Biomarker: Clinical Validation for Intended Use Joop van Gerven professor of clinical neuropsychopharmacology Centre for Human Drug Research Leiden The Netherlands to the memory of Hermann Fuder Lecture Contents What are biomarkers? question-based drug development What can you do with them? examples from GABA-ergic research Biomarker Definitions A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. (NIH Biomarkers Definitions Working Group, 2001) A quantitative measure that is on the causal path between drug administration and effect. (EU COST-B Biomarker Working Party, Danhof, 2005) type 0 type 1 type 2 type 3 type 4 type 5 type 6 phenotype drug target target physiological patho- clinical genotype concentration occupancy activation response physiological response response …the causal path… A Practical Biomarker Definition: Tools to Answer Questions in Drug Development population action site drug development is case building pharmacology clinical window Question-Based Drug Development: main issues for early development 1. Does the drug reach its target? 2. Does the drug have pharmacological activity/-ies? 3. Does the drug affect intended (patho)physiological processes? 4. What is the window between desired and undesirable effects? Example 1 First-in-human study Fast- and short-acting benzodiazepines New sedative in anesthesia Two new compounds vs midazolam Question-Based Development: Action Site 1: does the drug reach its target? Question-Based Development: Action Site 1: does the drug reach its target? Membrane Receptors/Ion Channels GABA-A-receptors glutamate NMDA channel L-type Ca2+ channel Membrane Transporters 5HT-transporter *18F-flumazenil dopamine-transporter p-Glycoprotein * Vesicular Transporters vesicular Monoamine Transporter-2 vesicular Acetylcholine Transporter Neurotransmitter Precursors F-DOPA Enzymes MAO-A, MAO-B acetylcholinesterase Question-Based Development: Action Site 1: does the drug reach its action site? single rising dose study of two novel benzodiazepines vs positive control •1 mg •2 mg •3 mg •500 •midazolam •500 •450 •400 •400 •350 •SPV (deg/sec) •SPV •300 •SPV (deg/sec) •300 •200 •250 •0 •60 •120 •180 •240 •300 •0 •50 •100 •150 •Time (min) •effect compartment concentration (µg/L) Ro 8684: shorter duration of Ro 6791: more potent than midazolam, action than midazolam equipotent at 3 mg (+20 µg/L) Dingemanse J, Van Gerven JMA, Schoemaker HC et al. Integrated pharmacokinetics and pharmacodynamics of Ro 48-6791, a new benzo¬diazepine, in comparison to mida¬zolam during first administration to healthy male subjects. Br J Clin Pharmacol 1997;44:477 -486 Van Gerven JMA, Roncari G, Schoemaker HC et al. Integrated pharmacokinetics and pharmacodynamics of Ro 48-8684, a new benzo¬diazepine, in comparison to midazolam during first administration to healthy male subjects. Br J Clin Pharmacol 1997;44:487-493 Question-Based Development: Pharmacology 2: does the drug have a pharmacological effect? [C] E PK/PD Question-Based Development: Pharmacology 2: does the drug have a pharmacological effect? GABAA R concentration-related effects are pharmacological biomarkers! Question-Based Development: Pharmacology 2: how relevant are the pharmacological effects? A. Can biomarkers show competitive (dis)advantage? B. Can biomarkers predict adverse effects? C. Can biomarkers predict therapeutic doses? effect profiling positive controls NeuroCart: multimodal CNS-profiling in early drug development • Saccadic and smooth pursuit eye movement • Memory testing • Adaptive tracking • Finger tapping • Body sway • Visual analogue scales • Psychometric questionnaires NeuroCart • Electroencephalography • Polysomnography • Other CNS function tests • Symbol Digit Substitution Test • Critical Flicker Fusion • Stroop Conflict Task • Neuroendocrine measures • Autonomic function tests Data-Intensive Phase 1 ScreenCNS -180 -120 -75 -60 -45 0h 30 60 75 90 105 120 135 150 180 195 210 240 255 270 6h 8h 12h 21h FU practice Assessment Informed Consent X Demography X Incl./Exclusion X Medical history X Physical examination X Body Weight X Virology X Thyroid function test X Routine Lab +Urinalysis X X X Urine drug screen X X Concomitant Medications X X X Breath alcohol test X Meals/snack X XXXX Drug administration X Verbal learning X Delayed recall X Cognitive testing X 2X X X XXX X Adaptive trackingX XXXXXXXXXXXXX PK/PD Saccadic eye movements X XXXXXXXXXXXXX Smooth pursuit X XXXXXXXXXXXXX Body sway X XXXXXXXXXXXXX VAS (Bond & Lader) X XXXXXXXXXXXXX VAS (Bowdle) X XXXXXXXXXXXXX EEG X X XX X X XX XX XXX NeuroCart PK blood sampling X XXXX X X X X X XX X X Auricular temperature X X X XXX XXX Respiratory rate X X X Orthostatic BP/Pulse X X Supine BP /Pulse X X X XXX XXX Resting 12-Lead ECG X X X AE follow up X X X X XXX XXX Discharge from unit X Multimodal Pharmacological Effect Profiling: PK/PD-analyses show drug-specific pharmacological effect profiles VAS alertness SPV adaptive tracking body sway 3.2 40 660 5 3.0 20 600 ) 0 % e ( 2.8 0 540 manc -5 or f r e 2.6 ng P -20 i k 480 -10 (mm) Sway Log Body ac GABA-agonists r Delta VAS Alertness (mm) a T t 2.4 Saccadic Peak Velocity (deg/sec) Velocity Peak Saccadic -40 420 Del -15 -60 2.2 360 -20 -120 0 120 240 360 480 600 720 840 -120 0 120 240 360 480 600 720 840 -120 0 120 240 360 480 600 720 840 -120 0 120 240 360 480 600 720 840 Time (min) Time (min) Time (min) Time (min) 600 70 3.2 6 550 3.0 60 0 ) 2.8 500 mm) ( ay w ance (% -6 50 S 2.6 ody 450 rform e B -12 G 2.4 VAS Alertness (mm) VAS Alertness ng P LO Saccadic Peak Velocity (deg/sec) Velocity Peak Saccadic 40 acki M-antagonists r 400 T -18 2.2 30 2.0 350 -24 -60 0 60 120 180 240 300 360 420 480 540 600 -60 0 60 120 180 240 300 360 420 480 540 600 -60 0 60 120 180 240 300 360 420 480 540 600 -120 0 120 240 360 480 600 720 840 Time (min) Time (min) Time (min) Time (min) 590 3.2 580 4 570 560 3.0 80 3 550 540 530 2 2.8 520 CB1-agonists 60 510 1 500 2.6 490 0 480 2.4 470 -1 (mm) Sway LOG Body 40 460 VAS Alertness (mm) VAS Alertness Saccadic peak velocity (deg/sec) velocity peak Saccadic 450 -2 440 2.2 430 -3 420 2.0 20 410 (%)(change) performance Tracking average -4 -60 0 60 120 180 240 300 360 420 480 540 600 -120 0 120 240 360 480 600 0246810 0 120 240 360 480 600 Time (min) Time (min) Time (min) … Time (h) Multimodal Pharmacological Effect Profiling: effect profiles are drug-class-specific VAS ALERTNESS VAS EXTERNAL VAS INTERNAL SACCADIC PEAK VELOCITY SMOOTH PURSUITADAPTIVE TRACKINGBODY SWAY SLEEP During night Sleep deprivation 1 night L-830409 0.25 mg PO L-830409 0.75 mg PO L-830982 0.5mg PO L-830982 1.5mg PO PARTIAL L-83982 2mg PO GABAA Bretazenil 0.5mg SL Diazepam 10mg PO Lorazepam 2 mg PO Lorazepam 2 mg PO Lorazepam 2mg PO Midazolam 0.1mg/kg IV Midazolam 0.1mg/kg IV GABAA Midazolam 0.1mg/kg IV Nitrazepam 5mg PO Nitrazepam 5mg PO (Jap) RO486791 10mg IV RO488684 10mg IV SL651498 2.5mg PO SL651498 25mg PO Temazepam IV Temazepam 20mg PO Temazepam IV Fast Zolpidem 10mg PO Breta 0.5mg SL+Ethanol 5.0% IV Diaz 10mg PO+Ethanol 0.6g/L TC Ethanol 0.6g/L TCI ETHANOL Ethanol 0.6g/L TCI Ethanol 0.6g/L TCI THC 2+4+6+6mg IH THC 2+4+6+8mg IH THC ORG 28611#6 IV ORG26828 #5 ug/kg IV AVE16255HTP 120 100mg mg PO 5HTP 100mg PO + Carbidopa 5HTP 100mg PO + Carbidopa 5HTP 200 mg PO + Carbidopa 5HTP 200mg PO 5HTP 200mg PO+Carb+Dom 10 mg 5HTP 200mg PO+Carb+Gran 2mg 5HTP 200mg PO+Carbidopa 5HTP 5HTP 300 mg PO + Carbidopa 5HT Dexfenfluramine 0.5mg/kg PO Amitriptyline 50mg PO 5HT ANT Rizatriptan 10mg PO Sumatriptan 50mg PO mCPP 0.1mg/kg IV mCPP 0.5mg/kg PO SB742457 50mg PO SB742457 50mg PO + Risper 2mg Risperidone 2mg PO DOPAMINE ANT Sulpiride 400 mg PO DOPAMINE Haloperidol 3mg PO Lisuride 0.2 mg PO GPI1 100 mg PO GPI1 300 mg PO GPI1 750 mg PO Scopolamine 0.5mg IV Scopolamine 0.5mg IV OTHER MK0869 160mg PO MK0869 160mg PO+Amitriptyline Talnetant 200mg PO Org25935 0.5mg PO R213129 30mg ACT-078573 1000mg PO ACT-078573 400mg PO O SPO2 80% 2 SPO2 90% 0 6 2 6 20 20 40 . 0 0 0 0 0 0 0 0 0 0 0 5 -60 -40 - -0.4 -0.2 0.0 0.2 0.4 0 0.8-0.4 -0.2 0.0 0. 0.4 0 50 00 -5 5-30 -20 -1 1 -30 -20 -1 10 . .5 . -1 -1 -0.5 0 0.5 1 1 2 2 EOD (5-95% CI) EOD (5-95% CI) EOD (5-95% CI) EOD (5-95% CI) EOD (5-95% CI) EOD (5-95% CI) EOD (5-95% CI) Example 2 First-in-human study New hypnotic Orexin antagonist vs zolpidem Question-Based Development: Pharmacology benchmarking biomarkers vs positive controls a) Adapative tracking performance b) Saccadic peak velocity 10 40 20 5 0 first-in-man of orexin -20 0 -40 Placebo -60 Placebo -5 Zolpidem Zolpidem antagonist 1000 mg -80 1000 mg 400 mg 400 mg -100 Mean change from baseline (%) change from baseline Mean -10 200 mg 200 mg 100 mg (degree/s) baseline from change Mean 100 mg -120 -15 -140 0 2 4 6 8 10 12 0 2 4 6 8 10 12 single-ascending dose Time after administration (h) Time after administration (h) NeuroCart battery c) Body sway d) Smooth pursuit 720 20 zolpidem as positive 600 Placebo Zolpidem 480 1000 mg 10 400 mg 360 200 mg control 100 mg 240 0 120 0 Placebo Zolpidem -10 -120 1000 mg Mean change from baseline (%) change baseline from Mean Mean change from baseline (mm) baseline from change Mean 400 mg -240 200 mg 100 mg -360 -20 0 2 4 6 8 10 12 almorexant 200-400 mg 0 2 4 6 8 10 12 Time after administration (h) Time after administration (h) similar to zolpidem 10 mg somewhat less postural e) Delta Pz −Oz f) Theta Pz −Oz 1.5 1.5 Placebo Placebo Zolpidem Zolpidem 1000 mg 1000 mg instability