medwireNews: A once-daily regimen of the thyroid hormone analogue Triac normalised serum levels of tri-iodothyronine (T3) in a phase II trial of paediatric and adult patients with transporter monocarboxylate transporter (MCT)8 deficiency.
“In the absence of any other available effective therapies, our findings show that Triac is the first disease-modifying treatment for patients with MCT8 deficiency”, the study investigators report in The Lancet Diabetes & Endocrinology.
Recognising the burden of severe underweight, tachycardia and muscle wasting in this population, the team hopes that “[a]melioration of the thyrotoxicosis with Triac treatment could benefit patients with MCT8 deficiency irrespective of their age.”
Writing in a linked comment, Andrew Bauer (Children’s Hospital of Philadelphia, Pennsylvania, USA) agrees, describing Triac as “an exciting and uncommon opportunity to potentially improve the lives of patients with a profoundly disabling form of developmental delay and intellectual disability”.
Forty-six male patients with a confirmed SLC16A2 mutation were recruited to the multinational study. The median age of the group was 7.1 years; 24% were aged less than 4 years, 41% were aged 4–10 years, 24% were 11–18 years and the remaining 11% were adults.
The patients were given an initial oral Triac (3,3’,5-tri-iodothyroacetic acid, or tiratricol) dose of 350 µg/day, increasing in 350 µg increments until the serum total T3 concentration had decreased to the target range of 1.4–2.5 nmol/L, explain W Edward Visser, from Erasmus Medical Centre in Rotterdam, the Netherlands, and co-workers.
The 45 patients with at least one follow-up assessment took an average daily Triac dose of 38.3 µg/kg to reach their target T3 serum level, with levels falling from baseline by a significant 61%, from an average of 4.97 nmol/L to 1.82 nmol/L after 12 months.
This was accompanied by significant reductions from baseline in mean serum thyroid-stimulating hormone (TSH, from 2.91 to 1.02 mU/L, free thyroxine (free T4, 9.5 to 3.4 pmol/L), total T4 (56.0 to 24.4 nmol/L) and reverse T3 (0.12 to 0.04 nmol/L), the researchers write.
Secondary endpoints were assessed in 40 patients who completed 12 months of treatment, demonstrating a significant 0.27 standard deviation increase in the weight-for-age Z score, translating to an average 2.7 kg gain when a progressive reduction would otherwise have been expected, Visser et al write.
In addition, resting heart rate and average heart rate fell by an average of 9 and 5 beats per minute, respectively, and average systolic blood pressure showed an 18 percentile point decrease, which reduced the proportion of patients with systolic hypertension from 34% to 9%.
The researchers also report results for the Gross Motor Function Measure 88 scale, finding that the greatest benefits occurred among the seven patients with a completely inactivating mutation who began Triac before age 4 years, with two achieving at least 20% on the measure within 12 months, which they say “roughly reflect[s] the ability to sit independently and achieve full head control in different postural positions.”
Safety analysis of the 46 patients who received at least one dose of Triac identified three patients who experienced a transient increase in perspiration and three with transient irritability, all of which were thought to be treatment-related. None of the trial participants required a dose reduction or discontinued treatment because of adverse events.
Post-hoc analysis of 10 patients during a long-term treatment extension demonstrated that the reductions in T3, TSH and free T4 were maintained, the investigators observe.
Moreover, premature atrial contractions “completely subsided” in three of seven children, and one patient who showed atrial fibrillation at baseline no longer did so at 12 and 36 months, they say. Similarly, the improvement in bodyweight-for-age Z score was maintained and seven of eight children continued to improve with regard to weight, height and BMI.
Visser et al note, however, that the trial was not designed to determine the effect of Triac on neurodevelopment, as most patients had passed “the small window of opportunity to modulate brain development.”
“A phase 2 trial (NCT02396459; not yet recruiting) will investigate the effects of Triac on neurodevelopmental outcomes in very young children”, they say.
Discussing this aspect, Bauer comments that “[o]n the basis of the in-vivo mouse models, and what is known about brain neuroplasticity, there is very good reason to be optimistic that the earlier the initiation of therapy, the greater the positive effects on neurocognitive development.”
By Lynda Williams
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Lancet Diabetes Endocrinol 2019; doi: 10.1016/ S2213-8587(19)30155-X