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AASLD 2017: Immune Modulator Inarigivir Looks Promising for 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 (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 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 25, 50, 100, or 200 mg once daily, or else a placebo, for the first 12 weeks. Everyone then switches to 300 mg tenofovir DF monotherapy for the second 12 weeks. Yuen reported findings from the initial cohort, which received the 25 mg dose.

This cohort included 20 patients who were either hepatitis B treatment-naive or had been off therapy for more than 6 months; 60% were men, most were Asian, and the mean age was 41 years. 9 inarigivir recipients were hepatitis B "e" antigen (HBeAg)-positive and 7 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 coinfection 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 log). 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 logat 12 weeks and -3.96 logat 24 weeks. In the HBeAg-positive group the corresponding reductions were -0.37 logand -4.48 log.

Levels of HBV RNA, indicating active viral replication, also fell during treatment, but this was mostly limited to HBeAg-negative people. Among the 7 HBeAg-negative participants, 3 had undetectable HBV RNA at week 12 and 5 did so at week 24.

Three HBeAg-negative patients saw a sustained reduction in HBsAg levels of more than -0.5 log on inarigivir alone at week 12. Six people (3 HBeAg-negative and 3 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 log 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 25 mg 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 25 mg dose did not activate innate or adaptive immune responses in the prior HCV studies, but doses of 200 mg or higher did so.

In a November press release, Spring Hill announced initial results from the 50 mg hepatitis B cohort. This analysis included 10HBeAg-positive, 4 HBeAg-negative, and 4 placebo patients. Inarigivir at this dose was also well tolerated with no serious adverse events.

HBV DNA fell by mean of -1.05 log in the HBeAg-negative patients and -0.61 log 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 25 mg cohort. One HBeAg-positive patient had a greater than 0.5 log reduction in HBsAg, but the 4 HBeAg-negative participants saw no major reduction in HBsAg.

The 100 mg 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.



MF Yuen, C Coffin, M Elkhashab B et al. SB 9200 an oral selective immunomodulator is safe and efficacious in treatment-naive, non-cirrhotic HBV patients: Results from Cohort 1 of the ACHIEVE trial. AASLD: The Liver Meeting. Washington, DC, October 20-24, 2017. Abstract 39.

S Locarnini, D Wong, K Jackson et al. Novel anti-viral activity of SB 9200, a RIGI agonist; results from Cohort 1 of the ACHIEVE trial. AASLD: The Liver Meeting. Washington, DC, October 20-24, 2017. Abstract 25-LB.