The document summarizes Session III of a conference on pre-clinical proof-of-concept and development. It includes presentations on: 1. Edward Spack discussing the session overview and requirements for an Investigational New Drug (IND) application. 2. David Weiner presenting on what makes a clinical candidate, including factors like target selection, lead optimization, pre-clinical safety assessments, and estimating human starting doses. 3. Steve Perrin presenting on optimization and characterization of mouse models of neurodegeneration. 4. Barry Greenberg presenting on the value of biomarkers in preclinical development and translatable endpoints.

1. SESSION III
Pre-Clinical Proof-of-Concept and
Development
Chair — Edward G. Spack, PhD, Fast Forward, LLC
Session Overview
Edward G. Spack, PhD, Fast Forward, LLC
What Makes a Clinical Candidate?
David Weiner, MD
Requirements for an IND
Edward G. Spack, PhD, Fast Forward, LLC
Optimization and Characterization of Mouse Models of Neurodegeneration
Steve Perrin, PhD, ALS Therapy Development Institute
Value of Biomarkers in Preclinical Development: Translatable Endpoints
Barry Greenberg, PhD, Toronto Dementia Research Alliance

2. SESSION III:
Pre-clinical Proof-of-Concept and Development
Phase I - Safety
HTS
Med Chem Phase II – Efficacy
Dose
ADME
Phase III – Definitive
Efficacy & Safety
PD
PK NDA
BLA
Label
TPP
Janus
IND

3. SESSION III:
Pre-clinical Proof-of-Concept and Development
David Weiner: What Makes a Clinical Candidate?
Edward Spack: Requirements for an IND
Steve Perrin: Optimization and Characterization of Mouse Models of Neurodegeneration
Barry Greenberg: Value of Biomarkers in Preclinical Development: Translatable Endpoints

4. What Makes a Clinical Candidate?
Alzheimer’s Drug Discovery Foundation
February 13, 2012
Dr. David M Weiner MD

5. Goals of the Presentation
 Highlight various factors that need to be
considered in choosing a viable candidate for
clinical investigation
 Pre-clinical characteristics
 Preparing for first in human studies
 Objectives and goals for (early) clinical
development
 Discuss clinical dynamics of the treatment
landscape, TPP, and time

6. Improving patient care and clinical
outcomes is the motivating goal
 Symptomatic treatments targeted to the clinical
symptoms which underlie morbidity
 Existing drugs are often indicated to treat the “signs and
symptoms” of neurological disease
 To improve upon existing therapeutic modalities where the
current benefit/risk is favorable (PD, MS)
 To develop therapies for aspects of disease that at present lack
robust approved therapies (AD, ALS, HD, etc…)
 Disease modifying or “neuroprotective” therapies
 Holy Grail of drug development in neurological diseases

7. Target Selection
Biology, physiology, and occasionally the pathophysiology of
your target dictate and can continually influence your clinical
development planning
 Location, location, location and…..function?
 Methodologies to assess target engagement in early clinical development
 Imaging (ligand based, functional)
 Physiological
 Pharmacological
 Guide target organ toxicological assessments
 Prioritize potential adverse effect profiles and tailored safety assessments
 Dermatologic, ocular, special cardiovascular
 Pathophysiology
 Enriched patient (sub) population
 Development of objective biological or novel subjective clinical outcomes

8. The course and pathogenesis of multiple sclerosis (MS)
Disease course
Pathology Perivascular inflammation Microglia activation Axonal loss
Axonal transection
Persistent demyelination Gliosis
Adapted from Compston and Coles, Lancet (2002 & 2008)

9. Existing Targets in MS
Lymph node
Natalizumab
IFNs
Glatiramer acetate
FTY720
FTY720
Ofatumumab Ocrelizumab
LY2127399 BAFF
Approved drugs Drugs in development
Adapted from Linker, Kieseier, and Gold Trends Pharmacol Sci (2008)

10. Lead Optimization
Take you best and brightest forward!
 Optimization efforts are critical to produce a potential clinical candidate with
favorable pharmaceutical characteristics
 ADMET
 Sacrifice absolute potency versus selectivity for optimal metabolic
characteristics
 PK 4000
Mean Plasma Levels (ng/ml)
3500
3000 2778,50 2721,50 2782,40 2776,70
2538,00
2500
2000 1793,60
1500
862,21 1353,10 1430,90
1243,30 1308,20
1000 1233,30
404,80
500 657,66
0
Baseline week 2 week 4 week 8 week 12 week 18 week 24
Low Low (P2) Low (P3) High High (P2) High (P3)

11. Animal to Human Transition
Pre-Clinical safety assessments Pre-clinical efficacy assessments
 Required for IND  Not required for an IND
 Chronic dosing  Animal efficacy models of human
 Route of administration neurological disease often lack
 Determination of TI (Go wide!)
validity and/or are biased towards
specific pharmacological
 Exposures required for a PD
mechanisms
effect versus those at which
 Are we missing gems?
adverse effects appear
 Focus on complex in vivo
pharmacological and physiological
 Optimizing leads for ADMET outcomes to explore the role of
 Often evidence for robust BBB target in human biology
penetration, and detailed central
PK/PD relationships are lacking
 PK/PD marker development
 Drug disposition, sites of
 Translatable methodologies
metabolism, DDI are important
aspects  Biomarker development
 Collaborate early

12. Pre-Clinical Assessments
How do we optimally predict that human dosing will be safe?
 Safety Pharmacology
 Specialized studies designed to define both known (cardiac-small
molecules) and anticipated (ocular for DA agonists) physiological effects
that will impact safety margins
 Toxicology/Toxicokinetics
 Best if an exposure/toxicological relationship can be established
 Correlate with extended pharmacology
 Length of exposure (single dose, multiple dose, week/month) to support
length of clinical dosing
 Will evolve over time
 Estimation of Human Starting Dose
 Established guidelines for isometric scaling
 May differ based on species metabolism

13. Regulatory
Interactions should be “Early and Often”
 Consider regulators as partners in development
 Pre-IND Meeting
 Highly recommended for novel targets, novel indications, and for initial
IND’s from smaller sponsors
 Nothing lost by requesting a meeting
 Must have specific questions regarding your potential product, clinical trial
design, or early development plan
 Safety monitoring plans for clinical trials

14. Clinical Trial Design
Have a Clinical Development Plan (CDP)
 Target indication with aspirational goals for a target product profile (TPP)
 Confirm mechanism related biology/pharmacology in early clinical studies
 Explore relevance of biology/pharmacology in multiple patient populations or
sub-populations if possible ($$$$/time/partner)
 Core elements
 Patient population
 Starting dose, route of administration, dosing intervals, and dosing
duration
 Safety assessments, timing, and degree of PK evaluations
 Clinical, biological, physiological evaluations
 Avoid trying to accomplish too much in a single study!

15. Clinical Outcomes Measure
Development Stage Dependent and “Forward Looking”
 First in human / First in Disease Populations (Phase 1/1b)
 Safety, tolerability and early indication of TI
 Clinical assessments, safety measures, targeted clinical scales
(UPDRS/VAS, etc…)
 Strong consideration for first in human studies to be done in a patient, not
NHV, population
 Differential tolerability in neurodegenerative populations
 Characterization of pharmacological effect
 Amyoid based therapies and serum/CSF amyloid determinations
 Lymphocyte dynamics in MS therapies
 Plan/Initiate special studies
 PET/pharmacodynamic studies
 Food effect/Renal/Hepatic/DDI

16. Clinical Outcome Measures (II)
Development Stage Dependent and “Forward Looking”
 Proof of Mechanism/Relevance (Phase 1b)
 Incorporated into initial studies, additional cohorts in adaptive trial design,
or small dedicated study
 Explore various populations/disease indications, use deep phenotyping,
explore objective outcomes measures, and test feasibility and clinical
dynamics of novel technologies
 Proof of Clinical Concept (Phase 2)
 Clinically relevant, often subjective, outcome measures (1o)
 Biologically relevant, objective outcome measures that will ideally/hopefully
correlate with clinical outcomes (2o)
 Initial QOL/HE/ and clinical differentiation measures (Non-hierarchical 2o)
 Registration Studies (Phase 3)
 Evidence for clinical efficacy measures should be developed through
extensive interactions with regulatory agencies
 Safety, special safety, and importance of long-term exposures to support
chronic treatment indications

17. Treatment Landscape
 Medical Need
 Competitive Profile
 Aim high
 Incremental improvements

18. Improving patient care and clinical
outcomes is the motivating goal
 Symptomatic treatments targeted to the clinical
symptoms which underlie morbidity
 Existing drugs are often indicated to treat the “signs and
symptoms” of neurological disease
 To improve upon existing therapeutic modalities where the
current benefit/risk is favorable (PD, MS)
 To develop therapies for aspects of disease that at present lack
robust approved therapies (AD, ALS, HD, etc…)
 Disease modifying or “neuroprotective” therapies
 Holy Grail of drug development in neurological diseases

20. AMRITATM
Indicated for the prevention and treatment of Alzheimer’s
Disease
 Take one tablet by mouth daily with or without food
 Side effects include: headache (1%)…..
 No drug-drug interactions or medical contraindications to use
 Pre-clinical characteristics
 Highly potent and selective inhibitor of a novel target expressed only in
CNS, GMP manufacturing is simple, low cost of goods, no impurities, stable
at RT, shelf life of > 3years
 Reversible toxicological findings at exposures 50 fold greater than
therapeutic exposures
 Safety TI > 100
 >90% oral bioavailability, linear pharmacokinetics, T1/2 of 16 hrs, no
accumulation, excreted unchanged in urine, 10X brain/plasma ratio
 Target without polymorphism, no genetic or pharmacological
modifiers, nearly 100% response rate, no tolerance over time

21. Persistence and Serendipity!