imdusiran (AB-729) / Arbutus - LARVOL DELTA

The small interfering RNA imdusiran as single and multiple doses in healthy, randomised individuals and non-randomised individuals with chronic hepatitis B (AB-729-001): a phase 1a/b trial. (PubMed, Lancet Gastroenterol Hepatol) - P1 | "Single and multiple doses of imdusiran were safe and well tolerated in healthy individuals and in individuals with chronic hepatitis B, supporting drug development of imdusiran as a future treatment targeting functional cure for chronic hepatitis B."

Journal • P1 data • Dermatology • Fatigue • Fibrosis • Hepatitis B • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pain • Respiratory Diseases

Arbutus Biopharma Corporation (NASDAQ:ABUS) announced today that the U.S. Food and Drug Administration has granted Fast Track designation to imdusiran for treating chronic hepatitis B. (Investing.com) - "According to the press release statement, eight patients with chronic hepatitis B achieved functional cure in Phase 2a clinical trials following treatment with imdusiran and nucleos(t)ide analogue therapy combined with either pegylated interferon alfa-2a or low dose nivolumab plus an immunotherapeutic."

Fast track • Hepatitis B

Study Investigating the Safety and Immunogenicity of AB-729 and VTP 300 in Virologically Suppressed CHB Participants (ANZCTR) - P2 | N=62 | Completed | Sponsor: Arbutus Biopharma | Active, not recruiting ➔ Completed

Trial completion • Hepatitis B • Infectious Disease • Inflammation

Open-Label Study of AB-729, Nucleos(t)Ide Analogue and Pegylated Interferon Alfa-2a in Subjects With Chronic Hepatitis B Infection (clinicaltrials.gov) - P2 | N=43 | Completed | Sponsor: Arbutus Biopharma Corporation | Active, not recruiting ➔ Completed

Trial completion • Hepatitis B • Infectious Disease • Inflammation

IM-PROVE I: HBV GENOTYPE RESPONSIVENESS TO PEGYLATED INTERFERON ALFA-2A MAY BE ENHANCED WITH IMDUSIRAN COMBINATION TREATMENT (AASLD 2025) - "In this limited dataset, the majority of subjects who achieved HBsAg response during IFN treatment with or following IDR dosing were GT B or C. These findings contrast with historical data from IFN therapy and suggest that IDR may enhance IFN responsiveness in CHB patients with specific HBV GTs. Further studies in larger cohorts are warranted to confirm these observations."

Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation

ELEVATED SOLUBLE IMMUNE BIOMARKERS IN SUBJECTS WITH HBSAG LOSS AFTER TREATMENT WITH IMDUSIRAN AND IMMUNOTHERAPEUTIC AGENTS IN THE IM-PROVE I AND IM-PROVE II STUDIES (AASLD 2025) - "IM-PROVE II assessed 24W of IDR lead-in followed by the immunotherapeutic VTP-300, VTP-300 + low dose nivolumab (LDN), or placebo. IDR treatment is associated with increases in soluble immune biomarkers in both IM-PROVE I and IM-PROVE II studies. In subjects who lost HBsAg and had anti-HBs antibodies, a greater breadth and magnitude of immune biomarker increases were observed in IM-PROVE I subjects compared to IM-PROVE II. In both studies, subjects who showed increases in soluble immune biomarkers on-treatment met NA discontinuation criteria and had baseline HBsAg ≤1000 IU/mL."

Biomarker • Clinical • IO biomarker • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation

IMDUSIRAN (AB-729) IS SAFE AND WELL-TOLERATED AFTER REPEAT DOSING IN CHRONIC HEPATITIS B PATIENTS: AN INTEGRATED SAFETY ANALYSIS OF PHASE 1 AND 2 IMDUSIRAN CLINICAL TRIALS (AASLD 2025) - P1, P2 | " Safety data including clinical and laboratory results was pooled (n=151) and evaluated from a Phase 1 trial (AB-729-001; ACTRN12620000295943) and three Phase 2 combination treatment trials of IDR with immunotherapies (AB-729-201; NCT04980482, AB-729-202; ACTRN12622000317796) or a capsid assembly modulator (ABI-H0731-204; NCT04820686). IDR therapy in patients with CHB was safe and well tolerated when administered at both 60 mg and 90 mg dose levels every 8 weeks for 4 – 6 doses (24 – 48 weeks) and through up to 48 weeks of follow up after IDR dosing."

Clinical • P1 data • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Liver Failure

A Multiple Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AB-729 Administered by Subcutaneous Injection to Subjects with Chronic Hepatitis B Infection (ANZCTR) - P1 | N=96 | Completed | Sponsor: Arbutus Biopharma Corporation | Active, not recruiting ➔ Completed

Trial completion • Hepatitis B • Infectious Disease • Inflammation

A Single Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AB-729 Administered by Subcutaneous Injection to Subjects with Chronic Hepatitis B Infection (ANZCTR) - P1 | N=167 | Completed | Sponsor: Arbutus Biopharma Corporation | Active, not recruiting ➔ Completed

Trial completion • Hepatitis B • Infectious Disease • Inflammation

A Study to Investigate the Safety, Tolerability and Pharmacokinetics, of AB-729 Administered by Subcutaneous Injection to Healthy Subjects (part 1) (ANZCTR) - P1 | N=24 | Completed | Sponsor: Arbutus Biopharma Corporation | Active, not recruiting ➔ Completed

Trial completion • Hepatitis B • Infectious Disease • Inflammation

Off-treatment antiviral efficacy and safety of repeat dosing of imdusiran followed by VTP-300 with or without nivolumab in virally-suppressed, non-cirrhotic subjects with chronic hepatitis B (CHB) (EASL 2025) - "Preliminary off NA treatment follow-up data suggest that repeat dosing of IDR followed by VTP-300 + LDN was well- tolerated and led to HBsAg loss in 3 out of 13 subjects, with 2 approaching functional cure. Additional follow-up data will be presented."

Clinical • Late-breaking abstract • Endocrine Disorders • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Open-Label Study of AB-729, Nucleos(t)Ide Analogue and Pegylated Interferon Alfa-2a in Subjects With Chronic Hepatitis B Infection (clinicaltrials.gov) - P2 | N=43 | Active, not recruiting | Sponsor: Arbutus Biopharma Corporation | Trial primary completion date: May 2024 ➔ Mar 2025

Trial primary completion date • Hepatitis B • Infectious Disease • Inflammation

Data highlighted in late-breaker poster presentation shows that imdusiran achieves functional cure in chronic hepatitis B (cHBV) patients when combined with VTP-300 and low dose nivolumab (GlobeNewswire) - P1b/2a | N=55 | IM-PROVE II (NCT04778904) | Sponsor: Barinthus Biotherapeutics | "All 3 patients had baseline HBsAg <1000 IU/mL. 25% (2/8) of Group C patients with baseline HBsAg <1000 IU/mL who received nivolumab reached functional cure with an overall functional cure rate in Group C of 15.3% (2/13)….Compared to placebo (Group B) more patients treated with imdusiran and VTP-300 (Group A) were able to remain off NA therapy even without achieving functional cure."

P2a data • Hepatitis B

IM-PROVE I: characterization of chronic hepatitis B (CHB) subjects with functional cure or HBV DNA suppression after completion of imdusiran plus short courses of pegylated interferon alfa-2a (IFN) and discontinuation of nucleos(t)ide analogue (NA) therapy (EASL 2025) - No abstract available

Clinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

IM-PROVE I: characterization of chronic hepatitis B (CHB) subjects with functional cure or HBV DNA suppression after completion of imdusiran plus short courses of pegylated interferon alfa-2a (IFN) and discontinuation of nucleos(t)ide analogue (NA) therapy (EASL 2025) - " Among the 6 subjects who achieved FC, mean (±SD) age was 51 (±2.8) years, 3/6 were male, 5/6 were Asian, and ongoing NA therapy at BL included 1/6 on entecavir and 5/6 on tenofovir based-therapy, with a mean (±SD) duration of current NA treatment of 7.8 (±2.6) years. Within this small group of subjects who achieved FC or HBV DNA<LLOQ after NA discontinuation in the IM-PROVE I study, HBsAg at baseline and at the time of NA d/c appear to be the only factors associated with FC, with no apparent differences in other baseline characteristics or HBV biomarkers collected, including HBcrAg and HBV RNA. Additional analysis of this dataset is ongoing, and these BL characteristics and HBV biomarkers should continue to be evaluated in larger trials."

Clinical • Hematological Disorders • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Neutropenia • IFNL3

IM-PROVE I: Rapid loss followed by transient increases in HBV RNA in chronic hepatitis B subjects during treatment with imdusiran and pegylated interferon alfa-2a is associated with HBsAg seroclearance (EASL 2025) - "Subjects who achieved functional cure after combination treatment with IDR + IFN showed rapid HBV RNA decline during IDR lead-in, with 5/6 subjects achieving HBV RNA undetectability during this period. Transient elevations in HBV RNA were observed to occur during the IFN treatment period which was associated with further HBsAg decline and loss in some FC subjects."

Clinical • Hepatitis B • Hepatitis C • Hepatology • Infectious Disease • Inflammation

Arbutus to Present Imdusiran and AB-101 Data at EASL Congress 2025 (GlobeNewswire) - "Arbutus Biopharma Corporation...announced that five abstracts, including one late-breaker, have been accepted for presentation at the European Association for the Study of the Liver (EASL) Congress 2025 taking place May 7 - 10, 2025 in Amsterdam, Netherlands."

Clinical data • Hepatitis B

Long-Term Follow-up Study for Subjects With CHB Previously Treated With Imdusiran (AB729) (clinicaltrials.gov) - P=N/A | N=50 | Recruiting | Sponsor: Arbutus Biopharma Corporation | Not yet recruiting ➔ Recruiting | N=35 ➔ 50

Enrollment change • Enrollment open • Hepatitis B • Hepatology • Infectious Disease • Inflammation

SOLUBLE IMMUNE BIOMARKER PROFILING OF CHRONIC HEPATITIS B SUBJECTS TREATED WITH IMDUSIRAN IN COMBINATION WITH PEGYLATED INTERFERON ALFA REVEALS PHASES OF IMMUNE ACTIVATION (AASLD 2024) - "IDR treatment in combination with IFN was associated with distinct phases of soluble immune biomarker signatures. Immune biomarkers associated with Th1 immune activation and regulation of inflammation were observed in subjects during IDR lead-in, coinciding with the establishment of a plateau in HBsAg reduction. Secondary transient elevations of these immune biomarkers were observed to occur during IFN treatment and were followed by appearance of Th2 immune biomarker signatures that were associated with HBsAg seroconversion."

Biomarker • Clinical • Combination therapy • IO biomarker • Hepatitis B • Hepatology • Infectious Disease • Inflammation • BTLA • CD86 • IL10 • IL12A • IL13 • IL4 • IL5 • IL6 • IL7 • LAG3 • PD-1 • PD-L1

HBV TARGET SITE FOR THE RNA INTERFERENCE THERAPEUTIC IMDUSIRAN IS HIGHLY CONSERVED IN CHRONIC HEPATITIS B SUBJECTS (AASLD 2024) - "Background: Imdusiran (AB-729, IDR) is an N- Acetylgalactosamine-conjugated small interfering RNA (siRNA) currently being investigated in multiple combination studies, including pegylated interferon-alfa 2a (AB-729-201, IM-PROVE I) and the immunotherapeutic VTP-300 (AB-729-202, IM-PROVE II) for the treatment of chronic hepatitis B (CHB). The IDR target site is highly conserved in baseline samples from CHB subjects enrolled in IDR clinical studies assessed to date. In vitro testing in an HBV cell-based model confirmed retention of IDR activity against tested variants, suggesting that these SNPs have no apparent influence on HBsAg declines in subjects treated with IDR. Imdusiran has demonstrated clinical activity against HBV genotypes A-E."

Clinical • IO biomarker • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Control of Hepatitis B Virus with Imdusiran, a Small Interfering RNA Therapeutic. (PubMed, ACS Infect Dis) - "Imdusiran did not intrinsically stimulate cytokine release in healthy donor human whole blood, supportive of its mechanism of action as a direct acting RNA interference antiviral. Taken together, these data support imdusiran in combination treatment approaches toward chronic hepatitis B functional cure."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Study Investigating the Safety and Immunogenicity of AB-729 and VTP 300 in Virologically Suppressed CHB Participants (ANZCTR) - P2 | N=62 | Active, not recruiting | Sponsor: Arbutus Biopharma | Recruiting ➔ Active, not recruiting | N=40 ➔ 62

Enrollment change • Enrollment closed • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IFNG

Study of Imdusiran (AB-729) in Combination With Intermittent Dosing of Durvalumab in Subjects With Chronic HBV Infection (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Arbutus Biopharma Corporation | N=30 ➔ 0 | Trial completion date: Jul 2027 ➔ Aug 2024 | Recruiting ➔ Withdrawn | Trial primary completion date: Feb 2027 ➔ Aug 2024

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

i-LIVER: Intrahepatic and Peripheral Responses to Imdusiran (AB-729) in Chronic Hepatitis B (clinicaltrials.gov) - P2 | N=10 | Recruiting | Sponsor: University of Maryland, Baltimore | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Imdusiran (AB-729) administered every 8 weeks for 24 weeks followed by the immunotherapeutic VTP-300 maintains lower HBV surface antigen levels in NA-suppressed CHB subjects than 24 weeks of imdusiran alone (EASL-ILC 2024) - "Study AB-729-202 is an ongoing, randomized, double-blinded Phase 2a study assessing the safety, pharmacodynamics and immunogenicity of repeat doses of imdusiran followed by VTP-300 ± low dose nivolumab or placebo in nucleos(t)ide analogue (NA) suppressed, non-cirrhotic CHB subjects. Repeat dosing of imdusiran for 24 weeks followed by VTP-300 was well-tolerated and contributes to the maintenance of lower HBsAg levels compared to placebo in subjects who have reached EOT and follow up Wk 60. More subjects who received VTP-300 have qualified to stop NA therapy at EOT and all remain off therapy. Additional on-treatment, follow-up and NA discontinuation data including HBV parameters and immunology data will be presented."

Clinical • Hepatitis B