On January 27, 2021 Zymeworks Inc. (NYSE: ZYME), a clinical-stage biopharmaceutical company developing multifunctional biotherapeutics, reported that the Company has begun enrolling patients into the expansion cohort portion of the ongoing Phase 1 clinical trial for ZW49, its novel HER2-targeted antibody-drug conjugate (ADC) (Press release, Zymeworks, JAN 27, 2021, View Source [SID1234574344]). Supporting data from the Phase 1 dose escalation portion were highlighted today via a webcast and conference call and are summarized below.
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Phase 1 Dose Escalation Study Design
The dose escalation portion of the study employed a standard 3 + 3 design to evaluate escalating doses within different dosing regimens including once every two week (Q2W) and once every three week (Q3W) schedules with the objective of selecting a dose and schedule to advance into the expansion cohorts.
To date patients from sites across the US and Canada with a variety of heavily pretreated HER2‑positive cancer types have been enrolled, including breast cancer, gastroesophageal adenocarcinoma, gynecologic cancers, non-small cell lung cancer, anal cancer, and colorectal cancer.
ZW49 Safety and Tolerability
In the 35 patients who have received ZW49 across all dosing regimens, there have been no dose limiting toxicities, no treatment-related hematologic toxicities including neutropenia or thrombocytopenia, no treatment-related pulmonary toxicity including interstitial lung disease or pneumonitis, and no treatment-related liver toxicity. There have been no treatment-related deaths.
Over 90% of treatment-related adverse events have been mild or moderate (Grade 1 or 2) in severity, with the most common being keratitis, fatigue, and diarrhea, which have been reversible and manageable in an outpatient setting. There have been no discontinuations due to treatment-related adverse events, and the maximum-tolerated dose has not yet been established.
ZW49 Interim Antitumor Activity
ZW49 has demonstrated antitumor activity across all regimens and dose levels evaluated to date, including at the starting dose of 1 mg/kg Q2W. Partial responses and stable disease per RECIST 1.1 have been observed in both Q2W and Q3W dosing regimens, with the Q3W regimen starting to demonstrate a dose-response relationship. Beginning at the initial dose of 2.0 mg/kg Q3W, several patients experienced stable disease including some with disease control greater than four months. At the highest doses tested in the Q3W of 2.5 or 3.0 mg/kg there were six response-evaluable patients with centrally confirmed HER2‑positive disease spanning several different tumor types. The antitumor activity in these six patients consisted of two patients with confirmed partial responses and two patients with stable disease, three of which are still active on study. This regimen is currently enrolling patients at the 3 mg/kg dose with the potential to add new escalation cohorts.
"We are encouraged by the antitumor activity we are seeing so far with ZW49 and look forward to accelerating development by expanding our dataset in disease-specific cohorts," said Diana Hausman, M.D., Chief Medical Officer of Zymeworks. "In addition, the differentiated safety profile allows us to continue in dose escalation, with the opportunity to fully realize the therapeutic potential for ZW49."
Expansion Cohort Phase
Based on the antitumor activity demonstrated by ZW49, three indication-specific expansion cohorts utilizing the 2.5 mg/kg Q3W regimen are open and enrolling patients. These include HER2-positive breast cancer, HER2-positive gastroesophageal adenocarcinoma, and a basket cohort of other HER2-positive cancers. The expansion cohorts are actively enrolling at sites in U.S. and Canada, and are expected to open soon at additional sites in South Korea and Australia in collaboration with our partner, BeiGene.
"I believe ZW49 is on track for becoming the HER2 ADC that delivers efficacy without compromising safety," said Ali Tehrani, Ph.D., President and CEO of Zymeworks. "These data highlight that ZW49 can potentially provide physicians and their patients with a differentiated alternative to currently-approved HER2 ADCs. We look forward to presenting additional data at a medical conference later this year."
About ZW49
ZW49, Zymeworks’ second product candidate, is a novel bispecific HER2-targeted ADC developed using Zymeworks’ proprietary Azymetric and ZymeLink platforms. ZW49 combines the unique design of zanidatamab with a proprietary cytotoxin and cleavable linker resulting in enhanced internalization and tumor cell killing. ZW49 is currently in a Phase 1 clinical trial and is being developed for several indications characterized by HER2 expression, especially for patients whose tumors have progressed or are refractory to HER2-targeted agents and those that express lower levels of HER2 and are ineligible for treatment with existing HER2-targeted therapies.
About ZymeLink Antibody-Drug Conjugates
The ZymeLink ADC platform is a modular suite of proprietary cytotoxins (cell-killing drugs), customizable linkers, and conjugation technologies designed for targeted delivery of cytotoxins to diseased cells with optimal safety and efficacy. The ZymeLink platform can be combined with a diverse array of targeted therapies, including traditional antibodies and Azymetric bispecific antibodies, to deliver cell-killing compounds to diseased target cells. These modular technologies are designed to develop next-generation ADCs with broad therapeutic windows.