“Three highs” and other chronic disease drugs, is there still room for innovation?
On October 9, 2002, the FDA officially confirmed that the Indian generic drug company Ranbaxy became the first company to submit a generic application for “Lipitor”. Pfizer’s “Lipitor” is the world’s first drug with sales exceeding 10 billion US dollars, and it is the well-deserved “Drug King” before the advent of the era of targeted drugs.
No matter how amazing a variety is, it will one day complete its historical mission. This is the iron law of the pharmaceutical industry. With the introduction of cheap generic drugs, the treatment needs of the “three highs” have been greatly satisfied, so that for many years since then, there have been no major varieties of chronic diseases in the world.
The world may be changing.
In 2015, Amgen and Sanofi delivered two PCSK9 drugs to the lipid-lowering market at the same time, setting off a new round of research and development of lipid-lowering drugs around the world. hot.
PCSK9, whose full name is proprotein convertase subtilisin 9, is the 3rd gene related to cholesterol metabolism discovered by humans, and thus has become the latest lipid-lowering drug. popular target. What it targets is the absolute king in the field of blood lipid lowering, the statins represented by “Lipitor”.
Minet data shows that in 2021, the PCSK9 market size at home and abroad will be close to US$2 billion. However, as of June this year, only 3 PCSK9 drugs have been launched in the world, and there are less than 50 research projects. On June 13 this year, Innovent’s PCSK9 drug tolesizumab applied for listing, and it is expected to become the first domestic PCSK9 drug. Behind Innovent, leading innovative pharmaceutical companies such as Hengrui, Junshi, and Kangfang are also developing this drug. target drugs.
A monoclonal antibody to be “injected” can really beat the cheap oral lipid-lowering drugs?
Next “Statins”
In fact, in 2002, when Indian companies started imitating “Lipitor”, Pfizer could still enjoy a 9-year patent protection period.
Statins have been on the market since the 1990s, and patents expired before 2010. “Lipitor” is a long-standing variety. According to Pfizer’s patent attorney at the time, Jeffrey Myers, it felt like “a pirate ship rubbed its own ocean ship” when he heard that a company wanted to imitate “Lipitor”.
From what it said at the time, Pfizer was actually very reluctant to give up its identity as “the largest pharmaceutical company in the universe”. After all, after chronic disease drugs, Pfizer did not have much accumulation of anti-cancer targeted drugs, and Pfizer vaguely felt that it might miss an era.
In fact, there is still room for development of drugs for chronic diseases.
In 2003, scientists at the Necker-Enfants Malades Children’s Hospital in France discovered that a gene called PCSK9 appears to have a role in keeping cholesterol stable in the body. There is a low-density lipoprotein receptor on the surface of human liver, which can break down cholesterol, and PCSK9 can bind to the receptor and destroy its components. “Harmful” low-density lipoprotein cholesterol (LDL-C) cannot be broken down and can enter the bloodstream in large quantities, eventually leading to diseases such as atherosclerosis.
Statins work by directly inhibiting the production of bad cholesterol. While PCSK9 inhibitors can restore the normal function of the body to decompose cholesterol, this is two completely different development ideas from statins. Following this idea, major pharmaceutical companies such as Amgen, Sanofi, Pfizer, and Eli Lilly have begun to follow up the research and development of PCSK9 drugs.
As research progressed, scientists began to realize PCSK9’s potential to surpass statins. Generally speaking, moderate-intensity statins can reduce LDL-C by 30%, and this ratio can only reach about 50% in high-intensity administration, and it is easy to cause obvious adverse reactions. But PCSK9 inhibitors are more potent.
Some scholars have done a comparison, single-agent PCSK9 inhibitors can reduce cholesterol by about 60%, twice as effective as simvastatin and pravastatin The above are also better than rosuvastatin and “Lipitor” atorvastatin, which can reduce cholesterol by about 50%.
In 2019, in the “ESC/EAS Dyslipidemia Management Guidelines” jointly issued by the European Society of Cardiology and others, all LDL-C indicators above 1.8mmol/L are classified as cardiovascular diseases. For high-risk groups, this indicator has been reduced by 0.8 units compared with the previous standard. This indicator is also widely accepted by the global clinical community, which means that more patients will need more aggressive drugs.
PCSK9 inhibitors have established themselves in the industry.
Time is real money
Third-class companies make products, second-class companies make brands, and first-class companies set standards. This sentence is very applicable in the pharmaceutical industry, although it is cruel.
So far, there are only three PCSK9 inhibitors in the world that are qualified to “set standards” and serve the standard of dyslipidemia, namely Amgen’s ilovolumab, Alisizumab, jointly developed by Sanofi and Regeneron, and Novartis’ siRNA drug inclisiran, which was first approved in December 2020.
Ilolimumab and alecizumabapproved in China in 2019, and will be included in the National Medical Insurance Directory by the end of 2021;inThe progress of clisiran in China is still in the phase III clinical stage.
The biggest advantage of “standard setting” is its almost monopoly on the market. The sales of the three drugs have continued to grow since their launch. In particular, Amgen’s ilovolumab has successfully entered the US$1 billion single-product club in 2021, occupying more than 70% of the market share of PCSK9 drugs.
Looking at the domestic situation, by 2021, the terminal PCSK9 inhibitor drug market in key public hospitals in the provinces and cities will be 64.63 million yuan, the growth rate will reach 112% , the overall market capacity is much larger than this number. Especially after the inclusion of medical insurance, the heavy volume of the two products this year is expected.
Predecessors have already made a successful road, and companies that follow the trend are flocking to it. According to the statistics of Southwest Securities, as of June this year, there were 49 PCSK9 target-related projects under research in the world. Most of them have entered the clinical stage, mainly monoclonal antibodies, of which they are in phase III clinical trials. There are 5 stages.
Data source: Southwest Securities (as of June 2022)
PCSK9 is a rare “blue ocean” target with confirmed curative effect and low competition in the current pharmaceutical market. Whoever completes Phase III as soon as possible will win a bigger cake.
It is worth mentioning that in the competition of PCSK9 targets, domestic enterprises have already been at the forefront. At present, the PCSK9 projects of Hengrui Medicine, Junshi Biotechnology, and Kangrong Dongfang, a subsidiary of Kangfang Biotechnology, have simultaneously started Phase III clinical trials at home and abroad. In addition, the pipelines of companies such as Tianguangshi, Frontier Bio, and Tasly have also entered the clinical stage.
Domestic companiesdeclared clinical trials mostly in the period of 2017-2018, basically following the trend after Amgen and Sanofi products released data R&D. Among them, Innovent Bio and Kangfang Bio have the same time for clinical application, and Hengrui Medicine’s clinical application is slightly later than the first two.
But today, the gap between several companies has widened considerably. The Health Knowledge Bureau noticed that at the end of 2021, Kangfang Bio’s PCSK9 inhibitor had just completed Phase II clinical trials and was about to start Phase III; Hengrui Medicine, which started 10 months later than Kangfang Bio, was carrying out Hypercholesterolemia III at that time. Clinical trials have been in progress for several months.
It is conceivable that even if Innovent’s products are approved first, Hengrui or Kangfang will follow soon, and the time window will be very short.
The monoclonal antibody is just the starting point
The concern for PCSK9 inhibitors is not peer-to-peer speed, but statins that already have a solid market foundation.
Minenet data shows that as of the beginning of June this year, there were more than 70 lipid-lowering drug brands on the market in China, of which nearly nine were statin products. In 2021, the consumption of statins and compound drugs in public hospitals in key provinces and cities will account for 84.58% of the lipid-lowering market.
Traditional lipid-lowering drugs have been used for decades. It does not mean that they can be changed. Even most doctors believe that PCSK9 inhibitors are only complementary drugs to statins. , is mainly used in the case of severe intolerance of statins or insufficient efficacy of statins alone.
The European Heart Journal, the top journal of heart disease research, has published data: in a survey of more than 4 million patients, the proportion of statin intolerance was only 9% about. In this market alone, PCSK9 inhibitors cannot even recover the research and development costs.
To change the minds of tens of thousands of cardiovascular specialists across the country, companies may have to spend a lot of effort on doctor education.
Moreover, most of the current PCSK9 inhibitorsare monoclonal antibodies, which need to be injected. Cardiovascular disease is a chronic disease that requires long-term medication. Although aliximab and ilovolumab can be injected every 10 days or half a month, they still do not match the medication habits of middle-aged and elderly people.
There is another factor. After entering the medical insurance through price negotiation, the current domestic price of two PCSK9 inhibitors is around 300 yuan, and it takes 20 to 30 drugs a year. Reimbursing a large portion, patients may still spend several thousand dollars a year. Comparatively, in the field of domestic lipid-lowering drugs, more than 70% of the varieties are collected in a centralized manner. Looking at statins alone, the average drop is close to 90%, which is already the price of cabbage.
For many Chinese seniors, spending an extra two or three hundred dollars a month is not a small expense.
Among the three PCSK9s already on the market, Novartis’ inclisiran is unique. This product can directly prevent the production of PCSK9 protein in the liver, and it does not need to be injected for ten days and a half months. After two injections in the first three months, one injection every six months is enough.
Inclisiran’s global sales in the first quarter of this year have surpassed all of 2021, reaching $14 million. Some analysts even believe that due to strong competition from inclisiran, the sales growth of Amgen’s ilovolumab this year may not be as good as before.
In addition, researchers are also exploring more possibilities for PCSK9 targets. For example, AstraZeneca is currently developing antisense therapy, and the PCSK9 oral small-molecule drugs deployed by Novo Nordisk, Jia Yue Pharmaceutical, Xin Litai and other companies, The fastest progress has reached Phase II clinical stage.
Who says there is no new world for chronic disease medication?
Writing | Gu Yue
Editing｜Jiang Yun Jia Ting
Operations｜Valley
Illustration | Visual China
#cholesterol##statin##targeted drug#