On January 8, 2016 Tokai Pharmaceuticals Inc. (NASDAQ: TKAI), a biopharmaceutical company focused on developing and commercializing innovative therapies for prostate cancer and other hormonally driven diseases, reported the presentation of new data describing the novel mechanism by which galeterone degrades the androgen receptor (Press release, Tokai Pharmaceuticals, JAN 8, 2016, View Source;p=RssLanding&cat=news&id=2127712 [SID:1234508732]). Galeterone, Tokai’s lead product candidate, is being developed for the treatment of men with metastatic castration-resistance prostate cancer (mCRPC).
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The presentation, "Galeterone-induced Degradation of the Androgen Receptor Involves Inhibition of a Deubiquitinating Enzyme," was one of three made by Tokai researchers at the ASCO (Free ASCO Whitepaper) Genitourinary Cancers Symposium this week in San Francisco. Additional presentations highlighted favorable results from a drug-drug interaction study involving galeterone and oral midazolam, and described Tokai’s progress in implementing a novel clinical trial assay for selecting AR-V7+ patients for enrollment in the ongoing pivotal Phase 3 ARMOR3-SV study.
Presentation Overview
Galeterone is a highly selective oral small molecule drug candidate that disrupts androgen receptor (AR) signaling by degrading the androgen receptor. Galeterone has been demonstrated to induce AR degradation in forms of the disease that exhibit full-length AR, as well as in those with a truncated AR where the ligand-binding domain is not present, such as in AR-V7+ and AR567es+ disease. These and earlier observations demonstrate that an intact ligand binding domain is not required for galeterone-induced AR degradation.
To elucidate the galeterone mechanism further, researchers conducted a series of biochemical and cell-based in vitro studies which pinpointed two deubiquitinating enzymes that galeterone inhibits – USP12 and USP46. By doing so, galeterone induces AR degradation through a unique mechanism that does not exist with other currently available AR-targeting agents. These new data provide a strong preclinical rationale for galeterone’s enhanced ability to induce AR degradation, even in the absence of the ligand binding domain.
"These data provide a view into the novel activity of galeterone and highlight its potential to treat segments of the mCRPC population currently underserved by available therapies," said Jodie Morrison, President and Chief Executive Officer of Tokai. "These data further support the rationale for the ARMOR3-SV pivotal study and inform our ongoing clinical development strategy as we seek to advance galeterone for all patient populations who may benefit."