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On September 30, Genentech, a division of Roche, entered into a major agreement with Rueger, with Genentech successfully acquiring Rueger's portfolio of next-generation CDK inhibitors for $850 million in upfront cash and other potential milestone payments. This transaction not only refreshes the down payment record for the foreign authorization of domestic molecules, but also marks a new milestone in the cooperation between the two sides. The previous record was held by Benefi Tianheng's agreement with BMS for the BL-B01D1 molecule, which was valued at $800 million. It is worth noting that the transaction between Benefi Tianhengand BMS only involves a single molecule BL-B01D1, which is already in the late clinical stage, and both parties share the subsequent overseas clinical costs. The collaboration with Genentech builds on a broader portfolio of next-generation CDK inhibitors, which is expected to include the Phase I CDK2/4/6 inhibitor RGT-419B and the preclinical CDK2 inhibitor QR-6401. Under the terms of the agreement, Genentech will be responsible for the global clinical development, manufacturing and commercialization of these products after the end of the existing Phase 1 clinical phase. Recently, the field of CDK inhibitors has become a hot spot pursued by many companies. In addition to Genentech, Beigene also announced the introduction of ETX-197, a CDK2 inhibitor from Onsun Pharma, at the end of November last year. Although the amount of the upfront payment was not disclosed, taking into account potential future milestone payments and sales sharing, the total value of the deal is up to $1.33 billion. With some generic CDK4/6 inhibitors entering the market in bulk, some investors are questioning whether the competitive landscape on the CDK inhibitor circuit has reached saturation. However, leading companies such as Roche and Beigene are still actively developing next-generation CDK inhibitors, which has a profound scientific and commercial logic behind it. CDKs (cyclin-dependent kinases), as an important member of the serine/threonine protein kinase family, play a crucial role in cell cycle regulation. CDK family targets are mainly divided into two categories: one is involved in cell cycle regulation and related mitosis, such as CDK1, 2, 4, 6; The other group is mainly involved in transcriptional regulation and phosphorylation of RNA polymerase II, such as CDK7, 8, 9, 11. Among them, CDK4/6 and CDK2 have attracted much attention due to their important roles in the development of tumors. CDK4/6 is a key condition protein in the human cell division and proliferation cycle, which can trigger the cell cycle transition from the growth phase (G1 phase) to the DNA replication phase (S phase). In many cancer cells, CDK4/6 is overexpressed, which promotes the disorderly proliferation of cancer cells through over-phosphorylation and inhibition of Rb protein. Therefore, CDK4/6 inhibitors can inhibit the proliferation of tumor cells by blocking the cell growth cycle in the G1 phase. CDK2 plays a key role in the early phase of DNA synthesis (G1 phase) and the phase of DNA synthesis (S phase) of the cell cycle, and its overexpression is closely related to the abnormal regulation of the cell cycle and the excessive proliferation of cancer cells. From a market perspective, breast cancer, as the world's largest malignant tumor (accounting for about 24.5% of all malignant tumors), provides a broad application space for CDK inhibitors. In particular, the large population of HR+/HER2- advanced breast cancer patients (about 60%-70%) makes endocrine therapy combined with CDK4/6 inhibitors a first-line treatment in this area. This also explains why CDK4/6 inhibitors can occupy an important position in the treatment of breast cancer and create a large drug market size. Despite the proliferation of blockbuster drugs in recent years, existing and older CDK4/6 inhibitors inevitably have several shortcomings, the most significant of which are drug toxicity and resistance. First, in terms of toxicity, hematotoxicity is the most common side effect of CDK4/6 inhibitors. These inhibitors inhibit cell proliferation by blocking the cell cycle, thus killing rapidly dividing cells, but this mechanism also leads to myelosuppression, which reduces blood cell production. Specifically, neutropenia, leukopenia, anemia, and thrombocytopenia are the most common hematological toxic side effects of commercialized CDK4/6 inhibitors. In addition, CDK4/6 inhibitors may also cause gastrointestinal adverse reactions, which should not be ignored. Second, in terms of drug resistance, although CDK4/6 inhibitors have achieved remarkable results in improving disease control in HR+/ HER2-breast cancer patients, 15-20% of patients still develop primary resistance to the drug at the beginning of treatment, while 30-40% of patients develop resistance gradually over the course of treatment. The mechanisms of drug resistance are complex and diverse, including but not limited to ESR1 gene mutation, upregulation of PI3K/AKT/mTOR signaling pathway, and BRCA2 gene mutation. In view of the influx of generic drugs of the older generation of CDK4/6 inhibitors and the urgent need to solve the existing toxicity and drug resistance problems, the new generation of CDK inhibitors ushered in more development opportunities. The RRT-419B that Roche is concerned about is a new generation of CDK2/4/6 small molecule inhibitor developed by Rueger Pharmaceutical. The drug is not commercially available worldwide, and its kinase activity profile has been optimized to target "better" safety and resistance CDK inhibitors from the outset. Regal's RRT-419B shows unique ingenuity in both design ideas and drug mechanisms, and has achieved preliminary validation of ideas in existing breast cancer clinical data. Unlike existing commercialized CDK inhibitors, which mainly inhibit subtypes 4 and 6, RGT-419B aims to reduce the occurrence of resistance to existing CDK4/6 inhibitors by increasing the inhibition of CDK2 subtypes, thereby achieving long-term efficacy. When CDK4/6 activity is inhibited, expansion of Cyclin E and activation of the oncogene MYC lead to up-regulation of MYC and activation of CDK2. CDK2-CyclinE, as a compensatory pathway, phosphorylates Rb, thereby releasing E2F transcription factors and promoting tumor cell proliferation. This process is the key to the development of acquired resistance to CDK4/6 inhibitors. Preliminary data from overseas studies such as Pfizer's CDK2 inhibitor PF-07104091 also revealed an association between CDK2 activation and acquired resistance to CDK4/6 inhibitors. In December 2023, Rueger presented the latest clinical data for RGT-419B at the SABCS Conference. The drug performed well in a Phase 1a clinical trial of monotherapy in 12 patients with HR+/ HER2-metastatic breast cancer receiving CDK4/6is and ET progression: three patients achieved partial response (PR) and continued treatment; Six patients received RGT-419B for more than 24 weeks; The drug was safe and well tolerated, no dose-limiting toxicity occurred, and no patient stopped treatment due to adverse events. Given the huge potential of next-generation CDK inhibitors in second-line breast cancer monotherapy, and the successful performance of commonly used second-line endocrine drugs such as fluvestrant in the market (such as the peak sales of $1.028 billion for fluvestrant in 2018), the global market for next-generation CDK inhibitors is expected to reach at least $2-3 billion. That is one of the reasons Roche is willing to bet so heavily. Faced with such a broad market prospect, many domestic pharmaceutical companies have also devoted themselves to the research and development of a new generation of CDK2/4/6 inhibitors or CDK2 inhibitors. One kind of large pharmaceutical companies further expand the development of CDK2 inhibitors on the basis of CDK4/6 inhibitor layout, such as Hengrui Pharmaceutical and First Sound Pharmaceutical; The other category is the first to enter the CDK inhibitor track of Biotech or big pharmaceutical companies such as Ruge Pharmaceutical, Stone pharmaceutical Group and Homology Kang Pharmaceutical. These companies are advancing the CDK inhibitor field and competing for future market share through continuous research and development and innovation. Although most of the CDK2/4/6 inhibitors that have entered the clinical stage in China are still in the early clinical stage, and most of them have not yet been validated by clinical data, it can be observed from the transaction cases of Regal Medicine and Beigene that these two authorized molecules have been deeply optimized by AI technology. From the information that has been made public, the AI pharmaceutical platform has played a key driving role in Genentech/Regal Pharma's RGT-419B and Beigene/Angsen Pharma's ETX-197 project. It is worth noting that the high degree of similarity among CDK family members makes the development of highly selective CDK2 inhibitors a great challenge. If the molecular selectivity is insufficient, it may lead to off-target phenomenon, which will affect the efficacy and safety of the drug. With the assistance of the AI model Kinetic EnsemNET, Onson has successfully identified a key hidden dynamic binding pocket of CDK2, thereby developing a potential BIC CDK2 candidate with high activity, high selectivity and a wide therapeutic window, which lays the foundation for its subsequent collaboration with Beigene. On the other hand, Ruge Pharmaceutical relied on its self-developed AI-assisted new drug research and development platform CARD to achieve the best selective screening of multiple CDK targets, and successfully promoted the clinical trial process of RGT-419B in the United States. From the licensing trend of CDK inhibitors, we can take a lesson: in the future, investors may need to pay more attention to the investment opportunities of Biotech companies that use AI technology to solve the difficult drug target or hot target iterative drug development challenges.

- Initial safety & efficacy in Urothelial Carcinoma (UC), Esophageal Squamous Cell Carcinoma (ESCC) and Biliary Tract Carcinoma (BTC) patients will be presented from clinical studies evaluating BL-B01D1, an EGFRxHER3 bispecific topoisomerase inhibitor- based antibody-drug conjugate (ADC) REDMOND, Wash., Sept. 9, 2024 /PRNewswire/ -- SystImmune, Inc. (SystImmune), a clinical-stage biotechnology company, today announced that three abstracts on BL-B01D1, a potentially first-in-class EGFRxHER3 bispecific antibody drug conjugate (ADC) will be presented at the European Society for Medical Oncology (ESMO) Congress 2024 taking place on September 13–17 in Barcelona, Spain. BL-B01D1 is being jointly developed by SystImmune and Bristol Myers Squibb under an exclusive license and collaboration agreement. Expanded results from clinical trials of BL-B01D1 will include data from patients with advanced stages of Urothelial Carcinoma, Biliary Tract Carcinoma, and Esophageal Squamous Cell Carcinoma and having multiple cycles of prior therapies. The data to be presented at ESMO highlights continued progress in BL-B01D01 clinical development and builds upon the previously reported clinical data in lung and breast cancer patients at ASCO, ESMO and SABCS in 2023. "These data support our continued conviction that BL-B01D1 has a manageable safety profile and add to the body of evidence that shows encouraging signals of efficacy across a wide variety of tumors" said Jonathan Cheng, M.D., CMO of SystImmune. "This positions BL-B01D1 as a versatile therapeutic option that may address the unmet medical needs of patients with limited treatment options. We are committed to advancing this therapy through clinical trials, exploring its potential not only as a monotherapy but also in combination with other agents, to improve outcomes for cancer patients globally." Details on the presentations at ESMO are below: BL-B01D1, an EGFR x HER3 Bispecific Antibody-drug Conjugate (ADC), in Patients with Locally Advanced or Metastatic Urothelial Carcinoma (UC) Session Title: Proffered paper session 1: GU tumours, non-prostate Presentation Number: 19590 Speaker: Dingwei Ye (Shanghai, China) Session Date & Time: Friday, September 13th, 2024, 2:00 PM-3:30 PM CEST BL-B01D1, an EGFR x HER3 Bispecific Antibody-drug Conjugate (ADC), in Patients with Locally Advanced or Metastatic Biliary Tract Carcinoma (BTC) Presentation Number: 54P Speaker: Zhihao Lu (Beijing, China) Onsite Poster display date: Monday, September 16th, 2024 BL-B01D1, an EGFR x HER3 Bispecific Antibody-drug Conjugate (ADC), in Patients with Locally Advanced or Metastatic Esophageal Squamous Cell Carcinoma (ESCC) Presentation Number: 1426P Speaker: Liu Chang (Beijing, China) Onsite Poster display date: Monday, September 16th, 2024 About BL-B01D1 The company is developing BL-B01D1, a bispecific antibody-drug conjugate (ADC) that targets both EGFR and HER3. These proteins are highly expressed in most epithelial tumors. The tetravalent BL-B01D1 has two binding domains for distinct Growth Factor Receptors that drive cancer cell proliferation and survival. Inheriting the SI-B001 mechanisms of action, BL-B01D1 blocks EGFR and HER3 signals to cancer cells, reducing proliferation and survival signals. Upon antibody mediated internalization, BL-B01D1 is trafficked to cancer cell lysosomes and liberates its therapeutic payload that induces genotoxic stress activating pathways leading to cancer cell death. About SystImmune SystImmune is a clinical-stage biopharmaceutical company located in Redmond, WA. It specializes in developing innovative cancer treatments using its established drug development platforms, focusing on bi-specific, multi-specific antibodies, and antibody-drug conjugates (ADCs). SystImmune has several assets in various stages of clinical trials for solid tumor and hematologic indications. Alongside ongoing clinical trials, SystImmune has a robust preclinical pipeline of potential cancer therapeutics in the discovery or IND-enabling stages, representing cutting-edge biologics development. Forward-Looking Statements Any research and development information provided by SystImmune is intended for general information purposes only. Such information is not intended to provide complete medical information. We do not offer patient-specific treatment advice and if you have medical conditions, please see your medical doctor or healthcare provider. This press release may contain forward-looking statements with the meaning of Section 27A of the Securities Act of 1933, as amended, Section 21E of the Securities Exchange Act of 1934, and the Private Securities Litigation Reform Act of 1995, which reflects the expectations regarding the company's goals, strategies, results of operations, performance, business prospects, and opportunities, including but not limited to the ability to gain Investigational New Drug status for the resulting new product and the ability to develop a successful formulation. Terms such as "anticipates," "believes," "expects," "estimates," "could," "intends," "may," "plans," "potential," "projects," "will," "would" and other similar expressions, or the negative of these terms, are generally indicative of forward-looking statements. While SystImmune, Inc. believes that expectations expressed in the forward-looking statements are based on the company's reasonable assumptions and beliefs in light of the information available to the company at the time such statements are made, it cannot give assurance that such forward-looking statements will prove to have been correct. Such forward-looking statements are not fact and are subject to uncertainties and other factors that could cause actual results to differ materially from such statements. We undertake no obligation to update any forward-looking statements contained in this press release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events. For additional information about the company, please visit . SOURCE SystImmune, Inc.