In analysis of gene therapy deaths, Astellas points to underlying liver issues

Astellas has shared a detailed look at the four deaths in its AT132 gene therapy clinical trial. Writing in The Lancet Neurology, the drugmaker explained that the liver toxicity seen in the trial differs from cases linked to other therapies—and made the case that the drug can still provide transformative clinical benefits.  

The paper presents data collected in the ASPIRO trial through Feb. 28, 2022. By that time, the FDA had put the study of children with X-linked myotubular myopathy (XLMTM), a life-threatening condition that causes muscle weakness and respiratory distress, on clinical hold for a second time in response to a fourth death. The study remains on hold. 

Astellas shared details of the events leading up to the four deaths in the paper. All four patients had cholestatic liver failure at the time of death. Five of the 20 surviving dosed participants suffered serious treatment-related hepatobiliary adverse events.

Analyses of antibodies, cellular markers and other factors suggest the adverse events weren’t caused by immune responses, although Astellas lacks the data to draw firm conclusions. The four patients who died all received immunosuppressive regimens, but the drugs had no apparent benefits. Liver toxicities caused by other gene therapies have responded to immune-modulating therapies.

Assessments of the surviving participants revealed liver laboratory abnormalities before and after dosing with AT132. The abnormalities included features thought to be linked to intrahepatic cholestasis, a liver condition that causes the buildup of bile acids, and may have been implicated in the deaths. 

Going into the clinical trial, the potential link between XLMTM and cholestatic liver disease was “largely unrecognized,” according to the researchers. The paper cites multiple case series and reports that have described the link since Astellas and the FDA paused ASPIRO, plus details of Dynacure’s decision to stop a trial of an antisense nucleotide in a related myopathy in response to liver enzyme elevations.

Astellas is continuing to investigate how AT132 exacerbates liver conditions. Addressing the safety issues may unleash a therapy that showed some clinical promise in the trial. Astellas linked the therapy to improvements on respiratory parameters, including reductions in ventilator use, that the researchers see as evidence AT132 can provide “transformative clinical improvements.”

The investigations may benefit Astellas even if it fails to resurrect AT132. In June, the drugmaker struck a deal for exclusive rights to Kate Therapeutics’ preclinical XLMTM gene therapy KT430, which uses a novel MyoAAV capsid to deliver a functional copy of the MTM1 gene. AT132 uses an AAV8 vector to deliver the gene.