• Integrins – Targets for New Therapeutics
• Age-related Macular Degeneration – Blindness in the Elderly
• Treatment for Cancer – Inhibition of Angiogenesis

Integrins – Targets for New Therapeutics

Integrins, a class of receptors found in many cell types, are responsible for cell proliferation, migration, adhesion, and differentiation. Survival signals from the extracellular matrix are mediated through these receptors into the cells, influencing several biological pathways. In the last few years, Jerini’s scientists and several other research groups have shown that α5β1 integrin plays a critical role in angiogenesis (formation of new blood vessels), inflammation, and fibrosis. Excessive angiogenesis occurs in a range of indications including cancer, diabetic blindness, age-related macular degeneration (AMD), rheumatoid arthritis, and psoriasis. The fact that this integrin is significantly upregulated in disease processes, and only expressed to a limited extent in normal cells, forms the basis for a new and safe therapeutic approach.
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Age-related Macular Degeneration – Blindness in the Elderly

In age-related macular degeneration (AMD), the leading cause of blindness in people over the age of 55, angiogenesis, inflammation, and fibrosis are observed. Based on Jerini’s studies showing that α5β1 integrin is highly upregulated in typical AMD lesions, the company has been the first to sucessfully develop a small molecule α5β1 integrin receptor antagonist that is active in the subnanomolar range. Preclinical results have shown the drug’s potential as a treatment for AMD. In comparison to other therapies, Jerini’s drug candidate not only blocks angiogenesis, induced by multiple growth factors, but also inhibits the downstream effects of other growth factors and the often concurrent physiological processes leading to inflammation and fibrosis. JSM 6427 is also a potential drug candidate for combined use with other approved anti-VEGF therapies. Jerini’s wholly-owned subsidiary, Jerini Ophthalmic, Inc., will focus on the further development of JSM 6427 and in October 2007, treated its first patient in a Phase I clinical trial for AMD and the results are expected in the second half of 2008.
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Treatment for Cancer – Inhibition of Angiogenesis

Given that tumors are unable to grow beyond a volume of 1-2 mm³ without blood supply, the inhibition of angiogenesis is an important approach to cancer therapy. The therapeutic potential of angiogenesis inhibitors to treat tumor diseases has been demonstrated by the approval of Avastin® and Nexavar®. However, the anti-angiogenic drugs currently marketed are mainly used in combination with chemotherapy. Most important is that α5β1 integrin has been shown to be highly expressed in the tumor vasculature of cancer patients, with only low expression seen in normal blood vessels. This selective integrin expression opens up a new approach for improved cancer therapy. With an α5β1 integrin antagonist, tumor vessels can be targeted specifically, thereby potentially minimizing the undesirable side effects of chemotherapy, which acts on healthy as well as cancer cells. Jerini is developing highly specific, orally available small molecule α5β1 integrin antagonists for the treatment of solid tumors. Initial testing of these drug candidates has shown positive efficacy and tolerability.


Publications:

Umeda N, Kachi S, Akiyama H, Zahn G, Vossmeyer D, Stragies R, Campochiaro PA. Suppression and regression of choroidal neovascularization by systemic administration of an a5b1 integrin antagonist, Mol Pharmacol. 2006; 69, 1820-1828

Dietrich T, Onderka J, Bock F, Zahn G, Stragies R, Kruse FE, Cursiefen C. Selective inhibition of lymphangiogenesis by integrin a5 blockade – Functional role of integrins in lymphangiogenesis, J Am Path. 2007 May 24; [Epub ahead of print]

Roland Stragies, Gunther Zischinsky, Frank Osterkamp, Ulf Reimer, Dörte Vossmeyer, Grit Zahn, Design and synthesis of a new class of selective Integrin a5b1 Antagonists J Med Chem, 2007

Dominik Heckmann, Axel Meyer, Luciana Marinelli, Grit Zahn, Roland Stragies, Horst Kessler. Probing Integrin Selectivity: Rational Design of Highly Active and Selective Ligands for the a5b1 and avb3 Integrin Receptor, Angewandte Chemie Int Ed Engl. 2007;46(19):3571-4

Muether, P. S.; Dell, S.; Kociok, N.; Stragies, R.; Zahn, G.; Kirchhof, B.; Joussen, A. M. Integrin a5b1-Inhibiting Small Molecule Reduces Corneal Neovascularisation. Exp Eye Res 2007, in press

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