Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial

Abstract

Summary Background Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis. Methods In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months’ follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585. Findings Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were −0.73 log IU/mL in group 1 (95% CI 0.17–1.31; p=0.03) and −1.54 log IU/mL in group 2 (1.21–1.93; p<0.0001). Lonafarnib serum concentrations correlated with HDV RNA change (r2=0.78, p<0.0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0.75 days [SE 0.24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0.952 [SE 0.06] vs 0.739 [0.05], p<0.001), and the HDV half-life was 1.62 days (0.07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups. Interpretation Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV. Funding National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

“…Several candidates are being evaluated in clinical trials mainly in combination with PegIFNa and/or NA including HBV/HDV entry inhibitors (Myrcludex-B), 244,245 drugs inhibiting the release of HBsAg (nucleic acid polymers), 246 and inhibitors of the prenylation of the large HDV antigen. 243,247 Whenever possible, enrollment in these new clinical trials should be considered, either as a rescue of PegIFNa failure or to improve treatment success rate in naïve patients.…”

Diagnosis, management and treatment of hepatitis delta virus infection: Turkey 2017 Clinical Practice Guidelines

“…For those who have at least 2 log 10 IU/mL of a decrease in HDV RNA at the end of treatment or who become negative at the end of the treatment and recurrence again, the logical approach seems to be continuing the antiviral treatment without stopping or reinitiating at the time of a recurrence. During recent years, studies performed on humans with prenylation inhibitors (35), hepatocyte entry inhibitors (36) and nucleic acid polymers (37) seemed promising for the near future.…”

Pharmacokinetics and Pharmacodynamics Modeling of Lonafarnib in Patients with Chronic Hepatitis Delta Virus Infection

“…The complete details of this study have been presented elsewhere. (6) All subjects provided written informed consent. The study was approved according to the Declaration of Helsinki by the Institutional Review Board of the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH.…”

“…(6) Samples were collected before the first dose, at 6, 12, 18, 24, 36, 48, and 72 hours after the first dose and on days 7, 14, 21, and 28.…”

“…(6) While LNF has demonstrated potential promise in the therapy of CDH, a better understanding of the doseresponse effect between LNF and HDV could facilitate treatment optimization. Thus, the aim of this study was to estimate the pharmacokinetic (PK), pharmacodynamic (PD), and viral kinetic (VK) parameters during LNF therapy for CDH and to predict the LNF dose needed to achieve 99% efficacy.…”