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

Number of companies dedicated to biotechnology: 570 (incl. 13 start ups) Number of employees in dedicated biotechnology companies 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

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 active substances tested in research lab will be placed on the market Drug development process source: Report: The German Biotechnology Sector 2014, biotechnologie.de

sterna biologicals GmbH - Company Overview ObjectiveDevelopment of novel DNAzyme-based therapies for chronic inflammatory diseases Lead Product SB010 for moderate and severe Th2-driven asthma Founded in2006 Employees10 Further Indications Atopic Dermatitis Ulcerative Colitis LocationMarburg, Germany Psoriasis COPD

DNAzymes as therapeutic agents DNAzyme specifically binds to target mRNA 1 DNAzyme cleaves GATA-3 mRNA 2 Decomposition of cleavage products; DNAzyme continues cleavage activity 3 Reduced mRNA levels resulting in decrease of translated protein with subsequent biological consequences

GATA-3 is the Master Transcription Factor in Th2-driven Inflammatory Diseases Source: Barnes P. JCI 118 (2008): GATA-3 plays a central role in the allergic inflammatory response Orchestrates a wide range of Th2- mediated cytokines, in particular IL- 4, IL-5, IL-9, and IL-13 Recent evidence that GATA-3 is also expressed directly in Mast cells, Epithelial cells, and Eosinophils further supports central role of GATA-3 By targeting GATA-3 directly, SB010 impacts multiple Th2-dependent downstream pathways (“broad spectrum“ approach)

Homburg et al. ``Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with T H 2- 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)Biodistribution of the GATA-3-specific DNAzyme hgd40 after inhalative exposure in mice, rats and dogs. 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)Toxicity profile of the GATA-3-specific DNAzyme hgd40 after inhalation exposure.Absence of unspecific innate immune cell activation by GATA-3-specific DNAzymes. Sel et al. "Effective prevention and therapy of experimental asthma using a GATA-3 specific DNAzyme." JACI (2008)Effective prevention and therapy of experimental asthma using a GATA-3 specific DNAzyme. Schmidts et al. " Protective effect of drug delivery systems against the enzymatic degradation of dermally applied DNAzyme." Int J Pharm (2011)Protective effect of drug delivery systems against the enzymatic degradation of dermally applied DNAzyme. Schmidts et al. " Development of drug delivery systems for the dermal application of therapeutic DNAzymes." Int J Pharm (2012)Development of drug delivery systems for the dermal application of therapeutic DNAzymes.

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

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

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

Toxicological program on the example of SB010 for asthma treatment

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

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

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

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

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] First in class II a: explorative POC study [multiple dose, patients] II b. Proof of concept study [multiple ascending dose, patients] Phase II clinical trial Primary goal: efficacy & safety ( patients, months to years) The number and design of clinical trials may vary depending on country and regulatory agency

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 quality requirements value risk Is it realistic for academic spin-off to place the drug on the market?

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

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

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