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Focusing on High-Growth Projects, Over 80,000 Investment Elites Are Paying Attention
On November 21, BeOne Medicines and Ensem Therapeutics reached a cooperation agreement. BeOne Medicines introduced the CDK2 inhibitor ETX-197, while Ensem Therapeutics received an upfront payment, potential future milestones, and sales royalties. The total transaction amount is up to 1.33 billion US dollars.
(Source: Onsen Pharma official website)
Although a week has passed since the transaction event occurred, its underlying implications are worth careful examination.
Although the upfront payment for this transaction has not been disclosed, the total amount of the deal is believed to exceed everyone's expectations. Is a preclinical molecule really worth that much?
Behind the Significant "Premium" in Transactions, the "Innovative Drug Leader" Has Plunged into the "R&D Black Hole."”。The "Top Achiever" of the CDKs Family
CDKs (Cyclin-Dependent Kinases) are members of the serine/threonine protein kinase family and play a crucial role in cell cycle regulation. CDK family targets are mainly divided into two categories: one participates in cell cycle regulation, related to mitosis, with subtype representatives including CDK1, 2, 4, and 6; the other mainly participates in transcriptional regulation, modulating the phosphorylation modification of RNA polymerase II, with subtype representatives including CDK7, 8, 9, and 11.The cell cycle refers to the entire process that a cell undergoes from the completion of one division to the end of the next division, which is divided into two phases: interphase (which is further divided into G1, S, and G2 phases) and mitotic phase (M phase).CurrentlyThe CDKs family target that has garnered the most favor from oncology researchers undoubtedly includesCDK4/6、These two major targets, CDK2.
CDK4/6It is a key conditional protein in the human cell division and proliferation cycle, capable of triggering the cell cycle to progress from the growth phase (G1).Period) to DNA replication phase (SPeriod) Transformation;CDK4/6 is overexpressed in many cancer cells, leading to the hyperphosphorylation and suppression of Rb protein, which results in disordered proliferation of cancer cells.CDK4/6 inhibitors can arrest the cell growth cycle in the G1 phase, thereby inhibiting tumor cell proliferation.CDK2It plays a key role in the G1 phase (pre-DNA synthesis phase) and S phase (DNA synthesis phase) of the cell cycle, capable of activating downstream signaling molecules and promoting the normal progression of the cell cycle. According to available data,CDK2 OverexpressionIt causes abnormal regulation of the cell cycle and is directly related to the excessive proliferation of cancer cells.，CDK2 inhibitors have thus become a popular research and development direction.Currently, there are five CDK4/6 inhibitors available on the global market: Pfizer's Palbociclib, Simcere Pharmaceutical's Trilaciclib, Novartis' Ribociclib, Hengrui Pharma's Dalpiciclib, and Eli Lilly's Abemaciclib.The main core area of CDK4/6 inhibitors is breast cancer indications, and their combination with endocrine therapy has become the new standard for first-line, second-line, and early adjuvant treatment in HR+/HER2- breast cancer patients (accounting for 70% of all cases).CDK4/6 InhibitorsThe global market size has approached 9 billion US dollars.In contrast, there are currently no CDK2 inhibitors approved for marketing globally, but several candidates have entered clinical stages (which can be broadly categorized into pan-CDK and selective CDK2). Setting aside multi-blockers of the CDKs family, Pfizer is currently the frontrunner in terms of progress.PF-07104091 is being advanced for the exploration of indications such as breast cancer, small cell lung cancer, non-small cell lung cancer, and ovarian cancer.
(Source: Pharma Intelligence Network)BeOne Medicines introduced ETX-197 from Ensem Therapeutics, which is not particularly advanced in terms of R&D progress, but is claimed to be a "potential BIC candidate drug.""；ForETX-197, a highly selective CDK2, BeOne Medicines has its own plans.1) Potential Direction Synergy: A review of the development history of CDK2 inhibitors shows that hematologic malignancies and breast cancer are the main research and development directions, which aligns with BeOne Medicines' areas of expertise and strategic focus.2) The Potential of CDK2 in Breast Cancer:ETX-197 canComplements BeOne Medicines' clinical CDK4 inhibitors; activation of CDK2 is a common resistance mechanism to CDK4/6 inhibitors.Combined Inhibition of CDK2 and CDK4/6 Promising for Breast Cancer PatientsAnti-tumor effect.The Perilous CDK2 Development
According to the statistics from "Medicine Geek Stop," as of November 23, 2023, there are a total of 63 global pipelines targeting CDK2, of which 47 have been abandoned, leaving 16 active pipelines. Among these, 10 pipelines are in or prior to Phase I clinical trials.A Collection of Past Failed Molecular Cases, PartialThe failure of CDK2 inhibitors may stem from multiple reasons:1) The experiment found that although the use of CDK2 inhibitors led to a rapid decrease in CDK2 substrate phosphorylation, subsequent activity rebounded (e.g., CDK1 helped re-phosphorylate its substrates), causing the CDK2 inhibitor to become ineffective.
2) The early stagnation in the development of a large number of CDK2 inhibitor molecules was partly due to insufficient selectivity of candidate compounds, leading to off-target effects in trials and causing numerous severe side effects.Among them, clinical failures or stagnations caused by drug side effects account for the majority.As with Nuvation's CDK2/4/6 inhibitor NUV-422, which was once at the forefront, several patients in Phase I developed uveitis. No related cause or solution was found, ultimately leading to clinical failure.Similarly, for ocular adverse events, Blueprint's CDK2 inhibitor BLU-222 observed visual adverse events in a limited number of patients during the Phase I/II clinical trial (Photosensitivity and Blurred Vision), which was partially suspended by the FDA in February 2023, and later resolved by reducing the dosage and discontinuing treatment.Besides, even MNCs couldn't escape.The "R&D Black Hole" in the CDK2 Field, inBefore PF-07104091, PfizerIn early 2018, the Phase 1/2a clinical trial of the CDK2/4/6 inhibitor PF-06873600 was initiated, ultimatelyPfizer StopsThe development of the drug.Whether BeOne Medicines' ETX-197 can stand out in such a perilous R&D field remains to be seen.BeOne Medicines' Solid Tumor Efforts
From the analysis of BeOne Medicines' product revenue in the first three quarters of 2023, as zanubrutinib accelerated its market expansion in the U.S. during Q3, the company's prominence in the hematological malignancies field has begun to overshadow its focus on solid tumors, giving investors a sense of "imbalance" between the two areas of development.
Of course, as the "big brother of innovative drugs," BeOne Medicines naturally understands that if it wants to make a significant impact in solid tumors with zanubrutinib's success in CLL/SLL, it must follow the same strategy used for hematological malignancies by targeting major indications.
According to BeOne Medicines' interim report, excluding the existence of "basic drugs" like PD-1, it is not difficult to see that the company's several major late-stage solid tumor pipelines are mainly focused on lung cancer, gastrointestinal cancer, and other related areas.
(Source: Company's 2023 Mid-Year Report)Although it has temporarily missed the ADC layout opportunity in the short term, BeOne Medicines' recent series of actions undoubtedly signal that the company cannot afford to miss out on the strategic positioning in breast cancer—the leading cancer among women.
Among several major late-stage pipelines, BeOne Medicines' PARP inhibitor shows considerable potential in the triple-negative breast cancer patient population.As early as July this year, BeOne Medicines partnered with Luye Pharma to secure the commercial rights in China for Baotuo Wei (Goserelin Microsphere Formulation), followed by further developments in September.The breast cancer indication of Botenovi has been approved for marketing by the CDE.Represented by goserelinGnRH agonists are the first choice for OFS in premenopausal women with hormone receptor-positive early breast cancer. BeOne Medicines may have followed its research and development.CDK4/6、PD-1The original intention and idea is to establish an advantage in a disease area starting from early patients ("traffic entry point").Believe that this time, with such a substantial total amount, the acquisition of Ensem Therapeutics' CDK2 is also part of the company's long-term strategy for breast cancer, as the commercialization channel capabilities for female tumors are gradually being established.Notably, CDK4 inhibitorsBGB-43395It is one of BeOne Medicines' key projects in the breast cancer indication.Currently Globally Approved and MarketedCDK4/6 inhibitors all have limitations, with common side effects such asNeutropenia, such as abemaciclib causing a relatively high incidence of diarrhea and elevated transaminases.With BeOne Medicines' me-better and best-in-class strategy, it may not only aim to develop a better next-generation CDK4/6 inhibitor but also harbor greater ambitions of implementing "interceptive" treatments for early-stage patients across all breast cancer subtypes through a comprehensive combination layout of inhibitors targeting the CDKs family.Conclusion:Let's look forward to how BeOne Medicines, which missed the early opportunity in the ADC field, can achieve success in capturing the market share of breast cancer drugs in China and even globally.
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