ABI-H2158 / Assembly Biosci, BeiGene - LARVOL DELTA

Preclinical characterization of ABI-H2158, an HBV core inhibitor with dual mechanisms of action. (PubMed, Antiviral Res) - "ABI-H2158 also potently blocked the formation of cccDNA in de novo HBV infections with ECs of ∼200 nM in HepG2-NTCP and PHH assays. These results indicate ABI-H2158 has dual mechanisms of action, inhibiting both early and late steps of the HBV replication cycle."

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

Safety, pharmacokinetics, and antiviral activity of ABI-H2158, a hepatitis B virus core inhibitor: a randomized, placebo-controlled Phase 1 study. (PubMed, J Viral Hepat) - P1 | "In conclusion, ABI-H2158 in cHBV patients following 14 days of dosing was well tolerated and demonstrated potent antiviral activity. Safety and pharmacokinetics supported future QD dosing."

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

A Study of ABI-H2158-containing Regimens in Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2a | N=88 | Terminated | Sponsor: Assembly Biosciences | Trial completion date: Jan 2023 ➔ Dec 2021 | Active, not recruiting ➔ Terminated; Study stopped due to a safety signal of drug-induced liver injury in subjects receiving 2158

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

A Study of ABI-H2158-containing Regimens in Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2a; N=80; Active, not recruiting; Sponsor: Assembly Biosciences; Recruiting ➔ Active, not recruiting; Trial primary completion date: Jan 2023 ➔ Oct 2021

Clinical • Enrollment closed • Trial primary completion date • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Assembly Bio Announces Decision to Discontinue Clinical Development of ABI-H2158 (GlobeNewswire) - "Assembly Biosciences, Inc...today announced its decision to discontinue development of ABI-H2158 (2158) following the observation of elevated ALT levels consistent with drug-induced hepatotoxicity in an ongoing Phase 2 trial....After communicating the company’s decision to the FDA, the FDA noted that 2158 would also be placed on clinical hold....VBR is being evaluated in two ongoing triple combination studies for which initial on-treatment data are anticipated during 2022. ABI-H3733 (3733) has completed its Phase 1a study and initial data is planned to be announced at an upcoming medical meeting. Additionally, the company expects to advance its recently-selected core inhibitor candidate ABI-4334 (4334) into clinical development in 2022."

Clinical data • Discontinued • New trial • Trial suspension • Hepatitis B • Infectious Disease

"$ASMB Assembly Bio Announces Decision to Discontinue Clinical Development of ABI-H2158 https://t.co/X7N5NCCckE" (@stock_titan)

Clinical

[VIRTUAL] Second generation Hepatitis B Virus core inhibitors ABI-H2158 and ABI-H3733 have enhanced potency and target coverage for both antiviral inhibition and covalently closed circular DNA establishment activities (EASL-ILC 2021) - "We currently have 3 core inhibitors in clinical development: vebicorvir (VBR, Phase 2), ABI-H2158 (2158, Phase 2) and ABI-H3733 (3733, Phase 1)... VBR, 2185, and 3733 achieve plasma concentrations significantly above EC50 and paEC50 for antiviral activity. The second generation compounds 2158 and 3733 show enhanced potency and exposures that cover cccDNA prevention activity at significant multiples of paEC50 at Cmin."

Hepatitis B • Hepatology • Infectious Disease • Inflammation

Assembly Biosciences Presents Data from HBV Core Inhibitor Programs at the International Liver Congress EASL 2021 (GlobeNewswire) - P2, N=92; NCT03780543; P2, N=73; NCT03576066; Sponsor: Assembly Biosciences; "Assembly Biosciences, Inc...announced data from its three clinical-stage core inhibitor programs, vebicorvir (VBR or ABI-H0731), ABI-H2158 (2158), and ABI-H3733 (3733), in an oral presentation and two poster presentations during the International Liver Congress™ 2021, the Annual Meeting of the European Association for the Study of the Liver (EASL), taking place virtually June 23-26, 2021...data evaluating human plasma and estimated liver concentrations of VBR, 2158, and 3733 in relation to their respective protein-adjusted EC50 values in primary human hepatocytes...combination therapy with VBR and NrtI for an extended period was well-tolerated and resulted in deep virologic suppression, but did not result in sustained virologic response in any patient who met prospective treatment stopping criteria."

Clinical data • P2 data • Hepatitis B • Infectious Disease

Assembly Biosciences to Present Data from HBV Core Inhibitor Programs at The International Liver Congress EASL 2021 (GlobeNewswire) - P2, N=73; NCT03576066; P2, N=92; NCT03780543; Sponsor: Assembly Biosciences; "Assembly Biosciences, Inc...announced that three abstracts have been accepted for presentation during the International Liver Congress™ 2021, the Annual Meeting of the European Association for the Study of the Liver (EASL) taking place virtually June 23-26, 2021. During the meeting, data from Assembly Bio’s three core inhibitor programs, vebicorvir (VBR), ABI-H2158 (2158) and ABI-H3733 (3733), will be featured in an oral presentation and two poster presentations...Discontinuation of VBR+NrtI treatment was well-tolerated, but sustained virologic response was not achieved. Further data analyses suggest core-related antigen level may be important in future discontinuation criteria. Other studies with VBR+NrtI in multi-drug combinations will evaluate potential finite treatment regimens."

Clinical data • P2 data • Hepatitis B • Infectious Disease

[VIRTUAL] Antiviral activity, pharmacokinetics and safety of the second-generation hepatitis B core inhibitor ABI-H2158 in Phase 1b study of patients with HBeAg-positive chronic hepatitis B infection (EASL-ILC-I 2020) - "Results from this Phase 1b study demonstrate that ABI-H2158 has potent antiviral activity and a favourable safety profile when administered once daily for 14 days supporting further evaluation in combination with nucleos(t)ide analogues in Phase 2. Table 1. 100 mg (n=7) ABI-H2158 300 mg (n=7) 500 mg (n=7) Placebo (n=6) HBV DNA change from Baseline (log10 IU/mL), mean (range) pgRNA change from Baseline (log10 U/mL), mean (range) Cmax, ng/mL AUC0-24, hr*ng/mL a n=6 -2.3 (-3.0 to -1.7) -2.1 (-2.7 to -1.5) 3,390 46,100 -2.5 (-3.3 to -0.8) -2.2 (-2.6 to -1.4) 8,400 112,000 -2.7 (-3.2 to -1.7) -2.0 (-3.5 to -1.3)a 9,890a 133,000a -0.1 (-0.3 to 0.1) -0.1 (-0.2 to -0.1) - -"

Clinical • Late-breaking abstract • P1 data • PK/PD data • Hepatitis B • Hepatology • Infectious Disease • Pain

Assembly Biosciences Reports First Quarter 2021 Financial Results and Recent Updates (GlobeNewswire) - "Anticipated Milestones and Events...Interim data from Phase 2 study with ABI-H2158 in H2 2021...Chief Scientific Officer, William Delaney, PhD, to present at the Chronic Hepatitis B Drug Development Virtual Summit, May 6, 2021...Research and development expenses were $18.6 million for the three months ended March 31, 2021, compared to $23.0 million for the same period in 2020."

Commercial • P2 data • Hepatitis B • Infectious Disease

A Study of ABI-H2158 in Healthy Volunteers and Patients With Chronic Hepatitis B (clinicaltrials.gov) - P1; N=80; Completed; Sponsor: Assembly Biosciences; Recruiting ➔ Completed

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

[VIRTUAL] AMINO ACID SUBSTITUTIONS IN THE INHIBITOR BINDING POCKET OF HBV CORE PROTEIN CONFER DIFFERENTIAL CHANGES IN SUSCEPTIBILITY TO THREE GENERATIONS OF HBV CORE INHIBITORS (AASLD 2020) - "Here we describe the in vitro resistance profiles of vebicorvir (VBR; ABI-H0731), ABI-H2158 (2158), and ABI-H3733 (3733), 3 generations of structurally distinct core inhibitors with increasing in vitro potency against encapsidation of viral RNA and delivery of existing nucleocapsids to establish cccDNA...Transfected cells were treated with VBR, 2158, 3733 or entecavir (ETV) for 1 week after which the amount of replicating HBV DNA in the cells was evaluated by qPCR... Although all HBV core inhibitors are known to bind the same pocket, specific amino acid substitutions in the region confer differential changes in the resistance profile of structurally distinct small molecules suggesting that specific interactions between the protein and the inhibitors modulate drug susceptibility. ETV retains activity against all tested core protein mutations suggesting that combination therapy with NrtIs may prevent viral breakthrough due to pre-existence or potential emergence of core..."

Late-breaking abstract

Assembly Biosciences Reports Second Quarter 2020 Financial Results and Recent Highlights (GlobeNewswire) - "China Collaboration with BeiGene: On July 20, 2020, Assembly announced its license and collaboration agreement with BeiGene, Ltd. for Assembly’s portfolio of three clinical-stage core inhibitors (ABI-H0731, ABI-H2158, ABI-H3733) in China including Hong Kong, Macau and Taiwan; Assembly received $40 million upfront and is eligible to receive approximately $500 million in total potential future milestone payments....BeiGene will contribute the initial funding for clinical development in China, with development costs for the territory shared equally thereafter."

Licensing / partnership • Hepatitis B

Assembly Biosciences Reports Second Quarter 2020 Financial Results and Recent Highlights (GlobeNewswire) - "ABI-H2158 (‘2158), Assembly’s second-generation, more potent core inhibitor candidate: Assembly initiated a multi-center, randomized, placebo-controlled Phase 2 trial to evaluate ‘2158 with entecavir versus placebo with entecavir in treatment naïve HBeAg positive patients with chronic HBV infection; The U.S Food and Drug Administration granted Fast Track designation for ‘2158 for the treatment of chronic HBV Infection....Anticipated Milestones and Events:...Phase 1b clinical data on multiple dose cohorts will be presented as a late-breaking poster at EASL."

Fast track designation • P1 data • Trial status • Hepatitis B

"$ASMB Announces FDA Fast Track Designation Granted to ABI-H2158 for the Treatment of Chronic Hepatitis B Virus Infection" (@BioStocks)

Fast track designation • Hepatitis B • Infectious Disease

A Study of ABI-H2158-containing Regimens in Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2a; N=80; Recruiting; Sponsor: Assembly Biosciences; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Hepatitis B • Infectious Disease

A Study of ABI-H2158-containing Regimens in Participants With Chronic Hepatitis B Virus Infection (clinicaltrials.gov) - P2a; N=80; Not yet recruiting; Sponsor: Assembly Biosciences

Clinical • New P2a trial • Hepatitis B • Infectious Disease

A Study of ABI-H2158 in Healthy Volunteers and Patients With Chronic Hepatitis B (clinicaltrials.gov) - P1; N=80; Recruiting; Sponsor: Assembly Biosciences; Trial completion date: Apr 2020 ➔ Oct 2020; Trial primary completion date: Feb 2020 ➔ Aug 2020

Clinical • Trial completion date • Trial primary completion date

A Study to Assess CYP3A4 Modulator, Oral Contraceptive, and pH Modifier Drug Interactions for ABI-H2158 in Healthy Adults (clinicaltrials.gov) - P1; N=80; Completed; Sponsor: Assembly Biosciences; Not yet recruiting ➔ Completed

Clinical • Trial completion

A Study to Assess the Relative Bioavailability and Food Effect of ABI-H2158 in Healthy Adults (clinicaltrials.gov) - P1; N=15; Completed; Sponsor: Assembly Biosciences; Recruiting ➔ Completed

Clinical • Trial completion

THE SECOND-GENERATION HEPATITIS B VIRUS (HBV) CORE INHIBITOR (CI) ABI-H2158 IS ASSOCIATED WITH POTENT ANTIVIRAL ACTIVITY IN A 14-DAY MONOTHERAPY STUDY IN HBeAg-POSITIVE PATIENTS WITH CHRONIC HEPATITIS B (CHB) (AASLD 2019) - "Results from the initial 100 mg low dose of ABI-H2158 cohort demonstrated potent antiviral activity, a favourable safety profile when administered for 14 days, and support once daily dosing in CHB patients. Data from additional cohorts may be presented if available at the time of the conference."

Clinical • Late-breaking abstract • Monotherapy

A Study to Assess CYP3A4 Modulator, Oral Contraceptive, and pH Modifier Drug Interactions for ABI-H2158 in Healthy Adults (clinicaltrials.gov) - P1; N=80; Not yet recruiting; Sponsor: Assembly Biosciences

Clinical • New P1 trial

A Study of ABI-H2158 in Healthy Volunteers and Patients With Chronic Hepatitis B (clinicaltrials.gov) - P1; N=80; Recruiting; Sponsor: Assembly Biosciences; Trial completion date: Oct 2019 ➔ Apr 2020; Trial primary completion date: Aug 2019 ➔ Feb 2020

Clinical • Trial completion date • Trial primary completion date

A Study to Assess the Relative Bioavailability and Food Effect of ABI-H2158 in Healthy Adults (clinicaltrials.gov) - P1; N=15; Recruiting; Sponsor: Assembly Biosciences

Clinical • New P1 trial