Pfizer Inc. (NYSE: PFE) today announced updated Phase 1b clinical data on PF-06939926, an investigational gene therapy being developed to treat Duchenne muscular dystrophy (DMD). The preliminary data from 9 ambulatory boys with DMD, aged 6 to 12 (mean age: 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. 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. Three serious adverse events (SAEs) were recorded, two of which reflected likely complement activation. While these two SAEs were severe in nature, all three events fully resolved within 2 weeks, providing encouragement that close monitoring and early intervention can help mitigate the effects of complement activation. This new dataset, which includes updated 12-month results on safety, dystrophin expression, and exploratory functional endpoints for 3 additional boys, was presented for the first time during a virtual oral session today at the American Society of Gene & Cell Therapy (ASGCT) Annual Meeting.
DMD is a devastating and life-threatening X-linked disease 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, and unfortunately, usually succumb to their disease by the time they are in their late twenties. It is estimated that there are ~10-12,000 individuals affected with DMD in the US.
“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, PhD, Chief Scientific Officer, Pfizer Rare Disease Research Unit. “ 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 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.”
Data presented at the ASGCT virtual meeting included results from the study of 9 ambulatory boys with DMD, aged 6 to 12 (mean age: 8 years). Three of those 9 patients received a one-time intravenous infusion of PF-06939926 at 1E14 vector genomes per kilogram (vg/kg) (considered to be the low dose) and the other 6 received a one-time intravenous dose of 3E14 vg/kg (considered to be the high dose).
Preliminary Safety Results
The primary endpoint of the Phase 1b study is to assess the safety and tolerability of this investigational gene therapy in ambulatory boys with Duchenne muscular dystrophy through 12 months following treatment. Based on the data to date, the most common adverse events (AEs) suspected to be related to PF-06939926 (occurring in >40% of patients) were vomiting, nausea, decreased appetite, and pyrexia. There was no evidence of clinically relevant anti-dystrophin responses or hepatic dysfunction with the protocol-defined daily glucocorticoid regimen.
Among the 9 patients, 3 serious adverse events (SAEs) were reported in the first 14 days following administration, one more SAE than at Pfizer’s previous update. Importantly, each of these SAEs was fully resolved and at their last clinic visits, all patients were doing well. The first SAE involved persistent vomiting resulting in dehydration, which required admission for IV anti-emetics and fluids. The second SAE involved acute kidney injury with atypical hemolytic uremic syndrome (aHUS)-like complement activation, which required hemodialysis and treatment with eculizumab. The most recent SAE involved thrombocytopenia with aHUS-like complement activation which required platelet transfusion and treatment with eculizumab. Based on safety observations over the course of the study, Pfizer amended the clinical study protocol to include increased monitoring and management regimes, which helped enable timely intervention and mitigation in the case of the third SAE.
Results from Secondary and Exploratory Endpoints
Secondary endpoints of the clinical study included measurement of mini-dystrophin concentration by liquid chromatography mass spectrometry (LCMS) and distribution within muscle fibers by immunofluorescence.
Dystrophin concentrations in healthy or “normal” muscle, or muscle with no known disease, vary widely between samples and individuals, and no industry standard currently exists for defining a “normal” level. Historically, dystrophin concentration was measured by Western Blot. However, due to limitations of this methodology, Pfizer leveraged its internal expertise in immuno-affinity mass spectrometry protein quantification and developed a proprietary assay to measure dystrophin concentration with a wide dynamic range and low variability. This novel LCMS assay isan anti-peptide antibody enriched, immunoaffinity liquid chromatography tandem mass spectrometry (IA LCMS/MS) assay that has been validated by Pfizer in preclinical species and human tissues and discussed with the United States Food and Drug Administration (FDA).
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 3 patients in the low dose cohort showed that the mean percent normal dystrophin at 12 months was 24.0%. For the 3 patients in the high-dose cohort for whom 12-month data are available, the mean percent normal dystrophin at 12 months was 51.6%. Comparisons between baseline and post-treatment measures were significant (p < 0.005 at 2 months [N=9], and p < 0.05 at 12 months [N=6]). The increases in dystrophin levels observed at 2 months were generally sustained at 12 months, and 5 of the 6 boys showed an increase in mini-dystrophin concentration between the 2- and 12-month time points.
New results from open muscle biopsies of the biceps at both dose levels using an updated digital platform and analysis with a new quantitative imaging algorithm show dystrophin immunofluorescence, measured as the proportion of muscle fibers expressing dystrophin. Of the 3 patients in the low dose cohort, the mean percent positive fibers was 28.5% at 2 months and 21.2% at 12 months. Of the 6 patients in the high dose cohort, the mean percent positive fibers at 2 months was 48.4%. For the 3 patients in the high dose cohort for whom 12-month data are available, the mean percent positive fibers was 50.6% at 12 months.
Functional assessments are considered exploratory in this study, due to the small number of planned patients and the risk for bias in an open-label study. However, preliminary results for the North Star Ambulatory Assessment (NSAA) are available for the six patients with at least 1 year of follow-up, 3 of whom received PF-06939926 at the low dose and 3 of whom received it at the high dose. While baseline natural history NSAA scores are variable, generally scores are stable or decline in DMD patients over 6 years old, with the rate of progression associated with the baseline age and function. This pattern has been reported in a natural history database from the UK (Muntoni et al, PLoS ONE, 2019). The patients in Pfizer’s Phase 1b study, showed a significant functional improvement from baseline NSAA scores after one year, compared with the scores in an independent, external control group derived from recent prior clinical trials involving boys with DMD, who were matched specifically by age, weight and function (i.e. median loss of 4 points in NSAA total score for external placebo group [N=61] vs. improvement of 3.5 points in the Phase 1b patients [N=6], p = 0.003).
A second exploratory analysis using MRI showed a reduction in fat fraction in the thighs of boys treated with the high dose at 12 months post-treatment. Boys with DMD typically exhibit a progressive loss of contractile or lean muscle and replacement with fat and fibrotic tissue. In this study, a reduction in fat fraction was observed in boys from the high dose-treated cohort when compared to an external placebo group, suggesting that gene therapy may have improved muscle fiber health and quality in these boys. No reduction in fat fraction was seen in the low dose group.
“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,” said Cheng. “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.”