A joint World Federation of Hemophilia (WFH) and National Hemophilia Foundation (NHF) statement* is issued on two deaths reported in orphan disease gene therapy clinical trial (*on behalf of the WFH Coagulation Product Safety, Supply, and Access Committee):
We have become aware of two patient deaths in an AAV8 gene therapy Phase 1/2 clinical trial in X-linked myotubular myopathy (XLMTM). This is a devastating disease with survival frequently not beyond early childhood. Children born with XLMTM are missing a protein important for muscle function, and often need ventilator assistance shortly after birth. The gene and protein have been identified, thus the prospect of using gene therapy to replace the defective gene is being pursued by biopharma and academics. A dose escalation trial to establish safety and efficacy of an intravenous AAV8 gene therapy conducted by Audentes Therapeutics, a subsidiary of Astellas, found that at the highest dose level, 3E14 vector genomes/kg (3脳1014 or 300 trillion vectors per kilogram), three participants developed severe hepatobiliary disease, which is liver and bile duct damage. In two participants, multiple complications led to death. Individuals with XLMTM have a range of medical complications due to multi-organ system damage beyond the muscles, which may also have contributed to their deaths. Patients treated at 1/3 the dose, 1E14 vector genomes/kg (1脳1013 or 100 trillion vectors per kilogram), were reported as doing well. Our thoughts are with the families of the young boys who died.
The dose of vector, 3E14 vector genomes/kg (3脳1014 or 300 trillion vector genomes/kg), is among the highest used in AAV clinical trials. Some groups, largely those targeting muscle, are delivering intravenous doses in this range, including an approved product for spinal muscular atrophy (Zolgensma). Some evidence of toxicities from other AAV vectors has been seen at these dose levels in other clinical trials and preclinical non-human primate studies. For comparison, natural infections with any viruses may expose us initially to hundreds or thousands of viral particles. Vaccines often deliver 1E6 (1脳106), or 1 million inactivated or killed viruses in order to make antibody responses. Since most AAV traffics to the liver when delivered intravenously, regardless of where its intended target organ is, the liver must manage a large viral load, which can cause toxicity to the organ, especially if the liver is damaged beforehand. Individuals with XLMTM have a number of multi-organ system problems that may have contributed to the deaths, but Audentes did not specify such conditions in the deceased patients.
XLMTM is a rare (1 in 50,000 males) serious, life threatening, neuromuscular disease that impairs muscle development. Due to severe breathing problems individuals usually survive only into early childhood. To be included in the study, patients were required to need mechanical ventilatory support. Patients with significant underlying liver disease were excluded from the XLMTM study. (NCT03199469, www.clinicaltrials.gov). Unlike hemophilia, where clinical trial participants are age 18 or older, all of the participants in the Phase 1/2 XLMTM study were 5 years of age or younger.
In hemophilia studies, where participants in clinical trials are screened for good liver function, the highest AAV vector dose used in clinical studies is 6E13 vector genomes/kg (6脳1013 or 60 trillion vector genomes/kg), or about 20% of the dose administered in the Audentes trial.聽Other clinical trials in hemophilia use AAV doses approximately 1-3% of those used in the Audentes trial.
Thus, the vector doses used in hemophilia are significantly lower than those used in this trial. It is important to emphasize that the assays used to measure the vector are not standardized between laboratories, therefore the dose in the Audentes trial implicated in the deaths should be considered approximate. In addition, empty viral capsids in the material were not stated and may contribute to the total AAV8 burden delivered to the patients.
In each disease-specific gene therapy, the patient population, and individual patients need to assess the benefit/risk of undergoing the therapy. XLMTM, in which significant illness and death develop at a very young age, is different from other diseases such as hemophilia, where multiple therapeutics are available to effectively manage the disease.
Please see the letter sent from Audentes to a X-linked myotubular myopathy patient organization. We do not have a complete story, and the company has not made a clarifying statement other than the attached letter to the XLMTM organizations. We will update this as more information becomes available and hope the company will provide more information soon.
To read the Audentes letter please click here.
To read the EHC-EAHAD Joint statement on AAV8-based ASPIRO clinical trial click here.