Prenylation inhibitor lonafarnib lowers hepatitis delta viral load during therapy

Lonafarnib, a farnesyl transferase inhibitor that interferes with viral assembly, reduced hepatitis delta virus (HDV) levels by more than 3 log₁₀ 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, Austria. Combining lonafarnib with pegylated interferon for 8 weeks led to significantly greater HDV RNA declines than lonafarnib alone, but boosting with ritonavir achieved the same 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 with HBV and HDV co-infection.

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 analogues 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 of 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 leukaemia and progeria (a rare genetic disease characterised by accelerated ageing).

As reported at The Liver Meeting, the annual meeting of the American Association for the Study of Liver Diseases (AASLD), in 2014, a phase 2a study by the US National Institutes of Health (NIH) found that 100mg twice-daily lonafarnib monotherapy for 4 weeks reduced HDV RNA by mean of -0.7 log₁₀, with only a third of patients having at least a 1 log₁₀ reduction – the same proportion as pegylated interferon plus tenofovir in the HIDIT-2 study. Raising the lonafarnib dose to 200mg twice-daily increased the mean HDV RNA reduction to -1.6 log₁₀ and 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 three people in each study arm (lonafarnib and ritonavir are taken orally; pegylated interferon is injected):

• Lonafarnib 200mg twice daily

• Lonafarnib 300mg twice daily

• Lonafarnib 100mg three times daily

• Lonafarnib 100mg twice daily + 100mg ritonavir once daily

• Lonafarnib 100mg twice daily + pegylated interferon 180mcg once weekly.

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.

During the first 4 weeks of treatment, HDV viral load levels fell by a mean of -1.5, -1.6 and -2.0 log₁₀ in the lonafarnib 100mg three-times-daily, 200mg twice-daily and 300mg twice-daily arms, respectively, thereby matching or exceeding responses in the NIH trial. Moreover, the decline in HDV RNA was more rapid than seen with interferon and tenofovir in the HIDIT-2 trial.

The largest decrease was observed in the lonafarnib 100mg twice-daily arm with ritonavir boosting: a mean -2.2 log₁₀ decrease in HDV RNA. Pharmacokinetic analysis showed that ritonavir raised serum lonafarnib concentrations by more than three-fold compared to monotherapy. The average decrease was slightly lower in the lonafarnib plus pegylated interferon arm, at -1.8 log₁₀.

During the second month of treatment HDV RNA continued to fall. In the ritonavir-boosted lonafarnib arm, two people saw continued but less steep declines, while the third had a greater than -5.0₁₀ log decrease and reached an undetectable level (mean for arm: -3.2 log₁₀). In the lonafarnib plus pegylated interferon arm, two people had sustained steep declines reaching approximately -3.5 log₁₀, while the third had a smaller decrease (mean for arm: -3.0 log₁₀). 

After stopping therapy at week 8, all study participants saw their HDV RNA levels rise again, though only one had returned to the baseline level by the end of post-treatment follow-up at 12 weeks.

Lonafarnib was generally safe and well-tolerated. The most frequently reported side-effects were gastrointestinal symptoms, loss of appetite and weight loss. Adverse events were mild to moderate (grade 1-2). Side-effects appeared to be more common in the 200mg and 300mg lonafarnib dose arms, but not more frequent or severe in the interferon-containing arm. Yurdaydin noted lonafarnib has been administered for two years in progeria trials with no apparent safety issues.

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 US have designated hepatitis delta as an orphan disease due to the small overall 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 US Food and Drug Administration has granted fast-track status to lonafarnib for hepatitis delta, allowing for speedier review and approval.