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The U.S. Food and Drug Administration (FDA) has lifted a clinical hold on Audentes Therapeutics’ ASPIRO trial studying the AT132 as a potential treatment for X-linked myotubular myopathy (XLMTM), a rare neuromuscular disease. The agency placed the hold on the Astellas company’s trial after two patients died in the trial.
“We are grateful for the efforts of our team and investigators who have worked tirelessly to answer the FDA’s questions and we now look forward to resuming this study,” according to a statement made by Natalie Holles, the President and Chief Executive Officer of Audentes Therapeutics. “We want to again extend our deepest sympathies to patients’ families impacted by the events earlier this year. We are deeply committed to the continued safe development of AT132 for the families and patients living with XLMTM, a disease with no existing treatments.”
XLMTM, a life-threatening neuromuscular disease, includes hallmark symptoms such as muscle weakness, respiratory failure and early death. The associated rate of mortality is approximately 50% in the first 18 months of life, and this increases to an additional 25% by the age of 10 years in those who survive past infancy. The genetic disease is caused by a MTM1 gene mutation. Approximately 1 in 40,000 to 50,000 newborn males are diagnosed with the disease.
In addition, the majority of patients with XLMTM need ventilator support, and most patients also require for nutritional support via a gastrostomy tube. There is currently a significant unmet need for effective XLMTM treatments that not only reduce the burden of the disease’s symptoms, but that also prolong life. Audentes Therapeutics hopes AT132, an AAV8 vector consisting of a functional copy of the MTM1 gene, may be the answer to this unmet treatment need.
In May, Audentes Therapeutics said that a patient in the ASPIRO trial who received a high dose of AT132 died from sepsis. Additionally, another two patients who received high doses of the experimental drug also had serious side effects during treatment, and one of these two patients later experienced progressive liver dysfunction. The patient who had liver dysfunction later died because of a bacterial infection, in addition to sepsis. In August, the company said another death was caused by gastrointestinal bleeding.
But despite these deaths, the FDA says the study can continue following a comprehensive review of the events. The ASPIRO trial, a two-part, open-label ascending dose study, is currently examining the safety and preliminary efficacy of AT132 in children with XLMTM younger than five years old. The study, which builds on previous studies supporting the drug’s safety, includes adverse events and certain laboratory measures and assessments of neuromuscular and respiratory function as primary endpoints. Additional secondary endpoints include disease burden and health-related quality-of-life as well as muscle tissue histology and biomarkers.
Audentes Therapeutics says it is currently “working to complete all clinical and regulatory activities necessary to resume dosing” and also “plans to have discussions at a future date with the regulators on the path forward toward global registration filings for AT132.”
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XLMTM是一种危及生命的神经肌肉疾病，包括肌肉无力，呼吸衰竭和早死等标志性症状。在出生后的头18个月内，相关的死亡率约为50%，而在婴儿期后存活的人中，这一比率在10岁时增加到额外的25%。这种遗传病是由MTM1基因突变引起的。大约每40 000至50 000名新生儿中就有1人被诊断患有此病。