Biomarkers for Hypothesis Testing

Transcription

1 Biomarkers for Hypothesis Testing Definition for Drug Development: Biomarker = Any Measure of a Drug Action Proximal to a Clinical Effect Biochemical (PET, MRS & CSF* for CNS drugs) Physiological EEG, FDG PET, fmri, ASL, etc Behavioural (Responses to T asks) Definition for CNS Disease State Biomarker = Quantifiable Measure in Brain Tissue* (including CSF) associated with Severity or Course of Clinical Symptoms * Plasma and Urine can be Utilized when Established to Reflect CNS

2 Biomarkers & Drug Development Antidepressants CSF Reductions in MHPG and 5HIAA CSF Reductions of MHPG, 5HIAA & HVA after MAOIs Antipsychotics Variable changes in CSF HVA D 2 and 5HT2 Receptor Occupancy (PET) Agents for Alzheimer s Disease CSF Measures related to AChE Inhibition CSF Measures of beta amyloid turnover MRI & Amyloid load in Brain (PET ligand) Multiple Sclerosis MRI and CSF

3 What % of Mechanisms Tested? Adis R & D Database Classification of Classes of Compounds that have at least Entered Phase I >75 Potential Antidepressant T argets 50 Antipsychotic T argets >150 T argets for Alzheimer s Disease!!

4 Potential T argets for Depression Adenosine A1 receptor antagonists Adenosine A2 receptor antagonists Alpha 1 adrenergic receptor agonists Alpha 2 adrenergic receptor antagonists AMPA receptor agonists Apoptosis stimulants Benzodiazepine receptor inverse agonists Beta-adrenergic receptor agonists Beta 3 adrenergic receptor agonists Calcium channel agonists Cholinergic receptor agonists Nicotinic receptor agonists Nicotinic receptor antagonists Alpha4-beta2-nicotinic-receptor-antagonists Corticotropin-releasing factor antagonists Corticotropin releasing factor receptor 1 antagonists Corticotropin releasing factor receptor 2 antagonists Cyclo-oxygenase 2 inhibitors Dopamine receptor agonists Dopamine D2 receptor agonists Dopamine D3 receptor agonists Dopamine receptor antagonists Dopamine D1 receptor antagonists Dopamine D2 receptor antagonists Dopamine D3 receptor antagonists Dopamine D4 receptor antagonists Dopamine plasma membrane transport protein antagonists Dopamine release stimulants Dopamine uptake inhibitors Enkephalinergic receptor modulators Serotonin 2 receptor antagonists Excitatory amino acid antagonists Fatty acid amide hydrolase inhibitors

5 Depression (cont.) G protein-coupled receptor modulators GABA receptor agonists GABA A receptor agonists GABA B receptor antagonists Glucocorticoid receptor antagonists Glutamate agonists Glutamate receptor antagonists Histamine H1 receptor antagonists Immunosuppressants L-lactate dehydrogenase stimulants Melanocortin receptor agonists Melanocyte-stimulating hormone inhibitors Melatonin receptor agonists Melatonin MT1 receptor agonists Melatonin MT2 receptor agonists Monoamine oxidase inhibitors Monoamine oxidase A inhibitors Monoamine oxidase B inhibitors Neurokinin antagonists Neurokinin 1 receptor antagonists Neurokinin 2 receptor antagonists Neurokinin 3 receptor antagonists Neurotransmitter modulators Neurotransmitter inhibitors NMDA receptor modulators NMDA receptor agonists NMDA receptor antagonists Norepinephrine release stimulants Norepinephrine reuptake inhibitors Opioid receptor agonists P38 mitogen-activated protein kinase inhibitors

6 Depression (cont.) Phospholipase A2 inhibitors Plasma membrane neurotransmitter transport protein inhibitors Platelet aggregation antagonists Progesterone receptor antagonists Serotonin receptor antagonists Serotonin 1 receptor antagonists Serotonin 1A receptor antagonists Serotonin 1B receptor antagonists Serotonin 1C receptor antagonists Serotonin 1D receptor antagonists Serotonin 2 receptor antagonists Serotonin 2A receptor antagonists Serotonin 2B receptor antagonists Serotonin 2C receptor antagonists Serotonin 3 receptor antagonists Serotonin receptor agonists Serotonin 1A receptor agonists Serotonin 1B receptor agonists Serotonin 1D receptor agonists Serotonin 2C receptor agonists Serotonin 3 receptor agonists Serotonin release stimulants Serotonin reuptake stimulants Serotonin uptake inhibitors Sigma-1 receptor agonists Sigma-1 receptor antagonists Sodium channel antagonists Substance P inhibitors Substance P release inhibitors Thyrotropin releasing hormone agonists Type 4 cyclic nucleotide phosphodiesterase inhibitors Vasopressin 1b receptor antagonists Virus replication inhibitors

7 Potential and Known T argets for Schizophrenia Adrenergic receptor antagonists Alpha 2 adrenergic receptor antagonists Alpha 2c adrenergic receptor antagonists Alpha 1 adrenergic receptor agonists Alpha4 beta2 nicotinic receptor agonists Alpha7 nicotinic acetylcholine receptor modulators Alpha7 nicotinic acetylcholine receptor agonist AMP A receptor modulators CB1 cannabinoid receptor antagonists Cyclo-oxygenase 2 inhibitors Dopamine receptor agonists Dopamine D2 receptor agonists Dopamine D3 receptor agonists Dopamine D4 receptor agonists Dopamine receptor antagonists Dopamine D1 receptor antagonists Dopamine D2 receptor antagonists Dopamine D3 receptor antagonists Dopamine D4 receptor antagonists Dopamine D5 receptor antagonists GABA receptor agonists GABA A alpha 3 receptor agonists Glutamate agonists Glutamate release antagonists Glycine NMDA-associated agonists Glycine reuptake inhibitors Glycine transporter 1 inhibitors Ion channel modulators Metabotropic glutamate receptor agonists Metabotropic glutamate receptor 2 agonists Metabotropic glutamate receptor 3 agonists

8 Schizophrenia (cont.) Microtubule-associated protein modulators Muscarinic M1 receptor agonists Neurokinin 1 receptor antagonists Neurokinin 2 receptor antagonists Neurokinin 3 receptor antagonists Neurotensin antagonists Neurotransmitter receptor modulators Nicotinic receptor modulators Norepinephrine reuptake inhibitors Opioid receptor antagonists Phosphodiesterase 10A inhibitors Phospholipase A2 inhibitors Serotonin 1A receptor agonists Serotonin 1C receptor antagonists Serotonin 2 receptor agonists Serotonin 2C receptor agonists Serotonin 2 receptor antagonists Serotonin 2A receptor antagonists Serotonin 2B receptor antagonists Serotonin 3 receptor antagonists Serotonin 6 receptor antagonists Sigma receptor agonists Sigma receptor antagonists Sodium channel antagonists Stem cell stimulants T achykinin receptor antagonists T au protein inhibitors Tubulin polymerisation promoters

9 Potential & Known T argets for Alzheimer's Disease 3-beta hydroxysteroid dehydrogenase inhibitors Acetylcholine release stimulants Acetylcholinesterase inhibitors Adenosine A1 receptor modulators Adenosine A2 receptor modulators Adenosine triphosphatase stimulants Adenosylmethionine decarboxylase inhibitors Adenylate cyclase stimulants Adrenergic receptor agonists Advanced glycosylation end product inhibitors Alpha adrenergic receptor antagonists Alpha 1 adrenergic receptor antagonists Alpha 2 adrenergic receptor antagonists AMPA receptor agonists Amyloid inhibitors Amyloid beta-protein inhibitors Amyloid precursor protein secretase inhibitors Angiogenesis inhibitors Antioxidants Hypoxia-inducible factor-1 alpha inhibitors Apolipoprotein A I stimulants Apoptosis stimulants Benzodiazepine receptor inverse agonists Beta-secretase inhibitors Butyrylcholinesterase inhibitors Calcium channel agonists Cannabinoid receptor agonists Carnitine acetyltransferase stimulants

10 Alzheimer's Disease (cont.) CB1 cannabinoid receptor antagonists CCR5 receptor antagonists Cdc2 kinase inhibitors Cell differentiation stimulants Cell membrane permeability enhancers Cell-replacements Central nervous system stimulants Chelating agents Chloride channel agonists Cholinergic receptor modulators Muscarinic receptor agonists Muscarinic M1 receptor agonists Muscarinic M4 receptor agonists Muscarinic receptor antagonists Muscarinic M2 receptor antagonists Muscarinic M3 receptor antagonists Cholinergic receptor modulators (cont.) Nicotinic receptor modulators Alpha4-beta2-nicotinic-receptor-modulators Alpha4 beta2 nicotinic receptor agonist Alpha7 nicotinic acetylcholine receptor modulators Alpha7 nicotinic acetylcholine receptor agonists Corticotropin-releasing hormone stimulants Cyclo-oxygenase 2 inhibitors Cytokine modulators Cytokine inhibitors Cytokine synthesis inhibitors DNA topoisomerase II inhibitors DNA-directed RNA polymerase stimulants

11 Alzheimer's Disease (cont.) Dopamine receptor agonists Dopamine D1 receptor agonists Dopamine D2 receptor agonists Dopamine D2 receptor antagonists Dopamine uptake inhibitors Estrogen receptor modulators Estrogen receptor agonists Estrogen receptor antagonists Fibroblast growth factor stimulants Free radical scavengers Nitric oxide synthase type II inhibitors G protein-coupled receptor modulators GABA modulators GABA A receptor agonists GABA A alpha 2 receptor agonists GABA A alpha 3 receptor agonists GABA B receptor antagonists GABA-A receptor antagonists Gamma secretase modulators Gamma-secretase inhibitors Glial cell line-derived neurotrophic factor agonists Glucocorticoid receptor antagonists Glucose stimulants Glutamate agonists Glutamate receptor antagonists Glutamate release antagonists Glycine agonists Glycine NMDA-associated agonists Glycine reuptake inhibitors Glycogen synthase kinase 3 inhibitors Gonadotropin releasing hormone agonists Gonadotropin releasing hormone antagonists Growth hormone releasing factor agonists Histamine H3 receptor antagonists HMG-CoA reductase inhibitors

12 Lumbar Puncture Blood contamination of the CSF cannot be avoided during the lumbar puncture. This contamination is variable and complicates the characterization of the normal CSF protein profile.

13 GSI: CSF Sampling from Cisterna Magna Ported (CMP) Conscious Rhesus Monkeys 3 mg/kg = red plot Aβ40 (pm) 600 * PO Dose ** ** Time (hr) Baseline samples taken at -20, -1 & 0 hr predose crossover design ** p<0.05 vs. Vehicle, 0.3 mpk & 1 mpk * p<0.05 vs. Vehicle & 0.3 mpk statistics shown for 24 hr only Vehicle, n=8 L' mpk, n=6 L' mpk, n=6 L' mpk, n=6 L' mpk, n=4

14 Alzheimer's Disease (cont.) Immunomodulators Immunophilin modulators Immunostimulants Immunosuppressants Insulin-like growth factor I agonists Intercellular signalling peptide and protein stimulants Interleukin 2 stimulants Lipid peroxidation inhibitors L-lactate dehydrogenase stimulants Melatonin MT1 receptor agonists Melatonin MT2 receptor agonists Membrane transport protein inhibitors Microtubule protein inhibitors Microtubule-associated protein modulators Mitochondrial protein stimulants Mitochondrial-permeability-transition-pore-modulators Mitogen-activated protein kinase inhibitors Mitosis inhibitors Mixed-lineage kinase inhibitors Monoamine oxidase inhibitors Monoamine oxidase B inhibitors Monoamine uptake inhibitors Nerve growth factor stimulants Neuropeptide stimulants Neurotransmitter modulators Neurotransmitter stimulants NF-kappa B inhibitors Nitric oxide donors Nitric oxide synthase type II inhibitors NMDA receptor agonists NMDA receptor antagonists Notch signalling pathway inhibitors Opioid receptor agonists Ornithine decarboxylase inhibitors

15 Alzheimer's Disease (cont.) Oxidoreductase stimulants Peptide stimulants Peroxisome proliferator-activated receptor agonists Peroxisome proliferator-activated receptor gamma agonists Phospholipase A2 inhibitors Phosphoric diester hydrolase inhibitors Plasminogen activator inhibitor-1 antagonists Platelet activating factor inhibitors Platelet activating factor stimulants Platelet aggregation antagonists Potassium channel antagonists Progesterone receptor antagonists Prolyl endopeptidase inhibitors Prostaglandin endoperoxide synthase inhibitors Prostaglandin synthase inhibitors Protein synthesis stimulants Reactive oxygen species stimulants RNA synthesis inhibitors Selective estrogen receptor modulators Serotonin modulators Serotonin 1A receptor agonists Serotonin receptor antagonists Serotonin 1A receptor antagonists Serotonin 2 receptor antagonists Serotonin 2A receptor antagonists Serotonin 3 receptor antagonists Serotonin 4 receptor antagonists Serotonin 6 receptor antagonists Serotonin uptake inhibitors Sigma-1 receptor agonists Signal transduction pathway inhibitors Sodium channel antagonists Somatotropin receptor antagonists Spermidine/spermine N1-acetyltransferase stimulants

16 Alzheimer's Disease (cont.) STAT transcription factor inhibitors Survivin protein inhibitors Synuclein inhibitors T au protein inhibitors Tubulin polymerisation promoters T estosterone congener stimulants Thromboxane A2 synthase inhibitors Thyrotropin releasing hormone agonists Transcription factor inhibitors Transcription factor AP-1 inhibitors Tubulin inhibitors Tumour necrosis factor inhibitors Tumour necrosis factor production inhibitors Type 4 cyclic nucleotide phosphodiesterase inhibitors Vesicular monoamine transporter 2 inhibitors Virus replication inhibitors

17 Application to Decision Making? 1970 s Refutation of Selectivity Hypothesis of NE vs 5HT Uptake Inhibition using CSF 1980 s D 2 Occupancy, Efficacy and Side Effects affecting Dose Selection of Antipsychotics 1990 s Present - Growing Use of PET occupancy to select doses and test hypotheses 2000 s Functional Brain Imaging to Set Doses? CSF and PET studies to stratify populations (e.g. Alzheimer s Disease)

18 Can Current Biomarkers Deliver? Yesfor: Downstream Biochemistry in CSF PET Ligands for Antagonists & Amyloid Load Functional Imaging to Set Doses (qeeg, ASL?) Structural Changes Not Yet for: Agonists, partial agonists, modulators, etc. Specificity of disease state and integrated effects of drugs to individualize diagnosis and treatment