Pfizer’s gene therapy promising for Duchenne muscular dystrophy (DMD)

Pfizer Inc. has revealed revised clinical Phase 1b results on PF-06939926, an investigational gene therapy to treat Duchenne muscular dystrophy (DMD).

Potential breakthrough therapy for boys with Duchenne muscular dystrophy (DMD)

Preliminary data from 9 ambulatory boys with DMD aged 6 to 12 years (mean age: 8 years) suggests that the PF-06939926 intravenous administration has been tolerated well during the infusion period, promising efficacy controllable safety including the more serious in nature adverse events.

The therapy produced stable and statistically meaningful improvements among a range of efficacy-related outcomes followed up at the 12 months post-infusion period. Moreover sustained levels of mini-dystrophin representation were achieved as well as progress on the North Star Ambulatory Assessment (NSAA), rating scale formally recognised as a measure for a muscle function test.

Seng Cheng, PhD, Chief Scientific Officer at Pfizer’s Rare Disease Research Unit stated:

“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.”

“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. 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.”

Serious Adverse Events (SAEs)

There were three serious adverse events (SAEs) recorded, two of which reflect likely complement activation. Although these two SAEs were serious in nature, all three cases were completely resolved within 2 weeks, giving hope that close observation and early action will help reduce the impact of the complement activation. This latest 12-month revised data results on safety, dystrophin expression, and investigative functional outcomes for 3 additional boys, was introduced to the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting for the first time during a digital oral session on May 15.

Duchenne Muscular Dystrophy (DMD)

Duchenne muscular dystrophy (DMD) is a debilitating and life-threatening X-linked disease caused by mutations in the gene encoding dystrophin necessary for proper stabilisation and functionality of the muscle membrane. It is a serious genetic disorder of progressively deteriorating muscle degeneration and weakness with age to the point that patients in their early twenties need wheelchair assistance and, typically succumb to their illness as soon as they are in their late 20s. The statistic shows that there are around ~10-12,000 people affected by DMD in the US.

Dystrophin distribution

New encouraging data from open biceps muscle biopsies at both dose levels utilising a modified digital technology displays the dystrophin immunofluorescence estimated as the proportion of the dystrophin-expressing muscle fibres. The mean ratio of positive fibres of 3 patients in the low dose cohort was 28.5 percent at 2 months and 21.2 percent at 12 months. The mean percentage of dystrophin -expressing fibres in 2 months was 48.4 percent of the 6 patients in the high dose group. The available data for the 3 patients in the high dose study shows that the proportion of positive fibres was 50.6 percent over 12 months.

Functional assessment

Patients in the Phase 1B Pfizer analysis demonstrated substantial functional progress from baseline NSAA scores after one year compared to scores data in a separate, external test group resulting from previous clinical trials involving DMD boys who were precisely aligned by age, weight and function. A second exploratory study using MRI revealed a decrease of the fat fraction in the thighs of boys tested at 12 months post-treatment with the high dose.

Boys with DMD usually show a gradual loss of contractile or lean muscle and replacement with fat and fibrotic tissue. For this analysis, as compared to an external placebo cohort, a reduction in the fat fraction was observed in boys from the high-dose-treated group indicating that gene therapy might have increased muscle fibre health and quality in these boys. No decrease in fat fraction was observed.

Pfizer’s CSO, Seng Cheng siad:

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

“We also want to give our heartfelt thanks to all the patients, their families, the researchers, investigators, other clinicians and advocacy organizations for their passion, expertise and engagement in helping to advance clinical research and care for the Duchenne muscular dystrophy community.”

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