NEW YORK – Zymeworks plans to begin clinical trials this year of two therapies targeting mesothelin (MSLN) and folate receptor α (FRα) in difficult-to-treat tumors including ovarian and non-small cell lung cancer.
In June, the US Food and Drug Administration gave the Vancouver, Canada-based company clearance to begin clinical studies of its T-cell-targeting bispecific antibody ZW171 in MSLN-expressing cancers, and in July, the FDA cleared another investigational new drug application for testing the antibody-drug conjugate ZW191 in patients with FRα-expressing cancers.
The two new clinical-stage candidates are the latest to emerge from Zymeworks' discovery program, which incorporates a range of proprietary protein engineering technologies. The firm's lead compound, zanidatamab, is a HER2-targeted bispecific antibody developed on the Azymetric platform, which makes certain amino acid modifications in the heavy and light chains of an antibody and converts them from monospecific to multispecific antibodies.
Zymeworks licensed rights to advance zanidatamab in the US, Europe, and Japan to Jazz Pharmaceuticals in 2022. In May, Jazz said the FDA accepted a biologics license application seeking approval for zanidatamab as a second-line treatment for unresectable, locally advanced, or metastatic HER2-positive biliary tract cancer. Zymeworks has also licensed rights to advance zanidatamab in the rest of Asia, Australia, and New Zealand to BeiGene. Beyond biliary cancer, Jazz and BeiGene are developing the drug in HER2-positive gastroesophageal adenocarcinoma, gastrointestinal cancers, breast cancer, and other HER2-expressing cancers.
Now, with ZW171 and ZW191, Zymeworks is hoping to gain footholds in pancreatic cancer, NSCLC, and gynecological tumors such as ovarian cancer. This is keeping with its mission to develop therapies for cancers that lack treatment options and that are associated with poor outcomes.
Like zanidatamab, ZW171 is a multispecific antibody developed on Zymeworks' Azymetric platform. It comprises a region that binds mesothelin and another that binds CD3, a surface antigen on T cells, to activate T-cell-mediated killing of tumor cells.
Mesothelin is an attractive target in cancer because it is highly expressed in many solid tumors, particularly ovarian cancer. However, it has proven to be a challenging target in drug development because while it is expressed at high levels in tumor cells, mesothelin is also present in normal cells. Zymeworks CEO Paul Moore said that traditional antibody-drug conjugates have not shown adequate anti-tumor activity, and researchers developing mesothelin-targeted bispecific or multispecific T-cell engagers have been stymied by high rates of cytokine release syndrome.
Zymeworks has attempted to address those problems by tailoring the geometry of the molecule to the intended binding sites to favor binding to cancer cells while sparing normal cells. The firm also used a binding epitope with lower affinity for CD3, which allows for higher dosing without inducing cytokine release syndrome.
Moore explained that the firm positions and "tunes the affinity of" the mesothelin and CD3 binding sites such that the drug preferentially binds to tumor cells that have higher levels of mesothelin and does not bind well to normal cells with lower levels.
In preclinical models, ZW171 was safe and showed anti-tumor activity with preferential killing of MSLN-overexpressing cells and reduced peripheral T-cell activation, cytokine release syndrome, and effects on non-tumor cells.
Moore said that up to 90 percent of ovarian and pancreatic cancers express mesothelin, as do about 50 percent of lung cancers and up to 20 percent of colorectal cancer. The company has not yet decided whether to use an enrichment strategy to select patients with mesothelin-expressing cancers in planned clinical studies of ZW171. "We may want to do that, once we get more experience in the clinical trial," he said, adding that initially, the upcoming Phase I clinical trial of ZW171 will enroll all comers in cancer indications that are known to be mesothelin-expressing, but the firm will collect data on mesothelin expression to inform future development.
According to Moore, in an all-comers trial, investigators will be able to study the correlation between mesothelin expression levels and anti-tumor activity and estimate a cutoff level for a potential enrichment strategy. If the firm employs a biomarker selection strategy too soon, he said, it runs the risk of excluding some patients with lower mesothelin expression who could benefit from the therapy.
Zymeworks researchers will enroll about 160 people with advanced or metastatic cancers in the trial, which will have a two-part design. In the first part, they will explore the safety and tolerability of ZW171, and in part two, they'll evaluate anti-tumor activity. To be eligible for the trial, patients must have cancers that are refractory to all standard-of-care therapies or have no available standard treatments. Moore said the company expects to begin the trial later this year.
The firm is also preparing to launch a clinical trial of the folate receptor α (FRα)-targeted topoisomerase inhibitor ZW191 by the end of the year. The compound is designed to target cancer cells expressing high, mid, and low levels of FRα, which is found in about 75 percent of ovarian and NSCLC. In preclinical studies, ZW191 improved anti-tumor activity compared with ImmunoGen's FRα-targeted ADC Elahere (mirvetuximab soravtansine) in ovarian tumor models expressing low levels of FRα and improved or had comparable activity in models with high FRα expression. The drug was also tolerated by nonhuman primates.
Moore said that other drug candidates targeting FRα require patients to have relatively high levels of expression of the receptor. "Only 25 percent of the population of ovarian cancer patients, for instance, [express the] folate receptor at a high enough level," he said. The company is hoping that while it may not reach 100 percent of patients, ZW191 will be able to treat a much larger proportion of FRα-expressing tumors than previously possible.
Moore said initially Zymeworks will also begin with an all-comers approach for its planned Phase I trial of ZW191 and then consider enrichment strategies based on learnings from the trial. "Enrichment strategies may also depend on the tumor type," he noted. "In tumor types where the tumor target is overexpressed in a high percentage of patients, there may not be a need to enrich, while in tumor types where the tumor target is overexpressed in a lower percentage of patients, an enrichment strategy may be needed."