Spin-off in Practice: German Biotech Experience from a Polish Perspective

1. Spin-off in practice German experience from Polish perspective Dr. Agnieszka Turowska Warsaw, 2015

2. Number of companies dedicated to biotechnology: 570 (incl. 13 start ups) • Number of employees in dedicated biotechnology companies 16.950 • Over 90 drugs in clinical trial testing • R&D expenditure of dedicated biotechnology companies 899 Mio.€ • The German Biotechnology Sector 2014 source: Report: The German Biotechnology Sector 2014, biotechnologie.de

3. 10-15 years for a drug to travel from the research lab to the patient. • 1 to 3 billion euros is the cost of a new drug development from the research lab to the patient • 1 in 10 000 active substances tested in research lab will be placed on the market • Drug development process source: Report: The German Biotechnology Sector 2014, biotechnologie.de

4. Objective Lead Product Founded in Employees Location Development of novel DNAzyme-based therapies for chronic inflammatory diseases SB010 for moderate and severe Th2-driven asthma 2006 10 Marburg, Germany • sterna biologicals GmbH - Company Overview • Atopic Dermatitis • Ulcerative Colitis • Psoriasis • COPD Further Indications

5. 1 DNAzymespecificallybindstotargetmRNA DNAzymecleaves GATA-3 mRNA Decompositionofcleavageproducts; DNAzymecontinuescleavageactivity 2 3 • DNAzymes as therapeutic agents ReducedmRNAlevelsresulting in decreaseoftranslatedprotein with subsequent biologicalconsequences

6. GATA-3 plays a centralrole in theallergicinflammatoryresponse • Orchestrates a widerangeof Th2-mediated cytokines, in particular IL-4, IL-5, IL-9, and IL-13 • Recentevidencethat GATA-3 is also expresseddirectly in Mast cells, Epithelialcells, andEosinophilsfurthersupportscentralroleof GATA-3 • BytargetingGATA-3 directly, SB010 impacts multiple Th2-dependent downstreampathways (“broadspectrum“ approach) • GATA-3 is the Master Transcription Factor • in Th2-driven Inflammatory Diseases Source: Barnes P. JCI 118 (2008): 3546-3556.

7. Homburg et al. ``Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma`` J Allergy Clin Immunol (2015) Turowska et al. ``Biodistribution of the GATA-3-specific DNAzyme hgd40 after inhalative exposure in mice, rats and dogs." Toxicol Appl Pharmacol (2013) Fuhst et al. ``Toxicity profile of the GATA-3-specific DNAzyme hgd40 after inhalation exposure." Pulm Pharmacol Ther. (2013)Dicke et al. "Absence of unspecific innate immune cell activation by GATA-3-specific DNAzymes." Nucleic Acid Ther (2012) Sel et al. "Effective prevention and therapy of experimental asthma using a GATA-3 specific DNAzyme." JACI (2008) Schmidts et al. " Protective effect of drug delivery systems against the enzymatic degradation of dermally applied DNAzyme." Int J Pharm (2011) Schmidts et al. " Development of drug delivery systems for the dermal application of therapeutic DNAzymes." Int J Pharm (2012)

8. Preclinical program • Toxicology and local tolerability studies • Investigational Medical Product (IMP) • Phase I clinical trial • Phase II clinical trial • Phase III clinical trial • Phase IV clinical trial • Key development milestones for biotech • spin-off company

9. To know and understand the pathogenesis of the disease • To identify crucial pathways and interfere with them by appling a drug molecule • To demonstrate specificity of the molecule (target regulation) • To proof efficacy in in vitro and in vivo animal model(s) • To determine optimal and minimal effective dose • To determine optimal application regimen • To evaluate uptake, kinetics and distribution • To investigate potential off-target effects • To develop analytical method of drug detection • Time: 1-3 years, outsourcing vs internal development • Preclinical program

10. Preclinical program • Toxicology and local tolerability studies • Investigational Medical Product (IMP) • Phase I clinical trial • Phase II clinical trial • Phase III clinical trial • Phase IV clinical trial • Key development milestones for biotech • spin-off company

11. Toxicological program • on the example of SB010 for asthma treatment

12. Toxicological program • on the example of SB010 for asthma treatment • Certified Good Laboratory Practice (GLP) Facility • Parallel vs. sequential proceeding (risk/benefit ratio) • The number and design of toxicology studies may differ depending on country and regulatory agency • Time: 1-3 years

13. Preclinical program • Toxicology and local tolerability studies • Investigational Medical Product (IMP) • Phase I clinical trial • Phase II clinical trial • Phase III clinical trial • Phase IV clinical trial • Key development milestones for biotech • spin-off company

14. GMP (Good Manufacturing Practice) certified manufacturing • Stability studies (min. 6 months) • Certified Packaging • Transport & distribution • Investigational Medical Product (IMP)

15. Preclinical programm • Toxicology and local tolerability studies • Investigetional Medical Product (IMP) • Phase I clinical trial • Phase II clinical trial • Phase III clinical trial • Phase IV clinical trial • Key development milestones for biotech • spin-off company

16. Phase I clinical trial Primary goal: safety & tolerabilty (20-80 subjects, weeks to months) • Clinical Trial Overview First in class First in man I a: safety & tolerability [single dose, healthy subjects] I b: safety & tolerability [multiple doses, healthy subjects] I c: safety & tolerability [single dose, patients] • Phase II clinical trial • Primary goal: efficacy & safety (30 -200 patients, months to years) First in class II a: explorative POC study [multiple dose, patients] II b. Proof of concept study [multiple ascending dose, patients] • The number and design of clinical trials may vary depending on country and regulatory agency

17. Preclinical program • Toxicology and local tolerability studies • Investigational Medical Product (IMP) • Phase I clinical trial • Phase II clinical trial • Phase III clinical trial • Phase IV clinical trial • Key development milestones for biotech • spin-off company value risk quality requirements Is it realistic for academic spin-off to place the drug on the market?

18. Scientific publications • Conference presentations & posters • Reports from preclinical and toxicological studies a including raw data • Documents submitted to regulatory agencies: Investigator´s Brochure (IB), clinical trial protocol, Investigational Medical Product Dossier (IMPD) • Audit reports of the external collaborators • SOP (Standard Operating Procedure) process overview • Evaluation criteria

19. The goal & destination of academic spin-off should be defined at the beginning based on: human resources, financial status, potential of research facility • Interaction with business partners is inscribed in the nature of academic spin-off • Therefore, quality standards required by business partners have to be fullfilled (or exceeded!) in order to ensure collaboration and secure seed financing • Meeting quality standards in practice means that the structure of academic spin-off should be carefully designed (professional writer & quality control, GLP) • Summary

20. Thank you