AB-506 / Arbutus - LARVOL DELTA

Design, synthesis, and structure-activity relationship of a bicyclic HBV capsid assembly modulator chemotype leading to the identification of clinical candidate AB-506. (PubMed, Bioorg Med Chem Lett) - "Key compounds demonstrated excellent cellular potency in addition to favorable ADME and pharmacokinetic profiles and were shown to be highly efficacious in a mouse model of HBV replication. Aminoindane derivative AB-506 was subsequently advanced into clinical development."

Journal • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Safety, pharmacokinetics, and antiviral activity of the capsid inhibitor AB-506 from Phase 1 studies in healthy subjects and those with hepatitis B. (PubMed, Hepatol Commun) - "In the follow-up study in HS, 2 additional Asian HS had Grade 4 flares, suggesting that AB-506 hepatotoxicity contributed to the ALT elevations. The AB-506 development program was terminated because of these findings."

Clinical • Journal • P1 data • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Liver Failure

Design, synthesis, and structure-activity relationship of a bicyclic chemotype leading to the identification of the HBV capsid inhibitor clinical candidate AB-506 | Poster Board #2974 (ACS-Fall 2022) - "Based on excellent in vitro and in vivo antiviral activity and desirable in vitro ADME properties in addition to a pharmacokinetic profile consistent with once daily dosing, aminoindane derivative AB-506 was selected for progression into clinical development. In phase 1b trials, q.d. dosing of AB-506 in HBV patients resulted in multi-log10 reductions in HBV DNA and RNA, however, further development was discontinued due to the observation of ALT elevation in some subjects."

Clinical • Developmental Disorders • Fibrosis • Gastrointestinal Cancer • Hepatitis B • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cancer • Liver Cirrhosis • Oncology • Solid Tumor

The identification of highly efficacious functionalised tetrahydrocyclopenta[c]pyrroles as inhibitors of HBV viral replication through modulation of HBV capsid assembly. (PubMed, RSC Med Chem) - "Herein we report the further optimisation of clinical candidate AB-506 through core modification with a focus on increasing oral exposure and oral half-life. Maintenance of high levels of anti-HBV cellular potency in conjunction with improvements in pharmacokinetic properties led to multi-log reductions in serum HBV DNA following low, once-daily oral dosing for key analogues in a preclinical animal model of HBV replication."

Journal

Preclinical characterization of AB-506, an inhibitor of HBV replication targeting the viral core protein. (PubMed, Antiviral Res) - "In vitro combinations of AB-506 with NAs or an RNAi agent were additive to moderately synergistic. AB-506 exhibits good oral bioavailability, systemic exposure, and higher liver to plasma ratios in rodents, a pharmacokinetic profile supporting clinical development for chronic hepatitis B."

Journal • Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation

[VIRTUAL] Hepatitis B virus core protein variants observed in a first-in-human placebo-controlled study of a core protein inhibitor (EASL-ILC-I 2020) - " HBV DNA extraction was performed on plasma collected from the 24 non-cirrhotic, HBeAg- positive or -negative, HBV DNA-positive subjects enrolled in AB-506-001 (randomized 10:2 per cohort to AB-506 versus placebo) and 28 subjects that were screened but not enrolled in the study... These findings highlight the importance of conducting molecular epidemiology studies to assess the prevalence of circulating CI-resistant variants as well as developing next-generation CIs with improved coverage of these variants."

Clinical • P1 data • Hepatitis B • Hepatology • Infectious Disease

SAFETY, TOLERABILITY, PHARMACOKINETICS (PK), AND ANTIVIRAL ACTIVITY OF THE CAPSID INHIBITOR (CI) AB-506 IN HEALTHY SUBJECTS (HS) AND CHRONIC HEPATITIS B (CHB) SUBJECTS (AASLD 2019) - "AB-506 was generally safe and well-tolerated and robust antiviral effects were observed in CHB subjects. The ALT flares observed in CHB subjects may be immune-mediated and may lead to beneficial declines in HBV markers."

Clinical • Late-breaking abstract • PK/PD data

"#AASLD19 #HBV $JNJ JNJ-64530440 seems to be the new leader in capsid assembly modulator class : potent HBV DNA reduction + Good safety. *Mean hbv dna red. at day 28 (ph1b data)* - 3.3 $JNJ - 2.9 ABI-H0731 $ASMB - 2.8 AB-506 $ABUS - 2.7 RO7049389 $RHHBY" (@CaesarBiotech)

Clinical

Function and drug combination studies in cell culture models for AB-729, a subcutaneously administered siRNA investigational agent for chronic hepatitis B infection (EASL-ILC 2019) - "Standard HBV cell lines can be used to characterize the activity of the AB-729 siRNA whereas two primary hepatocyte systems were able to model both the cell entry functionality and anti-HBV activities of AB-729. Preclinical investigations demonstrate that AB-729 and AB-506 when combined have distinct but mechanistically compatible antiviral activities and may feasibly be used in future combination therapeutic regimens."

Preclinical