#MDA2021 – DMD Gene Therapy PF-06939926 Continues to Show Promise

Editor’s note: The Muscular Dystrophy News Today team is providing in-depth coverage of the 2021 MDA Virtual Clinical and Scientific Conference, March 15–18. Go here to read the latest stories from the conference.

The investigational gene therapy PF-06939926 continues to demonstrate an acceptable safety profile and the potential for substantial benefits in motor function in boys with Duchenne muscular dystrophy (DMD), according to the latest data from a Phase 1b clinical trial.

The results were reported at the 2021 MDA Virtual Clinical & Scientific Conference, in an oral presentation titled “Safety and efficacy of PF-06939926 gene therapy in boys with Duchenne muscular dystrophy: Update on data from the Phase 1b study.”

DMD, which usually affects only boys, is characterized by a deficiency in the protein dystrophin, which is essential for the structural integrity of muscle fibers. Patients’ muscle strength and motor function gradually decline over time with DMD.

Pfizer‘s PF-06939926 uses a harmless adeno-associated virus (AAV9) to deliver a mini-dystrophin gene, which encodes a smaller but functional version of dystrophin to muscle cells. It is designed to slow or stop muscle degeneration.

The ongoing Phase 1b study (NCT03362502) is evaluating the safety and tolerability of PF-06939926 in boys who can walk at least 10 meters (about 33 feet) without assistance. The study is now enrolling boys who lost their ability to walk this distance before age 17.

Eligible participants received glucocorticoids for six months and a stable daily dose for at least three months before the study. 

The trial’s primary goal is the incidence of dose-limiting safety or intolerability, as assessed by treatment-related adverse events, or side effects. Secondary objectives include measuring the levels and distribution of the mini-dystrophin protein in muscle biopsies. 

Functional tests include the North Star Ambulatory Assessment or NSAA rating scale of motor function, with a maximum score of 34 indicating fully independent function. The median NSAA score before treatment — called the study’s baseline — was 27. Participants will be monitored for up to five years. 

So far, 19 boys, ranging in age from 6 to 12 (median age 8 years), have received PF-06939926. Three received a low dose — of 1E14 vector genomes (vg)/kg) — while 16 received a higher dose of 2E14 vg/kg.

For comparison, the scientists used data from a group of DMD patients who received a placebo during previous clinical trials, matching this study’s participants in age, weight, and functional abilities. The median NSAA scores in the control group declined by 4 points over one year. 

NSAA scores from three low-dose patients and three high-dose participants were reported at the conference. Compared with the control group, two patients in the low-dose group and all three high-dose patients showed higher or at least no decline in NSAA scores, “which is very unusual for this age range,” said Beth Belluscio MD, PhD, executive director and global clinical lead at Pfizer, who presented the data. 

“Even the participant who started the study at age 12, that had a lack of decline at one year, who had this very stable score, is also significantly outside the norm,” she added. 

Side effects or adverse events occurred in more than 30% of boys in the high-dose group and included vomiting, fever, decreased platelets, nausea, decreased appetite, fatigue, and headache. 

Serious adverse events (SAEs) were reported in three participants. One boy experienced dehydration and two had acute kidney injury and low levels of platelets related to the activation of the complement system — part of the immune system that supports microbe clearance. All SAEs were resolved within three weeks. 

The decrease in platelets following treatment appeared to follow a consistent pattern, with the lowest levels occurring about 10 days post-infusion. However, most assessments stayed in the normal range. 

“We think there may be a similar pattern that’s observed across different gene therapies, and we hope to work with other companies to better understand this type of event,” Belluscio said. “In addition, we’re looking into the possible mechanisms underlying the platelet reduction and other reactions which we believe to be immune-related. And, we plan to share this information as well, in the near future, with the hope that it will benefit all communities for whom gene therapy is being developed.”

Elevated liver enzymes at four weeks also were observed in two of the 19 boys, as measured by GLDH levels, a test not affected by muscle disease. A temporary increase in glucocorticoids resolved GLDH levels within 15 days. 

“We feel confident that we have an acceptable safety profile and that we have the means to minimize risk. We can move forward with multiple aspects of the program,” Belluscio said. 

After the third SAE, changes to the study protocol were implemented, such as close monitoring of patients within the first two weeks after dosing and increased doses of glucocorticoids post-infusion. Since then, none of the subsequently treated boys experienced SAEs. 

Overall, the findings support the use of higher glucocorticoid doses after gene therapy and the continued use of this treatment’s high dose. Additionally, they outline the motor function gains seen to date compared with no treatment.

Dosing has begun in the CIFFREO study (NCT04281485), a Phase 3 trial that will evaluate the therapy’s safety and efficacy in up to 99 boys with DMD able to walk independently. Recruitment is open at sites in Italy, Israel, Russia, and Spain.

The company said it is planning a second Phase 3 study to test PF-06939926 in men who cannot walk without assistance.