Abstract 17059: Single and Multiple Dose Pharmacokinetics, Pharmacodynamics and Safety of a Novel PCSK9 Synthesis Inhibitor, ALN-PCSsc, in Subjects With Elevated LDL Cholesterol
Background: ALN-PCSsc (PCSK9si) is an RNAi therapeutic consisting of double-stranded oligonucleotide covalently linked to N-acetylgalactosamine targeting PCSK9 mRNA in hepatocytes. The potency for silencing PCSK9 has been shown in animals with durable suppression of PCSK9 protein and marked reduction in LDL-C levels. This is the first study evaluating the PK, PD, safety and immunogenicity of PCSK9si in subjects with elevated LDLC ≥100 mg/dL.
Methods: This was a randomized, single-blind, placebo-controlled; single ascending dose (SAD) and multiple dose (MD) study of PCSK9si administered subcutaneously (SC) to 51 subjects enrolled in 9 cohorts. Doses studied were 25, 100, 300, 500 and 800 mg in the SAD phase, and 125 mg QW, 250 mg Q2W, 300 and 500 mg Q4W in the MD phase. Serial blood and pooled urine samples were collected to assess PK profiles and urinary excretion of PCSK9si. PK parameters were calculated using non-compartmental analysis.
Results: After SC administration of PCSK9si, peak plasma concentrations were observed by 4 hours with a dose-proportional increase in Cmax and AUC. Mean t1/2 was ~ 6.5 hours across SD cohorts. There was no accumulation of PCSK9si plasma concentrations following multiple weekly, bi-weekly or monthly dosing. Mean fraction excreted unchanged in the urine (Fe) was around 25%. Largest mean percent reductions from baseline in the SD and MD cohorts, for PCSK9 were 79.4 % and 85.2 %, respectively, and for LDL-C were 55.1% and 55.7 %, respectively. PD responses at doses above 25 mg were maintained through 180 days for all PCSK9si treated SD and MD cohorts. A sigmoid Emax model best described the exposure-response relationship between PCSK9si concentrations and knockdown of PCSK9. No anti-drug antibody against PCSK9si was detected. PCSK9si was generally well tolerated and no SAEs were reported.
Conclusions: Plasma PK of PCSK9si was dose proportional and consistent across doses and regimens. Dose dependent and sustained decreases in PCSK9 and LDL-C were observed following single and multiple dosing. This data supports further testing in a Phase 2 dose range finding study in a larger patient population with hypercholesterolemia.
Author Disclosures: P. Chaturvedi: Employment; Significant; I am a currently an amployee of Alnylam Pharmaceuticals. S. Bellibas: Employment; Significant; currently an employee of The Medicines Company. D.G. Kallend,: Employment; Significant; currently an employee of The Medicines Company. K. Fitzgerald: Employment; Significant; currently an employee of Alnylam Pharmaceuticals. G.J. Robbie: Employment; Significant; currently an employee of Alnylam Pharmaceuticals. P.L. Wijngaard: Employment; Significant; currently an employee of The Medicines Company.
- © 2016 by American Heart Association, Inc.