Safety, tolerability and pharmacokinetics (pk) of single and multiple doses of alg-010133, an s-antigen transport inhibiting oligonucleotide polymer (stops) for the treatment of chronic hepatitis B

Abstract

Background and aims: To evaluate the safety, PK and antiviral activity of ALG-010133, a STOP molecule designed to reduce hepatitis B surface antigen (HBsAg) in chronic hepatitis B (CHB) patients. Method: This is a three-part, multicenter, double-blind, randomized, placebo-controlled study. In Parts 1 and 2, each cohort consisted of 8 healthy volunteers (HV) randomized to ALG-010133 or placebo in a 3:1 ratio. Each cohort in Parts 1 and 2 received a single or threeweekly subcutaneous (SC) doses, respectively. Part 3 is evaluating cohorts (N = 10 each; 8 ALG-010133, 2 placebo) of virologically suppressed CHB patients who will receive study drug weekly for 12 weeks. Safety assessments (adverse events (AEs), vital signs, electrocardiogram (ECG) and laboratories), viral markers (Part 3) and plasma/urine PK samples (Parts 1 and 2) were collected throughout study conduct. Reported here are preliminary blinded results in Parts 1 and 2. Available Part 3 data will also be presented at the conference. Results: In Part 1, 7 cohorts (N = 56 HVs) received a single 20, 50, 75, 125, 160 or 200 mg (100 mg/ml and 200 mg/ml) SC dose of ALG010133/placebo. In Part 2, 2 cohorts (N = 16 HVs) received three weekly 120 or 180 mg SC doses. There were no serious AEs, premature discontinuations, or dose-limiting toxicities. All treatment emergent AEs (TEAEs) were mild (Grade 1) or moderate (Grade 2) except for one Grade 3 injection site reaction (ISR) that occurred in a subject in the 200 mg cohort. The most commonly occurring (≥3 subjects) TEAEs in Part 1 were injection site bruising (n = 11), ISRs (erythema/rash; n = 7), headache (n = 7), nausea (n = 4) and diarrhea/ loose stools (n = 3) and, in Part 2, ISRs (n = 3). There was no dose relationship to severity or frequency of AEs. All treatment-emergent laboratory abnormalities were Grade ≤2 with the exception of three (Grade 3, n = 2; Grade 4, n = 1) exercise-related creatine kinase elevations. No clinically significant PE, vital signs, or ECG abnormalities were reported. ALG-010133 exposures increased in a greater than dose-proportional manner with moderate variability after single doses. Median tmax was 2–10 hours. Plasma ALG-010133 achieved steady state and did not accumulate with weekly dosing over 3 weeks. Doses of 100–200 mg are projected to result in antiviral activity. Conclusion: ALG-010133 was generally safe and well tolerated in HV as single and multiple SC doses up to 200 and 180 mg, respectively. The PK exposures achieved are expected to result in antiviral activity, supporting the ongoing evaluation in CHB patients.