Zymeworks Highlights ZW191 Ovarian Cancer Responses, Roche Deal Upside

Key Points

• ZW191 showed encouraging activity in heavily pretreated, platinum-resistant ovarian cancer, with confirmed response rates of 65% at 6.4 mg/kg and 55% at 9.6 mg/kg. The lower dose had a more favorable safety profile, though the data remain immature.
• Zymeworks’ proposed Roche collaboration for DLL3-targeting ZW209 could provide $55 million upfront, $40 million at Phase 1b initiation, up to $718 million in milestones, and tiered royalties. Roche would fund and eventually assume responsibility for development and commercialization.
• The company is emphasizing partnerships to reduce its capital burden, saying it is unlikely to independently fund multiple Phase 3 studies for ZW191 while continuing to invest selectively in internal R&D, acquisitions, royalty opportunities and share repurchases.

Zymeworks NASDAQ: ZYME outlined a partnering-focused research strategy, presented updated clinical data for its ZW191 antibody-drug conjugate in platinum-resistant ovarian cancer, and discussed its recently announced collaboration with Roche for the DLL3-targeting T-cell engager ZW209.

The company said its agreement with Roche remains subject to clearance under the Hart-Scott-Rodino Act. Under the proposed collaboration, Zymeworks would receive a $55 million upfront payment and a further $40 million upon initiation of a Phase 1b study. The deal also includes up to $718 million in potential development, regulatory and commercial milestones, plus tiered royalties ranging from high single digits to mid-teens.

Adam Schayowitz, Zymeworks’ head of R&D, said Roche is expected to fund research and development for ZW209, including the Phase 1a study, while Zymeworks will conduct the initial global trial. Roche would assume responsibility for subsequent development and commercialization under the agreement.

“We believe that this structure allows us to advance our science, to limit the long-term capital burden on our own balance sheet, and to retain meaningful upside if the program succeeds,” Schayowitz said.

ZW209 Targets DLL3-Positive Tumors

ZW209 is a trispecific T-cell engager designed to target DLL3-positive tumors, including small cell lung cancer and other neuroendocrine tumors. The molecule simultaneously engages DLL3 on tumor cells and CD3 and CD28 on T cells. Zymeworks said its design seeks to provide tumor-directed T-cell activation and conditional costimulation while limiting unintended activation.

Paul Moore, Zymeworks’ chief scientific officer, said conventional T-cell engager approaches can face challenges in solid tumors because of limited T-cell infiltration and T-cell exhaustion within the tumor microenvironment. ZW209’s CD28 component is designed to support T-cell activation, proliferation and survival when CD3 engagement has already occurred.

In preclinical studies, Zymeworks said ZW209 showed enhanced target-dependent T-cell proliferation, survival and antitumor activity compared with DLL3-directed CD3 bispecific approaches, including tarlatamab. The company reported no T-cell activation, cytokine activation or T-cell fratricide in the absence of DLL3-expressing cells. It also said repeat dosing at 10 mg/kg was well tolerated in non-human primates and that the molecule showed antibody-like pharmacokinetics.

The company said it expects the first patient dosing in its global Phase 1a study in 2026, while management later said it planned to enroll the first patient before year-end. Early clinical evaluation is expected to focus initially on safety before assessing response rates, tolerability and potential combination approaches.

ZW191 Shows Responses in Heavily Pretreated Ovarian Cancer

Zymeworks also presented updated results from its ongoing ZW191-101 trial of ZW191, a folate receptor alpha-targeting antibody-drug conjugate for platinum-resistant ovarian cancer. The study enrolled patients regardless of folate receptor alpha expression and without limits on prior lines of therapy.

Among 80 patients with a median follow-up of seven months, 37 received ZW191 at 6.4 mg/kg and 43 received 9.6 mg/kg every three weeks. Most patients had high-grade serous carcinoma and had received a median of four prior treatment lines.

• In high-grade serous platinum-resistant ovarian cancer, confirmed objective response rates were 65% at 6.4 mg/kg and 55% at 9.6 mg/kg.
• Disease control rates were 100% and 92%, respectively.
• The six-month progression-free survival rate was 65% at both doses.
• Median progression-free survival was 7.9 months at 6.4 mg/kg and 9.8 months at 9.6 mg/kg, although Zymeworks said the data remained immature.

Sabeen Mekan, chief medical officer, said responses were observed across folate receptor alpha expression levels. The median duration of response had not been reached at the data cutoff, and 45% of participants remained on treatment.

Grade 3 or higher adverse events occurred in 54% of patients at 6.4 mg/kg and 74% at 9.6 mg/kg. Zymeworks said the lower dose had fewer dose reductions and a more favorable hematologic safety profile. Management said it may consider evaluating another dose depending on a future partner’s interest, combination strategies and the maturation of efficacy data.

The company said it is working with adviser MTS to seek external funding through partnerships or collaborations for further ZW191 development. Chief Executive Officer Ken Galbraith said Zymeworks is unlikely to independently fund multiple Phase 3 studies for the program, citing growing competition and the increasing importance of combination regimens in earlier treatment settings.

Ziihera Data and Capital Allocation

Zymeworks also highlighted data presented by partners Jazz Pharmaceuticals and BeOne from the HERIZON-GEA-01 study of Ziihera-containing regimens in first-line HER2-positive advanced gastroesophageal adenocarcinoma.

At a median follow-up of 35.3 months, the combination of Ziihera, tislelizumab and chemotherapy achieved median overall survival of 27 months and reduced the risk of death by 35% compared with trastuzumab plus chemotherapy, according to the company. Nearly 40% of patients receiving the triplet regimen were alive at three years, compared with 22.9% in the comparator group.

Galbraith said Zymeworks plans to balance internal R&D investment, selective acquisitions and royalty opportunities, partnerships and share repurchases. The company said it has generated nearly $1 billion in payments from partnering activities to date and views collaborations as a way to advance programs while reducing capital requirements and retaining milestone and royalty participation.

About Zymeworks (NASDAQ:ZYME)

Zymeworks Inc is a biopharmaceutical company focused on discovering, developing and commercializing multifunctional biotherapeutics for cancer and other serious diseases. The company is headquartered in Vancouver, British Columbia, and has historically operated internationally through research, development and collaboration activities.

Zymeworks' technology platforms include Azymetric, which is designed to support the development of engineered antibody therapeutics, and ZymeLink, which enables the creation of antibody-drug conjugates and other targeted therapies.

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