Lonafarnib regimens ‘exceed end-of-treatment response’; oral therapy may be viable in HDV
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Treatment with lonafarnib boosted with ritonavir, with or without peginterferon alfa, resulted in significant virological and biochemical response in patients with chronic hepatitis D virus infection, according to data presented.
“As of yet, there is no FDA-approved therapy for this severe disease,” Ohad Etzion, MD, director of the department of gastroenterology and liver diseases at Soroka Medical Center in Israel, said at EASL Congress. “Therefore, treatment of HDV still presents an urgent, unmet medical need.”
He continued: “Lonafarnib showed suppression of HDV levels in a proof-of-concept study, followed by several phase 2 clinical trials showing improved efficacy of lonafarnib when boosted with ritonavir and/or when combined with pegylated interferon alfa for 24 weeks.”
In the global, phase 3 D-LIVR clinical trial, Etzion and colleagues assessed the safety, tolerability and efficacy of lonafarnib boosted with ritonavir, with and without pegylated interferon alfa, vs. placebo for treatment of chronic HDV infection. Key inclusion criteria included compensated liver disease, HDV RNA greater than 500 IU/mL, elevated alanine transaminase and HBV DNA less than 20 IU/mL.
Of 908 individuals screened, researchers included 407 patients (mean age, 42.7 years; 69% men), who were assigned to oral lonafarnib with ritonavir (n = 178), combination lonafarnib with ritonavir plus peginterferon alfa (n = 125), peginterferon alfa alone (n = 52) or placebo (n = 52) for 48 weeks with a 24-week follow-up.
The primary outcome of interest was the composite of a least a 2-log decline in HDV RNA and normalization of ALT at week 48. Secondary outcomes included histological improvement with at least a 2-point drop in Ishak histology activity index without worsening of fibrosis.
Results from intention-to-treat analysis showed that lonafarnib treatment arms had a statistically significant difference over placebo in the primary composite endpoint, with 10.1% of patients in the oral arm and 19.2% in the combination arm achieving the primary endpoints compared with less than 2% in the placebo arm.
Additionally, virological response was achieved in 14.6% of patients in the oral arm and 32% in the combination arm compared with 3.8 % with placebo, as well as ALT normalization in 24.7%, 34.4% and 7.7%, respectively.
“Looking at the dynamics of virological and biochemical response throughout treatment, we observed a steep initial decline continuing until week 12 to 16 followed by a rebound, which occurred to a lesser extent in the combination arm,” Etzion said.
Researchers obtained evaluable liver biopsies in 229 patients and reported statistically significant histologic improvement was only achieved in the combination arm (P = .0139). “To the best of our knowledge this is the first time histological improvement of statistical significance was seen in a chronic HDV study,” Etzion noted.
Of 312 patients who completed a full 48-week course of treatment and 24 weeks of follow-up, there was a higher response rate observed in both treatment arms compared with placebo at weeks 48 and 72.
Discontinuation rates (19%) and dose interruptions (45%) were comparable among all groups, and side effects were also similar — generally mild to moderate and mostly gastrointestinal-related. There were 40 incidences of severe adverse events reported across all treatment arms, as well as three deaths.
“In this landmark study, both lonafarnib arms achieved the composite primary endpoint vs. placebo,” Etzion said. “Key secondary endpoints were also met. And for the first time, statistically significant improvement in histology was seen in the combination arm. This further strengthens our assessment of the potential utility of this treatment and could also predict improved long-term clinical outcomes. Both lonafarnib treatment regimens were safe and well-tolerated.”
He continued, “The encouraging 24 weeks of treatment responses that actually exceed the end-of-treatment response rates suggest for the first time that finite, oral-based therapy may be possible at least in a subset of patients with chronic hepatitis D.”
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Etzion O, et al. Abstract GS-012: Week 48 results of the phase 3 D-LIVR study: a randomized double-blind, placebo-controlled trial evaluating the safety and efficacy of lonafarnib-boosted with ritonavir with or without peginterferon alfa in patients with chronic hepatitis delta. Presented at: EASL Congress; June 21-24, 2023; Vienna (hybrid meeting).
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