The Duchenne community has been eagerly awaiting news about a Phase 2 Randomized, Placebo-Controlled, Multiple-Ascending-Dose Study of ACE-031 in ambulant, steroid-treated boys with Duchenne (A031-03). We were all disappointed to hear the study was terminated and hoping to understand what were the results of the study in terms of safety and pharmacologic effects and what expectations we might have with regard to next steps for ACE-031. We needed a therapeutic dose of HOPE!
This week at the World Muscle Society Congress in Portugal, Acceleron and investigators presented summary data from this Phase 2 study, which was conducted in Canada.
In the context of trials, the participants are referred to as subjects. To begin, 24 subjects participated in the trial. For inclusion into the trial, the subjects had to be ambulant boys with Duchenne who were age four or older and currently on a stable dose of corticosteroids. The average age of participants in the study was approximately ten years old.
The primary objective of the study was to evaluate the safety and tolerability of multiple escalating doses of ACE-031 in ambulatory steroid-treated boys with Duchenne. Several secondary objectives were also investigated.
In each cohort, subjects were randomized (randomly assigned) to receive placebo or ACE-031. In the first cohort, nine boys received 0.5mg/kg q4 weeks (0.5 mg ACE-031 per kg of body weight given every four weeks) over a period of 12 weeks. Safety data was reviewed prior to the start of the second cohort. The second cohort of 12 boys was randomized to receive 1.0 mg/kg q2 weeks over a period of 12 weeks. Subjects were followed for 12 weeks after the treatment period was completed.
There were no serious or severe adverse events (AEs) in the study, nor did any AEs lead to discontinuation. There were no clinically significant changes observed in safety lab results. The most frequent adverse events were injection site redness (occurring in approximately 50% of ACE-031 or placebo-treated subjects); mild nosebleeds (occurring in 0%, 11% and 56% of subjects given placebo, ACE-031 0.5 mg/kg q4 weeks and ACE-031 1.0 mg/kg q2 weeks, respectively) and telangiectasias (small, dilated blood vessels within the skin), occurring in 5 out of 9 subjects in the ACE-031 1.0 mg/kg q2 weeks group only.
There was a significant increase in average total body lean mass (which includes skeletal muscle, measured by DXA) that appeared to be dose-dependent, indicating the amount of increase may be correlated to the dose of ACE-031. The maximum average increase was 5.4% after 24 weeks, noted in both ACE-031 treated groups. With the small number of subjects in this study, there was inadequate statistical power to detect a difference in the 6-minute walk test (6MWT), however, the trends showed the average 6MWT distance was maintained in the boys on ACE-031 over the 24 weeks, but declined in the placebo group (i.e., those not on ACE-031).
Bone mineral density of the lumbar spine (lower back) as determined by DXA scan, showed a significant increase at day 169 as compared to the baseline measurement in the 1 mg/kg every 2 week dosing cohort. Additionally, there was less gain in total body fat mass for the subjects on ACE-031 and this correlated with the distance walked in the 6MWT.
As mentioned last June, Acceleron and Shire remain committed to the development of ACE-031 and are working hard with regulatory agencies. As their partnership moves forward, Acceleron and Shire will continue to explore the relationships between adverse events, multiple clinical outcomes and ACE-031 dose exposure in their clinical and non-clinical programs.
The Duchenne community wishes Acceleron and Shire Godspeed.