Major research: This new drug can effectively improve hypercholesterolemia and reduce the risk of cardiovascular disease

According to the World Health Organization, atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of death worldwide.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major risk factor for ASCVD. Studies have shown that lowering LDL-C levels is proportional to reduced cardiovascular risk. Inclisiran sodium injection is a new small interfering nucleic acid (siRNA) drug that lowers LDL-C and targets proprotein convertase subtilisin/kexin type 9 (PCSK9). It was officially approved for marketing by the National Medical Products Administration in August 2023. Inclisiran sodium uses the natural process of RNA interference in the human body to bind to the mRNA encoding the PCSK9 protein, reduce its level through RNA interference, prevent the liver from producing PCSK9 protein, thereby reducing LDL-C levels and reducing the risk of cardiovascular disease. The drug is currently approved for use in patients with adult heterozygous familial hypercholesterolemia (HeFH) who are intolerant or insensitive to statins.

The Journal of Atherosclerosis and Thrombosis recently published a study aimed at evaluating the efficacy, safety, and pharmacokinetics of increslan sodium in patients with HeFH. ORION-15 is a single-country (Japan), phase II, randomized, placebo-controlled, double-blind study, including a 14-day screening period and a 12-month double-blind treatment period. A total of 312 subjects with confirmed hypercholesterolemia (including HeFH) were included, with a baseline LDL-C level of 114.0 mg/dl. All subjects were randomized into 55 increslan sodium 100 mg group, 101 in 200 mg group, 99 in 300 mg group, and 57 in placebo group. On day 1, day 90, and day 270, subjects were subcutaneously injected with increslan sodium 100, 200, or 300 mg or placebo, respectively. The primary endpoint of the study was the percentage change in LDL-C from baseline at 180 days.

The results of the study showed that at day 180, all doses of Inksilan sodium showed significant reductions in LDL-C and PCSK9 (both P < 0.0001). More than 86% of the subjects in the Inksilan sodium group achieved the 2017 lipid management goals of the Japanese Atherosclerosis Society, while only 8.9% of the placebo group did. The mean plasma half-life of Inksilan sodium was 6.8 (2.0) ~ 7.6 (0.8) h. The incidence of adverse events in the Inksilan sodium group was similar to that in the placebo group, and most safety events were mild to moderate, with good drug safety.

Conclusions: Inkstone sodium 100, 200, and 300 mg showed clinically meaningful and statistically significant reductions in LDL-C and PCSK9 at day 180, which remained consistent over 12 months, reflecting that Inkstone sodium is effective, safe, and well tolerated in Japanese patients with hypercholesterolemia, including HeFH.

In the current clinical treatment practice in my country, the drug with the largest reduction in LDL-C is PCSK9 inhibitor (such as alirocumab, etc.). Inksilan sodium has the same reduction in LDL-C as PCSK9 inhibitors, but the duration of efficacy is longer and the effect is more stable. Inksilan sodium also has certain advantages in the administration cycle. The booster injection is injected 3 months after the first injection, and only 2 injections are required each year thereafter, which greatly facilitates patients. PCSK9 inhibitors need to be used at least once every 2 or 4 weeks. At the same time, many elderly patients with hypercholesterolemia have poor compliance, and the phenomenon of "eating one meal and stopping one meal, eating three days and stopping two days" is more common. Secondly, the repeated fluctuation of LDL-C levels is not conducive to reducing the risk of cardiovascular disease. The use cycle of Inksilan sodium twice a year is conducive to the stable control of blood lipids in patients with poor compliance. Inksilan sodium has good safety for liver and kidney function, and the elderly and patients with hypercholesterolemia with liver and kidney dysfunction do not need to adjust the dosage. At present, the drug has been officially approved for marketing in my country. It is believed that its application prospects will be broader with the passage of time.

Figure 1 Experimental design

Table 1 Demographics and baseline characteristics of the subjects

Figure 2 Mean percentage change in LDL-C during the study period

Figure 3 Mean percentage change in PCSK9 during the study period

Table 2 a and b Proportions of patients achieving JAS 2017 and JAS 2022 lipid management targets at days 180, 270, and 360 (Note: a represents the overall population; and b represents the HeFH subgroup)

Compiled by Liu Shengnan

Editor: Lulu

Review丨Wang Shenchong