Global First-in-Class HER3 ADC Nears Market Launch as Chinese Innovators Secure Over $9 Billion in Global Out-Licensing Deals

HER3It is expressed in a variety of solid tumors, including breast cancer, lung cancer, etc.,HER3Overexpression and Non-Small Cell Lung Cancer (NSCLC) are closely related to the metastasis of cancer cells, poor prognosis, and the reduction in patient survival rates.。HER3The signaling pathway has been scientifically confirmed to be associated with anti-EGFR/HER2The drug resistance mechanism of the therapy is closely linked. This discovery provides new therapeutic insights for combating non-small cell lung cancer, makingHER3Becoming a TreatmentHighly promising for solid tumors such as non-small cell lung cancerTarget, has already attracted numerous pharmaceutical companies to enter the race and compete for the market.。

In the global competitive landscape of HER3 ADC,Daiichi Sankyo's HER3-DXd Has Submitted for Marketing Approval, Poised to Cross the Finish Line First, breaking the dilemma that HER3 is difficult to target due to the lack of significant kinase activity.Endeavor BioMedicinesRecently completed a $132.5 million Series C financing, with part of the funds to be used to advance the clinical proof-of-concept study of ENV-501, an ADC candidate drug targeting HER3.

The performance of innovative enterprises in China is particularly active,Baili Tianheng、Hengrui Medicine, Innovent Biologics, Duality Biologics,Yilian BiologicsCompanies are making frequent progress. Excellent technical platforms become the sails for going overseas,YL202 from Yilian Bio goes overseas to BioNTech, HER3/EGFR ADC from Baili Tianheng goes overseas to BMS, with a potential total cooperation amount exceeding 9 billion US dollars.Emerging targets are being explored by companies both in China and abroad.HER3The vast blue ocean.

At the end of last year,Daiichi Sankyo/MerckAnnouncementU.S. FDAAccepted the Biologics License Application for their developed HER3 ADC candidate product HER3-DXd (U3-1402) and granted it Priority Review status for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who have previously received two or more systemic therapies. The FDA's Prescription Drug User Fee Act (PDUFA) date is set for June 26, 2024.HER3-DXd is expected to become the world's first approved innovative therapy targeting the HER3 pathway.。

This HER3 ADC was developed by Daiichi Sankyo using its proprietary DXd ADC technology. It is composed of a fully humanized anti-HER3 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload (a derivative of exatecan, DXd) via a cleavable tetrapeptide linker. In October 2023,Daiichi Sankyo and Merck Reach $22 Billion Global Collaboration, jointly develop and commercialize three new ADC drugs, including HER3-DXd.

Recently, Endeavor BioMedicines announced the successful completion of a $132.5 million Series C financing round. The proceeds will be used to advance the clinical development of its investigational small-molecule therapy ENV-101 for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). Additionally, the funds will support the clinical proof-of-concept study of ENV-501 for HER3-positive solid tumors.ENV-501 is a next-generation ADC targeting HER3, combining advanced chemical and genetic properties to optimize drug delivery to tumors, thereby enhancing its efficacy and reducing off-target toxicity.Endeavor plans to launch the Phase 1/2 clinical trial of ENV-501 in 2024.

SystImmune, a wholly-owned subsidiary of Baili Tianheng, developedBL-B01D1 is the world's first EGFR/HER3Bispecific antibodyADC, whose monotherapy for end-stage nasopharyngeal carcinoma and second-line esophageal squamous cell carcinoma has entered Phase III clinical trials.Clinical development progress is second only to Daiichi Sankyo and Merck's HER3-DXdBL-B01D1 adopts an enzymatically cleavable linker, with the payload being TOP I, a camptothecin derivative ED04 independently developed by Baili Tianheng, and the DAR value is 8. In terms of mechanism of action, due to its unique structural characteristics,SI-B001 does not directly bind to HER3, thereby avoiding the inhibition of molecules on targets that maintain normal physiological functions. The drug has low toxic and side effects, which is expected to bring a wider therapeutic window.

At the 2023 ASCO Conference, Baili Tianhe updated the progress of BL-B01D1 in nasopharyngeal carcinoma, with a total of 28 subjects with nasopharyngeal carcinoma who had undergone at least one efficacy evaluation.Objective Response Rate (ORR) was 53.6%, and Disease Control Rate (DCR) was 100%.In December 2023, Baili Tianheng partnered with BMS for over $8 billion to develop and commercialize BL-B01D1. On March 11 this year, Baili Tianheng received the first payment of $800 million.

SHR-A2009 is an ADC independently developed by Hengrui Medicine targeting HER3,Can specifically bind to HER3 on the surface of tumor cells, and then be internalized into the cells and transported to lysosomes, where it is hydrolyzed to release free toxins.At the beginning of this year, SHR-A2009 was granted Fast Track designation by the U.S. FDA for the treatment of metastatic NSCLC with EGFR mutations whose disease has progressed after third-generation EGFR-TKI and platinum-based chemotherapy. This makes it the first innovative drug in Hengrui Medicine's history to receive U.S. FDA Fast Track designation. Previously, the clinical trial application for SHR-A2009 as a monotherapy for the treatment of advanced/metastatic solid tumors had received dual approval from both China and the United States.

On April 15 this year, the clinical trial application for IBI133, a HER3 ADC candidate product developed by Innovent Biologics, received implied approval. It is reported that IBI133 has already initiated a Phase 1/2 clinical trial (NCT06170190) in Australia last December, targeting patients with solid tumors.

DB-1310 is an ADC product targeting HER3 developed by DualityBio based on its DITAC technology platform. It consists of a novel humanized anti-Her3 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor via a cleavable maleimide linker, with a DAR value of approximately 8. In May 2023, the clinical trial application for DB-1310 was accepted by the CDE for the treatment of advanced/metastatic solid tumors and is currently in Phase 1/2 clinical trials. It demonstrated excellent tumor inhibition effects and safety in preclinical studies.Demonstrated excellent synergistic tumor inhibition effects when combined with EGFR small molecule inhibitors.

YL202, a novel ADC candidate drug targeting HER3 developed by MedLink Biotech, has also gained significant favor from global pharmaceutical giants.In October 2023, Yilian Biotech announced a collaboration agreement with BioNTech,Granting BioNTech Global Rights Outside Greater China for YL202。This transaction will pay a $70 million upfront payment, along with additional development, regulatory, and commercialization milestone payments.The potential total amount exceeds 1 billion US dollars.

The ADC Platform Technology TMALIN Developed by Yilian BiotechnologyWhile achieving high DAR value uniformity and stable conjugation, further broaden the therapeutic window of ADC drugs and enhance their efficacy in treating solid tumors.Non-clinical studies have shown that YL202 mediates effective tumor-killing effects. In vivo pharmacodynamic (PD) studies have demonstrated that YL202 exhibits dose-dependent anti-tumor activity in both human tumor cell xenograft models and human tumor xenograft models expressing HER3. Currently, YL202 has completed Phase 1 clinical trials in patients with advanced non-small cell lung cancer and breast cancer, and future research will explore its potential in prostate cancer and esophageal squamous cell carcinoma indications.

On February 27 this year, MultitudeTherapeutics' ADC candidate AMT-562 targeting HER3 was approved for clinical trials for the treatment of advanced solid tumors. AMT-562 consists of a novel anti-HER3 antibody Ab562, a hydrophilicity-enhanced linker MC-VA-PABC, and the payload exatecan.The antibody portion Ab562 has the potential to reduce potential toxicity and improve tumor penetration; the payload exatecan has higher cytotoxic potency than its derivative deruxtecan (DXd).. A phase 1 clinical study targeting advanced solid tumors is currently underway in Australia. The study shows that AMT-562 has the potential to become a HER3-targeted ADC with a wider therapeutic window, capable of overcoming drug resistance.

On September 18, 2023, SIBP-A13, a HER3-targeted ADC new drug independently developed by Shanghai Institute of Biological Products, China National Pharmaceutical Group (Sinopharm), received clinical trial approval from the NMPA, and is planned to be used in clinical trials for patients with advanced malignant solid tumors.

SIBP-A13 is based on the third-generation ADC technology developed in China.With advantages such as cleavable linkers, potent payload activity, and anti-tumor "bystander effect"SIBP-A13 efficacy study data shows that it can effectively inhibit the growth of various tumors and has therapeutic potential for multiple solid tumors such as lung cancer and breast cancer. Preclinical pharmacokinetic and toxicology studies indicate that SIBP-A13 demonstrates good stability in animals, with significantly lower levels of free small molecules compared to similar products, showing favorable safety and tolerability.

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