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New Data Presented at AACR Meeting Support the Clinical Potential of Semafore`s Novel PI3K Prodrug


Al Musella's Comments: (This is his personal views and are not necessarily the views of the Musella Foundation!)



Website: http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/04-19-2005/0003435721&EDATE=

Posted on: 04/19/2005

New Data Presented at AACR Meeting Support the Clinical Potential of Semafore's Novel PI3K Prodrug


- Prominent Cancer Advisors Are Encouraged by SF 1126's Unique Mechanism and Promising Initial Results in a Variety of Pre-Clinical Cancer Models -

INDIANAPOLIS and ANAHEIM, Calif., April 19 /PRNewswire/ -- Semafore Pharmaceuticals, Inc., an emerging leader in small molecule cancer therapies addressing critical cell signaling pathways, today presented new in vivo data further demonstrating the potential utility of SF1126, the company's PI3K inhibitor delivered as a tumor-targeting prodrug. Despite the growing attention given to the importance of the PI3 kinase (PI3K) pathway in treating cancer, there currently are no PI3K inhibitors in clinical trials for oncology. The data presented today are the latest from a series of preclinical studies that demonstrate the potential safety, efficacy, and biological target activity of SF1126 and support its progress to clinical trials by early 2006. The data are being presented by Semafore researchers at the 96th Annual Meeting of the American Association for Cancer Research (AACR).

The PI3K pathway is a critical intercept point in cell signaling that controls multiple cellular functions including angiogenesis, apoptosis, migration, invasion and metastasis. Inhibiting PI3K is expected to minimize the possibility that alternative pathways will stimulate malignant cell growth. The high degree of interest in this pathway also reflects the fact that activation of PI3K is associated with resistance to Herceptin and a number of other cancer drugs, as well as to radiation treatment.

"SF1126 is a highly specific inhibitor of this well-characterized cell-signaling pathway that plays a crucial role in the life and death of cancer cells," said Gordon Mills, M.D., Ph.D., scientific advisor to Semafore and chairman, Department of Molecular Therapeutics at MD Anderson Cancer Center. "SF1126 achieves prolonged knockdown of PI3K in vivo with significant anti-tumor activity at multiple dose levels, and is well-tolerated. We are especially interested too in the fact that the Semafore prodrug shows activity against all three distinct isoforms of the PI-3 kinase pathway, which is important because each isoform may play a different role in cancer development. We look forward to helping to test whether this promising profile is confirmed in human studies."

Preclinical studies with SF1126 have demonstrated promise in a variety of cancers, including glioma, prostate, non-small cell lung, ovarian, and breast cancer. Researchers at Semafore, the National Cancer Institute, MD Anderson, Duke University, Johns Hopkins University, Emory University, Indiana University, the University of Pennsylvania, and others are also in the process of assessing SF1126 in colon cancer, melanoma, multiple myeloma, leukemia and other cancer types.

"SF1126 may be the first representative of a promising new class of drugs. In addition to sensitizing cancers to standard therapies, it affects both the tumor neovasculature and the tumor itself -- it's a dual effect," said Jonathan Simons, M.D., director of the Winship Cancer Center at Emory University and pro-bono science advisor to Semafore. "SF1126 may achieve these multiple effects at least in part by controlling levels of HIF-1a, which our studies at Emory have shown is a key transcription factor controlling angiogenesis and the production of VEGF. The data presented today are very promising in their demonstration that SF1126 reduces levels of HIF-1a in a dose dependent manner."

The importance of the Pl3K pathway in promoting tumor angiogenesis was discovered by Donald Durden, M.D., Ph.D., now senior scientific advisor to Semafore.

"Semafore's SF1126 builds upon our work to harness the power of a well-characterized PI3K inhibitor compound originally used as a research tool," said Dr. Durden, now at Emory University School of Medicine and a scientific director of the AFLAC Cancer Center at Emory. By targeting SF1126 to tumor neovascularization and delivering it as a prodrug, this compound has been transformed into an anticancer agent that appears to be safe and biologically active with an attractive pharmacokinetic profile -- everything one would want to see in a clinical candidate. These new data expand and confirm the promising data in the IND package for SF1126 which is currently being assembled."

The data presented at the AACR meeting show for the first time that high doses of SF1126 demonstrate significant efficacy, with up to 91% tumor growth inhibition, and were well tolerated in a multi-dose two week treatment study of mouse models of human prostate cancer. The doses were 50 and 100 mg/kg administered 7 times over two weeks of the six and one half week study period. The safety data presented are the first comprehensive analyses of such high dosages of this potent PI3K inhibitor, and they show that the treated mice exhibited no significant body or organ weight loss relative to controls. Also, their blood glucose and insulin levels were normal after 24 hours, and all blood cell count levels (white and red blood cells, hemoglobin, hematocrit, and platelet) were within normal ranges and statistically no different than controls.
Semafore researchers are also presenting data on key drug-like qualities of SF1126, including in vivo evidence of PI3K targeting and prolonged knockdown of the PI3K signal, complete shutdown of angiogenesis, and evidence that SF1126 controls tumor cell migration and the transcriptional activity of HIf-1a.

Poster Title: Targeting critical signaling pathways with a Pan-PI-3 kinase inhibitor: Focus on Safety and Efficacy of SF1126, HIF1a and the angiogenic process. Session Title: Late-Breaking Abstracts: Poster Session 1; 4/19/2005 8:00am-12:00pm; Exhibit Hall B-D, Anaheim Convention Center.

Authors: Jing Dong Su, Joseph R. Garlich, Xiaodong Peng, Toni Miller, Mary Patterson, Veranika Pazharskaya, Donald L. Durden. Semafore Pharmaceuticals, Inc., AFLAC Center for Cancer Research, Winship Cancer Center, Emory University School of Medicine.

About Semafore

Semafore is an Indianapolis-based drug discovery and development company focused on small molecule modulators of the PI3 Kinase (PI3K) and PTEN cell signaling pathway, one of the most promising target pathways for multiple disorders, including the company's focus -- cancer. Semafore is one of the first biopharmaceutical companies to focus on PI3K and PTEN and has successfully discovered and is developing a portfolio of drug candidates. These programs have the potential to be the first of a new class of targeted cancer agents. The company's lead clinical candidate, SF1126, is a pan-PI3K inhibitor, and the company expects to file an IND in early 2006, with subsequent studies in brain, breast, prostate, and ovarian cancers. Semafore has also discovered the first drug-like PTEN inhibitors for cell protection, therapeutic angiogenesis and cancer sensitization. These compounds have exciting potential to completely change the way cancer and other disorders are treated. For more information, see the company's Website http://www.semaforepharma.com .

Contacts:
Semafore Pharmaceuticals, Inc. Media:
Derek A. Small Stephen Gendel
Director of Corporate Development GendeLLindheim BioCom Partners
(317) 876-3075 (212) 918-4650
SOURCE Semafore Pharmaceuticals, Inc. Web Site: http://www.semaforepharma.com



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