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Pharmacology-Guided Dose-Escalation of First-In-Class Drugs Almorexant (ORX1/2-Antagonist) and Rimonabant (CB1-Antagonist)

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Pharmacology-Guided Dose-Escalation of First-In-Class Drugs Almorexant (ORX1/2-Antagonist) and Rimonabant (CB1-Antagonist) Pharmacology-Guided Dose-Escalation of First-in-Class Drugs almorexant (ORX1/2-antagonist) and rimonabant (CB1-antagonist) Joop van Gerven, MD, PhD professor of clinical neuropsychopharmacology, Leiden University director CNS research, Centre for Human Drug Research Contents: • causes of failed development • getting the pharmacology right for highly selective innovative drugs Failed Clinical Trials in Phase II/III Phase II Phase III Arrowsmith J. Trial watch: Phase II failures: 2008-2010. Nat Rev Drug Disc 2011:10:328-9 Arrowsmith J. Trial watch: Phase III and submission failures: Nat Rev Drug Disc 2011:10:82. Determinants of Drug Efficacy pharmacologyvariability etiology Cohen AF. Developing drug prototypes: pharmacology replaces safety and tolerability? Nat Rev Drug Discov. 2010;9:856-65 …25 Drugs Withdrawn After Launch… Drug Approved Withdrawn License Reason amineptine (Survector) 1978 2000 22 abuse, acne cisapride (Propulsid) 1993 2000 7 cardiac arrythmia troglitazone (Rezulin) 1999 2000 1 liver failure alosetron (Lotronex) 2000 2000 1 ischemic colitis phenylpropanolamine (Dexatrim) 1970's 2000 30 haemorrhagic stroke cerivastatin (Lipobay, Baycol) 1997 2001 4 rhabdomyolysis rapacuronium (Raplon) 1999 2001 2 bronchospasm trovafloxacin (Trovan) 1998 2001 3 liver failure ⅓ pharmacologic AEs: levomethadyl 1993 2003 10 abuse, cardiac arrythmia -predictable rofecoxib (Vioxx) 1999 2004 5 cardiac risk pemoline (Cylert) 1975 2005 30 liver failure -dose-related valdecoxib (Bextra) 2004 2005 1 cardiac risk natalizumab (Tysabri) 2004 2005 1 leucoencephalopathy Tc fanolesomab 2004 2005 1 allergy hydromorphone (Palladone ER) 2004 2005 1 alcohol interaction pergolide (Permax) 1988 2007 19 valve regurgitation tegaserod (Zelnorm) 2004 2007 3 cardiac risk lumiracoxib (Prexige) 2006 2008 2 liver failure aprotinin (Trasylol) 1993 2008 15 cardiac risk rimonabant (Acomplia) 2006 2008 2 depression efalizumab (Raptiva) 2003 2009 6 leucoencephalopathy sibutramine 1988 2010 22 cardiac risk gemtuzumab ozogamicin (Mylotarg) 2000 2010 10 lack of efficacy drotrecogin alfa (Xigris) 2001 2011 10 lack of efficacy pharmacological effect/predictable at time of registration 27% pharmacological effect/predictable after time of registration 9% drug-class specific rare adverse drug reaction 36% rare idiosyncratic/allergic adverse drug reaction 36% 1980-2000: Dose Reductions After Launch • 27% of all new FDA-registrations of CNS-active drugs • 79% safety-related • three times more often in ’95-’99 than in ’80-’85 Cross J, Lee H, Westelinck A, Nelson J, Grudzinskas C, Peck C. Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999. Pharmacoepidemiol Drug Saf 2002;11:439-46 Optimizing Drug Action: getting the pharmacology right Traditional – tolerated dose T E Use traditional approach for modern drugs T E Pharmacology-Based Phase I T E P pharmacological effects: essential for therapeutic action PD-effect 1 M-o-A PD-effect 2 R -clinical effect PD-effect 4 PD-effect 3 -type A adverse effects -therapeutic range Which Binding Level Is Required for Therapeutic Activity? Drug Class Pharmacological Activity Receptor Occupancy Antipsychotic DA2 competitive - 60-80% antagonist - 17-67% for clozapine Anxiolytics GABA-A positive allosteric - 5-30% for benzodiazepines modulator - >60 for new partial subtype selective compounds Antidepressant 5HT transporter inhibitor - 50->80% CNS stimulants DA transporter inhibitor - 50-80% New compound New mechanism - often no availaible tracer - usually unknown occupancy Talbot PS, Laruelle M. T he role of in vivo molecular imaging with PET and SPECT in the elucidation of psychiatric drug action and new drug development. European Neuropsychopharmacology 12 (2002) 503–511 Optimizing Drug Action: pharmacology-guided dose selection for first-in-class CNS-active drugs Case 1: dual-orexin antagonist almorexant Case 2: cannabinoid CB1 antagonists surinabant and rimonabant Pharmacology-Guided Dose Selection - Case 1: Almorexant –first Dual ORX1/2-Antagonist (DORA) • first-in-class with theoretical narcolepsy-like AEs: – sleep attacks – cataplexy VAS alertness external perception VAS – hypnagogic hallucinations – sleep paralysis • SAD: extensive CNS-profiling – alertness adaptive tracking body sway – motor control – psychomimetic effects – sleep EEG • benchmarking with zolpidem 10mg – (adverse) effect profile sleep EEG δ-power – indications of sleep promotion Hoever P, De Haas S, Winkler J, Schoemaker RC, Chiossi E, Van Gerven J, Dingemanse J. Orexin receptor antagonism, a new sleep-promoting paradigm: First-in-humans study with almorexant. CPT 2010;87:593-600 Case 1: PK/PD-based dose selection of almorexant 5 mg zolpidem Case 1: confirmation of safe effective low dose • sleep-promotion • low pharmacological activity • no harmful narcolepsy-like effects Hoever P et al. Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial. CPT 2012;91:975-85 9351 four Pharmacology-Guided Dose Selection – Case 2: rational development of CB1-antagonists • no PD-effects in healthy subjects • develop THC-challenge model • determine peripheral/central pharmacological activity using PK/PD • determine relevant inhibition levels in clinical trials isolation of THC for inhalation VAS Alertness 1 5 0 Body Sway 90 3 0 0 80 1 0 0 70 60 50 50 40 VAS Alertness (mm) Paper 0 2 0 0 30 20 -120 0 120 240 360 480 600 -5 0 Time (min) ne baseli from (mm) change sway Body 0 1 2 0 2 4 0 3 6 0 4 8 0 6 0 0 T i m e (m i n ) VAS ‘Feeling high’ T HC Pl a c e b o T HC (ng/mL) Heart Rate 1 0 0 80 70 1 0 0 60 50 90 40 80 30 20 70 0 Psychedelic VAS (mm) 11 10 (bpm) rate Heart 0 1 2 0 2 4 0 3 6 0 4 8 0 6 0 0 0 60 -10 T i m e (m i n ) -120 0 120 240 360 480 600 50 Time (min) 0 1 2 0 2 4 0 3 6 0 4 8 0 6 0 0 T i m e (m i n ) T HC Pl a c e b o development of THC challenge and PK/PD-model Klumpers LE et al. Surinabant, a selective CB1 antagonist, inhibits THC-induced central nervous system and heart rate effects in humans. Br J Clin Pharmacol. 2013;76:65-77 Pharmacologically active doses of surinabant: peripheral effects up to 40% peripheral suppression 100 Observed SR Population SR 0 mg Population SR 5 mg Population SR 20 mg 90 Population SR 60 mg 80 60mg SD 10mg MD Mean (SD) HR (bpm) HR (SD) Mean 70 (%) rate reductionHR 20mg SD 5mg MD 5 mg SD 2.5mg MD 60 -1 0 1 2 3 4 5 6 7 8 9 10 Time from surinabant dose (h) SD dose (mg ) dose-dependent suppression of THC-effects PK/PD-analysis Klumpers LE et al. Surinabant, a selective CB1 antagonist, inhibits THC-induced central nervous system and heart rate effects in humans. Br J Clin Pharmacol. 2013;76:65-77 Ferrona G, Klumpers L, Van Gerven J, Roy C. PK and PK/PD modeling of CB1 blocker antagonism of THC induced CNS and Heart Rate effects. PAGE Poster 2010 Pharmacologically active doses of surinabant: central effects 60% central suppression 100 80 60mg SD 10mg MD 60 40 VAS Feeling high (mm) VAS high reduction rate (%) rate reduction high VAS 20 0 -9 0 -3 0 30 90 150 210 270 330 390 450 510 570 Ti m e (m i n ) SD dose (mg ) dose-dependent suppression of THC-effects PK/PD-analysis Klumpers LE et al. Surinabant, a selective CB1 antagonist, inhibits THC-induced central nervous system and heart rate effects in humans. Br J Clin Pharmacol. 2013;76:65-77 Guan Z, Klumpers LE, Oyetayo B, Heuberger J, Van Gerven JMA, Stevens J, Freijer JI. Pharmacokinetic/ pharmacodynamic modelling and simulation of the effects of different CB1 antagonists on ∆9-tetrahydrocannabinol challenge tests in healthy volunteers. (submitted) Phase IIa clinical trail: weight gain during smoking cessation CB1-inhibition 10% 20% 40% 40% 1.50 1.00 0.50 weight change during smoking cessation (kg) 0.00 placebo 2. 5 m g 5 m g 10 m g r imonabant 20 m g surinabant (all treated) (ceased smokers) •Tonstad S, Aubin HJ. Efficacy of a dose range of surinabant, a cannabinoid receptor blocker, for smoking cessation: a randomized controlled clinical trial. J Psychopharmacol 2012;26:1003-9 •Rigotti NA, Gonzales D, Dale LC, Lawrence D, Chang Y; CIRRUS Study Group. A randomized controlled trial of adding the nicotine patch to rimonabant for smoking cessation: efficacy, safety and weight gain. Addiction 2009;104:266-76 CB1-inhibition of clinically active rimonabant dose: central (60%) > peripheral (40%) suppression rates 60mg SD 20mg MD 60mg SD 20mg MD 5mg SD 5mg MD weight reduction? < psychiatric adverse effects? Peripherally restrictive CB1-antagonists: improved therapeutic window? drinabant TM38837 40% peripheral → 30% central suppression 40% peripheral → 15% central suppression weight reduction? >> psychiatric adverse effects? Conclusions • For selective drugs, pharmacodynamically active concentrations in healthy subjects are often closely related to therapeutic levels • Pharmacokinetic-pharmacodynamic relationships are an important aspect of ‘proof-of-pharmacology’ • Pharmacology-guided dose escalation - allows maximization of therapeutic window - may avoid adverse events associated with unnecessarily high doses - increases confidence in dose optimization Clinical Pharmacology in Clinical Trial Design .
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