Pfizer’s DMD Gene Therapy Continues to Show Promise, Phase 1b Trial Shows

Pfizer’s experimental gene therapy PF-06939926 promotes sustained production of a shorter but functional version of dystrophin — the protein lacking in Duchenne muscular dystrophy (DMD) — and improves motor abilities in boys with the disorder, according to updated data from a Phase 1b trial.

“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 [DMD], a devastating disease for which there remains a significant medical need,” Seng Cheng, PhD, senior vice president and chief scientific officer of Pfizer’s rare disease research unit, said in a press release.

Results so far continue to support the initiation of a placebo-controlled Phase 3 trial to evaluate PF-06939926’s safety and effectiveness in boys with DMD.

“We are advancing our Phase 3 program as quickly as possible and plan to begin dosing patients in the second half of 2020 pending regulatory approval,” Cheng added.

The findings were presented at the American Society for Gene & Cell Therapy annual meeting, recently held online, in an oral presentation titled “Safety and Tolerability of PF-06939926 in Ambulatory Boys with Duchenne Muscular Dystrophy: A Phase 1b Multicenter, Open-Label, Dose Ascending Study” (abstract No. 617).

Duchenne is caused by deficient production of dystrophin — an essential protein for muscle integrity — due to mutations in the DMD gene.

PF-06939926 uses a modified and harmless adeno-associated virus (AAV) — AAV9 — to deliver the mini-dystrophin gene, a shorter but functional copy of the DMD gene, specifically to muscle tissue.

By providing a source of functional mini-dystrophin protein to the most affected tissues, this one-time treatment is expected to slow or halt muscle degeneration in people with DMD.

The U.S.-based, multicenter Phase 1b trial (NCT03362502) was designed to evaluate the safety, tolerability, and preliminary effectiveness of PF-06939926 in 15 boys with DMD who are able to walk without assistance. The trial is still recruiting participants, ages 4 to 12; more information can be found here.

Participants are assigned to receive a one-time intravenous infusion (directly into the bloodstream) of PF-06939926 at a dose of 1E14 vector genomes (vg)/kg (low dose) or 3E14 vg/kg (high dose) and are followed for up to five years after treatment.

The trial’s primary goal is to assess the safety and tolerability of PF-06939926, while secondary goals include assessing the levels and localization of the mini-dystrophin protein in muscle biopsies.

Changes in the NorthStar Ambulatory Assessment (NSAA) rating scale — a validated measure of motor function — and in muscle fat fraction (a marker of DMD severity) are among the trial’s exploratory goals.

Data from the first six treated participants showed that PF-06939926 had a manageable safety profile and successfully promoted the production of mini-dystrophin protein in muscle tissues. In addition, boys who were followed for at least one year after receiving the low dose showed mild improvements in motor function.

The newly presented results include one-year findings from three additional participants, for a total of nine boys (with a mean age of 8). Three boys were given the low dose of PF-06939926, while the other six received the high dose.

Treatment with PF-06939926 was well-tolerated during the infusion period and the most common adverse events thought to be associated with treatment were vomiting, nausea, decreased appetite, and fever.

Three serious adverse events were reported in the first 14 days following treatment, which were fully resolved at the latest clinic visits.

PF-06939926 resulted in a significant increase in mini-dystrophin levels in muscle tissues at two months, which were sustained at one year. Boys treated with the high dose of PF-06939926 showed higher levels of mini-dystrophin and mini-dystrophin-positive muscle fibers than those treated with the low dose.

Notably, boys given the therapy showed a median improvement of 3.5 points in the NSAA score at one year, which significantly differed from the 4-point loss reported for boys with DMD, who were matched for age, weight, and function, and given a placebo in previous clinical trials.

Also, compared with prior controls, participants treated with the high dose of PF-06939926 (but not the ones given the low dose) showed a reduction in muscle fat fraction in the thighs, suggesting that the therapy improved muscle fiber health and quality.

“We believe these data support the view that administration of PF-06939926 at a dose of 3E14 vg/kg can lead to [production] of potentially therapeutic levels of mini-dystrophin that may translate to a measurable improvement in muscle function and health in DMD patients,” said Cheng.

“Our program has the potential to be the first DMD gene therapy Phase 3 trial to start using a commercial-scale manufacturing process. If the program is successful, this manufacturing capability is expected to help position us to deliver this medicine to patients quickly following regulatory approval,” he added.

Debra Miller, CureDuchenne’s founder and CEO, said in a separate press release: “We are pleased to see such encouraging data from Phase 1b and to see Pfizer progress to planning a global Phase 3 gene therapy clinical trial for Duchenne muscular dystrophy.”

CureDuchenne Ventures played an integral role in PF-06939926’s development through an early investment in Bamboo Therapeutics’ Duchenne program. Bamboo was the original developer of the therapy and was later acquired by Pfizer.

“It’s investments like these that take a long-term vision of what the Duchenne community needs and is continued proof of our success leveraging venture philanthropy to provide it,” Miller said.

PF-06939926 received orphan drug designation from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, as well as the FDA’s rare pediatric disease designation in May 2017.