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ADC pharmaceutical companies do not want to "hide into the dust", they must do a good job in the "life event" of project establishment!

 Last Update: 2022-10-31
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For the hot tumor immunotherapy track, 2014 is destined to be an extraordinary year
.
In July, Opdivo (O drug) was approved for marketing in Japan, becoming the first PD-1 drug
approved for marketing.
Two months later, in September, Keytruda (K drug) was first approved by the US FDA, becoming the first PD-1 new drug
approved by the FDA.
Three months later, on December 22, Opdivo was also approved by
the FDA.
Since then, Merck's K drug and Bristol-Myers Squibb's O drug have launched a world-renowned "KO competition", and also led to the PD-1 war
that burned all over the world.

Now that the capacity of the PD-1 is saturated, who can start the next global war?

The answer must include ADC, it must be it!

ADC (Antibody Drug Conjugate), that is, antibody conjugate drug, known as "magic bullet", "biological missile"
.
Components include: antibodies, drug carriers, linkers
.
ADC drugs conjugate monoclonal antibodies and drug molecules together through linkers, and use the specific targeted transport of drug molecules to target tissues to play a role, thereby reducing the systemic side effects of drugs, improving drug treatment windows and expanding the therapeutic potential
of antibodies.

Up to now, 14 new ADC drugs, including the famous DS-8201, have been approved worldwide, and more than 400 new ADC drugs are under
development.
The performance of Chinese pharmaceutical companies in the ADC track is also very eye-catching
.
Remegen, Kolum Pate, CSPC, etc.
, frequently sell self-developed ADC projects to large European and American pharmaceutical companies, with high transaction amount and great influence, which has attracted the attention of overseas pharmaceutical companies and become an example
of China's new drugs successfully going abroad.

Figure 2.
(Image source: Drug Times)

According to Evaluate Pharma and BCG, the global ADC market is expected to reach $12.
9 billion in 2024, with a compound annual growth rate of about 35% from 2018 to 2024, and is expected to reach more than $16 billion
in 2026.
The huge market scale, clinical success beyond expectations, and R&D innovation of technology platforms have effectively promoted ADC innovative drugs from laboratory research and development to industrialization and commercialization
.

ADC hot has been recognized by the industry, and even has been somewhat overheated, Merck offered $40 billion to acquire Seagen, an old company in the ADC track, and GSK directly invested $1.
46 billion to buy an ADC drug that is still in the preclinical stage, which is staggering
.
In 2020 alone, about $40 billion in ADC transactions were completed, of which AstraZeneca and Daiichi Sankyo reached a cooperation to jointly develop a number of the latter's core ADC drugs, spending $13 billion
in just one and a half years.
Coincidentally, on September 13, 2020, Gilead Science announced the $21 billion acquisition of Immunomedics, which is a sensation and still has no aftermath
.

The big war, on the verge of breaking out!

Crowded and brutal difficult track

Calling ADC the next PD-1 is neither right nor wrong, it is equal in heat, no, because ADC is a more testing track for research and development strength
.

The new PD-1 and PD-L1 drugs such as K drugs and O drugs are all monoclonal antibodies and are very mature molecular entities, although the mechanism is complex, but the manufacturing process is limited
.

In contrast, the ADC drug process is much more complex, and different components and synthesis processes require different matching production plants
.
The CMC data required for IND application is at least three times
that of monoclonal antibodies.
It should be pointed out that the drug-loaded part of ADC drugs is usually a highly active and highly toxic component, so the quality and safety requirements of the related production process are much higher and stricter than ordinary biological drugs, which means that enterprises may need to spend more than one billion dollars to build plant equipment and establish corresponding quality and safety operation standard systems
.

In addition, companies need to train highly specialized personnel to operate
according to standard procedures.
For ADC companies, if the research and development fails or the sales volume after the market does not meet expectations, the investment in hardware, software and other aspects may cause huge waste
.
Based on factors such as high cost, difficult production and uncertain return on investment, 70% of the global ADC pharmaceutical companies currently entrust CDMO companies
.

For small molecule drugs and antibody drugs, companies often establish a rich and balanced pipeline that includes multiple drug candidates
.
Based on the complexity of ADC molecules, demanding technical requirements, and high R&D and production costs, it becomes very impractical to adopt such a strategy, and companies need to "smash" limited funds on the most promising ADC drug, all eggs in one basket, and the risk will become extremely
high.

AbbVie's Rova-T was a high-profile ADC drug
.
The selected targeted DLL-3 protein is expressed in about 80% of patients with small cell lung cancer (SCLC), while it is rarely expressed in normal tissues, making it an ideal ADC drug target
.
Data from a phase I study published in 2016 showed an objective response rate of 38% in 50% of patients with DLL-3>, which is expected to break the deadlock of decades of no progress in the post-line treatment of SCLC, causing shocks
in the industry.

Unfortunately, in subsequent confirmatory studies, neither first-line, second-line nor combined use has been able to repeat the previous research data, and now Rova-T's name
is no longer heard.
And because AbbVie was overconfident, it skipped phase II clinical trials and directly carried out multiple phase III clinical trials, resulting in huge research and development costs, with losses of up to $5.
8 billion
.

For large companies, phase III failures, despite the huge losses, are not unbearable, and for biotech, phase II clinical failures are devastating enough
.

On May 13, 2022, CytomX Therapeutics, a small biotech company, announced the Phase II clinical study data of its ADC drug candidate, Praluzatamab ravtansine, and CytomX decided not to pursue the project alone due to less than expected results, and the failure of the product also indirectly led to CytomX laying off 40% of its workforce after two months to maintain cash flow
.

Even the leading company of ADC, Daiichi Sankyo, will inevitably fail in this field
.

On October 29, 2021, Daiichi Sankyo announced in its quarterly report that it had abandoned the development of DS-6157, an ADC drug targeting the GPR20 protein of gastrointestinal stromal tumor (GIST), because it did not have a clear response
to GIST patients at any dose level of phase I dose escalation.

Daiichi Sankyo cannot guarantee the Phase I clinical success rate of drug candidates, let alone the companies that follow Follow? If a company that is clustered in PD-1 fails, the reason is likely that the sales of the drug after the market are not as expected, and the company that is clustered in the ADC may fail to even make the product
.

Therefore, how to efficiently screen out a high-quality, differentiated PCC (preclinical drug candidate) is very important for players in the ADC track, whether the drug candidate is good or not, it is best to verify
it before clinical practice.

Another popular ADC drug of Daiichi Sankyo DS-8201 has shown great potential
before clinical practice.
As early as 2016, an in vitro evaluation report on DS-8201 was published in Cancer Science, including cell line selection, parallel artificial membrane permeability determination, in vitro cell growth test, in vivo xenograft research, in vivo luciferase imaging, immunohistochemical analysis, etc
.

After strict control analysis with anti-HER2-DXd and T-DM1, it can be seen that DS-8201 has shown great advantages
in many in vitro and in vivo models.

Figure 3: a.
Growth inhibitory activity
of ADCs against KPL-4 and MDA-MB-468 cells.
Flow cytometry analysis data
.
Number of
KPL-4 and MDA-MB-468 viable cells.
(Source: Cancer Sci.
2016 Jul; 107(7):1039-46）

Figure 4: a.
Antitumor activity
of ADCs in NCI-N87 and MDA-MB-468-Luc xenograft models.
Expression
of HER2 in co-seeding tumors.
(Source: Cancer Sci.
2016 Jul; 107(7):1039-46）

Figure 5: a.
Imaging data
of luciferase activity.
b.
Luciferase activity
.
C.
Estimated tumor volume
.
(Source: Cancer Sci.
2016 Jul; 107(7):1039-46）

This year's ASCO conference hall after the ADC new drug DS-8201 report burst into endless applause
.
This scene has disappeared in the global pharmaceutical industry for many years, and it is such preclinical data that makes Daiichi Sankyo dare to conduct head-to-head control studies and analysis of DS-8201 and T-DM1 in phase III clinical trials, laying the foundation for
its subsequent success.

Preclinical evaluation is important

Looking back at the research and development process of small molecules, large molecules and other drugs, we will understand that solid preclinical research can improve the success rate
of drug approval.
In a well-known colloquial phrase, it is: win at the starting line!

As the 1:10:100 principle describes, in the early stages, there are more choices and less
cost of trial and error.
This is the same meaning
as the phrase "Fail Early, Fail Cheap" that overseas pharmaceutical professionals often hang on.

Figure 6.
(Source: Network)

In July this year, China CDE issued the Technical Guidelines for Non-clinical Research of Antibody Conjugate Drugs (Draft for Comments), which clarified the direction
for the development of preclinical ADC drugs.

Figure 7: (Source: NMPA official website)

Not long ago, in a keynote lecture on "Preclinical Pharmacology and Efficacy Evaluation of ADC Drugs", Dr.
Yixiang Chung, Head of Asia Pacific, CrownBiosciences, gave a detailed interpretation
of all aspects of the guiding principles.

According to Dr.
Zhong, CDE's ADC guidelines emphasize the importance of pharmacological and pharmacodynamic studies of ADC drugs and point out some key details
.
It is very important
for new drug R&D companies to confirm the druggability of PCC molecules according to the guiding principles and carry out experiments that meet IND requirements accordingly.

A phenomenon worth paying attention to is that there are many CDMO companies in China that layout the ADC track, such as: WuXi United Alliance, Maybarry, Dongyao Pharmaceutical, Zhenhao Biologics, but the high-quality companies that provide preclinical research related to ADC drugs do not seem to be very conspicuous
.

In the United States, non-repeatable preclinical research wastes $28 billion a year, and the situation at home should not be optimistic
.
Therefore, for pharmaceutical companies in the ADC track, doing preclinical research well and doing a solid job can not only win at the starting line and win the whole race, but also save a lot of money
.

Founded in 2006, CrownBio has grown into a global new drug R&D technology platform company, providing in vivo and in vitro model efficacy testing, drug screening, drug metabolism analysis and translational medicine, with operations
in the United States, the United Kingdom, the Netherlands and China.

In order to meet the rigid needs of many R&D companies in the hot track of ADC, this CRO veteran will keep pace with the times, integrate his own business, and launch a one-stop pharmacological and pharmacodynamic service platform that meets IND declaration, which has enabled many pharmaceutical companies and biotechnology companies to apply
for IND drugs of various sizes and ADC molecules.
At present, it has more than 3,000 PDX tumor models, more than 700 compliant tumor cell lines and more than 500 tumor organoid models, as well as upstream and downstream related gene sequencing, protein analysis, cell detection and histological pathological analysis platforms
.

It has launched a one-stop pharmacological and pharmacodynamic service platform that meets IND declaration, which has enabled many pharmaceutical companies and biotechnology companies to apply
for IND applications for various large and small molecule drugs and ADC molecules in China, the United States, Europe and Australia.

In the development of ADC drugs, CrownBio provides a one-stop platform
for pharmacological efficacy studies and IND declarations.
The key points of ADC drug-related pharmacological research mentioned above CDE include: affinity detection of ADC and target; ADC endocytic capacity confirmation; the effect of free toxins on cell production; In vitro tumor cell suppression experiments; In vivo tumor model pharmacodynamic model; bystander killing effect; ADC FC-side mediation; Target receptor-mediated function; PK and toxicology services, etc
.

ADC affinity detection with the target; ADC endocytic capacity confirmation; the effect of free toxins on cell production; In vitro tumor cell suppression experiments; In vivo tumor model pharmacodynamic model; bystander killing effect; ADC FC-side mediation; Target receptor-mediated function; PK and toxicology services, etc
.

Conclusion

For pharmaceutical companies, especially for Chinese pharmaceutical companies that are currently in a pile of targets, serious involution and fierce competition, ADC is indeed a rare golden track
for new drug research and development based on the characteristics of multiple cancers, multiple organs and multiple targets.
The ADC can "accommodate" more players
than the PD-1.
The first generation ADC, the second generation ADC, and the third generation ADC are already on the market, is the fourth generation ADC still far away? Is the fourth-generation ADC capable of challenging the DS-8201? However, the new ADC drugs represented by DS-8201 have exceeded the level of play, constantly attacking the city, seizing the next indication, and even opening up a new position of HER2 low expression, and making the ADC track "unable to tolerate" most players
.

A number of well-known pharmaceutical companies with global layout of ADC track have successively disclosed that their clinical trials and development have been negatively affected by the strong development of DS-8201, and there is competition
with DS-8201, including patient resources, clinical trial speed, and application speed.
Under pressure, the company made strategic adjustments to the R&D pipeline, gave up its strategy, and even replaced its CEO
.

Finally, we borrow the names of two recent very hot movie blockbusters to summarize
.
In such a cold environment, doing a good job in preclinical research and selecting high-quality and powerful PCCs to advance to the clinic is a "life event"
faced by every pharmaceutical company.

If they blindly take "shortcuts" or simply copy, ignoring the importance of preclinical research or paying enough attention and investment, then these pharmaceutical companies are likely to gradually fall behind and eventually "disappear into the dust"
.

Resources

Leading the New Revolution in Drug Screening and Improving the Success Rate of Drug R&D – A Brief Discussion on CrownBio and Organoid (PDO) Technology | Pharmaceutical Times interviewed Dr.
Xiaoxi Xu of CrownBio

Double revenue, helping 50% of FDA-approved cancer innovative drugs in recent years! ——Dr.
Qixiang Li shares the secrets of CrownBio's rapid expansion

The 4th CrownBio International Biomedical Symposium · June 30 Zhangjiang, Shanghai

There are dreams that are the most beautiful, hope to follow! ——Optimistic about China, global layout, CrownBio will settle in Zhongshan!

Gather advantages and give full play to CrownBio helps Chinese companies win the crown jewel of new drug research and development as soon as possible!

Different animal models, the same new drug dream! - CrownBio's CVMD story

Under the wave of new technology, can humanized animal models turn impact into motivation and empower new drug research and development again?

Born PDX, what kind of PDO (organoids)? See how organoids on the cover of Science can help new drug development!

HER2 ADC Terminator?! How many "bright futures" of new drugs have been lost by "DS-8201"?

The road to ADC drug innovation

The most commercially successful ADC to date: Kadcyla

ADC payload and research progress are detailed

ADC outbreak, half-year revenue doubled, AstraZeneca.
.
.

ADC trading price quadruples in 4 years: the more Big Pharma rolls, the more Biotech gets better

Talk about the development momentum of ADC drugs

Mersana's next-generation ADC technology platform

104 Chinese new drug companies sail to sea! Good news on the ADC track! Kolumbotai overtook Big Brother Stone Medicine | Medicine Age to Sea series

How do tumor cells "commit suicide by poisoning"? Analysis of endocytosis characteristics of multiple ADC drugs

4 months in advance! FDA approved ADC drug Enhertu (DS-8201) for the treatment of "HER2 low expression" breast cancer patients, the market is expected to expand 5 times!

Good news of domestic ADC is frequent! With the development of Claudin 18.
2, Chinese pharmaceutical companies have led the world, and "mergers and acquisitions" and "cooperation" may become a new trend

Lost the second instance! The blockbuster ADC drug Enhertu is still found to be infringing
.
Inventory of pharmaceutical companies' patent disputes, powerful drugs are all sued.
.
.

Expected to break the ADC limitations? Based on its new ADC platform, ConjuAll, LegoChem has entered into a research collaboration and licensing agreement with Glycotope

Today's ADC is very similar to the PD-1 of the past

Which product will "dominate" the ADC field: the global sales forecast ranking of marketed ADC drugs

DS-8201 is another indication to be applied for marketing, and a variety of domestic ADCs break through ideas and represent enterprises

Tonight at 8pm! Professor Wang Xiaojia, Professor Luo Sheng and Dr.
Xiao Liang will explain "ADC Explosions, Hot Spots and Future"! | The 4th session of the International CMO Academy

Domestic ADC competition landscape

Heavy rumors! Pharmaceutical giant Merck is evaluating the possibility of
acquiring ADC "scholar" Seagen.
Seagen's stock price soared!

Big talk ADC - blockbuster, hot and future! | The 4th session of the International CMO Academy

Moving forward: Inventory of ADC connector upgrades

Recent research advances in ADC biocoupling technology

DS-8201 "dominates" the HER-2 target, who can meet the domestic ADC players

Hengrui Pharmaceutical develops HER3 ADC

Resistance mechanisms of ADC drugs

Last night, AZ/Daiichi Sankyo issued an announcement
.
DS-8201 "Lung Cancer Indication" is also about to be approved, anti-HER2 ADCs have to consider what to do next.
.
.

Just! The blockbuster ADC drug DS-8201 was accepted by the NMPA, and AZ spent $6.
9 billion on it!

The potential target that has not been drugged in the past 30 years has become a "giant meat grinder", can ADC make it the next "PD-1-like" explosive model?

Faced with the pressure of the DS-8201, Roche chose to cut the price of the T-DM1 by 52%, and the HER2 ADC is about to usher in a big melest

Progress and hidden dangers of bispecific antibody ADC drugs!

Only one drug in the world has been approved, and the annual sales can reach "4 billion US dollars"! ADC Target Nova: TROP-2

The development history of the third generation ADC is in full swing, let's learn about its development process

"Biological missile" ADC, the research and development boom is timely

Gilead 2021: $5.
6 billion for remdesivir and $380 million for Trop2 ADCs

Homogenized ADC drug manufacturing, selective site modification strategy

Representative structure of FDA-approved ADCs

WuXi Live Room | Introduction to the coronavirus drug and vaccine efficacy platform; Preclinical efficacy and translational studies of ADC drugs

【Medicine Cajun】Chinese medicine has broken out again! Urothelial carcinoma ushered in the first ADC, two new breast cancer drugs were approved, Hengrui Pharmaceutical, Remegen Bio.
.
.

Patent layout strategy analysis of ADC technology

Domestic ADC financing inventory in 2021

Pfizer's innovative ADC therapy has been approved in China to treat leukemia

10,000 words long text! ADC is full of smoke, phase III clinical herds are chasing the deer: the "inside" and "outside" of veteran players; HER2 target controversy; The new target "Three Musketeers", innovation does not stop at the target

The "connectivity technology" that cannot be ignored: the last mile of ADC competition

Fight on the same stage! CD19 target set CAR-T, bispecific antibody, monoclonal antibody, ADC four-way "flowering"

ADC leading biotech company Remegen Biotech Science and Technology Innovation Board key content!

Collection! ADC panorama overview (payload, linker, conjugate, and endocytosis)

ADC Pharmaceutical Company Financing Inventory in 2021 (January-October)

Antengene and LegoChem Biosciences have entered into a collaborative development and licensing option agreement for novel antibody conjugate drugs (ADCs).

The battle for antibody-conjugated drug (ADC) target Nova-Trop2 is on the verge of breaking out

New drugs for cervical cancer | The world's first ADC has been approved, is the bispecific antibody still far away?

NEJM: ADC drug treatment for non-small cell lung cancer clinical trial, significant effect

A wave of HER2 ADC innovation! Ke Lun, Rongchang, Fosun.
.
.
What is the competitive specialty?

Breast cancer antibody treatment pattern: monoclonal antibody/bispecific antibody/ADC blooming!

ADC Ice and Fire! Star Company shares fell to a dollar
.
CMC is really critical!

Clinical progress of ADC drugs for new targets

Heavy news! Addison Pharmaceutical's new anti-AIDS drug was approved for marketing; The first new MUC1 ADC drug in China was approved for clinical trials; GSK new AIDS drug launched
commercially.

。
。

BMS also passed "618"! Spent $3.
1 billion on the Eisai ADC drug Halaven

Antibody Drug Conjugates (ADCs): The "magic bullet" in cancer treatment

Dry! From the ASCO conference, the latest clinical research results of domestic bispecific antibodies, ADCs and CAR-T are seen

Bioconjugate Chemistry Journal Recommended! The team of Wang Wenyuan and Wang Zhaoyin of the Institute of Organic Engineering of the Chinese Academy of Sciences reported on the new dual-function ADC platform

Inventory of more than 100 antibody drugs approved by the FDA! Dual antibodies, ADCs.
.
.
Where is the new flashpoint?

"Magic Bullet" ADC drug 10 billion gold track competition intensifies! Domestic catch-up acceleration, 2 models have been declared for listing, Genting Xinyao, Remegen Bio.
.
.
.

TROP2-ADC Battle: The latest progress of the First Third Kyo Communists announced, who will carry the flag after the defeat of the domestic Bio-Tyco?

Zynlonta, the first new ADC drug targeting CD19, has been approved! Helps treat large B-cell lymphoma

Heavy news! Lilly began the supply of new cancer drugs in China, Qilu introduced MUC1 ADC drugs, Biogen multiple sclerosis new drug was approved, and Merck terminated the research and development of
a new crown drug.

。
。

ADCs are poised for growth: 11 marketed products and new drugs under development will compete for a $10 billion market

The first ADC to target ADAM9, the IMGC936

Heavy news! Sorrento acquired Essen Pharma for US$488 million, BeiGene Guangzhou Biopharmaceutical Manufacturing Facility approved, Qilu Next Generation ADC approved Phase 3, and GKN partnered
with I-Mab.

。
。

ADC drugs on the rise? Qilu, Shiyao, Hengrui.
.
.

A list of approved and investigational ADC drugs and targets predicts that the oncology market size will exceed $16 billion

Dr.
Yuli Xie | The big era of new drugs: small molecule breakthroughs, bispecific antibody ADC outbreaks, the return of RNA kings, can biological phase transitions achieve the next Nobel Prize?

Stomach cancer | Following breast cancer, the AstraZeneca/Daiichi Sankyo ADC drug Enhertu was approved by the FDA to treat HER2+ gastric cancer

The results of the world's first triple-negative breast cancer Trop-2 ADC drug phase III study were amazingly unveiled

Is Seagen succeeding Seattle Genetics, a pioneer and his ADC drug about to start a new chapter in health?

The key four elements and development trends of ADC drug development

WuXi Live Room | Biopharmaceutical Series (3): Meet the Challenge and Break the Innovation Barrier: Customized Solutions for Antibody Conjugate Drug ADCs

With a $6 billion big order setting off another ADC trend, can domestic companies ride the wind and waves in the giant surrounding?

2020 Global ADC Drug Development Report

PPT sharing | Antibody conjugate drug ADC industry research - magic bullet for treating cancer

Immunomedics antibody conjugate drug (ADC) clinical trial ends early Stocks soared

ADC drugs and reviews to be released in 2020

Early bird ticket last day! PD-1, PDO, Protac, Biosimilar, ADC, Anti-Cancer Drug Conference gathers industry hotspots!

FDA approves first chemoimmunotherapy! Genentech ADC drug Polivy! For relapsed or refractory diffuse large B-cell lymphoma (DLBCL)

Tianxing Pharmaceutical authorized ADC Therapeutics to develop safe antibody conjugates using next-generation antibody precision masking technology

Terus Pharmaceuticals' ADC TRS005 received clinical trial approval

Antibody conjugate drug (ADC) research report (below) | Cathay Capital Biotechnology Team

Antibody conjugate drug (ADC) research report (top) | Cathay Capital Biotechnology Team

Seattle Genetics canceled all clinical studies of the blood cancer drug SGN-CD33A, and ADC drug development suffered another setback

Looking at Europe, these 10 biocompanies are "bullish" (BioNTech, Oxford Nano, CRISPR, ADC.
.
.
).
）

【Editor】Research report on antibody conjugate drug (ADC).

Congratulate! Genentech and WuXi AppTec scientists invent novel ADC linker technology

Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T.
Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity.
Cancer Sci.
2016 Jul; 107(7):1039-46.

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