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F - Immunological Aspects of Gene Therapy and Vaccines -> Immunological Aspects of Gene Therapy and Vaccines (Includes host responses, therapy/prevention of infectious diseases; excludes cancer immunotherapy and cancer vaccines)

A Collaborative Analysis by Clinical Trial Sponsors and Academic Experts of Anti-transgene SAEs in Studies of Gene Therapy for DMD

Type: Oral Abstract Session

Presentation Details
Session Title: Late-Breaking Abstracts I
Location: Salon H
Start Time: 5/17/2022 9:15
End Time: 5/17/2022 9:30

Currently four sponsors have ongoing clinical trials to evaluate the safety and/or efficacy of investigational gene therapies for the treatment of Duchenne muscular dystrophy (DMD). All approaches use an adeno-associated virus, albeit of different serotypes, to deliver various versions of a shortened dystrophin transgene driven by different promotors. Recently, serious adverse events (SAEs) characterized by muscle weakness with variable cardiac involvement occurred in five patients, across three trials, with a strikingly similar clinical presentation and time course. Following the events, all four sponsors chose to collaborate and share relevant clinical and laboratory data and further convened an international panel of experts to analyze the SAEs, minimize their recurrence, and assess potential therapeutic and preventative strategies.
The SAEs observed exhibited generally consistent clinical presentations including extremity and bulbar muscle weakness, occurring approximately 3-7 weeks following investigational gene therapy infusion. Other findings were noted in some individual patients including severe respiratory muscle compromise and increased cardiac troponin-I levels. Following various immunosuppressive and supportive therapies, muscle strength improved, and cardiac enzyme levels normalized over 6-8 weeks after onset.
Given that similar events were observed across multiple investigational gene therapy products with different capsids, promoters, and transgene sequences, they are most likely to be a specific transgene/genotype-related ‘class effect.’ The hypothetical mechanism is thought to involve a T-cell mediated immune response to the expressed transgene protein in a cross-reactive immunological material (CRIM)-negative setting, determined by the patient’s genotype. Supportive evidence includes: 1) SAEs only occurred in patients with genomic deletions including N-terminal epitopes which are present in the transgene protein, 2) when positive ELISpot (T-cell) tests were recorded in patients with SAEs, they were reactive specifically to the corresponding N-terminal peptide pool, and 3) preliminary epitope mapping of anti-dystrophin antibodies from one patient suggests a prominent signal at the transgene Hinge1 segment within the N-terminus of dystrophin.
The unique and timely formation of an open, collaborative working group including four sponsors of the ongoing studies and multiple academic experts was instrumental in being able to quickly identify an anti-transgene mechanism and the associated risk factors for observed SAEs. A plan for further investigation is underway to comprehensively define the immune mechanism and associated risk factors. This collaborative approach and its conclusions may have implications to mitigate risks in gene therapy development programs beyond DMD.

Carsten G. Bonnemann1, Beth A. Belluscio2, Serge Braun3, Carl Morris4, Teji Singh5, Francesco Muntoni6

1Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, NIH, Bethesda, MD,2Pfizer, New York, NY,3Genethon, Evry-Courcouronnes, France,4Solid Biosciences, Cambridge, MA,5Sarepta Therapeutics, Cambridge, MA,6Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
 C.G. Bonnemann: None.

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