optimizing preclinical proof of concept

OPTIMIZING PRECLINICAL PROOFOF CONCEPT

Presenter:

Wendy Hill, M.Sc., Gap Strategies Inc.

Presentation - May 13th, 2008

OPTIMIZING PRECLINICAL PROOF OF CONCEPT

Drug Development Timeline

Discovery /Preclinical Phase I Phase II Phase III Review /

Approval

16 2 3 1-2

Years

30% 70% 70% 80%

Overall success rate: <10% for products entering Phase 1

% Success Rate

< 1%


Yearly Drug Development Costs

Discovery/Discovery/PreclinicalPreclinical

Phase Phase I/III/II Phase Phase IIIIII

55

MillionsMillionsofofdollarsdollars

5050


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


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


Indication Selection

Early on must have some idea of potential indication for drug ordevice 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 developmentpathway, strategy for development…)


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 intopreclinical POC (prophylaxis vs. treatment models)

Return to this plan to ensure consistency in development process

Should form part of your Business Plan


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 diseaseprocesses that differ from the human

Difficult to recreate the human disease condition in an animal

Animals that more closely resemble the human condition areexpensive and difficult to work with (primates)

WHAT STRATEGIES CAN BEEMPLOYED TO….


… Learn More about MOA and TargetIndication 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 ofthese compounds as positive control

Design protocols that mimic the course of disease and the application of theintervention (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


… 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 animaltoxicity studies

Animal safety and toxicity studies are usually performed on “normal” animals that maynot 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 onStrategies to Identify and Mitigate Risks for First-In-Human Clinical Trials withInvestigational Medicinal Products - July 19 2007

FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in InitialClinical Trials for Therapeutics in Adult Healthy Volunteers - July 2005


Selection of the Maximum RecommendedStarting Dose (MRSD)

No observed adverse effectlevels (NOAEL) OR

pharmacologically active dose(PAD)/minimal anticipated

biological effect level (MABEL)

Conversions of selected doseto human equivalent dose

(HED)

Determine MRSD based onHED and safety factors


… 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 humanapplication and human physiology Look at in vitro binding studies and choose species that is similar to

humans


… 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 tothis

Choose established CRO or academic collaborators that work under“GLP-like” standards


… Support Commercialization


Size of Potential Early Alliances


… 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 preclinicalmodels – What do they need to see to be convinced of animalefficacy?


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 strategysupports this plan

In the absence of funding seek out academic collaborations (ex. NIHintramural 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


Summary

Establish your development plan BEFORE embarking on preclinicaldevelopment

Make sure you understand the physiology of your targeted disease and yourcompound and design your nonclinical POC and studies accordingly

Seek advice from those who have experience