Innovative technology iterations four ADC drugs with competition

On December 22nd, Pfizer's injection was approved by Oga Tuzu gabbed in China, and adaptation was adult patients with acute lymphocytic leukemia in recurrence or refractory precursor B cells.

2020 is the first year of my country's ADC drug, the AdceTris of Wuta and the Kadcyla of Roche have been listed. In 2021, Rongchang Biology Her2 ADC - Vivi West Sites were batch, marking the birth of domestic ADC drugs. With the listing of Oga Tuzhu monocontrol, 4 ADC drugs have been approved, and this paper will be analyzed by four ADC drugs to advise ADC's investment.

1, Oga Tuzhu

Ogauzumab Ozums (BESPONSA, Berbosa) is a Targeted CD22 ADC drug, which is jointly developed by Pfizer and partners. Oga Tuzpu monocomplications are made of humanized IgG4 mono-anti-INOTUZUMAB, which can be cut, and clamycin, DAR = 6.

From structural analysis:

(1) Inotuzumab is a monoclonal against CD22 that binds to CD22 targets on the surface of the cell membrane. CD22 is a specific target of B cell acute lymphocyte cells, high expression of 90% of acute lymphocyte cells.

(2) The 腙 key belongs to the wickled Linker, relies on acid hydrolysis, and the phenomenon of breaking in the blood. Studies have found that the 腙腙 is stable in the blood for about 30 minutes, so the ADC drug that uses the 腙 key can only be used for blood tumors, and cannot be used for the treatment of solid tumors.

(3) Clinism is an alkenne antibiotic, which belongs to DNA inhibitors. When the ADC drug is cleaved, the gratin is hydrolyzed from the conjugate, enters the nucleus, combined with DNA small ditch, resulting in a DNA double helix chain break, cancer cell death. It is worth mentioning that Pfizer is very favored in the design of ADC drugs, which uses clinicin as small molecular toxins in MyLOTARG and BESPONSA.

In August 2017, FDA accelerates the BESPONSA listing, indications for adult recurrence or refractory B cells before body acute lymphocyte leukemia (ALL). BESPONSA's listing license is based on stage III INO-VATE ALL test. The test results show that the complete relief rate (Cr) of patients in the BESPONSA group is 81% (95% CI: 72% -88%), the CR of the chemotherapy group is only 29 % (95% CI: 21% -39%). In all Cr patients, patients undergoing BESPONSA treatment had a negative rate of 78% (95% CI: 68% -87%), and this number of chemotherapy group was 28% (95% CI: 14% -47%). In addition, the median total survival (OS) of the BESPONSA group was 7.7 months, and the chemotherapy group data was 6.2 months, and the OS did not improve significantly.

BESPONSA has been approved for more than 4 years in the United States, but sales do not seem to be optimistic. According to Pfizer 2020 earnings, in the main drug sales list, Zirabev (Beaxumab) achieves $ 143 million in sales, ranking list. BESPONSA sales data did not appear in the list, so BESPONSA was sold or less than $ 100 million in 2020. In addition, the British National Health Insurance Association (Nice) was rejected by BESPONSA for adult leukemia at BESPONSA. The reason is that Nice believes that BESPONSA's patient survival is not significant, this decision until the end of 2018.

2, Vitobuximab

In August 2020, Wutian Pharmaceutical Injection was Witbuxi monoclon (AdceTris, Affili) officially listed in China, and the indication of CD30 positive recurrence / refractory systematic intervalent large cell lymphoma (SALCL) and Classic Hodgkin lymphoma (CHL).

Witbuximab vedotin is an ADC drug targeted CD30, which consists of a human murine chimeric anti-Brentuximab, a proline-valine diptide, and MMAE, a targeted CD30. Dar = 4. AdceTris was first developed by Seattle Genetics, 2009, the company has reached an agreement with Wudata, and the latter received Adcetris in addition to commercial power outside the United States and Canada.

From structural analysis:

(1) Brentuximab is a monoclonal antibody that targets CD30, and CD30 is a tumor necrotic factor super family member, which is highly expressed in classic Hodgkin lymphoma, interval, large cell lymphoma, normal activation B or T cells and NK Cells are not expressed in normal cells.

(2) MMAE is a tubulin inhibitor, can combine to G2 / M phase cell cycle arrest and cytoplasmic tubulin, a cell death, is widely used in medicine ADC. Compared with other Auristatin toxoid MMAF, MMAE because they do not carry a charge, can play a transmembrane bystander effect (Bystander effect), causing bystander. In 2011, Adcetris approved by the FDA listed as the world's second paragraph of ADC approved drugs on the market, at present, Adcetris has approved six indications worldwide, including AVD program associated with the first-line treatment with chemotherapy cHL, for at least twice the preamble of chemotherapy after the failure of classical Hodgkin lymphoma. Tests showed that for inter relapsed or refractory anaplastic large cell lymphoma, 58 cases among 97% of patients with relapsed or refractory systemic anaplastic large cell lymphoma achieved tumor shrinkage, 5-year survival was increased to 60 %. For classical Hodgkin's lymphoma, 94% of patients with relapsed or refractory classical Hodgkin lymphoma can achieve tumor shrinkage, median overall survival (OS) increased from 27.6 months to 40.5 History month.

Thanks to a number of indications, Adcetris sales steady growth, global sales have exceeded $ 1.2 billion. In 2020, Adcetris implemented in the US and Canada market sales of $ 658 million, other markets achieved sales of 59.4 billion yen (US $ 556 million), a total of $ 1.214 billion. It Clarivate forecast, Adcetris global sales in 2024 will exceed 20 billion dollars.

3, Amy trastuzumab

After January 2020, Amy trastuzumab won NMPA approved for marketing, indications received taxanes joint song tocilizumab-based neoadjuvant therapy, still remaining invasive lesions, HER2-positive early adjuvant treatment of breast cancer patients. June 2021, Amy trastuzumab in the country approved the second indication, accepted the HER2-positive taxanes and trastuzumab monotherapy treatment for unresectable locally advanced or metastatic breast cancer patients.

Amy trastuzumab (Kadcyla, T-DM1) Roche developed a HER2 ADC drugs by trastuzumab, MCC linker and DM1 composition, DAR = 3.5. DM1 is a microtubule inhibitor, can damage the microtubule network within the cells, resulting in cell cycle arrest and apoptosis. T-DM1 using non-cleavable Linker, so no bystander effect.

Amy trastuzumab won US approval to market in 2013, now has approved the treatment of patients with HER2 positive metastatic breast cancer and adjuvant treatment of HER2-positive early breast cancer patients. Among them, Amy trastuzumab HER2-positive locally advanced or metastatic breast cancer indication approved based EMILIA study, the test results show that the lapatinib + capecitabine compared coast, T-DM1 significantly improved patients median PFS (9.6 vs. 6.4 months), overall survival (OS) is also extended from 25.1 months to 30.9 months, the objective response rate was 43.6%, significantly higher than 30.8%.

With a significant effect and unique mechanism, Amy trastuzumab emerge rapidly in the global market, 2019 has been among the "blockbuster." In 2020 the global market sales of 1.745 billion Swiss francs, an increase of 25%.

4, Wei Dixi trastuzumab

June 2021, Wei Dixi trastuzumab won NMPA approved for marketing for the treatment received at least two kinds of HER2 overexpressing metastatic gastric cancer patients with locally advanced or systemic chemotherapy.

Wei Dixi injection trastuzumab (RC48) is Rongchang biological drugs developed a HER2 ADC by Disitamab, MC-Val-Cit-PAB MMAE and composition, DAR = 4. Which, Disitamab is a different epitope of HER2 trastuzumab and the HER2 higher affinity novel antibody, trastuzumab, the EC50 of 20.1pM, while the EC50 Disitamab only 6.4pM.

Wei Dixi trastuzumab gastric cancer indication approved based on a single-arm, open, Ⅱ of multi-center pivotal clinical trials, research data indicate that Wei Dixi trastuzumab treatment of advanced gastric objective response rate was 24.4% the median progression-free survival (PFS) of 4.1 months, and median overall survival (OS) was 7.6 months. This study has shown that vitamin Brindisi previously received trastuzumab in two or more lines and chemotherapy in patients with locally advanced or metastatic gastric cancer outstanding efficacy.

More gratifying is that in 2021 Medicare negotiations, Wei Dixi trastuzumab hand in Thailand it Sipp, successfully into Medicare, is the first and only included in health insurance directory of ADC products. In addition, in August 2021, Rongchang biological and genetic Seattle reached an exclusive worldwide license agreement with the potential of up to $ 2.6 million will be awarded Wei Dixi trastuzumab interest in the Asian region outside Seattle gene, the amount of the deal refresh a record for overseas pharmaceutical companies authorized to trade single species China.

5, summary

As Oga Tuzu gabbed, there were 4 listing ADC drugs in my country. From the perspective of research and development, the ADC drug represents the forefront of technology, and the future development momentum is strong. However, from the perspective of commercialization, in my country, ADC drugs have a higher price due to high prices, and there is a distance from commercialization. According to the rice data, T-DM1 is priced as above 2,7632 yuan / branch, and the price of Vitobuximi is also up to 15620 yuan / branch. Therefore, for high-priced drugs, it is the key to the introduction of medical insurance. At present, the current Rongchang's vastittoid antimony has taken the lead in incorporating medical insurance. In addition to paying attention to drug prices, indications are another key factor affecting drug sales. Oga Tuzu gabbar has been listed in the United States for many years, but it is difficult to sell data, which is less related to the number of patients with ALL indications. And Nebuxi monoclonal anti-sales continued to rise, on the one hand, in the case of compatibility, the crowd is closely related, breast cancer and classic Hodgkin lymphoma patients have more mice, on the other hand, constantly Broadensitive indications have expanded the use scenario of drugs, such as Wigbuxhaima has been approved for six indications.

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