Zymeworks halts ZW171 clinical trial due to challenging target.

Zymeworks has decided to discontinue clinical development of ZW171, a T cell engager targeting cancers driven by mesothelin. The decision is based on completion of the planned cohorts of the Phase 1 trial in ovarian cancer and non-small cell lung cancer, and after establishing a maximum tolerated dose.

Zymeworks Inc. (Nasdaq: ZYME) 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 cytokine release syndrome was manageable, the trial revealed dose-limiting toxicities related to mesothelin-targeted effects. The company determined that further dose evaluation would not support a favorable benefit-risk profile. 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. Zymeworks discontinues ZW171 cancer program due to safety concerns despite completing Phase 1 dose escalation, focusing resources on other pipeline candidates. The termination came after completing the planned dose escalation portion of the Phase 1 trial and establishing a maximum tolerated dose. The critical issue identified was 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—it's expressed not only on tumor cells but also on normal mesothelial cells lining the pleura, peritoneum, and pericardium. While cytokine release syndrome was manageable, the off-target toxicity created an insurmountable safety hurdle. From a development perspective, this outcome illustrates the "fail fast" principle in biotechnology. Rather than continuing investment in a compound with fundamental safety limitations, Zymeworks 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).

This portfolio management approach, while disappointing for the mesothelin program, represents prudent resource allocation for a clinical-stage company with multiple candidates. The disconnect between promising 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 that have complex safety considerations.

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