fordadistrogene movaparvovec (PF-06939926) / Pfizer - LARVOL DELTA

Cardiac safety of fordadistrogene movaparvovec gene therapy in Duchenne muscular dystrophy: Initial observations from a phase 1b trial. (PubMed, Mol Ther) - "One 16-year-old non-ambulatory DMD participant experienced fatal cardiogenic shock 6 days after high-dose of FM. With the exception of participants with DMD with advanced cardiac fibrosis, assessments of cTn-I, LVEF by cMRI, and progression of late gadolinium enhancement suggest low cardiac toxicity from FM in ambulatory DMD participants in this study."

Journal • P1 data • Cardiovascular • Duchenne Muscular Dystrophy • Fibrosis • Gene Therapies • Genetic Disorders • Immunology • Muscular Dystrophy • TNNI3

Complement Activation in a Phase Ib Study of Fordadistrogene Movaparvovec for Duchenne Muscular Dystrophy. (PubMed, Mol Ther) - P1 | "However, these early events should be considered related to the benefit-risk profile when using rAAV-based gene therapy for the treatment of DMD. ClinicalTrials.gov identifier: NCT03362502."

Journal • P1 data • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

AAV mini-dystrophin gene therapy for Duchenne muscular dystrophy: a phase 1b trial. (PubMed, Nat Med) - P1 | "Fordadistrogene movaparvovec (PF-06939926) is an adeno-associated virus serotype 9 gene therapy containing a miniaturized dystrophin being developed for DMD, which aims to restore functional protein to muscle...ClinicalTrials.gov registration no. NCT03362502 ."

Journal • P1 data • Acute Kidney Injury • Atypical Hemolytic Uremic Syndrome • Cardiovascular • Duchenne Muscular Dystrophy • Fatigue • Gene Therapies • Genetic Disorders • Hematological Disorders • Muscular Dystrophy • Nephrology • Pain • Pediatrics • Renal Disease • Thrombocytopenia

In vitro and clinical assessments of muscle specific promoters in driving gene expression and long-term cardiac efficacy in Duchenne muscular dystrophy (ASGCT 2025) - P1, P1/2 | "Three of these products include zildistrogene varoparvovec (SGT-001), an AAV9 vector containing a CK8 promoter, fordaditrogene movaparvovec (PF-06939926), an AAV9 vector containing an hCK promoter, and delandistrogene-moxeparvovec (SRP-9001, ElevidysÒ), an AAVrh74 vector containing a MHCK7 promoter. This two-part study illustrated the Desmin promoter was superior to the others in transfecting skeletal muscle and cardiac function was preserved over time in patients treated with gene therapy. Further studies are needed to test efficacy of each promoter in human cardiomyocytes and additional long term follow up is needed to understand the effects of DMD gene therapy are sustained in cardiac muscle."

Preclinical • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Recurrent Rhabdomyolysis and Fatality Following Administration of AAV Microdystrophin Gene Therapy (ASGCT 2025) - "A 4-year-old boy with dystrophinopathy died 14 months following systemic administration of fordadistrogene movaparvovec, an AAV microdystrophin gene therapy...The timing of the onset of clinical symptoms, consistent with the expression of the microdystrophin transgene and his subsequent clinical course presents several learnings and key questions regarding AAV gene therapy, including the implications of in frame deletion on patient selection, approaches to investigation and management of potential immune mediated adverse events and considerations of the risk versus benefit ratio for AAV gene therapy in individual patients. Disease Focus of Abstract:Muscular Dystrophy (all forms)"

Gene therapy • Cardiovascular • Duchenne Muscular Dystrophy • Gene Therapies • Immune Modulation • Immunology • Inflammation • Muscular Dystrophy • Musculoskeletal Pain • Myositis • Pain • MB

Stimulation with Self Peptides Led to Interleukin-17 Secretion by Peripheral Blood Mononuclear Cells from an AAV-Treated Patient with Duchenne Muscular Dystrophy and Unexplained Fatality (ASGCT 2025) - "A 4-year-old boy treated with fordadistrogene movaparvovec had recurrent cycles of severe muscle pain, myoglobinuria and acute critical hyperCKaemia until his unexplained fatality 14 months following gene therapy...The work described here was funded by Pfizer. Disease Focus of Abstract:Muscular Dystrophy (all forms)"

Clinical • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • Musculoskeletal Pain • Pain • IFNG • IL10 • IL17A • MB

AAV9 Neutralizing Antibody Seroconversion in Household Contacts Of Participants With Duchenne Muscular Dystrophy Receiving Fordadistrogene Movaparvovec (ASGCT 2025) - P, P2, P3 | "The results of this study indicate that the risk of developing NAbs and ADAs to AAV9 through contact appears to be low in a setting where household contacts have been advised to practice good hygiene. The study results should be interpreted with caution due to the small sample size of 8 household contacts. Specifically, the finding that 0% of household contacts displayed NAb seroconversion was based on results from only 3 individuals, since only 3 household contacts were negative for NAbs at baseline."

Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Hepatic-Restricted Microdystrophin Expression Induces Immune Tolerance and Enhances Transgene Expression in Dystrophin-Deficient Mdx Mice (ASGCT 2025) - "µDys9.2 differs from PF-06939926 and SRP-9001 by including the nNOS binding domain, and from SGT-001 by including R3 and excluding R23...Group 1 received the anti-CD20 regimen, followed by AAV-Des-µDys9.2 i.v. administration (1 × 10¹⁴ vg/kg) at eight weeks of age, along with continuous sirolimus dosing until week 12... Hepatic-restricted and nonhepatic µDys9.2 delivery, combined with IMS, enhances transgene expression and immune tolerance in mdx mice, improving efficacy and safety. Disease Focus of Abstract:Rare Diseases"

Preclinical • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Hepatology • Muscular Dystrophy • Rare Diseases • Respiratory Diseases • FOXP3 • IL2RA

A Study to Evaluate the Safety and Tolerability of PF-06939926 Gene Therapy in Duchenne Muscular Dystrophy (clinicaltrials.gov) - P1 | N=23 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: May 2025 ➔ Aug 2025

Trial completion date • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

A Study to Understand the Long-term Safety and Effects of an Experimental Gene Therapy for Duchenne Muscular Dystrophy. (clinicaltrials.gov) - P3 | N=6 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: May 2039 ➔ Aug 2025 | Trial primary completion date: May 2039 ➔ Aug 2025

Trial completion date • Trial primary completion date • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • TNNI3

Study of Fordadistrogene Movaparvovec in Early Stage Duchenne Muscular Dystrophy (clinicaltrials.gov) - P2 | N=10 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Jan 2029 ➔ Jun 2025

Trial completion date • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • TNNI3

Study of Fordadistrogene Movaparvovec in Early Stage Duchenne Muscular Dystrophy (clinicaltrials.gov) - P2 | N=10 | Active, not recruiting | Sponsor: Pfizer | Trial primary completion date: Dec 2024 ➔ May 2025

Trial primary completion date • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • TNNI3

A Study to Evaluate the Safety and Tolerability of PF-06939926 Gene Therapy in Duchenne Muscular Dystrophy (clinicaltrials.gov) - P1 | N=23 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Mar 2026 ➔ May 2025

Trial completion date • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • CRP

A Study to Understand the Long-term Safety and Effects of an Experimental Gene Therapy for Duchenne Muscular Dystrophy. (clinicaltrials.gov) - P3 | N=5 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | N=250 ➔ 5

Enrollment change • Enrollment closed • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • TNNI3

Study to Evaluate the Safety and Efficacy of PF-06939926 for the Treatment of Duchenne Muscular Dystrophy (clinicaltrials.gov) - P3 | N=122 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Apr 2029 ➔ Apr 2039

Trial completion date • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

What Are the Key Themes and Sentiments Captured Through Social Listening in Response to Recent Changes in the Duchenne Muscular Dystrophy Treatment Landscape? (ISPOR-EU 2024) - " Using a social media listening platform (Brandwatch), we assessed the difference in stakeholder sentiment before and after the fordadistrogene movaparvovec announcement (June 12 th 2024), and after the announcement of the delandistrogene moxeparvovec-rokl approval (June 20 th 2024). The variability in sentiment in the DMD population over a relatively short time period confirms the ability of social media listening to capture patient perspectives quickly. However, this variability in sentiment over a 10 day time-period also points to a need for methodological scrutiny to reduce bias in social media listening data collection."

Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

A Study to Evaluate the Safety and Tolerability of PF-06939926 Gene Therapy in Duchenne Muscular Dystrophy (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: Pfizer | Phase classification: P1b ➔ P1

Gene therapy • Phase classification • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • CRP

Two year muscle MRI observations from a phase 1b trial of fordadistrogene movaparvovec (PF‐06939926) for Duchenne muscular dystrophy (DMD) (ESGCT 2023) - P1b, P2 | "An external reference (ER) cohort was derived from DMD participants (n = 48) with ≥1 yr of randomized domagrozumab treatment (active→placebo, placebo→active, or active→active) from trial NCT02310763 and met eligibility criteria for this trial. Thigh MRI findings are further supported by evaluating upper limb MRI measure. After dosing with FM, quantitative muscle MRI measurements show favorable changes up to 2-yrs that correlate with functional outcomes."

P1 data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Study of Fordadistrogene Movaparvovec in Early Stage Duchenne Muscular Dystrophy (clinicaltrials.gov) - P2 | N=10 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Jun 2028 ➔ Jan 2029 | Trial primary completion date: Jul 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • TNNI3

Fordadistrogene movaparvovec for Duchenne muscular dystrophy: 3-year functional outcomes and changes in thigh and upper-limb muscle volume (MDA 2024) - "Prior to enrollment, 50% of participants were using daily deflazacort and 50% daily prednisone/prednisolone. At 3y, a clinically meaningful preservation of motor function was observed in participants with DMD aged 6 to <8y receiving FM vs an external control. Sustained increases in upper-limb muscle volume were observed. CFB in NSAA was moderately strongly correlated with %CFB in thigh muscle volume."

Late-breaking abstract • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

CIFFREO, a phase 3, randomized, double-blind, placebo-controlled study of fordadistrogene movaparvovec in Duchenne muscular dystrophy (DMD) (MDA 2024) - P3 | "CIFFREO aims to compare the safety and efficacy of FM with placebo in participants with DMD. ClinicalTrials.gov: NCT04281485"

Clinical • Late-breaking abstract • P3 data • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy • Pediatrics

DAYLIGHT, a phase 2 study of fordadistrogene movaparvovec in participants with early-stage Duchenne muscular dystrophy (MDA 2024) - P2 | "Exclusion criteria include any mutation affecting any exon between 9-13 inclusive, a deletion that affects exons 29 and 30, or a deletion affecting any exon between 56-71 inclusive, known contraindication to eculizumab, cardiac pathology eg myocarditis, prior gene therapy treatment, prior or current glucocorticoid treatment, and positive test for neutralizing antibodies to AAV9. DAYLIGHT aims to assess the safety and mini-dystrophin expression of FM in participants with DMD aged ≥2 to <4 years, prior to the development of significant muscle damage. As FM is designed to provide a functional form of dystrophin, it is hypothesized to have clinically meaningful benefits in participants with early DMD."

Late-breaking abstract • P2 data • Cardiovascular • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Inflammation • Muscular Dystrophy • TNNI3

Cardiac safety of fordadistrogene movaparvovec in Duchenne muscular dystrophy after 3 years follow-up from a phase 1b trial (MDA 2024) - "Natural history studies suggest LVEF declines in DMD patients at a rate of ~1.6% per year. Study participants who received a single infusion of fordadistrogene movaparvovec showed LVEF declines consistent with natural history. Appearance of new LGE signal is expected during typical DMD progression and our findings appear consistent with this natural course."

Clinical • P1 data • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy

Longitudinal changes of Anti-AAV9 and Anti-AAVrh74 antibodies in treated and untreated patients (MDA 2024) - "Subjects received SGT-001 (N=7), Zolgensma (N=7), PF-06939926 (N=2), AT132 (N=1), LYS-SAF302 (N=1), PGTC PD-AAV004 (N=2), all AAV9 products... 169 untreated subjects (115 male) with 1 plasma/serum sample for analysis were included. Median age was 13 (3-37). Of these, 92 (54%) were seropositive for Anti-AAV9 IgG at initial collection."

Clinical • CNS Disorders • Gene Therapies • Immunology

Disease progression modeling of NSAA total score in Duchenne Muscular Dystrophy and treatment effects of fordadistrogene movaparvovec (MDA 2024) - P=N/A, P1b, P2, P3 | "Median simulated CFB at 1 year was greater following FM administration compared with natural disease progression, and higher for younger (6 - < 8 years old) than older (≥ 8 years old) baseline ages. Conclusion The indirect response model described the data well, predicting slower disease progression following FM treatment particularly for younger participants."

Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy