Will PCSK9 inhibitors become the main lipid-lowering drugs in the future?

Cardiovascular disease (CVD) morbidity and mortality remain high worldwide, accounting for approximately one-third of global deaths, and under the influence of metabolic risk factors such as obesity, dyslipidemia, type II diabetes, and hypertension, it has become a Huge challenge, public health and burden of family life

 Among them, atherosclerotic cardiovascular disease (ASCVD) has received more attention

The number of deaths from cardiovascular disease is expected to increase to nearly 24 million annually by 2030, and myocardial infarction or stroke experienced by ASCVD patients is inextricably linked to high plasma cholesterol levels

 The association between high cholesterol and increased risk of cardiovascular events is mainly related to low-density lipoprotein-cholesterol (LDL-c), which is converted from very low-density lipoprotein particles (VLDL), and LDL carries cholesterol to form LDL-c and transport it To peripheral tissues, also including the dysfunctional subendothelial vessel wall, the space under the vessel wall is oxidatively stressed, promoting the oxidation of LDL to ox-LDL, which activates the inflammasome (NLRP3) of macrophages to enhance Vascular inflammation and ASCVD

 Statins (such as Lipitor) are clinical first-line therapy and are designed to block cholesterol synthesis because the rate-limiting enzyme for cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reduction, is inhibited Enzyme statins are effective in lowering total cholesterol (TC) and low-density lipoprotein (LDL)

However, this therapy is not indicated for adults with primary hypercholesterolemia (heterozygous family HeFH, non-heterozygous family HoFH) and statin-intolerant patients who often require additional lipid-lowering drugs to achieve LDL- C's goal

Discover PCSK9

Thus, in 2003, a French team led by Catherine Poirot and a Canadian team led by Nabil G.

• Prodomain (aa 31 - 152)

• Catalytic domain (aa 153-421);

• Hinge-CHRD domain (aa 422-692)

  
  

PCSK9 and LDLR mainly interact with the EGF-A domain through their respective catalytic domains, and the CHRD of PCSK9 is required to trigger the degradation of LDLR, which has triggered a wave of research and development of PCSK9 inhibitors by domestic and foreign pharmaceutical companies: Monogenic Pharmaceuticals, confirm, AstraZeneca, Betagenon, Merck, Pfizer, as well as domestic companies such as Cinda, Kefeiping, Hengrui, Junshi, Xinlitai, and Ruibo Biology are all in this field

Existing PCSK9 inhibitor drugs

PCSK9 inhibitors reduce circulating LDL-C levels primarily through two mechanisms:

• 1.

  
  

• 2.

  
  

Monoclonal antibodies or antibody-mimicking proteins clear LDL-C by directly inhibiting the binding of PCSK9 to LDLR

Small molecule peptide drugs can act on the catalytic site of PCSK9 protein to make it allosteric, thereby affecting the binding of PCSK9 to LDLR

In another mechanism for inhibiting PCSK9 synthesis, AZD8233, a PCSK9-targeting antisense oligonucleotide (ASO) drug jointly developed by AstraZeneca and Ionis, targets and inhibits the translation of PCSK9 mRNA in hepatocytes and protein synthesis

Leqvio: a siRNA-based PCSK9 inhibitor

Novartis' lipid-lowering drug Inclisiran, traded under the brand name Leqvio, was approved for marketing in the EU in September 2020 and was approved by the U.

It is an innovative cholesterol-lowering (LDL-C) injectable drug and one of three PCSK9 inhibitors listed in the world
.

After Leqvio enters hepatocytes, it binds to RNA-induced silencing complex (RISC) and messenger RNA encoding PCSK9 protein binding under the mediation of the antisense strand, interfering with the transcriptional expression of specific genes after a nucleotide sequence complementary to reduce PCSK9 mRNA levels, Prevents the expression of PCSK9 protein in the liver, thereby reducing the degradation of LDLR after the lysosomal endogenous LDLR-PCSK9 complex, and enhances hepatic clearance of LDL in the blood by increasing the LDLR circulating-c to achieve the goal of lowering LDL levels ability
.

In an 18-month (540-day) double-blind, randomized, placebo-controlled Phase III clinical trial, Leqvio was primarily used to treat 3655 patients with heterozygous familial hypercholesterolemia (ORION-9)
.
and outcomes in patients with atherosclerotic cardiovascular disease (ASCVD) (ORION-10) and in patients at ASCVD or ACSVD-equivalent risk requiring further LDL-C reduction after statin therapy (ORION-11)
.

The primary endpoint of the study was the percent change in LDL-C from baseline to Day 510, and the time-adjusted percent change in LDL-C from Day 90 (baseline) to a maximum of Day 540
.

All three studies met the primary endpoint
.
At the same time, the safety of the drug was evaluated for 540 days
.
CeVD patients in the Leqvio group had a mean reduction in LDL-C of 55.
2% from baseline to day 510 compared with the placebo group (P<0.
0001)
.

Twice-a-year injections of Leqvio: Will it make PCSK9 inhibitors more competitive?

By 2021, Leqvi sales will reach $12 million (Figure 2)
.
Leqvio's initial results are also impressive compared to publicly traded Sanofi/Regeneron's Praluent and Amgen's Repatha
.
Due to better patient compliance with Leqvio:

A second injection 3 months after the initial treatment followed by two injections per year can control LDL cholesterol between 50-60%;

Both Praluent and Repatha require injections twice a month
.

Analysts at GlobalData had predicted that Leqvio would bring Novartis $2.
5 billion by 2027, more than expected sales of Praluent and Repatha
.

Currently, Leqvio is still in trials for cardiovascular therapy, which are expected to be completed in 2026
.
Whether Leqvio can be approved by the US FDA for cardiovascular indications will be our continued focus
.
 

Statins that implement centralized drug collection are arguably the most cost-effective treatment for cholesterol lowering
.
In adult patients with familial hypercholesterolemia, established cardiovascular disease, or statin intolerance, PCSK9 inhibitors alone or in combination with statins remain somewhat competitive
.

 The research and development cost of monoclonal antibodies is the main reason for its high price, which will inevitably increase the economic burden of patients; the compliance of oral PCSK9 inhibitors is the best, but its research and development process still has a long way to go
.
After all, the low bioavailability of oral formulations is still an unavoidable problem, and the production cost of oral formulations will also be higher than that of injectable formulations
.

 At present, high drug pricing, formulation selection and high bioavailability are common challenges faced by major pharmaceutical companies in developing PCSK9 inhibitors
.