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Semafore Pharmaceuticals Presents New Clinical Data on Novel Prodrug Dual PI3K-mTOR Inhibitor in B-Cell Malignancies and Solid Tumors

INDIANAPOLIS--(BUSINESS WIRE)--Jun 21, 2010 - Semafore Pharmaceuticals today announced the presentation of preliminary clinical data demonstrating that SF1126 has clinical activity in chronic lymphocytic leukemia (CLL). SF1126 is a novel peptidic prodrug that converts to LY294002, one of the most widely studied small molecule inhibitors of both phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR). The results were presented at Cambridge Healthtech Institute's 8th Annual Next-Gen Kinase Inhibitors Oncology & Beyond Conference being held June 21-23, 2010, in Cambridge, Massachusetts.

“Recent data demonstrate that pan-PI3K inhibition may have desirable effects on chemotaxis and proliferation inhibition in CLL cells over delta isoform-selective PI3K inhibition,” Daruka Mahadevan, M.D. Ph.D., Director, Phase I Program, Arizona Cancer Center. “This provided a rationale to clinically explore the therapeutic activity of pan-PI3K inhibition with SF1126. While early, we are encouraged by the observed pharmacodynamic and clinical activity of SF1126 in two CLL patients, in addition to more mature data from solid tumor patients.”

Poster Title – “Update on the Novel Prodrug Dual mTOR-PI3K Inhibitor SF1126”

Solid Tumors

In an ongoing phase I dose escalation study in patients with solid tumors, SF1126 is administered twice per week on days one and four by a 90-minute intravenous infusion in cycles consisting of 4 weeks. To date 19 of 33 (58%) evaluable patients showed stable disease as best response with a median duration of 13 weeks (range 8 to +64) and a mean duration of about 19 weeks. Of particular note are three patients with stable disease for six months or longer, including a renal cell carcinoma patient previously resistant to the mTOR inhibitor temsirolimus with stable disease for 64 weeks that is still on study representing possible evidence of abrogating resistance to mTORC1 inhibition.

In the ongoing Phase I study the maximum tolerated dose was not reached, with the maximum administered dose being 1,110 mg/m2. SF1126 is well tolerated with the most common grade 1/2 adverse events being nausea, vomiting, diarrhea, fever, and fatigue. Dose levels above 140mg/m2 exceed levels of drug exposure found to be effective in preclinical xenograft studies.

B-cell Malignancies

Results of in vitro studies recently presented at the American Association for Cancer Research (AACR) annual meeting demonstrated broad anti-tumor activity with SF1126 across six lymphoma cell lines and supported expansion of the Phase I clinical evaluation in patients with certain B-cell malignancies, such as such as CLL, indolent non-Hodgkin's lymphoma (NHL), and mantle cell lymphoma (MCL).

Preliminary results from the first two CLL patients dosed in the Phase I expansion into B-cell malignancies suggest clinical activity of SF1126 manifested by changes in lymphocyte counts and pharmacodynamic marker indicative of blocking the pathway and inducing apoptosis.

About SF1126 and the PI3K Pathway

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is vital to several essential biological processes, such as cell growth, survival, motility, and metabolism. PI3K is commonly altered in human cancers, making inhibition of the target attractive for cancer therapy. However, the role of PI3K in a wide range of normal biologic processes raises potential concerns about its inhibition in non-cancerous tissues.

As the only PI3K/mTOR inhibitor prodrug currently in development, SF1126 is designed to overcome these concerns by accumulating preferentially in tumor tissue in an attempt to maximize efficacy and minimize toxicity. SF1126 is a peptidic prodrug that converts to LY294002, one of the most widely studied dual PI3K/mTOR inhibitors that historically suffered from poor solubility. LY294002 is conjugated to an Arg-Gly-Asp (RGD) peptide via a pH cleavable linker to form SF1126, which has improved properties for clinical use. As a prodrug with improved solubility and site selectivity due to targeting of RGD-recognizing integrin receptors, SF1126 opened up a new avenue for the clinical development of LY294002.

To date, nearly 50 patients with solid tumors or hematological malignancies have been treated with SF1126 in Phase I trials. Administration of SF1126 at doses ranging from 90 to 1,110 mg/m2 has been generally well tolerated with the most common treatment-related adverse events have been nausea, vomiting, diarrhea, fever, and fatigue.

About Semafore Pharmaceuticals

Semafore Pharmaceuticals is a private, clinical-stage biotechnology company dedicated to the discovery and development of novel small molecule signal transduction inhibitors targeting the phosphoinositide-3-kinase (PI3K) pathway for the treatment of cancer and other serious diseases. In addition to SF1126, the Company is developing SF2626, a next-generation dual MEK/PI3K inhibitor that is designed to simultaneously inhibit an additional key pathway critical to cancer progression using a single molecule. For more information see the company's web site at


Contact: Semafore Contact:
Michael D. Becker
Acting Chief Executive Officer, Semafore Pharmaceuticals
President and Chief Executive Officer, MD Becker Partners LLC


Posted: June 2010