HER2 Plus Breast Cancer: The "Land of Dragons" for Domestic ADC Drugs?

Antibody association drugs (ADCs) through monoclonal antibodies and tumor cell surface specific antigen binding, cytotoxic drugs directed to the tumor lesions, with the release of small molecular toxins, can be achieved with DNA groove or microtubulin binding and other mechanisms to induce apoptosis of cancer cells, play the drug's cytotoxicity, thus, for HER2 positive breast cancer patients to provide a new treatment option.
ADC is also considered to be one of the key directions for the development of monoclonal antibody drugs over the next decade, especially in the field of tumor-targeted therapy.
the global ADC market is expected to reach $12.9 billion in 2024, with a compound annual growth rate of about 35% between 2018 and 2024, according to Evaluate Pharma and BCG.
Currently, the most commercially successful ADC drug in the world is Kadcyla (Ermetrotoju, T-DM1), which is the second-tier standard treatment for HER2-positive breast cancer internationally, with global sales of CHF 1,393 million in 2019 (CHF 1,295 million in the first three quarters of 2020, up 37% YoY).
May 2019, Kadcyla was also approved by the FDA as an ancillary treatment for HER2-positive early breast cancer patients who still have impregnated diseases after receiving treatment with yewane and curly bead monoantigen, and the market space has been further expanded.
was followed by Enhertu (DS-8201a), a joint development by The Third Republic and AstraZeneta, which was first approved by the FDA in December 2019 to treat HER2-positive breast cancer.
Given the large her2-positive breast cancer population that can afford to have multiple innovative ADC drugs, there are still huge market opportunities for second-line after-treatment, an area that may be the "land of dragons" for HER2 ADC drugs.
At present, in addition to the above two approved HER2-positive breast cancer ADC drugs, in the first echelon of research and development is the East China PharmaceuticalSTA013, Rongchang bio-virdixito monoanti and Baotai BAT8001, and so on, with the potential competition is inevitable.
It is well known that safety and effectiveness are the main factors for pharmaceuticals to compete in the clinical development stage, and affordability, accessability and commercial promotion are one of the key factors for competition in the commercialization phase of products.
recent health care negotiations PD-1 price war attracted attention, just reflects the differentiation of product positioning, approval of the first-in-the-market advantage and the importance of the industrialization of manufacturers.
This paper briefly summarizes several HER2 ADC drugs that have been listed abroad and are the leading in domestic development from the perspectives of drug structure, development progress, clinical data, commercial potential, etc. for your reference.
Kadcyla (Emequto Bead Monoanti), developed by ImmunoGen and Genentech, is the world's first ADC drug to treat HER2-positive breast cancer, with two adaptations in February 2013 and FDA approval in May 2019: 1) complementary treatment for advanced metastasis HER2-plus breast cancer that has received octojutamol and/or yew alcohol, and 2) complementary treatment for HER2-positive early breast cancer patients who still have invasive lesions after a new complementary treatment (Yersulene combined octojutamol).
From a structural point of view, Kadcyla is combined with the micro-tube inhibitor drug DM1 (Metansin derivative) by the crater bead monoantigen through a stable thioether connection MCC (4-N-Malayamide methyl-1-steride) with the micro-tube inhibitor drug DM1 (Metansin derivative), whose generic name emtansine refers to the complex of MCC and DM1.
drug/antibody ratio (DAR) is 3.5, which means that an antibody carries an average of 3.5 DM1 molecules.
chemical structure is as follows: In the mechanism of action, Enmetro-bead monoantitor binds to her2 subjectivity to release the cytotoxic decomposition product containing DM1 in the cell through the mediated internalization of the subject and the degradation of the lysosome.
DM1 binds to micro-tube proteins, interfering with intracellular micro-tube networks, leading to cell cycle blocking and apoptosis.
addition, the Ometrobe single resistance itself inhibits the HER2 subject signal, plays an ADC role, inhibits the expression of HER2 breast cancer cells HER2 extracellular domain shedding.
because Kadcyla is already relatively familiar, the clinical data are no longer repeated.
Kadcyla is currently the most commercially successful ADC drug in the world.
In the Chinese market, Kadcyla was first approved for listing in early 2020 for the initial treatment of early HER2 plus breast cancer patients with residual invasive lesions after the new complementary treatment, the current price is 19282 yuan (100mg), 27633 yuan (160mg), if the drug is given once every 3 weeks, the drug burden is heavier.
, Kadcyla was not selected in the 2020 National Health Care Negotiations, and it remains to be seen to what extent the market can expand only through the drug-giving program.
In addition, Kadcyla's adaptation certificate for HER2 advanced breast cancer has not been approved in China, so the drug accessability of patients with advanced HER2-positive breast cancer who have received quarry bead single resistance in China has not been initially resolved, which is also an opportunity for domestic ADC drug filling and differentiation competition.
Enhertu (DS-8201a), developed jointly by The Third Republic and AstraZenecom, was first approved by the FDA in December 2019 for the treatment of adult patients with non-removable or metastasis HER2-positive breast cancer who have previously received two or more anti-HER2 treatments.
, Enhertu is currently mainly used in third- and end-line therapies.
structure of Enhertu includes curvature bead monoantin, topological isomerase inhibitors, and four peptides that can be cleavaged in the connection sub-parts.
common name, deuxtecan refers to a complex consisting of a protease-cut Malayamide teetotide joint and a topological isomer inhibitor DXd.
Enhertu carries about 8 deuxtecan molecules per antibody.
Enhertu's FDA approval is based on data from the Phase II DESTINY-Breast01 study.
AstraZeneta updated the study's findings at the SABCS 2020 meeting in December.
184 HER2-positive breast cancer patients who progressed after Kadcyla treatment (more than two anti-HER2 therapies have been received in the past, with a medium line number of 6 (range: 2-27)) and a medium follow-up of 20.5 The objective mitigation rate (ORR) was 61.4% (113/184), the medium response duration was 20.8 months, the medium PFS was 19.4 months, and the disease control rate was 97.3%.
in the exploration of total lifetime (OS), the medium total lifetime was 24.6 months and the 18-month survival rate was about 74%.
But safety is not enough in Enhertu, its treatment period of 3 or more adverse events (TEAE) occurred more, due to adverse reactions caused by the proportion of drug suspension is close to 20%, so the drug label carries a black box warning.
Enhertu's domestic registration of breast adaptation is aimed at patients with her2 low expression and has now advanced to Phase III.
this is different from the FDA's currently approved allergens, but does not rule out Enhertu's subsequent filing of HER2-positive breast cancer registrations.
the commercialization of the company, Enhertu was developed jointly by AstraZeneta and the first three giants, and the prospect of commercialization is not to be underestimated.
is currently priced at about $2,406 (100 mg) internationally, while AstraZeneta reported sales of $63 million in the first three quarters of 2020, according to AstraZeneta's 2020 results.
TAA013 TAA013 was developed by Dongying Pharmaceuticals and is currently in phase III clinical stage.
This ADC is a new derivative of curto-bead monoantigen and micro-tube inhibitor metan connected by a stable thioether bond (curto-bead monoantigen-MCC-DM1), which can be regarded as a similar drug of Kadcyla, and has been registered in China for a Phase I study and a Phase III study.
According to the results presented at the 2020 SABCS Conference, the TAA013 Phase I dose climbing study used a "3-3" method for dose climbing, all patients received crater bead monoantigen therapy, and many patients received too many lines of rapapatini, pyridoxine, Patoju monoantigen and other HER2 target drug treatment, the average number of lines treated in the past is 4.
results showed that the clinically recommended dose of 3.6 mg/kg dose group of 10 patients with 1 case of disease relief, 6 cases of disease stabilization, 3 cases of disease progression, and 1 patient with more than 500 days of medication, the patient's medium PFS for more than 5 months.
From the clinical data, TAA013 in terms of safety advantages, each dose group did not observe dose-limiting toxicity, most adverse events are 1-2 levels, after the suspension of the drug can be automatically restored, did not cause a permanent suspension of the drug.
considering Kadcyla as a second-line and later therapy, orR (43.6%) and PFS (9.6 months) in the EMILIA study, the results of Phase III of TAA013 are still worth looking forward to.
Phase III study of TAA013 was first published on June 3, 2020, and the first patients were admitted to the group on July 22, mainly in the partial late stage of non-excision that failed to be treated with octozhu monotherapy. In patients with metastasis HER2-positive breast cancer, the evaluation of the efficacy and safety differences between TAA013vs Lapatini and Capatamine is the first T-DM1 drug in China to enter Phase III after Kadcyla.
Phase III study design of TAA013 is basically the same as Kadcyla's Phase III EMILIA study design, targeting second-line therapies for patients with HER2-positive advanced breast cancer.
At present, Kadcyla, DS-8201a and other treatment certificates for advanced HER2-positive breast cancer second-line and later therapies have not yet been approved in China, a period of time away from medical insurance coverage, patients receiving too much line anti-HER2 treatment are not available, TAA013 in this segment of the population to Chinese patients to bring treatment options worth looking forward to, but also the domestic ADC differentiated commercial competition cut point.
In addition, Dongtong has its own antibody primary and joint workshop, able to complete the production of ADC drugs in the same location, commercial production costs are relatively low, in the cost of product treatment will naturally be more popular.
, drug affordability may become a natural competitive advantage for TAA013.
Wei Dixito monoanti (RC48-ADC) Wedixito monoantigen resistance was developed by Rongchang Bio, consisting of recombinant humanized HER2 monoantigen and MMAE through cysteine and lysate, and the development of her2-positive breast cancer adaptation certificate is currently in phase II clinical research. the clinical development strategy of
-Wei Dixito monoantigen is more characteristic, for HER2-positive gastric cancer has been submitted for listing in China, for HER2-positive urethra skin cancer has been FDA, CDE breakthrough therapy certification.
But on breast cancer, a large tumor species, the fastest progress in the vircistosis is for HER2 low expression of local late stage or metastasis breast cancer, has been carried out Phase III clinical, and the clinical development of HER2-positive breast cancer is in Phase II.
this also reflects Rongchang bio to the different market positioning of wedisitto single resistance, gastric cancer, urethra skin cancer as the highest priority of the adaptation to develop.
commercialization, Rongchang Bio's commercial production GMP facility has an annual output of 2.3 million bottles of antibodies and 1.5 million bottles of ADC, and its industrialization capability is equally unquestionable.
, the high probability of the production capacity of the Wedixito monoantigen will give priority to meeting the fastest progressing gastric cancer adaptation.
ARX788 ARX788 was developed by Ambo Bio and Zhejiang Pharmaceuticals based on the next generation ADC technology platform to precisely blend non-natural amino acids into the predetermined bits on the HER2-specific monoclonal antibody chain and to a co-price the AS269 to non-natural amino acids through a step-by-step coupling reaction in aqueous solutions.
/antibody ratio (DAR) for ARX788 is 1.8.
HER2-positive breast cancer adaptation of ARX788 is currently in Phase II/III, and at the recent SABCS 2020 conference, ARX788's HER2-positive Stage I breast cancer test data in China were published, with a queue ORR of 1.5 mg/kg of 74% (14/19) and a DCR of 100%.
safety, ARX788 resulted in 488 adverse events (TEAEs) during treatment, most commonly elevated liver enzymes, fatigue, hair loss and dry eyes, according to SABCS 2019 Conference data.
reported six cases of severe acute respiratory distress syndrome, of which 1 case (grade 3 pneumonia, 2.0%) was considered to be associated with ARX788;
ARX788's joint development is an important step in zhejiang medicine's innovative drug layout, Zhejiang medicine's commercialization ability is indisputable, but public information shows that its ADC preclinical research and production process development services still need to rely on external forces.
BAT8001 BAT8001 is the first ADC drug developed by Baeotelli, which is made up of anti-HER2 monoclonal antibodies that are co-priced with the toxin-connecting device Batansine, a medanin derivative, through a stable thioether bond.
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