Zymeworks Receives FDA Clearance for ZW251, Novel Glypican-3 Targeted ADC for Hepatocellular Carcinoma
核心洞察
The FDA has cleared Zymeworks' investigational new drug application for ZW251, a first-in-class antibody-drug conjugate targeting glypican-3 (搜索) for hepatocellular carcinoma (搜索) treatment.
ZW251 incorporates Zymeworks' proprietary topoisomerase 1 (搜索) inhibitor payload and demonstrated strong anti-tumor activity in preclinical studies with favorable tolerability up to 120 mg/kg in non-human primates.
The Phase 1 clinical trial is expected to begin in 2025, marking the second ADC from Zymeworks' pipeline to advance to clinical development using their proprietary payload technology.
Zymeworks Inc. announced that the U.S. Food and Drug Administration has cleared the investigational new drug application for ZW251, a novel glypican-3 (搜索) (GPC3 (搜索))-targeted antibody-drug conjugate incorporating the company's proprietary topoisomerase 1 (搜索) inhibitor payload, ZD06519, for the treatment of hepatocellular carcinoma (搜索) (HCC).
Novel ADC Design Targets Major Liver Cancer
ZW251 represents a potential first-in-class ADC engineered to selectively target GPC3 (搜索), which is expressed in over 75% of HCC cases. The drug is composed of a humanized IgG1 antibody conjugated to a novel camptothecin-based topoisomerase 1 (搜索) inhibitor using a validated peptide cleavable linker. A drug-antibody-ratio of four was selected for ZW251, as a lower DAR potentially could unlock a broader range of dose levels—a potential benefit for HCC patients who are commonly challenged by impaired liver function due to chronic liver disease and cirrhosis.
Strong Preclinical Performance
In preclinical studies, ZW251 demonstrated strong activity across a range of HCC models, including patient-derived xenografts exhibiting varying levels of GPC3 (搜索) expression. The compound showed noteworthy tolerability in non-human primate toxicology studies at doses up to 120 mg/kg, supporting its clinical development potential.
"This advancement marks the second ADC from our wholly-owned pipeline, utilizing our proprietary TOPO1i payload, to progress into clinical development, reinforcing confidence in our approach," said Paul Moore, Ph.D., Chief Scientific Officer of Zymeworks. "Like ZW191, which is currently in clinical trials, ZW251 utilizes the same payload paired with an optimized antibody."
Clinical Development Timeline
Zymeworks plans to commence Phase 1 clinical studies for ZW251 in 2025. The company's observations with ZW191 in ongoing clinical trials provide a foundation for the clinical development of this second ADC utilizing the same proprietary payload technology.
Moore noted that ZW251's novel design, unique mechanism of action, and promising preclinical activity offer the potential to meaningfully improve upon the current standard of care for HCC, either as a monotherapy or in combination with other treatments.
Expanding ADC Pipeline
ZW251 joins Zymeworks' growing pipeline of wholly-owned product candidates. The company is currently conducting Phase 1 studies for ZW171 and ZW191, with ZW251 expected to enter clinical trials in 2025. This expansion demonstrates Zymeworks' expertise in both antibody-drug conjugates and multispecific antibody therapeutics targeting novel pathways in areas of significant unmet medical need.
The company has also achieved regulatory success with zanidatamab, a HER2 (搜索)-targeted bispecific antibody that has received accelerated approval from the U.S. FDA and conditional approval from China's NMPA for treating adults with previously-treated, unresectable or metastatic HER2-positive biliary tract cancer (搜索). The European Commission has granted conditional marketing authorization for Ziihera® for similar indications.