ABSTRACT
Background: TFV is a nucleotide analogue whose active form, TFV diphosphate (TDP), inhibits reverse transcription of hepatitis B virus (HBV) and is the active metabolite of HBV treatment TFV alafenamide (TAF). NCO-48F is a novel TFV prodrug designed to increase the liver concentration and maximize efficacy and/or potency while reducing drug exposure outside of the liver. NCO-48F is expected to minimize kidney and bone toxicity by reducing systemic exposure of TFV. Method(s): Safety, tolerability, pharmacokinetics (PK), and anti-HBV activity of multiple daily oral doses of 4 and 20 mg of NCO-48F, compared with 25 mg TAF, were evaluated in a randomized, open-label, active-controlled, parallel-assignment study in adult subjects with treatment-naive HBV infection (3 groups of 8 subjects each). Each subject was administered NCO-48F or TAF daily for 28d and followed for 28d after the last dose. Result(s): Preliminary data from 12 subjects (4 subjects/group) were available for analysis. NCO-48F at 4 mg and 20 mg and TAF were safe and well tolerated. No subjects had a serious adverse event (AE) or were discontinued due to an AE. There were no clinically significant or dose-dependent changes in hematology, clinical chemistry, urinalysis, electrocardiograms, or vital signs. One treatment-emergent AE was reported by 1 NCO-48F 4 mg subject (COVID-19 infection) which was not considered drug-related. NCO-48F was orally absorbed with Cmax observed within 30 minutes. NCO-48F was metabolized to TFV and rapidly cleared. Minimal urinary excretion of intact NCO-48F was detected, consistent with conversion to TFV. TFV Cmax was observed within one hour of NCO-48F administration, a faster uptake than observed after TAF administration. TFV elimination kinetics appeared similar after administration of either NCO-48F or TAF. Plasma concentrations of NCO-48F and TFV increased approximately dose proportionately. Over 28d of treatment, declines in serum HBV DNA levels (log10 IU/mL) were observed among all dose groups, and mean changes in HBV DNA at day 28 were -2.12 and -3.29 for NCO48F 4 mg and 20 mg, and -3.27 for TAF. Three subjects treated with NCO48F 20 mg had levels below limit of quantitation during treatment, and recovery of HBV DNA levels was slower during the follow- up period compared to subjects treated with TAF. Conclusion(s): NCO-48F is a promising agent for the treatment of HBV, demonstrating excellent safety and PK properties, and declines in HBV DNA comparable to TAF.