Bulevirtide leads to sustained improvement for people with hepatitis D

The entry inhibitor bulevirtide (Hepcludex) led to a reduction in hepatitis delta virus (HDV) viral load, lower liver enzyme levels and improvement in fibrosis after 48 weeks of follow-up, according to findings presented last week at the 2022 International Liver Congress (ILC) in London. Another study of real-world bulevirtide use in France also showed virological and biochemical improvement.

Hepatitis delta is a defective virus that can only replicate in the presence of hepatitis B virus (HBV). Over time, chronic hepatitis B can lead to severe liver disease, and people with HBV/HDV co-infection experience more aggressive disease progression. People who carry both viruses are more likely to progress to decompensated cirrhosis, develop liver cancer or need a liver transplant. It is estimated that around 3% of people with hepatitis B – or about 15 million people worldwide -- have HDV, but accurate numbers are lacking due to limited testing.

“[Hepatitis D] is definitely the most severe form of chronic viral hepatitis. These patients have a really high risk for developing liver cirrhosis at an early age and also an increased risk for liver cancer. Until recently…the majority of patients could not be treated at all,” presenter Prof. Heiner Wedemeyer of Hannover Medical School in Germany said during an ILC press briefing. “The good message for our patients is that…the drug works. For us in the hepatitis D field, it’s a really exciting time and it’s game-changing for patients.”

Bulevirtide, from Gilead Sciences, is a first-in-class entry inhibitor that blocks surface receptors that HBV and HDV use to enter liver cells. By interfering with the hepatitis B lifecycle, the drug 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. An application for approval by the US Food and Drug Administration is pending.

Wedemeyer presented the latest results from the phase III MYR301 trial (ClinicalTrials.gov NCT03852719), which enrolled 150 adults with chronic hepatitis B and D in Europe and Russia. Nearly 60% were men, most were White and the mean age was approximately 42 years. Most were hepatitis B ‘e’ antigen (HBeAg) negative. They had elevated ALT liver enzyme levels and nearly half had liver cirrhosis. More than half had previously received interferon therapy, and about 60% were concurrently treated with HBV nucleoside analogue antivirals.

The participants were randomly assigned to receive immediate treatment with 2mg (the EMA approved dose) or 10mg once-daily injections of bulevirtide or to delay treatment for 48 weeks. The study is ongoing; the delayed treatment arm will start on the 10mg dose of bulevirtide, and all groups will continue treatment through week 144 with an additional 96 weeks of post-treatment follow-up.

At ILC 2021, Wedemeyer reported interim data at 24 weeks, showing that 55% of people in the 2mg bulevirtide arm and 68% in the 10mg arm either reached an undetectable plasma 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. The likelihood of reaching a combined endpoint of virological and biochemical response (ALT normalisation) was 37% in the 2mg arm and 28% in the 10mg arm, but no one in the delayed treatment group did so.

The longer-term data presented at this year’s meeting show that responses improved with further treatment. At 48 weeks, 71% in the 2mg bulevirtide arm and 76% in the 10mg arm met the virological endpoint, including 12% and 20%, respectively, with undetectable HDV viral load. More than half (51% and 56%, respectively) achieved normal ALT levels.

(Another analysis, presented at the Liver Meeting last fall, showed that intrahepatic HDV RNA levels within the liver steeply declined in a subgroup of 66 people who underwent paired liver biopsies, with 33% in the 2mg bulevirtide group and 52% in the 10mg group reaching undetectable levels.)

Looking at the combined primary endpoint, 45% in the 2mg arm and 48% in the 10mg arm achieved both viral load reduction and ALT normalisation, as did 2% in the delayed treatment group. Treatment benefits were generally consistent across all patient subgroups, though people without cirrhosis had somewhat better responses. In addition, liver stiffness (a measure of fibrosis) improved by about 3% in the two bulevirtide dose groups while worsening slightly in the delayed treatment arm.

Bulevirtide had little effect on hepatitis B. Small declines in HBV DNA were seen in people who were not taking nucleoside analogues, but no one achieved hepatitis B surface antigen (HBsAg) loss, considered a functional cure.

Bulevirtide was safe and generally well tolerated. Severe adverse events (8%-10%), serious adverse events (2%-4%) and severe laboratory abnormalities (10%-12%) were uncommon, and no one discontinued treatment due to adverse events. Injection site reactions, which were mostly mild to moderate, occurred twice as often in the higher-dose arm (16% vs 30%). Bulevirtide blocks a bile salt transporter, and bile salt increases were common, but no one taking either dose experienced symptomatic elevations. A related analysis observed no resistance to bulevirtide through 48 weeks.

Looking at the balance of benefits and side effects, these findings confirm prior study results showing that the 10mg dose does not appear to work better overall than the 2mg dose approved by the EMA.

Another analysis from the MYR301 trial, presented by Prof. Maria Buti of Hospital Universitario Valle Hebron in Barcelona, showed that study participants treated with the 2mg dose of bulevirtide reported greater improvements in a variety of measures of health-related quality of life compared with the delayed treatment group, including general health, physical and social functioning, mental health, vitality, pain, and hepatitis-specific limitations and health distress.

What’s more, an analysis of the French BuleDelta cohort, which comprises people with HDV who were treated with bulevirtide since September 2019, found that these promising clinical trial results were borne out in the real world.

This analysis included 115 patients. Most (70%) were men, but the participants were more diverse than those in the MYR301 trial (43% African, 29% Asian and 26% European descent). Just over half had cirrhosis. About 80% were taking nucleoside analogues, and 50 received interferon in addition to bulevirtide. The median duration of bulevirtide treatment was about 18 months – considerably longer than the randomised trial so far.

Overall, 58% achieved at least a 2-log decline in HDV RNA (including 24% with an undetectable HDV viral load) and 46% experienced ALT normalisation by 24 weeks. About a quarter met both endpoints. Virological response rates were substantially higher in people who also received interferon, but ALT normalisation was more likely in those who did not. The combined virological and biochemical response rates were 34% in the bulevirtide plus interferon group and 17% in the non-interferon group.

Among the 55 patients with 48-week data available, virological response rates were 85% with bulevirtide plus interferon and 69% without interferon. ALT normalisation rates were 39% and 61%, respectively, yielding corresponding combined response rates of 35% and 31%.

Adverse events were more common in the real-world cohort than in the clinical trial. Fifteen people (12%) experienced serious adverse events attributed to bulevirtide, which were similarly likely with or without interferon, and 13 temporarily or permanently discontinued bulevirtide, interferon or both.

Wedemeyer noted that there are still questions that remain to be answered, including how long should treatment with bulevirtide continue and whether it should be combined with interferon. But the new drug is already helping patients.

“We may well be entering into a new golden age of hepatology science,” EASL secretary-general Prof. Thomas Berg of Leipzig University Medical Centre said in a press release. “There is respite coming for those people living with hepatitis D and we are making progress towards finding a cure for hepatitis B, which affects millions of people around the world. The science is inching us towards a potential public health revolution.”