View
222
Download
5
Category
Preview:
Citation preview
1
Gaps Between Biomarkers andSurrogate Endpoints:
CNS
Hermann FuderTransatlantic Strategies in Early Drug
DevelopmentDüsseldorf, 19-21 February 2006
2
Overview
• Definitions Biomarker, Surrogate, ClinicalEndpoint
• Biomarker in Psychiatry• Biomarker in Neurology
3
Definition of Biomarker
• A characteristic that is objectively measured andevaluated as an indicator of normal biologicprocesses, pathogenic processes, or pharmacologicresponses to a therapeutic intervention
• FDA Pharmacogenomics Guidance definespossible, probable and known valid biomarkercategories depending on available scientificinformation on the marker
4
Unintended effectUnintended effectAffected by interventionAffected by interventionNot affected by interventionNot affected by intervention
Not usefulNot useful
Ideal markerIdeal marker
Partly usefulPartly useful
Confusing markerConfusing marker
Biomarker Validation
WellWellWell DiseaseDiseaseDisease
BiomarkerBiomarkerBiomarker
WellWellWell DiseaseDiseaseDisease
BiomarkerBiomarkerBiomarker
WellWellWell DiseaseDiseaseDisease
BiomarkerBiomarkerBiomarker
WellWellWell DiseaseDiseaseDisease
BiomarkerBiomarkerBiomarker
5
Definition ofSurrogate Endpoint
• A biomarker intended to substitute for aclinical endpoint. A surrogate endpoint isexpected to predict clinical benefit (or harm, orlack of benefit) based on epidemiologic,therapeutic, pathophysiologic or otherscientific evidence
6
Surrogates
• to increase the likelihood of providing beneficialeffects on clinical efficacy endpoints
• validity for a given treatment not necessarilyapplicable for another treatment with differentmechanism of action
• do in most cases not replace clinical efficacyendpoints in definitive trials (Phase III)
7
Definition ofClinical Endpoint
• A characteristic or variable that reflects how apatient feels, functions or survives
• Except for survival, all these involveintermediary measurement
8
Clinical Effects of AtypicalAntipsychotics
• Clinical efficacy in schizophrenic patients (acutetreatment of psychotic episodes and relapseprevention)– Positive and Negative Symptoms Scale (PANSS)
• % patients responding by reduction in PANSS by 30%
– Clinical Global Impression (CGI)
• Safety/Tolerability– ESRS, BAS, AIMS, prolactin, QTc, weight, glucose
and lipid metabolism
9
Biomarkers for Antipsychotics
• Biomarkers in early clinical development– PET (« local PK in area of interest in CNS »):
• D2 and 5-HT2 receptor blockade for atypicals
– Quantitative EEG– prolactin
• Surrogates– ?
10
PET Study for CNSReceptor Occupancy
PET Images with 11C - Raclopride Binding to D2 Receptorsin Human BrainBefore Aripiprazole During Aripiprazole During Aripiprazole
2 mg/day, 14 days 30mg/day, 14 days
11
Changes in qEEG by New Atypical
long lasting action
no sedation
rapid onset
rapid onset
12
qEEG in Healthy Subjectsand Answers to Questions
• Penetration of blood brain barrier?• Dose response relationship, minimum CNS active dose?• Time course of pharmacodynamic effect?• PK/PD?• Sedation?• Limitations:
– Healthy subjects very sensitive to low doses of antipsychotics– Applicability to patients unclear– Status of validation incomplete– Relevance of qEEG for new modes of actions beyond typical or
atypical antipsychotics unclear
13
Prolactin: a Useful Biomarkerfor Antipsychotic Efficacy?
from de Visser et al. 2001
14
Clinical AntipsychoticTrials of Intervention
Effectiveness (CATIE)
15
CATIE: AntipsychoticsInvestigated and Doses
• Mean modal doses/day(total number of schizophrenic patients:1493)
– olanzapine 20 mg– perphenazine 21 mg– quetiapine 543 mg– risperidone 4 mg– ziprasidone 113 mg
16
Outcome CATIE: Time toDiscontinuation of Treatment
longer for olanzapine than for quetiapine, risperidone,perphenazine, and ziprasidone regarding:
• for any cause• for lack of efficacy• owing to patient’s decision
no difference between the drugs:• owing to intolerable side effects
17
Other AEs
• Prolactin increase: only with risperidone, notfor other antipsychotics
• Weight gain ≥7%: olanzapine 30%, others 7-16%
• Risk Metabolic Syndrome: more witholanzapine than others, ziprasidone reducedthe risk
• QTc prolongation: no differences
18
Prolactin: a Useful Biomarkerfor Antipsychotic Efficacy?
• Apparently not of predictive value for clinicalefficacy under real life conditions of treatmentwith most 2nd generation antipsychotics, at bestperhaps for some D2 receptor blockers
• Indicator for supramaximal doses of someantipsychotics?
19
NK1 Antagonists forDepression?
20
NK1 Antagonist in CNSIndications
• Aprepitant (MK-0869) successfully registered and launched inUS 2003 against nausea and emesis in cancer patients underemetogenic chemotherapy (Emend™)
• Aprepitant under evaluation for depression in Phase III basedon a large positive Phase II trial and a small negative Phase IItrial with lower dose
• Dosing in Phase III trials based on results from PET studies(determination of CNS NK1 receptor occupancy over time) andPhase II trial with positive outcome
• Expectation/hope: first new antidepression concept/target in 10years
21
NK1 ReceptorOccupancy in
CNS:Displacementby Aprepitant
• Frank & Hargreaves 2003
22
Aprepitant for Depression
• Nov. 12, 2003--Merck & Co., Inc. announced todaythat it is discontinuing its Phase III clinicaldevelopment program for its substance P antagonistinvestigational product, MK-0869, for the treatmentof depression.
• The Phase III clinical program was halted because thecompound failed to demonstrate efficacy for thetreatment of depression.
23
Are NK1 AntagonistsUseful in Depression?
• Effect on development portfolios of a number of otherpharmaceutical companies?
• Potential reasons for negative outcome of Phase III trials withaprepitant:– Unrelated to aprepitant and other NK1 antagonists:
Antidepressant trials frequently negative (up to 50%)– Related to aprepitant: not effective enough or results too
variable?– Related to all other NK1 antagonist: Will one be shown to be
effective in depression in future trials?• If not: Are CNS NK1 receptors an adequate target in
depression?
24
Biomarkers in Neurology
• Multiple Sklerosis– MRI (supportive evidence of benefit for registration and
labelling of interferon-1-ß)• Stroke (entry criteria for infarct size and penumbra; potential
endpoints for intervention studies)– diffusion and perfusion MRI,– perfusion CT
• Alzheimer’s Disease– volumetric MRI,– MR spectroscopy,– FDG-PET,– SPECT,– amyloid PET,– microglial tracers, ß-amyloid, Tau-proteins
25
Neuroimaging in CNSDrug Development
Uppoor et al. 2005 (CDER, FDA)Neuroimaging studies in CNS drugs approved
from 1995 to 2004• 106 NDAs approved in Neuropharmacology
Division• 15 (out of 106) included neuroimaging studies• 5 (out of 15) receptor occupancy• 2 (out of 15) support POC
Recommended