Immune modulator inarigivir looks promising for people with hepatitis B

Inarigivir, or SB 9200, an immune-modulating drug that has a dual mechanism of action against hepatitis B virus (HBV), reduced levels of HBV DNA, RNA and antigens, and potency was enhanced when followed by tenofovir, according to early results from the ACHIEVE trial presented at the recent 2017 AASLD Liver Meeting in Washington, DC.

Nucleoside/nucleotide antivirals like tenofovir disoproxil fumarate (DF) (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude) can suppress HBV replication over the long term during therapy. But they usually do not lead to a cure – as indicated by loss of hepatitis B surface antigen (HBsAg) and development of anti-HBs antibodies – and researchers are working on several therapies they hope will offer better options.

Inarigivir soproxil, being developed by Spring Bank Pharmaceuticals, is an oral immune modulator that activates RIG-I (retinoic acid-inducible gene I), a pattern recognition receptor that plays a role in detecting viruses like HBV and initiating immune responses against them. Inarigivir fights HBV both by interfering with viral replication and by stimulating the production of interferons, which trigger antiviral immune responses. In earlier trials, it also showed modest activity against hepatitis C virus (HCV).

Man-Fung Yuen of the University of Hong Kong reported results from the first cohort in Part A of the phase 2 ACHIEVE trial, which is evaluating various doses of inarigivir followed by tenofovir DF.

Participants are randomly assigned to receive inarigivir monotherapy at doses of 25mg, 50mg, 100mg or 200mg once daily, or else a placebo, for the first 12 weeks. Everyone then switches to 300mg tenofovir DF monotherapy for the second 12 weeks. Yuen reported findings from the initial cohort, which received the 25mg dose.

This cohort included 20 people who were either hepatitis B treatment-naive or had been off therapy for more than six months. Sixty per cent were men, most were Asian and the mean age was 41 years. Nine inarigivir recipients were hepatitis B 'e' antigen (HBeAg)-positive and seven were HBeAg-negative They had modestly elevated alanine transaminase (ALT) levels and mild fibrosis. People with advanced fibrosis or cirrhosis, liver cancer, poor kidney function or co-infection with HCV, hepatitis delta or HIV were excluded.

Overall, participants taking inarigivir saw only a small decrease in HBV DNA during monotherapy while the placebo group had a small rise, so at week 12 viral load had fallen significantly more in the inarigivir group (mean -0.58 vs +0.33 log₁₀). As expected, both groups saw steep viral load drops after switching to tenofovir DF.

However, HBV DNA fell more during inarigivir monotherapy in HBeAg-negative compared with HBeAg-positive patients. In the HBeAg-negative group, viral load decreased by a mean -0.86 log₁₀ at 12 weeks and -3.96 log₁₀ at 24 weeks. In the HBeAg-positive group, the corresponding reductions were -0.37 log₁₀ and -4.48 log₁₀.

Levels of HBV RNA, indicating active viral replication, also fell during treatment, but this was mostly limited to HBeAg-negative people. Among the seven HBeAg-negative participants, three had undetectable HBV RNA at week 12 and five did so at week 24.

Three HBeAg-negative patients saw a sustained reduction in HBsAg levels of more than -0.5 log₁₀ on inarigivir alone at week 12. Six people (three HBeAg-negative and three HBeAg-positive) experienced this much HBsAg decline at week 24 after switching to tenofovir DF. Several HBeAg-positive patients also saw a decline in HBeAg levels, averaging -0.54 log₁₀ at week 24.

Inarigivir was generally safe and well tolerated, with no serious adverse events or severe laboratory abnormalities reported. The most common adverse events were fatigue, headache and gastrointestinal symptoms. Three people had their dose reduced due to ALT 'flares', or sudden steep increases.

The better performance of inarigivir in the HBeAg-negative group suggests that this low dose works better in people with lower baseline viral load, the researchers suggested.

In a related poster on the mechanism of action of inarigivir, investigators concluded that the 25mg dose resulted in significant antiviral effects on HBV replication, with the drug appearing to inhibit HBV directly at the level of RNA packaging (encapsidation) and copying (reverse transcription). They added that the 25mg dose did not activate innate or adaptive immune responses in the prior HCV studies, but doses of 200mg or higher did so.

In a November press release, Spring Hill announced initial results from the 50mg hepatitis B cohort. This analysis included ten HBeAg-positive, four HBeAg-negative and four placebo patients. Inarigivir at this dose was also well tolerated with no serious adverse events.

HBV DNA fell by mean of -1.05 log₁₀ in the HBeAg-negative patients and -0.61 log₁₀ in the HBeAg-positive group. HBV RNA also fell more in the HBeAg-negative group, all of whom became undetectable at the end of inarigivir monotherapy. These declines were about double those seen in the 25mg cohort. One HBeAg-positive patient had a greater than 0.5 log₁₀ reduction in HBsAg, but the four HBeAg-negative participants saw no major reduction in HBsAg.

The 100mg cohort is now enrolling and results from the higher dose cohorts are forthcoming. Researchers plan to study initial combination therapy using both inarigivir and tenofovir alafenamide, Gilead Science's new, better-tolerated version of the drug.

"The antiviral dose response in both HBV DNA and HBV RNA at a dose not yet associated with full immune activation is encouraging and supports further development as we move towards combination therapies with inarigivir serving as a potential backbone treatment, with the ultimate goal of achieving elevated functional cure rates for HBV patients," said Spring Hill chief medical officer Nezam Afdhal.