Hepatitis D Pipeline Looks Promising BY MICHAEL VLESSIDES
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nterim results from a new phase 3 trial support the safety and efficacy of monotherapy with bulevirtide (Hepcludex, Gilead) in patients who have chronic infection with the hepatitis delta virus (HDV). Coupled with recent data on oral HDV regimens, the pipeline for treating this rare, challenging form of hepatitis looks promising. The interim phase 3 study, an international, multicenter investigation, concluded that treatment with bulevirtide for 24 weeks was associated with significant decreases in viral RNA and improvements in biochemical disease activity. The researchers said the findings confirm the August 2020 conditional approval by the European Commission of bulevirtide. The first-in-class entry inhibitor has received a breakthrough therapy designation from the FDA in the United States. Bulevirtide is a peptide derived from the hepatitis B surface antigen (HBsAg). “In previous phase 2 trials [MYR202/ MYR203], we showed that if you inject hepatitis D patients with this peptide [daily] 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 analysis of the MYR301 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 of 96 weeks. The
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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 reduction 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). 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). 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). The level of HBsAg did not show relevant declines in all but one patient at week 24. “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 who received the study drug. “As was expected, bile acids increased because bulevirtide’s mode of action blocks a bile salt transporter,” Dr. Wedemeyer said. “But 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.” continued on page 42
