Bayer Inks $1.3B Deal for Kumquat’s KRAS G12D Inhibitor Ahead of IPO Filing

On August 12, Bayer and Kumquat Biosciences announced an exclusive global licensing and collaboration agreement to develop and commercialize the latter's self-developed KRAS G12D inhibitor, aiming to provide durable therapies for KRAS patients suffering from lethal malignancies such as pancreatic cancer, lung cancer, and colorectal cancer.

Kumquat Biosciences received FDA Investigational New Drug (IND) approval for its KRAS G12D inhibitor in July 2025. Under the agreement, Kumquat is responsible for initiating and completing the Phase Ia study, while Bayer will carry out further development and commercial activities, enhancing its early-stage precision oncology pipeline.

Under the terms of the agreement, Kumquat will receive up to $1.3 billion (approximately 9.332 billion yuan) in total payments, including upfront, clinical and commercial milestones, as well as additional tiered royalties on net sales. Additionally, Kumquat retains exclusive negotiation rights for participating in profit and loss sharing in the United States.

In 1982, the rat sarcoma viral oncogene homolog (RAS) was discovered. This was the first human tumor gene to be identified and is the most frequently mutated oncogene in human cancers. Mutations in the RAS gene can lead to the production of permanently activated RAS proteins, causing hyperactive signaling within cells even in the absence of incoming signals. These overactive signals affect cell growth and division, eventually leading to cancer. Studies have shown that cancers caused by such mutations account for approximately 30% of human cancers.

KRAS mutations are the most common type in the RAS gene family, accounting for approximately 85% of cases and occurring in nearly 25% of human cancers, thus being dubbed the "king of cancer targets." In human cancers, KRAS gene mutations appear in close to 90% of pancreatic cancers, 30%-40% of colon cancers, 17% of endometrial cancers, and 15%-20% of lung cancers (mostly non-small cell lung cancer). These mutations also occur in various other cancer types, including cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, and breast cancer.

For decades, this "king of targets" has not been conquered, due to:

Directly inhibiting KRAS activity may affect normal human cells.KRAS has a wide range of functions, and its normal activity "supplies" the needs of normal cell functions. If drugs that directly inhibit KRAS are selected, there may be high toxicity and strong side effects. Moreover, KRAS is highly homologous with NRAS and HRAS, and may inhibit the activity of the latter two.

KRAS lacks a "protein pocket" structure that traditional small-molecule drugs can bind to, meaning there are no obvious binding sites on the surface of the KRAS protein, making it difficult to synthesize a compound that can specifically target and inhibit its activity.

KRAS has a very strong binding affinity with GDP and GTP, and its intracellular concentration is extremely high, making it difficult for inhibitors that directly target the GTP-binding site of KRAS to be effective.When KRAS binds to guanine nucleotide diphosphate (GDP), it remains inactive; when bound to guanine nucleotide triphosphate (GTP), it becomes active and can activate downstream signaling pathways. Mutations in KRAS cause it to remain constantly bound to GTP, locking KRAS in an active state and continuously activating downstream signaling pathways, which stimulates cell proliferation and migration, ultimately leading to tumor formation. Theoretically, targeting the binding site of KRAS and GTP with small molecules could inhibit the interaction between KRAS and GTP. However, the normal intracellular concentrations of GDP and GTP are a million times higher than what is required for binding to KRAS. Therefore, creating a small molecule drug with binding affinity comparable to GDP and GTP is extremely challenging.

Designing a drug that selectively inhibits the activity of mutant KRAS protein without affecting the activity of other normal KRAS proteins requires the drug to have excellent selectivity for the mutant KRAS.

In recent years, breakthroughs in the research of covalent inhibitors targeting KRAS mutants have made it possible to target KRAS mutants through allosteric sites, also giving rise to multiple small-molecule covalent inhibitors targeting KRAS mutants. On May 29, 2021, the FDA granted accelerated approval for Lumakras, developed by Amgen, to enter the market, breaking the long-standing "undruggable" curse associated with the KRAS gene.

To date, four KRAS G12C inhibitors have been approved for marketing globally: Amgen's Lumakras, BMS/Mirati's Adagrasib, Innovent Biologics/Geneforce Biotech's Fuzorasib, and CT&TQ Pharma/InventisBio's Geosorasib. The initial indications for all these drugs are for advanced non-small cell lung cancer (NSCLC) with KRAS-G12C mutations.

Among KRAS mutation types, the proportions of different mutation types vary, and the mutation incidence rates differ across cancers. The G12D mutation accounts for approximately 26%, making it the most common KRAS mutation type in human cancers. It is most frequently observed in 37% of pancreatic ductal adenocarcinoma (PDAC), 13% of colorectal cancer (CRC), and 4% of non-small cell lung cancer (NSCLC). The G12V mutation accounts for about 20.7%, while the G12C mutation accounts for approximately 13%.

Currently, there are no approved KRAS G12D inhibitors available on the market globally. This means that the KRAS G12D inhibitor acquired by Bayer this time is highly likely aimed directly at pancreatic cancer, known as the "king of cancers." PDAC is the most common type of pancreatic cancer, accounting for approximately 85% of cases, and currently has almost no treatment options other than chemotherapy, with a five-year survival rate of less than 10%. As the sixth leading cause of cancer-related deaths globally, the incidence of pancreatic cancer continues to rise each year. It is projected that by 2050, new cases will increase by 95.4%, with the total number of new cases worldwide possibly reaching 998,663.

Kumquat Biosciences was founded in 2018 and is supported by OrbiMed, Sequoia Capital, EcoR1, Lilly Asia Ventures, and Roche Venture Fund. It was co-founded by two Chinese-American entrepreneurs, Dr. Yi Liu and Dr. Pinda Ren, a "golden duo" who previously co-founded Wellspring Biosciences, Kura Oncology, and Intellikine (acquired by Takeda in 2012). Tracing back further, they worked together at the Genomics Institute of the Novartis Research Foundation (GNF).

In 2007, Professor Kevan M. Shokat, a member of the National Academy of Sciences of the United States, led the establishment of Intellikine, a drug discovery company focused on the PI3K (phosphoinositide kinase) pathway, and brought three candidate drugs to clinical trials. Duvelisib (also known as Copiktra), a small molecule drug for the treatment of small lymphocytic lymphoma, was approved by the FDA and launched in 2018. Dr. Yi Liu and Dr. Pinda Ren served as the Vice President of Drug Discovery and Vice President of Chemistry of the company, respectively.

Professor Shokat's most renowned work was published in Nature in 2013, where he discovered a hidden groove (binding site) in the KRAS mutant and used a covalent bonding approach to solve the issue of KRAS being an "undruggable" target, paving the way for Amgen's development of LUMAKRAS. His lab utilizes tools such as synthetic organic chemistry, protein engineering, structural biology, biochemistry, and cell biology to focus on discovering novel small-molecule tools and drug candidates targeting protein/lipid kinases, GTPases, and RNA helicases.

Following innovative strategies targeting KRAS mutants, Professor Shokat, Dr. Liu Yi, and Dr. Pingda Ren successively founded Araxes Pharma, Wellspring Biosciences, Kura Oncology, and Kumquat Biosciences to develop covalent inhibitor small molecule drugs targeting KRAS G12C and other KRAS mutants (including KRAS G12D).

When Kumquat was founded, the "golden duo" had already worked together for over fifteen years. The founding team wanted a name that reflected the vitality and unity of its members, so they chose kumquat — revered in many cultures for boosting energy and nutrition, symbolizing longevity, prosperity, and good fortune. In Asian cultures, kumquats are displayed at home and exchanged as gifts during Lunar New Year celebrations to welcome the arrival of spring and the new life it brings. In ancient societies, it was often used in traditional medicine.

In 2021, Kumquat Biosciences reached a collaboration with Eli Lilly involving a $70 million upfront cash payment and equity investment, plus potential payments of up to $2 billion. Under the agreement, Kumquat will leverage its small-molecule immuno-oncology (IO) platform to discover new clinical candidates, and Lilly has the option to select a certain number of candidates for further development and commercialization globally (excluding Greater China). Kumquat retains the rights to develop and commercialize each candidate selected by Lilly in Greater China, but Lilly has the option to co-commercialize in Greater China. Additionally, Kumquat can opt to co-develop and co-commercialize in the U.S. a certain number of candidates chosen by Lilly.

In 2024, Kumquat Biosciences announced an exclusive licensing agreement with Takeda worth $130 million in upfront payments and up to $1.2 billion in potential milestone payments — to co-develop novel immuno-oncology (I/O) small molecule inhibitors for commercialization as monotherapy and/or combination therapies. After completing Phase I clinical trial activities, Kumquat will grant Takeda global development and commercialization rights for the program, with Takeda taking over subsequent development and all commercialization activities.

This form is similar to the recent collaboration with Bayer. Advancing to Phase I/Ia clinical trials not only demonstrates the original developer's strong confidence in their own product but also reflects the partner’s recognition of the Biotech’s early clinical capabilities. The substantial upfront cash payments/equity investments/recent payments in several rounds of cooperation also show the high regard and trust that MNCs have in Kumquat Biosciences.

Bayer's financial report for 2024 shows that the company's global revenue reached 46.606 billion euros, a year-on-year increase of 0.7%. As one of Bayer's core businesses, prescription drugs achieved sales of 18.131 billion euros last year, a year-on-year increase of 3.3%.

"2025 Global Media Day" public information shows that Bayer considers 2025 as its "critical turning point." One reason is that its star anticoagulant product, Xarelto® (rivaroxaban), affected by patent expiration, led to a 14.7% year-on-year decline in sales in 2024. Meanwhile, in 2025, Bayer will launch six products with blockbuster drug potential and accelerate the expansion of indications for existing products in the future.

In the field of oncology, nearly one-third of the new molecular entities in Bayer's R&D pipeline are focused here, covering all stages of clinical development. Bayer is currently advancing the clinical development of multiple innovative and differentiated projects, including oral small molecule tyrosine kinase inhibitors and a Targeted Radiopharmaceutical Therapy (TRT) portfolio. Nubeqa® (darolutamide), a prostate cancer drug, joined the "billion-dollar club" in September 2024, becoming the growth engine of Bayer's oncology pipeline. In January this year, Bayer submitted the third indication application for this drug in China, which will further expand its market coverage in the field of prostate cancer treatment.

In the field of cardiovascular diseases, Bayer is actively expanding its cardiology portfolio. The company has launched Beyonttra® (acoramidis), a drug used to treat transthyretin amyloid cardiomyopathy (ATTR-CM). Additionally, Bayer is researching a novel antithrombotic therapy—Asundexian—aimed at preventing recurrence in ischemic stroke patients receiving standard antiplatelet therapy. Meanwhile, Bayer plans to launch Kerendia® (finerenone), a chronic kidney disease medication, by the end of the year for treating common heart failure.

In the cell and gene therapy (CGT) field, Bayer previously established and expanded its presence in cell and gene therapy through the acquisition of American biopharmaceutical companies AskBio and BlueRock. In 2024, AskBio further collaborated with the Chinese pharmaceutical company Belief BioMed to advance research and explore innovative gene therapy solutions targeting disease areas via liver-directed therapeutic pathways.

In addition to the aforementioned areas, Bayer is also continuously expanding into other fields. For instance, in the field of women's health, Bayer plans to launch elinzanetant, a non-hormonal innovative drug for treating moderate to severe vasomotor symptoms in menopausal women. Stefan Oelrich introduced that this drug is expected to be launched for the first time in 2025, providing menopausal women with a non-hormonal treatment option.

In the field of ophthalmic treatment, EyleaTM 8mg, with its longer treatment intervals, is expected to become the new standard therapy for its approved indications—neovascular (wet) age-related macular degeneration (nAMD) and diabetic macular edema (DME). Currently, the Center for Drug Evaluation of China's National Medical Products Administration is reviewing the relevant study data.

After the expiration of Rivaroxaban's patent, Bayer heavily invested in KRAS G12D inhibitors, hoping to recreate a key oncology engine comparable to Darolutamide. As mentioned earlier, the KRAS G12D inhibitor targets a vast market of advanced solid tumors, including pancreatic cancer and colorectal cancer.

More participants are entering this market.

Among the KRAS G12D inhibitors under research, HRS-4642 developed by Hengrui Medicine is the first domestically produced KRAS G12D inhibitor approved for clinical trials in China. Phase 1 clinical research progress was presented at the 2025 AACR Annual Meeting for the treatment of advanced solid tumors with KRAS G12D mutations. KRAS G12D inhibitors from several innovative pharmaceutical companies, including Jecure Pharma, HaiboWei Pharma, and Junshi Biosciences/ViGEN BioPharma, have also entered the clinical development stage.

In 2023, AstraZeneca made an upfront payment of $24 million and potential payments of up to $395 million for the preclinical small-molecule candidate drug UA022 targeting the KRASG12D mutation developed by YouSen JianHeng, securing a global exclusive licensing agreement.

Reference: VCBeat "Bayer AG's Global President of Prescription Drugs, Stefan Oelrich: Facing Challenges, Strengthening Cooperation, and Continuously Increasing Investment in the Chinese Market"