Phase 3 Trial of Bulevirtide Yields Positive Results

The synthetic lipopeptide bulevirtide holds promise for people who have chronic hepatitis D infection, a recent article in the New England Journal of Medicine asserted. The article discussed the results of a phase 3 trial of bulevirtide, which supported the findings of phase 1 and 2 trials that the therapy is safe and effective for hepatitis D patients. Hepatitis D virus (HDV) occurs only in people already infected with hepatitis B (HBV); coinfection can portend a more difficult disease course and a greater chance of negative outcomes than infection with HBV only.

A team of scientists at Hannover Medical School in Germany enrolled 150 adult patients with chronic hepatitis D into 3 cohorts in a 1:1:1 ratio. One cohort received subcutaneous injections of 2 mg of bulevirtide daily for 144 weeks; another cohort received subcutaneous injections of 10 mg of bulevirtide daily for 144 weeks; and the control group received no treatment for 48 weeks, then received subcutaneous injections of 10 m of bulevirtide daily for 96 weeks.

The primary endpoint was a combination of an undetectable level of hepatitis D RNA or a level that had been lowered by at least 2 log10 IU per milliliter, along with normalization of levels of alanine aminotransferase (ALT), at 48 weeks. Excessive levels of ALT can signify liver disease.

Nearly half (48%) of subjects in the 10-mg group and 45% of those in the 2 mg group achieved this combined response by 48 weeks, compared with 2% of those in the control group. The study’s secondary endpoint was an undetectable level of hepatitis D RNA by 48 weeks, achieved by 20% of those in the 10-mg group, 12% of those in the 2-mg group, and none of those in the control group.

ALT levels had lowered to the normal range by week 48 in 56% of subjects in the 10-mg group, 51% of subjects in the 2-mg group, and 12% of controls. The study’s authors noted that in patients who achieved a combined response by 48 weeks, ALT levels largely normalized by 24 weeks while hepatitis RNA levels kept lowering until 48 weeks.

“This is indeed a very important observation,” Heider Wedemeyer, MD, director, Department of Gastroenterology, Hepatology, Infectious Disease and Endocrinology at Hannover Medical School, told Contagion. “Bulevirtide is blocking entry [of the virus into cells and] not interfering with already infected cells. Decline in HDV RNA therefore reflects loss of infected cells. This indicates that recently infected cells rather than longtime infected cells mainly contribute to ALT increases.”

The FDA has not approved bulevirtide, although the drug has been approved by the European Medicines Agency (EMA) in the 2-mg injection format. The British public health agency, NICE, also has approved it. Wedemeyer noted that at the time the EMA approved bulevirtide, safety data on the 2-mg dose was more comprehensive than for the 10-mg dose. The higher dose is known to more frequently cause elevated levels of bile salts, although scientists are unsure how this impacts patients. “As most patients show good responses with 2 mg, this remains the preferred dose at this stage,” Wedemeyer said. “Future studies will need to investigate if some individuals with suboptimal response to 2 mg would benefit from higher BLV doses.”

In addition to changes in ALT and HDV RNA levels, study participants in both the 2-mg and 10-mg cohorts of bulevirtide experienced reduced liver stiffness at week 48, with similar levels of improvements in both. In the 55% of subjects for which liver biopsies were available at baseline and at week 48, those in the 2-mg and 10-mg cohorts tended to see histological improvements. By contrast, a greater percentage of the control group displayed more severe fibrosis during the course of the study.

While no severe side effects related to bulevirtide occurred in the 2-mg and 10-mg cohorts, those groups combined did experience more mild to moderate reactions than the control group. These included headache, itching, fatigue, weakness, upper abdominal pain, injection-site reactions, and joint pain. None of the symptoms led to subjects discontinuing bulevirtide.

The study’s limitations include the fact that it was not blinded due to ethical concerns, although the authors point out that objective laboratory measurements confirmed all findings; it did not include all genotypes of HBV and HDV; and most patients were white, with a paucity of subjects of other races included.