Astellas’ Friedreich’s ataxia gene therapy cleared for clinical study after earlier version stumbled

After hitting a speed bump in its first attempt at developing a gene therapy for Friedreich’s ataxia, Astellas is ready to put a new version in the clinic.

On Thursday, the Japanese drugmaker announced the FDA has cleared its IND for ASP2016. The company is hoping to dose the first patient in the second half of 2024, according to Richard Wilson, who leads genetic regulation at Astellas Gene Therapies.

The announcement came as part of the company’s quarterly earnings report. Days before, Astellas disclosed that it took a $260 million writedown on AT808, the gene therapy candidate obtained as part of its $3 billion acquisition of Audentes. While AT808 never made it through the preclinical stage, it will live on — Astellas is dividing it into two separate programs to target two different aspects of Friedreich’s ataxia, the company told Endpoints News. ASP2016 is the first.

Friedreich’s ataxia, a rare disease caused by the mutations in the gene for the protein frataxin, can cause both cardiac and neuromuscular complications, Wilson said. Addressing both in a single shot, as Astellas and several other companies had tried to do, turned out to be an “incredibly complicated problem” because of challenges in distribution, expression levels and therapeutic window, he said.

Frataxin, as Wilson put it, is “one of those Goldilocks proteins” — either having too much or too little would be dangerous. With ASP2016, which targets the cardiac complications of the condition, Astellas employed a mild promoter so that the AAV8-delivered gene therapy produces “just enough” protein in the target tissue.

“Our intention really has been to try and get as many cardiomyocytes transduced as we can, but not to produce such an overwhelming amount of frataxin protein that it would produce toxicity,” he said.

ASP2016 would be Astellas’ third gene therapy to be tested in humans. The company is running a Phase 1/2 study for AT845 in late-onset Pompe disease. It’s also still working to resolve a clinical hold placed on AT132 in September 2021, after several patients with X-linked myotubular myopathy (XLMTM) died.

Astellas has previously suggested the patient deaths had to do with the exacerbation of an underlying liver condition that was poorly understood. It’s exploring protocol changes as part of its investigation.

“We’ve completed the bulk of that work now; we still have some [chemistry, manufacturing and controls] activities ongoing,” Wilson said, adding that the company feels “on track to address the current FDA questions.”

Having licensed a second gene therapy candidate for XLMTM last June, Astellas is also looking to generate IND-enabling safety data for that program, dubbed KT430.

“There’s no headline to kind of announce about XLMTM right now, other than the team continues to work incredibly hard,” Wilson said. “It’s a bit of a ‘stay tuned’ message.”

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