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With the prominent effect of biological products in the field of anti-tumor, the amazing therapeutic effect of macromolecular biological drugs, major pharmaceutical companies have frantically poured into the research and development of macromolecular drugs, and biological products have become one of the fastest growing industries in the
pharmaceutical industry in recent years.
Almost all of the world's top ten drugs are macromolecular biological drugs, and the sales of one adalimumab are as high as $19.
9 billion.
However, even though macromolecular drugs have ended the domination of more than 90% of small molecule drugs in the last century, they have also carried great pressure in the "involution" competition, patent cliffs, focused target concentration, and Me-too swarming.
.
.
Macromolecule drugs are also starting to show fatigue in the commercial premium on the payment side
.
In 2022, the trend of monoclonal antibodies has swept through, and bispecific antibodies and antibody conjugates (ADCs) have repeatedly broken the ceiling
of drug R&D project transactions.
Large molecule drugs are on the rise, has the golden age of small molecule drugs passed? New concept ADC/drug conjugate, AI drug data, stem cell therapy, preventive vaccines, gene editing, cell therapy, etc.
, who will be the next big potential area?
Compared with small molecule drugs, biological products have strong targeting, high specificity, small toxic side effects, and have unique advantages and can provide better supplements
.
The essence of the competition between the two is the update and iteration
of drug development technology.
Comprehensive analysis, small molecule blockbuster drugs are limited by the narrowing of innovation space, and the proportion is gradually declining
.
Even if the patent expires for macromolecular drugs, because they have a unique multi-dimensional structure, the biotransformation in vivo is extremely complex, difficult to be accurately imitated, the patent barriers are relatively high, the imitation is relatively difficult, and lasting profits can be obtained
.
This also leads to the fact that macromolecular biosimilars will not significantly reduce the price of the original drug, thus attracting a large number of pharmaceutical companies to take root in biopharmaceutical research and development
.
According to statistics, among the top 20 drugs sold globally in 2021, the top 10 drugs sold globally in 2021, there are 6 biological drugs (including 2 new crown vaccines), 4 chemical drugs, and the top 4 are biological drugs; In the TOP20, there are 14 biological drugs and 6 chemical drugs, including 8 antibody drugs
.
The two drugs
Comirnaty and Spikevax that have caused changes due to the impact of the new crown epidemic are excluded.
Among the macromolecule drugs, AbbVie's Humira exceeded $20 billion for the first time, Merck's PD-1 antibody Keytruda reached $17.
2 billion, and another PD-1 monoclonal antibody was Opdivo of Bristol-Myers Squibb, ranking 11th
.
VEGFR fusion protein Eylea and IL-12/IL-23 antibody Stelara sold $9.
2 billion in 2021, nearly the 10 billion mark
.
With more and more pharmaceutical companies and innovative biotech entering the market, several slightly hot targets and even bispecific antibody target combinations are being done at the same time, and the once blue ocean has become a red ocean
.
Although the market scale has reached a peak, there are more and more hidden dangers behind this, the homogeneous competition in product research and development is increasing, the difficulty of new drug research and development is getting higher and higher, and spending more research and development funds has not brought more new products
.
In this context, pharmaceutical companies have tried to differentiate their designs and carry out technological update iterations, for example, they have set their sights on dosage form reform
.
The vast majority of traditional macromolecular drugs are administered
intravenously by infusion.
However, intravenous preparations also have a high incidence of adverse reactions, long treatment time, and damage to the patient's blood vessels
.
In contrast, subcutaneous injection preparations have advantages in treatment time, ease of operation, adverse reactions, and combination of drugs, so subcutaneous injection preparations have become a new choice
.
In May 2020, Johnson & Johnson's subcutaneous injectable daratumumab was approved by the FDA for marketing
.
In the first half of 2020, daratumab generated sales of $1.
8 billion
.
Two years later, in the first half of 2022, daratumab sales reached $3.
842 billion, a year-on-year increase of 37.
3%.
Behind the high growth, the conversion of subcutaneous preparations is indispensable
.
According to Johnson & Johnson, in the United States and European markets, the conversion rate of daratoo intravenous injection to subcutaneous injection reached 85% and 80%
respectively.
The same is true of Roche's trastuzumab
.
Trastuzumab, one of Roche's old troikas, saw sales decline after
the patent expired.
In the first half of 2022, global sales of trastuzumab were CHF 1.
179 billion, down 16%
year-on-year.
Roche has developed a compound subcutaneous injection
formulation of trastuzumab.
In terms of medication time, subcutaneous preparations can be administered within 2-5 minutes, compared with 30-90 minutes required for intravenous infusions, and the treatment time is greatly reduced; In a phase III HannaH study, Roche also demonstrated that blood trastuzumab levels and clinical efficacy (pCR 45.
4% vs.
40.
7%) in patients receiving subcutaneous injection showed non-inferiority compared with intravenous injection, with a similar
safety profile.
Asian patient data is broadly consistent
with the global population.
In addition to trastuzumab, Roche is also deploying a subcutaneous injection of the PD-L1 product atezolizumab
.
In August 2022, Roche announced that the Phase III clinical trial IMscin001 study of atezolizumab for locally advanced/metastatic NSCLC patients who have failed platinum therapy who have not received tumor immunotherapy has reached the common primary endpoint of non-inferiority to marketed intravenous atezolizumab, and Roche will subsequently declare the marketing
of subcutaneous PD-L1 to the FDA.
The layout of subcutaneous injection is far more than Johnson & Johnson, Roche, but also AstraZeneca, Merck, Bristol-Myers Squibb, AbbVie, and Pfizer in MNC
.
Dosage form reform is just one of many
paths to try to break through.
Some investors believe that even though macromolecular drugs are currently in a bottleneck, this can only be a more difficult slope on the track, and investing in seizing historical opportunities will definitely obtain returns
far beyond the average social rate of return.
In the face of increasingly fierce competition in the field of monoclonal antibodies, the rapid rise of bispecific antibodies and antibody conjugate (ADC) drugs, the form of mainstream antibody drug research and development is grim, how to differentiate the layout, make new breakthroughs in subdivided fields or the current big test
of macromolecule drug development.
The domestic market is also catching up, and a large number of pharmaceutical innovation companies that have risen rapidly in the past ten years, following the completion of pipeline layout and market segmentation in the pure monoclonal antibody field, are entering a new round of growth cycle in the face of rapid iteration of biological drug innovation technology, fusion protein, bispecific antibody, ADC and other fields
.
From the trend of tumor immunity led by PD-1, to the reform of drug regulatory review and approval launched in China in 2015, to the convenient listing and financing path provided by the Science and Technology Innovation Board and the new regulations of Hong Kong stocks, domestic macromolecule new drugs have achieved exponential growth in recent years, from single digits in 2014 to the number of three-digit declarations today
.
These years of explosive development of macromolecular drugs are also years of vigorous development of innovative pharmaceutical enterprises in China
.
In the top 30 innovative ranking of Chinese antibody drug companies, we have seen names
that have disrupted the domestic and even international pharmaceutical industry in recent years.
It is worth noting that in addition to the above-mentioned Biotech/Biopharma, domestic established large pharmaceutical companies, such as Hengrui Pharmaceutical, Chia Tai Tianqing, CSPC Pharmaceutical Group, Qilu Pharmaceutical, Kelun Pharmaceutical, etc.
, have also made clear transformations and overcome difficulties in the field of macromolecular drugs
.
However, whether from the perspective of the technology iteration path of overseas pharmaceutical companies or the review of China's local drug R&D development process, the domestic biomedical industry research and development has now been overly concentrated, although macromolecular drugs still have undiscovered potential, but the homogeneous competition brought by thousands of troops crossing the single wooden bridge must do more harm than good
.
In the face of the uproar in the field of macromolecular biomedicine and the phenomenon of domestic pharmaceutical companies gathering in the "red sea", enterprises with a sense of crisis have begun to explore new technologies and new drugs, focus on cutting-edge tracks, and try to master cutting-edge technologies to ensure that they still maintain their leading edge
under the new wave of medical technology updates.
"Innovative drugs need to be more 'innovative'
.
" Experts pointed out that the state has introduced a series of policies to encourage innovation, but does not want to see everyone homogenized development, resulting in waste
of research and development resources.
With the continuous advancement of medical insurance negotiation policies, drugs continue to drop to reasonable prices, and innovative drugs on the same track can only obtain admission tickets if they are of better price, which will force enterprises to make efforts to difficult and unknown places to innovate
again.
According to CSPC Group's 2022 mid-year financial report, in the first half of this year, its revenue was 15.
610 billion yuan, an increase of 12.
9%
year-on-year.
The two core old businesses of APIs and mature drugs are stable
.
Surprisingly, its breakthroughs in the research and development of innovative drugs:
In the first half of 2022, the R&D expenditure was 1.
884 billion yuan, with about 300 research projects, including more than 40 small molecule innovative drugs, more than 40 large molecule innovative drugs, and more than 30 new preparations, involving anti-tumor, immune and respiratory, psychoneurological, cardiovascular and cerebrovascular, metabolic and anti-infection fields
.
At present, there are 4 innovative drug candidate NDAs, more than 50 clinical trials, 1.
195 billion license out transactions, and the results of mRNA technology platform have landed.
.
.
In addition, as a representative of domestic innovative pharmaceutical companies, BeiGene's move is also the focus
of attention of industry insiders.
At present, BeiGene has more than 60 new drugs under development, carefully analyzing BeiGene's development in recent years, BeiGene's layout is not only limited to the PD-1 monoclonal antibody, BTK inhibitor and PARP inhibitor that have been commercialized, but also in ADC, PROTAC, antibody fusion protein, cell therapy and mRNA therapy and many other cutting-edge technologies
.
Even Genor Biopharma, which suffered from the "storm" of falling stock prices and the resignation of the founder in 2022, is still on a difficult road of transformation, in addition to the currently approved product Jiayoujian (infliximab), the research and development process of GB226 (gerolimab) continues to accelerate
in the research products.
"The company has built a world's first/differentiated, immuno-oncology bi/multi-specific antibody R&D platform
for early discovery.
In June this year, it reached a cooperation with Abogen Biosciences to jointly develop oncology drug research and development
based on mRNA technology.
Genor Biopharma said that since its listing in 2020, the company has made corresponding pipeline adjustments according to the foreseeable overheating of the antibody track, and the promotion of key projects has been within the planning expectations, and some products under development are exceeding expectations, such as the CDK4/6 inhibitor GB491 (Lerociclib) for the treatment of breast cancer is scheduled to submit an NDA
in the second half of 2023.
Not only that, a large number of startups exploring cutting-edge technologies have also begun to enter the innovation core circle of the pharmaceutical industry
.
In the field of cell therapy, the breakthrough of CAR-T products in the field of solid tumors is the direction
that cutting-edge scholars are working on.
For example, KATI Medical Company has independently developed a flexibly activated DAP-CAR-T solid tumor technology platform for the CAR-T architecture design for the solid tumor microenvironment, which is expected to improve the adaptability of the CAR-T cell tumor microenvironment and reduce clinical side effects
.
Other new cell therapies are also in full swing, such as Shize Biologics' commitment to developing stem cell treatment protocols to treat diseases such as Parkinson's disease; Blood Biotech is committed to the research and development of novel cell therapy and stem cell therapy for in vitro regenerative hematopoietic lineage (including blood cells and immune cells); Yuesai Biotech is committed to developing a new generation of cell therapy drugs based on human pluripotent stem cell technology for the treatment of neurodegenerative diseases, rare diseases and tumors.
.
.
In the field of gene therapy, the limelight in the field of gene therapy is CRISPR gene editing technology, Doudna and Charpentier and Chinese scientist Zhang Feng have also caused a sensation in the industry
because of the patent of the technology in eukaryotic cells.
However, the patent battle does not affect the high activity
of a hot technology in the development of pharmaceutical frontiers.
In terms of CRISPR technology, CoginBio is developing gene therapies by combining the gene editing technology platform CRISPR 2.
0 with a new AAV delivery system; Yaotang Biotech is developing in vivo gene-editing drugs
for genetic diseases and cardiovascular diseases through the continuous development and optimization of CRISPR-Cas, base editing and other next-generation gene editing tools, as well as innovative improvements to next-generation mRNA production platforms and lipid nanocarrier (LNP) assembly processes.
In addition, a number of companies focus on the development of AAV-mediated gene therapy, such as Star Altovi, which focuses on the research and development of innovative drugs for inner ear hearing loss and other related diseases; Weimei focuses on the development of new AAV vectors and the promotion of the hearing loss gene therapy pipeline; Stareye Biotech uses self-developed new capsids to achieve intravitreal injection with traditional antibody drugs, focusing on the development of
gene therapy drugs for ophthalmic diseases.
In addition, new anti-tumor therapies including peptide conjugate drugs, nano-poly-antibody molecules, innovative bispecific antibodies, tumor vaccines and other domestic innovative frontier technologies are blooming
.
From "a hundred enterprises and thousands of resistances" to "a hundred flowers blooming", it is the result of technological changes and the pursuit of
development by every pharmaceutical company.
