Bulevirtide is a potential cure for hepatitis B and D

16 Apr 2019 Liz Highleyman
Originally published on www.infohep.org

Bulevirtide, formerly known as Myrcludex B, led to suppression of hepatitis delta virus (HDV) and a functional cure of hepatitis B virus (HBV) in some people with both viruses when combined with pegylated interferon-alfa-2a, according to a presentation at the 2019 International Liver Congress last week in Vienna.

"The results of this trial suggest that bulevirtide is a promising treatment for chronic HDV infection, and that the combination of bulevirtide and peg-IFN-alfa has the potential to cure HBV/HDV co-infection in some patients," said Prof Heiner Wedemeyer of Essen University Hospital in Germany.

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

There is currently no approved therapy for HDV, though it is sometimes treated with peg-IFN-alfa. Nucleoside/nucleotide antivirals for hepatitis B, such as tenofovir disoproxil fumarate (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude), can suppress HBV replication during therapy but usually do not lead to a cure, as indicated by hepatitis B surface antigen (HBsAg) clearance and antibody seroconversion.

Bulevirtide is an experimental entry inhibitor that binds to the receptor HBV uses to enter liver cells (known as sodium taurocholate co-transporting polypeptide or NTCP), thereby both interfering with the lifecycle of HBV and preventing HDV replication.

Wedemeyer presented findings from a phase 2b clinical trial assessing the safety and efficacy of bulevirtide plus pegylated interferon-alfa-2a. At last year's EASL meeting he presented a study of bulevirtide in combination with tenofovir DF. That study showed that although bulevirtide suppressed HBV and HDV replication, is usually did not lead to a cure.

The present study included 60 people with HBV/HDV co-infection. They were randomly allocated to four treatment arms:

  • 180 mcg peg-IFN-alfa-2a alone
  • 2mg bulevirtide plus peg-IFN-alfa-2a
  • 5mg bulevirtide plus peg-IFN-alfa-2a
  • 2mg bulevirtide alone.

Peg-IFN-alfa-2a was given as a once-weekly subcutaneous injection while bulevirtide was given as a daily injection. All participants were treated for 48 weeks with a 24-week follow-up period after completing therapy.

HDV viral load levels fell steeply during treatment in the two combination therapy arms and modestly in the bulevirtide and peg-IFN-alfa monotherapy arms. But while HDV RNA levels rebounded after stopping treatment in the two monotherapy and 5mg combination arm, it remained suppressed in the 2mg combo arm, Wedemeyer reported.

Nine of 15 people (60%) taking the 2mg bulevirtide combination and six of 15 (40%) taking the 5mg combo achieved undetectable HDV RNA by the end of treatment at week 48, compared with two people (13%) in each monotherapy arm. At 72 weeks, eight (53%) and four (27%) people in the respective combination arms still had suppressed HDV, but no one in the monotherapy arms had sustained suppression.

In addition, six of 15 people in the 2mg combination arm and two of 15 in the 5mg combo arm had greater than a 1-log decline or undetectable HBsAg at week 72. Looking at both combination arms together, 27% had HBsAg loss and 20% experienced seroconversion, considered a functional cure, according to Wedemeyer. No one taking either monotherapy had HBsAg loss or seroconversion.

ALT liver enzyme normalisation was observed in 37% of people taking the combinations and 67% of those on bulevirtide alone at 48 weeks. But whereas ALT normalisation was sustained in the combo arms, it was lost in the bulevirtide monotherapy arm.

Treatment was generally safe and well tolerated. No serious adverse events occurred during the treatment period and there were no discontinuations due to bulevirtide-related side-effects, Wedemeyer reported. A total of 155 bulevirtide-related adverse events were observed through week 72, most of them mild. Bile salts increased during treatment but returned to normal soon after stopping therapy. Most adverse events were related to peg-IFN-alfa, which is known to be difficult to tolerate.

"Entry inhibition with [bulevirtide] in combination with [peg-IFN-alfa-2a] bears curative potential in patients with chronic hepatitis B/D co-infection," the researchers concluded. "Presented data indicate a future role for the treatment of chronic hepatitis B."

Wedemeyer noted that this is the largest clinical trial and the best results ever seen for HDV. Given that virus levels rebounded after stopping therapy, he said that longer treatment durations will be explored in phase III studies.