Zymeworks halts plans for phase 2 ADC trial to mull 'evolving clinical landscape'

Antibody-drug conjugates (ADCs) may be one of the hottest dealmaking areas this year, but that hasn't stopped Zymeworks from halting phase 2 plans for its HER2 ADC to assess the “evolving clinical landscape.”

The bispecific ADC combines Zymework’s lead asset, a HER2-targeted bispecific antibody called zanidatamab, with a toxic chemotherapy. The company hailed “promising results” from a phase 1 trial of zanidatamab zovodotin, also known as ZW49, as a monotherapy for an array of HER2-expressing cancers at the end of 2022.

Since then, Zymeworks has mapped out the next steps for the development of zanidatamab zovodotin, which would have involved a phase 2 trial of a 2.5-mg/kg dose of the ADC every three weeks in combination with Merck & Co.’s checkpoint inhibitor Keytruda for patients with HER2 overexpressing non-small cell lung cancer.

However, while zanidatamab zovodotin “remains ready” for the trial, “the initiation of the planned phase 2 study has been deprioritized, pending more clarity from the evolving clinical landscape,” Zymeworks disclosed in a full-year earnings report yesterday.

“We continue to explore potential development and commercial collaborations for zanidatamab zovodotin,” the biotech added.

BeiGene handed back Asia rights to the ADC in September 2023 following a 2018 deal that saw Zymeworks in line for up to $195 million in potential milestone payments. The end of that agreement didn’t affect the companies' separate licensing arrangement over zanidatamab.

The HER2 ADC market is dominated by AstraZeneca and Daiichi Sankyo’s Enhertu as well as Roche’s Kadcyla. Seagen has a HER2 ADC, disitamab vedotin, in-licensed from RemeGen.

Despite this competitive space, Zymeworks was still insisting as recently as January that zanidatamab zovodotin “represents a unique and differentiated product candidate among the HER2 ADCs currently under active development.”

“We anticipate the results of this [phase 2] study may provide the rationale for one or more registrational studies, which we would expect to undertake with a future collaboration partner,” the company said in a strategic look at the year ahead.

But with zanidatamab zovodotin now on ice, Zymeworks’ attention is focused on zanidatamab. Zymework’s partner Jazz Pharmaceuticals announced in January that it has launched a rolling approval submission to the FDA for second-line biliary tract cancers. The submission is expected to be completed in the first half of the year.

Apart from the tissue factor ADC XB002, which is being led by Exelixis, Zymeworks’ other ADC programs remain in preclinical development—like the folate receptor-⍺ targeted topoisomerase-1 inhibitor ZW191.

Zymeworks entered the year with $456.3 million in cash and equivalents, which CEO Kenneth Galbraith said in yesterday’s release will “support the development of our expanded portfolio of clinical and preclinical product candidates into the second half of 2027.”