First-in-class sounds good, not easy to do!

PD-1, CD47.
.
.
Almost every popular target is "overcrowded.
" PD-1 is about to usher in a situation where six companies compete on the same stage in China, and the number of CD47 entering the clinical stage is close to 20, and many Is the head player
.

Me-too and Fast-Follow have spurred the rise of China's innovative drug field, but they have also been criticized by the industry due to the waste of clinical resources and the reduction in the rate of return on R&D investment
.

On July 2, 2021, the Center for Drug Evaluation (CDE) of the National Food and Drug Administration issued a draft of "Guiding Principles for Clinical Research and Development of Anti-tumor Drugs Oriented by Clinical Value", which proposed "Development of clinical value-oriented anti-tumor drugs.
Drug development"
.

But innovation is not easy
.

Facing such challenges, what attempts and responses are Chinese pharmaceutical companies doing? Bigpharma, Biopharma and Biotech, what are the different answers for companies of different sizes? Someone is answering
.

01 Bigpharma's road to innovation

In the 21 years since its listing, the market value once exceeded 500 billion yuan.
As the “big brother of pharmaceutical stocks”, Hengrui is the most representative case of chemical preparation leading transformation of innovative drugs
.

In terms of R&D and innovation, Hengrui has adopted a "three-step" strategy
.

The first step is to increase R&D investment and improve the R&D technology platform
.

The second step is to strengthen the construction of talents
.

The third step is to improve the innovation system and improve the innovation platform
.

In terms of product pipeline layout, Hengrui has more than 40 products under development, covering tumor, immunity, metabolism and other fields
.

Hengrui has its own unique ideas for the construction of the First-in-class pipeline
.

Hengrui's layout of First-in-class is also based on the global market
.
"The Chinese market is an inherent market, and it can definitely be obtained.
What the overseas market can obtain is the maximization of innovation value
.
Therefore, for Chinese companies to be First-in-class, they need to consider domestic and foreign policies at the same time
.
First of all.
The problem to be guaranteed is to analyze the commonalities and differences between the West and China
.
Products that are clinically differentiated still have advantages overseas
.
" Zhang Lianshan said at the 2021 China Medical Innovation 100 Summit
.

In addition, Zhang Lianshan also said that in the development process, you must understand your First-in-class products, and strictly abide by the international standardization process during the development process to reduce blindness
.
In addition to self-developed products, Hengrui is also enhancing pipeline innovation by introducing external products with First-in-class potential
.
Recently, Hengrui spent 1.
3 billion yuan to obtain the exclusive commercialization rights of Wanchun Bulin's First-in-class potential product Punabulin in Greater China to quickly deploy the future First-in-class product market
.

02 Entering Biopharma's Innovation Road

On August 25, BeiGene announced its latest early stage R&D pipeline layout and development progress at the investor conference call on Global R&D Day
.
According to BeiGene, it currently has more than 50 preclinical projects, of which about half have Fist-in-class potential, and more than 10 projects will enter the clinical phase in the next 24 months
.

In May of this year, BeiGene's HPK1 inhibitor BGB-15025 capsule clinical application was officially accepted by NMPA for the treatment of solid tumors
.
So far, BeiGene has entered the clinical stage as "the first self-developed drug candidate with First-in-Class potential in the true sense"
.

From the completion of the first domestically produced new drug to the sea, to the rapid advancement of First-in-class products into the clinic, BeiGene has delivered good results at every important node
.
In addition to HPK1 inhibitors, BeiGene's OX40 monoclonal antibody BGB-A445 and TIM3 monoclonal antibody BGB-A425 also have First-in-Class potential
.

At present, BeiGene's preclinical team has more than 650 people, and it is expected to reach 800 by the end of this year
.
In addition to expanding the R&D team, BeiGene has also increased its layout in cutting-edge technology.
It has high-throughput screening, virtual screening, chemically activated degradation technology CDAC, functional genomics technology, ADC and other technology platforms, which are First-in-Class Provide a "toolbox" for drug development
.

BeiGene's construction achievements in research and development are mainly derived from its famous "willingness" in research and development
.
From 920 million U.
S.
dollars (approximately 5.
97 billion U.
S.
dollars) in 2019 to 8.
452 billion U.
S.
dollars in 2020, Baiji has repeatedly overwhelmed many pharmaceutical companies in R&D investment, ranking first
.
The R&D investment in the first half of this year has reached US$6.
77 (approximately 4.
37 billion yuan)
.
The annual increase in R&D investment costs can also show Baekje's determination to truly innovative drugs and confidence in its own products
.

Like Baekje, Cinda is also accelerating the layout of First-in-class
.
At the 2020 R&D Day event, Yu Dechao, the founder, chairman and CEO of Cinda, once stated that Cinda’s two core strategic goals for the next 5-10 years are to achieve the global launch of First-in-class innovative products and the realization of Cinda Bio Business globalization
.
At present, Cinda has 23 product pipelines, many of which are under development with First-in-class potential
.

03 "Small but Beautiful" Biotech's Innovation Road

Comparing the innovation paths of multinational pharmaceutical companies, it can be seen that the innovation "growth engines" of many large international companies come from small but technologically advanced companies
.

As the first Bruton's tyrosine kinase (BTK) inhibitor, Ibrutinib has quickly become the fastest-growing product in the leukemia field since its launch.
It has successfully ranked among the top 5 best-selling drugs in the world, and has also provided AbbVie with business Growth "new engine"
.
This product was jointly developed by the biotechnology company Pharmacyclics and Johnson & Johnson
.
In March 2015, AbbVie spent US$21 billion to acquire Pharmacyclics and obtained the US market development rights of Ibrutinib
.
On August 23, Pfizer/BioNTech's mRNA COVID-19 vaccine COMIRNATY® was officially approved by the FDA, and the world's first FDA-approved mRNA COVID-19 vaccine with complete Phase III data was born
.

A similar path is being staged in China
.

On August 26, Wanchunbulin licensed the exclusive commercialization rights of the anti-tumor drug punabulin in Greater China to Hengrui Medicine at a price of 1.
3 billion yuan
.
Pranabrin is a guanine nucleotide exchange factor (GEF-H1) activator and a drug with great first-in-class potential, used to prevent the neutralization of non-myeloid malignant tumors induced by chemotherapy Granulocytopenia (CIN)
.

Like other drugs with First-in-class potential, the research and development of pranablin has not been smooth sailing
.

Huang Lan, the co-founder, chairman and CEO of Wanchun Pharmaceutical (the parent company of Wanchunbulin), discovered in 2007 that a company had been making a drug called pranabulin since 1999, but it was still far away from the market.

.
Since pranabulin is a component extracted from marine microorganisms, the mechanism of the drug is not very clear, so it can only be seen that it has a certain clinical effect, but the prospect is unknown
.
In 2013, Wanchun Pharmaceutical bought the global R&D and commercialization rights of Panabrin
.

Through in-depth research and analysis of the subspecies of the clinical trial population, Wanchun Medicine has found a new immune target-GEF-H1, which makes ponabrine a drug with first-in-class potential
.
In the Phase II clinical trial of prinabulin for lung cancer, Wanchun Medicine found that the drug has a significant effect on the prevention of leukopenia caused by chemotherapy, so it turned to the research on neutropenia first
.

The current standard therapy for CIN is G-CSF (granulocyte colony stimulating factor) drugs, but their onset is slower, with more bone pain side effects, and there is still a huge unmet need
.
Pranabrin can reverse the blocking formation of neutrophils in the bone marrow induced by chemotherapy drugs, maintain the level of neutrophils in the normal range, and achieve the effect of early protection of white blood cells in the bone marrow.
-CSF's mechanism of action to reduce the occurrence of early CIN
.
In September 2020, Pranabrin has successively obtained the dual certification of "Breakthrough Therapy Product" in the field of prevention of CIN by the Chinese and US Drug Administration
.
In 2021, the NDA application for the CIN indication of punabulin was accepted by the United States and China successively, and was granted the "priority review" qualification
.
At present, the global phase III clinical study of Pranabrin in second and third-line non-small cell lung cancer patients (EGFR wild-type) has reached the primary endpoint.
Wanchunbulin plans to submit an NDA application for this indication in the first half of 2022
.

In addition to Wanchun Bulin's own technology to give drugs with uncertain futures Fist-in-class potential, Suoyuan Bio is also using its own advanced technology to solve the bottleneck problem of Fist-in-class potential drugs that multinational pharmaceutical companies have no choice but to give up
.

In 2014, Suoyuan Biotechnology introduced DB102 (Enzastaurin) with First-in-class potential from Eli Lilly
.
This is a potent and selective PKCβ inhibitor for tumor treatment.
Currently, there is no new drug targeting this target in the world
.
Eli Lilly chose to give up because DB102 failed to achieve the expected efficacy in phase III clinical trials for two indications
.
After analyzing the clinical results, Suoyuan Biotechnology found that the drug has a therapeutic effect in some patient groups.
Therefore, it acquired the DB102 project from Eli Lilly and owns all the rights and interests in the global R&D, production and sales of the drug
.

Suoyuan Biosciences used the biomarker discovery platform to conduct a large-scale whole-genome scan of the samples from Eli Lilly's Phase III clinical trial.
After analysis and big data calculations, it discovered and determined a new pharmacogenomic biomarker DGM1 (Denovo Genomic Marker 1)
.
Preliminary test data show that after DGM1-positive patients receive the combination of DB102 and the current international first-line therapy, their survival period is significantly improved compared to the control group who only takes the current international first-line therapy, and DB102 has an effect on diffuse large B-cell lymph.
The first-line therapy for high-risk patients with tumors (DLBCL) has a significant therapeutic effect, which can better make up for market vacancies
.

Among the first-line treatments for DLBCL, Rituxan has been among the top 20 global drug sales in recent years
.
In 2020, the global sales of Ritual China reached US$4.
52 billion (approximately 29.
27 billion U.
S.
dollars), and Ritual China's combination drugs and drugs that complement the population are expected to have a significant market share
.
DB102 has been approved by the FDA and the European Commission (CEC) as an orphan drug for DLBCL.
It is currently undergoing international multi-center phase III clinical trials and is expected to be unblinded in mid-2022
.

In addition to the field of DLBCL, the performance of DB102 in the field of glioma (GBM) cannot be ignored
.
The current first-line therapy for GBM is surgery and postoperative combined radiotherapy and temozolomide.
The patient's survival rate is only 15 months.
There has not been a better drug regimen in the past ten years, and there are still long-term unmet clinical needs
.
In addition to the orphan drug designation for GBM granted by the FDA and the European Commission, DB102 also obtained the rapid review channel qualification granted by the FDA in July 2020
.
The granting of the qualification for the rapid review channel not only reflects the FDA's recognition and support for the precision medicine that gives the drug "new life", but also reflects the urgent need of the market for this therapy
.
At present, the first-line international multi-center phase III clinical trial of DB102 for GBM has completed the first patient administration, and it is expected to be unblinded in 2025
.

It is difficult to develop first-in-class drugs, so most pharmaceutical companies do not have first-in-class potential drugs in their pipelines, or there is only one drug
.
The prospectus submitted by Suoyuan Biotechnology in July this year shows that the company currently has five R&D pipelines with First-in-class potential and two R&D pipelines for Class 1 new drugs
.

From the field of diseases involved, Suo Yuan is not limited to first-in-class drug breakthroughs in the field of oncology, but also focuses on the field of central nervous system diseases
.

Compared with the boom in the field of oncology, the field of central nervous system diseases is still a field of huge unmet need with few attentions
.
Taking Alzheimer’s disease (AD) as an example, data shows that there will be approximately 25 to 35 million Alzheimer’s patients in the world in 2020, and the treatment market will be around US$4.
5 billion, with a compound annual growth rate in the past five years.
It is 1.
91%
.
However, the drugs approved for marketing are few and controversial, and the treatment needs of many patients have not been met
.
Many pharmaceutical companies chose to give up after suffering from Alzheimer's disease.
Only a few still insisted.
Suo Yuan was one of them
.
Currently, Suoyuan is being explored for Alzheimer's disease targeting α-2C adrenergic receptor (AR) inhibitor DB105
.

In addition to Alzheimer's disease, Suo Yuan is also exploring diseases such as depression (TRD) and schizophrenia (SCZ)
.
Suoyuan’s DB104 is an oral serotonin, norepinephrine and dopamine triple reuptake inhibitor for the treatment of refractory depression (TRD).
The biomarker DGM4 has been discovered and is expected in the second half of 2021.
Apply for an international multi-center phase IIb clinical trial, which is expected to become the first central nervous system companion diagnostic drug
.

In addition, Suoyuan Biotech also owns the global rights and interests of five innovative drugs DB102, DB103, DB104, DB105, and DB106, and the global rights and interests of two innovative drugs DB107 and DB108 excluding China (including Hong Kong, Macau and Taiwan)
.

Suoyuan Bio's innovative model of "turning waste into treasure" has also attracted discussions in the industry
.
"A drug that a resource-rich multinational company like Eli Lilly has given up.
Can a small-scale innovative pharmaceutical company really make it?" Realistic issues
.

A senior industry insider who is familiar with the Suoyuan model answered: "The development of this drug through the biomarker discovery platform requires the close cooperation of experts in pharmacy, bioinformatics, genomics, etc.
It is a complex systemic Engineering requires strong professional knowledge and technical know-how
.
In multinational pharmaceutical companies, departments with different technical directions may not be in the same location.
The use of high-intensity collaborative operations in the development of drugs with unknown futures and smaller markets seems to be cost-effective.
High
.
A small and concentrated team like Suo Yuan has exactly this advantage
.
"

Source innovation is a matter that requires highly sophisticated talents, advanced technology, abundant capital and sufficient time
.
A scientist in the industry who focuses on source innovation said in an interview with the E-pharmaceutical manager: The root cause of homogeneity is that only 1% of domestic investment institutions are truly capable and willing to invest in true source innovation
.
Capital and time are largely in the hands of investment institutions.
Does the investment institution have sufficient patience and courage to truly accompany the growth of the source innovative company?

In an investor’s opinion, there are two reasons why few investment institutions have invested in true source innovation companies before: one is that they are willing to be the source under the background of insufficient cutting-edge technology and the prevailing Me-too and Fast-follow.
There are few innovative companies, and investment institutions want to invest and there are no good projects to invest; the other is that investors have insufficient understanding and judgment of cutting-edge technologies and are more willing to choose projects with benchmarking or successful experience
.
As more and more biotechnology companies choose to challenge the source of innovation, and the investor team's professional knowledge becomes more and more abundant, these deficiencies will also be well improved
.
"We will pay more attention to technology when we invest now, and want to get as close to the'source' as possible,
" said the investment
.

Another investor said that patience to accompany the source innovation project to grow together will not be what the investment institution is willing to do, but what it has to do
.

The investor analyzed: "The target is clear, foreign companies have target companies, and the products have reached clinical phase II or phase III.
Companies with products with such attributes are undoubtedly the favorite type of projects for investment institutions
.
However, such projects are very good.
It is popular, valuations continue to rise, it is difficult to enter in the later period, and the cost is high
.
However, it is difficult to say whether such a company's future products can support high valuations, and it is also risky, and even the primary and secondary markets are inverted.
phenomenon
.
in this case, some venture capital firms will choose to earlier, more innovative projects, at least can afford the price and risk
.
Since last year, we also saw some doing First-in-class start-up project It has been favored by well-known investment institutions, and more and more investment institutions have tried such projects
.
"

China's source innovation requires not only the iteration of technology, the persistence of scientists, and the supplement of capital, but also the continuous improvement of the ecological system
.
American Biotech has been in the forefront of the global biomedicine field for decades and cannot do without the support of the capital market
.
However, Nasdaq made its products have First-in-class potential but is still in the clinical phase I and II of the Biotech company listed, and smoothly introduced funds into the field of biomedicine
.
The launch of the China Science and Technology Innovation Board is also to encourage and support real innovation and to help more innovative companies develop better
.
CDE’s "Clinical Value-Oriented Anti-tumor Drug Clinical Research and Development Guidelines" for soliciting comments will also provide a better growth environment for biopharmaceutical companies that truly do source innovation
.
It is foreseeable that with the improvement of the policy system and the efforts of innovators and investors, the Chinese market will also usher in more first-in-class global innovative companies
.