Session 3 part 1
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Transcript of Session 3 part 1
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
SESSION III:Pre-clinical Proof-of-Concept and Development
HTS
ADME
PK
Med Chem
PD
Phase I - Safety
TPP Janus
Phase II – EfficacyDose
Phase III – DefinitiveEfficacy & Safety
BLALabel
NDA
IND
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
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!