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1857
ALN-HBV, a GalNAc-siRNA Enhanced Stabilization Chemistry RNAi Therapeutic for the Treatment of Chronic Hepatitis B Virus Infection
Laura Sepp-Lorenzino1, Marc Abrams2, Leon Carayannopoulos2, Martin Koser2, Steve Ludmerer2, Klaus B. Charisse1, Daniel Freed-man1, Vasant Jadhav1, Kallanthottathil G. Rajeev1, Greg Hinkle1, Satya Kuchimanchi1, Martin A. Maier1, Muthiah Manoharan1, Rachel Meyers1, Stuart Milstein1, Andrew G. Sprague1;
1Alnylam Pharmaceuticals, Cambridge, MA; 2Merck, West Point, PA
Background: Although nucleos(t)ide DNA polymerase inhibitors and interferon effectively reduce viral titers in chronic hepatitis B, these therapies fail to eradicate the infection in ∼90 %of treated patients. Even in the absence of viral replication, high plasma levels of non-infectious, HBsAg-containing, subviral particles are thought to mediate immunological tolerance. Reduction in HBsAg plasma levels of >0.5 log is the single best predictor of immunological cure (viral antigen seroclearance and seroconversion to HBsAb+ve status). An RNAi therapeutic targeting the HBV genome has the potential to achieve a “functional cure” by effectively decreasing expression of tolerogenic HBsAg, in addition to inhibiting all steps of the HBV life cycle. Methods and Results: Proof-of-concept pharmacology was generated in chronically-infected chimpanzees (n=4) treated with a siRNA targeting a conserved HBV region formulated as a lipid nanoparticle (LNP). When administered as a single 0.25 mg/kg IV dose, the RNAi therapeutic showed a mean 1.9 log decrease in viral DNA with >2 log reduction in the subject with the highest viral titer. The effects were RNAi-specific as determined with a control siRNA-LNP formulation, and mediated by an RNAi mechanism as detected by 5′RACE. In multi-dose, dose-escalation chimp studies, doses of 0.125 to 0.5 mg/kg achieved mean (and maximum) reductions of 2.9 (>4) log in viral titers and 2.0 (2.3) log in HBsAg. In one animal with >5X elevated ALT levels at baseline, administration of the RNAi therapeutic was associated with LFT normalization. In addition, two animals showed 2-3X ALT elevations ∼1-2 months post dosing that included increases in interferon-gamma and interleukin-6, suggestive of potential “therapeutic flares” related to immune clearance of infected hepatocytes. A therapeutic RNAi candidate, ALN-HBV, consisting of a GalNAc-targeted, Enhanced Stabilization Chemistry (ESC) siRNA conjugate designed for SC administration is being optimized and characterized for activity in vitro and in vivo. Conclusion: A single siRNA targeting a conserved region in the HBV genome induced specific, potent and durable silencing of HBV viral transcripts and tolerogenic HBsAg. The clinical development strategy for ALN-HBV envisions finite treatment in combination with standard-of-care nucleos(t)ide analogs as a means for inducing a functional cure in CHB patients.
Disclosures:
Laura Sepp-Lorenzino - Employment: Alnylam
Steve Ludmerer - Employment: Merch & Co
Klaus B. Charisse - Employment: Alnylam Pharmaceuticals
Daniel Freedman - Employment: Alnylam Pharmaceuticals
Vasant Jadhav - Employment: Alnylam Pharmaceuticals
Kallanthottathil G. Rajeev - Employment: Alnylam Pharmaceuticals
Greg Hinkle - Employment: Alnylam Pharmaceuticals
Satya Kuchimanchi - Employment: Alnylam Pharmaceuticals
Martin A. Maier - Employment: Alnylam Pharmaceuticals
Muthiah Manoharan - Employment: Alnylam Rachel Meyers - Employment: Alnylam Pharmaceuticals
Stuart Milstein - Employment: Alnylam
Andrew G. Sprague - Employment: Alnylam Pharmaceuticals
The following people have nothing to disclose: Marc Abrams, Leon Carayannopoulos, Martin Koser
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发表于 2014-10-15 07:29
