Tragara Reports Interim Results of Phase 1b Study of TG02 and Carfilzomib in Multiple Myeloma

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Maximum tolerated dose (MTD) identified and expansion cohort open to enrollment; Minimal Response (MR) or better has been observed in 25% of 8 patients treated to date at the MTD or higher

Tragara Pharmaceuticals, Inc.

To date, 25% of patients treated at the MTD or higher have achieved an MR or better, including one VGPR sustained for 4 cycles in a patient who had previously failed carfilzomib

Tragara Pharmaceuticals, Inc. today reported early clinical observations from an ongoing Phase 1b trial of TG02, the company's unique oral cyclin dependent kinase (CDK) inhibitor, in combination with carfilzomib in patients with relapsed or refractory multiple myeloma (MM). The study has successfully identified the maximum tolerated dose (MTD); to date, 25% of patients treated at the MTD or higher have achieved a Minimal Response (MR) or better, including one Very Good Partial Response (VGPR) sustained for 4 cycles in a patient who had previously failed carfilzomib. Overall, the combination of TG02 and carfilzomib was generally well tolerated. The study is being conducted at multiple sites in the United States.

“We are encouraged by the clinical benefit observed to-date in the dose escalation cohorts,” said Thomas M. Estok, president and CEO, Tragara Pharmaceuticals. “There remains a significant unmet need for multiple myeloma patients who have relapsed or are refractory to existing treatments, and we look forward to the results of the ongoing expansion cohort”.

“The combination of TG02 and carfilzomib has demonstrated a manageable safety profile while showing promising clinical activity,” said Craig C. Hofmeister, M.D., Assistant Professor at The Ohio State University, College of Medicine, and principal investigator. ”I am particularly encouraged by the fact that the clinical responses observed were with patients that had previously relapsed during carfilzomib treatment. Additional treatment options for this patient population are needed”.

Early Clinical Observations
The study is an open-label dose-escalation phase 1b trial in which TG02 is combined with carfilzomib in patients with relapsed or refractory multiple myeloma to determine the MTD and recommended Phase 2 dose (RP2D). The trial is open to patients who have received at least two prior therapies, including a proteasome inhibitor and an immunomodulatory agent. Patients also qualify who have received at least one prior therapy and one or more of the following high-risk cytogenetic abnormalities (i.e., deletion of chromosomes 17p or 1p, amplification of chromosome 1q, or the chromosomal translocation t(4:14)) that predict poor prognosis and reduced responsiveness to current standard-of-care therapies: Secondary objectives include assessment of safety, tolerability, anti-tumor activity, pharmacokinetics (PK), and exploratory biomarkers. In the dose escalation portion of the study, 14 patients were dosed in four cohorts. TG02 was administered orally at doses of 150 mg to 300 mg BIW for 3 weeks with a one week drug holiday in 28-day cycles.

Early clinical observations from the dose escalation include:

  •     MTD was reached at 250 mg BIW.
  •     Most frequently reported treatment-related adverse events were gastrointestinal-related (that were manageable with prophylaxis) and fatigue.
  •     The median number of prior therapies is 6.0, and 11/14 (79%) patients had relapsed following carfilzomib treatment prior to the study.
  •     2 of 8 patients who received treatment at the MTD or higher have an MR or better: One patient, who had received a total of 7 prior therapies (including carfilzomib for 5 months with the best reported response of stable disease, but then relapsed), achieved a very good partial response (VGPR)
  •     To date, 9/14 (64%) patients have achieved stable disease or better for ≥2 cycles.

Tragara is currently enrolling patients into an expansion cohort of this protocol. An additional 4 patients have been dosed in the ongoing expansion cohort but are not yet evaluable. Additional data is expected in early 2015.

About TG02
TG02 is a unique, oral multi-kinase inhibitor which combines the benefits of inhibiting important cyclin dependent kinases (CDK’s) equipotently with JAK2, FLT3, and ERK5 inhibition. TG02 exerts its antitumor activity primarily via its potent CDK9 inhibition, which leads to the depletion of key survival proteins, such as Mcl-1, resulting in p53-independent apoptosis of a wide range of tumor cells. TG02 development will initially focus on the treatment of hematologic malignancies, including multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), based on the consistent anti-tumor activity that has been observed across a broad spectrum of hematologic cancer models, including those resistant to currently available therapies. In these models, TG02 demonstrated both single agent activity and synergy when administered with current standard of care therapies. Subsequent development will focus on an important group of solid tumors with unmet medical need, such as small cell lung cancer, triple negative breast cancer, and melanoma, which will also benefit from this mechanism of action, complemented with the benefits of inhibiting both JAK2 and ERK5, and depleting other CDK9-dependent proteins such as c-MYC and VEGF. These pathways affect disease progression and survival in hematologic malignancies and solid tumors.

TG02 is currently being evaluated in two separate phase I clinical trials in patients with MM and CLL in the United States.

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.

Rationale for the Combination
Multiple myeloma cells are dependent upon the anti-apoptotic protein Mcl-1 for survival. The rationale for the combination of TG02 and carfilzomib is based on the ability of both agents to target Mcl-1 via independent mechanisms. Carfilzomib upregulates the protein NOXA, which inhibits Mcl-1 in the cell. TG02 inhibits CDK9, which downregulates the production of Mcl-1, reducing the level of Mcl-1 in the cell by blocking its replenishment. The combination of these treatments has been shown to have synergistic effects in human myeloma cell lines.

About Tragara
Tragara Pharmaceuticals, Inc. is a privately held pharmaceutical company based in San Diego, California. The company is focused on the clinical and commercial development of proprietary medicines for the treatment of cancer. TG02 is a unique, oral multi-kinase inhibitor which combines the benefits of inhibiting important cyclin dependent kinases equipotently with JAK2, FLT3, and ERK5 inhibition. TG02 exerts its antitumor activity via its potent CDK9 inhibition, which leads to the depletion of key survival proteins, such as Mcl-1, resulting in p53-independent apoptosis of a wide range of tumor cells. 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, Morgenthaler Ventures, ProQuest Investments and RusnanoMedInvest.

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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Chris LeMasters