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First Patient Dosed in Phase I Dose-escalation Study with MORAb-202

Published on 05th December

A first patient has been enrolled into a Phase I cancer study of the novel investigational antibody-drug conjugate MORAb-202, being developed by Morphotek, a subsidiary of Eisai.

The Phase I trial, which is being conducted in Japan and referred to as MORAb-202-J081-101, is a first-in-human, dose-escalation study evaluating the safety and preliminary efficacy of MORAb-202 in patients with solid tumors that express folate receptor alpha (FRα), a membrane-bound protein with high affinity for binding and transporting physiologic levels of folate into cells.[1]

FRα levels are generally high in specific malignant tumors of epithelial origin compared to normal cells, and are positively associated with tumor stage and grade.[1]

The combination of farletuzumab linked to the regulatory-approved eribulin mesylate has shown robust antitumor effects in a number of preclinical FRα-expressing tumor models…

Following completion of the dose-escalation phase used to establish initial safety and optimal dosing, additional subjects will be enrolled to further study safety and preliminary efficacy of MORAb-202 in select tumor types, including triple-negative breast and endometrial cancers.

MORAb-202 is a novel investigational ADC that uses a cathepsin-cleavable linker to combine investigational monoclonal antibody farletuzumab, targeted at FR-alpha, with the microtubule inhibitor payload, eribulin mesylate.

Monoclonal antibody
Farletuzumab is a humanized antibody targeting FRA and has been studied in clinical trials in patients with FRA-expressing tumors.  FRA expression is observed in a large number of cancers, including endometrial, gastric, non-small cell lung, ovarian and triple-negative breast, but is largely absent from normal tissue.

Image 1.0: Formula of halichondrin B, a natural product that was isolated from the marine sponge Halichondria okadai.

Discovered and developed by Eisai, eribulin is a synthetic analog of halichondrin B, a natural product (a large naturally occurring polyether macrolide) that was isolated from the marine sponge Halichondria okadai.

First in the halichondrin class, eribulin mesylate (Halaven®), approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for metastatic disease, including an anthracycline and a taxane in either the adjuvant or metastatic setting, is a microtubule dynamics inhibitor.

Mechanism of Action
This general characteristic of eribulin mesylate places it in the group of drugs that includes Vinca alkaloids, dolastatins, and cryptophycin. However, its tubulin interactions appear to be unique.

The drug is believed to work primarily via a tubulin-based mechanism that causes prolonged and irreversible mitotic blockage, ultimately leading to apoptotic cell death.  Additionally, in preclinical studies of human breast cancer, eribulin mesylate demonstrated complex effects on the tumor biology of surviving cancer cells, including increases in vascular perfusion resulting in reduced tumor hypoxia, and changes in the expression of genes in tumor specimens associated with a change in phenotype, promoting the epithelial phenotype, opposing the mesenchymal phenotype.

Finally, eribulin mesylate has been shown to decrease the migration and invasiveness of human breast cancer cells.

“We are excited to have initiated this Phase ( study and to transition MORAb-202 into the clinical development stage,” noted Nicholas Nicolaides, President and CEO of Morphotek.

“The combination of farletuzumab linked to the regulatory-approved eribulin mesylate has shown robust antitumor effects in a number of preclinical FRA-expressing tumor models, which makes this experimental agent a potential promising ADC candidate for FRA-positive cancers, ” Nicolaides concluded.

Last Editorial Review: November 5, 2017

Featured Image: Patient receiving treatment Courtesy: © 2017. Fotolia | Used with permission.

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