Plenty of momentum for inarigivir

HOPKINTON, Mass.—This year’s International Liver Congress, the 2019 Annual Meeting of the European Association for the Study of the Liver held last month in Vienna, saw Spring Bank Pharmaceuticals Inc. share positive results from its inarigivir Phase 2 dose-escalation ACHIEVE trial for patients with chronic hepatitis B virus (HBV). Inarigivir is an orally administered hepatic-selective immunomodulator as part of a combination regimen for chronic HBV that Spring Bank hopes will provide a safe, selective method for boosting functional cure rates.

“The data from the ACHIEVE trial demonstrate a clear dose-dependent antiviral response on HBV DNA and HBV RNA with inarigivir treatment,” said Prof. M.F. Yuen, chief of gastroenterology and hepatology at the University of Hong Kong and principal investigator for the ACHIEVE trial. “Importantly, inarigivir treatment of HBeAg-negative patients in this study suggests a rapid down-regulation of cccDNA transcription. The HBsAg response of a 0.5log10 or greater reduction in the inarigivir-treated patients is the best reported to date with an oral agent in the treatment of chronic HBV patients, with a similar genotype distribution of responders to that reported for interferon, the only approved immunomodulator treatment for chronic HBV.”

In a presentation of top-line results for all ACHIEVE cohorts, it was shown that inarigivir demonstrated a dose-dependent effect on HBV DNA and HBV RNA in the fourth cohort of the trial over the 12-week dosing period. Inarigivir 200 mg monotherapy dosing resulted in a mean decrease of 1.54log10 in HBV DNA with a range of 0.71log10 to 3.26log10, and a mean decrease of 1.14log10 in HBV RNA with a range of 0.08log10 to 4.88log10. This treatment cohort also saw a uniform antiviral response in all patients, particularly the high viral burden HBeAg-positive patients who failed to respond to lower doses of inarigivir monotherapy. In all patients, HBV DNA and HBV RNA responses strongly correlated with baseline HBsAg, baseline IP-10 and the decline of IP-10 at week 12, comparable to the experience with interferon in this disease.

In all dosing cohorts, 16 of 62 evaluable patients (26 percent) treated with inarigivir saw a 0.5log10 or greater reduction in HBsAg at week 12 or week 24 and were categorized as responders. The mean reduction of HBsAg in this population was 0.8log10, with a range of 0.5log10 to 1.4log10. The HBsAg response to inarigivir was deemed to be genotype- and host-dependent.

Overall data implied a significant shutdown of viral transcription by inarigivir in HBeAg-negative patients, with HBV RNA undetectable at week 12 in all patients treated with inarigivir at the 50mg, 100mg and 200mg doses, with a concomitant undetectable HBcrAg in the majority of those patients. At week 24, those responses were sustained with the switch to tenofovir disoproxil fumarate 300mg and associated with 18 of the 22 (82 percent) HBeAg-negative patients presenting with undetectable HBV DNA.

The drug was well tolerated at all doses, with treatment-emergent adverse events ranging from mild to moderate in severity and the rate of those events being similar between the active and placebo cohorts. The fourth cohort saw one Grade 3 event (hypertriglyceridemia) that was not sustained on retesting, and a placebo patient was hospitalized with a serious adverse event of knee pain.

A study in healthy volunteers, which evaluated a 400mg dose for chronic HBV patients, found that this dosing level led to a rapid, uniform increase in activation markers of innate immunity on circulating peripheral monocytes and dendritic cells. This effect was sustained over a 10-day dosing period without evidence of tolerance. Participants also saw an activation of CD8+ T cells and downregulation of NK cells, and a lack of systemic cytokine activation secondary to the intra-hepatic targeting of inarigivir, which makes for an encouraging tolerability profile. Spring Bank based its recent initiation of the CATALYST trials on these data, and the global CATALYST trials will evaluate the 400mg dose in treatment-naïve and virally suppressed chronic HBV patients.

In a recent conference call regarding the ACHIEVE trial data, Martin Driscoll, chairman, president and CEO of Spring Bank, spoke of another new trial initiated, saying “I am also pleased to report we have now launched our liver biopsy study. This is an important study looking at the inter-hepatic immunomodulatory profile of the 400mg dose of inarigivir. This trial involves a baseline liver biopsy and then patients will be treated for six weeks, 400mg. At the conclusion of the six weeks of treatment, another biopsy will be done. We’re optimistic that we could have data from this particular trial to present at a scientific conference perhaps as recent as before the end of this year. So it’s an exciting time for our company.”

“The increasing antiviral response seen at the 200 mg dose, especially in high viral burden patients, and the clear evidence of innate immune activation at the 400 mg dose in healthy volunteers with good tolerability, has led Spring Bank to choose 400 mg as the inarigivir dose to move forward into longer studies focused on HBV cure,” noted Dr. Nezam Afdhal, chief medical officer of Spring Bank Pharmaceuticals. “We have developed a comprehensive strategic clinical trial program that takes into account both patient and viral heterogeneity that we anticipate will inform our Phase 3 strategy moving into 2020.”