News
Release date:2024/12/5 23:00:56

On December 4, 2024, Merus announced that the FDA has approved its HER2/HER3 bispecific antibody, Zenocutuzumab (Bizengri), for the treatment of adults with advanced, unresectable, or metastatic non–small cell lung cancer (NSCLC) or pancreatic ductal adenocarcinoma (PDAC)  harboring a neuregulin 1 (NRG1) gene fusion who had disease progression on or after prior systemic therapy.

This groundbreaking approval makes Zenocutuzumab the first HER3-targeting antibody to reach the market and the 13th bispecific antibody approved by the FDA.

NRG1 is a ligand that binds to human epidermal growth factor receptor (HER) 3, promoting HER2/HER3 heterodimerization and oncogenesis, which drives tumor growth. NRG1 gene fusions are rare but potent oncogenic genomic events observed in specific cancer types, including NSCLC and PDAC. However, treatment options for patients with NRG1 fusion-positive (NRG1+) cancers are extremely limited.

Zenocutuzumab is a bispecific antibody designed to target the extracellular domains of HER2 and HER3, inhibiting the formation of HER2/HER3 dimers and preventing NRG1 from binding to HER3. This mechanism suppresses cell proliferation and the PI3K-AKT-mTOR signaling pathway. Additionally, Zenocutuzumab enhances antibody-dependent cellular cytotoxicity (ADCC), offering a multifaceted approach to combating tumor growth.

Zenocutuzumab

Figure 1. Structure of Zenocutumab, image source: Merus official website

The approval of Zenocutuzumab is based on data from the eNRGy trial, a multicenter, open-label Phase I/II clinical study that enrolled patients with advanced, unresectable, or metastatic NRG1+ PDAC or NRG1+ NSCLC.

In the NRG1+ PDAC cohort (n=30), Zenocutuzumab demonstrated an overall response rate (ORR) of 40%, with response durations ranging from 3.7 months to 16.6 months. Among NRG1+ NSCLC patients (n=64), the treatment achieved an ORR of 33%, with a median response duration of 7.4 months.

About HER3

HER3, a member of the HER family, was discovered over 30 years ago in 1989. Research has shown that HER3 is highly expressed in multiple cancer types and is closely linked to tumor metastasis and disease progression, making it a promising oncology target. However, due to its extremely weak intracellular tyrosine kinase activity, HER3 has historically posed challenges for drug development. Efforts to create HER3-targeting monoclonal antibodies have largely failed, casting doubt on the viability of HER3 as a drug target. Recent advances in technologies like antibody-drug conjugates (ADCs) and bispecific antibodies, however, have significantly improved HER3's druggability.

In fact, the first HER3-targeted therapy to reach approval was expected to be HER3-DXd, developed by Daiichi Sankyo and Merck. On December 22, 2023, the FDA accepted the Biologics License Application (BLA) for HER3-DXd based on data from the Phase II HERTHENA-Lung01 trial, granting it priority review with a PDUFA target date of June 26, 2024. However, due to issues with a third-party manufacturing facility, the FDA issued a Complete Response Letter (CRL) on the PDUFA date, temporarily declining approval.

Figure 2. Stucture of HER3-DXd

HER3-DXd is designed using  Daiichi Sankyo's proprietary DXd ADC technology, combining a fully human anti-HER3 IgG1 monoclonal antibody, a cleavable tetrapeptide linker, and a topoisomerase I inhibitor. In October 2023, Merck entered into a collaboration agreement with Daiichi Sankyo, securing global rights (excluding Japan) to develop and commercialize HER3-DXd and two other ADC products for a total transaction value of $22 billion.

The approval of Zenocutuzumab marks a significant milestone and opens the door for more HER3-targeted therapies to follow. As several companies make rapid progress in this area, the landscape of HER3 treatments is becoming more diverse, offering new possibilities and hope for patients.

References:
[1] https://ir.merus.nl/news-releases/news-release-details/merus-announces-fda-approval-bizengrir-zenocutuzumab-zbco-nrg1 Merus Announces FDA Approval of BIZENGRI® (zenocutuzumab-zbco) for NRG1+ Pancreatic Adenocarcinoma and NRG1+ Non–Small Cell Lung Cancer (NSCLC) Based on Safety and Efficacy Data From the eNRGy Study
[2] https://www.merck.com/news/patritumab-deruxtecan-bla-submission-receives-complete-response-letter-from-fda-due-to-inspection-findings-at-third-party-manufacturer/ Patritumab Deruxtecan BLA Submission Receives Complete Response Letter from FDA Due to Inspection Findings at Third-Party Manufacturer

Previous:Targeted Therapies for Systemic Lupus Erythematosus (SLE) Next:Small Nucleic Acid Drugs Expected to Be Approved by 2025
Top