A brief history of drug development at PCSK9.

PCSK9 (pre-protein-converting enzyme oxalolytic 9/kexin9) was discovered in 2003, after which studies confirmed that PCSK9 was associated with cholesterol levels in the human body, with LDL levels 40% lower in people with PCSK9 deficiency and 88% lower incidence of heart disease.
more than a dozen companies subsequently competed for PCSK9, and in 2007 AMSC took the lead in analyzing PCSK9 crystal structures, and tests confirmed that PCSK9 works by closely integrating with LDL-R.
PCSK9 inhibitor antibody drugs Aliocumab and Evolocumab were approved for market by the FDA and EMA in 2017.
company in the PCSK9 competition, all the way to the lead, would have been expected to be the first to go public.
Sanofi and Regeneration used priority vouchers ($67.5 million) from BioMarin to shorten the approval process and eventually get FDA approval for the listing four months ahead of Amgen.
1 PCSK9 from discovery to the development of clinical development of drugs At the same time as the fierce competition for therapeutic antibody drugs, siRNA drugs also opened their own era in the early 20th century.
, which was acquired by Novart in 2019, is a siRNA drug targeted at PCSK9mRNA that has long been expected to be a fat-lowering, transformative therapy.
the first critical Phase III study published by ESC in September 2019, 300mg of subsurfic injections a year all reached primary and secondary endpoints, and tolerance and safety were good.
this will be significantly better than monoantigens in terms of patient compliance and cost of use in the future, and if approved for market, it will successfully achieve a "de-dimensional blow" to monoantigens.
focus of anti-lipid drugs shifted from statins to PCSK9 Atherosclerosis Cardiovascular Disease (ASCVD), one of the highest morbidity and mortality rates in the world.
the occurrence and development of ASCVD is closely related to blood lipid abnormalities.
of blood lipid abnormalities is the LDL-C (LDL Cholesterol) theory, LDL-C has a causal relationship with ASCVD.
meta-analysis showed that for every LDL-C reduction of 1 mmol / L (38 mg / dl), the rate of CHD events decreased by approximately 22%.
statins reduce LDL-C levels by inhibiting axylaminase (AMG-CoA) reductase, which has been a core lipid-lowering drug since statins were introduced in 1987.
PCSK9 is a secretion-type serine protease synthesized by the liver that binds to LDLR (low-density lipoprotein lipolyst) to degrade it, reducing LDLR's removal of LDL-C (LDL-C) from the blood, resulting in LDL-C accumulation in the body and an increased risk of CVD disease.
two PCSK9 inhibitors currently listed abroad have been approved by NMPA to enter China.
statins are still the first- and second-class preferred drugs for treating ASCVD, there are still some statins that do not reach patients or the maximum dose of LDL-C therapy target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
China CDC research shows that the treatment rate and control rate of blood lipid abnormalities in China is at a low level, and a DYSIS-China study reveals that only 31.4% of high-risk/very high-risk patients in China have achieved LDL-C targets after statin therapy.
clinical trials have shown that PCSK9 inhibitor drugs lower LDL-C levels and can promote statins to lower LDL-C levels.
Table 1 2019 European ESC/EAC Blood Lipid Abnormality Guide PCSK9 Inhibitor Recommended Medications Source Network Public Information PCSK9 In the field of research and marketed drugs Listed antibody drugs: Repatha and Praluent Repatha Repatha (commonly known as Evolocumab) developed by Amjin Corporation of the United States, on August 27, 2015 approved by the FDA.
July 31, 2018, it was approved by the NMPA to list as a pure family high cholesterolemia (HoFH) in adults or adolescents over 12 years of age, and in adult atherosclerotic cardiovascular disease (ASCVD) patients, reducing the risk of myocardial infarction, stroke, and coronary haemodysis reconstruction.
STUDY by Evolocumab showed that 27,564 patients with ASCVD and LDL-C levels of 70mg/dL (1.8mmol/L) were included, based on his statin therapy. Evolocumab significantly reduced the compound primary critical endpoint of cardiovascular disease death, myocardial infarction, stroke, unstable angina hospitalization or coronary blood transport reconstruction, and significantly reduced the secondary compound critical endpoint of cardiovascular disease death, myocardial infarction, and stroke.
Evolocumab reduced LDL-C levels by an average of 59%, and the baseline average decreased from 92 mg/dL (2.4mmol/L) to 30 mg/dL (0.78mmol/L) (P.lt;0.001).
, Evolocumab: Placebo (1344 (9.8): 1563 (11.3), HR, 0.85 (95% CI, 0.79-0.92)), P.lt;0.001.
end point, Evolocumab: placebo (816 (5.9): 1013 (7.4), HR, 0.80 (95% CI), (0.73-0.88),P.lt;0.001.
an OSLER-1 trial that assessed the continued effectiveness and safety of Evolocumab in treating hypercholesterolemia in different patient populations over a five-year period without significant adverse reactions, and Evolocumab reduced LDL-C from a baseline average of 140 mg/dL to 61 mg/dL.
year, adverse reactions were similar to those in the placebo group, with no increase in the rate of adverse reactions over time and a decrease in adverse reactions at the injection site.
2 Evolocumab's long-term efficacy and safety for the treatment of hypercholesterolemia Praluent Praluent (commonly known as Aliocumab) was developed by Sanofi in collaboration with Regeneratives and was approved by the FDA on July 24, 2015.
December 28, 2019, NMPA-approved listing of adult patients with primary hypercholesterolemia (hybrid familial and non-family) or mixed lipid abnormalities;
ODYSSEY study showed that Alirocumab significantly reduced the risk of stroke and ishemic stroke by reducing atherosclerotic lipoproteins such as LDL-C, and the trial included 18,924 patients (614 in China) with ASCVD and LDL-C levels of 70mg/dL (1.8mmol/L) in statins On the basis of medication, LDL-C decreased by 62.7% (37.6mg/dL VS 93.3mg/dL) and LDL-C by 54.7% (53.3mg/dL VS 101.4mg/dL) in the 48th month.
key endpoints were reduced adverse heart events (MACE, including coronary heart disease death, acute myocardial infarction, ischemic stroke, unstable angina), MACE (9.5% VS 11.1%), HR0.85 (95% CI, 0.78-0.93), P.lt;0.001) compared to placebo.
secondary critical endpoint of coronary heart disease death, acute myocardial infarction, reduced risk of isothemia stroke (10.3% VS 11.9%), P s 0.0003.
But sales of the two drugs fell short of expectations, on the one hand, regulators were cautious about the safety of chronic diseases, and insurers limited them to the sick;
2018, Sanofi and Amven have launched a price war to increase the market share of PCSK9 inhibitors, starting at an initial price of about $14,000 per year (Repatha, $14,100/year; Praluent, $14,600/year) to $5,850/year.
Figure 3 Repatha and Praluent Global Sales (Source: Company Annual Report/Pharmaceutical Consulting Team Collated Analysis) IN the study of drug global research and development PCSK9 as a potentially heavy-weight fat-lowering drug, there are 70 PCSK9 drugs in the study, clinical status distribution (Figure 4), with biological drugs accounting for the majority of 67%.
27 antibody drugs in biological drugs, 5 vaccines, 3 siRNA, etc., the specific quantitative distribution (Figure 5), chemical drugs have a small molecule synthesis peptide.
Figure 4 PCSK9 in the research drug global research and development status (Pharmaceutical Advisory Team finishing analysis) Figure 5 Global PCSK9 in the study of drug types and quantities (Pharmaceutical Consulting Team finishing analysis) domestic enterprise layout domestic PCSK9 in research drugs have 17, 14 pharmaceutical and biological enterprises involved, clinical distribution in Figure 6.
drugs on the market are Amjin's Evolocumab and Sanofi's Arrocumab.
domestic clinical trials in the study of drugs are national 1 new drugs, including 2 small molecule drugs and 5 monoclonal antibody drugs, specific information (Table 2).
Figure 6 Clinical Status Distribution of PCSK9 Drugs in China (Source: Drug Database/Pharmaceutical Advisory Team) Table 2 Domestic PCSK9 National Class 1 New Drug Research and Development Progress Source: Drug Database/Pharmaceutical Advisory Collation In addition, PCSK9 Preclinically There are 8 drugs, 2 no progress reports, respectively, Jiaxin bio GB-236, in the drug screening stage, no progress report;
6 are in active preclinical research and development status, specific information (Table 2).
Table 3 Preclinical PCSK9 Drug Information Summary Data Source: Drug Database/Pharmaceutical Advisory Team Collation Opportunities or Challenges? How is the price of antibody drugs controlled relative to statins? A new generation of siRNA products is on the verge of becoming available at a time when Repatha and Praluent are not yet dominant in the market and peaking.
whether antibody drugs in THE PCSK9 will be "de-dimensionally combated" and a net, there may be different answers, but the historical laws of the development of biological drugs are destined for a new generation of siRNA drugs to win.
the current era, product iterations have never been so fast, are these questions that need to be considered at home?" Pfizer and Roche's exit in this area may not all be the cause of neutral antibodies, after all, Roche's Tecentriq (PD-L1 monoantigen) immunogenicity is not low, Roche is still pushing hard.
the breakthrough of new drug projects is far from immediate, "cross-border" competitors are always everywhere.
can see the competitive pattern and trend in the track selection and project project, it needs to be carefully analyzed and judged.
PCSK-9 Other articles: 1, 2 injections a year - groundbreaking PCSK9 targeted RNAi drug inclisiran significantly reduced LDL-C30%! 2, $9.4 billion acquisition of the SIRNA drug inclisiran, which targets PCSK9 Reference: 1. Piper DE, Jackson S et al. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Structure. 2007 May; 15(5):545-52. 2. Professional Heart Daily: Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Spite (ORION-10) 3. Horton J D, Cohen J C, Hobbs H. PCSK9: a convertase that cos LDL catabolism . Journal of lipid research, 2009, 50 (Supplement): S172-S177. 4. Gitt AK. et al. Data Brief 2016 Sep.29:9. SC-CHN-AMG145-00415-1019:616-620 5. Marc S. Sabtine, M.D., M.P.H., Robert P. Giugliano et al. Evolocumab and Clinical Outcomes in Patients with Cardio Disease. N Engl J Med 2017; 376:1713-1722 6. Szarek M, White HD, Schwartz GG et al. Alirocumab Reduces Total Nonfatal Ca.