After cutting dose because of deaths, Astellas pauses gene therapy trial as new liver issue arises

Astellas’ $3 billion bet on Audentes Therapeutics has hit yet another setback. Months after getting a clinical hold lifted, Astellas has voluntarily paused a gene therapy clinical trial after a patient suffered liver problems at the lower, supposedly safer dose.

Going into 2020, Astellas planned to file for approval of AT132 in a rare neuromuscular disease by the end of the year. Instead, three deaths linked to liver failure among the 17 patients who received the high dose of the AAV8 vector gene therapy led to a clinical hold. The FDA lifted the hold in December after Astellas dropped the high dose.

Now, Astellas has voluntarily paused screening and dosing of additional participants in response to abnormal liver function test results in a patient who received the low dose. The patient had a history of intermittent liver disease, but the organ appeared to be normal at the start of the study. 

Astellas is now monitoring the patient while investigating the situation ahead of talks with the data monitoring committee and study investigators. The FDA is yet to put the trial on clinical hold, but Astellas discussed the possibility of that happening in its statement to disclose its voluntary pause. 

RELATED: Audentes sees FDA hold lifted after 3 trial deaths blighted $3B program

Having already switched to the low dose, which contains less than half the vector genomes per kilogram of body weight of the high dose, it is unclear whether Astellas has room to go lower. The AT132 dose at which the latest serious adverse event occurred is the lowest tested in the clinical trial, although other gene therapies have worked at lower doses. 

Astellas’ low dose is slightly higher than that used in Novartis’ Zolgensma and notably higher than doses of other investigational systemic gene therapies such as uniQure’s hemophilia B prospect. Other groups have tested gene therapies at levels close to the AT132 high dose—for example, Pfizer in its Duchenne muscular dystrophy program—only to row back in response to toxicity issues. 

All of the aforementioned gene therapies use different viral vectors than AT132 does, but AAV8 has been used in other candidates without causing the sort of adverse events seen in the Astellas study.

RELATED: Astellas takes $540M impairment charge over Audentes' gene therapy trial hold

The latest setback raises further doubts about Astellas’ chances of generating a return on its $3 billion takeover of Audentes. In April, Astellas took a $540 million impairment loss related to AT132, and the continued woes of the gene therapy could have further financial consequences.  

“This is relatively immaterial to future profits but might trigger a non-cash impairment charge if development fails to proceed, or if commercial prospects are otherwise damaged,” analysts at Jefferies wrote in a note to investors.