MODERATE IMPACT – The FDA placed a clinical hold on the FORTIS phase 1/2 trial of AT845 following a case of peripheral sensory neuropathy in one trial participant.
- FORTIS is evaluating AT845, an investigational AAV8-based gene replacement therapy in adults with late-onset Pompe disease
- To date, the serious adverse event (SAE) has been classified by the site investigator as Grade 1 (mild in severity) and deemed serious due to medical significance
- The FDA informed Astellas that it did not have sufficient information to assess the risks to subjects and requires additional information about the SAE
- A written explanation for the basis of the hold will be issued by the FDA and sent to Astellas within the next 30 days
Although Astellas’ AAV8 platform is currently the only clinical stage AAV-based gene therapy with the potential to deliver functional GAA in muscle (including skeletal and cardiac muscle), Astellas has had several recent setbacks that cast doubt on its ability to carry AT845 to the finish line. Earlier this year, Astellas terminated development for 3 gene therapy candidates for Duchenne muscular dystrophy. Last year, the FDA placed a clinical hold on Astellas’ trial for AT132 gene therapy for X-linked myotubular myopathy based on liver toxicity and patient deaths. Although AT845 uses the same vector platform as AT132, there has been no reports of significant liver toxicity with AT845. However, at WORLD Symposium 2022, 1 out of 3 treated patients had elevated transaminases. Also, liver toxicity in the AT132 trial was based on higher doses (≥1.3×1014 vg/kg) than what’s been tested in the FORTIS AT845 trial to-date (≤6.0×1013 vg/kg; a 1 x1014 vg/kg dose is planned). Thus, even if the clinical hold is lifted on FORTIS, safety concerns may remain.