One year data from ambulatory boys in a phase 1b, open-label study of fordadistrogene movaparvovec (PF-06939926) for Duchenne muscular dystrophy (DMD)

Clinical Trials
53
Russell Butterfield, MD, The University of Utah
Perry Shieh, MD, University of California, Los Angeles, David Geffen School of Medicine
Florence Yong, PhD, Pfizer Inc, New York, NY
Michael Binks, MD, Pfizer
Tara G. McDonnell, BA, Pfizer Inc, New York, NY
Kelly A. Ryan, MS, BSN, Pfizer Inc, New York, NY
Beth Belluscio, MD, PhD, Pfizer
Srividya Neelakantan, PhD, Pfizer Inc, New York, NY
Daniel Levy, MD, PhD, Pfizer
Pamela F. Schwartz, PhD, Pfizer Inc, New York, NY
Edward Smith, MD, Duke University Hospital

Background: Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in low levels of dystrophin protein, which protects muscle from damage during contraction. DMD causes progressive muscle weakness, typically resulting in loss of ambulation at approximately 12-years of age. Fordadistrogene movaparvovec (PF-06939926) is an adeno-associated virus serotype-9 (AAV9) gene-replacement construct containing a truncated dystrophin transgene (mini-dystrophin), which aims to restore functional protein to the sarcolemmal membrane. We present 1-year data from ambulatory participants in a phase 1b, multicenter, single-arm, open-label trial (NCT03362502) investigating the safety and tolerability of fordadistrogene movaparvovec for DMD.
Methods: Ambulatory boys with a genetic diagnosis of DMD and receiving a stable, daily glucocorticoid regimen were eligible. Fordadistrogene movaparvovec was administered as a single intravenous infusion, at low- or high-dose. Primary outcome was safety and tolerability. Mini-dystrophin expression and distribution in biceps muscle biopsies were analyzed by liquid chromatography–mass spectrometry and immunofluorescence, respectively. Functional endpoints included change from baseline in the North Star Ambulatory Assessment (NSAA) and other measures of motor and respiratory function.
Results: Nineteen ambulatory boys received fordadistrogene movaparvovec (n=3 low-dose; n=16 high-dose). Median age at gene therapy was 8.8 years (range: 6.2–13.0 years); median baseline NSAA total score was 27 (range 17–32); median follow-up: 18 months (range 13–38 months). Three treatment-related serious adverse events occurred (dehydration, acute kidney injury, thrombocytopenia); all resolved within 15 days. Median change from baseline to 1-year in NSAA total score was (+)1 point vs. (–)4 points for an external control cohort (placebo trial participants of similar age, weight, baseline function, and stable steroid use). Additional data on safety/tolerability, mini-dystrophin expression and distribution, and functional assessments will be presented.
Conclusion: Preliminary results indicate that fordadistrogene movaparvovec has an acceptable safety profile and potential to benefit ambulatory DMD patients by slowing or preventing loss of function.
Disclosure: This study (NCT03362502, C3391001) is sponsored by Pfizer.