SESSION IIIPre-Clinical Proof-of-Concept and Development Chair — Edward G. Spack, PhD, Fast Forward, LLC Session OverviewEdward G. Spack, PhD, Fast Forward, LLC What Makes a Clinical Candidate?David Weiner, MD Requirements for an INDEdward G. Spack, PhD, Fast Forward, LLC  Optimization and Characterization of Mouse Models of NeurodegenerationSteve Perrin, PhD, ALS Therapy Development Institute  Value of Biomarkers in Preclinical Development: Translatable EndpointsBarry Greenberg, PhD, Toronto Dementia Research Alliance 

What Makes a Clinical Candidate?

Alzheimer’s Drug Discovery Foundation

February 13, 2012

Dr. David M Weiner MD

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

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

Target SelectionBiology, 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

The course and pathogenesis of multiple sclerosis (MS)

Adapted from Compston and Coles, Lancet (2002 & 2008)

Disease course

Perivascular inflammation

Axonal transectionPersistent demyelination

Microglia activation Axonal loss

Gliosis

Pathology

Existing Targets in MS

Adapted from Linker, Kieseier, and Gold Trends Pharmacol Sci (2008)

Ocrelizumab

LY2127399 BAFF

Ofatumumab

IFNs

Glatiramer acetate

FTY720

FTY720

Approved drugs Drugs in development

Natalizumab

Lymph node

Lead OptimizationTake 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

Mean

Pla

sm

a L

evels

(n

g/m

l)

1308,201430,901353,10

1243,301233,30

657,66

404,80

2776,702782,402721,502778,502538,00

862,21

1793,60

0

500

1000

1500

2000

2500

3000

3500

4000

Baseline week 2 week 4 week 8 week 12 week 18 week 24

Low Low (P2) Low (P3) High High (P2) High (P3)

Animal to Human TransitionPre-Clinical safety assessmentsPre-clinical efficacy assessments

Required for IND Chronic dosing Route of administration Determination of TI (Go wide!)

Exposures required for a PD effect versus those at which adverse effects appear

Optimizing leads for ADMET Often evidence for robust BBB

penetration, and detailed central PK/PD relationships are lacking

Drug disposition, sites of metabolism, DDI are important aspects

Not required for an IND Animal efficacy models of

human neurological disease often lack validity and/or are biased towards specific pharmacological mechanisms

Are we missing gems? Focus on complex in vivo

pharmacological and physiological outcomes to explore the role of target in human biology

PK/PD marker development Translatable methodologies

Biomarker development Collaborate early

Pre-Clinical AssessmentsHow 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

RegulatoryInteractions 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

Clinical Trial DesignHave 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!

Clinical Outcomes MeasureDevelopment 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

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

Treatment Landscape

Medical Need

Competitive Profile Aim high Incremental improvements

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

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

AMRITATM

Persistence and Serendipity!