A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

Abstract

BACKGROUND Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol. METHODS In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442.)

Novel approaches to lipid-lowering therapy

“…[6] As opposed to the mAbs, inclisiran reduces the activity of PCSK9 by inhibiting synthesis of the enzyme, acting at the level of protein translation via RNA interference in the liver. Unlike mAbs, inclisiran only needs to be administered once every 3 -6 months.…”

Antisense Oligonucleotides and Therapeutical Monoclonal Antibodies as a Basement for Novel Biological Lipidlowering Drugs

“…В последнее время фирма "Alnylam Pharmaceuticals", США провела еще одно КИ I фазы с под-кожным ведением ALN-PCS, которое продемонстри-ровало устойчивое снижение PCSK9 и ХС-ЛНП в течение 180 дней после однократной инъекции [19]. Разовое введение инклизирана в дозе 300 мг и выше, так же как и ежемесячное (300 мг) или раз в 2 нед.…”

Advances in dyslipidemia management for prevention of atherosclerosis: PCSK9 monoclonal antibody therapy and beyond

“…Inclisiran (ALNPCSsc) is a long-acting, subcutaneously delivered, synthetic siRNA directed against PCSK9 that is taken up specifically by hepatocytes. Fitzgerald and colleagues (39) recently demonstrated in a phase 1 trial involving randomization of healthy volunteers to inclisiran or placebo, that a single 300 mg dose of inclisiran was able to reduce the PCSK9 level by 75% and LDL-C levels of 51% for 6 months or longer (Figure 3), with two dosages reducing LDL-C by 57% at 6 months. This product appeared to be very well-tolerated and offers the potential for bi-or tri-annual dosing.…”