Kosan Announces Selection of KOS-2187 as Motilide Clinical Candidate at World Congress of Gastroenterology Meeting
7:30 AM EDT September 12, 2005
Kosan Biosciences Incorporated (Nasdaq: KOSN) today presented here at the World Congress of Gastroenterology 2005 preclinical data supporting the selection of KOS-2187, a novel erythromycin-based motilin agonist, or motilide, as a clinical candidate for the treatment of gastrointestinal motility disorders such as gastroparesis and gastroesophageal reflux disease (GERD).
Erythromycin is an effective treatment for gastroparesis; however, some of its properties, including antibiotic activity, are not appropriate for a drug designed for chronic use over a patient's lifetime. Earlier efforts to produce erythromycin analogs with reduced antibiotic activity resulted in compounds that lost efficacy in repeated dosing regimens (tachyphylaxis). These compounds also block the hERG channel in the heart, a finding associated with an increased risk for dangerous arrhythmias, or irregular heart rhythms.
In one presentation ("KOS-2187: An Orally Active Motilin Agonist with an Improved Safety Profile," Abstract #LB-015), Kosan scientists describe the properties of KOS-2187 that make it an optimal candidate for further development. KOS-2187 is a potent motilin agonist that lacks undesirable antibiotic activity and retains activity in a model of tachyphylaxis. In vitro studies indicate that KOS-2187 is at least 20-fold more potent as a motilin agonist than erythromycin and has a 10-fold weaker affinity for the hERG channel than erythromycin. Testing in a validated dog model showed that KOS-2187 has high oral bioavailability, is rapidly absorbed, and significantly accelerates gastric emptying.
"These results demonstrate that KOS-2187 addresses the serious limitations of first-generation erythromycin analogs," said Pieter Timmermans, Kosan Senior Vice President, Preclinical Development. "We have initiated studies to support the entry of this compound into human clinical trials, expected to begin in the second half of 2006."
A second presentation ("Optimized Motilin Agonist Prokinetics," Abstract #DR-0158) describes the approach employed by Kosan scientists to design safe and effective motilin agonists. Early erythromycin derivatives with high potency, reduced antibiotic activity, and decreased tachyphylaxis were used as scaffolds for structural optimization to reduce the hERG interaction and further decrease the potential for tachyphylaxis. Resulting lead candidates were evaluated in a series of in vitro assays that demonstrated negligible antibiotic activity, minimal tachyphylaxis, and a five- to 40-fold greater potency over erythromycin. In addition, the lead candidates had significantly lower effects of hERG channel inhibition than erythromycin. In vivo studies confirmed oral availability and the ability to accelerate gastric emptying.
About Kosan
Kosan Biosciences currently has two first-in-class anticancer agents in Phase II and Phase Ib clinical trials: KOS-862 (Epothilone D) and 17-AAG, an Hsp90 (heat shock protein 90) inhibitor and geldanamycin analog. Kosan's most advanced compound, KOS-862, which is in two Phase II clinical trials and multiple Phase Ib clinical trials, and its follow-on compound, KOS-1584, which is in Phase I clinical trials, are partnered with Roche through a global development and commercialization agreement. Kosan is developing 17-AAG and a second-generation geldanamycin analog, KOS-1022 (DMAG), that is in Phase I clinical trials, in collaboration with the NCI. Kosan is also conducting Phase I and Phase Ib clinical trials of its proprietary formulation of 17-AAG, KOS- 953. Kosan has generated a pipeline of additional product candidates for gastrointestinal motility, infectious diseases and cancer based on its proprietary technologies for discovering, developing and manufacturing polyketide analogs. All of Kosan's product candidates, including those in clinical development, are polyketides. Polyketides are an important class of natural products that have yielded numerous pharmaceuticals for the treatment of cancer, infectious diseases, high cholesterol, transplant rejection and other diseases. For additional information on Kosan Biosciences, please visit the Company's website at www.kosan.com. |
