Innovating the development of traditional medicine industry

The Bright Moment of ADC Drugs and the International Journey of Domestic Pharmaceutical Innovation —— Excerpted from the September Update of Medical Frontier

The most impressive thing about pharmaceutical frontier innovation in September was that ADC drugs ushered in a high-light moment, and the other was a small outbreak of new domestic pharmaceutical innovation forces on the journey of internationalization.

1).ADC Therapeutics submitted a marketing application for treating DLBCL to the FDA in September for the ADC drug (Lonca) of CD 19. Lonca achieved an objective remission rate of 48.3% and a complete remission rate of 24. 1% in the key phase II four-line therapy, with strong curative effect; In the same month, ADC Therapeutics also released preclinical data of ADC drug (Cami) for CD25. Cami can effectively consume Tregs, thus enhancing the anti-tumor effect of immune system. The product has been in the key phase II trial of Hodgkin's lymphoma.

2) The first, third and third ADC drugs targeting HER2 (Deruxtecan) were approved for the third-line treatment of HER2-positive metastatic gastric cancer in Japan in September, which reduced the death risk of patients by 465,438+0% (the median survival time in the treatment group was 65,438+02.5 months, while that in the chemotherapy group was 8.4 months); In addition, 13 * * released the latest phase I data of ADC drugs for HER3 (U3- 1402) in Shanghai ESMO 2020, and achieved an objective remission rate of 25% and a disease control rate of 70% among patients with EGFR-positive non-small cell lung cancer who failed to be treated with various tyrosine kinase inhibitors, which is also an outstanding curative effect.

3) Seattle Genetics and Genmab put forward the key phase 2 data of TF-targeted ADC drugs (tisotumab vedotin) in the treatment of recurrent and metastatic cervical cancer, and achieved an objective remission rate of 24% and a median survival time of 12. 1 month, while the objective remission rates were less than 15% and less than 65438. In the same month, Seattle Genetic Company and AstraZeneca Company announced that the ADC drug (Padcev) for Nectin4 jointly developed in the phase III clinical trial of urothelial cancer patients receiving chemotherapy and immunotherapy, compared with the chemotherapy control group, the death risk was reduced by 30%, reaching the main end point of phase III.

4). At the annual meeting of ESMO2020, ImmunoMedicines announced that the third negative breast cancer was treated with Trodelvy, an ADC drug targeting Trop2, achieving an objective remission rate of 35% and a median survival time of 65,438+02.1month. In contrast, the objective remission rate in the control group was only 5%, the median survival time was 6.7 months, and the risk of death was reduced by 52%. In addition, immunologists also released the key phase 2 clinical data of Trodelvy in the treatment of metastatic urothelial cancer, achieving an objective remission rate of 365,438+0%, a progression-free survival time of 5.4 months and a median survival time of 65,438+00.5 months, which is also obviously better than chemotherapy.

It can be seen that in the past September, the research and development of ADC drugs showed explosive performance. In addition to R&D progress, the layout of large pharmaceutical companies in the ADC field is also remarkable. Less than two months after AstraZeneca reached a $6 billion cooperation agreement with 1 * * in July, Gilead announced on September 3, 2020 that it would spend $265.438 billion to acquire immunomedicine and other drugs for Trop2.

Rongchang Bio is the most advanced ADC in China. In August, it reported the production of the first domestic ADC drug (RC48) for the treatment of HER2-positive gastric cancer. In September, the indication of RC48 in the treatment of HER2-positive urothelial carcinoma was recognized by FDA as a breakthrough therapy. At the same time, Rongchang Bio also announced a new clinical trial of ADC drugs for c-Met in September.

We are optimistic about the prospects of engineering antibodies including ADC and McAb, and have shared the logic in the previous roadshow report: the evolution of biological science has multiple dimensions, one of which is the "continuous improvement of transformation and intervention" in the same technical field.

In the field of polypeptide drugs, we have witnessed the evolution direction of biotechnology from "natural extraction" to "human recombination" and then to "engineering transformation". For example, the essence of the first generation of pig/bovine insulin is natural extraction, the second generation of recombinant human insulin is humanized transformation, and the third generation of insulin is based on various engineering transformations of recombinant human insulin;

Due to the larger molecular weight, the real industrialization breakthrough of monoclonal antibody drugs is 15 years later than that of polypeptide drugs, but it is expected to follow a similar evolutionary path: the first generation of mouse-derived monoclonal antibodies is roughly equivalent to the natural extraction stage, and the second generation of humanized monoclonal antibodies is roughly equivalent to the recombinant humanized transformation stage. With the maturity and popularization of humanization technology, it is more and more difficult to screen new targets. Maybe monoclonal antibody drugs will continue to open up more market space and enter the "engineering era". Logically speaking, creating unprecedented molecules is an important basis for creating unprecedented curative effects;

Therefore, from the first half of "recombinant humanization" to the second half of "engineering transformation", the key lies in whether the engineered antibody with "unprecedented" structure can achieve "unprecedented" clinical efficacy-this can be logically deduced in advance. For example, ADC drugs can make use of the precise targeting of monoclonal antibodies to enable highly toxic chemotherapy drugs to achieve precise targeted therapy that was impossible before; For another example, bispecific antibodies can restrict the two targets, which can not only realize physical connection, but also realize double confirmation, further increase the targeting and greatly improve the safety. Now, more and more clinical data are also confirming the logical advantages of engineering antibodies such as ADC and double antibody. In this context, the monoclonal antibody industry is also entering the second half characterized by "engineering antibodies", and there should be no small industrial opportunities. There are many companies in biotechnology in Hong Kong.

In addition to the outbreak of ADC in September, the internationalization process of domestic pharmaceutical innovation companies also ushered in a small outbreak in September.

1). Tianjing Bio reached a strategic cooperation with AbbVie on September 4th, and Tianjing Bio authorized the overseas rights and interests of its CD47 monoclonal antibody lemzoparlimab to AbbVie for development. Tianjing Bio received a down payment of US$ 65.438+US$ 800 million, a first-phase clinical mileage of US$ 20 million, the highest mileage of US$ 654.38+US$ 740 million and a double-digit sales commission.

2). Cornerstone Pharmaceutical Co., Ltd. (02616) reached a strategic cooperation with Pfizer on September 30, and Cornerstone Pharmaceutical Co., Ltd. authorized the mainland market rights of its PDL 1 product Sugarlizumab to Pfizer, for which Cornerstone Pharmaceutical Co., Ltd. will receive a maximum mileage of 280 million US dollars and additional classified patent royalties; At the same time, Pfizer subscribed for the equity of Cornerstone Pharmaceutical at a price of HK$ 65,438+03.37 per share equivalent to US$ 200 million.

3). Junshi Bio (688180) announced on September 10 that the indication of Treeplizumab in the treatment of nasopharyngeal carcinoma was recognized as a breakthrough therapy by the FDA, and the indication was recognized as an orphan drug by the FDA in May this year.

4). Rongchang Bio announced on September 2 1 day that the indication of Verdesituzumab (RC48) in the treatment of HER2-positive urothelial cancer has been recognized as a breakthrough therapy by the FDA, and this product was just recognized as a fast track by the FDA a few months ago.

5).Panthera stem cell cancer early screening liquid biopsy product was recognized as a breakthrough therapy by FDA on September 30th, becoming the first product recognized as a breakthrough medical device by FDA in China. The prospective clinical data of Panthera HCCscreen shows stronger sensitivity and specificity than the retrospective study of liver cancer early screening products published by Exact Sciences, an old early screening company.

The performance of domestic medical innovation in September can be said to be a "blowout": in the years before September this year, domestic medical innovative products were only approved by FDA for breakthrough therapy twice (Zebutinib from Baekje Shenzhou and LCAR-B38M cell preparation from legendary creatures); In September, domestic enterprises won two breakthrough therapeutic drugs and 1 breakthrough medical devices approved by FDA in one breath in just one month!

In addition, in terms of international external authorization, we don't consider the projects that Hengrui, Baekje and Kangfang didn't have the following three external authorizations, which were truly authorized to multinational pharmaceutical giants at high prices and were substantially promoted, and the legendary LCAR-B38M was authorized to Johnson & Johnson, and Xinda Xinli monoclonal antibody was authorized to Lilly several times; In September, in just one month, Tianjing authorized Abby and Cornerstone authorized Pfizer for two large transactions.

This is an exciting event, which essentially shows that the innovation ability of domestic medicine has begun to be recognized by the mainstream markets in developed countries, and it is a clear symbol of the rise of domestic medicine innovation.

The innovation tide of domestic pharmaceutical industry began to grow around 20 1 1, Baekje, Cinda and Junshi were established around 20 1, and Hengrui and Tianqing were determined to innovate and transform around 201/,which coincided with the time when the whole society began to strengthen the will to transform. Since 20 15, the reform of drug examination and the development of capital market have further accelerated the understanding of innovative transformation industries, and pharmaceutical innovation has gradually become the knowledge of the industry. Around 20 15 years, more new start-ups were born, and their innovative layout gradually entered the harvest period after 20 17 years, and more and more domestic innovative products began to enter the public's field of vision.

However, while domestic medical innovation is rising, there are also systemic risks: such a strong innovation trend attracts too many resources. Take 1 the number of clinical acceptances of innovative drugs as an example, which has soared year by year since 20 17, and is expected to exceed 700 in 2020, reaching 10 years ago. Moreover, according to the current growth trend, the number of domestic 1 new drugs accepted in the next two years is likely to exceed1000-an exaggerated figure. With the stage and volume of the pharmaceutical market in China, it is possible to produce at most 10-20 domestic new drugs every year, which will mean that more than 95% of the existing innovative drugs will be doomed to failure.

There are many specific catalytic forces behind the oversupply of domestic innovation, including the "innovation anxiety" brought by the expectation of generic drug restructuring to traditional pharmaceutical companies, and the typical phenomenon of "staking the land" by emerging enterprises in the early stage of industrial megatrends. However, with the progress of various products and the development of the industry, a large number of so-called 1 new drugs have started or will soon enter the "fake period". It is predicted that in the next few years, a number of innovative products and innovative pharmaceutical companies will face the challenge of life and death-a large number of innovative products and innovative pharmaceutical companies will fall, while a large number of new drug manufacturing forces will rise strongly. Under the joint action of two trend forces, industry innovation will also enter relatively fierce competition, with higher innovation and comprehensive ability.