A thorough analysis of bulevirtide in real life showed a similar safety and efficacy profile to the clinical trials to treat Hepatitis Delta virus (HDV).
HDV is only transferred to patients who already have Hepatitis B virus. However, it can cause the most severe form liver disease that is viral. It can cause cirrhosis in 5 years and hepatocellular carcinoma within 10 years.
Bulevirtide is a novel medication that mimics hepatitis B surface antigen, binds to its receptor on hepatocytes and stopping HDV virus particles from binding to it. The drug received conditional marketing approval by the European Medicines Agency in 2020 and has received a breakthrough therapy designation from the US Food and Drug Administration.
The study was presented at the annual meeting of the American Association for the Study of Liver Diseases by Victor De Ledinghen, PhD who is an associate professor of hepatology and the head of the Hepatology and liver transplantation unit at Bordeaux (France) University Hospital.
After bulevirtide was approved by the French National Agency for Medicines and Health Products in 2019 the early access program was established. Patients suffering from severe liver fibrosis (F3) and compensated cirrhosis (F3) or patients with F2 Fibrosis and amyl transferase levels greater than twice the upper limit of normal for a period of 6 months or more were eligible to be treated. Patients were treated with bulevirtide on its own (n = 77) or in combination with peg-interferon (n = 68) as per their physician.
The researchers defined virologic efficacy as HDV RNA levels that are undetectable or decreased by at least 2 log 10 from the baseline. They defined biochemical efficacy as ALT levels of less than 40 IU/L.
A per-protocol analysis was conducted that included all patients in the bulevirtide treatment group, but excluded 12 from the combination group who stopped taking peg-interferon (n = 56). Nineteen patients in bulevirtide group had a treatment modification, and seven discontinued treatment. Five patients in the combined group were treated with a modification, and 14 patients stopped treatment. The combination group had a lower median log 10 IIU/mL at 12 month (-5.65 against 3.64), although the study was unable to be compared. At 12 months, the combination group had 93.9% virologic efficacy, in contrast to 68.3% in the bulevirtide group.
The two groups had similar mean ALT levels at 12 months (48.91 and 48.03 IU/mL and 48.03 IU/mL, respectively) However, more patients in the bulevirtide group having normal ALT levels (40 IU/L or less 48.8 percent opposed to 36.4%). A combined response is defined as having no detectable HDVRNA or greater than 2log 10 at baseline and normal ALT levels. It is 39.0% in the bulevirtide and 30.3% in the combination groups.
Nineteen patients in the bulevirtide group had an adverse event, compared to 43 in the combined group. The two groups were comparable in the frequency of grade 3-4 adverse events (7 versus 6) and discontinuation due adverse events (2 versus 3) deaths (0 in both) injection site reactions (2 in both), liver-related adverse events (4 versus 2), and elevated bile acid (76 against an average of 68).
In the Q&A session following the presentation De Ledinghen was asked if there was a preferred regimen for HDV patients. “It depends on the degree of tolerance you have to peg-interferon, because of all the side effects. We need predictive factors to predict the response of interferon to virology. He said that even though there is no preference right now however, he believes that we should be looking at the factors that predict the virologic response.
The EMA’s conditional approval for bulevirtide was based on the results of phase 2 clinical trials, while the phase 3 clinical trials are still in progress. Anna Lok, MD, was asked to provide a comment on the study. “This was a highly unusual move by the EMA to grant what is similar to an emergency approval for usage, even though the clinical trials in phase 2 are ongoing.” Lok is an Internal Medicine professor, Director of Clinical Hepatology, and the Assistant Dean for Clinical Research at the University of Michigan in Ann Arbor.
She noted that the phase 2 research revealed that the combination with peg-interferon seems to be a beneficial combination for HDV suppression, whereas monotherapy with bulevirtide may have a greater effect on normalizing ALT levels. The experience in the real world confirms these findings.
However, the actual data raised some concerns. “The significant number of patients who needed dose modifications or discontinuations really concerned me. This seems to be the case in both treatment groups. Lok said that although they didn’t go into too many details about the reasons patients required treatment adjustments, one must assume that this was due to adverse effects.
She also said that the per-protocol approach, instead of an intention-to-treat study is a weak point of the study. The number of patients being studied has decreased over time- up to 40% of patients did not have test results at month 12. This makes you think about the fate of those patients. Lok said that many people did not respond. In this case the overall response rate is significantly lower.”
The study was funded by Gilead. De Ledinghen has financial connections to Gilead and Echosens Hologics, Hologics and Intercept Pharma. Tillotts is Orphalan, Alfasigma. Bristol Myers Squibb and Siemens Healthineers. Lok has no relevant financial disclosures.
The original article appeared on MDedge.com which is part of the Medscape Professional Network.
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