ORLANDO, Florida — Patients with Allan-Herndon-Dudley syndrome (AHDS), an extremely rare, X-linked disorder causing moderate to severe intellectual disability and problems with movement, show significant improvement in total triiodothyronine (T3) levels in response to treatment with the T3 analog triiodothyroacetic acid (triac), according to new research.

“Our preliminary results show that triac treatment rapidly reduces thyroid-stimulating hormone [TSH] and subsequently reduces serum T3 and free thyroxine (T4) levels, and in all patients, we have been able to bring T3 levels into normal ranges,” explained coauthor Stefan Groeneweg, a PhD and MD candidate at the Rotterdam Thyroid Center, Erasmus, the Netherlands.

“We have also been able to observe the first putative beneficial effects on the peripheral phenotype,” he observed, which importantly included weight gain.

Reporting the preliminary data from the Triac Trial here at the 2015 International Thyroid Congress and Annual Meeting of the American Thyroid Association (ITC/ATA), Mr Groeneweg described impressive results seen in the first 15 patients of an expected 35 to 40 planned to be treated over the course of a year.

Asked to comment, Heike Heuer, PhD, of the Leibniz Institute for Age Research–Fritz Lipmann Institute, Jena, Germany, who has conducted triac research on mice, agreed that the current results are impressive.

“The findings are pretty encouraging and indicate that triac treatment is indeed successful in normalizing the odd thyroid-hormone parameters of the AHDS patients,” Dr Heuer told Medscape Medical News.

Patients Gained Weight With Triac

In addition to having neurocognitive disabilities including axial hypotonia (head drop) and progressive spasticity with severe developmental delays, patients with AHDS — who are usually always male — typically also have abnormal serum thyroid-function tests, including low-normal T4, high T3, and high-normal TSH.

The condition is known to be caused by mutations in the thyroid-hormone transporter MCT8 (also known as the SLC16A2 gene, Mr Groeneweg explained. At present, no effective treatment is available, but Dr Groeneweg said triac “appears to be an ideal candidate drug for AHDS as it enters the cell by bypassing MCT8, and once inside the cell it acts and is metabolized like T3.”

He noted that triac is also attractive because there is already significant clinical experience with the drug in adults and children alike in the treatment of resistance to thyroid hormone.

The drug is used in France for therapy of resistance to thyroid hormone and adjuvant therapy of thyroid cancer but is not approved for use in the United States or Canada, where warnings were issued in the 1990s regarding its use and marketing as a weight-loss aid.

In the new trial, the patients all have AHDS with severe disturbances in neuropsychological development, as well as problems with primitive reflexes, elevated tendon reflexes, dystonia, and central hypotonia; they range in age from 8 months to 66 years.

After treatment in a dose-escalation phase for an average of 6 months, with doses of 350 to 1400 µg/day (12 to 40 µg/kg) of triac, patients showed significant suppression of TSH levels (median reduction from 3.1 to 0.9 mU/L; P = .003), which resulted in a rapid and substantial reduction in T3 (4.4 to 2.0 nmol/L; P = .003).

Improvements have also been observed in levels of alkaline phosphatase, indicating bone health (P = .028); sex-hormone–binding globulin (SHBG), a proxy for liver function (P = .062); and creatinine, indicative of kidney and muscle function (P = .005).

Nearly all patients presented with tachycardia, with heart rates above 100 beats per minute (bpm), which decreased to 80 to 90 bpm after treatment, Mr Groeneweg said.

And patients under 20 also showed weight gain, which was notable due to the marked weight loss that occurs with AHDS, he added.

“To see patients under the age of 20 gaining weight was perhaps the most important observation that we’ve seen so far,” Mr Groeneweg said. “There was a median weight change of about 20% already in just 6 to 9 months of treatment, which is a huge improvement.”

Dr Heuer noted: “Particularly, the increase in body weight during the very short time period of treatment is a very promising sign, as the patients usually have difficulties with gaining weight due to the serum T3 levels that produces effects of thyrotoxicosis.”

Dr Heuer also presented research at the meeting showing a mouse model for AHDS that responded to triac treatment in the first 3 weeks of life had normalized brain development and even had normalized locomotor deficiencies. Dr Heuer noted, however, there are some safely concerns about the treatment in humans that need to be further evaluated.

“A major concern is certainly the question of whether triac treatment would lead to a tachycardia. Based on the current patients’ data, however, this kind of side effect was not noted.”

One patient dropped out of the trial due to noncompliance; no side effects have been reported in any of the patients, Mr Groeneweg said.

Results Encouraging, but More Work Needed

With the study ongoing, the initial results are promising, noted coauthor Edward Visser, MD, PhD, also of the Rotterdam Thyroid Center.

“Our trial has a dose-escalation phase and already with the lowest dose, there is a decrease in T3 levels,” he told Medscape Medical News. “The improvements in T3 levels are certainly what we hoped for.”

He cautioned, however, that more research is needed to better understand the therapy’s true benefits: “Although the interim results are encouraging, I would like to stress that we have to await the final and full evaluation.

“Furthermore, we would like to emphasize the importance in global collaboration with rare diseases in order to get uniform diagnosis, therapy, and management of patients with rare diseases,” he added.

If positive effects are confirmed in the current trial, the researchers plan to expand the research to aTriac Trial II, which is intended to build on those international collaborations and look at potential neurocognitive improvements with the treatment.

The feasibility of such neurocognitive improvements is currently difficult to predict, Dr Visser noted.

“Although brain development is likely already disturbed in utero, one could also expect some catch-up in development after birth if triac treatment is initiated,” he explained. “The earlier triac treatment is commenced, the more likely it is that beneficial effects can be observed.”

Ultimately, however, triac treatment will not likely not represent the final answer for AHDS, Dr Visser said.

“Theoretically, gene therapy or gene repair in a very early phase, in utero, would be the ideal therapy. However, such…possibilities are still far away from human application. But for now, we believe triac may be a reasonable” option.

The study received funding from ZonMw: The Netherlands Organization for Health Research and Development.