[Trend] Pharmaceutical giants enter the "slimming season": Johnson & Johnson, Novartis, Pfizer

Source: Pharmaceutical R&D Social Platform    Author：谢雨礼

Primer

You should be free to write your own feelings at the invitation of the 43th event. Some people say that now is the best moment for China's biomedical innovation. But in the end, what kind of projects we should innovate and invest in, how to carry out research and development, the differences are still very large. Some people are optimistic about originality, and some people insist on imitation. Combine the iconic events of Baekje Shenzhou landing on Nasdaq and talk about your own views.

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Now is the most beautiful moment for China's biomedical innovation. The fall of US biotech stocks has not changed people's views. Because too many landmark events have occurred in the past year. The rapid development of biotechnology, represented by tumor immunotherapy, seeks to address unmet clinical needs and restart the “blockbuster” era in traditional areas such as cancer and cardiovascular. Domestic, CFDA hurricane reform, Cinda Bio and Hengrui and other multi-billion dollar deal, Baekje Shenzhou landing on NASDAQ, the return of overseas elites, the improvement of new drug development platform, the wind investment Chasing, indicating that China will usher in the development of new drug development.

The enthusiasm for new drug research and development is high, but the nature of its high investment and high risk has not changed. Therefore, most people still think that China is only suitable for imitating innovation, that is, keeping up with foreign mature targets and adopting a “me-too” strategy. Of course, the meaning of today's mature targets has changed, and is no longer limited to the targets that have already been marketed, but also those that are in the development stage, but with a relatively mature research base and development tools. These targets may be at very early stages, such as second or earlier. The author also agrees that there is still too little original research on the value of new drug development in China, and “me-too” is also a helpless choice. However, doing "me-too" does not mean that there is no original thinking and research. On the contrary, if you want to win in the fierce competition, you must have a deep understanding of the basic research in the field, and put forward relevant hypotheses, if necessary, have to carry out relevant research to verify. Only under the guidance of the original thinking of “hypothesis-driven” can the chance of “me-better” or “best-in-class” be improved.

The traditional “me-too” R&D is generally to choose a hot target, identify compound skeletons and benchmarking compounds (often listed or the fastest-growing), start to renovate and wrap patents, establish assays or send out screenings. The main goal is to increase activity or improve PK or improve safety. However, these activities, PK and safety indicators and screening methods are generally the logic that has been applied to benchmark compounds. The "me-better" is then defined based on higher activity, lower dose, higher selectivity, and the like. In fact, a "better" drug is not necessarily related to activity and dosage. For example, pitavastatin is the most active in statins, and the dose is only 1/10 of Lipitor, but few doctors believe that pitavastatin is “me-better”. The selectivity is high, but also depends on who is selective, and some off-target can improve the efficacy, and the benefits outweigh the risks. In short, "me-better" requires a lot of clinical data support, and the difficulty is not smaller than first-in-class. If there is no original thinking, there is no "hypothesis", just simply go to the indicators defined by the big company, it is difficult to compete with it. Big companies can make a lot of money, such as profiling or other expensive tests for hundreds of kinases or receptors, and we can't. Therefore, we only have to fight for intelligence, based on a large amount of research literature, to present our own unique insights, and to guide the design and screening of drugs. Let's take the familiar Baekje Shenzhou product line as an example to talk about how to guide the development of “me-too” drugs with original thinking in practice.

Judging from Baekje's open product line, it is still the “me-too” route, and four products have entered the early clinical stage. The earlier one was the B-raf inhibitor BGB-283. The first generation of B-raf inhibitors vemurafeib and dabrafenib, a variant variant of B-rafv600e, has been marketed for the treatment of melanoma with the B-rafv600e variant. BGB-283 was differentiated based on two hypotheses: inhibition of B-raf dimers and EGFR. The first generation of B-raf drugs inhibited the B-raf monomer but stimulated the dimerization of the B-raf monomer. The double-polymerized B-raf promotes tumor growth. Therefore, one side effect of the first generation of drugs is the induction of secondary tumors. A large number of basic studies have shown that B-raf dimerization is also one of the important factors that produce drug resistance and Ras mutation to promote tumor growth. Therefore, B-raf dimer inhibitors can overcome drug resistance, as well as tumors used for Ras mutation. The second hypothesis comes from a Nature article in 2012 that attempts to answer a question that has long puzzled people: about 10% of bowel cancers carry B-raf mutations, but the first generation B-raf inhibitors The treatment effect of colon cancer is very poor, and the effective rate is only about 5%. This Nature article believes that because of EGFR feedback activation, dual inhibitors of B-raf and EGFR may improve the efficacy. Baekje has conducted a number of in vitro and in vivo studies to confirm this hypothesis (see article by Baekje, molecular cancer therapeutics, 2015, 14, 2187). Therefore, in the development of BGB-283, Baekje did not follow the traditional “me-too” route, simply to make a “more active, better PK” compound, but based on the hypothesis, it was differentiated. It is currently the only clinically B-raf inhibitor that inhibits both dimers and EGFR. This may also be the reason why this compound is seen by MerckSenoro.

Baekje's PARP inhibitor BGB-290 and the PD-1 inhibitor BGB-A317 are also "hypothesis-driven", but are much simpler and clearer. For example, the first generation PARP inhibitor Olaparib has approved ovarian cancer for BRCA mutation. Numerous studies have shown that PARP inhibitors may be effective against brain cancer and brain metastases. Compared to the first generation, BGB-290 optimizes its brain penetration ability, which may show advantages in brain tumors. Abbvie's Reliparib (phase III) also has similar advantages and has been validated in the clinic. The main difference in Baji's PD-1 inhibitor, BGB-A317, is to further reduce the binding of mAbs to Fc receptors, thus potentially reducing side effects and increasing efficacy. It is common knowledge that Fc-mediated ADCC causes side effects, but it also reduces the efficacy of PD-1 inhibitors in a study just published in 2015. Baekje had such an idea, but it happened to happen. It is not known.

Baekje's BTK inhibitor BGB-3111 recently released Phase I clinical data, and its efficacy and safety have shown its potential to outperform the heavyweight ibrutinib, which has attracted widespread attention. However, the author believes that this is a product that Baekje has no idea at all. The ibrutinib listing is quite tortuous, and it has been difficult, which has left a lot of room for improvement for the latecomers. According to traditional practices, Baekje improved activity and selectivity, improved PK, and found me-better. The clinical data of Phase I was also very convincing and seemed to be very successful. However, with the release of Acerta's ACP196 (III) data, not only is the effect better, but also solves the problem of ibrutinib bleeding, which has become a best-in-class, which is also an important reason for AZ's -- billion acquisition. Compared with ACP196, BGB-3111 is not only slow to develop, but also me-worse. The opportunities around the world are very limited. In fact, there are a lot of basic research on BTK and ibrutinib, and there is a chance to propose some hypotheses to guide drug design and research and development. For example, in 1998, an article was published, and TEC kinase regulates platelet function. Ibrutinib has a strong inhibitory effect on TEC and may therefore be the cause of major bleeding. According to data released by Baekje, the inhibitory effect of BGB-3111 on TEC is slightly weaker than that of ibrutinib, but IC50 is comparable to BTK and has no selectivity (the selectivity of ACP196 is about 20 times). Therefore, BGB-3111 did not solve the bleeding problem. In stage I, there was a 24% subcutaneous congestion adverse reaction, and recently a major bleeding event of grade 3 or higher was announced. There is still a disadvantage in not solving the bleeding problem. BTK inhibitors also have therapeutic effects on autoimmune diseases such as rheumatoid arthritis, and many drugs including ACP196 are also conducting clinical research in this area. But these are chronic diseases, and the risk of bleeding will kill the prospects of BGB-3111. BGB-3111 is highly selective for EGFR, and the risks and benefits of this selectivity are worthy of scrutiny. Although EGFR brings side effects such as Rash and diarrhea, it is also a target for lung cancer. Ibrutinib is actively expanding its indications and conducting clinical research on non-small cell lung cancer. Studies have also shown that the inhibition of EGFR by ibrutinib may contribute to its efficacy. In addition, the ITK signaling pathway inhibits NK cells, thereby inhibiting human immune attacks, which may be detrimental to efficacy. Therefore, increasing the selectivity of ITK may increase the efficacy of the compound. BGB-3111's ITK selectivity is superior to ibrutinib, which may be one of the reasons for its better efficacy. In general, the biggest mistake of this product, Baekje is that there is no reasonable hypothesis for the problem of large bleeding of ibrutinib. If the hypothesis that TEC kinase is causing major bleeding is proposed at the time and the relevant research is confirmed, it is one of the primary tasks to solve the TEC selectivity in research and development. If it is not solved, it cannot advance. If the compound solves the bleeding problem and the efficacy is comparable to that of ACP196, it can maintain its potential for competition. The capital market's expectations and valuations for Baekje will be completely different.

Conclusion

Today, China has elements of research and development of new drugs such as policies, ideas, platforms and capital. However, the nature of high-input and high-risk new drug research and development is beyond the standard, and it faces competition from big global companies and the best Biotech. It is appropriate to choose “me-too” at our strategic level. However, on the tactical level, we must have original spirit, we must have good scientific literacy, and we must have the ability to propose and verify reasonable hypotheses. Of course, the hypothesis is not necessarily successful. For example, the dimer hypothesis mentioned above does not receive clinical data support at the Her-2 target. A clinical study led by Professor Xu Binghe LUX-Breast1 showed that the use of the Her-2 dimer inhibitor afatinib in patients with trastuzumab-resistant breast cancer did not improve PFS or even shorten Overall survival. But there is no idea, satisfied with simple activity improvement and PK improvement, and the clinical results depend on the day to eat, obviously it is difficult to win in the fierce competition. For investors, this is even more important. Many Biotech exit mechanisms are acquired or listed by big companies. Without a story, there is no expectation. Looking at me-too with original thinking may be the main theme of R&D and investment in China for a long time to come.

About the author: Xie Yuli, graduated from the Chemistry Department of Nankai University. In 2001, he received a Ph.D. from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. He was a postdoctoral researcher in the Department of Chemistry at Columbia University. During the United States, he worked as a project director at the University of Columbia Medical School and Merck's joint lab for project evaluation and new drug development. After returning to China, he held various positions in pharmaceutical companies, including the director of the Shanghai Research Institute of Yangzijiang Pharmaceutical Group and the deputy director of the Shanghai Drug Research and Development Center in Daxie, Japan. He is currently the director of WuXi PharmaTech's CMC office, engaged in new drug project, project management and market research. He has published more than 30 academic papers and won 5 international patents and 3 Chinese invention patents. 15 years of experience in the development of new drugs and generic drugs, familiar with international and domestic regulations, policies and markets.