inarigivir soproxil (SB 9200) / Gilead, Sino Biopharm - LARVOL DELTA

Ascending dose cohort study of inarigivir - A novel RIG I agonist in chronic HBV patients: Final results of the ACHIEVE trial (EASL-ILC 2019) - "We report here the final results of the ACHIEVE trial, an ascending dose cohort study of 12 weeks of inarigivir followed by a switch to 12 weeks of tenofovir (TDF) 300mg daily in treatment naïve HBV patients. 80 patients were randomized to inarigivir (25,50,100 and 200mg) daily or placebo in a 4:1 ratio for 12 weeks and then all patients were switched to TDF. The ACHIEVE trial confirms the safety and anti-viral efficacy of inarigivir up to 200mg daily and further studies at doses of up to 400mg daily in combination with TDF or added to NUC suppressed patients are underway.Figure: Pbo E+vePbo E-veEpos 25mgEneg25mgEpos50mgEneg50mgEpos100mgEneg100mgEpo- s200mgEneg200mgn889711513487Age354837433647344642- 52M:F7:15:35:53:39:25:07:63:14:42:5ALT85538275756- 575905473HBV DNA7.644.757.865.697.794.558.205.957.884.95GT A11GT B2643344325GT C6151718162GT D211"

Clinical • Dyslipidemia • Pain

A Human Liver Organoid Screening Platform for DILI Risk Prediction. (PubMed, J Hepatol) - "The high throughput and liver-on-chip system exhibit enhanced in vivo-like function and demonstrate the potential utility of these platforms for hepatotoxicity risk assessment. Tenofovir-inarigivr associated hepatotoxicity was observed and correlates with the clinical manifestation of DILI observed in patients."

Journal • Hepatology • Liver Failure

A phase 2, open-label, randomized, multiple dose study evaluating Inarigivir in treatment-naïve patients with chronic hepatitis B. (PubMed, Liver Int) - "12-week Inarigivir up to 200 mg dose was associated with reduction of HBV DNA, HBV RNA and antigen levels. A trend for greater HBsAg reduction was observed in Inarigivir pre-treated patients after switching to tenofovir."

Journal • P2 data • Hepatitis B • Hepatology • Immune Modulation • Infectious Disease • Inflammation

Activation of DDX58/RIG‑I suppresses the growth of tumor cells by inhibiting STAT3/CSE signaling in colon cancer. (PubMed, Int J Oncol) - "In addition, the RIG‑I agonist, SB9200, induced proliferation, migration and invasion of human colon cancer. On the whole, the present study demonstrates that DDX58/RIG‑I affects the proliferation of tumor cells by regulating STAT3/CSE signaling in colon cancer. The findings presented herein suggest that DDX58/RIG‑I activation may be an effective treatment strategy, and DDX58/RIG‑I agonists may be potential therapeutic candidates for colon cancer."

IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • DDX58

Study to Evaluate the Safety and Antiviral Activity of Inarigivir Soproxil (Formerly: GS-9992) Plus Tenofovir Alafenamide (TAF) for 12 Weeks in Adults With Chronic Hepatitis B (CHB) (clinicaltrials.gov) - P2 | N=123 | Terminated | Sponsor: Gilead Sciences | Completed ➔ Terminated; Study was terminated due to sponsor's decision to not pursue further development of inarigivir soproxil in chronic hepatitis B.

Trial termination • Hepatitis B • Hepatology • Infectious Disease • Inflammation

[VIRTUAL] New Agents for Treatment of HBV Infection: Targeting the Immune System (APDW 2021) - "A phase 2 study in untreated patients failed to show any significant HBsAg decline with 12-week course of vesatolimod and tenofovir disoproxil fumarate (TDF) combination...Phase 2 study of selgantolimod in combination with nucleos(t)ide analogue in virologically suppressed patients showed mild decline of HBsAg in up to 20% of patients after 24 weeks of treatment...Phase 1 study on inarigivir showed dose-dependent HBV DNA reduction and HBV RNA reduction after 12-week treatment, and 26% of patients had HBsAg reduction of >0.5 log IU/ml...A phase 1 study using low dose nivolumab, a monoclonal antibody blocking PD1, has shown HBsAg decline in virologically suppressed patients with a single patients clearing HBsAg. Newer formula of PD1 and PD L1 blockade using GalNac targeting are under development for liver-specific therapeutic effect against HBV."

Hepatitis B • Hepatology • Immune Modulation • Immunology • Infectious Disease • Inflammation • Oncology • IFNG • IL12A • TLR8 • TNFA

[VIRTUAL] Safety, efficacy, & pharmacodynamic (PD) activity of 12 weeks treatment with oral RIG-I agonist, inarigivir (IRIG), plus 48 weeks of tenofovir alafenamide in adult patients with chronic hepatitis B: a phase 2 collaboration study (EASL-ILC 2021) - "No dose dependent changes in HBV DNA or HBsAg were observed with IRIG ≤400 mg+NUC. IRIG was generally safe and well tolerated at doses ≤400 mg for 12WK. IRIG development has been discontinued due to IRIG-related hepatoxicity."

Clinical • P2 data • PK/PD data • Constipation • Gastrointestinal Disorder • Hepatitis B • Hepatology • Immune Modulation • Infectious Disease • Inflammation • Pain

Study to Evaluate the Antiviral Activity of Inarigivir Soproxil (GS-9992) Plus Tenofovir Alafenamide (TAF) for 12 Weeks in Adults With Chronic Hepatitis B (CHB) (clinicaltrials.gov) - P2; N=123; Completed; Sponsor: Gilead Sciences; Active, not recruiting ➔ Completed; Trial completion date: May 2021 ➔ Jan 2021

Clinical • Trial completion • Trial completion date • Hepatitis B • Hepatology • Infectious Disease

NOD2/RIG-I Activating Inarigivir Adjuvant Enhances the Efficacy of BCG Vaccine Against Tuberculosis in Mice. (PubMed, Front Immunol) - "Consistent with an increase in immunogenicity of adjuvant treated APCs, the Inarigivir-BCG vaccine combination induced robust protection against tuberculosis in a mouse model of MTB infection, decreasing the lung burden of MTB by 1-log10 more than that afforded by BCG vaccine alone. The Inarigivir-BCG combination was also more efficacious than a muramyl-dipeptide-BCG vaccine combination against tuberculosis in mice, generating better memory T cell responses supporting its novel adjuvant potential for the BCG vaccine."

Journal • Hepatitis B • Hepatology • Infectious Disease • Respiratory Diseases • Tuberculosis • IL12A • IL1B • TNFA

[VIRTUAL] Liver toxicity in the Phase 2 Catalyst 206 trial of Inarigivir 400mg daily added to a nucleoside in HBV EAg negative patients (EASL-ILC-I 2020) - "We describe an unusual, heterogeneous DILI observed after a mean of 16 weeks of inarigivir (400mg daily) added to a NUC. Further studies are ongoing to identify causality and mechanisms. These findings have implications for trial design in HBV ‘cure’ studies and liver safety parameter monitoring."

Clinical • Late-breaking abstract • P2 data • Cholestasis • Hepatology • Immunology • Liver Failure • Metabolic Disorders • Pain • Pancreatitis

[VIRTUAL] Mechanism of action studies of inarigivir, a novel immunomodulator against chronic hepatitis B (EASL-ILC-I 2020) - "The in vitro and in vivo studies support the MOA of Inarigivir involving the activation of hRIG-I to produce IFNs and cytokines and mediate antiviral activity in CHB patients."

Hepatitis B • Hepatology • Immune Modulation • Immunology • Infectious Disease • Inflammation • Targeted Protein Degradation • CXCL10 • IL6

Review article: clinical pharmacology of current and investigational hepatitis B virus therapies. (PubMed, Aliment Pharmacol Ther) - "There are promising investigational therapies for HBV infection. Increasing the potential for HBsAg loss may result in more patients achieving functional cure. However, many knowledge gaps remain such as pharmacokinetics in those with HBV, cirrhosis and renal impairment but also the interaction potential between investigational therapies, risk-benefit profiles, and potential for drug interactions with medications used to treat comorbidities associated with aging."

Clinical • Journal • Review • Fibrosis • Hepatitis B • Hepatology • Immunology • Infectious Disease • Renal Disease

Evaluating the Safety and Efficacy of Inarigivir in Non-cirrhotic, Hepatitis B e Antigen-negative Subjects Infected With HBV Virus and Receiving or Stopping Treatment With a NUC Inhibitor (clinicaltrials.gov) - P2; N=64; Terminated; Sponsor: Spring Bank Pharmaceuticals, Inc.; Active, not recruiting ➔ Terminated; Safety

Clinical • Trial termination • Hepatitis B • Infectious Disease • Non-alcoholic Fatty Liver Disease • IL10 • IL6 • PCR

Spring Bank Pharmaceuticals initiates a phase I clinical trial for SB 9200 in HCV-infected patients (PRNewswire) - P1, N=64; NCT01803308; Sponsor: Spring Bank; "Spring Bank ...initiated dosing in a Phase I study of SB 9200 ...treatment of HCV infection ...designed to assess both the safety and antiviral efficacy of SB 9200 ...based on the Company's proprietary Small Molecule Nucleic Acid Hybrid (SMNH) technology platform ...trial is currently being conducted in Australia with plans to expand into clinical sites in New Zealand."

Enrollment status • New P1 trial • Hepatitis C Virus

SB 9200, a novel agonist of innate immunity, shows potent antiviral activity against resistant HCV variants. (PubMed) - J Med Virol - "Using the HCV capture-fusion assay, we show that SB 9200 is active against diverse HCV genotypes and is also effective against HCV derived from patients who relapse following direct-acting antiviral treatment, including viruses containing known NS5A resistance-associated sequences. These data confirm the broad antiviral activity of SB 9200 and indicate that it may have clinical utility in HCV patients who have failed to respond to current antiviral regimens."

Journal • Biosimilar • Hepatitis C Virus • Immunology

Evaluating the Effects of Inarigivir on Immune Response and Viral Markers in Chronic Hepatitis B Patients (clinicaltrials.gov) - P2; N=8; Terminated; Sponsor: Spring Bank Pharmaceuticals, Inc.; N=16 ➔ 8; Trial completion date: Nov 2020 ➔ Dec 2019; Active, not recruiting ➔ Terminated; Trial primary completion date: Nov 2020 ➔ Dec 2019; Study was halted due to suspected liver injury in another study with Inarigavir

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Hepatitis B • Infectious Disease

Evaluating the Safety and Efficacy of Inarigivir in Non-cirrhotic, Hepatitis B e Antigen-negative Subjects Infected With HBV Virus and Receiving or Stopping Treatment With a NUC Inhibitor (clinicaltrials.gov) - P2; N=60; Active, not recruiting; Sponsor: Spring Bank Pharmaceuticals, Inc.; Trial completion date: Jun 2022 ➔ Jun 2020; Trial primary completion date: Jun 2022 ➔ Jun 2020

Clinical • Trial completion date • Trial primary completion date • Hepatitis B • Infectious Disease • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • IL10 • IL6 • PCR

Evaluating the Safety and Efficacy of Inarigivir in Non-cirrhotic Treatment Naive Subjects Infected With Hepatitis B Virus (clinicaltrials.gov) - P2; N=5; Terminated; Sponsor: Spring Bank Pharmaceuticals, Inc.; N=60 ➔ 5; Trial completion date: Aug 2022 ➔ Apr 2020; Active, not recruiting ➔ Terminated; Trial primary completion date: Aug 2022 ➔ Apr 2020; Evidence of liver injury in a separate Inarigavir study

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Hepatitis B • Infectious Disease • IL10 • IL6

ACHIEVE: A Study Evaluating the Safety, Pharmacokinetics, and Antiviral Efficacy of SB 9200 in Subjects Infected With Chronic HBV (clinicaltrials.gov) - P2; N=80; Completed; Sponsor: Spring Bank Pharmaceuticals, Inc.; Active, not recruiting ➔ Completed; N=200 ➔ 80; Trial completion date: Jul 2021 ➔ Feb 2020; Trial primary completion date: Jul 2021 ➔ Feb 2020

Clinical • Enrollment change • Trial completion • Trial completion date • Trial primary completion date

Mechanism of action studies of inarigivir, a novel immunomodulator against chronic hepatitis b (EASL-ILC 2020) - No abstract available

Evaluating the Safety and Efficacy of Inarigivir in Non-cirrhotic, Hepatitis B e Antigen-negative Subjects Infected With HBV Virus and Receiving or Stopping Treatment With a NUC Inhibitor (clinicaltrials.gov) - P2; N=60; Active, not recruiting; Sponsor: Spring Bank Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • IL10 • IL6 • PCR

Evaluating the Effects of Inarigivir on Immune Response and Viral Markers in Chronic Hepatitis B Patients (clinicaltrials.gov) - P2; N=16; Active, not recruiting; Sponsor: Spring Bank Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

Evaluating the Safety and Efficacy of Inarigivir in Non-cirrhotic Treatment Naive Subjects Infected With Hepatitis B Virus (clinicaltrials.gov) - P2; N=60; Active, not recruiting; Sponsor: Spring Bank Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • IL10 • IL6

"$SBPH Stops Dosing and Enrollment in All Inarigivir Studies in Subjects With Chronic HBV https://t.co/EmFPGOnOwv" (@BioStocks)

Clinical

Study to Evaluate the Antiviral Activity of Inarigivir (GS-9992) Plus Tenofovir Alafenamide (TAF) for 12 Weeks in Adults With Chronic Hepatitis B (CHB) (clinicaltrials.gov) - P2; N=123; Active, not recruiting; Sponsor: Gilead Sciences; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed