A second patient with X-linked myotubular myopathy (XLMTM) has died after receiving a high dose of Audentes Therapeutics' investigational gene therapy product, AT132, as part of the ASPIRO clinical trial, the company said. XLMTM is a rare, inherited genetic neuromuscular disorder characterized by muscle weakness that is most typically severe but can range from mild to profound. The disorder is caused by mutations in the myotubularin (MTM1) gene. AT132 uses an adeno-associated virus serotype 8 (AAV8) vector to deliver a working copy of the gene. Preliminary findings indicate that the immediate cause of death was sepsis, the company said in a letter to the XLMTM patient community. Within the first 4 to 6 weeks after AT132 dosing, the patient had progressive liver dysfunction characterized by hyperbilirubinemia, which did not respond to standard treatment. Despite aggressive treatment, the patient's condition worsened, and he ultimately died of bacterial infection and sepsis. Last month, the company reported the first patient death in the trial, also from sepsis. Although investigations surrounding both deaths are ongoing, preliminary findings indicate that the clinical course was similar in the two patients who died, the company said. "Notable features" of the two patients who died and a third patient who suffered serious adverse events after AT132 dosing include older age, heavier weight, preexisting hepatobiliary disease, and receipt of the high dose of AT132. None of the six patients who received a low dose of AT132, including four with a previous history of hepatobiliary disease, have developed serious adverse events involving the liver, "despite being years out from treatment," the company said. Prior to the two patient deaths, Audentes, in consultation with the ASPIRO clinical trial data monitoring committee, halted further dosing of patients currently enrolled in the clinical trial. The trial is now on a clinical hold by the US Food and Drug Administration (FDA). Source
