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
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
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
- 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
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.
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.