g., MCT10 or OATP). This has a T3 mimetic effect that inhibits TSH secretion through negative feedback, finally restoring T4 and T3 levels that protect patients from the debilitating peripheral manifestations such as tachycardia and weight loss.
2. Reduction of Circulating Thyroid Hormones: Tiratricol-induced decrease in TSH-driven synthesis of thyroid hormones may also offer lowered circulating T4 and T3. Such a lowering of circulating levels would prevent and minimize excessive effects of these hormones on the peripheral tissues that uptake hormones through alternative transporters (i.e., liver and heart), causing diminished peripheral tissue hyper metabolism and toxicity.
3. Potential Brain Benefits: Tiratricol may enter the central nervous system via non-MCT8 transporters, conferring restricted-but-functionally meaningful T3-like activity in the brain, thereby alleviating the manifestations of central hypothyroidism. It is not expected, however, that this would have a major influence on neurodevelopmental outcomes, as this effect is secondary to its peripheral effects.
Clinical Evidence and Approval Pathway
The decision of the EMA follows promising results from clinical trials (Triac Trial I and Triac Trial II) showing Emcitate’s efficacy in reducing serum T3 levels and improving metabolic parameters.
Triac Trial I (NCT02060474) is multicentric, open-label, single-arm, phase II, and pragmatic trial; where the effectiveness and safety of oral Triac were analyzed in male pediatric and adult MCT8 deficient patients in eight European countries and one site in South Africa.
One other independent long-term clinical trial grants the basis for this approval, carried out at the Erasmus Medical Center, Rotterdam, Netherlands, where the efficacy and safety of Emcitate were studied on 67 patients with MCT8 deficiency. In this international pragmatic real-life cohort, data were collected retrospectively in MCT8-deficient patients from a consortium of 33 hospitals in 18 countries, who have received off-label therapy with T3 analogue Triac. Eligible subjects were patients with MCT8 deficiency (the latter being confirmed by the presence of pathogenic mutation in SLC16A2 gene), regardless of their age or co morbidity, treated off-label with Triac.
Emcitate is currently being investigated in the Triac Trial II (NCT02396459) Phase II study in very young MCT8 deficiency patients (<30 months of age) looking at possible disease modifying effects of early neurocognitive and neurodevelopmental intervention.
In value-based Phase 2/3 pivotal trials, patients treated with tiratricol showed significant reductions in complications of thyrotoxicosis, such as tachycardia and weight loss, during stabilization in metabolic rates. The therapy was generally well tolerated, with adverse effects of thyroid hormone modulation, such as transient changes in heart rate.
Safety profile in those treated with Emcitate included excessive sweating, irritability, anxiety, and nightmares.
Emcitate received orphan drug designation from the EMA, underscoring its importance for a condition with unmet medical needs. The approval facilitates access across the EU, with post-marketing surveillance planned to monitor long-term outcomes.
Significance of the Approval
One of the paediatric endocrinologists who participated in the trials noted that “Emcitate, being a turning point in the history of managing AHDS, focuses on the very cause for thyrotoxicosis, improving the quality of life and possibly extending survival for these patients.”
This authorization also shows EMA’s dedication toward improving therapies for rare diseases. Families with AHDS previously restricted to symptomatic care now have a validated treatment normalizing a critical aspect of the disease.
Implications
Although Emcitate isn’t going to cure AHDS or reverse neural damage, it taking care of all peripheral complications is a huge step forward. The study performed provides evidence that future studies will do further combinations with therapies targeting neurological symptoms. Approval in other parts of the world, including the United States, where it is estimated that one in every 70,000 boys suffers from AHDS, will be the expectation of the manufacturer as well.
Conclusion
The endorsement of Emcitate by the EMA gives hope to the AHDS community, exemplifying the opportunity in targeted drug development. As the first medicine approved to treat this devastating disorder, Emcitate sets a powerful precedent for future innovations in rare disease medicines, pointing to the value of scientific collaboration and regulatory support for orphan therapies.
References:
1. Groeneweg, Stefan et al., Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial, The Lancet Diabetes & Endocrinology, Volume 7, Issue 9, 695 – 706
2. Ferdy S van Geest, Stefan Groeneweg, Erica L T van den Akker, et al, Long-Term Efficacy of T3 Analogue Triac in Children and Adults with MCT8 Deficiency: A Real-Life Retrospective Cohort Study, The Journal of Clinical Endocrinology & Metabolism, Volume 107, Issue 3, March 2022, Pages e1136–e1147, https://doi.org/10.1210/clinem/dgab750
3. Egetis announces topline results of the Phase 2 Triac Trial II with Emcitate® (tiratricol) for MCT8 deficiency, Egetis Therapeutics, 19June 2024
4. European Commission approves Egetis’ Emcitate® (tiratricol) as the first and only treatment for patients with MCT8 deficiency, Egetis Therapeutics, 13 February 2024
5. First treatment for peripheral thyrotoxicosis in patients with Allan-Herndon-Dudley syndrome, European Medicine Agency, 13 December 2024
6. Sarret C, Oliver Petit I, Tonduti D. Allan-Herndon-Dudley Syndrome. 2010 Mar 9 [Updated 2020 Jan 16]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26373/
7. Jackie Gilbert, Thyrotoxicosis – investigation and management, Clinical Medicine, Volume 17, Issue 3, 2017, Pages 274-277, https://doi.org/10.7861/clinmedicine.17-3-274
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