Jun 29, 2020

NHF has learned of the recent death of a patient who had been participating in a gene therapy clinical trial for a rare muscle disorder known as X-Linked Myotubular Myopathy (XLMTM), which occurs almost exclusively in males and is characterized primarily by a progressive weakening of the muscles and a degradation of muscle tone. The trial participant had received a single intravenous dose of AT132, an investigational gene therapy candidate developed by Audentes Therapeutics, which specializes in adeno-associated virus (AAV) vector-based genetic therapies for people with serious rare neuromuscular diseases.

This represents the second death in as many months of a patient who had been dosed with AT132 as part of the ASPIRO trial, which is designed to evaluate safety and efficacy of the therapy in subjects with XLMTM who are less than five years old. For more information about the ASPIRO trial go to clinicaltrials.gov.

AT132 and other investigational therapies being developed by Audentes employ proprietary AAV8 vectors, which are a variation on the type of vectors that are being investigated in several ongoing gene therapy trials for other rare conditions, including several for hemophilia. It is for this reason and in the spirit of transparency that NHF is sharing this update with the bleeding disorders community. And while we caution against drawing conclusions on the future of bleeding disorders and gene therapy, we recognize the importance that all stakeholders have access to the information.

We have included an excerpt from a June 23rd letter from Audentes to the XLMTM Patient Community which provided more information on the two patients deaths:

  • Preliminary findings indicate that the immediate cause of death was sepsis. This patient had progressive liver dysfunction characterized by hyperbilirubinemia that occurred within the first 4-6 weeks following AT132 dosing, and which did not respond to standard treatment. This patient received aggressive medical treatment for his liver dysfunction, including hospitalization and close clinical observation. Unfortunately, his condition worsened, and he ultimately succumbed to bacterial infection and sepsis. Additional information surrounding the death is being collected at this time.
  • As was the case with the patient death we shared last month, this patient was also one of three older patients who received AT132 at the dose of 3x1014 vg/kg in whom we have recently observed new serious adverse events (SAEs) of hepatobiliary disease. Although the investigations around both deaths are ongoing, preliminary reports indicate that the clinical course was similar in the two patients who passed away.
  • Notable features among the three patients with these SAEs include older age, heavier weight, evidence of preexisting hepatobiliary disease, and dosing with the higher dose of 3x1014 vg/kg. It should be noted that among the six patients treated at 1x1014 vg/kg, including four with a previous history of hepatobiliary disease, none have developed liver SAEs, despite being years out from treatment.

For expert guidance and recommendations relevant to gene therapy trials for the hemophilia community please refer to the following documents created by NHF’s Medical and Scientific Advisory Council (MASAC):

MASAC Document Regarding Risks of Gene Therapy Trials for Hemophilia.

MASAC Recommendation for Liver Biopsies in Gene Therapy Trials for Hemophilia.

Questions or concerns relevant to specific hemophilia gene therapy trials should be directed to your physician and hemophilia treatment center care team.