Hepatitis D (HDV) is a replication-defective viral infection that uses the hepatitis B (HBV) surface antigen as its envelope protein. HDV infection can be associated with severe liver disease which can lead to cirrhosis, hepatocellular carcinoma and liver failure. Presently, there are no drugs approved for the treatment of this life-threatening disease.
“Although significant advances have been made in the treatment of chronic viral hepatitis over the past decade, targeting HDV remains a major challenge because of the unconventional nature of the virus and the severity of its disease.”
The United States (US) Food and Drug Administration (FDA) has released a draft guidance to assist sponsors in the clinical development of potential HDV therapies, from non-clinical development through to Phase III trials. The general drug development considerations discuss non-clinical and early-phase clinical development such as antiviral activity and resistance, target populations and safety considerations.
For phase III efficacy trials, the guidance states that a double-blind placebo-controlled trial would be preferred, although a three-arm randomised controlled trial could be used, with pegylated interferon-α, a commonly used treatment not specifically indicated for HDV, as a comparator product. Following the approval of a drug, a randomised controlled superiority or non-inferiority trial comparing the investigational drug (IND) against an active comparator is recommended.
As there are no efficacy endpoints which have predicted clinical benefit, the FDA has provided an example of a primary endpoint to support accelerated approval of a treatment for chronic HDV, and a secondary endpoint for a chronic suppressive therapy for HDV. The endpoints should confirm efficacy, via long-term follow-up, for clinical outcomes like a decrease in progression of cirrhosis, carcinoma and liver-related fatality. The sponsor is encouraged to request a Type C formal meeting to discuss the chosen novel endpoint with the Division of Antiviral Products (DAVP).
Investigational anti-HDV drugs may be eligible for the FDA’s expedited programs such as fast track, breakthrough therapy, and priority review designations, because of the lack of approved therapies. Sponsors are encouraged to collaborate with the DAVP through the pre-investigational new drug application (pre-IND) consultation program, to discuss the development of drugs with unique considerations based on mechanism of action, novel treatment approaches, or the use of novel biomarkers.
The draft guidance can be accessed here.