S1189 Safety and Efficacy of Oral TLR8 Agonist, Selgantolimod, in Viremic Adult Patients With Chronic Hepatitis B

Introduction: Selgantolimod (GS-9688, SLGN) is an oral, Toll-like receptor 8 agonist in clinical development for the treatment of chronic hepatitis B (CHB). Here we present the results through week 48 on the safety and efficacy of 24 weeks of SLGN treatment in viremic CHB patients. Methods: In this multicenter, double-blind, phase 2 study, viremic CHB patients were randomized (2:2:1) to SLGN 3 mg, 1.5 mg, and placebo (PBO) once a week for 24 weeks in combination with tenofovir alafenamide. Safety assessments included monitoring of treatment emergent adverse events (TEAE) and laboratory abnor-malities. The primary efficacy end point was the proportion of patients with ≥1 log10IU/ml decline in HBsAg levels from baseline at week 24. Exploratory end points include changes in pharmacodynamic (PD) markers (e.g. IL-12p40 and IL-1RA) and changes in peripheral T- cell, myeloid and NK-cell subsets. Results: 67 patients (39 HBeAg-positive) were randomized. Baseline characteristics were similar across groups: majority were Asian (98.5%), male (58%) with a median (IQR) age of 47 (35–54) years, HBsAg level of 4.1 (3.5–4.7) log10IU/ml, and HBV DNA level of 7.5 (5.4–8.3) log10IU/ml. No patients achieved the primary end point of ≥1 log10IU/ml decline in HBsAg levels at week 24; however, 3 (6%) patients in the SLGN-treated achieved HBsAg decline ≥0.5 log10IU/ml compared to none in the placebo group. At week 48, 4 (7.4%) patients in the SLGN-treated group (including the 3 subjects at week 24) while none in the placebo group achieved HBsAg decline ≥0.5 log10IU/ml. Most frequent (≥10% SLGN-treated) TEAE (SLGN v PBO) were: nausea (26% v 0%), headache (15% v 15%), vomiting (17% v 0%), fatigue (15% v 0), and dizziness (11% v 0%). Grade ≥3 TEAE were observed in 0 (SLGN) v 7.7% (PBO) subjects; 1 subject (SLGN 3 mg) discontinued study due to TEAE of vomiting and abdominal pain. Most patients treated with SLGN showed decline of immune cell subsets in the circulation 4 h after dosing, concurrent with increases of circulating IL-12p40 and IL-1RA. Cell populations that decreased in the circulation included effector and memory T cell subsets. These parameters reverted to baseline values at 24 h post-dosing. Conclusion: Oral SLGN up to 3 mg once weekly for 24 weeks is safe and well-tolerated. SLGN can induce sustained HBsAg declines of ≥0.5 log10IU/ml in some patients out to Week 48. Further evaluation of SLGN in combination with immunomodulatory and antiviral agents is planned.