FDA rejects Gilead’s bulevirtide for hepatitis D, compensated liver disease
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The FDA issued a complete response letter to Gilead indicating it cannot approve the company’s new drug application that seeks approval of bulevirtide for chronic hepatitis D virus infection and compensated liver disease.
In its letter, the FDA cited concerns over the manufacture and delivery of bulevirtide, a first-in-class investigational entry-inhibitor; however, no new studies to assess the safety and efficacy of the drug have been requested.
“While we are disappointed with this outcome, we remain confident in the benefits bulevirtide could potentially bring to people living with HDV in the U.S.,” Merdad Parsey, MD, PhD, chief medical officer at Gilead Sciences, said in a press release. “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 FDA so that we may bring bulevirtide to people living with HDV in the U.S. as soon as possible.”
Conditionally approved in the European Economic Area in 2020, bulevirtide was granted orphan drug designation by the FDA in 2015 and breakthrough therapy status in 2018. Gilead had submitted its U.S. application for bulevirtide in the fourth quarter of 2021, seeking approval for its 2 mg injection for adults with HDV and compensated liver disease.
Gilead noted that, since acquiring MYR GmbH and bulevirtide in 2021, the company has been working to implement process improvements to the manufacturing of bulevirtide, noting that it “will continue to discuss manufacturing and product delivery improvements with the FDA.”
Perspective
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William Carey, MD
Hepatitis D is an uncommon virus in the United States, as it occurs only in those infected with hepatitis B virus. This curious fact is explained by the unusual nature of HDV — it is a defective RNA virus that depends on HBV to provide its required outer coating. Individuals can acquire HDV at the same time they become infected with hepatitis B (co-infection) or after a person with chronic hepatitis is exposed to HBV (super-infection).
The importance of HDV is that is tends to cause more serious liver injury and is not amenable to the customary drugs, such as nucleoside analogues (NA), that are so effective in suppressing HBV and reducing liver injury. Until now, the best treatment for HDV is long-term use of interferons — agents with serious debilitating side effects, intolerable to many.
The good news is that there is a drug effective in the management of HDV: In 2020, the European Commission approved bulevirtide, a new drug that blocks entry of virus into hepatocytes. A recent study in The Lancet Infectious Diseases demonstrated that up to 77% of patients given bulevirtide in addition to an NA met the study end point (marked reduction or undetectable HDV virus RNA) compared with only 4% who received NA alone. This and other studies demonstrate the effectiveness of this drug.
The FDA granted bulevirtide orphan drug status in 2015, paving the way for accelerated approval. However, the agency rejected the application for approval of bulevirtide. The disapproval letter provided no criticism of the data supporting the utility of this drug. The sole basis was concern about quality control in the manufacturing and delivery process. Gilead Sciences, the drug manufacturer, plans further discussions with the FDA.
It seems likely that issues of concern to the FDA are manageable and we may see full FDA approval for this drug once those issues are addressed. Until then, treatment options for the few people with HDV infection in the U.S. remain limited.
Wedemeyer H, et al. Lancet Infect Dis. 2022;doi:10.1016/S1473-3099(22)00318-8.
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