Zymeworks Discontinues Cancer Therapy ZW171 Due to Lack of Benefit-Risk Profile

Zymeworks has discontinued clinical development of ZW171, a cancer therapy, due to a lack of benefit-risk profile consistent with the desired monotherapy target product profile. The decision was based on the completion of the planned cohorts of the Phase 1 trial of ZW171 in patients with ovarian cancer and non-small cell lung cancer. Ongoing participants will continue treatment at the discretion of their investigator.

Zymeworks Inc. (Nasdaq: ZYME), a clinical-stage biotechnology company, has announced the discontinuation of clinical development for ZW171, a T cell engager targeting mesothelin-driven cancers. The decision follows the completion of Phase 1 trial dose escalation cohorts in ovarian cancer and non-small cell lung cancer patients [1].

While the trial revealed manageable cytokine release syndrome, dose-limiting toxicities related to mesothelin-targeted effects were identified. These toxicities were deemed inconsistent with the desired benefit-risk profile, leading to the discontinuation of further development [1].

Zymeworks determined that the trial results indicated an unfavorable benefit-risk profile due to dose-limiting toxicities consistent with mesothelin-related on-target off-tumor effects. This highlights a common challenge with mesothelin as a target, as it is expressed not only on tumor cells but also on normal mesothelial cells lining the pleura, peritoneum, and pericardium [1].

Current trial participants may continue treatment at their investigator's discretion. Zymeworks continues to advance other pipeline candidates, including the ongoing Phase 1 trial of ZW191, planned Phase 1 study for ZW251 in 2025, and an IND filing for ZW209 in early 2026 [1].

The discontinuation of ZW171 represents a significant setback in Zymeworks' oncology pipeline. The company is redirecting resources to more promising candidates, including ZW191 (currently in Phase 1), ZW251 (Phase 1 expected in 2025), and ZW209 (IND filing planned for early 2026) [1].

This decision underscores the "fail fast" principle in biotechnology, where resources are redirected to more promising candidates. The disconnect between preclinical activity and clinical reality with ZW171 also reinforces the limitations of preclinical models in predicting human toxicity profiles, particularly for novel modalities like T cell engagers [1].

Zymeworks remains committed to advancing its broader product pipeline, including the ongoing Phase 1 trial of ZW191 and the initiation of a Phase 1 study for ZW251 expected in 2025. The company is also preparing an IND filing for ZW209, a DLL3-directed trispecific T cell engager, planned in the first half of 2026 [1].

References:

[1] https://www.stocktitan.net/news/ZYME/zymeworks-announces-decision-to-discontinue-clinical-development-of-qezs3habk5i6.html