**: Briana***
Author: Mi Duo.
In just two or three years, the global ADC drug market has started to run fast, and the enthusiasm for drug research and development and capital continues to rise. However, while the limelight is gaining momentum, the ADC track has become saturated: hot target pharmaceutical companies are piling up, and every time a pipeline with a little potential appears, the mncs are rushing to it, leaving more and more space for latecomers to develop.
However, it is undeniable that ADC has been a relatively successful cutting-edge technology in recent years, and its success has also greatly ignited the enthusiasm of pharmaceutical companies for the research and development of conjugated drugs.
Flexible
PDC standing on the shoulders of peptides
Peptides are important active molecules of organisms and are indispensable in various important physiological processes. Institutionally, the polypeptide structure design is flexible, can achieve a variety of different functional needs, not only can be used as a coupling object with ** or targeted function, but also plays an important "bridge" role in the coupling of a variety of molecules, on this basis, PDC came into being.
Mechanism of action of PDC
As a kind of conjugate, PDC basically retains the same composition of the conjugated drug, that is, the form of "localized ligand-linker-effector molecule", and PDC is composed of three parts: polypeptide (homing peptide), linker and charged carrier.
Schematic diagram of PDC structure, source: public information.
The main role of peptides is to achieve target localization, and the choice of peptides will affect the endocytosis efficiency of PDC drugs, and have a significant impact on pharmacokinetics, efficacy and index. The commonly used peptides in PDC are cell-targeting peptides and cell-penetrating peptides.
Similarities: PDCs are very similar to ADCs.
In essence, there is no difference between the linker and ADC of PDC drugs, and the payload of PDC also involves many types, such as nuclides, MMAE, docetaxel (TH1902), PARP inhibitors, etc.
In terms of design principle, PDC is similar to ADC in that it conjugates cell-targeting peptides to drug molecules to enhance the targeting of the drug, so that the drug is concentrated in the target tissue, thereby reducing its relative concentration in other tissues, improving efficacy and reducing adverse reactions.
In terms of mechanism of action, PDC is also similar to ADC, which covalently links targeted peptides and cytotoxins through decomposable link chains in cells, precisely targets specific receptors of tumor cells, and controllably releases cytotoxins to kill tumor cells.
The difference: PDC's unique advantages.
PDC integrates the advantages of peptides, so compared with ADC drugs, PDC has many advantages: small molecular weight, strong tumor penetration, good tumor inhibition effect on solid tumors, and due to its small size, it is also easy to synthesize a single homogeneous substance; low immunogenicity; Due to the strong permeability of tumor tissues, PDC can accumulate at high concentrations at the target, so chemotherapy drugs with relatively low toxicity and widely used in clinical practice such as doxorubicin and paclitaxel can be selected. In addition, due to the prokaryotic expression or chemical synthesis, the PDC production process is simple and easy to scale-up, and the production cost is low.
PDC vs. ADC.
Data**: Collation of publicly available information.
Precise anti-cancer
Assists that target **
Cancer is a disease with the fastest development and the biggest breakthrough in the past 10-15 years, and the research on tumor methods and cutting-edge drugs has always been a hot topic in the pharmaceutical industry. From the current point of view, the first cancer has moved from the era of chemotherapy and radiotherapy to the era of precision. According to Frost & Sullivan data, targeted drugs dominate the global anti-tumor drug market, with a market share of up to 604%, while the proportion of immuno** and chemotherapy drugs was 234% vs. 163%。
Drug conjugates have a high degree of selectivity and targeting, and ADCs have become the "darlings" of the drug research and development industry at a time when targeting ** has become the mainstream, but the disadvantages of ADC itself such as structural complexity, high production costs, and high track saturation have made entrants walk on thin ice.
Therefore, PDC is expected to become a new generation of anti-tumor targeted drugs after small molecule drugs, monoclonal antibodies, and ADC drugs by virtue of its many advantages over ADCs, and PDC drugs can be developed in a variety of indications: esophageal tumors, breast tumors, metastatic non-small cell lung cancer, advanced solid tumors, etc., which are also these incomparable advantages that make PDC gradually warm.
A hundred flowers bloom
PDC drugs at home and abroad have a wide range of layouts
There are only two PDC drugs approved for marketing in the global market, namely Lutathera and Pepaxto, but the road to market for Pepaxto can be described as twists and turns.
On February 26, 2021, after receiving accelerated approval from the FDA, Pepaxto voluntarily withdrew from the market on October 22 of the same year due to safety issues. Subsequently, in January 2022, Oncopeptides withdrew Pepaxto's delisting application on the grounds that it wanted to re-examine the clinical data, but unfortunately, after nearly 5 months of review, on December 7, 2022, the FDA followed the opinions of the members of the expert committee and officially announced the withdrawal of the accelerated approval of Pepaxto and banned its sale in the market. While Oncopeptides appealed the FDA's withdrawal in August 2023, on February 23, 2024, the FDA issued a final decision to revoke Pepaxto's approval. As a result, the only PDC drug currently on the market is Novartis' Lutathera, which was launched in January 2018.
In terms of research, according to incomplete statistics, there are currently more than 40 PDC drug pipelines under development in the world, and nearly 20 pipelines are in the stage and above.
Drugs under investigation.
PDC is an investigational drug.
Data**: Public data collation.
Among them, it is worth mentioning Novartis's Pluvicto, the drug has been approved in the United States, the European Union, France, Canada, Taiwan, China, Novartis is actively exploring the Chinese mainland market, Pluvicto in China's ** hormone-sensitive prostate cancer research is in the clinical stage, and there is also **castration resistance prostate cancer clinical research stage.
Drugs under investigation.
PDC is an investigational drug.
Data**: Public data collation.
In terms of clinical progress, the fastest progress is ANG1005 developed by Angiochem in Canada, which has completed phase II clinical trials in the United States and Canada, and the trial has shown that ANG1005 can significantly prolong survival, has good efficacy on brain metastases, and has a safety profile similar to that of ordinary paclitaxel without severe allergic reactions. The Phase III clinical trial protocol of Ang1005** breast cancer leptomeningeal metastasis has been approved by the FDA and is being carried out simultaneously in the United States and Canada, and Sinogene has obtained the exclusive rights to develop and commercialize paclitaxel trevatide in Greater China.
BicycleTherapeutics has three bicyclic peptide-toxin conjugates (BT1718, BT5528, BT8009) for tumors, which are used in the screening of a variety of disease targets and diseases, among which BT-5528 is expected to overcome the major safety issues caused by ADC-targeting EPHA2, and all three products are currently in clinical phase II.
In China, Tongyi Pharma has developed a series of anti-tumor drug conjugates by virtue of the Bi-engaging Ligand-Mediated Selective Targeting (BI-ENGAGING Ligand-Mediated Targeting) technology platform. Among them, CBP-1008 is the first self-developed FR target conjugate drug in China and the world's first two-ligand drug conjugate, and the R&D progress of PDC in China is also the fastest, and it is currently in phase II clinical trials.
Drugs under investigation.
PDC is an investigational drug.
Data**: Public data collation.
In October 2023, Sevapeptide Biotech also joined the domestic PDC track, and according to the information on the official website of CDE, the PDC drug SC-101, which is conjugated by linkers to the peptide and tubulin inhibitor targeting Nectin-4 protein for the injection of Class 1 new drugs of Sevadia, was approved for clinical trial, which is also the first PDC product Nectin-4 targeted drug in China.
In addition, BGC022 is currently undergoing dose expansion studies at the 125mg M dose level, including cervical, ovarian and gastroesophageal cancers. CBX-12 reported good news in the 2023 ASCO, and its activity and safety in solid tumors enhanced its potential for ** cancer.
On the whole, from the perspective of global R&D regions, North America is the leading region of the global PDC market due to the gathering of the world's largest pharmaceutical companies, which maintain a high sensitivity to PDC, and some companies have invested a lot of money in R&D. Among them, Bicycle Therapeutics has a bacteriophage bicyclic peptide technology and peptide chemical modification technology platform, based on which a number of PDCs have been developed.
In addition, thanks to the optimization of the regulatory environment and the increasing demand for targeting**, companies in the Asia-Pacific region have been more active in the global PDC market in recent years, especially Japan, which is at the forefront of PDC drug research and development. Among them, Japan's Peptidream is a leading PDC company, which has laid out more than 40 PDC projects, and has non-exclusively licensed PDPS technology to more than 10 companies around the world in the past ten years, including Bristol-Myers Squibb, Novartis, Eli Lilly, Merck, Takeda and other multinational giants, as well as leading RNAI company Alnylam.
Compared with overseas R&D, the progress of domestic PDC drug research is relatively backward, however, as a conjugated drug standing on the shoulder of peptides, in recent years, with the increasing clinical recognition of domestic peptide drugs, patients' demand for peptide drugs is increasing, and driven by technology, demand, policy and other factors, the scale of China's peptide drug market is growing rapidly, and the research and development of PDC has received more and more attention in China, and more and more companies are involved in the development of PDC. Shengnuoji Pharmaceutical, Xinglian Peptide Biotechnology and other companies have begun to emerge.
Puzzles to overcome
The $200 billion market is yet to be tapped
Although PDC has many advantages, and many companies have begun to deploy it, PDC still has limitations, that is, the circulatory stability is poor, it will be quickly cleared by the kidneys, and it must be stable within the circulation to prevent the early release of cytotoxic payloads and lead to systemic exposure; Due to the presence of gastrointestinal proteases, similar to protein-based drugs, PDC drugs cannot currently be taken orally and can only be administered by intravenous injection, limiting their clinical application.
However, fortunately, in view of the poor cycling stability of PDCs, different nanoparticles have been used to enhance the stability of PDCs, that is, PDCs are combined with gold nanoparticles (AUNPS). In addition, in view of the limitations of the drug delivery method, it may be possible to design the delivery system of oral macromolecule drugs in the future, and adopt appropriate carriers or structural modifications to prevent the degradation of enzymes in the gastrointestinal system and ensure the absorption of PDC into the blood, and the limitations of PDC are gradually being overcome.
According to Frost & Sullivan**, the global anti-tumor drug market is expected to reach $210 billion in 2022 and $483 billion by 2030, with targeted drugs accounting for 42% of the anti-tumor drug market. The global peptide drug market is also gradually expanding, and is expected to reach $141.8 billion by 2030.
As a PDC backed by the two major "double king" markets of global tumor-targeted drugs and peptides, there is no doubt that its prospects are very broad.
Conclusion
The explosion of ADC has lit up the future of PDC, although PDC is still a blue ocean, but PDC has opened up a new world for itself with its irreplaceable advantages such as small molecular weight, low immunogenicity, and wide selection of cytotoxic drugs. Although the current R&D progress of enterprises gathered overseas, in recent years, with the rapid development of China's economy and society and the change of life mode, the vitality of drug R&D innovation has shown a rapid upward trend, among which the peptide drug market is also growing rapidly, and PDC, as one of the dark horses, cannot be underestimated in the future.
Looking at the current drug accumulation track in China, biosimilars, PD-1 L1, and ADC drugs are "overcrowded", and PDC drugs may be another way for China's drug conjugate development enterprises. From concept to maturity, ADC took 100 years, and the current PDC is just like the ADC in the past, which is in the stage of "accumulating small streams".
Reference: Biologics CMC
8.$600 million market size, PDC drug development and market analysis.
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