MTM1

The preliminary results are from the ASPIRO open label trial conducted by Astellas Pharma with a gene therapy designed and developed preclinically by Genethon After gene therapy treatment, 16 of the 24 children can breathe without assistance, 20 can sit up, 12 can stand and 8 can walk without support (see video of one patient’s progress - ) The trial has been paused to investigate severe side effects which caused the death of four children PARIS--(BUSINESS WIRE)-- Genethon, a unique non-profit gene therapy R&D organization founded by the French Muscular Dystrophy Association (AFM-Telethon), today announced The Lancet Neurology published online preliminary results of a clinical trial conducted by Astellas Pharma using a gene therapy developed by Genethon for X-linked myotubular myopathy, a rare genetic muscle disease affecting 1 in 50,000 newborn boys. Myotubular myopathy is caused by mutations in the MTM1 gene encoding myotubularin, a protein involved in muscle cell function. Characterized by extreme muscle weakness and severe respiratory distress, 50% of affected children die before age 18 months and 75% die before age 10. The gene therapy uses an adeno-associated viral vector (AAV8) to deliver a copy of the MTM1 gene. Of 24 children enrolled in the ASPIRO trial, conducted in France, Germany, Canada and the U.S., 16 of them can now breathe without assistance, 12 stand up on their own, and 8 can walk. The trial has been paused for an investigation into the origins of the complications responsible for the deaths of 4 children, who showed signs of pre-exiting hepatobiliary pathology. “These clinical results show both how spectacularly effective gene therapy can be, and the challenges that remain, particularly in terms of side effects in certain contexts,” said Frederic Revah, Genethon CEO. “While our teams are already committed to understanding and anticipating these issues, the knowledge gained from this clinical trial, which highlights certain limitations and particular hepatic susceptibilities, is rich in lessons for the entire scientific community.” Ana Buj-Bello, Director of Research at Inserm and head of Genethon’s Neuromuscular Diseases and Gene Therapy team, designed the gene therapy. She is one of the authors on The Lancet Neurology article and co-authored the preclinical work that led to the ASPIRO trial. Dr. Buj-Bello remarked, “I've devoted my entire career working on myotubular myopathy. It took years of research to imagine, design and demonstrate the efficacy of the gene therapy for this very severe and complex disease. Even though we absolutely must understand the reasons for the adverse effects observed in this clinical trial, it is exceptional to see children who were known to be doomed make incredible progress thanks to this drug candidate.” See the video of one patient’s progress in France. This patient was treated at I-Motion, the Institute of Myology’s French pediatric clinical trials center: Genethon entered an agreement with Audentes Therapeutics in 2014 for the preclinical development of the gene therapy. Astellas acquired the gene therapy in 2019 with the company’s acquisition of Audentes. About Genethon As a pioneer in the discovery and development of gene therapies for rare diseases, Généthon is a non-profit laboratory that was established by AFM-Telethon. A first gene therapy for spinal muscular atrophy to which Généthon contributed has obtained a product license. With more than 200 scientists and professional staff, Genethon is pursuing its aim to develop therapies which change the lives of patients suffering from rare genetic diseases. Thirteen products developed by Genethon are in clinical trial for diseases of the liver, blood, immune system, muscles and eyes. Seven other products could enter clinical trials over the next five years. More information at .

Astellas is continuing to investigate how AT132 exacerbates liver conditions. 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.

A preliminary data analysis published in The Lancet Neurology throws light on four deaths that occurred in a Phase I/II study of children with X-linked myotubular myopathy (XLMTM) who received Astellas' experimental MTM1 gene replacement therapy AT132 (resamirigene bilparvovec). The ASPIRO trial, which has been on FDA clinical hold since 2020 following the first two reported deaths, also revealed a potential risk factor that could inform future trials of patients with the rare neuromuscular disease.Astellas acquired the gene therapy through its purchase of Audentes Therapeutics for around $3 billion in 2020. "We are grateful for the opportunity to share this important analysis," stated Richard Wilson, senior vice president and primary focus lead for genetic regulation at Astellas. "While we continue our efforts to address the ongoing clinical hold for ASPIRO, this publication serves to provide information that may guide efforts aimed at advancing promising therapies for XLMTM," he said.The analysis focuses on data as of February 2022 from 24 boys with XLMTM who received a single infusion of AT132 at one of two doses – 1.3 x 1014 vg/kg or 3.5 x 1014 vg/kg – compared with a control group comprised of two subjects who were enrolled, but not dosed, and 12 children from a natural history study. All participants were ventilator-dependent at baseline, and only three were able to sit independently for 30 seconds, although none had achieved more advanced milestones.'Substantial' motor function benefitBy 24 weeks post-dosing, the lower-dose cohort demonstrated an estimated 77.7% greater reduction in mean hours of ventilator support, while in the higher-dose group, the rate was 22.8%. In addition, 16 participants, including six at the lower-dose and 10 at the higher-dose, achieved ventilator-independence as of the data cut, with researchers noting this was an "unexpected outcome." There were also "substantial improvements" in motor function, including acquiring the ability to sit, stand and walk independently, "an exceedingly rare occurrence in this population," investigators added. Five participants at the lower-dose and three in the higher-dose cohort were able to walk independently.By contrast, among the 14 total participants in the non-treated cohort, none achieved ventilator-independence while five were able to sit unassisted for 30 seconds by the end of 48 weeks. No other motor milestones were achieved in this group.Key issues with liver healthHowever, researchers wrote that "the unprecedented findings of ventilator-independence and acquisition of motor milestones in ASPIRO should be carefully weighed against the potential for fatal adverse events in the context of a life-threatening disease." Three deaths occurred in the higher-dose cohort, followed by one death in the lower-dose cohort. Beginning within the first four weeks after dosing, all participants saw increases above the upper limit of normal range (>ULN) in direct and total bilirubin values, with similar increases in ALT, AST and γ-glutamyl transferase. Further, they experienced progression to severe treatment-related decompensated liver injury, characterised by ascites, poor hepatic synthetic function, or both. All had progressed to cholestatic liver failure at the time of death. Researchers noted that the four patients had evidence of cholestasis that pre-dated dosing with AT132, but they still met dosing eligibility criteria for the study."The deaths of four dosed participants with evidence of pre-existing cholestasis highlights the need to better understand the role of hepatobiliary disease in the natural history of XLMTM and the potential interaction of AAV-mediated gene therapy in this setting," the study authors wrote.