On October 9, 2021. Shanghai Zhimeng Biopharma, Inc. announces the completion of phase 1a clinical study on its novel HBV capsid inhibitor ZM-H1505R and the presentation of the results in the upcoming 2021 annual meeting of the America Association for the Study of Liver Diseases (AASLD) held on November 12-15, 2021.
This phase 1a trial was a randomized, double-blind, placebo-controlled study in healthy subjects to evaluate the safety, tolerability, and pharmacokinetics (PK) of ZM-H1505R following oral administration of single ascending dose (SAD) and multiple ascending doses (MAD). In the SAD part of the study, 40 healthy subjects were randomized 3:1 to receive 25, or 75, 150, 300, and 450 mg of ZM-H1505R or placebo. In the MAD part of the study, 24 healthy subjects were randomized 3:1 to receive 75, or 150 and 300 mg of ZM-H1505R or placebo, once-daily for 14 consecutive days.
The results showed that single oral doses of 25-450 mg of ZM-H1505R were generally safe. No serious adverse events (AEs) or AEs leading to discontinuation were reported, and most AEs were Grade 1 in severity. ZM-H1505R displayed a T1/2 of 11-18h, a liner and dose-proportional increase in plasma exposure (AUC), and a C24 of 162-6170 nM. High-fat food had a moderate effect on PK of ZM-H1505R, causing about 40% reduction in its plasma exposure.
Results from oral administration of 75, 150, or 300 mg, once daily, for 14 consecutive days showed that ZM-H1505R was safe and well tolerated. Twelve subjects (50.0%) reported a total of 19 treatment-emergent adverse events (TEAEs), including 11 of 18 subjects who received ZM-H1505R and 1 of 6 who received placebo. The most common TEAEs were gastrointestinal symptoms (reported in 4 of 18 subjects receiving ZM-H1505R and 1 of 6 receiving placebo) and were all deemed mild. One subject in the 300mg cohort discontinued study participation due to the increases in amylase and lipase. There were no deaths or SAEs. Following MAD of ZM-H1505R, its mean plasma AUC and Cmax increased in a dose-proportional manner. A steady-state was achieved by day 7 with a T1/2 of 12.2-21.7h. At day 14, the mean plasma Cmin, at 75, 150, and 300mg doses were 6.3, 18.2, and 37.5 folds of its protein-binding adjusted HBV DNA EC50, respectively.
These results warrant further clinical evaluation of ZM-H1505R for the treatment of chronic hepatitis B. A phase 1b study is currently ongoing to evaluate its safety, tolerability, pharmacokinetics and preliminary anti-HBV efficacy in naïve chronic hepatitis B patients following 28-day of q.d. oral administration. The results from this 1b study will be presented in the 2022 international liver disease congress.