Zymeworks Begins Phase 1 Trial of ZW171 for Advanced Mesothelin Cancers

Zymeworks Inc., a clinical-stage biotechnology entity listed on Nasdaq, has initiated its first-in-human Phase 1 trial for the investigational therapy ZW171. This therapy aims to treat advanced or metastatic ovarian cancer, non-small cell lung cancer (NSCLC), and other cancers expressing mesothelin (MSLN). The trial, with the identifier NCT06523803, focuses on assessing the safety and tolerability of ZW171.

Mesothelin is highly expressed in a variety of tumors, notably ovarian cancer (~84%) and moderately to strongly in NSCLC (~36%). These percentages make MSLN an attractive target for treatment development using Zymeworks' proprietary T cell engager technology. Preclinical studies have highlighted ZW171's ability to selectively target and destroy MSLN-overexpressing cells while activating T cells dependent on MSLN, reducing the risk of on-target, off-tumor toxicity, and peripheral T cell activation, as well as cytokine release syndrome.

At the 2023 American Association for Cancer Research Annual Meeting, data revealed that ZW171 outperformed benchmarks in tumor models expressing MSLN and was well tolerated in cynomolgus monkeys up to doses of 30 mg/kg.

Dr. Jeff Smith, Executive Vice President and Chief Medical Officer at Zymeworks, expressed satisfaction with the initiation of the clinical evaluation of ZW171 for ovarian cancer and NSCLC. He highlighted the therapy's potential effectiveness and favorable tolerability based on preclinical results. This trial is a significant milestone in the effort to provide new treatments for difficult-to-treat cancers. Dr. Smith also mentioned the company's ambition to advance two therapeutic candidates, ZW171 and ZW191, into clinical studies within the year.

The Phase 1 study will enroll around 160 adult patients with advanced MSLN-expressing cancers. It will be conducted in two parts. Part 1 will focus on evaluating the safety and tolerability of ZW171 through dose escalation in patients with advanced ovarian cancer and NSCLC. Secondary endpoints will include pharmacokinetics and confirmed objective response rate. Part 2 will involve dose expansion across three cohorts—ovarian cancer, NSCLC, and a basket cohort comprising patients with any MSLN-expression. This part will assess the anti-tumor activity of ZW171, with primary endpoints centered on safety and tolerability, and secondary endpoints on progression-free survival, duration of response rates, and overall survival.

Zymeworks plans to conduct the study at various investigator sites located in the United States, Europe, and the Asia-Pacific region. Dr. Smith noted the growing interest in ZW171, which he believes offers a promising and unique approach to treating advanced mesothelin-expressing cancers. The trial is designed to quickly generate clinical data to establish ZW171's differentiated product profile compared to other mesothelin-expressing therapeutics currently in development.

ZW171 is a bispecific antibody that promotes T cell-mediated tumor cell killing by binding both to the extracellular domain of the MSLN protein on tumor cells and to CD3 on T cells. High levels of MSLN expression are common in ovarian cancer, NSCLC, mesothelioma, and other cancers. The unique design of ZW171, including a novel low-affinity anti-CD3 binder, aims to improve the therapeutic window by minimizing on-target, off-tumor effects and cytokine release syndrome while maintaining potent anti-tumor activity. This selective binding to tumors aims to enhance tolerability and anti-tumor activity against MSLN-expressing cancers. Preclinical models have shown that ZW171 induces potent, preferential killing of MSLN-overexpressing cells while reducing the risk of on-target, off-tumor activity, peripheral T cell activation, and cytokine release syndrome.

Zymeworks is committed to discovering, developing, and commercializing novel biotherapeutics to make a significant impact on the lives of people affected by difficult-to-treat cancers and other diseases. The company’s therapeutic platforms and drug development engine enable the precise engineering and development of highly differentiated antibody-based therapeutic candidates. Zymeworks' pipeline includes ZW171 and ZW191, and the company is actively recruiting for Phase 1 studies. Additionally, Zymeworks' platforms have been leveraged through partnerships with global biopharmaceutical companies.