PD-1 new drug PKO/K drug biosimilar drug who will win?

Recently, the first PD-1 similar drug in China has come, and the first PD-1 innovative drug has withdrawn.

On March 5, Biotech announced the termination of the clinical development of its PD-1 product.

On the surface, this seems to be just bad news for one company and good news for another company.

Biotech uses data to describe this concern: Judging from the clinical data of various PD-1 monoclonal antibodies, it is estimated that in the next 2-3 years, there will be more than 20 PD-1 products on the market globally, and the market competition is becoming increasingly fierce.

Of course, the pharmaceutical companies that choose to develop PD-1 are not without such a situation, so in the early stage of the project, the differentiation of indications took a place.

Data shows that carrelizumab has registered more than 270 clinical studies (including real-world studies) in China, of which more than 80% of the combined therapy; Sintilizumab and Teriplizumab are also disclosed in China More than 100 clinical studies have been conducted, of which nearly 80% are combination therapies; more than 70% of the more than 60 clinical studies registered in China for tislelizumab are combination therapies.

In 2021, it is expected that there are still 2-4 PD-1 products approved in China.

The most extreme result of the trial deduction, after 5 years, these PD-1 products are finally approved, plus the biosimilar drugs that have survived the expiration of the O drug patent, at that time, PD-1 will enter a price that can only fight for the price.

01 PD-1 biosimilar is here!

The first domestically produced O drug biosimilar drug surfaced.

On February 25, 2021, Luye Pharmaceutical announced that its subsidiary Boan Bio-Nivolumab (O drug) biosimilar drug (LY01015) clinical trial application has been officially accepted by the Center for Drug Evaluation (CDE).

As we all know, domestic PD-1 has become the Red Sea market, and the arrival of biosimilar drugs will undoubtedly intensify market competition.

With the protection of the patent period, if it does not break through the O drug patent in some fields, its biosimilar drug will be on the market at the earliest five years later.

Obviously, Luye Pharma was already aware of the situation when deciding to imitate the O drug, and did a good job of psychological construction of the price.

But Green Leaf's consideration may not stop there.

In addition, in addition to LY01015, Boan Biosciences has many other biosimilar drugs under research that are intensively advancing.

"In fact, the PD-1 biosimilar drug may not be limited to Luye Pharma.

And internationally, companies that make O drugs and K drugs biosimilar drugs have already blossomed everywhere.
As early as April 2019, Xbrane, a Swedish company specializing in the development of biosimilar drugs, announced that it would accelerate the development of its O-drug biosimilar drugs, and the current state is in the preclinical stage.
On September 1, 2020, another Australian-based biosimilar company NeuClone announced that the two biosimilars (K drugs and O drugs) it is actively developing are in the late stage of preclinical development.

In addition, the participation of third-party giant companies in the upstream of the industry chain has rendered the scene of PD-1 biosimilars coming from all directions from the side.
According to E-pharmaceutical managers, Sartorius has begun to provide pharmaceutical companies with comprehensive analysis solutions for O-drug biosimilars, including combined analysis, biological analysis, physical chemistry, and structural characterization, with the purpose of accelerating the development of drugs.
development process.
This is a German company with a history of 151 years.
It mainly provides innovative laboratory equipment and products for biopharmaceutical companies and various scientific research institutions, as well as a complete set of biopharmaceutical equipment and disposable solutions.

In the face of a fully competitive market and the sweeping biosimilar drugs, who will be the next one to be "scared off" by Biotech? Latecomers, is it really inferior to PD-1 biosimilars to make PD-1 new drugs?

02 Is it really better to make PD-1 new drugs than to make PD-1 biosimilar drugs?

The core of answering this question is to calculate the ultimate benefits of the enterprise.

A PD-1 investor told the E drug manager that he used to calculate the cost when he invested in PD-1.
He believed that if a company can reduce the production cost of the entire industry by 50%, any drug can be successful.
No need to think about how to promote.
It is often difficult for biosimilars to have bargaining power, especially PD-1.
The key to success is that the cost is low enough.

For the time being not limited to PD-1, we need to answer a question first, is it a good business to make biosimilar drugs?

In recent years, with the expiration of patent protection for multiple “blockbuster”-level original biopharmaceuticals with global sales of more than 1 billion U.
S.
dollars, the research and development of biosimilar drugs has shown a blowout trend.
At present, my country has the largest number of research and development products and enterprises participating in research and development in the world.
According to statistics, as of the end of 2020, there are more than 700 biosimilar drugs under research in the world, while nearly 300 are under research in China.

The pursuit of the industry seems to indicate that this is a "good business.
" The team of Professor Ding Jinxi of China Pharmaceutical University once stated that with the continuous acceleration of domestic biosimilar research and development, the demand for clinical substitution of biosimilar drugs will become more prominent in the next 3-5 years.

Demand is one aspect of business considerations, and "economy" may be the other.

From a policy point of view, the development of biosimilar drugs can reduce some processes when certain conditions are met, thereby saving time and capital investment.
For example, NMPA stipulates that if the preliminary pharmacy comparison experiment shows that there is no difference or little difference between the candidate similar drug and the reference drug, then only the clinical comparison test of pharmacodynamics and immunogenicity can be carried out.
The FDA stipulates that when a comprehensive pharmacy and in vitro comparison test proves that the candidate drug is sufficiently similar to the reference drug, repeated dosing toxicity tests and phase II clinical trials can be exempted.
On this basis, when clinical pharmacological experiments also prove that the candidate drug is sufficiently similar to the reference drug, clinical similarity can be established without conducting phase III clinical comparison trials.
The EMA, which has issued the "Guidelines for Biosimilar Drugs (Draft)" since 2004, is more mature and relaxed.

According to statistics, the general development time of biosimilars currently on the market in my country from IND to marketing application takes 5.
25 years, and the average marketing review cycle is about 15 months.
That is, it takes about 6.
5 years for a biosimilar drug from IND to market, while it takes about 8 to 10 years for a biologic original research drug.
As my country's biosimilar drug review and approval policies become more and more perfect, the future approval time will inevitably become shorter and shorter.

In terms of capital investment, data shows that a biosimilar drug generally needs to invest 100 million to 300 million U.
S.
dollars, while biological original research drugs cost about 800 million to 1 billion U.
S.
dollars.
This is also a time to test the strength of various companies.
Take Fuhong Hanlin's trastuzumab-like drug as an example.
The investment cost about 1 billion yuan before and after the drug, which is still "profitable" compared to the original research drug.

As for the follow-up market sales? Overseas can refer to the sales of adalimumab biosimilar drugs, which belong to the same tens of billions of "blockbuster" drugs with PD-1.
In November 2018, shortly after Novartis Sandoz officially launched the price of adalimumab-like drug (Hyrimoz), the company lowered the price to 37%~40% of the original research Merlot.
At that time, there were Amgen and Biogen.
Two companies have adalimumab-like drugs.

Some investors who are familiar with the sales model of overseas generic drugs told E drug managers that the listing of overseas generic drugs is a free replacement system.
They basically agree with the consistency of generic drugs.
Whether it is a pharmacist or a patient, the pharmacy will automatically replace the generic drugs when they come out.
It won't take long for 80% of sales to switch to generic drugs.
Although the clinical alternatives of biosimilar drugs are more controversial, some countries have already started.
For example, in the year when the patent of Aber Repair Merlot expired, the Danish health care system almost completely switched to adalimumab biosimilars.
87% of the cost.

The current adalimumab biosimilars are in urgent need of volume, because AbbVie extended the patent period of Humira in the United States to 2023, and the United States accounted for three-quarters of sales (75% in 2019).
As for the exact data, according to the "2020 Global Adalimumab, Infliximab, Etanercept Similar Drug Market Report" quoted by Business Wire, it is expected that these three biosimilar drugs will increase from 2.
2 billion U.
S.
dollars in 2019 By 2020, the compound annual growth rate of 2.
27 billion US dollars is 3.
24%.
The report also predicts that the aforementioned products will reach 7.
5 billion US dollars in 2023, with a compound annual growth rate of 48.
94%.

Domestic biosimilar drugs have just begun, but some companies have achieved substantial growth.
In 2020, Qilu Pharmaceuticals China's first bevacizumab biosimilar has sales of 1.
8 billion yuan in the first year of its launch, and sales of original research drugs are estimated to be 2.
6 billion yuan.
"Sales and cost are both the key to her victory, because biosimilar drugs fight for price.
" As we all know, Qilu Pharmaceuticals has always been known in the industry for "dare to lower prices and can reduce prices".
In each collection, Qilu Pharmaceuticals almost always It is the player with the most and the lowest winning bids.
When many companies are talking about suffering from "collective sourcing", the company always posts good news every time.

What is the reason? An investor close to Qilu told the E-pharmaceutical manager: "You will understand when you visit the factory in Qilu.
" Qilu has a very good control of production costs, so he has never been afraid of centralized procurement.
This is also made by making generic drugs for many years.
Experience, whether it is a chemical generic drug or a biosimilar drug.

In the PD-1 competition, the efficiency of capital use and the control of production costs are particularly important, especially for the latecomers who are queuing.
So, how much does it cost to make a PD-1 in China? Hengrui’s 2019 annual report showed that its two indications for PD-1 Hodgkin’s lymphoma and hepatocellular carcinoma have reached the approved production stage, and a combination drug for the treatment of non-small cell lung cancer and single-agent esophageal squamous cell carcinoma has reached the declared production stage.
As well as a number of clinical indications, a total of 740 million yuan has been invested.
Of course, today is different from the past.
Some companies have revealed that only one phase III clinical trial of PD-1 now requires 300 million to 500 million yuan.

On the one hand, this difference is inseparable from the company, on the other hand, it reflects the unknown truth behind the development of PD-1.
The above-mentioned companies revealed that the recruitment efficiency of PD-1 clinical patients has been getting lower and lower in recent years, and some people cannot be recruited at all.
Clues may be found in the unfinished phase I clinical trial that Biotech has abandoned.
CDE data shows that the clinical inclusion of solid tumor indications included 15 patients, while the target enrollment was 27; and in EBV 100 people are planned to be enrolled in related gastric cancer (the first announcement is January 8, 2019), but there is no actual recruitment.

Patient recruitment is an urgent problem for PD-1 developers.
If the patient has not been recruited, the resulting trial stagnation will undoubtedly be fatal to some companies with weak financial strength and weak R&D pipelines, and even the termination of R&D.
Biotech is an example of voluntarily giving up in the balance of benefits and costs.
Whether there will be more examples in the future, we can wait and see.

For biosimilar drugs, the aforementioned problems can be relatively reduced due to the reduction of test links.
But "purchasing the original research drug used in the test process is also a big expense, as well as the drugs used in the test produced by oneself.
This part depends on the supply of subsequent products after the market.
For example, if you use a small-capacity machine to produce, After being approved for marketing, it can only be produced with small machines and will face greater supply pressure.
However, when a large-capacity machine is used for production once, only a small proportion of the batch of samples used for testing are used for testing, and most of them need to be destroyed "Some corporate sources familiar with biosimilar drugs revealed.

"Of course clinical is only a one-time cost, but also need to pay attention to the operating cost, that is, the production cost including raw materials and fixed asset depreciation.
" The aforementioned PD-1 investor pointed out, "When a new production process appears, if the entire industry can be The production cost is reduced by 50%, and any drug can be successful, and there is no need to consider promotion; but if the cost can only be reduced by 30%, there will be uncertainty, because competitors can make up for it through refined operations and management.
The upper gap.
” Therefore, whether it is an original drug or a biosimilar drug, it depends on the cost, including the dosage form, which will also affect the cost.
For example, PD-1 now has water injection and powder injection, and the industry-wide PD-1 cost is about 70~100 USD/gram, you can refer to it when calculating benefits.