Early Trial Results May Hold Promise for Patients With HDV

New clinical trial results may offer hope to the 0.11% of Americans with a hepatitis D virus (HDV) infection, according to a recently published editorial in the New England Journal of Medicine that provided context for data showing the efficacy of bulevirtide in patients with this rare disease.¹ The editorial accompanied the research findings published in the same issue.²

HDV occurs almost exclusively in individuals with a chronic hepatitis B virus (HBV) infection, explained editorial author Marc G. Ghany, MD, MHSc. Ghany is section chief of the clinical hepatology research section, liver disease branch at the National Institute of Diabetes and Digestive and Kidney Diseases.

Due to its low prevalence in the United States, chronic HDV is covered under the FDA’s Orphan Drug Designation program.

The condition is also linked with a faster progression to liver failure and cirrhosis, Ghany explained, and is associated with a higher rate of liver cancer compared with other chronic viral hepatitis forms.

Currently, no therapy is approved for chronic HDV in the United States. However, the findings from an ongoing, multicenter phase 3 trial assessing the safety and efficacy of bulevirtide (NCT03852719) offer encouraging results for patients.

Bulevirtide is a synthetic lipopeptide that “irreversibly binds to sodium taurocholate cotransporting polypeptide, the hepatocyte entry receptor for both HDV and HBV,” Ghany wrote. The treatment prevents new infection by blocking viral entry, he added.

Based on early phase studies, bulevirtide did receive conditional marketing authorization from the European Medicines Agency in July 2020 for patients with compensated chronic HDV. For patients with HDV, therapy goals include improved survival by preventing progression to cirrhosis, liver cancer or failure, Ghany noted.

In the current phase 2 study, patients were assigned to receive either 2- or 10-mg doses of the treatment once a day for 144 weeks. A control group received no therapy for the first 48 weeks, then received 10 mg of bulevirtide once a day for 96 weeks.

After the treatment arm of the trial was completed, all patients were scheduled for a 96 week follow-up period.

“The primary end point was a combined response at week 48 of an undetectable HDV RNA level, or a level that declined by at least 2 log10 IU per milliliter from baseline, and normalization of the [alanine aminotransferase (ALT)] level,” Ghany wrote.

While just 2% of the control group achieved this primary end point response, it was reached by 45% of patients in the 2-mg group and 48% in the group that received 10 mg.

Combined response rates were similar across subgroups including among those with cirrhosis.

Following week 48, “HDV viremia was undetectable in 12% of patients in the 2-mg group and 20% in the 10-mg group, as compared with 0% in the control group,” Ghany added.

However, no reductions in HBV surface antigen levels were seen, prompting concerns that treatment responses may not last.

In addition, “whether a decline in HDV viremia from baseline of 2 log10 IU per milliliter or more and normalization of the ALT level, as assessed at week 48 of treatment, would translate into a clinical benefit is uncertain,” Ghany noted.

Additional research is also needed to address remaining questions, including whether the clinical benefit in individuals with a 2-log10 IU per milliliter decline in HDV viremia level would be similar to patients who have undetectable viremia, he said.

More studies are also needed to ascertain the appropriate dose and duration of therapy in these patients, along with long-term treatment safety.

The current trial did not have sufficient power to detect differences in primary end point responses between the 2 groups who received different doses, marking a limitation.

Although the European Medicines Agency approved the 2-mg dose of bulevirtide and “recommended that therapy can be continued as long as clinical benefit is maintained,” the agency did not define clinical benefit, Ghany wrote.

Overall, results of the current trial “offer a glimmer of hope for an orphan disease, and the final results of the trial are eagerly awaited,” he concluded.

References

1. Ghany MG. A glimmer of hope for an orphan disease. N Engl J Med. 2023;389(1):81-82. doi:10.1056/NEJMe2304147

2. Wedemeyer H, Aleman S, Brunetto MR, et al. A phase 3, randomized trial of bulevirtide in chronic hepatitis D. N Engl J Med. 2023;389(1):22-32. doi:10.1056/NEJMoa2213429