RARE Daily

Pfizer Reports Positive Phase 1B Results for DMD Gene Therapy

May 15, 2020

Rare Daily Staff

Pfizer said results from its phase 1b clinical study of its experimental Duchenne muscular dystrophy gene therapy showed it provided durable and statistically significant improvements across multiple endpoints but resulted in a number of serious adverse events the company called “manageable.”

Duchenne muscular dystrophy (DMD) is a rare, genetic, neuromuscular condition that is caused by mutations in the gene encoding dystrophin, which is needed for proper muscle membrane stability and function. Patients present with muscle degeneration that progressively worsens with age to the extent that they require wheelchair assistance when they are in their early teens. People with the condition often don’t live beyond their late twenties.

PF-06939926 is an experimental, recombinant adeno-associated virus serotype 9 (AAV9) capsid carrying a shortened version of the human dystrophin gene (mini-dystrophin) under the control of a human muscle-specific promotor. The AAV9 capsid was chosen as the delivery vector because of its potential to target muscle tissue.

Pfizer initiated the phase 1b multi-center, open-label, non-randomized, ascending dose study of a single intravenous infusion of PF-06939926 in 2018. The goal of the study is to assess the safety and tolerability of this investigational gene therapy. Other objectives of the clinical study include measurement of dystrophin expression and distribution, as well as assessments of muscle strength, quality and function.

The preliminary data from nine ambulatory boys with DMD, aged 6 to 12 (mean age of 8 years) indicate that the intravenous administration of PF-06939926 was well-tolerated during the infusion period, with encouraging efficacy and manageable safety events, even when considering those adverse events that were more severe in nature, Pfizer said.

The treatment provided durable and statistically significant improvements across multiple efficacy-related endpoints measured at 12 months post-infusion, including sustained levels of mini-dystrophin expression and improvements on the North Star Ambulatory Assessment (NSAA) rating scale, which is a validated measure of muscle function.

Secondary endpoints of the clinical study included measurement of mini-dystrophin concentration by liquid chromatography mass spectrometry (LCMS). Using this LCMS assay, “normal” concentrations of dystrophin were established to compare to secondary endpoint results in patients. These “normal” reference levels were based on pooled skeletal muscle biopsies from 60 pediatric samples.

In the phase 1b trial, new results from open muscle biopsies of the biceps of the three patients in the low dose cohort showed that the mean percent normal dystrophin at 12 months was 24.0 percent. For the three patients in the high-dose cohort for whom 12-month data are available, the mean percent normal dystrophin at 12 months was 51.6 percent. Comparisons between baseline and post-treatment measures were significant. The increases in dystrophin levels observed at two months were generally sustained at 12 months, and five of the six boys showed an increase in mini-dystrophin concentration between the two- and 12-month time points.

“Based on the encouraging preliminary efficacy data and manageable safety events from our phase 1b study, we believe we may have a potential breakthrough therapy for boys with Duchenne muscular dystrophy, a devastating disease for which there remains a significant medical need,” said Seng Cheng, chief scientific officer for the Pfizer Rare Disease Research Unit.

Cheng said the company is advancing to a phase 3 program as quickly as possible and plans to begin dosing patients in the second half of 2020 pending regulatory approval.

Pfizer’s program has the potential to be the first DMD gene therapy phase 3 trial start using a commercial-scale manufacturing process. If the program is successful, this manufacturing capability is expected to help position Pfizer to deliver the therapy to patients quickly following regulatory approval.


Photo: Seng Cheng, chief scientific officer for the Pfizer Rare Disease Research Unit


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