TOKYO, September 1, 2021 - Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., “Astellas”) announced 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 (XLMTM).
This decision follows the reporting of a recent serious adverse event (SAE) in a study participant due to abnormal liver function tests (LFTs) observed in the weeks following dosing of the AT132 investigational gene therapy product at a lower dose (1.3x1014 vg/kg). 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, an Investigational New Drug (IND) clinical hold has not been issued. In the U.S., an IND clinical hold is an order issued by the U.S. Food and Drug Administration (FDA) to the sponsor of a clinical trial to delay a proposed clinical trial or suspend an ongoing clinical trial. If Astellas receives a clinical hold letter, it will review the content and determine next steps.
As reported in some XLMTM patients, the participant has a history of intermittent cholestasis. However, prior to dosing, this participant had a normal liver ultrasound; and the participant’s 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, M.D., 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.”
To date, 24 ASPIRO participants have received AT132: seven at the 1.3x1014 vg/kg dose and 17 at the 3.5x1014 vg/kg dose. Three participants previously treated at the 3.5x1014 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 1.3x1014 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.
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