Tragara’s TG02 Anti-Tumor Activity is Produced via the Depletion of Anti-apoptotic Proteins Mcl-1 and XIAP

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TG02 maintains depletion of these proteins for 16-24 hours which induces high levels of apoptosis in tumor cells.

Tragara Pharmaceuticals, Inc.

We believe that TG02 represents a first-in-class opportunity to treat cancer via this fundamental mechanism with a pharmaceutically capable agent

Tragara Pharmaceuticals, Inc. today described the mechanism of action by which its novel oral agent, TG02, has demonstrated anti-tumor activity in both hematological and solid tumors. TG02 is a small molecule that equipotently targets the major signaling pathways involving the key cell cycle and transcriptional cyclin-dependent kinases (CDKs) as well as ERK5 and JAK2. The dominant anti-tumor mechanism of action of TG02 is derived from its ability to deplete the survival proteins Mcl-1 and XIAP, driving tumor cells into apoptosis. Key to this effect is the ability of TG02 to maintain this effect for 24 hours following a single oral dose. Importantly, the mechanism of action for TG02 functions independently of p53 status, which could provide benefit to patients with poor prognosis genotypes that are resistant to many standard-of-care drugs.

In a study recently presented at AACR, researchers at M.D. Anderson demonstrated that the apoptotic activity of TG02 was due to its potent inhibition of CDK 7 and 9, which blocks transcription and results in the depletion of short-lived anti-apoptotic proteins to which many tumor cells are dependent, such as Mcl-1 and XIAP. Maintaining this depletion for 16-24 hours induces high levels of apoptosis. TG02’s oral dosing flexibility and supportive pharmacokinetic profile provide the capability to effectively sustain this depletion; previous efforts by some other drugs to modulate Mcl-1 have fallen short in part due to pharmaceutical and pharmacodynamic limitations.

“The ability of TG02 to induce apoptosis through the depletion of survival proteins, coupled with its drug-like profile and oral dosing flexibility, provides a compelling rationale for a broad exploration of its clinical utility,” said Thomas Estok, president and CEO, Tragara Pharmaceuticals, Inc. “We believe that TG02 represents a first-in-class opportunity to treat cancer via this fundamental mechanism with a pharmaceutically capable agent."

In addition, this mechanism makes TG02 an attractive companion for combination therapy. Depletion of survival proteins also lowers the apoptotic threshold for other anti-cancer drugs, including chemotherapy and targeted agents, whose therapeutic benefit is often reduced or eliminated in the presence of overexpressed Mcl-1. The utility of this mechanism has been demonstrated in multiple in vivo hematological and solid tumor models where TG02 has shown synergy with a variety of standard-of-care agents.

TG02 is currently in phase I clinical testing in patients with acute leukemia and in patients with multiple myeloma in the United States. An interim report on the progress of this study will be presented at the annual meeting of the American Society for Clinical Oncology (ASCO) in Chicago; a poster will be shown during the “Leukemia, Myelodysplasia, and Transplantation” Poster Session on Monday, June 4, from 1:15 PM to 5:15 PM, in S Hall A2. A phase I clinical study in patients with CLL will be initiated later in 2012.

About TG02
TG02 is a novel orally available, small molecule that targets - equipotently - the major signaling pathways involving ERK5, JAK2 and key cell cycle and transcriptional cyclin-dependent kinases (CDKs), with excellent pharmacological and pharmaceutical properties. Preclinical models demonstrate that TG02 has the unique ability to deplete the short-lived survival proteins Mcl-1 and XIAP, and maintain this depletion for greater than 24 hours after a single dose, producing and promoting apoptosis (programmed cell death) to occur. This mechanism produces both single agent activity and synergy when administered with current standard of care therapies.

TG02 development is initially focused on the treatment of acute hematologic malignancies, including MM and chronic lymphocytic leukemia (CLL); Tragara also will explore the therapeutic potential of the compound’s depletion of key survival proteins in solid tumors. TG02 is currently in phase I clinical testing in patients with acute leukemia and in patients with MM in the United States. A phase I clinical study in patients with CLL is planned for 2012.

In early 2010, TG02 was selected by the Multiple Myeloma Research Foundation as a winner of its Biotech Investment Award, which represents a multi-year research grant commitment to fund the early-stage drug development of novel compounds that show potential in treating MM.

About Tragara
Tragara Pharmaceuticals, Inc. is a privately held pharmaceutical company based in San Diego, Calif. The company is focused on the clinical and commercial development of proprietary medicines for the treatment of cancer and inflammation. Tragara’s TG02 is an oral multi-kinase inhibitor that targets the major signaling pathways involving ERK5, JAK2 and several important cyclin-dependent kinases. Tragara is managed by a team of entrepreneurs with both Big Pharma and Biotech experience in the development and commercialization of oncology therapeutics. Its investors include: Domain Associates, Mitsubishi International Corporation, Morganthaler Ventures, Oxford BioScience Partners and ProQuest Investments.

Tragara strives to provide much-needed therapies that will contribute to patient health through better survival and an increase in the quality of life. For more information, visit http://www.tragarapharma.com.

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