Rare Daily Staff
Astellas Pharma said that it has voluntarily paused screening and dosing of additional participants in its ASPIRO clinical trial evaluating AT132 in patients with X-linked myotubular myopathy following the report of a recent serious adverse event in a study participant due to abnormal liver function tests observed in the weeks following dosing of the experimental gene therapy product at a lower dose.
X-linked myotubular myopathy (XLMTM) is a rare, serious, life-threatening 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. Currently, only supportive treatment options, such as ventilator use or a feeding tube, are available.
This is the second time the ASPIRO trial has been put on hold, placed by the U.S. Food and Drug Administration after a patient developed liver complications and died from organ failure, with two more patients dying after the trial was halted. The hold was lifted in December following agreement with FDA to lower the dosage.
The current serious adverse event (SAE) occurred in a patient who had received a lower dose of the experimental gene therapy. Astellas voluntarily halted screening and dosing, reported the SAE to regulatory agencies, and is engaged in dialogue with regulators about this SAE.
At this time, the FDA has not issued an Investigational New Drug (IND) clinical hold. If Astellas receives a clinical hold letter, it will review the content and determine next steps.
As reported in some XLMTM patients, the participant with the SAE has a history of intermittent cholestasis. However, prior to dosing, this participant had a normal liver ultrasound; and the participant’s liver function tests (LFTs), reflecting normal bilirubin levels, were within eligibility criteria. Astellas will continue to closely monitor the participant’s status.
“We will continue to work with the site investigator and site hepatologist to closely monitor this participant,” said Nathan Bachtell, senior vice president and head of Gene Therapy, Medical & Development at Astellas. “As we learn more about the case, we will incorporate any new observations into our ongoing investigation in order to have a well-informed discussion with the independent Data Monitoring Committee, our Liver Advisory Panel, and study investigators. Given previous hepatic events within the program, any one SAE needs to be viewed both individually and in the context of the broader program as we move forward. We remain committed to the development of AT132 and the XLMTM patient community. We will provide additional information about our investigation at the appropriate time.”
AT132 is an AAV8 vector containing a functional copy of the MTM1 gene, for the treatment of XLMTM with potential to provide patients with significantly improved outcomes based on the ability of AAV8 to target skeletal muscle and increase myotubularin expression in targeted tissues following a single intravenous administration.
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.
To date, 24 ASPIRO participants have received AT132: seven at the 1.3×1014 vg/kg dose and 17 at the 3.5×1014 vg/kg dose. Three participants previously treated at the 3.5×1014 vg/kg dose developed progressive cholestatic hepatitis and subsequent decompensated liver failure. These three participants thereafter died of either sepsis (2 participants) or a gastrointestinal bleed (1 participant), all of which were a consequence of liver failure.
In December of 2020 the clinical hold was lifted after the FDA reviewed the modifications to the ASPIRO trial protocol, which included a reduction of dosing to the 1.3×1014 vg/kg dose level. The participant associated with this current SAE was dosed in the summer of 2021, after the original clinical hold was lifted. The initial elevation of hepatic lab values was noted within the first month of dosing. Despite the voluntary pause in screening and dosing, the Astellas Medical Monitor and ASPIRO investigators will continue to monitor all study participants for all safety outcomes.
AT132 has been granted Regenerative Medicine and Advanced Therapy, Rare Pediatric Disease, Fast Track, and Orphan Drug designations by the FDA, and Priority Medicines and Orphan Drug designations by the European Medicines Agency.