RNA interference and its potential applications to chronic HBV treatment: results of a Phase I safety and tolerability study

Background: RNA interference (RNAi) provides an attractive tool to modulate biological systems, and ultimately, to treat human diseases. We describe early results from a Phase lb, first-in-human safety and tolerability study of an RNAi-based therapy, NUC B1000, among patients with mild to moderate chronic HBV. Methods: Three subjects received a single 5 mg DNA dose of NUC B1000 as part of a planned dose escalation study. Results: All participants reported pharyngitis, chills, myalgia and fever approximately 4-7 h after dosing. All subjects were asymptomatic after a single antipyretic dose with no symptom recurrences. Measurements of interferon (IFN)-alpha and -gamma, interleukin (IL)-10, 12 18, 8 and 6, and tumour necrosis factor-alpha performed before and after dosing revealed cytokine increases before study drug administration. After drug administration, IFN-gamma and IL-10 increased in two patients; IL-8 increased in one. Most increases returned to pretreatment levels within 1 week. Two patients were subsequently successfully treated with entecavir indicating that NUC B1000 does not compromise subsequent antiviral therapy. Conclusions: Thus far, NUC B1000 appears safe and well-tolerated; safety and efficacy studies across a larger, more diverse patient spectrum using increasing doses are needed to determine its appropriate role in the antiviral armamentarium.