Preclinical data support the potential anti-tumor activity and tolerability of a novel FR⍺ topoisomerase I inhibitor in ovarian cancer and NSCLC.
File applications supporting clinical studies for ZW191 in jurisdictions outside the United States are anticipated in the second half of 2024.
The FDA has cleared an investigational new drug application for ZW191, a novel folate receptor-⍺ (FR⍺) targeted topoisomerase I inhibitor (TOPO1i) antibody-drug conjugate (ADC) intended to treat patients with FR⍺-expressing tumors such as ovarian cancer, other gynecological cancers, and non–small cell lung cancer (NSCLC), according to a press release from the developer, Zymeworks Inc.1
Developers designed ZW191 using investigational TOPO1-based payload technology to target FR⍺ expression in tumors. The agent comes equipped with a drug-to-antibody ratio of 8, which is intended to balance its efficacy and tolerability profiles. Additionally, the treatment’s FR⍺ monoclonal antibody was formed based on enhanced internalization characteristics intended to augment its targeting of FR⍺ expression at low, mid, and high levels.
File applications supporting clinical studies for ZW191 in jurisdictions outside the United States are anticipated in the second half of 2024.
“Developed to target FR⍺, which is expressed in several types of difficult-to-treat cancers, ZW191 incorporates a novel antibody and drug-linker that provide a unique combination of antibody-linker stability and payload potency, together with strong bystander activity, which could result in improved efficacy and enable targeting lower levels of FR⍺ compared [with] previously developed drug candidates,” Paul Moore, chief scientific officer at Zymeworks, said in the press release.1 “We are pleased to reach this [Research & Development] milestone following on the heels of our recent FDA clearance for ZW171 in June and look forward to initiating clinical development of both ZW191 and ZW171 during 2024.”
Investigators previously presented preclinical data on the use of ZW191 in various FR⍺-expressing tumors at the 2024 American Association for Cancer Research Annual Meeting.2
Data from a poster presentation showed that treatment with ZW191 conferred improved activity compared with mirvetuximab soravtansine-gynx (Elahere) across ovarian tumor models expressing relatively low levels of FR⍺ as well as improved or similar activity in models with relatively high FR⍺ expression. Among tumors with FR⍺ expression H-scores of less than 150, tumor regression occurred in 83% (n = 5/6) and 33% (n = 2/6) of models treated with ZW191 and mirvetuximab soravtansine, respectively. Additionally, among models with H-scores of more than 150, investigators reported tumor regression in 100% (n = 4/4) and 100% (n = 4/4) of models, respectively.
Treatment with ZW191 also yielded activity across a range of relative FR⍺ expression levels in NSCLC, endometrial cancer, and triple-negative breast cancer models. Additionally, activity with ZW191 in these tumor types appeared to be improved or comparable with that of mirvetuximab soravtansine.
At repeated doses ranging from 10 mg/kg to 60 mg/kg, ZW191 did not produce any mortality or body weight effects. Treatment also elicited no ophthalmic effects, and any toxicity appeared to be non-adverse and reversible. Investigators also reported favorable preclinical pharmacokinetics, which supported the expectation that the agent may yield potent anti-tumor activity at a well-tolerated dose.
“A compelling preclinical activity profile supports ZW191 development across multiple tumor types,” the study authors wrote in the poster.2
In June 2024, the FDA cleared an investigational new drug application for ZW171, an investigational 2+1 T-cell–targeting bispecific antibody intended to treat those with mesothelin-expressing cancers.3
“ZW171’s unique design is intended to address the limitations of current bispecific T-cell engagers by enhancing tumor selectivity and improving safety. With promising preclinical results, ZW171 has the potential to provide a more effective and tolerable treatment option for patients with MSLN-expressing cancers, including ovarian cancer, [NSCLC], mesothelioma, and other cancers,” Moore said in a press release.3