At the Action Duchenne meeting in London on Saturday, Pfizer Inc. announced that it has completed a study in healthy volunteers with its antibody-based therapeutic to block the muscle protein myostatin, and is preparing to start recruitment for a phase II study in Duchenne this month. Watch Clinicaltrials.Gov next week for recruitment information (if you are registered in DuchenneConnect you will also receive a notification as soon as the trial is listed).
Myostatin is a naturally occurring protein in muscle that normally puts the breaks on muscle growth, so when this protein is absent or blocked muscle can grow larger than it normally would. Naturally occurring mutations in the myostatin pathway in many species of animals, including humans, result in very well-developed muscles and do not seem to cause any harm. Experiments in both mice and dogs that lack dystrophin have demonstrated that blocking myostatin results in more muscle mass, and importantly, improved strength and function.
Both Wyeth (MYO-029) and Acceleron/Shire (ACE-031) have previously tested different strategies to block the myostatin pathway in muscular dystrophy. The Wyeth drug was tested in adults with Becker muscular dystrophy, limb-girdle muscular dystrophy, and facioscapulohumeral muscular dystrophy. Participants experienced some injection site reactions and did not show improvements in the outcome measures. The ACE-031 Duchenne study, which used an antibody to the myostatin receptor, was stopped due to the occurrence of nosebleeds and telangiectasia (small dilated blood vessels near the surface of the skin).
The new Pfizer drug, currently designated PF-06252616, is also an antibody-based approach but one which is not predicted to trigger the same side effects seen with ACE-031 as it is very specific and does not block the molecule thought to be responsible for those problems. When Pfizer tested its myostatin blocking antibody in healthy volunteers who received 10mg of the drug by infusion every 2 weeks, they were able to show a statistically significant increase in muscle mass and volume after 120 days. None of the side effects seen in previous myostatin-blocking trials were experienced by volunteers in the Pfizer phase I study.
The phase II study in Duchenne for the Pfizer drug will be a randomized placebo-controlled trial with 105 participants, age 6 to less than 10 years. The participants will receive a 2-hour infusion every 4 weeks. Participants must be ambulatory and able to do the four stair climb in > 0.33 but < 1.6 stairs/second—the four stair climb will be the primary endpoint for the study (the company thinks that it is the best endpoint to show strength improvement and that it also may have less variability than some other functional endpoints). The study will have two periods and each period will run for 48 weeks. At the beginning of the study —boys will be randomized to one of three groups. The first group will receive study drug in period 1 and remain on a stable dose of drug in period 2. The second group will also receive study drug in period 1 but in period 2, they will switch to placebo. The third group will receive placebo in period 1 and then study drug in period 2. The study will be blinded so the participants and their families won’t know which group they are enrolled in. The primary analysis for the study will be based on the data collected from period 1. This design will allow the investigators to see both the effect of starting and stopping the drug as well as constant exposure over a long period of time to the same dose. It’s likely that the drug will actually take 2/3 of the second period of the trial to wash out in the group that is transitioned to placebo so participants in that group may still get some drug exposure during the placebo period of the study. An open label extension trial will be offered to all study participants after the phase II study is complete.
Sites for the study will be in the US, Canada, Japan, the United Kingdom, and possibly Italy. The majority of the trial sites will be located in the United States with rolling enrollment as sites are announced over the coming months; the first two sites will be posted on ClinicalTrials.gov soon.
Although the current plan is to conduct a confirmatory phase III study after completion of the phase II study, the company has addressed the possibility of an accelerated approval pathway with the FDA and says the regulators are “open to it,” noting that for the drug to receive accelerated approval there may need to be efficacy in multiple endpoints, not just the primary endpoint. Secondary endpoints include the Northstar, the Six-Minute Walk Test, measures of strength, muscle MRI, and DEXA scans.