Bulevirtide shows promise as maintenance therapy for hepatitis D

30 Aug 2020 Liz Highleyman
Originally published on www.infohep.org

High-dose bulevirtide (Hepcludex) combined with pegylated interferon alfa-2a (Pegasys) or tenofovir disoproxil fumarate (TDF; Viread) led to suppression of hepatitis delta virus (HDV), according to a presentation this week at the 2020 Digital International Liver Congress. What's more, a third of people taking bulevirtide with TDF maintained an undetectable HDV viral load after stopping the drug.

Hepatitis delta is a defective virus that can only replicate in the presence of hepatitis B virus (HBV). Over years or decades, chronic hepatitis B can lead to advanced liver disease including cirrhosis and liver cancer. People with HBV/HDV co-infection have more aggressive liver disease progression than those with HBV alone.

Bulevirtide (formerly known as Myrcludex) is a first-in-class entry inhibitor that binds to NTCP surface receptors that HBV uses to enter liver cells. This interferes with the hepatitis B lifecycle and thereby also prevents HDV replication. In July, the European Medicines Agency approved bulevirtide as the first treatment for hepatitis D. The approved dose is 2mg self-administered as a once-daily injection with or without nucleoside/nucleotide analogues such as TDF.

At the 2018 International Liver Congress, Prof. Heiner Wedemeyer of Essen University Hospital in Germany presented findings from a study of bulevirtide (2mg, 5mg or 10mg) plus TDF for 24 weeks, showing that the combination suppressed HDV replication more than TDF alone.

At last year's International Liver Congress, Wedemeyer reported results from a phase 2 study of 2mg or 5mg once-daily bulevirtide plus weekly pegylated interferon versus either drug alone for 48 weeks. HDV viral load fell steeply during treatment in the two combination arms, and about half of people who received the 2mg combination regimen still had undetectable HDV RNA at week 72.

The researchers then added two new arms, each with 15 participants, to evaluate a higher dose of bulevirtide. One group received 10mg once-daily bulevirtide plus weekly pegylated interferon, while the other received 5mg twice-daily bulevirtide plus TDF, both for 48 weeks.

At last year's AASLD Liver Meeting, Wedemeyer presented interim findings from these groups, showing that at the end of treatment, 87% of those taking 10mg once-daily bulevirtide plus pegylated interferon and 40% of those taking 5mg twice-daily bulevirtide plus TDF had undetectable HDV viral load.

This week's presentation included follow-up data six months after stopping bulevirtide. The group taking the pegylated interferon combination discontinued all treatment, while those assigned to the TDF combination dropped bulevirtide but stayed on TDF.

Five people (33%) who took 5mg twice-daily bulevirtide plus TDF still had undetectable HDV RNA at 72 weeks, an improvement over the 7% who did so in the earlier group that took 2mg bulevirtide alone. But only one person (7%) who took 10mg once-daily bulevirtide plus pegylated interferon had undetectable HDV RNA post-treatment – much lower than the 53% who did so in the earlier 2mg bulevirtide plus pegylated interferon arm.

Five of the fifteen people in each of the high-dose bulevirtide groups had normal ALT liver enzyme levels at 72 weeks.

No one taking bulevirtide plus TDF achieved at least a 1-log decline or loss of hepatitis B surface antigen (HBsAg). HBsAg clearance and hepatitis B surface antibody seroconversion is considered a cure. Two people taking 10mg bulevirtide plus pegylated interferon had an HBsAg response at week 72, one of whom was the sole individual with continued undetectable HDV RNA. Again, this was lower than the 40% HBsAg response rate seen in the earlier 2mg bulevirtide plus pegylated interferon arm.

Treatment was generally safe and well tolerated. Everyone experienced asymptomatic increases in bile salt levels during treatment, but these returned to normal soon after stopping therapy. No bulevirtide-related serious adverse events occurred over the 72 weeks, and there were no treatment discontinuations due to bulevirtide side effects. A majority of adverse events were related to pegylated interferon, Wedemeyer noted. Bulevirtide injection site reactions were uncommon.

Based on these findings, the researchers concluded that 10mg bulevirtide "is a safe and promising strategy for maintenance therapy of chronic hepatitis D" in people taking TDF for HBV. But increasing the dose of bulevirtide in combination with pegylated interferon had no added benefit, as the strong synergistic effect of these two drugs was already apparent at lower doses.

"Continuous HDV RNA decline can be achieved with bulevirtide monotherapy, and strong synergy with [pegylated interferon] against HDV was observed", Wedemeyer said in a conference press release. "This trial offers new treatment options for the most severe form of viral hepatitis."