PCSK9 inhibitors against statins, a new era of fat reduction!

Merck recently disclosed positive results from a Phase 2b clinical trial of its PCSK9 inhibitor MK-0616 in adults with hypercholesterolemia. The results showed that LDL-C decreased from 41.2% to 60.9 % after 8 weeks of treatment in the 4 dose groups (6mg, 12mg, 18mg, 30mg), and was clinically well tolerated. Based on this, Merck plans to initiate a Phase III pivotal study in the second half of this year.

MK-0616 is a tricyclic, orally available small molecule PCSK9 inhibitor. In the PCSK9 sector, where two mab and one siRNA therapy have been approved, oral small-molecule PCSK9 inhibitors offer advantages in accessibility and cost, which could further impact the cholesterol-lowering market dominated by statins.

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A new hope for lipid reduction -- PCSK9 inhibitors

Cardiovascular disease (CVD) is the leading cause of death worldwide, accounting for approximately 30% of all deaths worldwide. Atherosclerotic cardiovascular disease (ASCVD) is the main cause of death. Multiple risk factors are involved in the occurrence of ASCVD. Dyslipidemia characterized by low density lipoprotein cholesterol (LDL-c) or elevated cholesterol is an important risk factor. Reducing the level of LDL-c can significantly reduce the risk of ASCVD morbidity and mortality.

Currently, statins are the first-line clinical drugs for lipid control. This class of drugs can effectively reduce total cholesterol (TC) and low density lipoprotein (LDL) by blocking cholesterol synthesis. Atorvastatin (Lipitor), the BIC drug of the same class, reigned supreme for many years, with cumulative global sales of about $200 billion to date.

However, statin therapy is associated with adverse side effects, including statin related muscle symptoms, liver toxicity, the likelihood of developing type 2 diabetes, and the risk of hemorrhagic stroke. In addition, about 50% of individuals using statins fail to reduce their LDL-C levels to the desired level.

In recent years, proprotein-converting enzyme subtilin 9(PCSK9) inhibitors have provided new hope for the treatment of various types of refractory hypercholesterolemia patients and the management of blood lipid in patients with extremely high risk of ASCVD.

Unlike statins, which block cholesterol synthesis, PCSK9 inhibitors regulate blood lipids by degrading LDL-C.

In 2007, Amgen scientists first disclosed the crystal structure of PCSK9 and demonstrated that PCSK9 works by binding tightly to low-density lipoprotein receptors. Early clinical data for REGN727/SAR236553(alisiumab), developed by regenerative metascientists, was also soon released.

Data showed that PCSK9 monoclonal antibody monotherapy reduced LDL-C levels by 50-55%, and similar reductions were reported in patients with statin intolerance; In combination with other lipid-lowering treatments, such as statins or ezetimibe, LDL-C levels can be further modestly reduced.

PCSK9 inhibitors offer a new therapeutic paradigm for lowering LDL-C and are regarded as a major advance in the field of lipid-regulating drugs after statins.

To challenge statins, a $1 billion variety has been created

Currently, there are three PCSK9 inhibitors on the market worldwide, including two monoclonal antibodies and one small nucleic acid drug.

Evolocumab, developed by Amgen/Astellas, was first approved in Japan in March 2015 and in Europe in July for patients with inherited hypercholesterolemia or high-risk ASCVD, especially those who are intolerant to statins or do not respond well to high-intensity statins.

Alirocumab, developed by Regeneren/Sanofi, was approved by the U.S. FDA in July 2015, ahead of Amgen's Ilozumab, which was approved for similar indications, thanks to Sanofi's use of a priority review ticket.

In 2021, the sales revenue of Iloxumab reached $1.117 billion, making it one of the first blockbuster drugs. Sales continued to grow in 2022, reaching $1.296 billion. With revenue of $467 million, Regeneren/Sanofi's alisciumab 2022 has not achieved the same sales or growth rate as Ilozumab.

Both monoclonal antibodies are administered subcutaneously every two weeks, challenging the convenience of administration for chronic patients who need long-term medication.

Inclisiran (Leqvio), developed by Alnylam/ Novartis, is a long-lasting drug (once every six months after two injections in the first three months) that reduces the frequency of medication and greatly improves the convenience of medication.

Inclisiran, a PCSK9-targeting siRNA gene therapy developed and designed by Alnylam based on its GalNAc delivery system, was first approved in the EU in December 2020 for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia.

Inclisiran had sales of $112 million in 2022 because of its clinical strengths. Novartis sees Inclisiran as the next core growth area for the company, with sales of $4.644 billion in 2022 and Entresto.

In China, iloxumab and aliciumab were approved for marketing in 2018 and 2019, and Inclisiran filed its marketing application in late 2022. Inclisiran was already used by patients in several hospitals in Hainan Province in 2021 through the Boao Leccheng Advanced Medical Demonstration Zone.

Oral PCSK9 inhibitors show potential

With the launch of these three new drugs, the global development heat of PCSK9 inhibitors is unprecedentedly high. According to the global drug database, there are more than 40 PCSK9 inhibitor drugs under development worldwide, including antibodies, small interfering RNA (SiRNA), oral antisense oligonucleotide (ASO), gene editing, polypeptide small molecules and vaccines and other drug forms.

Lipid control is a long-term process, and convenience of administration is crucial for patients. The three PCSK9 inhibitors on the market are subcutaneous injection, which is inconvenient to use and has limited competitiveness in the face of oral administration and cost-effective statin drugs. Therefore, the development of novel oral PCSK9 inhibitors has become a hot topic.

To date, a number of oral PCSK9 inhibitors have entered clinical phase, including Merck MK-0616, Novo Nordisk NN-6435, Astrazeneca AZD-8233, and Siviel Pharmaceutical CVI-LM001.

MK-0616 is an oral form of PCSK9 inhibitor developed by Merck. It is a synthetic small molecule cyclic peptide that can be absorbed through the digestive tract to block the binding of PCSK9 and LDL-R. Just a few days ago, Merck announced positive results from its Phase 2b clinical trial, which was described at the beginning of this article.

NN-6435 (NNC0385-0434) is another small molecule polypeptide PCSK9 inhibitor developed by Novo Nordisk and currently in phase 1 and 2 clinical trials worldwide.

AZD8233 (ION-863633) is an oral antisense oligonucleotide (ASO) developed by AstraZeneca/ Ionis to effectively target PCSK9 mRNA in hepatocytes and prevent the synthesis of PCSK9. Subcutaneous dosage forms are in phase II clinical phase, and oral dosage forms are also under development.

In recent years, the PCSK9 project of domestic pharmaceutical companies has also made rapid progress. In terms of monoclonal antibodies, the most advanced is Cinda Bio's Toleximab, which was submitted to the CDE for marketing in June 2022. In addition, Junsil Biol's Angorizumab (JS-002), Hengrui Pharmaceutical's recaticimab (SHR-1209) and Kangfu Biol/Dongrui Pharmaceutical's Inucidumab (AK102) are all in phase 3 trials.

In terms of small molecule PCSK9 inhibitors, Civi-LM001 and DC371739 by Shanghai Institute of Pharmacology of Chinese Academy of Sciences have made rapid progress.

conclusion

Currently on the market, PCSK9 inhibitors have demonstrated the advantage of this target in lipid lowering, which brings hope for the treatment of hyperlipidemia and familial hypercholesterolemia. However, due to factors such as price and clinical accessibility, it has not been widely used in clinic.

Small-molecule PCSK9 inhibitor has the advantages of good stability, lower production cost and high patient compliance. If it can be successfully approved for market, it may further expand the use range of PCSK9 inhibitor and change the market pattern of lipid-lowering drugs.