Following a voluntary pause, a patient experiencing a liver AE has died and the trial is now on clinical hold.
This article was updated on September 15th, 2021 to reflect new information on trial participant status.
Astellas Pharma has announced that the patient experiencing the previously reported liver-related serious adverse event has died.1 Last week, the company said that they are pausing screening and dosing of new participants in their phase 1/2/3 ASPIRO trial (NCT03199469) of AT132 in patients with X-linked myotubular myopathy (XLMTM) following the liver-related serious adverse event (AE).2 In light of the patient death, the FDA has now placed another clinical hold on the trial.1
The participant that experienced the serious AE had abnormal liver function tests (LFTs) in the weeks following their treatment with a 1.3 x 1014 vg/kg dose of the investigational gene therapy, which is the lower of 2 doses being evaluated for safety and efficacy. The participant had a history of intermittent cholestasis but normal liver ultrasounds and normal bilirubin levels within eligibility criteria as seen on LFTs prior to dosing.
"We will continue to work with the site investigator and site hepatologist to closely monitor this participant," said Nathan Bachtell, MD, senior vice president and head, gene therapy, medical & development, Astellas, in a statement.2 "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.
ASPIRO, a phase 1/2, 2-part, multinational, randomized, open-label ascending dose trial, is evaluating the safety and efficacy of AT132 in patients with XLMTM under 5 years of age. It will assess primary end points such as efficacy through assessments of neuromuscular and respiratory function and safety through adverse events and laboratory measures. It will also assess burden of disease, health-related quality-of-life, muscle tissue histology, and biomarkers as secondary end points.
“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,” Bachtell added.2
While the FDA has not issued a clinical hold to the trial, Astellas has voluntarily enacted the pause and is in discussion with the FDA about the serious AE. ASPIRO has so far dosed 24 participants: 7 at the lower 1.3 x 1014 vg/kg dose and 17 at the higher 3.5 x 1014 vg/kg dose. This AE comes after the trial was halted in June 2020 following the deaths of 2 patients treated with the higher dose that developed progressive cholestatic hepatitis and subsequent decompensated liver failure.3 Following those 2 deaths, ultimately due to sepsis, a third patient died in September 2020 due to gastrointestinal bleeding while the trial was on hold.4
The FDA lifted the clinical hold in December 2020 after the ASPIRO trial protocol was modified to reduce all dosing to the lower 1.3 x 1014 vg/kg level.5
“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,” said Natalie Holles, former president and chief executive officer of Audentes, the former name of Astellas Gene Therapy, in a statement at that time.5 “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.”
The participant that developed the AE received the lower dose in the summer of 2021 after the hold was lifted. Hepatic lab value elevations were noted early on, in the first month of dosing. Astellas stated that their Medical Monitor committee and ASPIRO investigators will continue to closely monitor participants’ safety.