Parstatin: a novel pharmacological target for the development of new agents in the treatment of cardiovascular diseases Nikos E. Tsopanoglou Assistant Professor Department of Pharmacology, Medical School, University of Patras

Our discovery Human peptide (MW: 4468 Da) M 1 GPRRLLLVAACFSLCGPLLSARTRARRPESKATNATLDPR 41 PARstatin An endogenous molecule with potential therapeutic applications

Parstatin, a novel anti-angiogenic agent with ophthalmic therapeutic application Control Parstatin 2 x 75μgParstatin 2 x 100μg (Corneal model) Parstatin (Choroid model)(Retinal model) Control Parstatin It was established in three animal models with neovascular diseases

Parstatin protects myocardium from ischemia and reperfusion injury Control Parstatin It was established in animal model of I/R injury

Parstatin structure-function analysis M 1 GPRRLLLVAACFSLCGPLLSARTRA 26 T 24 RARRPESKATNATLDPR 41 T 24 RARRPESKATNATLDPR 41 Parstatin 1-26 protects myocardium from I/R injury Parstatin inhibits ocular neovascularization

The opportunity in neovascular ocular diseases Approved treatment only for age-related macular degeneration  Macugen® (Eyetech/Pfizer). - The average patient continues to lose vision and only a very small percent (5%) gained vision  Lucentis® (Genentech) - It is effective only in 35-40% of the patients - It cost $23.400/treatment and - the sales for 2008 for Lucentis were $880 million - the projected future sales are estimated to reach $9 billion/year - more than 35 million people currently suffer from ocular diseases in the USA - the annual cost of vision impairment from eye diseases in the USA alone is $68 billion

The opportunity in cardiovascular and renal diseases  Essential medical conditions in which I/R injury is playing a key role are: In cardiology – myocardial infarctions, cardiac and thoracic surgery and neurosurgery In neurology – stroke and brain traumas In transplantations – after every organ transplantation  There are no available approved treatments  It remains an unmet medical need for novel agents to treat, prevent or protect myocardium from the onset or severity of these conditions.

Publications 1.Zania P, et al. Parstatin, the cleaved peptide on proteinase-activated receptor 1 activation, is a potent inhibitor of angiogenesis. J Pharmacol Exp Ther, 2009, 328: Strande JL, et al. Parstatin: a cryptic peptide involved in cardioprotection after ischemia and reperfusion injury.Cardiovasc Res, 2009, 83: Routhu KV, et al. Parstatin (1-26): The putative signal peptide of PAR1 confers potent protection from myocardial ischemia-reperfusion injury. J Pharmacol Exp Ther, 2010, 332: Huang H, et al. Parstatin suppresses ocular neovascularization and inflammation. Invest Ophthalmol Vis Sci, 2010, 51: Zampatis ED, et al. The protease-activated receptor 1 possesses a functional and cleavable signal peptide which is necessary for receptor expression. FEBS Lett, 2012, 586: Diamantopoulos A, et al. Parstatin prevents renal injury following ischemia/reperfusion and radiocontrast administration. Am J Nephrol, 2012, 36:

Patent Applications 1. Tsopanoglou N.E and Maragoudakis M.E. Bioactive peptides and methods of use. Patent No: US 8,227,412 B2, filed March 25, Tsopanoglou et al. Parstatin peptides and uses thereof. U.S.A. Patent Continuation-in-Part Application, No: 12/645,991, filed December 23, Tsopanoglou et al. Peptides. International Patent Application (PCT), No: WO 2011/039584, filed August 5, Tsopanoglou et al. Peptides derivatives. U.S.A. Patent Application, No: 13/499,481, filed April 1, Tsopanoglou et al. Peptides derivatives. European Patent Application, No: EP , filed April 1, Tsopanoglou et al. Peptides derivatives. Australian Patent Application, No: , filed April 1, Tsopanoglou et al. Peptides derivatives. Canadian Patent Application, No: 2,776,778, filed April 1, 2012.

Our Mission and objectives Secure funds to develop Parstatin peptides to IND stage for at least one (1) indication (e.g. AMD) in a two year period To bring to the clinic novel drugs for the treatment of: - ocular angiogenesis-based diseases - ischemia/reperfusion injury-based diseases

Work Plan for Developing Parstatin peptides Seeking for investments Preclinical development  Research (mechanism of action)  Safety (toxicological studies)  Pharmacology (pharmacodynamic, pharmacokinetic studies)  Pharmacy (formulations, route of administration) IND submission to FDA or/and EMEA Parstatin Discovery and Development Process Post-launch Activities Registration Phase III Trials Phase II Trials PoC/Phase I Trials Early Clinical Safety and Efficacy Lead Optimization Hit Finding Target Identification and Validation Drug Discovery Early Development Full Development We Are Here IND

Advantage of Parstatin Project Solid scientific background of inventors with international collaborations Innovative, First in Class Product Well-thought Strategy of Development Intellectual property protection (USA, PCT patents) Unmet medical needs with a very large potential market Experienced, Balanced & Motivated Team which will proactively mitigate risks