Pfizer reported initial clinical data from a small phase 1b study of its investigational gene therapy for Duchenne muscular dystrophy that showed an increase in dystrophin levels two months after dosing, but the study is on hold until appropriate safety monitoring is completed due to a serious immune response in one study participant.

Investigators presented the data at the 25th Annual Parent Project Muscular Dystrophy Connect Conference in Orlando, Florida.  

Duchenne muscular dystrophy (DMD) is a serious genetic disease characterized by progressive muscle degeneration and weakness that primarily affects boys with symptoms beginning as early as three years of age. It is caused by an absence of dystrophin, a protein that helps keep muscle cells intact. In the absence of dystrophin, muscle cells deteriorate.

Pfizer’s investigational gene therapy, PF-06939926, is a recombinant adeno-associated virus serotype 9 (AAV9) capsid carrying a shortened version of the human dystrophin gene under the control of a human muscle-specific promotor.

Pfizer began the phase 1b study in 2018 to assess the safety and tolerability of its 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. Pfizer aims to enroll approximately 12 boys with DMD who are ambulatory and aged 5 to 12.

So far, six boys ranging in age from 6 to 12 years have received the one-time intravenous in one of two doses. Preliminary results from open muscle biopsies of the biceps taken two months after dosing show detectable mini-dystrophin immunofluorescence signals with a mean of 38 percent positive fibers taken from participants who received the lower dose of the therapy and a mean of 69 percent positive fibers taken from participants who received the higher dose.

Preliminary safety results found the most common adverse events suspected to be related to the gene therapy to be nausea, vomiting, decreased appetite, tiredness and/or fever, which were reported within a few days of dosing by four of six study participants. Nausea and vomiting symptoms were managed with oral antiemetics for three of the participants, but one was hospitalized for two days for intravenous antiemetics and replacement fluids. In all cases, vomiting and fever symptoms resolved within two to five days and the other symptoms resolved within one to three weeks.

Although immune responses occurred in all participants, one patient developed a rapid antibody response with activation of the complement system who had to receive intermittent hemodialysis, as well as two intravenous doses of a complement inhibitor. Pfizer has halted dosing of any other patients in the trial until it figures out why this happened, whether it was due to the viral vector used, and whether better monitoring might resolve the issue.

No industry standard currently exists for defining a “normal” range or threshold of dystrophin concentration, using an FDA-reviewed, Pfizer developed assay, the data showed that mini-dystrophin concentrations two months after dosing for all six DMD study participants were 10 to 60 percent of “normal.”

Although functional assessments are considered exploratory, due to the small number of planned study participants and the risk for bias in an open-label study, preliminary results for the NorthStar Ambulatory Assessment (NSAA) are available for the only two participants with at least one year of follow-up, both of whom received the lower dose of the gene therapy. These participants, who were 7 and 8 years upon study entry with baseline NSAA total scores of 24 and 25, respectively, showed mean increases of 4.5 points at the 12-month timepoint. While baseline natural history NSAA scores are variable, generally scores are stable or decline in DMD patients of the same age as these participants, with the rate of progression associated with the baseline age and function.

“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,” said Seng Cheng, senior vice president and chief scientific officer of Pfizer’s Rare Disease Research Unit. “We are looking forward to building on these initial data and advancing the development of this therapeutic modality.”

While Pfizer continues to collect data from this ongoing open-label study in boys with DMD, it is also in the planning stages for a global, randomized, placebo-controlled phase 3 study. This study is expected to begin in the first half of 2020.

“The emerging field of gene therapy has collaboration at its core as patients, scientists, clinicians, regulators, and payors all need to come together to share their experiences,” said Debra Miller, CEO and founder of CureDuchenne. “Without that collaboration, we wouldn’t have made the progress in our community’s understanding of the science that we’re proud is being presented today.”

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