Abstracts

Rationale: Rett syndrome (RTT) is a rare, severely debilitating disease characterized by developmental regression, stereotypical hand movements, seizures, and movement disorder. Deficient mitochondrial complex function and abnormal mitochondrial morphology in patients with RTT is often found. At present, no targeted treatment for Rett syndrome exists, and all treatment is supportive (e.g., therapy) or symptomatic (e.g., antiseizure and antispasmodic drugs). We are conducting a clinical trial to evaluate safety and tolerability of triheptanoin and efficacy of triheptanoin in subjects with RTT in improving seizure frequency and dystonia. Methods: This study summarizes findings of an open-label, single arm clinical trial of triheptanoin. Subjects with RTT who have observable seizures and/or dystonia despite medical management were recruited. Subjects must meet the criteria of an average of at least four seizures in one month and/or presence of dystonia at least four times in one month prior to the study. Seizures or dystonia must remain present at least four times per month on average during baseline period. We began with a two-month run-in period, followed by a challenge-dechallenge-rechallenge with triheptanoin. Safety and tolerability of triheptanoin at dose of 1-4 g/kg/day depending on age was examined over a four month maximum dose period. Data was collected on seizure and dystonia frequency and severity using diaries. Participants were examined every 2-2.5 months during the total course of 8.5 months and were interviewed by telephone during interim periods. Results: Of nine enrolled subjects, all are females with RTT between the ages of 3 and 21 years. No clinically significant abnormalities or adverse events were found due to laboratory values. One subject discontinued treatment prior to study conclusion due to frequent vomiting and diarrhea, and another subject discontinued due to diarrhea. Two subjects had not yet completed treatment at time of interim findings. Four of the five subjects who completed the course of treatment had intractable seizures. Two of those four subjects achieved greater than 50% seizure reduction. Seizure frequency was unchanged for one subject and worsened in the fourth. Of two subjects with frequent dystonia, one had improved total days of dystonia and one was unchanged. Moreover, improvement in dystonia did not show the expected worsening during the dechallenge period that was present in the two subjects whose seizures improved on treatment.  Conclusions: Triheptanoin is safe and well-tolerated in most participants with RTT over a treatment period of four months. Two of the four subjects with frequent seizures improved with triheptanoin treatment, and one of these has been followed into the extension period with sustained improvement. The effect of dystonia improvement was less robust than seizure improvement and was not supported by worsening dystonia when triheptanoin was withdrawn. Funding: Supported by Ultragenyx Pharmaceutical Inc.