Clinical Focus: Zymeworks Discontinues Development of ZW171 in Phase 1 Trial

Zymeworks Inc has voluntarily discontinued clinical development of its mesothelin-directed T-cell engager ZW171 following a phase 1 study (NCT06523803) in which further dose evaluation was determined to be unlikely to support a favorable benefit-risk profile.¹ The decision was announced in a press release from the clinical-stage biotechnology company, which cited the outcome of dose-escalation cohorts and the establishment of a maximum tolerated dose as the basis for the move.

“While this is a disappointing outcome given the promising preclinical activity observed with ZW171, we are deeply grateful to the patients, providers, and caregivers for their support and participation in the ZW171 phase 1 study,” said Kenneth Galbraith, chair and CEO of Zymeworks, in a press release. “As part of Zymeworks’ disciplined approach to the management of our broad product portfolio, we are committed to careful and consistent evaluation of clinical progress for each product candidate to ensure our resources are directed towards those product candidates with the greatest potential impact for patients. We continue to advance our broader product pipeline, including the ongoing phase 1 trial of ZW191 and the initiation of a phase 1 study for ZW251 expected in 2025. We are also preparing an [investigational new drug (IND)] filing for ZW209, our DLL3-directed trispecific T-cell engager, planned in the first half of 2026.”

The now-terminated trial of ZW171 was a first-in-human study designed to evaluate the safety, tolerability, and preliminary antitumor activity of the agent in patients with mesothelin-expressing cancers. While the company's preclinical data had shown promise, the clinical evaluation led to the conclusion that a monotherapy target product profile could not be achieved with the existing formulation.

This decision follows a similar move in 2024 to discontinue the clinical development of zanidatamab zovodotin (ZW49), a HER2-targeted bispecific antibody-drug conjugate (ADC), which resulted in a non-cash impairment charge of $17.3 million.² The company's focus is now on advancing other wholly owned pipeline candidates, including ZW191 and ZW251.¹

Zymeworks is also the developer of zanidatamab-hrii (Ziihera), which was granted accelerated approval by the FDA in November 2024 for the treatment of patients with previously treated, unresectable or metastatic HER2-positive biliary tract cancer.³ Zanidatamab also received conditional approval from the NMPA in China and conditional marketing authorization from the European Commission for this indication.¹

FAQs

Why was the clinical development of ZW171 discontinued?

Clinical development was discontinued because the phase 1 trial determined that further dose evaluation was unlikely to establish a favorable benefit-risk profile for the drug as a monotherapy.

What is a T-cell engager, and how was ZW171 supposed to work?

A T-cell engager is a type of bispecific antibody designed to bring a T-cell (a type of immune cell) into close proximity with a cancer cell. ZW171 was a mesothelin-directed T-cell engager, meaning it was engineered to bind to mesothelin on cancer cells and a CD3 receptor on T-cells to trigger an immune response against the tumor.

What happens to the patients who were enrolled in this clinical trial?

Patients enrolled in the trial would have been informed of the study's termination and would have been transitioned to follow-up care or alternative treatments as determined by their treating physician, in accordance with the study's protocol.

This article was generated with assistance from Google Gemini. It was edited and reviewed by Targeted Oncology staff. If you have any questions about the use of AI, please contact us.

REFERENCES:

1. Zymeworks Announces Decision to Discontinue Clinical Development of ZW171, a Mesothelin-directed T cell Engager. News release. Zymeworks Inc. September 2, 2025. Accessed September 2, 2025. https://tinyurl.com/49uzn4hp

2. Waldron J. Zymeworks halts plans for phase 2 ADC trial to mull 'evolving clinical landscape. News release. Fierce Biotech. March 7, 2024. Accessed September 2, 2025. https://tinyurl.com/muan6bnj

3. Jazz Pharmaceuticals Announces U.S. FDA Approval of Ziihera® (zanidatamab-hrii) for the Treatment of Adults with Previously Treated, Unresectable or Metastatic HER2-positive (IHC 3+) Biliary Tract Cancer (BTC). Published online November 20, 2024. Accessed September 2, 2025. https://tinyurl.com/3vt9ka3b