The Sisene Biotechnology Experience Jean Marsac, MD PhD CEO, Sisene Pépinière Paris Santé Cochin, Paris, France Olivier Rixe, MD, PhD Director, Experimental Therapeutics Program GRU Cancer Center, Augusta, GA
Disclosure Jean Marsac : none Olivier Rixe : consultant, stockholder, Sisene Oncology 2
Sisene Company Profile 2007 Creation of SISENE, a Biotechnology Company developing new patented drugs in cancer and ophthalmology. Founded in 2007 by Jean Plouët, MD, PhD Pioneer of angiogenesis research in France. Co-discoverer of Vascular Endothelial Growth Factor (VEGF). Exclusive license of two patents (CNRS, INSERM, IVS) : Novel anti-angiogenic agent and its use, in particular in cancer treatment NOV and NOV C-ter, in preclinical development. Mutated Netrin-4, fragments thereof and their use as medicines. Two products with innovative non VEGF-dependent mechanisms of action : NOV C-ter : solid tumors, inflammatory and neovascular eye diseases. Netrin-4 : neovascular eye diseases. From Proof of concept to Clinical Phase 1. 2013 10 employees, including 5 full-time researchers. 3
Sisene Corporate Pipeline Objectives Development of innovative anti-angiogenic products for cancer and eye diseases treatment Mode of Action Targeting cancer cells and microenvironment Inhibiting neovascularization Products NOV/NOV C-ter Netrin-4 Clinical Targets Fast-track in Glioblastoma Other cancers Eye diseases 4
Accelerated development. Sisene Corporate Strategy SISENE focuses on Target Product profiles: Oncology therapeutics: Glioblastoma Ophthalmology therapeutics: Angiogenic (AMD), inflammatory lesions of the eye (Uveitis) Fast track registration: First entering the clinic with a glioma cancer indication. Strategic alliance with a big Pharma. 5
Sisene Private and Public Partnerships Private Industry Academic Research Teaching Hospitals 6
Private and Public Partnerships Private Industry: THEA Lab. (Leading independent Ophthalmic Group in Europe). Academic Research: Teaching Hospitals : Georgia Health Sciences University (GHSU), National Cancer Institute (NCI), University of Cincinnati (UC), INSERM, Paris V and Paris VI Universities. Cohortes of patients, Phase I clinical units, Complementary clinical research : Predictive markers, Dose-responses studies, Safety-efficacy margin in patients, Medico-economic assessment. 7
Innovation Financial Tools and Support JEI : Young innovative company status Incubator : Lodge new start-ups companies OSEO : Public financial innovation support CIR : Research Tax Credit Various Research Grants : French (national ANR, regional Critt) USA (research alliance GHSU) University Hospitals : Specific clinical research budget for clinical trials (proof of concept) Eligible : SME, < 8 years old, independant, R&D expenses > 15% deductible charges Eligible : after scientific evaluation Refund : in case of commercial success Eligible : after scientific evaluation Principles : 35% - 50% of R&D expenses Refund : 100.000 balance after commercial success Eligible : after scientific evaluation Principles : 40% - 35% - 30% of R&D costs No refund (subvention) Eligible : after scientific evaluation No refund (subvention) Eligible : after scientific evaluation No refund (subvention) 8
EVENTS Sisene Biotech Early Development Financing FINANCING YEARS : Minister of Research Incubator Paris Biotech Industrial partner (THEA) 2007/2008 2009 2010 2011 2012 Creation Innovation Awards & Support Seed Money 1 050 K US / NIH Grants CRADA Three year financing plan Creation Sisene Onco Inc. US - GHSU US dev. financing Innovation support (OSEO) Industrial partner (THEA) Research Tax Credit (CIR) 4 655 K Grants : ANR / Critt / Cifre US Res. Agreement CRITICAL PATH Preclinical Development IND Possible financing gap! IND? 9
Sisene Biotechnology perspectives Implement a partnership through GHSU Georgia University. Speed-up the registration process through an investigator IND. Focus on fast track procedure on Glioblastoma. Consolidate a strategic alliance with a big pharma : To work on additional developments in Oncology. To optimize the time to market and the first commercial revenues. 10
Nov C-Ter NOV/CCN3 is a founder member of a multimodular secreted proteins family: CCN (CYR61, CTGF, NOV): N IGFBP VWC Hinge TSP-1 CT C NOV NOV C-ter consists of a truncated NOV containing the thrombospondin (TSP-1) and C-terminal (CT) domains: TSP-1 CT C NOV C-ter 11
Nov C-Ter Physiology NOV C-ter is detected in human biological fluids (serum, cerebrospinal fluid ). NOV NOV C-ter is physiologically detected in many tissues (brain, heart, kidney, adrenal cortex ). Pathology NOV C-ter Human serum (protein) NOV C-ter mediates NOV anti-tumor activities in several models such as: Anti-proliferative activity Human Glioblastoma (Bleau et al. 2007). Pro-apoptotic activity Human Adrenocortical Cancer (Doghman et al. 2007). Thibout et al. 2003 12
Inhibition (%) Inhibition (%) Milestone #1: NCI - Mechanism of Action (1) Endothelial cells proliferation and migration: 70 60 50 40 30 20 10 0 Proliferation 0,5 µm 5 µm Migration Tube formation assay (tested in Human, Porcine and Macaque endothelial cells) in vitro: 50 40 30 20 10 0 0,5 µm 5 µm - FBS 1% FBS 1% FBS NOV C-ter 1μg/ml 1% FBS NOV C-ter 5μg/ml 1% FBS NOV C-ter 10μg/ml 1% FBS NOV C-ter 80μg/ml PAE cells, 4 hours treatment 13
Milestone #2 : UCCI - Anti-tumor effect (GBM) Confirm the efficacy of NOV C-ter (125µg/injection) Evaluate the efficacy of a lower dose (12.5µg/injection) Human Xenograft Model (X12) Sham PBS NOV C-ter 125µg Day 9 Sham: stereotaxic surgery without tumor cells injection. No toxic effect of NOV C-ter has been observed. 14
Milestone #3 : GRU Cancer Center Incorporation of Sisene Oncology in the US (Augusta, GA) GRA Grant Ongoing experiments Zebrafish nodel Validation on other in vivo models Toxicology studies Additional mechanistic studies (in vitro) 15
HUVEC Proliferaiton inhibition (%) Milestone #4 : NCI - Mechanism of Action (2) 50 40 NOV C-ter Dose: 5µM A new class of agent 30 20 10 0 VEGF bfgf Adrenomedullin (AM) Apelin-13 Apelin N- terminal fragment 16
Mechanism of Action (3) A new class of agent NOV C-ter an original mode of action in endothelial cells: NOV C-ter inhibits Adrenomedullin- and Apelin-induced endothelial cells proliferation. VEGF and AM-induced MAP Kinase and Akt phosphorylation are inhibited by NOV C-ter. P-AKT P-p44/42 Total AKT Total p44/42 NOV-CT 100ug/ml AM 10nM NOV-CT 100ug/ml VEGFA 10ng/ml NOV-CT 100ug/ml AM 10nM VEGFA 10ng/ml Ctl NOV-CT 100ug/ml AM 10nM NOV-CT 100ug/ml VEGFA 10ng/ml NOV-CT 100ug/ml AM 10nM VEGFA 10ng/ml Ctl 17
Thank you! 18