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AASLD 2016: 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 recent AASLD Liver Meeting in Boston.

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 coinfection 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 analogs 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 from Hannover Medical School and colleagues conducted a Phase 2 study to evaluate the safety and efficacy of lonafarnib boosted with ritonavir in HBV/HDV coinfected patients.

Lonafarnib (brand name Sarasar), being developed for HDV by Eiger BioPharmaceuticals under a license 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 characterized by accelerated aging) and some types of cancer. It has been granted FDA Fast Track and orphan drug status 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 patients to reach higher, more effective doses and to take the drug for a longer duration.

This study included 15 HBV/HDV coinfected patients 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 log 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). 12 patients were taking nucleoside/nucleotide analogs at study entry and 10 had previously used interferon.

All patients in this open-label study started on 50 mg lonafarnib with 100 mg ritonavir twice-daily. If well-tolerated, lonafarnib doses were increased to 75 mg twice-daily after a minimum of 4 weeks, then to 100 mg twice-daily after a minimum of 2 weeks since the last dose escalation. Total treatment duration was 24 weeks.

All but 2 patients were able to increase their lonafarnib dose to 75 mg twice-daily, and 10 increased to 100 mg twice-daily. Of these, half remained on 100 mg through week 24 while half reduced their doses. That is, 5 people (33%) received the full dose for the full intended duration.

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

Half of the participants experienced ALT normalization by the end of treatment. Some patients experienced HBV DNA "flares" during treatment, but 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 2 completed 24 weeks of therapy; these 2 people had their doses reduced to 50 and 100 mg once-daily, but still ended up discontinuing treatment.

The most common adverse event was grade 1-2 (mild to moderate) diarrhea, experienced by all participants, followed by grade 1-2 weight loss (8 patients), nausea (7 patients), and loss of appetite (7 patients). 4 people experienced grade 3 adverse events (2 diarrhea, 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 patients to reach and maintain full doses through 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.

1/23/17

Source

H Wedemeyer, K Port, K Deterding, et al. A Phase 2 Study of Titrating-Dose Lonafarnib Plus Ritonavir in Patients with Chronic Hepatitis D: Interim Results from the Lonafarnib with Ritonavir in HDV-4 (LOWR HDV-4) Study. AASLD Liver Meeting. Boston, November 11-15, 2016. Abstract 230. View abstract