Assembly Biosciences has announced positive topline results from a Phase 1b clinical trial evaluating ABI-4334, an investigational next-generation capsid assembly modulator (CAM), in patients with chronic hepatitis B virus (HBV) infection. The study demonstrated potent antiviral activity and a favorable safety profile, supporting once-daily oral dosing across both tested dose levels.
Strong Antiviral Activity Across Dose Cohorts
The randomized, blinded, placebo-controlled Phase 1b study (ABI-4334-102) evaluated two dose cohorts of 10 subjects each, randomized 8:2 to receive either ABI-4334 at 150 mg or 400 mg, or placebo daily for 28 days. The study enrolled treatment-naive or off-treatment participants with HBeAg positive or negative chronic HBV infection.
In the predominantly HBeAg negative participants, mean declines in HBV DNA of 2.9 and 3.2 log10 IU/mL were observed over 28 days in participants receiving 150 mg and 400 mg doses, respectively. Among participants with detectable HBV RNA at baseline, mean declines of 2.5 and 2.3 log10 U/mL were observed over 28 days in the 150 mg and 400 mg cohorts, respectively.
"We are pleased to see that our most potent CAM, ABI-4334, achieved our target clinical profile with strong antiviral activity in both cohorts," said Anuj Gaggar, MD, PhD, chief medical officer of Assembly Bio. "These data support the ability of ABI-4334 to effectively inhibit viral replication at the lower 150 mg dose, while offering the potential to dose higher for purposes of maximizing inhibition of cccDNA formation."
Pharmacokinetic Profile Supports Once-Daily Dosing
The pharmacokinetic analysis revealed slightly higher than dose-proportional increases in clinical exposures from 150 mg to 400 mg, as measured by maximum concentration (Cmax) and area under the curve (AUC). Based on PK data from both cohorts and preclinical studies, daily minimum plasma trough concentrations (Cmin) at both dose levels achieved double-digit multiples over protein-adjusted EC50 for both antiviral activity and cccDNA formation.
ABI-4334 continued to demonstrate a half-life supportive of once-daily oral dosing across both dose cohorts. The 400 mg dose reached exposure levels at greater multiples of the target exposure anticipated to fully engage the second mechanism of action of CAMs - inhibition of formation of the viral reservoir, cccDNA.
Favorable Safety Profile Maintained
The safety analysis showed ABI-4334 was well-tolerated with a favorable safety profile in participants with chronic HBV infection. No pattern of safety signals was identified, and there were no serious adverse events or adverse events that led to study drug discontinuation.
Two grade three treatment-emergent laboratory abnormalities were observed: one alanine aminotransferase (ALT) elevation in a participant receiving 150 mg ABI-4334, and one total bilirubin elevation in a placebo recipient. Both elevations resolved with continued dosing of ABI-4334 and placebo, respectively. No other grade three or four treatment-emergent laboratory abnormalities were observed.
Gilead Partnership Reaches Key Milestone
The completion of this Phase 1b trial triggers an important milestone under Assembly Biosciences' collaboration agreement with Gilead Sciences. Gilead now has the right to opt in to an exclusive license for further development and commercialization of ABI-4334 after reviewing the Phase 1b option data package to be delivered by Assembly Bio.
"These results will support discussions on potential next steps for ABI-4334 with our partner Gilead as they evaluate their option to the program," Gaggar noted. The relationship between ABI-4334's observed antiviral activity and its exposure profile was consistent with having reached full engagement of the first mechanism of action for CAMs - inhibition of viral replication - at the lower 150 mg dose.
Implications for HBV Cure Research
Gaggar emphasized the broader implications for hepatitis B treatment: "We believe that maximizing direct antiviral activity and inhibition of cccDNA formation will be important components of regimens targeting cure of chronic HBV infection, and that achieving cure will likely require combination approaches with additional mechanisms still being explored by the field."
As expected given the patient population and 28-day treatment period, limited changes in viral antigens were observed in both cohorts. Assembly Bio expects to submit data from the trial for presentation at future scientific meetings.
