Several trial participants experienced concerning hepatobiliary events.
A late-stage clinical trial in patients with chronic hepatitis delta (CHD) infection is being discontinued, according to study sponsor Eiger BioPharmaceuticals.1 The phase 3 LIMT-2 study (NCT05070364) was assessing the efficacy and safety of peginterferon lambda in approximately 160 participants with well-compensated CHD infection.
Findings from a quarterly safety review revealed that 4 patients experienced hepatobiliary events that resulted in liver decompensation. These observations led the Data Safety Monitoring Board to recommend the discontinuation of the trial.
"The study discontinuation is disappointing, especially for patients with chronic hepatitis delta who have limited treatment options," said David Apelian, MD, PhD, MBA, CEO of Eiger, in a statement.1 "We will work closely with the FDA and our investigators to conduct an orderly termination of the LIMT-2 study in the interest of patient safety."
The phase 3, open-label, parallel-arm trial randomly assigned participants with well-compensated CHD infection to receive peginterferon lambda 180 mcg weekly for 48 weeks with 24 weeks of follow-up (n=105) or no treatment for 12 weeks followed by peginterferon lambda 180 mcg weekly for 48 weeks with 24 weeks of follow-up (n=53). All patients also received concomitant therapy with a 2nd generation anti-hepatitis B virus nucleos(t)ide analogues (NUC) for the duration of the study. The trial ultimately enrolled 158 participants across 48 sites in 12 countries.
Notably, treatment data from the second arm was not intended for the primary analysis; instead, it was being used to provide benchmark data in a parallel reference group for the expected rate of hepatitis D virus RNA suppression in participants who received 12 weeks of anti-HBV NUC therapy alone.
The primary end point was durable virologic response at 72 weeks, with hepatitis D virus RNA below the limite of quantitation at 24 weeks post-treatment.
This latest news is yet another blow to the hepatitis D treatment space, as there is a significant unmet need to address what is the most severe of hepatitis infections.
In October 2022, Gilead received a complete response letter from the FDA for its biologics license application for bulevirtide for the treatment of HDV in adults despite posting positive efficacy data. The FDA cited concerns about manufacturing and delivery of the drug.2
Phase 3 clinical trial results published in The New England Journal of Medicine3 in July 2023 demonstrated that participants randomly assigned to receive subcutaneous injections of bulevirtide 2 mg daily or bulevirtide 10 mg daily for 144 weeks met the primary end point, which was a combination of an undetectable level of hepatitis D RNA or a level that had been lowered by at least 2 log10 IU per milliliter from baseline, along with normalization of levels of alanine aminotransferase (ALT), at 48 weeks.
Nearly half (48%) of subjects in the 10 mg group and 45% of those in the 2 mg group achieved this combined response by 48 weeks, compared with 2% of those in the control group. Twenty percent of those in the 10-mg group, 12% of those in the 2-mg group, and none of those in the control group achieved undetectable level of hepatitis D RNA by 48 weeks. ALT levels had lowered to the normal range by week 48 in 56% of subjects in the 10 mg group, 51% of subjects in the 2 mg group, and 12% of controls. In patients who achieved a combined response by 48 weeks, ALT levels largely normalized by 24 weeks while hepatitis RNA levels continued to fall through 48 weeks.
Notably, the European Medicines Agency and NICE have approved bulevirtide 2 mg for this indication. No further studies of bulevirtide are ongoing or were required by the FDA. As such, Gilead said it would continue its communication with the regulatory agency to try to bring the drug to market in the US in the near future.2