Novartis Launches Phase III Trial in China for Inclisiran, the First PCSK9-Targeting siRNA Therapy for Primary Hypercholesterolemia

On November 10, the Insight database showed that Novartis’ inclisiran injection initiated Phase III clinical trials in China for the treatment of primary hypercholesterolemia. This drug is the first siRNA therapeutic targeting PCSK9.

Source: Insight Database (http://db.dxy.cn/v5/home/)

Inclisiran (development code: KJX839) is a long-acting RNAi lipid-lowering agent that conjugates double-stranded siRNA targeting PCSK9 with GalNAc targeting the asialoglycoprotein receptor on hepatocytes, thereby enhancing the stability of the siRNA molecule and enabling specific delivery to the liver.

As a long-acting lipid-lowering agent, inclisiran effectively reduces low-density lipoprotein cholesterol (LDL-C) levels in the bloodstream with only two subcutaneous injections per year, thereby achieving significant lipid-lowering effects. Compared with currently marketed PCSK9-targeting monoclonal antibodies and statin-based lipid-lowering drugs, which require dosing every two weeks or once monthly, inclisiran offers a unique therapeutic advantage in terms of patient adherence. The drug has currently been submitted for marketing approval in the United States and Europe. According to Clarivate’s 2020 drug forecast report, inclisiran is expected to become a blockbuster drug with annual sales exceeding $1 billion following its launch.

Inclisiran was developed by The Medicines Company (MDCO), which Novartis acquired last year for $9.7 billion, thereby gaining rights to Inclisiran. To date, nine clinical trials have been conducted on this drug, targeting heterozygous hypercholesterolemia (ORION-9) and patients with atherosclerotic cardiovascular disease (ASCVD) or at high risk for ASCVD (ORION-10 in North America and ORION-11 in Europe). Some of the study results have already been presented at the European Society of Cardiology (ESC) Congress and published in the New England Journal of Medicine (NEJM).

From: Insight Database (http://db.dxy.cn/v5/)

At the 2020 European Society of Cardiology (ESC) Congress, Novartis presented pooled data from two pivotal Phase III clinical trials, ORION-10 and ORION-11. These two Phase III trials enrolled more than 2,300 patients to evaluate the efficacy of inclisiran in lowering low-density lipoprotein cholesterol (LDL-C).

The results showed that among patients with atherosclerotic cardiovascular disease (ASCVD) who received inclisiran treatment for more than 17 months of follow-up, there was low inter-individual variability in efficacy. After placebo adjustment, 99% of patients achieved a reduction in LDL-C levels of ≥30%, with an average decrease of 54.1% from baseline. At any time point during the study, 88.4% of patients treated with inclisiran achieved at least a 50% reduction in LDL-C levels. Its safety and tolerability profile was similar to that of placebo.

Meanwhile, in the subgroup analysis of patients with statin intolerance, Inclisiran effectively reduced LDL-C levels over an 18-month follow-up period and demonstrated a favorable safety profile.

The Phase III clinical trial initiated in this study is an international, multicenter trial. Its primary objective is to demonstrate the superiority of KJX839 over placebo in reducing LDL-C levels from baseline to Day 330. The primary endpoint is the percentage change in LDL-C from baseline to Day 330. The trial is led by Principal Investigator Dr. Li Yong, Chief Physician at Huashan Hospital Affiliated to Fudan University, with participation from 20 medical institutions across multiple provinces and cities in China.

Currently, the lipid-lowering drug market is highly competitive, with PCSK9-targeting antibodies and statins already available. However, patient adherence is a critical issue in the management of such chronic conditions. Inclisiran offers distinct advantages in this regard, demonstrating favorable efficacy and safety profiles for patients with cardiovascular disease as well as those who are statin-intolerant. We anticipate smooth clinical progress for this drug in China, providing patients with a competitive new therapeutic option.