28 May 2014
TG02 also shown to be equally active in CLL cells from patients prior to and following twelve months of ibrutinib therapy.
Tragara Pharmaceuticals, Inc. today announced the preliminary results of new preclinical research showing the activity of TG02, the company's unique oral cyclin dependent kinase (CDK) inhibitor, in chronic lymphocytic leukemia (CLL). Researchers at The Ohio State University demonstrated that TG02 is highly active in CLL cells derived from patients (ex vivo) who had failed treatment with ibrutinib (Imbruvica®). A second preclinical study revealed that TG02 is equally active in CLL cells from patients prior to and following twelve months of ibrutinib therapy. These results follow earlier preclinical studies that have demonstrated TG02’s high level of activity in CLL and strong mechanistic rationale for the treatment of this malignancy.
In the first study, researchers at The Ohio State University tested TG02 in an ex vivo panel of malignant lymphocyctes collected from CLL patients who had responded to, but ultimately failed, treatment with the BTK inhibitor, ibrutinib. The results demonstrated that TG02 is highly active in these samples where the patients had ultimately relapsed or were refractory to ibrutinib therapy. Two predecessor CDK inhibitors, flavopiridol and dinaciclib, were also tested, but failed to produce similar levels of activity in these patient samples.
The second study, also conducted at The Ohio State University, compared the activity of TG02 in patient- derived circulating CLL cells that were collected prior to ibrutinib therapy and persisting after twelve months of ibrutinib treatment in the same patients. TG02 was highly active in both sets of samples, demonstrating that TG02 may be beneficial in combination with ibrutinib and can be expected to retain its activity in CLL after treatment with ibrutinib.
“TG02 has been consistently very active in our in vitro models derived from patients with CLL, including those with 17p depletion,” stated Amy Johnson, Ph.D., associate professor at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.
“TG02 in combination with ibrutinib may help reduce persistent lymphocytosis, reduce the risk of mutations which would render the disease resistant to ibrutinib, and possibly enhance the complete response (CR) rate,” said Thomas M. Estok, president and CEO, Tragara Pharmaceuticals. “Additionally, TG02 therapy may benefit patients who have failed ibrutinib. We look forward to continuing our TG02 development in the clinic to explore these possibilities.
TG02 is currently in phase I clinical testing as a single agent in patients with chronic lymphocytic leukemia (CLL) and in combination with carfilzomib in patients with multiple myeloma (MM). A phase 1 study in solid tumors is planned for later in 2014.
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. 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.Print
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