Astellas Discloses Death of Fourth Boy Enrolled in its Gene Therapy Trial

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Adeno-associated virus, illustration

Less than a year after halting its Phase I/II clinical trial of its adeno-associated virus (AAV) gene therapy candidate AT132 in patients with X-linked Myotubular Myopathy (XLMTM), Astellas Gene Therapies (formerly Audentes Therapeutics) acknowledged that a fourth boy has died during the trial.

Unlike the other three boys who all died last year in the Phase I/II ASPIRO trial (NCT03199469), the fourth—whose age has not been disclosed—received the lower dose of 1.3×1014 vg/kg.

The boy’s cause of death “is still pending,” Astellas said.

The three previous patients who died were treated with the trial’s higher dose of 3.5×1014 vg/kg before they started to demonstrate signs of liver dysfunction within 3 to 4 weeks after dosing. They developed progressive cholestatic hepatitis and subsequent decompensated liver failure. Two of the three later died of sepsis, while the third succumbed to a gastrointestinal bleed, all of which resulted from the liver failure.

In a presentation to investors last year, Audentes said that all three patients who died showed notable features that included older age, heavier weight, and evidence of pre-existing hepatobiliary disease.

Last year’s three deaths led the FDA to impose a clinical hold on the trial. The agency lifted that hold in December 2020, when Astellas eliminated the high dose, and agreed to dose patients at the lower dose.

“Still a very high dose”

“Although the dose was lowered from 3.5×1014 vg/kg, it still wasn’t a low dose. This new dose of 1.3e14vg/kg is still a very high dose, particularly for intravenous infusion, so the serious adverse events (SAEs) will still be the same as we’ve seen previously with ‘high-dose IV-administered’ AAVs,” Nicole Paulk, PhD, assistant professor, University of California, San Francisco (UCSF), told GEN.

Last year Paulk raised the questions of how safety vectors can be used at high doses, and whether they were necessary, in a commentary published last year in GEN.

“Although there is no magic cutoff, 1e14vg/kg does seem to roughly be where I’d put the bar for ‘high dose’ given the correlations between higher grade SAEs and AAVs IV-administered above that dose,” said Paulk, who is also an editorial board member of Human Gene Therapy, a journal published by GEN publisher Mary Ann Liebert Inc., Publishers.

The fourth boy was the first and only patient who received the lower dose after the FDA lifted its initial clinical hold last year. According to Astellas, he was dosed over the summer and showed abnormal liver function tests (LFTs) within weeks after dosing with AT132. An initial elevation of hepatic lab values was observed within the first month of dosing, Astellas said September 1.

“Prior to dosing, this participant had a normal liver ultrasound; and the participant’s LFTs, reflecting normal bilirubin levels, were within eligibility criteria,” Astellas stated at the time.

Following the abnormal LFTs, Astellas said it voluntarily paused screening and dosing of additional participants in ASPIRO, reported the SAE to regulatory agencies, and began engaging in dialogue with regulators about the event.

Astellas acknowledged Tuesday that it received an email from the FDA placing ASPIRO on a new clinical hold, with a written letter expected to be delivered to the company over the next several weeks.

The ASPIRO trial is designed to be a 26-patient multinational, open-label, ascending-dose, delayed-treatment concurrent control clinical study to evaluate the safety and efficacy of AT132 in subjects with XLMTM aged less than five years old.

Including the fourth boy, 24 ASPIRO patients have received AT132: 7 at the 1 × 1014 vg/kg dose and 17 at the 3 × 1014 vg/kg dose.

“Deepest sympathies”

“On behalf of Astellas, we extend our deepest sympathies to the participant’s family,” Nathan Bachtell, MD, senior vice president and head of gene therapy, medical, & development at Astellas, said in a statement. “We will investigate and review all findings with our independent data monitoring committee, our expert liver advisory panel, and the ASPIRO site investigators. We remain committed to the development of AT132 and the XLMTM patient community.”

The fourth boy who died was one of six patients that Astellas had planned to include at the lower dose after the resumption of dosing in July, the company disclosed to investors in its July 30 presentation of quarterly results for the first quarter of its 2021 fiscal year, ending June 30. The company initially planned for three patients at the lower dose, but doubled that to six.

AT132, which now carries the generic name resamirigene bilparvovec, is designed to deliver a functional copy of the MTM1 gene via an AAV serotype 8 vector, in order to transfect and express myotubularin in skeletal muscle cells. It was the lead gene therapy pipeline candidate of Audentes when it was acquired by Astellas for $3 billion, in a deal completed in January 2020.

Designated by Astellas as one of its “strategic” pipeline candidates. AT132 has received the FDA’s Rare Pediatric Disease, Fast Track, and Orphan Drug designations—as well as the PRIME and Orphan Drug designations of the European Medicines Agency.

“Learn from these tragedies”

Gene therapy pioneer James M. Wilson, MD, PhD, director of the gene therapy program at the University of Pennsylvania’s Perelman School of Medicine, noted in a GEN commentary published last year that patients with XLMTM and many other rare genetic diseases have no treatments, making it urgent for researchers to learn and apply lessons from the deaths of the AT132 patients.

“It is imperative that the scientific community work together with full transparency and cooperation to learn from these tragedies to assure that we can deliver safe and effective treatments to individuals living with rare genetic diseases such as MTM,” Wilson wrote.

In a tweet she posted Tuesday, Paulk called on Astellas to release vector lot information and clinical trial data “for the field to review.”

“As a field, we’re actively grappling with the influence of empty capsids in vector preparations. If we knew what the empty-to-full ratio was for these lots, then we could ascertain whether empties might be a contributing factor,” Paulk explained to GEN. “For example, if the lot was 99% full capsids then empties almost certainly didn’t play a role, but if the lot was only 50% full then now we have probable cause to study this further.”

“It’s still unclear what factors are at play here,” Paulk said. “We need far more data.”

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