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Assembly Bio drops hepatitis B drug after liver problems surface in clinical trial

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Hepatitis B drug developer Assembly Biosciences is winding down work on one of its experimental therapies after four patients in a mid-stage clinical trial showed signs of potential liver problems. Though the study has stopped, Assembly is continuing to monitor the patients while it also shifts its focus to other hepatitis B drugs in its pipeline.

The worrisome indicator was alanine transaminase, a liver enzyme whose elevated levels are consistent with liver toxicity caused by a drug. Assembly Bio has not yet definitively linked its drug, ABI-H2158, to those liver enzymes. But the South San Francisco-based biotech also said that no other causes for the higher enzyme levels have been found. The company has notified the FDA, and the agency said that the drug would be placed on a clinical hold.

ABI-H2158 is a type of drug the company calls a core inhibitor. The small molecule is designed to target the core protein, a viral structural protein of the hepatitis B virus that has no human equivalent and is involved in many aspects of the virus’s replication cycle.

The Phase 2 study of ABI-H2158 enrolled 88 patients randomly assigned to receive the Assembly Bio drug, plus the hepatitis B antiviral entecavir, or a placebo plus entecavir. The regimen was dosed once daily for up to 72 weeks. Assembly Bio said two patients in the ABI-H2158 arm developed liver enzymes at levels deemed Grade 4 adverse events, which are life threatening or disabling. Those patients stopped treatment. Two additional patients developed liver enzymes levels characterized as Grade 3, which is considered severe.

The Assembly Bio drug pipeline has additional core inhibitors, the most advanced of which is called vebicorvir. That antiviral has so far shown favorable safety and efficacy in patients treated for up to 18 months in a Phase 2 clinical trial. The company has said that it believes combination treatments are key to finding a cure for hepatitis B infection, and vebicorvir is also being evaluated in two triple combinations with currently available treatments and experimental ones. Preliminary data are expected next year.

Another core inhibitor, ABI-H3733, has completed Phase 1a testing and the company plans to report initial data at an upcoming medical meeting. One more core inhibitor, ABI-4334, is on track to proceed into clinical testing next year. In preclinical research, Assembly Bio said that this compound showed the potential to be the best in its drug class. The company also noted that both ABI-H3733 and ABI-4334 are structurally distinct from the now discontinued ABI-H2158.

Assembly Bio said that redirecting the resources from the discontinued hepatitis B program should help advance the development of the other assets more quickly, while also extending the amount of cash available to support its research into the second half of 2023. As of June 30, Assembly Bio $59.7 million in cash and cash equivalents, according to its second quarter 2021 financial report.

Assembly Bio has been pruning its pipeline. The company was partnered with Allergan on microbiome drug research, an alliance dating to 2017. After Allergan was acquired by AbbVie last year, that company proceeded with a pruning of its own, and decided to end the partnership, returning the rights to the microbiome program. Assembly Bio shopped the assets around but found no bidders. Late last year, the Assembly Bio board of directors decided to end the microbiome program and focus the company exclusively on hepatitis B drug research.

Photo: Sakramir, Getty Images

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