Interim results from a new phase 3 trial support the safety and efficacy of monotherapy with bulevirtide (Hepcludex, Gilead Sciences) in patients with chronic infection with the hepatitis delta virus.
The international, multicenter investigation concluded that 24 weeks of treatment with the first-in-class entry inhibitor was associated with significant decreases in viral RNA, and improvements in biochemical disease activity. The researchers said the findings affirm the August 2020 conditional approval by the European Commission of bulevirtide, which has received a breakthrough therapy designation from the FDA in the United States.
Bulevirtide is a peptide derived from the hepatitis B surface antigen. “In previous phase 2 trials [MYR202/MYR203], we showed that if you inject hepatitis D patients with this peptide on a daily basis with different doses, you get a linear decline in HDV RNA over time, which reflects a loss of infected cells,” said Heiner Wedemeyer, MD, the chair of the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical Hospital, in Germany.
The current study was a 24-week interim analysis of the MYR301 phase 3 trial, which comprised 150 patients (57% men; mean age, 41.8 years) coinfected with hepatitis B virus (HBV) and HDV. Participants in the trial were randomized to one of three groups: no antiviral treatment for 48 weeks followed by 10 mg daily of bulevirtide for 96 weeks (control arm A; n=51); 2 mg daily of bulevirtide (arm B; n=49); or 10 mg daily of bulevirtide (arm C; n=50).
Patients in arms B and C received the drug for 144 weeks, with a treatment-free follow-up period of 96 weeks. The primary end point of the trial was a combined response of undetectable HDV RNA or HDV RNA reduction of at least 210 IU/mL and normalization of alanine aminotransferase (ALT) at week 48. Secondary end points included undetectable HDV RNA, a fall in HDV RNA of at least 210 IU/mL, normalization of ALT, and a decline in HBsAg of at least 110 IU/mL.
In a presentation at the 2021 International Liver Congress (abstract LBP-2730), Dr. Wedemeyer reported that after 24 weeks, none of the patients in the control group (arm A) achieved a combined virologic and biochemical response, whereas 36.7% of patients in arm B and 28.0% of those in arm C did so (P<0.0001 vs. arm A).
Similar results were observed for HDV RNA, which fell by at least 210 IU/mL between baseline and week 24 in 3.8% of patients in arm A, 55.1% in arm B and 68% in arm C (P<0.0001 vs. arm A), according to the researchers. At week 24, normalization of ALT was achieved by 53.1% of patients in arm B and 38% in arm C, compared with 5.9% in arm A (P<0.0001). Levels of HBsAg did not show relevant declines in all but one patient at week 24, the researchers reported.
“The important message is that the findings of the phase 2 trials were exactly confirmed,” Dr. Wedemeyer said.
Safety analyses found that treatment-related adverse events were much more common in patients treated with the study drug. “As was expected, bile acids increased because bulevirtide’s mode of action blocks a bile salt transporter,” Dr. Wedemeyer explained. “Nevertheless, there were no unexpected serious adverse events.”
The researchers acknowledged that only a small proportion of patients had completely undetectable HDV RNA, but they were encouraged by the results. “This confirms that we can use the drug in a real-world setting,” Dr. Wedemeyer said. “These are exciting times for hepatitis delta patients.”
Tobias BÖttler, MD, an attending physician at the University Hospital Freiburg, in Germany, told Gastroenterology & Endoscopy News that bulevirtide has the potential to make a significant difference in managing patients with active hepatitis delta infection. “We still need to learn a lot with regard to dosing, treatment duration and possible combination therapies, as some data suggest that combination with interferon is even more potent,” he said. “It appears to be well tolerated with little side effects, based on the data we currently have. Going forward, we might even be able to use the drug in hepatitis B–monoinfected patients, but that requires a lot more data from clinical trials.”