Tokai Pharmaceuticals to Present New Galeterone Mechanism of Action Data at 2013 ASCO GU

Galeterone Demonstrates Differentiated Profile with Potent and Selective CYP17 Lyase Inhibition

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Tokai Pharmaceuticals, Inc., a biopharmaceutical company focused on developing new treatments for prostate cancer, today announced that new preclinical data demonstrating the differentiated potent and selective CYP17 lyase inhibition mechanism of action of its lead candidate, galeterone (TOK-001), will be presented today in a poster presentation titled, “Galeterone, Abiraterone, Orteronel and Ketoconazole Exhibit Differential Inhibitory Effects on CYP17 and Steroidogenesis,” abstract number 184, at the 2013 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) in Orlando, Fla.

“Galeterone, Abiraterone, Orteronel and Ketoconazole Exhibit Differential Inhibitory Effects on CYP17 and Steroidogenesis”

Androgens, or male sex hormones, are known to fuel tumor growth in prostate cancer, and therapies that reduce circulating androgen levels are the standard of care in early-stage prostate cancer. The CYP17 enzyme plays a central role in androgen synthesis, and therefore, drugs that inhibit CYP17 have been developed to treat castration-resistant prostate cancer (CRPC). However, CYP17 has both hydroxylase and lyase catalytic functions – lyase catalyzes androgen production and hydroxylase catalyzes mineralocorticoid synthesis, which maintain the body’s water and salt balance. Thus, selective hydroxylase inhibition causes build-up of progestogens and mineralocorticoids and reduction in cortisol levels in CRPC patients, resulting in secondary mineralocorticoid excess (ME), a clinical syndrome including edema, hypokalemia and hypertension. The reduction in cortisol triggers an ACTH feedback loop which is addressed with concomitant administration of the corticosteroid, prednisone. Because of prednisone’s poor tolerability profile and potential to activate mutant androgen receptor (AR) in CRPC, considerable interest has emerged in more selective CYP17 lyase inhibitors.

“We conducted these studies to gain a better understanding of CYP17 inhibition, one facet of galeterone’s unique triple mechanism of action, which also includes AR antagonism and AR degradation. CRPC patients treated with galeterone in our ARMOR1 Phase 1 trial did not exhibit dose-limiting toxicities or signs of ME, and did not require concurrent prednisone administration,” said Martin D. Williams, president and chief executive officer, Tokai Pharmaceuticals. “In these studies, galeterone exhibited potent and selective CYP17 lyase inhibition with minimal evidence of steroid changes associated with ME, which correlates to the Phase 1 clinical observations. Because ME is a commonly reported adverse event requiring prednisone in CRPC patients treated with other non-selective CYP17 inhibitors, such as abiraterone, we believe galeterone may represent an important new treatment option for CRPC patients due to its differentiated CYP17 inhibition and tolerability profile.”

Tokai analyzed the CYP17 inhibitors galeterone, abiraterone, orteronel and ketoconazole to determine each drug’s effects on CYP17 hydroxylase and lyase activities, and the steroidogenic pathway. Study results showed that all four drugs inhibited CYP17; however, potency and selectivity for hydroxylase and lyase varied significantly. Galeterone was the most potent CYP17 inhibitor that was also selective for CYP17 lyase, while conserving CYP17 hydroxylase function, and exhibiting minimal evidence of deleterious steroid changes associated with ME. These preclinical data recapitulate the Phase 1 clinical experience with galeterone where no ME was observed and no prednisone was required in CRPC patients. The poster presentation is available on Tokai’s website at www.tokaipharma.com/news-publications.php.

About Galeterone (TOK-001)

Galeterone is a proprietary small molecule, oral drug for the treatment of prostate cancer that disrupts androgen receptor signaling via a novel triple mechanism of action. In preclinical studies, galeterone acted as a highly selective CYP17 lyase inhibitor, as a potent androgen receptor antagonist, and decreased androgen receptor levels in prostate tumors – the only drug in development that has been shown to exhibit all three of these properties. Galeterone combines these three distinct mechanisms of action in one therapeutic compound. Results from the ARMOR1 Phase 1 clinical trial showed that galeterone demonstrated clinical activity and was well tolerated in patients with CRPC. Galeterone is currently being evaluated in a Phase 2 study, ARMOR2, in patients with CRPC as part of the ARMOR (Androgen Receptor Modulation Optimized for Response) clinical development program.

About Tokai Pharmaceuticals

Tokai Pharmaceuticals is a U.S. biopharmaceutical company focused on developing new treatments for prostate cancer. The company’s lead drug candidate, galeterone (TOK- 001), is the first investigational new drug that can decrease overall androgen receptor levels in prostate tumors and in which three distinct mechanisms of action are combined to disrupt androgen receptor signaling in one oncotherapeutic. Based in Cambridge, Massachusetts, Tokai is backed by Apple Tree Partners and Novartis Venture Fund. For more information on the company and galeterone, please visit www.tokaipharma.com.