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Studies Formed Basis for Recently Initiated Clinical Trial
Cambridge, MA, USA | June 18, 2008 | Molecular Insight Pharmaceuticals, Inc. (NASDAQ: MIPI) today announced three presentations at the Society of Nuclear Medicine (SNM) 55th Annual Meeting on preclinical data supporting its Trofex program for the detection, staging and monitoring of prostate cancer. The presentations described the synthesis, production and preclinical profile of two lead candidate compounds, MIP-1072 and MIP-1095. These compounds provide the foundation for the Company’s recently initiated clinical program and support Molecular Insight’s small molecule approach to the discovery and development of molecular imaging pharmaceuticals. Molecular Insight is conducting an exploratory clinical trial with the two lead candidates with the goal of selecting a compound for further commercial development.
MIP-1072 and MIP-1095 both target prostate-specific membrane antigen (PSMA), a protein that is highly expressed by prostate tumor cells. Molecular Insight’s Trofex program is designed to fill an important need in prostate cancer disease management by identifying and staging tumors, particularly in metastatic disease where patients have no obvious symptoms other than increasing levels of the established biomarker, prostate specific antigen (PSA). Detection and staging are important in designing appropriate treatment regimens for patients. Prostate cancer is the second leading cause of cancer-related deaths in men in the United States, with an estimated 28,000 deaths, according to the American Cancer Society. There will be an estimated 186,000 new cases diagnosed in 2008.
"PMSA is recognized as a promising target for molecular imaging of prostate cancer and these studies demonstrate that both compounds generate high quality images based on their specific binding to PSMA and accumulation in tumor cells," said John W. Babich, Ph.D., President and Chief Scientific Officer of Molecular Insight. "The research also demonstrates Molecular Insight’s ability to design, synthesize and optimize novel small molecule compounds with distinct pharmacokinetic profiles."
Study Details
Synthesis and Preclinical Evaluation
The first study, delivered as an oral presentation, described the synthesis and preclinical evaluation of the lead compounds from a series of small molecule PSMA inhibitors. MIP-1072 and MIP-1095 were selected for further evaluation after initial studies demonstrated that they competed for binding to PSMA on prostate cancer cells (with IC50 values of 24 +/- 8 and 10 +/- 3 nM, respectively), inhibited the NAALADase activity of PSMA, (Ki = 6 +/- 2 and 0.3 +/- 0.1 nM, respectively), bound to PSMA with high affinity (Kd = 3.8 +/- 1.4 and 1.08 +/- 0.03 nM, respectively) and internalized in prostate cancer cells. Peak tumor uptake in human tumor xenograft models ranged from 18-38 %/ID/g. Tumor uptake was completely blocked with a structurally unrelated compound. SPECT imaging demonstrated localization to PSMA (+) tumors and kidney but not in other tissues.
The study is entitled, "Small Molecule PSMA Inhibitors for Targeted Molecular Imaging of Prostate Cancer." The authors are: Shawn M. Hillier, Kevin P. Maresca, Frank J. Femia, Chris Barone, Craig N. Zimmerman, John A. Barrett, William C. Eckelman, John L. Joyal and John W. Babich, of Molecular Insight Pharmaceuticals; and Catherine A. Foss and Martin G. Pomper, of Johns Hopkins Medical Institutions.
In the second poster presentation, Molecular Insight reported on structure activity studies that led to the development of lead candidate compounds MIP-1072 and MIP-1095. The studies used a Glu-urea-Lys pharmacophore as the building block for a series of Glu-urea-X heterodimers. The studies established a structure activity relationship for two series of compounds. A benzyl lysine series of compounds showed a clear relationship between the nature of the halogen substituent and PSMA binding affinity. In addition, binding affinity was influenced by the position of the halogen atom on the aryl ring. The nature of the halogen atom had little effect on the binding affinity in the parasubstituted penylureido-Lys series.
The study is entitled: "The Development of an SAR with Small Molecule Inhibitors of Prostate Specific Membrane Antigen (PSMA)." Authors are Kevin P. Maresca, Shawn M. Hillier, Frank J. Femia, Chris Barone, Donna Keith, John L. Joyal, Craig N. Zimmerman, John A. Barrett, William C. Eckelman and John W. Babich, of Molecular Insight Pharmaceuticals.
Radiosynthesis
The third study, presented as a poster, reported on a high specific activity synthesis method for producing 123I-MIP-1095 for Phase 1 clinical trials. The radioiodination and purification procedure yielded a drug with high radiochemical yield (RCY), radiochemical purity (RCP), and specific activity (SA). 123I MIP-1095 was produced by radioiodination of the trimethyl-tin MIP-1095 tri-t-butyl ester precursor with Na123 I followed by the deprotection of the t-butyl ester groups. The high RCY, RCP, and SA compound was achieved through optimization of pH, reaction time and method of purification.
The study is entitled: "[123 I]-MIP-1095 for Targeting Prostate Cancer via Prostate Specific Membrane Antigen (PSMA): A High Specific Activity Radiosynthesis." The study authors are: Frank J. Femia, Kevin P. Maresca, Shawn M. Hillier, John C. Marquis, Eduard Luss-Lusis, Craig N. Zimmerman, John L. Joyal, Brian Abeysekera, James F. Kronauge and John W. Babich, of Molecular Insight Pharmaceuticals.
About Molecular Insight Pharmaceuticals, Inc.
Molecular Insight Pharmaceuticals (NASDAQ: MIPI) is a biopharmaceutical company specializing in the emerging field of molecular medicine, applying innovations in the identification and targeting of disease at the molecular level to improve healthcare for patients with life-threatening diseases. The company is focused on discovering, developing and commercializing innovative, molecular radiotherapeutics and molecular imaging pharmaceuticals with initial applications in the areas of oncology and cardiology. Its lead molecular radiotherapeutic product candidates, Azedra and Onalta, are being developed for detection and treatment of cancer. The company's lead molecular imaging pharmaceutical product candidate, Zemiva, is being developed for the diagnosis of cardiac ischemia, or insufficient blood flow to the heart. In addition, the company has a growing pipeline of product candidates resulting from application of its proprietary platform technologies to new and existing compounds. Molecular Insight Pharmaceuticals is based in Cambridge, Massachusetts and its website address is: www.molecularinsight.com.
SOURCE: Molecular Insight Pharmaceuticals, Inc. |
