Late-stage chronic hepatitis D trial halted due to safety concerns

A late-stage clinical trial in patients with chronic hepatitis D (CHD) infection is about to be halted, according to study sponsor Eiger BioPharmaceuticals.¹ The Phase 3 LIMT-2 study (NCT05070364) is evaluating the efficacy and safety of peginterferon lambda in approximately 160 participants with well-compensated CHD infection.

Quarterly safety review results revealed that four patients experienced hepatobiliary events leading to hepatic decompensation. These observations led the Data Safety Monitoring Board to recommend stopping the trial.

“The termination of this study is disappointing, especially for patients with chronic hepatitis D who have limited treatment options,” Eiger CEO David Apelian, MD, PhD, MBA, said in a statement.¹ “For the safety of our patients, we will work closely with the FDA and our investigators to terminate the LIMT-2 study in an orderly manner.”

Phase 3, open-label, parallel-arm trial randomized well-compensated CHD-infected participants to receive peginterferon lambda 180 mcg weekly for 48 weeks with follow-up for 24 weeks (n=105), or 12 weeks thereafter Pegylated interferon lambda 180 mcg weekly for 48 weeks without treatment and followed for 24 weeks (n=53). During the study period, all patients also received concomitant therapy with a second-generation anti-HBV nucleoside analogue (NUC). The trial ultimately enrolled 158 participants at 48 sites in 12 countries.

Of note, treatment data from the second cohort were not used in the primary analysis; instead, it was used to provide baseline data in the parallel reference cohort for HCV infection in participants who received 12 weeks of anti-HBV NUC alone. Expected rates of RNA inhibition.

The primary endpoint was durable virologic response at 72 weeks with hepatitis D virus RNA below the limit of quantitation at 24 weeks post-treatment.

This latest news is another blow to the hepatitis D treatment field, as there is an unmet need to address the most severe hepatitis infections.

In October 2022, Gilead received a complete response letter from the FDA to its biologics license application for the treatment of HDV in adults, despite Gilead releasing positive efficacy data. The FDA cited concerns about the production and delivery of the drug.²

Phase 3 clinical trial results published in New England Journal of Medicine³ The July 2023 study showed that participants randomized to receive subcutaneous bulevirtide 2 mg daily or bulevirtide 10 mg daily for 144 weeks met the primary endpoint of undetectable or reduced hepatitis D RNA levels. At 48 weeks, there was an increase of at least 2 log10 IU per milliliter compared with baseline, and alanine aminotransferase (ALT) levels also normalized.

Nearly half (48%) of the subjects in the 10 mg group and 45% of the subjects in the 2 mg group achieved this combined response at 48 weeks, compared with 2% in the control group. Over 48 weeks, 20% of people in the 10 mg group, 12% of people in the 2 mg group, and no one in the control group reached undetectable levels of hepatitis D RNA. By week 48, ALT levels had dropped to the normal range in 56% of subjects in the 10 mg group, 51% of subjects in the 2 mg group, and 12% of subjects in the control group. Among patients who achieved combined remission at 48 weeks, ALT levels were essentially normalized at 24 weeks, while hepatitis RNA levels continued to decline through 48 weeks.

Of note, bulevirtide 2 mg has been approved by the European Medicines Agency and NICE for this indication. The FDA has not requested or is conducting further studies on bulevirtide. Therefore, Gilead said it will continue to communicate with regulatory agencies and strive to bring the drug to the U.S. market in the near future.²

refer to

1. Eiger will discontinue the Phase 3 LIMT-2 trial of peginterferon Lambda in patients with chronic hepatitis D. Press Releases. September 12, 2023. Accessed 13 September 2023. https://www.prnewswire.com/news-releases/eiger-to-discontinue-phase-3-limt-2-tri-of-peginterferon-lambda-in-patient-with-chronic-hepatitis-delta-301925362. html
2. Gilead received a complete response letter from the U.S. FDA regarding the treatment of hepatitis D virus in adults with Bulevirtide. Press Releases. October 27, 2022. Accessed 13 September 2023. https://www.gilead.com/news-and-press/company-statements/gilead-receives-complete-response-letter-from-us-fda-for-bulevirtide – used to treat people with hepatitis D virus aldult
3.Wedemeyer H, Aleman S, Brunetto MR et al. Phase 3 randomized trial of bulevirtide in chronic hepatitis D. New England Journal of Medicine

. 2023;389(1):22-32. doi:10.1056/NEJMoa2213429