Bulevirtide appears safe and effective for hepatitis D

Liz Highleyman
Published:
28 June 2021
Heiner Wedemeyer at the EASL International Liver Congress 2021

The entry inhibitor bulevirtide (Hepcludex) suppressed hepatitis delta viral load and improved liver enzyme levels in a phase III clinical trial, according to late-breaking study results presented this week at the 2021 International Liver Congress.

Hepatitis delta virus (HDV) 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. It is estimated that 12 million people worldwide have both HBV and HDV.

"Hepatitis B stands for being back, because it's really very interesting, C stands for curable, E stands for emerging, but D stands for deadly," Prof. Heiner Wedemeyer of Hannover Medical Hospital in Germany said at a conference press briefing. "It's the most severe form of viral hepatitis causing a high risk of developing liver cancer and cirrhosis."

Bulevirtide (formerly known as Myrcludex) blocks surface receptors that HBV uses to enter liver cells. This interferes with the hepatitis B lifecycle and thereby also prevents HDV replication. In July 2020, the European Medicines Agency (EMA) granted conditional approval of bulevirtide as the first ever treatment for hepatitis D.

The provisional approval was based on data from phase II studies. At the 2018 International Liver Congress, Wedemeyer reported that bulevirtide plus tenofovir disoproxil fumarate suppressed HDV replication more than tenofovir alone. At the 2019 International Liver Congress, he reported that about half of patients treated with lower doses of bulevirtide (2mg or 5mg) plus pegylated interferon alfa for 48 weeks maintained an undetectable HDV RNA level six months later. Last year, he reported that a higher dose of bulevirtide (10mg) did not appear to work better than the lower doses.

At this year's meeting, Wedemeyer presented the first interim results from an ongoing phase III clinical trial, MYR301 (ClinicalTrials.gov NCT03852719), evaluating the long-term efficacy and safety of bulevirtide versus no immediate treatment.

In this study, 150 adults with chronic hepatitis delta in Europe, Russia and the US were randomly assigned to either immediate treatment with daily subcutaneous injections of 2mg or 10mg bulevirtide or delayed treatment. They could also use antivirals for hepatitis B. The trial's primary endpoint is efficacy and safety at 48 weeks, at which point participants in the delayed treatment arm will start 10mg bulevirtide. The total treatment duration will be 144 weeks. Wedemeyer presented interim results at 24 weeks.

More than half of the participants (57%) were men, 83% were White and the mean age was approximately 42 years. Nearly half had liver cirrhosis. ALT liver enzyme levels were elevated but below 10 times the upper limit of normal (mean of approximately 110 U/L).

After 24 weeks of treatment, 55% of people in the 2mg bulevirtide arm and 68% in the 10mg arm either reached an undetectable HDV viral load or experienced at least a 2-log decrease in HDV RNA from baseline, compared with just 4% in the delayed treatment arm. However, the magnitude of the decline was similar in both bulevirtide arms.

ALT normalisation was more frequent in the 2mg arm compared with the 10mg or delayed treatment groups (53%, 38% and 6%, respectively). The combined primary endpoint of virological and biochemical response was achieved by 37% and 28% of people in the 2mg and 10mg arms, respectively, but no one in the delayed treatment group. These findings confirm than the 10mg dose does not appear to be more effective overall than the 2mg dose approved by the EMA.

Bulevirtide had little effect on HBV viral load and no one achieved hepatitis B surface antigen (HBsAg) loss or seroconversion, considered a functional cure.

Treatment was generally safe and well tolerated. There were no serious adverse events related to bulevirtide and no one stopped treatment due to side effects. Injection site reactions were uncommon and mostly mild, but occurred more often in the higher-dose arm (6% vs 26%). Bulevirtide blocks a bile salt transporter and asymptomatic bile salt increases were common, but no one taking either dose of bulevirtide experienced symptomatic elevation during treatment.

"Bulevirtide monotherapy was safe and well tolerated in cirrhotic and non-cirrhotic patients with compensated chronic HDV, with most adverse events being mild to moderate," the researchers concluded. "These findings further support the conditional approval of bulevirtide 2mg in the EU."

"This was only 24-week interim data, only a very small number of patients had completely undetectable HDV RNA and there was no effect on HBsAg," Wedemeyer said. "This confirms we can use the drug in the real world, but we have to wait now for the presentation of the one-year data to be performed. These are exciting times for delta patients with a new treatment option, and safety and efficacy were confirmed."

Another research team presented further results from a phase IIb study of bulevirtide plus pegylated interferon. A total of 175 patients with chronic HDV infection were randomly assigned to receive 2mg or 10 mg bulevirtide plus pegylated interferon, 10mg bulevirtide alone or pegylated interferon alone.

People taking 2mg or 10mg bulevirtide plus pegylated interferon were more likely to see at least a 2-log decline in HDV RNA and to reach an undetectable HDV viral load. However, both ALT normalisation and combined virological and biochemical response were highest in the bulevirtide monotherapy arm.

References

Wedemeyer H et al. Bulevirtide monotherapy at low and high dose in patients with chronic hepatitis delta: 24 weeks interim data of the phase 3 MYR301 study. International Liver Congress, abstract LBP-2730, 2021.

Asselah T et al. Safety and efficacy of bulevirtide monotherapy and in combination with peginterferon alfa-2a in patients with chronic hepatitis delta: 24 weeks interim data of MYR204 phase 2b study. International Liver Congress, abstract OS-2717, 2021.