CSPC Pharmaceutical Group Announces $18.35 Billion Global Licensing Deal with BeiGene for AI-Discovered MAT2A Inhibitor SYH2039

On December 13, CSPC announced that it had entered into an exclusive licensing agreement with BeOne Medicines for the global development, manufacturing, and commercialization of SYH2039, CSPC’s novel methionine adenosyltransferase 2A (MAT2A) inhibitor, as well as any subsequent drugs composed of or containing this compound (the “Related Products”).

Pursuant to the agreement and in accordance with its terms and conditions, CSPC has agreed to grant BeOne Medicines an exclusive global license to develop, manufacture, and commercialize SYH2039 and related products. CSPC will receive a total upfront payment of $150 million and is entitled to receive up to $135 million in potential development milestone payments and up to $1.55 billion in potential sales milestone payments, as well as tiered royalties based on the annual net sales of the product. (The total value of the collaboration amounts to up to $1.835 billion, equivalent to approximately RMB 13.4 billion.)

SYH2039 is a clinical candidate drug obtained by CSPC through its AI-driven small-molecule drug design platform and is currently in Phase I clinical trials. The platform leverages AI technology to analyze the binding modes between target proteins and compound molecules, enabling targeted optimization of molecular druggability, ultimately yielding a highly active and selective small-molecule MAT2A inhibitor.

SYH2039 targets solid tumors harboring MTAP-deletion mutations. MTAP is a key enzyme in the salvage pathways of purine and methionine synthesis, catalyzing the conversion of MTA into ATP, dAMP, and methionine, thereby participating in cellular energy and protein synthesis. While MTAP is abundantly expressed in normal cells and tissues, high-frequency deletions or reduced expression are commonly observed in various malignant cell lines and tumor tissues.

It is estimated that this mutation occurs in 15% of patients with various types of cancer, most commonly in glioblastoma, pancreatic cancer, and non-small cell lung cancer.

Preclinical studies have demonstrated that SYH2039 effectively inhibits the growth of various MTAP-deleted tumor cells, including non-small cell lung cancer, glioma, gastroesophageal cancer, pancreatic cancer, and bladder cancer. It exhibits excellent in vitro and in vivo activity, along with favorable pharmacokinetic (PK) properties and a good safety profile, showing potential to become a best-in-class anti-tumor agent.

Furthermore, SYH2039 can be used as a monotherapy or in combination with various other drugs, including second-generation PRMT5 inhibitors, to achieve synergistic efficacy. PRMT5 is an emerging target in the field of “synthetic lethality.” Studies have shown that MTAP deficiency leads to the accumulation of its reaction substrate, methylthioadenosine (MTA). The binding of MTA to PRMT5 forms a PRMT5-MTA complex, which significantly inhibits PRMT5 activity. These findings suggest that inhibiting PRMT5 activity in MTAP-deficient tumors holds promise for killing cancer cells, representing a novel therapeutic strategy for cancer. According to incomplete statistics, more than 10 PRMT5 inhibitors worldwide have currently entered clinical trials.

It is reported that BGB-58067 is a PRMT5 inhibitor under development by BeOne Medicines for the treatment of solid tumors. It is designed to avoid the on-target hematologic toxicities associated with first-generation inhibitors and is expected to enter clinical development in 2024. The drug demonstrates high potency, selectivity, and blood-brain barrier penetration, holding the potential to become a "best-in-class" therapy.

Dr. Wang Lai, Senior Vice President and Head of Global R&D at BeOne Medicines, stated, “SYH2039, this MAT2A inhibitor, is a highly valuable addition to our solid tumor pipeline. We look forward to exploring the potential of this product, particularly in combination with our internally developed PRMT5 inhibitor, BGB-58067. These products are expected to work synergistically to advance the treatment of various solid tumors.”

The licensing of SYH2039 marks CSPC’s second major business development (BD) deal in recent times, not only highlighting the significant potential of its early-stage pipeline but also serving as strong evidence that CSPC is progressively building global competitive advantages and innovation capabilities.

As early as October this year, CSPC licensed its preclinical small-molecule lipoprotein(a) [Lp(a)] inhibitor YS2302018 to AstraZeneca for $2 billion, with an upfront payment of $100 million.

Lp(a) is a lipoprotein particle formed by the interaction of low-density lipoprotein (LDL) particles with apolipoprotein(a) [Apo(a)]. Epidemiological studies have shown that Lp(a) is an independent risk factor for cardiovascular disease, and research indicates that Lp(a) levels are positively correlated with the presence and severity of coronary heart disease.

Lp(a) is a key target in the field of lipid-lowering therapy and has become a focal point for competitive development by multinational corporations (MNCs). Preclinical data demonstrate that the inhibitor YS2302018 exhibits excellent pharmacokinetic profiles and superior efficacy both in vitro and in animal models, with no serious safety concerns. Therefore, it holds the potential to emerge as a novel therapeutic option for managing cardiovascular risk in populations with elevated Lp(a) levels.

Following the acquisition of YS2302018, AstraZeneca plans to utilize the asset not only for lipid-lowering indications but also in combination with other pipeline candidates, including the small-molecule PCSK9 inhibitor AZD0780.

Notably, YS2302018 was still developed based on CSPC’s AI-driven drug design platform. This platform leverages AI technology to analyze the binding modes between target proteins and existing compound molecules, enabling targeted optimization of their druggability, and ultimately identifying a highly potent Lp(a) small-molecule inhibitor with favorable developability.

The two blockbuster business development (BD) deals reveal that, although the assets involved were only at the preclinical and Phase I clinical stages, the transaction values each reached billions of US dollars, underscoring major pharmaceutical companies’ strong confidence in the potential of these drugs. Furthermore, endorsement from AstraZeneca, a leading multinational corporation (MNC), and BeOne Medicines, a pioneer in global expansion, unequivocally affirms the global development potential and value of these therapeutic candidates.

CSPC, a traditional pharmaceutical enterprise, faces numerous challenges, including the centralized procurement of its blockbuster oncology product, the approaching patent expiration of legacy nervous system drugs, and low liquidity in the Hong Kong stock market. However, as a leader among traditional pharmaceutical companies in transformation, CSPC has chosen to pursue differentiation and source innovation, making significant inroads into the field of AI-driven drug discovery. In recent years, CSPC’s R&D investment has consistently ranked among the top five domestic pharmaceutical companies. In 2023, CSPC’s R&D expenditure reached RMB 4.83 billion, accounting for 18.84% of its revenue.

CSPC stated in its annual report that the company’s R&D focus for small-molecule drugs is to build PROTAC and LYTAC platforms, as well as an AI-based screening platform.

In August 2023, CSPC partnered with two leading AI drug discovery companies, XtalPi and Insilico Medicine, in a single move, which was regarded as a significant step into the field of AI-driven drug development. CSPC also projected that its AI-enabled drug discovery would accelerate over the next five years, with more than 40 innovative drugs and novel formulations, as well as over 60 generic drugs, expected to reach the market.

This landmark collaboration, empowered by AI-driven drug discovery, has not only generated substantial cash flow for CSPC but also signifies that its R&D capabilities in developing novel targets based on AI-assisted design have gained recognition both domestically and internationally. This is just the beginning, and we look forward to more breakthroughs from CSPC in the future.