At the beginning of the new year, Innovent Biologics brought the first good news of going overseas. Recently, Innovent Biologics and Roche reached a global exclusive cooperation and licensing agreement on the new generation of DLL3 antibody-drug conjugates. Innovent Biologics granted Roche the exclusive rights to the global development, production and commercialization of IBI3009. The two parties will jointly be responsible for the early development of the ADC candidate drug, and Roche will be responsible for subsequent clinical development. Innovent Biologics will receive a total transaction amount of US$1.08 billion (including an initial payment of US$80 million and potential development and commercialization milestone payments of up to US$1 billion, as well as sales commissions).

Just a few days ago, Hengrui Medicine also reached a licensing cooperation for DLL3 ADC drugs. Hengrui Medicine licensed the overseas rights of SHR-4849 to IDEAYA Biosciences of the United States for a total amount of over US$1 billion.

DLL3 is a highly anticipated tumor immunotherapy target. It is expressed in a variety of solid tumors, especially in 80% of small cell lung cancer (SCLC) patients. It is expressed in small amounts or even not expressed in normal tissues, which provides a better solution for targeted therapy. In recent years, BD transactions around the DLL3 target have gradually heated up, and pharmaceutical giants such as Merck and Novartis have invested heavily in strategic layout. The enthusiasm for DLL3 drug research and development continues to heat up.

Potential best in class

Innovent Biologics said that the partnership with Roche is based on Roche's innovation in the ADC field to promote the research and development of IBI3009 in the treatment of small cell lung cancer and provide new treatment options for SCLC patients around the world. Innovent Biologics' official website stated that IBI3009 is a potential best-in-class DLL3 ADC candidate drug.

IBI3009 is designed and developed based on Innovent Biologics' proprietary novel topoisomerase I inhibitor (TOPO1i) platform. Preclinical data showed that IBI3009 exhibited encouraging anti-tumor activity in multiple tumor burden mouse models (especially in chemotherapy-resistant tumor types) and had a good safety profile.

On December 13, 2024, Innovent Biologics registered a Phase I clinical trial of IBI3009 for the treatment of small cell lung cancer and other neuroendocrine tumors on the Drug Clinical Trial Registration and Information Disclosure Platform. According to the registration information, the relationship between tumor DLL3 and SLFN11 expression levels and efficacy was explored. Referring to public information, according to the baseline data of patients in the SWOG S1929 study, the positive rate of SLFN11 in ES-SCLC patients was approximately 79%. SCLC-A is the most common subtype in SCLC patients, and there is a bimodal expression of SLFN11. DLL3 is also the highest expressed in SCLC-A, which can be used as a candidate therapeutic target. Therefore, Innovent selected SLFN11 as a biomarker.

Currently, IBI3009 has obtained clinical application (IND) approval in Australia, China and the United States, and the first patient in the Phase I clinical study will be dosed in December 2024.

According to the official website of Innovent Biologics, the company has also deployed DLL3/CD3 dual antibody IBI115.

Small cell lung cancer is an invasive, high-grade neuroendocrine cancer, accounting for 13%-15% of lung cancer diagnoses each year. Patients with small cell lung cancer have a poor prognosis, with a 5-year survival rate ranging from 27% for localized disease to 3% for metastatic disease. For limited-stage SCLC, surgical resection, adjuvant radiotherapy, and adjuvant chemotherapy are still common treatments. For extensive-stage SCLC, immunotherapy combined with chemotherapy is the first-line standard treatment; second-line treatment uses chemotherapy regimens such as irinotecan and rubitidin as standard treatment.

DLL3 is a member of the Notch ligand family and plays an important regulatory role in embryonic development, nervous system development, and cell differentiation. In the field of tumors, DLL3 is highly expressed in a variety of solid tumors, especially on the surface of about 80% of tumor cells of neuroendocrine origin such as small cell lung cancer, melanoma, glioblastoma multiforme, and small cell bladder cancer, and is transported to the cell membrane, making this target an ideal tumor treatment target.

At present, a number of DLL3 targeted drugs have entered the clinical research stage, and the indications are mainly small cell lung cancer and other neuroendocrine tumors. The types of drugs include bispecific/trispecific, ADC and other therapies. The fastest clinical progress is Amgen's CD3/DLL3 bispecific antibody Tarlatamab, which has been approved for marketing; the rest of the pipelines are in clinical phase II and before. Boehringer Ingelheim's CD3/DLL3 bispecific, Merck's CD3/DLL3/Albumin trispecific, and Zelgen Pharmaceuticals' CD3/DLL3/DLL3 trispecific are progressing faster. The products of Zai Lab, Zhangjiang Biopharma, Innovent Biologics and Baili Tianheng that have made faster progress in DLL3 ADC have all entered phase I clinical trials.

Tarlatamab is a potential first-in-class bispecific T cell adaptor (BiTE) targeting DLL3 and CD3. It was approved by the FDA in May 2024 for the treatment of extensive-stage SCLC that progresses during or after platinum chemotherapy. It is also the first DLL3-targeted TCE bispecific approved for the treatment of SCLC.

Data from the pivotal Phase II DeLLphi-301 study supporting the approval of Tarlatamab showed that Tarlatamab demonstrated excellent therapeutic efficacy: nearly 40% of trial participants had significantly reduced or even completely disappeared tumors, an objective response rate (ORR) of 40%, and the average duration of response was as long as 9.7 months. Later, in the updated DeLLphi-301 study results in September 2024: After receiving Tarlatamab treatment, a total of 72% of patients had tumor shrinkage; the disease control rate (DCR) was 70%.

The key clinical data and approval of Tarlatamab have brought important treatment breakthroughs for patients with small cell lung cancer, especially when traditional therapies are ineffective, providing patients with new treatment options and hope.

Zai Lab's ZL-1310 is an ADC candidate drug targeting DLL3. The drug uses a topoisomerase I inhibitor camptothecin derivative as a toxin and selects a protease-cleavable tripeptide as a linker, with a DAR value of 8. The product was first developed by Yilian Biopharmaceuticals. In April 2023, Zai Lab and Yilian Biopharmaceuticals reached a strategic cooperation and obtained all subsequent global clinical development and commercialization rights of ZL-1310. Currently, the product has entered the clinical phase I stage.

At the 2024ENA conference, Zai Lab orally reported the latest global phase 1a clinical data of ZL-1310. This clinical trial includes the results of 25 patients, of which 19 patients had evaluable tumor results. In terms of effectiveness, the ORR of patients who received at least one post-treatment evaluation was 74% (95%CI, 48.8, 90.9); ZL-1310 showed anti-tumor activity at all dose levels; patients with a DLL3 H-Score score greater than 5 (range: 5 to 260) showed tumor remission. In terms of safety, ZL-1310 is well tolerated at all dose levels, with most treatment-emergent adverse events (TEAEs) being grade 1 or 2, and grade 3 and above TRAEs being approximately 20%. Dose-limiting toxicity (DLT) was observed in the 2.4 mg/kg dose group.

Zai Lab plans to advance ZL-1310 into clinical trials for first-line/second-line SCLC and other DLL3-highly expressed tumors. ZL-1310 combined with platinum drugs and atezolizumab for the treatment of first-line SCLC is expected to enter the dose-escalation clinical trial phase in 2025.

ZG006 for injection is a trispecific antibody targeting CD3 and two different DLL3 epitopes developed by Zelgen Pharmaceuticals and its subsidiary Gensun Biopharma through its bi/multispecific antibody research and development platform. The product has been granted orphan drug designation by the U.S. FDA. ZG006 is the world's first trispecific antibody (CD3×DLL3×DLL3) targeting DLL3-expressing tumors, and is the world's first-of-its-kind molecular form. The anti-DLL3 end of ZG006 binds to different DLL3 epitopes on the surface of tumor cells, and the anti-CD3 end binds to T cells. ZG006 is currently in the second phase of clinical trials for third-line SCLC in China, and the United States has approved IND in April 2023.

Zelgen Pharmaceuticals is conducting a phase 1/2 clinical study of dose escalation and multi-cohort expansion of ZG006 in patients with advanced small cell lung cancer or neuroendocrine cancer for tolerability, safety, efficacy and pharmacokinetics. Preliminary research data showed that among 21 subjects with small cell lung cancer whose efficacy could be evaluated, 7 achieved partial remission (PR), 5 had stable disease (SD), and 4 of them were shrunken SD. Among the 9 SCLC subjects who received ZG006 10 mg and higher, the ORR was about 66.7% and the DCR was about 8.9%. ZG006 has excellent overall safety, and the severity of the vast majority of treatment-related adverse events in the 24 subjects was grade 1 or 2. The most common TRAEs were fever, anemia, and CRS, of which only one was grade 3 CRS.

From the perspective of BD, blockbuster BD transactions in the DLL3 field have frequently occurred, and pharmaceutical giants have spent a lot of money to purchase related assets. According to incomplete statistics, there have been 8 related transactions since November 2023, of which nearly half have a transaction value of more than US$1 billion. MNCs such as Merck, Novartis, and Roche are accelerating their layout.

In order to narrow the gap with multinational pharmaceutical companies, BeiGene, the "innovative drug leader", has been deploying the DLL3 field very early. In 2019, BeiGene reached a cooperation with Amgen and introduced Amgen's Tarlatamab through license-in. Currently, the drug has started phase III clinical research in China.

In 2016, AbbVie acquired Rova-T, a DLL3 ADC product in the Stemcentrx pipeline that was still in phase II clinical trials at the time, for US$5.8 billion, setting a record for the largest BD transaction in the DLL3 field. This product is the first DLL3 targeted drug to enter the clinic. Early clinical research data released by AbbVie showed that the total response rate of Rova-T was only 18%, and the median survival time was only 5.8 months, which was only one month longer than the standard treatment for SCLC. In subsequent clinical studies, Rova-T still failed to achieve the expected therapeutic effect. So AbbVie announced the suspension of all Rova-T development.

Novartis accelerated its layout in the DLL3 field, introducing Legend Biotech's DLL3 CAR-T and Mariana Oncology's DLL3 targeted peptide nuclear medicine with a total transaction amount of US$1.11 billion and US$1.75 billion respectively, and continued to deploy products related to the DLL3 field.

Merck acquired Harpoon Therapeutics for a total equity value of US$680 million in January 2024. The main purpose of this acquisition was to acquire a DLL3/CD3/Albumin triple antibody HPN328. HPN328 Phase 1/2 study data for patients with prostate neuroendocrine tumors and other neuroendocrine tumors showed that among patients with evaluable efficacy in the dose-optimized group, the confirmed ORR in SCLC was 50% (12/24), including 1 complete remission (CR).
Table 1 Major BD transactions in the DLL3 field

DLL3 is a highly anticipated target in the field of tumor treatment. The target is highly concentrated on the surface of tumor cells such as small cell lung cancer, providing possibilities for targeted therapy. Although AbbVie's first DLL3 ADC drug Rova-T failed in development, there was a sudden turn. In 2024, Amgen's CD3/DLL3 dual antibody Tarlatamab was approved for marketing, Zai Lab's DLL3 ADC also began to show its edge, and Zelgen Pharmaceuticals' CD3/DLL3/DLL3 triple antibody early development data showed excellent efficacy. The relevant products of Innovent Biologics and Hengrui Medicine are expected to be rapidly developed through overseas authorization. The development of DLL3 targeted drugs continues to heat up, which is expected to bring new treatment options to cancer patients.

https://news.yaozh.com/archive/44775.html