FDA Rejects Bulevirtide for Hepatitis D, Compensated Liver Disease

The FDA has issued a complete response letter (CRL) to Gilead Sciences, indicating that it cannot approve bulevirtide, an investigational entry-inhibitor for the treatment of adults with hepatitis D virus (HDV) infection and compensated liver disease, due to concerns about the manufacture and delivery of the therapy.

In spite of these concerns, no new studies to evaluate the safety and efficacy of bulevirtide were requested by the FDA. There remain no approved therapies for the treatment of HDV in the United States.

“While we are disappointed with this outcome, we remain confident in the benefits bulevirtide could potentially bring to people living with HDV in the United States. Today’s news does not change the safety and efficacy profile observed in clinical trials to date. We look forward to continuing our active discussions with the FDA so that we may bring bulevirtide to people living with HDV in the United States as soon as possible,” said Merdad Parsey, MD, PhD, chief medical officer, Gilead Sciences, in a press release.

Bulevirtide, which was acquired along with manufacturer MYR GmbH by Gilead in 2021, was conditionally approved in the European Economic Area in 2020 and granted orphan drug designation by the FDA in 2015 and breakthrough therapy status in 2018.

A recent study published in The Lancet Infectious Diseases showed that bulevirtide in combination with tenofovir disoproxil fumerate had positive results among patients with coinfection of hepatitis B virus (HBV) and HDV in a phase 2 trial.

Gilead had submitted its US Biologics License Application (BLA) for bulevirtide in the fourth quarter of 2021, seeking approval for its 2-mg injection for adults with HDV and compensated liver disease. The biopharmaceutical company said it has been working to implement process improvements to the manufacturing of bulevirtide since its acquisition and will continue to discuss manufacturing and product delivery improvements with the FDA.

The announcement marks a major setback for progress on the management of chronic HDV infection, the most severe form of viral hepatitis, which is associated with a poor prognosis and high rates of mortality. Requiring HBV for its replication, HDV infection affects nearly 5% of people globally who have chronic infection HBV, with infections occuring either simultaneously (co-infection) or after first being infected with hepatitis B (super-infection).

The number of HDV infections has decreased since the 1980s, due mainly to successful global HBV vaccination programs, but infection has been shown to disproportionately affect indigenous populations, recipients of hemodialysis, and people who inject drugs. HBV immunization can prevent infection, but treatment success rates for infected individuals are low.