The ground-breaking PCSK9-targeted RNAi drug inclisiran III was successfully studied

The Pharmaceuticals Company (TMC) recently released detailed data on THEON-10 clinical study of the siRNA lipid-lowering drug inclisiran III at the 2019 American Heart Association (AHA) Annual Scientific Meeting in Philadelphia. This is the second of three key Phase III clinical studies (ORION-9, ORION-10, ORION-11) of the drug, which showed that 300mg inclisiran was given 2 subsurfic injections a year, reaching all major and secondary endpoints, with good tolerance and safety.The ORION-10 study, a randomized, double-blind, placebo-controlled study conducted at 145 clinical centers in the United States, included a group of 1,561 patients with atherosclerotic cardiovascular disease (ASCVD) who had elevated LDL-C levels despite receiving the largest dose of LDL-C reduction therapy, such as statins or lysus. In the study, patients were randomly assigned to receive inclisiran (300 mg doses, once every 0, 3 months, and subsurfic injections every 6 months) or a placebo while receiving the maximum available dose of statins (co-use or unlinked equinox). The main endpoints are the percentage change in LDL-C from baseline to day 510 (17 months) of treatment and change in the percentage adjustment of LDL-C relative to baseline from day 90 (3 months) of treatment to day 540 (18 months). Key secondary endpoints include average absolute changes on the 510th day (17 months) of treatment, average absolute changes from the 90th day (3 months) to the 540th day (18 months), and changes in other lipids and lipoproteins.The results showed that the study reached all the main and secondary end points. In terms of the main endpoints, the placebo-adjusted LDL-C level decreased by 58% (p<0.0001) and the placebo-adjusted LDL-C level decreased by 56% (p<0.0001) on the 510th day of treatment. In the study, the overall adverse events in the placebo group and inclisiran treatment group were similar, with the same proportion of patients in 2 groups experiencing adverse events (26.3% vs. 22.4%), mortality (1.4% vs. 1.5%) and malignant tumors (3.3% vs. 3.3%) also comparable. The liver function trials in the placebo group and inclisiran treatment group (ALT 0.3% vs. 0.3%; AST 0.6% vs 0.5%) and serum creatinine elevation (3.9% vs. 3.9%) had similar clinical significance. 0.9% of placebo patients and 2.6% of inclisiran patients reported clinically related adverse events at the injection site, mostly mild and always short-lived."Cumulative exposure to high LDL-C levels is a high risk of heart attacks and strokes in the future for millions of people, especially those with ASCVD," said R. Scott Wright, a consultant cardiologist at the Mayo Clinic and a consultant in cardiology at the Mayo Clinic. Data from the ORION-10 study showed that inclisiran significantly and continuously reduced LDL-C during the six-month treatment period, and that its safety was similar to that of a placebo. TMCplans to submit inclisiran listing applications in the U.S. and Europe in the fourth quarter of 2019 and the first quarter of 2020, respectively. Patients who have completed phase III studies will now enter the ORION-8 study. ORION-8 is an open-label long-term expansion study in which patients who have completed ORION-9, ORION-10, orION-11 studies will receive a three-year inclisiran treatment to assess the efficacy, safety and tolerance of long-term treatment.Inclisiran is the first cholesterol-lowering therapy in the small interfering RNA (siRNA or sir-nah) category, targeting forward protein-converting enzyme oxalolytic 9 (PCSK9), a key mechanism for regulating LDL-C in the body. PCSK9 protein reduces the liver's ability to remove LDL-C from the blood, while LDL-C is recognized as a major risk factor for cardiovascular disease (CVD). The PCSK9 target offers a new treatment model against LDL-C and is considered the biggest advance in fat reduction since statins such as lipto.To date, two monoclonal antibody drugs targeting pcSK9 proteins have been approved for market, Repatha of Amgen and Praluent of Sanofi/Regenerative. Unlike monoantigen PCSK9 inhibitors, as an RNAi drug, inclisiran works by directly shutting down the production of PCSK9 proteins in the liver. Inclisiran is a siRNA that uses natural processes of human RNA interference, in combination with mRNA that encodes the PCSK9 protein, to reduce mRNA levels through RNA interference and to prevent the liver from producing PCSK9 proteins, thereby enhancing the liver's ability to remove LDL-C from the blood and reducing LDL-C levels.Currently, inclisiran is in Phase III clinical development, evaluating the ability to reduce LDL-C by taking medication twice a year. Inclisiran was developed by Alnylam Pharmaceuticals using its proprietary enhanced stability chemical ESC-GalNAc conjugate technology, which can chemically modify RNA fragments with GalNAc, improve stability and facilitate liver targeting of the drug. The Medicines Company has entered into a licensing and cooperation agreement with Allenylam for the global development, production and commercialization rights of inclisiran.Despite lagging behind other PCSK9 inhibitors, inclisiran only needs secondary subsurfic treatment convenience per year, giving it a good market penetration opportunity in the cholesterol-lowering drug market. Credit Suisse had forecast annual global sales of $1.13 billion by 2024. (Bio Valley)