Astellas Publishes Preliminary Results of Gene Therapy Trial Where Four Children Died

Rare Daily Staff

Astellas Pharma said The Lancet Neurology reported preliminary data analysis from the ASPIRO trial of its experimental gene therapy for the rare neuromuscular disease X-linked myotubular myopathy, a study in which four children died.

The AT132 IND and ASPIRO trial are currently on clinical hold.

XLMTM is a serious, life-threatening, rare neuromuscular disease that is characterized by extreme muscle weakness, respiratory failure, and early death. Mortality rates are estimated to be 50 percent in the first 18 months of life. For those patients who survive past infancy, there is an estimated additional 25 percent mortality by the age of 10. XLMTM is caused by mutations in the MTM1 gene that lead to a lack or dysfunction of myotubularin, a protein that is needed for normal development, maturation, and function of skeletal muscle cells. The disease affects approximately 1 in 40,000 to 50,000 newborn males.

XLMTM places a substantial burden of care on patients, families and the healthcare system, including high rates of healthcare utilization, hospitalization and surgical intervention. More than 80 percent of XLMTM patients require ventilator support, and the majority of patients require a gastrostomy tube for nutritional support. In most patients, normal developmental motor milestones are delayed or never achieved. Currently, only supportive treatment options, such as ventilator use or a feeding tube, are available.

Astellas is developing AT132, an AAV8 vector containing a functional copy of the MTM1 gene, for the treatment of XLMTM. AT132 may provide patients with improved outcomes based on the ability of AAV8 to target skeletal muscle and increase myotubularin expression in targeted tissues following a single intravenous administration. The preclinical development of AT132 was conducted in collaboration with Genethon.

The U.S. Food and Drug Administration granted AT132 Regenerative Medicine and Advanced Therapy (RMAT), Rare Pediatric Disease, Fast Track, and Orphan Drug designations. The European Medicines Agency granted AT 132 Priority Medicines (PRIME) and Orphan Drug designations.

ASPIRO is a two-part, multinational, randomized, open-label ascending dose trial to evaluate the safety and preliminary efficacy of AT132 in XLMTM patients less than five years of age. Primary endpoints include safety (adverse events and certain laboratory measures) and efficacy (assessments of neuromuscular and respiratory function). Secondary endpoints include the burden of disease and health-related quality-of-life, and muscle tissue histology and biomarkers.

The manuscript reports data as of February 28, 2022. At the time of this data cut, the study included 24 boys with XLMTM dosed with AT132. An exploratory analysis was conducted of two dosing cohorts who received a single infusion of AT132, compared with a control group comprised of two subjects who were enrolled but not dosed and 12 children from a natural history study.

At baseline, all participants were ventilator dependent, three were able to sit independently for 30 seconds, and none had achieved more advanced milestones. By 24 weeks post-dosing, the lower-dose cohort demonstrated an estimated 77.7 percent greater reduction in mean hours of ventilator support from baseline compared with controls. The higher-dose cohort demonstrated an estimated 22.8 percent greater reduction from baseline compared with controls. Of the 24 boys dosed in the study, 16 participants, including six at the lower-dose and 10 at the higher-dose, achieved ventilator independence as of the data cut. Five participants at the lower-dose and three participants in the higher-dose cohort were able to walk independently; several other major motor milestones were achieved after gene therapy.

There were three deaths in the higher-dose cohort (18 percent), followed by one death in the lower-dose cohort (14 percent). All four participants had ongoing hepatic and hepatobiliary serious adverse events (SAEs), which had progressed to cholestatic liver failure at the time of death. Treatment-emergent SAEs were observed in two of the seven participants at the lower-dose, and nine of 17 at the higher-dose. Five of the 20 surviving dosed participants had hepatobiliary SAEs.

Of the 14 participants in the non-treated cohort (two in the control group and 12 from a natural history study), none achieved ventilator independence while five were able to sit unassisted for 30 seconds by the end of the 48-week period. No other motor milestones were achieved.

“There is a real need for treatments for these patients. These preliminary data document for the first time that there is potential for gene therapy to provide clinical improvements in patients with XLMTM, including improvement in ventilator dependence and achievement of major motor milestones,” said Perry Shieh, professor of Neurology and Pediatrics at the University of California Los Angeles, and principal investigator for ASPIRO. “Additionally, important issues related to liver health in participants with XLMTM receiving gene therapy have been identified and will continue to require careful evaluation.”

Photo: Perry Shieh, professor of Neurology and Pediatrics at the University of California Los Angeles, and principal investigator for ASPIRO