IDEAYA Biosciences Inks $1.045B Deal with Hengrui for Global Rights to DLL3-Targeting ADC SHR-4849

On December 29, Hengrui Pharma announced that it had granted IDEAYA Biosciences, a U.S. company, an exclusive, paid license for the global development, manufacturing, and commercialization of its innovative Delta-like ligand 3 (DLL3) antibody-drug conjugate (ADC), SHR-4849, excluding the Greater China region.

Under the terms of the agreement, IDEAYA will pay Hengrui Pharma an upfront payment of $75 million, with cumulative R&D milestone payments not exceeding $200 million and cumulative sales milestone payments not exceeding $770 million. The total potential payments under this arrangement could reach $1.045 billion (approximately RMB 7.626 billion). In addition, Hengrui Pharma will receive tiered royalties ranging from low- to mid-double-digit percentages of actual annual net sales.

SHR-4849 is an antibody-drug conjugate (ADC) targeting DLL3, independently developed and owned by Hengrui Pharma. DLL3 is expressed in various solid tumors, including small cell lung cancer and neuroendocrine tumors, but has limited expression in normal tissues. Currently, no DLL3-targeting ADC products have been approved for marketing worldwide.

SHR-4849 Demonstrates Robust Antitumor Activity in Preclinical Models: SHR-4849 exhibits potent antiproliferative activity against various tumor cell lines with moderate to high DLL3 expression. It also demonstrates a significant bystander effect, killing DLL3-low-expressing cells by releasing toxins from the destruction of DLL3-high-expressing cells.

According to Hengrui Pharma’s announcement, the drug is currently undergoing Phase I clinical trials in China for advanced solid tumors. It is in the dose-escalation stage, and clinical responses have been observed in multiple dose cohorts. As of December 10, 2024, a total of 11 patients with small cell lung cancer (SCLC) were evaluable for efficacy at effective doses, among whom 8 achieved partial response (PR), resulting in an overall response rate (ORR) of approximately 73%. No treatment discontinuations due to drug-related adverse events have occurred to date, indicating a manageable safety profile.

Small cell lung cancer (SCLC) accounts for approximately 13%–17% of all lung cancer cases, with a median overall survival of only about one year and a five-year survival rate of merely 7% for patients with advanced-stage disease. Although most patients with extensive-stage SCLC initially respond to first-line therapy, they often experience rapid disease progression and require subsequent treatments, creating an urgent unmet clinical need for second- and third-line therapeutic options. As a highly prevalent malignancy lacking effective treatment modalities, SCLC has long been a key competitive arena for multinational corporations (MNCs). Given its high specificity and well-defined mechanism of action, the target DLL3 has already become a focal point of intense research and development activity:

In April 2016, AbbVie acquired Stemcentrx for $5.8 billion, gaining its antibody-drug conjugate (ADC) Rova-T (rovalpituzumab tesirine) for the treatment of small cell lung cancer (SCLC). Preclinical studies of Rova-T demonstrated superior antitumor efficacy in CDX and PDX models with high DLL3 expression, suggesting that DLL3 could be a promising target for ADCs. However, the development of Rova-T ultimately failed; late-stage clinical data showed an overall response rate of only 18% in SCLC patients, with a median overall survival (OS) of just 5.8 months—only one month longer than that achieved with standard SCLC therapies. Consequently, AbbVie discontinued the development of Rova-T in 2019.

However, the safety and efficacy of antibody-drug conjugate (ADC) therapies depend on numerous factors, including the drug-to-antibody ratio (DAR), the type of cytotoxic payload, and linker stability. Meanwhile, the design and transition from preclinical studies to clinical protocols can also have a significant impact. Although the initial clinical trial of an ADC failed, the evidence from Rova-T was sufficient to propel DLL3 into the top three therapeutic targets for small cell lung cancer (SCLC).

In May 2024, Amgen’s DLL3/CD3 bispecific antibody tarlatamab (Imdelltra) received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of extensive-stage small cell lung cancer (ES-SCLC) with disease progression following platinum-based chemotherapy, becoming the first approved drug targeting DLL3 worldwide. BeiGene holds the commercialization rights in China and has currently initiated a Phase III clinical trial domestically.

Tarlatamab is a bispecific T-cell engager (BiTE) targeting DLL3 and CD3. Phase 2 clinical data showed that among patients evaluable for antitumor activity and survival, the objective response rate (ORR) was 32% in the 100 mg group and 40% in the 10 mg group, whereas the ORR was only 15% in patients with relapsed disease who had previously received standard therapy. The median progression-free survival (PFS) was 4.9 months in the 10 mg group and 3.9 months in the 100 mg group. At 9 months of treatment, the estimated overall survival rates were 68% in the 10 mg group and 66% in the 100 mg group.

The remarkable efficacy has undoubtedly provided a significant boost to the global development of DLL3-targeted therapies, with multiple DLL3 drug deals flourishing worldwide: In April 2023, Zai Lab partnered with Ylian Biopharma to acquire global development and commercialization rights for its DLL3 ADC, YL212, which has currently initiated Phase I clinical trials in the United States. In November, Novartis acquired Legend Biotech’s DLL3 CAR-T therapy, LB2102, in a deal totaling $1.11 billion. Additionally, ABD-147, the world’s first DLL3-targeted radiopharmaceutical, received Investigational New Drug (IND) approval in 2024.

IDEAYA is an oncology precision medicine company dedicated to discovering and developing targeted therapies for patient populations identified through molecular diagnostics. Since its establishment in 2015, IDEAYA has garnered investment from prominent venture capital firms, including 5AM Ventures, Roche Venture Fund, Google Ventures, and WuXi AppTec. The company successfully completed its initial public offering (IPO) in 2021, raising over $300 million.

IDEAYA’s approach integrates the discovery and validation of translational biomarkers with drug development to identify patient populations most likely to benefit from its targeted therapies. IDEAYA is applying its research and drug discovery capabilities to emerging precision medicine targets such as synthetic lethality (SL).

IDEAYA has established a fully integrated synthetic lethality (SL) platform that enables a comprehensive range of research operations, including the discovery of synthetic lethality targets and biomarkers, drug discovery, functional genomics and pharmacological validation, translational research, and opportunity expansion. Leveraging this platform, IDEAYA has currently developed multiple pipeline candidates in various stages of investigation.

On July 31, IDEAYA entered into an agreement with Biocytogen to acquire the global exclusive option to license a bispecific antibody-drug conjugate (BsADC) featuring a first-in-class B7-H3/PTK7 topoisomerase inhibitor payload, with a potential total transaction value of up to $406.5 million.

Behind the collaboration worth over $1.5 billion lies IDEAYA’s search for combination partners for its multiple pipeline candidates in development.

Among these, IDE161, one of the core pipeline candidates, is a selective PARG inhibitor indicated for the treatment of adult patients with advanced or metastatic hormone receptor-positive (HR+) homologous recombination deficiency (HRD) solid tumors. Due to its favorable efficacy, IDEAYA has been granted Fast Track designation by the FDA, which also specifies its potential use in treating breast and ovarian cancer patients harboring BRCA1/2 mutations.

Yujiro S. Hata, Chairman and CEO of IDEAYA, stated, “As a monotherapy, IDE161 has demonstrated promising therapeutic efficacy in diseases such as endometrial cancer and colorectal cancer; however, combination therapy will unlock additional indications.” To this end, IDEAYA has been actively seeking molecules to pair with IDE161.

Previously released data showed that in preclinical lung cancer models, the combination of a topoisomerase I inhibitor (TOPOi) payload and IDE161 elicited a stronger response than either molecule used alone. Consequently, IDEAYA made two strategic moves in China, acquiring rights to two antibody-drug conjugates (ADCs) with TOPOi payloads: Biocytogen’s B7H3/PTK7 bispecific ADC BCG034 and Hengrui Pharma’s DLL3 ADC SHR-4849, which is the subject of this transaction.

Meanwhile, IDEAYA has also entered into R&D and clinical collaborations with multiple multinational corporations (MNCs) to explore the potential of combination therapies:

Partnered with Pfizer to evaluate the efficacy and safety of the combination therapy of IDE196 and Crizotinib for the treatment of uveal melanoma harboring GNAQ/GNA11 mutations; partnered with Amgen to assess the combination efficacy and safety of IDE397 (a MAT2A inhibitor) and AMG 193 (a small-molecule PRMT5 inhibitor) as a combination therapy in patients with MTAP-deleted solid tumors.

Strategic partnership with GSK, focusing on IDEAYA’s three synthetic lethality R&D projects targeting MAT2A, Polθ, and Werner helicase, while exploring potential collaborations between both parties’ R&D portfolios. Under this transaction, IDEAYA received a $100 million upfront cash payment and a $20 million equity investment.

ADCs are one of the key focus areas in Hengrui Pharma’s innovative drug pipeline.

Leveraging its modular ADC innovation platform (HRMAP), Hengrui Pharma has successfully obtained clinical trial approvals for 12 novel and differentiated ADC molecules, including SHR-4849. Among these, the HER2-targeting ADC SHR-A1811 (ruankang trastuzumab) has entered the marketing application stage, three products are in Phase III clinical trials, and six products are being developed synchronously on a global scale. Additionally, multiple innovative drug candidates are being deployed across various therapeutic areas for solid tumors.

From the perspective of target portfolio layout, in addition to common targets such as HER2, TROP2, CLDN18.2, and c-MET, Hengrui Pharma has also established pipelines for relatively untapped (“blue ocean”) targets, including the DLL3 ADC involved in this transaction, as well as PSMA ADC and LIV-1 ADC.

However, Hengrui Pharma’s previous license-out deals have primarily involved small-molecule drugs and antibody therapies, with only two ADC transactions (including the current collaboration with IDEAYA), both of which were significant high-value agreements. In October 2023, Merck secured global rights outside China for the PARP inhibitor HRS-1167 and the novel Claudin18.2 ADC SHR-A1904, with an upfront payment of €160 million and a potential total value of €1.415 billion, along with an option for co-commercialization in China.

With a strong precedent set, SHR-A1904 marks not only Hengrui Pharma’s first license-out deal with a multinational corporation (MNC) but also its inaugural foray into the global ADC market. A Phase III clinical trial for gastric cancer is currently underway in China, with Phase I data showing an objective response rate (ORR) of 55.6% and a disease control rate (DCR) of 88.9%.

Overall, Hengrui Pharma’s portfolio of innovative target-directed antibody-drug conjugates (ADCs) shares several common characteristics: a favorable global competitive landscape, with most candidates in the investigational new drug (IND) application or early clinical development stages; existing data and evidence of efficacy for the targeted antigens; a focus on indications with unmet clinical needs, such as small cell lung cancer and metastatic triple-negative breast cancer; prior engagement or strategic plans by multinational corporations (MNCs) or global ADC leaders in these areas; and leveraging the broad potential for ADC-based combination therapies.

Betting on “dark horse” targets, Hengrui Pharma’s ADC overseas expansion has successfully established dual pathways through both MNCs and star biotechs.

Furthermore, Hengrui Pharma has four ADC products granted Fast Track designation by the FDA, with clinical trials underway in multiple countries worldwide: SHR-A2009 (HER3 ADC), SHR-A2102 (Nectin-4 ADC), SHR-A1912 (CD79b ADC), and SHR-A1921 (TROP-2 ADC).

References:

VCBeat – IDEAYA Develops Novel Synthetic Lethality Cancer Therapies, Secures Over $300 Million in Total Funding and Partners with MNCs Including Amgen and GSK

VCBeat News – $2.93 Billion! Another Chinese Bispecific Antibody ADC Goes Global

VBInsight Database – Hengrui’s Three Breakthrough ADCs Also Show Potential for Global Expansion!