EASL 2015: Prenylation Inhibitor Lonafarnib Lowers Hepatitis Delta Viral Load During Therapy

alt

Lonafarnib, a farnesyl transferase inhibitor that interferes with viral assembly, reduced hepatitis delta virus (HDV) levels by more than 3 log in a Phase 2 study presented at the European Association for the Study of the Liver (EASL) 50th International Liver Congress last month in Vienna. Combining lonafarnib with pegylated interferon for 8 weeks led to significantly greater HDV RNA declines than lonafarnib alone, but boosting with ritonavir achieved an even greater effect with an all-oral regimen. HDV viral load rose again after stopping therapy, however, and researchers are now evaluating longer treatment durations.

Hepatitis delta is a small virus that can only replicate in the presence of hepatitis B virus (HBV). Over years or decades chronic hepatitis B can lead to advanced liver disease including cirrhosis and liver cancer. Disease progression is more rapid and more severe in people coinfected with both HBV and HDV.

There is currently no standard treatment for hepatitis D. Interferon can stimulate the immune response against both HBV and HDV, but hepatitis B treatment using nucleoside/nucleotide analogs such as entecavir (Baraclude) or tenofovir (Viread) only minimally suppresses HDV.  It is thought that HDV can continue to replicate in the presence of hepatitis B surface antigen (HBsAg) and HBV covalently closed circular DNA in the liver (cccDNA, an intermediate form that persists in the cell nucleus), so therapy that only reduces HBV DNA viral load is not enough to control HDV.

Cihan Yurdaydin from Ankara University School of Medicine in Turkey presented findings from the Phase 2 LOWR HDV-1 trial, a proof-of-concept study evaluating lonafarnib as the first oral treatment for hepatitis D.

Lonafarnib, being developed by Eiger BioPharmaceuticals and licensed by Merck, targets farnesyl transferase, an enzyme that modifies proteins through a process known as prenylation. This is a key step in the HDV lifecycle, and blocking prenylation interferes with assembly and packaging of new virus particles. Since lonafarnib acts against a human host enzyme rather than the virus itself, it should have a higher barrier to resistance than direct-acting antivirals. In addition to hepatitis delta, lonafarnib is also being studied as a treatment for leukemia and progeria (a rare genetic disease characterized by accelerated aging).

As reported at the 2014 AASLD Liver Meeting, a Phase 2a study by the U.S. National Institutes of Health found that 100 mg twice-daily lonafarnib monotherapy for 4 weeks reduced HDV RNA by mean of -0.7 log, with only one-third of patients having at least a 1 logreduction -- the same proportion as pegylated interferon plus tenofovir in the HIDIT-2 study. Raising the lonafarnib dose to 200 mg twice-daily increased the mean HDV RNA reduction to -1.6 logand the response rate to 100%.

The LOWR HDV-1 study aimed to identify an optimal lonafarnib regimen, looking at higher doses, more frequent administration, longer treatment duration, and combination therapy with either pegylated interferon alfa-2a (which has a different mechanism of action) or ritonavir (which boosts levels of other drugs by interfering with drug-processing CYP450 enzymes).

The study included 15 participants with chronic HBV and HDV infection recruited in Turkey. They were randomly assigned to the following regimens, with 3 people in each arm (lonafarnib and ritonavir are taken orally; pegylated interferon is injected):

Treatment continued for 4 weeks, at which point efficacy, pharmacokinetics, and tolerability were assessed. Participants in the ritonavir and interferon combination arms then continued on the same regimen for an additional 4 weeks.

Results

A dose-finding study called LOWR HDV-2 is now underway in Turkey, testing lonafarnib plus ritonavir combinations for longer durations. These findings "provide hope that extending treatment duration will have good results," Yurdaydin said.

An estimated 15 million people have hepatitis delta worldwide -- or about 5% of all people with hepatitis B. While Europe and the U.S. have designated hepatitis delta as an orphan disease due to the small numbers of people infected, prevalence is much higher in certain regions including Turkey, Russia, and parts of Central Asia, China, Africa, and South America.

Just before the Liver Congress Eiger announced that the U.S. Food and Drug Administration has granted fast-track status to lonafarnib for hepatitis delta, allowing for speedier review and approval.

5/12/15

Reference

C Yurdaydin, R Idilman, I Choong, et al. Optimizing the prenylation inhibitor lonafarnib 
using ritonavir boosting in patients with chronic delta hepatitis. 2015 International Liver Congress: 50th Annual Meeting of the European Association for the Study of the Liver (EASL). Vienna, April 22-26, 2015. Abstract O118.

Other Sources

Eiger BioPharmaceuticals. Eiger Bio Announces Interim Results of Lonafarnib in Combination with Ritonavir or Pegylated Interferon in Patients Infected with Hepatitis Delta Virus (HDV). Press release. April 27, 2015.

Eiger BioPharmaceuticals.FDA Grants Fast Track Designation to Eiger Bio’s Lonafarnib for Hepatitis Delta Virus (HDV) Infection. Press release. April 20, 2015.