Pfizer’s Gene Therapy Holds Promise in Treatment of DMD, Early Data Show

PF-06939926, Pfizer‘s experimental gene therapy for the treatment of patients with Duchenne muscular dystrophy (DMD), shows promising safety and efficacy results in a small group of boys with DMD, a Phase 1b trial shows.

The company presented the preliminary findings at the 25th Annual Parent Project Muscular Dystrophy (PPMD) Connect Conference, June 26-30 in Orlando, Florida.

DMD, the most common type of muscular dystrophy, is caused by mutations in the DMD gene, which provides instructions for the production of a protein called dystrophin. This protein provides structural support and protection for muscle fibers.

PF-06939926 is an investigational gene therapy designed to deliver a functional, yet shortened, version of the DMD gene to the muscles of patients with DMD.

It does so by using a viral delivery vector, called an adeno-associated virus serotype 9 (AAV9) capsid. This capsid has been chosen to transport the mini-dystrophin gene because of its ability to specifically target muscles.

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PF-06939926 has already received orphan drug and pediatric rare disease designations from the U.S. Food and Drug Administration (FDA), and orphan medical product designation from the European Medicines Agency (EMA) in May 2017.

The safety and efficacy of PF-06939926 are being tested in the multicenter, open-label, non-randomized, Phase 1b trial (NCT03362502), still recruiting participants. The company plans to enroll up to 12 ambulatory (able to walk without assistance) boys with DMD ages 5–12.

The trial’s primary endpoint will be to assess the safety and tolerability of PF-06939926. Secondary endpoints will include assessing the localization and measuring levels of the mini-dystrophin protein in muscle biopsies by immunofluorescence and liquid chromatography mass spectrometry (LCMS), respectively.

So far, six boys ages 6–12 have received a one-time intravenous infusion of PF-06939926 at a dose of 1E14 vg/kg or 3E14 vg/kg. Preliminary findings from this small group showed that:

• The most common adverse events likely related to treatment included nausea, vomiting, decreased appetite, tiredness, and fever, and were reported by four of the six children dosed;
• In all cases, adverse events were easily manageable and resolved within 2–5 days in the case of vomiting and fever, or 1–3 weeks in the case of the other side effects;
• All children developed immune reactions to treatment. These varied in specificity and severity; the most severe case required hospitalization and was resolved within 15 days;
• Immunofluorescence in muscle biopsies of the biceps performed two months after treatment revealed that 38% and 69% of muscle fibers from children who had received PF-06939926 at a dose of 1E14 vg/kg and 3E14 vg/kg, respectively, were positive for mini-dystrophin;
• LCMS in muscle biopsies showed that in all six boys, levels of the mini-dystrophin protein ranged between 300-1,800 fmol/mg, which corresponds to approximately 10–60% of normal levels;
• Among boys treated with PF-06939926 at a dose of 1E14 vg/kg, the mean expression level of mini-dystrophin was 23.6%; for those who received the highest dose, 29.5%;
• In two boys who received PF-06939926 at a dose of 1E14 vg/kg and were followed for at least a year, NorthStar Ambulatory Assessment (NSAA) scores had a mean increase of 4.5 points, indicating a mild improvement in motor abilities.

“Gene therapy for single-gene disorders is at a formative stage in its evolution, and the initial data we’ve seen in our study for Duchenne muscular dystrophy may exemplify the potential for this modality to change patients’ lives,” Seng Cheng, senior vice president and chief scientific officer of Pfizer’s Rare Disease Research Unit, said in a press release. “We are looking forward to building on these initial data and advancing the development of this therapeutic modality.”

While Pfizer continues to gather data from the ongoing Phase 1b study, it is making arrangements for a future global, randomized, placebo-controlled, Phase 3 trial of PF-06939926. The new trial will build on data generated by the current Phase 1b study, and is expected to launch by the beginning of 2020.