An experimental drug that blocks the entry of hepatitis B virus (HBV) and hepatitis delta virus (HDV) into liver cells suppressed HBV and HDV levels and led to improvement in liver fibrosis, according to a presentation at the 2018 International Liver Congress this month in Paris.
Hepatitis delta is a small 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 and liver cancer, and disease progression is more rapid and more severe in people co-infected with both HBV and HDV. Estimates suggest that people with both viruses are five times more likely to develop cirrhosis and liver cancer than those with HBV alone.
There is currently no approved therapy for hepatitis delta, though it is sometimes treated with pegylated interferon-alpha, and interferon-lambda is under study as an orphan drug. While pegylated interferon-alpha suppresses HDV viral load in about a quarter of people, relapse is common.
Nucleoside/nucleotide antivirals for hepatitis B, such as tenofovir disoproxil fumarate (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude), can suppress HBV replication long-term during therapy, but they seldom lead to a cure, as indicated by hepatitis B surface antigen (HBsAg) clearance. HDV uses HBsAg to replicate, and these antivirals generally have little effect on HDV levels.
Heiner Wedemeyer of Hannover Medical School in Germany reported final results from a phase 2b clinical trial assessing the safety and efficacy of Myrcludex B plus tenofovir DF in people with HBV/HDV co-infection. Myrcludex B binds to NTCP, the receptor HBV uses to enter cells in the liver.
This study included 120 people with HBV/HDV co-infection in Germany and Russia. Two-thirds were men, most were white and the mean age was 40 years. Half had cirrhosis and a third had elevated ALT levels more than three times the upper limit of normal. Almost all had HDV genotype 1. People with liver cancer, decompensated liver disease or additional infection with hepatitis C virus or HIV were excluded.
Participants were randomly allocated to four treatment arms. Three groups received tenofovir DF pre-treatment for 12 weeks, then added Myrcludex B at doses of 2mg, 5mg or 10mg, self-administered by subcutaneous infection once daily for 24 weeks, followed by tenofovir alone to week 48. The fourth group took tenofovir alone for the entire 48 weeks.
Most participants had completely suppressed HBV DNA after 12 weeks of tenofovir pre-treatment. After 24 weeks of Myrcludex plus tenofovir, 46.4% of people taking the 2mg dose and 46.8% of those on the 5mg dose had at least a 2 log10 decline in HDV RNA, rising to 76.6% for those treated with the 10mg dose. In comparison, only 3.3% of those allocated to use tenofovir alone had a substantial decline in HDV levels.
Median declines in HDV RNA from baseline were -1.75, -1.60 and -2.70 log10, respectively, in the three Myrcludex dose groups, versus just -0.18 in the tenofovir-only group.
HDV RNA levels soon rebounded, however, after Myrcludex was discontinued. At week 48 less than 20% of participants in all groups had a 2 log10 or greater decline in HDV RNA, and the median change was less than -0.5 log10. Wedemeyer reported that eight people had sustained HDV RNA suppression.
HBsAg levels mostly remained stable in all treatment groups, but a few people taking Myrcludex experienced steep transient declines and one person appeared to achieve HBsAg clearance that was sustained after stopping the drug. This suggests that the majority of HBsAg comes from integrated HBV, which is not targeted by Myrcludex, according to Wedemeyer.
About 45% of participants experienced ALT normalisation during combination treatment, which was not dose-related, but again the benefit was largely lost after stopping Myrcludex.
FibroScan liver stiffness measurements, a method of estimating fibrosis severity, improved in 80% of people taking Mycludex plus tenofovir at week 24, but also did so in nearly 60% of those receiving tenofovir alone.
HDV RNA declines in plasma correlated with decreases in HDV replication in the liver, according to a related study also presented at the conference. The accompanying reduction in ALT and inflammatory cytokines that reduced HDV levels can diminish liver inflammation, the researchers suggested.
Treatment was generally safe and well tolerated. There were eight serious adverse events, but only two ALT increases during the tenofovir-only follow-up period were deemed to be treatment-related, and no one stopped treatment due to Myrcludex-related side-effects. Thirteen per cent of Myrcludex recipients experienced ALT increases after stopping treatment but had no worsening of liver function. Only 5% reported injection site reactions. All adverse events resolved without problems, Wedemeyer reported.
The NTCP receptor that Myrcludex blocks acts as a bile acid transporter. Half the people taking the 2mg dose, 74% on the 5mg dose and 91% on the 10mg dose had increased bile acids, compared with 19% of those taking tenofovir alone. However, none of the participants reported pruritus, or itching, Wedemeyer noted.
“Blocking HBV/HDV entry with Myrcludex is a safe and promising strategy to treat chronic hepatitis delta,” the researchers concluded. “Optimal treatment durations and possible combination therapies need to be determined.”
Wedemeyer said that modelling studies suggest that two to three years of treatment with Myrcludex might be needed to eliminate HDV RNA.
By Liz Highleyman
Wedemeyer H et al. Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with tenofovir in patients with chronic HBV/HDV co-infection. The International Liver Congress, Paris, abstract GS-005, 2018. Journal of Hepatology 68:S3, 2018
Allweiss L et al. Strong intrahepatic decline of hepatitis D virus RNA and antigen after 24 weeks of treatment with Myrcludex B in combination with tenofovir in chronic HBV/HDV infected patients: interim results from a multicenter, open-label phase 2b clinical trial. The International Liver Congress, Paris, abstract PS-162, 2018. Journal of Hepatology 68:S90, 2018