Assembly Biosciences, Inc. announced promising interim efficacy, safety and pharmacokinetic (PK) results from two ongoing clinical studies of its investigational next-generation HBV core inhibitors, a Phase 1b clinical study of ABI-H3733 (3733) and a Phase 1a clinical study of ABI-4334 (4334). Assembly Bio specifically designed 3733 and 4334 to optimize potency against both new virus production (first mechanism) and formation of covalently closed circular DNA (cccDNA), the viral reservoir (second mechanism). Both compounds have demonstrated significantly increased potency preclinically against both mechanisms compared to first-generation core inhibitors.

This increased potency, particularly against cccDNA formation, is critical to Assembly Bio's HBV strategy to bring finite therapies and cures for those living with chronic HBV (cHBV) infection. Complete results of these clinical trials, when available, together with ongoing nonclinical and chronic toxicity studies, will inform future clinical development planning for Assembly Bio's next-generation core inhibitor programs. Phase 1b Study for 3733 – Study ABI-H3733-102: The ongoing Phase 1b clinical trial is a randomized, multi-center, double-blind and placebo-controlled study evaluating the safety, PK and antiviral activity of 3733, including changes in HBV DNA and other viral parameters associated with 3733 treatment in adults with cHBV infection who are treatment naïve or off treatment. Patients were randomized 8:2 between the new tablet formulation of 3733 and placebo for a period of 28 days.

The patient population for the data included here consists primarily of e-antigen negative patients. The study remains externally blinded, so individual patient data are not provided. The dose selected for the first cohort was 50 mg.

Given the potent antiviral activity observed at 50 mg, a 25 mg dose was selected for the second cohort to further explore the dose response curve of 3733. A dose of 100 mg has been selected for the third cohort, for which dosing is ongoing with initial data anticipated in the first quarter of 2023. 50 mg Cohort Efficacy (Viral Nucleic Acids): As of the data cutoff date of December 18, 2022, dosing in the 3733 Phase 1b trial has been completed for all 10 patients in the first cohort of 50 mg.

Nine of 10 patients enrolled were HBeAg negative, so efficacy data are provided for these patients. Interim efficacy results from this cohort at the data cutoff date include HBV DNA, HBV RNA and antigen measurements for all patients for the full 28-day dosing period. In the 50 mg cohort, six of eight patients receiving 3733 achieved HBV DNA less than the lower limit of quantification (

Data on HBV RNA declines were limited due to low baseline levels in predominantly e-antigen negative patients. 25 mg Cohort Efficacy (Viral Nucleic Acids): The second cohort, evaluating a dose of 25 mg, is fully enrolled. Nine of 10 patients enrolled were HBeAg negative, so efficacy data are provided for these patients.

In the five patients that have so far completed 28 days of treatment, the mean reduction in HBV DNA was approximately 1.9 logs. Data on HBV RNA levels were not available as of the data cutoff date. 50 and 25 mg Cohorts (Safety, PK and Viral Antigens): Safety data reported here reflect data received for both cohorts through the data cutoff date.

In these initial cohorts, all treatment-emergent adverse events (AEs) and laboratory abnormalities reported were Grade 1 or Grade 2. Further, no AEs led to treatment discontinuation, and no clinically significant ECG abnormalities or patterns of AEs or lab abnormalities were noted. The observed PK for the new tablet formulation of 3733 was consistent with predictions from preclinical studies, providing exposure equivalent to the liquid formulation evaluated in the Phase 1a study for 3733. Clinical PK exposures exhibited dose-proportional increases from 25 mg to 50 mg, as measured by maximum concentration (Cmax) and area-under-curve (AUC).

As expected given the 28-day dosing period, limited changes in viral antigens were observed in both the 50 mg and 25 mg cohorts. Phase 1a Study for 4334 – Study ABI-4334-101: The Phase 1a clinical trial is a randomized, blinded and placebo-controlled study evaluating the safety, tolerability and PK of 4334 following single ascending dose and multiple ascending dose administration in healthy subjects. The objectives of the study include assessment of the proportion of subjects with AEs, premature treatment discontinuation due to AEs and abnormal laboratory results.

Dosing has completed for all eight subjects in the initial 30 mg single dose cohort. In this cohort, 4334 had a mean half-life of 24 hours, supporting once-a-day (QD) dosing. Based on the PK data from this initial cohort and preclinical studies, daily minimum plasma trough concentrations (Cmin) are projected to achieve double-digit multiples of the protein-adjusted EC50 for both antiviral activity and against cccDNA formation at a low dose of 4334.

In this initial cohort, treatment-emergent AEs and laboratory abnormalities were mild to moderate and all were considered not related to study treatment. There were no clinically significant ECG abnormalities or patterns of AEs or laboratory abnormalities noted. A dose of 100 mg has been selected for the second single-dose cohort.

Dosing for the second cohort is complete and initial data from this cohort are anticipated in the first quarter of 2023.