Safety, pharmacokinetics, and antiviral activity of the S-antigen Transport Inhibiting Oligonucleotide Polymers (STOPS) drug candidate ALG-010133 in subjects with chronic hepatitis B

ABSTRACT

Background and aims: To evaluate the safety, pharmacokinetics (PK) and antiviral activity of ALG-010133, a STOPS molecule designed to reduce hepatitis B S-antigen (HBsAg) in chronic hepatitis B (CHB) patients. Method: This was a 3-part, multicenter, double-blind, randomized, placebo-controlled study. In Parts 1 and 2, single and multiple subcutaneous (SC) doses of ALG-010133were generallywell tolerated in healthy volunteers (Gane et al, EASL 2021). Part 3 evaluatedweekly SC doses of ALG-010133 or placebo × 12 weeks in virologically suppressed Hepatitis B e-antigen (HBeAg) negative CHB subjects (N = 10/cohort;8 active2 placebo). Reported here are preliminary blinded Part 3 safety, PK, and antiviral data;unblinded data will be presented at the conference. Results: 31 CHB subjects completed dosing and follow-up in Cohorts 1 (120 mg;N = 10), 2. (200 mg;N = 10), and 3 (400 mg;N = 11). Most subjects were male (61%) and 48% were white, with mean age 48 years, mean BMI 26.1 kg/m2 and baseline HBsAg across cohorts of 3.6 to 3.7 log10 IU/ ml. Therewas 1 unrelated serious treatment emergent adverse event (TEAE) (hospitalization for orchitis) and 1 unrelated TEAE (COVID-19 infection) resulting in premature study drug discontinuation. All TEAEs were Grade 1 or 2 in severity, except for 1 Grade 3 TEAE of injection site erythema (severity based only on surface area criteria of ≥100 cm2;required no treatment and resolved despite continued study drug dosing) and the aforementioned TEAE of orchitis (Grade 3). There was no dose relationship to severity or frequency for any TEAE. The most common (≥3 subjects) TEAEs were injection site erythema (n = 5), increased ALT (n = 4), injection site bruising (n = 4), increased AST (n = 3), and injection site pruritus (n = 3);none were assessed as clinically concerning. Although treatment-emergent ALT and AST elevations (n = 13) were observed, all were Grade 1 (<2.5x upper limit of normal [ULN]) or 2 (≥2.5 to <5x ULN) and none led to premature study drug discontinuation or were associated with symptoms or evidence of liver dysfunction. There were no other clinically significant lab abnormalities. No clinically significant physical examinations, vital signs, or ECG abnormalities were reported. Plasma ALG-010133 exposures increased more than dose proportionally between the 120 to 400 mg dose levels, with moderate variability and minimal accumulation. Compared to baseline, the magnitude of HBsAg decline at Week 12 was <0.1 log10 IU/ml for placebo and across all ALG-010133 dose levels, including the projected efficacious dose level of 400 mg (estimated to maintain total liver exposures >3x EC90 for HBsAg inhibition). Conclusion: ALG-010133 was safe and well tolerated with predictable PK properties when given to CHB subjects as multiple SC doses of up to 400 mg. No meaningful HBsAg reduction was observed across all cohorts. Further clinical development of ALG-010133 has been discontinued.