INDIANAPOLIS & SAN FRANCISCO—Aimed at increasing cure rates of hepatitis B virus (HBV) infection, Assembly Biosciences presented a late-breaker poster revealing successful interim results from Phase 1a and 1b studies of ABI-H0731, a novel antiviral in development for the treatment of chronic HBV, a devastating disease affecting 250 million people globally.
“The data, presented April 12 at The International Liver Congress, the Annual Meeting of the European Association for the Study of the Liver (EASL) in Paris, was from our ongoing Phase 1b monotherapy study for ‘731—showing excellent potency and dose response across patient cohorts, as well as a favorable safety profile,” said Derek Small, president and CEO of Assembly Biosciences.
According to the company, the interim study results support the advancement of ABI-H0731 into Phase 2a combination studies, expected to begin this summer.
“We are seeing viral load responses in both HBeAg-positive patients and HBeAg-negative patients that exceed our expectations,” Small says. “And we are planning to move ahead expeditiously with our Phase 2a clinical trial this summer. The first study will enroll HBeAg-positive patients on standard-of-care nucleoside therapy with fully suppressed viral loads. Patients will continue their nucleoside therapy and be randomized to either placebo or ABI-H0731 for six months.”
According to Small, this study is designed to demonstrate that ABI-H0731 can inhibit the generation of cccDNA molecules by showing a decline in the surrogate markers of cccDNA. A second Phase 2a study will enroll treatment-naïve HBeAg-positive patients and is designed to compare the antiviral effectiveness of standard-of-care nucleoside therapy alone with standard of care in combination with ABI-H0731 for six months. Assembly Biosciences anticipates results from these studies in the first half of 2019.
“Standard-of-care therapy with nucleoside medicines, such as entecavir or tenofovir, are good at blocking one step in viral replication of hepatitis B, but they have little to no effect on the key target: cccDNA which fuels the hepatitis B replication engine, maintaining chronic infection,” Small explains. “We believe that a combination approach of standard-of-care nuc therapy in combination with ‘731 will suppress viral load and stop new cccDNA from forming, potentially leading to cure.”
The late-breaker poster also outlined interim data from the ongoing Phase 1b antiviral efficacy study and a recently completed Phase 1a safety and pharmacokinetic (PK) study of ABI-H0731, a novel, oral core protein allosteric modifier (CpAM) with selective and potent activity against all major HBV genotypes.
Current rates of cure for patients with HBV infection are, at the highest, less than 10 percent of the 250 million people worldwide affected by this disease, Small says. Chronic HBV infection results in chronic inflammation and progressive liver damage, potentially leading to liver cirrhosis, hepatocellular carcinoma and more than 1 million deaths per year.
“We believe we have developed one of the strongest portfolios of potent, chemically distinct CpAMs, and ‘731 represents our first-generation therapeutic candidate,” he notes, adding that “Preclinical studies demonstrate a tenfold greater potency and enhanced PK properties relative to first-generation CpAMs. We also may select a third CpAM for advancement later this year.”
ABI-H0731-102 was a Phase 1a study designed to administer multiple dose levels of ABI-H0731 for 14 days to healthy volunteers. The primary objectives were to expand the safety, tolerability and pharmacokinetics database of ABI-H0731.
ABI-H0731-101b is a Phase 1b study designed to test multiple dose levels of ABI-H0731 for 28 days in treatment-naive HBV patients. The primary objectives are to measure the safety, tolerability and pharmacokinetics of ABI-H0731 and its initial antiviral potency when administered as monotherapy. The Phase 1b study enrolled cohorts composed of both HBeAg-positive and HBeAg-negative patients at a ratio of 7:5 respectively, with one patient in each group receiving placebo.
In this study, potent antiviral activity was observed across patient cohorts in a dose-dependent manner, Rich Colono, Assembly Biosciences executive vice president and chief scientific officer of Virology Operations, reported in a webcast. Specifically, in the ongoing 300 mg dose cohort, the mean overall decline from baseline is currently ≥2.8 log10 IU/mL, with ≥2.9 and 2.5 log10 IU/mL mean declines in HBeAg-positive and -negative patients, respectively.
Maximal viral load declines of 3.6 to 4.0 log10 IU/mL were observed in certain HBeAg-negative patients treated at all dose levels (100 to 400 mg). The company intends to report complete results from this study at a scientific conference later this year.
Across all cohorts in the Phase 1a and Phase 1b studies, ABI-H0731 was generally safe and well tolerated, Colono said, adding that no serious adverse events or dose-limiting toxicities were identified and there was no pattern of treatment-emergent clinical or laboratory abnormalities observed.
In his closing webcast remarks, Small stated that it is “exciting to move ahead” with the ‘731 studies.
“It is all toward our goal of increasing cure rates for patients in this global epidemic—HBV,” he concluded.
