The US Food and Drug Administration placed Audentes Therapeutics’ phase 2 gene therapy trial for a rare neuromuscular disease on hold following the deaths of two patients receiving the higher dose of the investigational treatment AT132. Both deaths were caused by progressive liver dysfunction followed by sepsis in patients who had pre-existing liver disease. The deaths add to emerging safety concerns surrounding the use of AAV vectors. The AT132 therapy treats X-linked myotubular myopathy, a life-threatening condition characterized by profound muscle weakness from birth. The disorder is caused by a mutation in the myotubularin 1 gene, the product of which is needed for normal skeletal muscle development. Audentes, acquired by Astellas Pharma for $3 billion, developed AT132 to deliver a working copy of the myotubularin-1 gene to patients using an adeno-associated virus-8 (AAV8) vector. Initial results were promising. Six patients who received a low dose (1× 1014 vector genomes (vg) per kilogram body weight), as well as one patient on the high dose (3× 1014 vg per kg), no longer needed ventilator support and could sit, stand or walk.

The high AT132 dose delivered in the phase 2 trial was the highest for any AAV-based gene therapy to date. None of the patients who received the lower doses had liver-related adverse events, despite underlying liver disease, suggesting that toxicity was related to the higher dose or the patients’ characteristics rather than to a systemic safety issue. In an editorial, gene therapy pioneer James Wilson and coauthor Terence R. Flotte noted that toxicity of AT132 mirrors that seen in a non-human primate model, in which AAV directly damaged liver cells. Toxicities have also emerged with other high-dose (at least 2× 1014 vg per kg) AAV gene therapies, such as AveXis’s Zolgensma (onasemnogene abeparvovec) for spinal muscular atrophy, as well as Solid Biosciences’ SGT-001 and Pfizer’s PF-06939926, both in trials for Duchenne muscular dystrophy. In those studies, adverse events were not related to altered liver function; toxicity in Duchenne muscular dystrophy trials largely resulted from an immune response to AAV.