Dive Brief:

Most gene therapies currently in development use small viruses called AAVs, or adeno-associated viruses, to shuttle helpful genetic material into human cells.

When given intravenously, as is usually the case, these AAV-based therapies travel straight to the liver, where they're then processed. The liver therefore acts as a window into how patients respond to treatment with gene therapy, and provides alerts when problems may arise.

Indeed, liver toxicity, often diagnosed by elevated enzyme levels but sometimes by damage to the organ,is the most common adverse event in clinical trials testing intravenously administered AAV vectors. And though toxicity can be managed, some cases are serious enough that they require longer care or even hospitalization.

In one example cited by the FDA, certain patients treated with Zolgensma, the Novartis gene therapy for spinal muscular atrophy, needed corticosteroids for more than seven months to deal with liver toxicity issues. According to the agency, among the roughly 800 patients who've received Zolgensma thus far, about a third have experienced at least one instance of liver toxicity.

Liver toxicity has also come into focus for AAV gene therapies targeting hemophilia, as well as for the one Astellas is developing. The safety concerns are significant enough that, later this week, the FDA is convening a group of gene therapy experts to assess the risks involved when using AAV vectors for gene therapy.

For Astellas, a voluntary pause on screening and dosing is another hard-felt setback.

So far, the AT132 trial has administered the therapy to 24 patients, with seven on the lower dose and 17 on the higher. Three participants on the higher dose developed a progressive form of hepatitis that led to liver failure. Those patients later died from either sepsis or gastrointestinal bleeding as a result of the liver failure.

One patient on the lower dose has now experienced liver problems too. Astellas said in a statement Wednesday that the patient, like some others with X-linked myotubularmyopathy, has a history of intermittent cholestasis, a condition which disrupts the flow of bile from the liver.

The company noted, though, that before receiving AT132, the patient had a "normal" liver ultrasound and liver function test results which met the trial's eligibility criteria.

Astellas said it will be closely monitoring the patient and, if the FDA ultimately issues a clinical hold, it will "review the content and determine next steps."

"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," said Nathan Bachtell, head of gene therapy, medical and development at Astellas.

"Given previous hepatic events within the program, any one [serious adverse event] needs to be viewed both individually and in the context of the broader program as we move forward," Bachtell added.

Astellas acquired AT132 through its $3 billion acquisition of Audentes Therapeutics, which has since been rebranded as an independent subsidiary named "AstellasGene Therapies." Amid this transition, the former chief executive at Audentes,Natalie Holles,left the combined company in April for undisclosed reasons.

Astellas is also working on other gene therapies for Pompe disease, Duchenne muscular dystrophy and myotonic dystrophy type 1.

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Astellas again hits pause on gene therapy trial - BioPharma Dive