D-LIVR topline results: Lonafarnib all-oral, combination regimens boost response in HDV
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Topline findings from the phase 3 D-LIVR trial showed that lonafarnib — boosted with ritonavir and in combination with peginterferon alfa — improved responses in patients with chronic hepatitis D virus, Eiger BioPharmaceuticals announced.
Lonafarnib, a first-in-class oral prenylation inhibitor, was granted orphan drug designation by the FDA in 2014 and breakthrough therapy status in 2018. Given the recent setback for rival Gilead’s bulevirtide for chronic HDV and compensated liver disease, this phase 3 data could position lonafarnib as a strong competitor in the race to HDV market.
“The results of this landmark study highlight three key findings,” Ohad Etzion, MD, director of gastroenterology and liver diseases at Soroka University Medical Center and D-LIVR co-lead investigator, said in an Eiger press release. “First, a small subset of patients with chronic HDV infection may achieve virologic and biochemical improvements with an all-oral regimen after 48 weeks of treatment. Second, combining lonafarnib and ritonavir with peginterferon alfa demonstrated the potential to nearly double the response rate.”
He added: “And third, and perhaps most importantly, based on these data, combination treatment may lead to significant histologic improvement, a generally accepted surrogate for improved future clinical outcomes for patients. We look forward to the 24-week post-treatment results of this study for assessment of the potential for finite therapy for chronic HDV infection.”
In the global, multicenter trial, patients with chronic HDV were randomized to receive one of two lonafarnib-based treatments: an all-oral arm of lonafarnib boosted with ritonavir (n = 178) and a combination arm of lonafarnib boosted with ritonavir combined with peginterferon alfa (n = 125). Each group was compared with a placebo group (n = 52).
The study also included a peginterferon alfa comparator group (n = 52) to assess contribution of effect only; however, the lonafarnib groups were not required to demonstrate superiority over peginterferon alfa. The primary endpoint was a composite of at least a 2-log decline in HDV RNA and alanine aminotransferase normalization after 48 weeks of treatment.
According to topline results at week 48, both lonafarnib treatment groups attained statistical significance vs. placebo in the composite primary endpoint as well as the component virologic and biochemical responses. Patients who received the all-oral therapy and combination therapy demonstrated a composite response of 10.1% (P = .0044) and 19.2% (P < .0001), respectively, vs. those receiving placebo (1.9%).
Patients who received all-oral therapy and combination therapy also exhibited statistically significant improved rates of ALT normalization of 24.7% (P = .003) and 34.4% (P < .0001), respectively, vs. those who received placebo (7.7%). Compared with the peginterferon alfa group, the composite response rate in the all-oral group was comparable (9.6% vs. 10.1%), whereas the composite response rate in the combination arm was twice that of the peginterferon alfa group (19.2% vs. 9.6%).
The researchers defined the key secondary histological endpoint as at least a 2-point improvement in histological activity index with no worsening of Ishak fibrosis scoring as defined by blinded assessment of paired liver biopsies (n = 229) collected at baseline and week 48. These endpoints were attained in 35 of 66 patients (53%, P = 0.0139) with statistical significance in the combination group vs. 8 of 30 patients (27%) who received placebo. Additionally, response was shown in 35 of 107 patients (33%, P = 0.61) in the all-oral group vs. placebo, whereas response in the peginterferon alfa comparator arm was 10 of 26 patients (38%).
The researchers reported that most treatment emergent adverse events were mild or moderate in severity, with gastrointestinal adverse events tied to lonafarnib being most frequently reported. The all-oral lonafarnib treatment groups reported serious treatment-emergent adverse events in 8% of patients and the combination lonafarnib group reported 14% vs. 10% of patients in the peginterferon alfa group and 4% in the placebo group.
Treatment discontinuation was common in both lonafarnib groups (all-oral: 9%; combination: 8%) compared with just 2% in the peginterferon alfa and placebo groups.
“We would like to extend our sincere gratitude to the patients, investigators and clinical study sites for their participation in this well-controlled, landmark study,” David Cory, president and CEO of Eiger, said in the release. “As we continue to analyze these topline data to fully understand the efficacy and safety profile of lonafarnib-based treatments in chronic HDV, we look forward to a pre-NDA meeting with FDA in the coming quarter and seeing the full dataset including the 24-week post-treatment data.”
The company noted that the remaining secondary endpoints — virologic, biochemical and composite responses at week 72 — are still being collected and will be reported mid-2023.
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