LO9: HBV RNAi INHIBITOR RG6346 IN PHASE 1b-2a TRIAL WAS SAFE, WELL-TOLERATED, AND RESULTED IN SUBSTANTIAL AND DURABLE REDUCTIONS IN SERUM HBsAg LEVELSMan-Fung Yuen1, Dr. Tien Huey Lim2, Dr. Won Kim3,Prof. Pisit Tangkijvanich4, Prof. Jung-Hwan Yoon5, Prof. William Sievert6, Prof. Wattana Sukeepaisarnjaroen7, Prof. Alexander Thompson8, Dr. Christian Schwabe9, Dr. Bob D. Brown10, Dr. Hardean Achneck10and Prof. Edward J. Gane9, (1)Queen Mary Hospital, the University of Hong Kong, Hong Kong, (2)Middlemore Hospial, Auckland, NZ, (3)Boramae Medical Center, Seoul National University Hospital, Seoul, Korea, (4)King Chulalongkorn Memorial Hospital, Bangkok, (5)Seoul National University Hospital, Seoul, South Korea, (6)Monash Health and Monash University, Melbourne, Australia, (7)Srinagarind Hospital, Khon Kaen University, Thailand, (8)St Vincent's Hospital Melbourne, Australia, (9)New Zealand Liver Transplant Unit, Auckland City Hospital and University of Auckland, Auckland, New Zealand, (10)Dicerna Pharmaceuticals Inc., Lexington, MA, USABackground:Chronic Hepatitis B (CHB) virus infection can cause progressive liver damage leading to cirrhosis and hepatocellular carcinoma. Currently CHB infection requires prolonged, often life-long, treatment with nucleos(t)ide analogs (NUCs). New treatments aim at achieving “functional cure,” i.e., durable clearance of serum HBsAg after finite therapy. RG6346 is a synthetic dsRNA conjugated toN-acetylgalactosamine that induces cleavage of mRNA encoding all forms of HBsAg in hepatocytes.Methods:This placebo controlled study was designed in 3 parts: SAD (Group A) in healthy volunteers (HV) (n=30; RG6346:placebo=2:1; doses=0.1, 1.5, 3.0, 6.0, 12.0 mg/kg), SD (Group B) in NUC-naïve patients with immune-active CHB (n=8; RG6346:placebo=5:3; dose=3.0 mg/kg), and MAD (Group C) in CHB patients with ≥ 12 weeks of NUC suppression prior to screening (n=18; RG6346:placebo=2:1; 4 monthly doses of 1.5 (C1), 3.0 (C2), and 6.0 mg/kg (C3) per cohort. Inclusion criteria in Groups B and C were HBeAg (+) with HBsAg > 1000 IU/mL, or HBeAg (-) with HBsAg > 500 IU/mL, and for Group B, serum HBV DNA > 2000 IU/mL, and ALT ≥ 35 U/L (males) or ≥ 30 U/L (females).Results:All doses were safe in HVs, with nearly dose proportional Cmax levels of RG6346. After 4 monthly SC doses in patients, the mean HBsAg decline from baseline was 1.39 log10IU/mL in C1, 1.80 in C2 and 1.84 in C3 at Day 112 (2/4 patients on RG6346 in C3 not yet reached Day 112). The max mean HBsAg reductions were 1.71 log10IU/mL in C1 on Day 168 (n=3), 1.88 in C2 on Day 140 (n=4), and 1.88 in C3 on Day 140 (n=2). The overall max reduction to date was 2.7 log10IU/mL (see Figure). Eighty (80) % of patients who reached at least Day-112 achieved > 1.5 log10IU/mL reduction, and 60% achieved HBsAg < 100 IU/mL regardless of HBeAg status. The longest enrolled patient in C1 maintained > 2 log10IU/ml HBsAg reduction from Day 336 through Day 448. In NUC-naïve patients, a single dose of RG6346 resulted in a mean HBsAg reduction of 1.01 log10IU/mL at Day 57. Several patients on RG6346 exhibited self-resolving ALT flares consistent with treatment-induced enhanced immune responses, as demonstrated by a decrease in viral markers and overall preserved liver function. No SAEs or dose limiting toxicities with RG6346 were observed. The most commonAEs in Groups B and C were related to mild injection site reactions.Conclusion:Treatment with RG6346 was safe and consistently induced large and durable reductions of HBsAg regardless of HBeAg 作者: StephenW 时间: 2020-11-4 18:44