Roche is paying Zymeworks $55 million upfront for ZW209, bagging global rights to a trispecific designed to improve on the rate and depth of responses achieved by Amgen’s Imdelltra.
ZW209 engages DLL3 on tumor cells while simultaneously binding CD3 and CD28 on T cells. The design is a twist on Imdelltra, a bispecific antibody that targets DLL3 and CD3 to turn the immune system against cancer cells. Amgen won FDA approval for Imdelltra in small cell lung cancer (SCLC) in 2024. Boehringer Ingelheim is moving a rival DLL3xCD3 bispecific through phase 3 development.
ZW209 is back in phase 1a, but Roche sees promise in the program. In addition to the upfront fee, the Swiss drugmaker will pay Zymeworks $40 million when ZW209 enters a phase 1b trial. The deal includes up to $718 million in additional development, commercial and sales-based milestones, plus royalties.
The argument that ZW209 is differentiated is supported by preclinical data that Zymeworks presented last year. Benchmarking ZW209 against a bispecific T-cell engager, the biotech reported improved T-cell fitness and antitumor activity. The trispecific achieved potent antitumor activity in multiple humanized SCLC xenograft models.
Zymeworks’ preclinical data offered early evidence that the trispecific design may improve outcomes. The biotech identified the low T-cell infiltration and poor T-cell function characteristic of SCLC as a barrier to strong responses to bispecific DLL3 drugs. T cells can become unresponsive when stimulated via CD3. Targeting CD3 and CD28 could mitigate the constraints on antitumor responses.
Roche will support early work to validate that hypothesis in humans. Zymeworks will run the phase 1a trial in collaboration with Roche, which will fund the study. Roche will be responsible for all work beyond the phase 1a trial. SCLC is a focus for Roche, which sells Tecentriq in the tumor type and is developing an antibody-drug conjugate with MediLink.
ZW209 is a test case for Zymeworks’ broader ambitions to improve on bispecific T-cell engagers. The drug candidate emerged from discussions about the functionality Zymeworks could add using the extra arm of a trispecific, Zymeworks CEO Kenneth Galbraith said at a Morgan Stanley event last month.
Zymeworks picked DLL3 as the first target in the belief it can “provide something extra” over Imdelltra, the CEO said. If ZW209 validates the approach, the biotech has many different targets it can apply the model to across a range of therapeutic areas, Galbraith added.