Optimizing Preclinical Proof of Concept

Slide 1: OPTIMIZING PRECLINICAL PROOF OF CONCEPT Presentation - May 13th, 2008 Presenter: Wendy Hill, M.Sc., Gap Strategies Inc.

Slide 2: Drug Development Timeline Years 6 1 2 3 1-2 Discovery / Review / Phase I Phase II Phase III Preclinical Approval < 1% 30% 70% 70% 80% % Success Rate Overall success rate: <10% for products entering Phase 1 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 1

Slide 3: Yearly Drug Development Costs 50 Millions of dollars 5 Discovery/ Phase I/II Phase III Preclinical OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 2

Slide 4: Why do drugs fail?  Toxicity (49%)  long term safety is still totally unpredictable  Bioavailability and half life (15%)  half life cannot be predicted, only guessed  Metabolism (3%)  drug/drug interactions; parent or metabolite  Man (33%)  understanding of pathophysiology is faulty OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 3

Slide 5: Early Animal Models  Follow-on to in-vitro testing  Used for target validation (transgenic knock-outs or knock-ins)  Used for the establishment of biomarkers (physiological, imaging …) to carry through clinical development  Used to select most promising development if multiple opportunities  Elucidate mechanism of action  Can be used for clinical dose determination  Provide preliminary toxicity finding in a disease model  Provide “Proof of Concept” for drug or device OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 4

Slide 6: Indication Selection  Early on must have some idea of potential indication for drug or device for this will direct preclinical development plan  Based on the manifestation of target in a disease process(es) select indication(s)  Mechanism of Action  Iterative process (medical need, market potential, ease of development pathway, strategy for development…) OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 5

Slide 7: Development Plan  Work backwards  Develop your plan or strategy through to approval  Costs, timelines, strategies, clinical trial designs  Important that the preclinical programme supports later development ex. incorporation of potential clinical trial design into preclinical POC (prophylaxis vs. treatment models)  Return to this plan to ensure consistency in development process  Should form part of your Business Plan OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 6

Slide 8: Issues with Animal Models  Not always predictive of human efficacy  Not always predictive of human drug metabolism  Small animals have compressed “life line” with accelerated disease processes that differ from the human  Difficult to recreate the human disease condition in an animal  Animals that more closely resemble the human condition are expensive and difficult to work with (primates) OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 7

Slide 9: WHAT STRATEGIES CAN BE EMPLOYED TO….

Slide 10: … Learn More about MOA and Target Indication  If target is widely applicable, study it in several different disease models (body of evidence)  Choose well-established models  Choose relevant species models (ex. pig for coagulation, dog for electrophysiology)  Choose models that have been predictive for other compounds and select one of these compounds as positive control  Design protocols that mimic the course of disease and the application of the intervention (is it treatment or prophylaxis?)  Develop validated assays for measurement of biomarkers collected during each study  Can be done as academic collaborations (NIH) not GLP OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 9

Slide 11: … Support IND Filing  For certain compounds like targeted biologics - you may realize a physiological effect (efficacy) at doses far lower than those determined to be dose limiting in animal toxicity studies  Animal safety and toxicity studies are usually performed on “normal” animals that may not express a disease target  Toxicities may be quite different in an “expressing” animal model  For these reasons both the FDA and EMEA have issued guidance documents  Committee for Medicinal Products for Human Use (CMPH): Guideline on Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials with Investigational Medicinal Products - July 19 2007  FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers - July 2005 OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 10

Slide 12: Selection of the Maximum Recommended Starting Dose (MRSD) No observed adverse effect levels (NOAEL) OR pharmacologically active dose (PAD)/minimal anticipated biological effect level (MABEL) Conversions of selected dose to human equivalent dose (HED) Determine MRSD based on HED and safety factors OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 11

Slide 13: … Support IND Filing  Include dose-finding and limited pharmacokinetic sampling  Include measures of toxicity  Bridge to preclinical safety species  Use drug that is as close to final GMP formulation as possible  Choose animal species that most closely resembles human application and human physiology  Look at in vitro binding studies and choose species that is similar to humans OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 12

Slide 14: … Ensure Quality of the Data and Results  Include a negative control as well  If possible “blind” the evaluation  Develop protocol for each study prospectively and try to adhere to this  Choose established CRO or academic collaborators that work under “GLP-like” standards OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 13

Slide 15: … Support Commercialization OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 14

Slide 16: Size of Potential Early Alliances OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 15

Slide 17: … Support Commercialization  Choose comparators that are relevant in the current market place  Protect or enhance patent position – time publications carefully  Engage potential partners or licensors in discussions of preclinical models – What do they need to see to be convinced of animal efficacy? OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 16

Slide 18: The Last Word  Utilize your animals to learn as much as possible for about your compound  Establish a Development Plan in order to ensure the preclinical strategy supports this plan  In the absence of funding seek out academic collaborations (ex. NIH intramural scientists)  Understand what will be required to enhance your financing opportunities  Protect your IP position (publications/contracts)  If you proceed to clinical continue parallel preclinical development OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 17

Slide 19: OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 18

Slide 20: Summary  Establish your development plan BEFORE embarking on preclinical development  Make sure you understand the physiology of your targeted disease and your compound and design your nonclinical POC and studies accordingly  Seek advice from those who have experience OPTIMIZING PRECLINICAL PROOF OF CONCEPT Slide 19