Lonafarnib lowers hepatitis delta levels with acceptable side-effects

The hepatitis delta virus (HDV) assembly inhibitor lonafarnib reduces HDV viral load and can be safely boosted with ritonavir to allow for higher and more effective doses with acceptable gastrointestinal side-effects, according to study results presented at the 2016 AASLD Liver Meeting in Boston in November.

Hepatitis delta is a small, defective virus that can only replicate in the presence of hepatitis B virus (HBV). Over years or decades chronic HBV infection can lead to advanced liver disease including cirrhosis and liver cancer. HBV/HDV co-infection is associated with more rapid and severe liver disease progression, and people who carry both viruses are more likely to develop cirrhosis and hepatocellular carcinoma than those with HBV alone.

Antiviral therapy using nucleoside/nucleotide analogues such as tenofovir (Viread or Vemlidy) can suppress HBV replication during treatment but usually does not lead to a cure, so long-term treatment is generally needed. There is no standard treatment for hepatitis delta, although pegylated interferon has been shown to suppress HDV replication at least temporarily.

Heiner Wedemeyer of Hannover Medical School and colleagues conducted a phase 2 study to evaluate the safety and efficacy of lonafarnib boosted with ritonavir in people with HBV/HDV co-infection.

Lonafarnib (brand name Sarasar), being developed for HDV by Eiger BioPharmaceuticals under a licence from Merck, targets farnesyl transferase, an enzyme that modifies proteins through a process known as prenylation. This is critical for the final step of the HDV lifecycle, and blocking prenylation interferes with assembly and packaging of new virus particles. Lonafarnib is also being studied as a treatment for progeria (a rare genetic disease characterised by accelerated ageing) and some types of cancer. It has been granted a European Medicines Agency orphan drug designation for HDV.

Previous research showed that lonafarnib reduced HDV RNA levels in a dose-dependent manner in short-term studies, but higher doses led to gastrointestinal side-effects. Administration with the CYP3A4 inhibitor ritonavir increases lonafarnib levels in the body with lower GI exposure.

The LOWR HDV-4 trial assessed whether rapid lonafarnib dose escalation with ritonavir would allow more people to reach higher, more effective doses and to take the drug for a longer duration.

This study included 15 people with HBV/HDV co-infection in Germany. About three-quarters were men, 80% were white and the median age was 40 years. At baseline the mean HDV RNA level was 6.8 log₁₀ IU/ml, the mean alanine aminotransferase (ALT) level was 118 IU/ml and the mean FibroScan transient elastography score was 14.6 kPA (18 is the usual cut-off for cirrhosis in people with HBV). Twelve people were taking nucleoside/nucleotide analogues at study entry and ten had previously used interferon.

All individuals in this open-label study started on 50mg lonafarnib with 100mg ritonavir twice daily. If well tolerated, lonafarnib doses were increased to 75mg twice daily after a minimum of four weeks, then to 100mg twice daily after a minimum of two weeks since the last dose escalation. Total treatment duration was 24 weeks.

All but two people were able to increase their lonafarnib dose to 75mg twice daily, and ten increased to 100mg twice daily. Of these, half remained on 100mg through week 24 while half reduced their doses. That is, five people (33%) received the full dose for the full intended duration.

All participants saw initial declines in HDV RNA, with a mean reduction of 1.91 log₁₀ from baseline through week 24. Nearly three-quarters had a greater than 1 log₁₀ decline and a third had more than a 2 log₁₀ decline. At 24 weeks one person had very low HDV RNA (32 IU/ml) and one had an undetectable level; both received the 100mg twice daily lonafarnib dose to week 24.

Half of the participants experienced ALT normalisation by the end of treatment. Some people experienced HBV DNA 'flares' during treatment, but Prof Wedemeyer explained that HDV appears to suppress HBV, so HBV rebounding as HDV goes down may indicate that treatment is working as expected.

Treatment was generally safe and well tolerated with no drug-related serious adverse events. While just over half of the participants (53%) required lonafarnib dose reduction, all but two completed 24 weeks of therapy; these two people had their doses reduced to 50mg and 100mg once daily, but still ended up discontinuing treatment.

The most common adverse event was grade 1-2 (mild to moderate) diarrhoea, experienced by all participants, followed by grade 1-2 weight loss (eight people), nausea (seven people) and loss of appetite (seven people). Four people experienced grade 3 adverse events (2 diarrhoea, 1 weight loss, 1 asthenia), but there were no grade 4 events.

The researchers concluded that rapid dose-escalation of lonafarnib plus ritonavir is feasible, allowing a third of people to reach and maintain full doses to week 24, although there was considerable inter-patient variability in response and tolerability. They added that slower dose escalation may increase tolerability and efficacy, but noted that another ongoing study (LOWR HDV-2) suggests that dose escalation may not be needed.