At-Risk Genotypes for DMD Gene Therapy Identified


Trial sponsors Pfizer, Sarepta, Genethon, and Solid Biosciences organized a group of experts to investigate shared serious AEs.

A working group established by sponsors in the clinical stage of developing gene therapies for the potential treatment of Duchenne muscular dystrophy has elucidated at-risk genotypes for anti-transgene serious adverse events (SAEs) shared across programs.

The group’s findings were presented at the American Society of Gene & Cell Therapy (ASGCT) 25th Annual Meeting, May 16-19, 2022, in Washington, D.C., by Carsten Bonnemann, MD, senior investigator, Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke/National Institutes of Health. 

“This was a quite unique working group that came together around SAEs that happened in ongoing clinical trials in DMD. The 4 sponsors in the clinic for DMD, Genethon, Pfizer, Saretpa, and Solid came together with a working group around these SAEs to openly share data, analyze it, and come up with solutions... on a fast track,” Bonnemann said during his presentation.

Shared structures, not including promoters, are found in the adeno-associated virus (AAV) vector microdystrophin gene therapies being developing Sarepta/Roche (SRP-9001; NCT05096221), Genethon (GNT 0004), Solid Biosciences (SGT-001; NCT03368742), and Pfizer (PF-06939926; fordadistrogenemovaparvovec; NCT04281485). All trials have seen occurrences of anti-transgene SAEs and all trials, excluding Genethon’s, which is being conducted in France, have previously been placed on clinical hold by the FDA.

READ MORE: Improved Function Observed Following Mini-Dystrophin Gene Therapy in DMD

Anti-transgene SAEs were observed in 5 participants across studies from the ages of 7 to 9 that were dosed with 1e13 to 2e14 vg/kg. Symptom onset ranged from day 24 to day 42 after dosing. SAEs commonly included a significant increase in muscle weakness with distinct bulbar and distal involvement including change in speech, difficulty swallowing, and loss in ambulation.

Three patients experienced delayed cardiac involvement, with increases in troponin, decreases in ejection fraction, and MRI abnormalities. Although all participants eventually recovered, some required respiratory support and all received multiple treatments including increased immunomodulation, steroids, and plasmapheresis. Myositis were confirmed by biopsy and creatine kinase elevations.

“When you look at the genotypes of the patients affected by these AEs something immediately becomes apparent. All of these patients had genomic deletions in the N terminal part of the gene. You can see that all of these deletions overlap with the N terminal part of the transgene so peptides are provided in the transgene and corresponding peptides in the patient are not present, they’re deleted,” Bonnemann shared of the group’s findings.

These findings were further supported by ELISpot data that showed that positive signals were directed against peptides from the N-terminus through Hinge-1 in participants with anti-transgene SAEs and epitope mapping supported a concomitant humoral response.

Bonnemann and colleagues also identified other mutations in related areas that other patients exhibited without any cardiac or skeletal SAEs, although 1 patient with the at-risk genotype also did not experience these SAEs. The group hypothesized that the SAEs are likely T-cell mediated. Their findings are already influencing clinical trials that are starting to exclude these at-risk genotypes although more research has to be done to understand the immune response and its effect on gene therapy efficacy.

"This was an amazing model of collaborative interactions between academic and industry sponsors... we propose that this may be a model for other risk strategies that are class related, and independent of the individual sponsor or agent. Finally...anti-transgene events have to be reckoned with across gene therapies and we need better strategies to monitor, predict and manage [them],” Bonnemann concluded.

For more coverage of ASGCT 2022, click here.

Bonnemann C. Anti-transgene SAEs in trials of gene therapy for DMD: A collaborative first analysis. Presented at: ASGCT 25th Annual Meeting, May 16-19, Washington D.C.
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