CONDUCTING THE RIGHT PROOF OF CONCEPT STUDY Michael F. Egan, MD Clinical Neuroscience, Merck
Introduction Drugs for some CNS targets (e.g. alpha7, PDE10, glutamate targets, muscarinic M1/M4 agonist, etc) could demonstrate efficacy in more than one disorder. Drugs for cognition: schizophrenia & AD Drugs for psychosis/agitation: schizophrenia, bipolar disorder, AD What is the optimal strategy for demonstrating efficacy for targets with pleiotropic effects, given constraints in pharma? The development program for an H3 inverse agonist (H3IA) provides a case study (and lessons learned). histamine 3 receptor: release modulating autoreceptor. Possible therapeutic indications Attention/wake promoting: ADHD, excessive daytime somnolence Cognition: AD, schizophrenia Others: obesity, tremor, etc
Which indication to target: factors to consider Evidence for target validation Evidence for relevant target engagement and pharmacodynamic effect. Medical need & approved products POC study design: E.g. cost, duration of treatment, internal expertise, probability of failed trial Development Path: compare Ph 2 & Ph 3 requirements for approval Regulatory issues Commercial considerations Company considerations: risk tolerance, pipeline, etc
Background on histamine and H3 receptor: evidence for target validation Clinical evidence implicating histamine, a biogenic amine, in human disease: First generation H1 antagonist antihistamines are sedating and impair cognition (primarily attention) Suggests that increased histamine could reduce sedation, increase alertness. Genetic: weak evidence for association with weight gain Preclinical Histamine releasing neurons are active only in wake, H1 agonists promote wakefulness. H1 and H2 receptor-mediated actions are mostly excitatory; H3 receptors act as inhibitory auto- and heteroreceptors. Efficacy of H3 antagonists in psychosis and cognition models Amphetamine hyperactivity, PPI 5 choice serial reaction time task (attention) Radial arm maze and Y maze (working memory Morris Water Maze (episodic memory) Social recognition Task Other: H3 IA inhibits feeding & wt gain, reduces tremor, etc
H3 receptor function H3 IA H3R signaling and Histamine Esbenshade, 2006
H3 antagonists exhibit broad efficacy in preclinical models of cognition, making cognition indications attractive Esbenshade, 2006
Merck approach Consider H3 IA (MK-0249) for multiple indications, based on prior reports of efficacy in preclinical models, including: Excessive daytime sleepiness (EDS) Attention deficit hyperactivity disorder (ADHD) Cognition in Schizophrenia Alzheimer s disease (AD) Essential tremor (ET): Obesity (OB) Replicate results from preclinical models showing efficacy. Develop translatable biomarkers for target engagement and pharmacodynamic effects PET ligand for occupancy in preclinical studies and humans Alerting effects: qeeg Alerting effects: sleep deprivation study Cognition effects: scopolamine model Based on these results, consider optimal development strategy
MK-0249 Phase I PK Summary Single doses up to 150 mg well tolerated t½ ~ 14 hours; Tmax ~ 3-4 hours Dose-related insomnia AEs @ >50 mg single doses Multiple doses (x 7 d) up to 12.5 mg well tolerated Higher doses associated with insomnia Alerting effects noted at 5-20 mg after single dose
Target engagement: model of receptor occupancy following multiple MK-0249 doses Predicted Receptor Occupancy (%) 100 1 mg Predicted Steady State RO between Dosing Interval 2 mg 3 mg 4 mg 5 mg 90 6 mg 7 mg 8 mg 9 mg 10 mg 80 70 60 50 40 0 4 8 12 16 20 24 Time (hr)
qeeg pharmacodynamic measures -related to wake promoting effects- show dose response to H3 IA with receptor occupancy as low as 60% qeeg dose-response for MK-3134 (~6h post-dose) Predicted Brain H3 RO Following Single MK-3134 Dose 20mg 5mg 1mg Predicted Receptor Occupancy (%) 100 90 80 70 60 50 40 30 20 10 0 1-mg MK-3134 5-mg MK-3134 25-mg MK-3134 0 6 12 18 24 Time (hr) Conclusion: 1. H3 IA produces dose-dependent increase in power for higher frequencies on qeeg 2. Suggests H3IA may improve attention &, possibly, other aspects of cognition. AJ Verma et al., unpublished.
Phase 1 study: excessive daytime somnolence model shows wake promoting effects of 10 and 50 mg; less effective than modafinil Mean (min) 30 25 20 15 10 Treatment Mean AUC (sd) MK-0249 10 mg 12784 (6181) MK-0249 10 mg (n=24) MK-0249 50 mg 13502 (6333) MK-0249 50 mg (n=24) Modafinil 200 mg 14624 (6350) Modafinil 200 mg (n=24) Placebo 7846 (4331) Placebo (n=24) 5 0 8 am -18-2 0 2 4 6 8 10 12 14 16 18 Hours
Scopolamine results: using Cogstate, 10 mg MK-0249 showed efficacy alone and combined with dopenezil (non-memory measures only) Cho, Maruff, Verma et al., 2011 Reaction time (RT) Choice RT Exec function Episodic memory Learning & memory Results support notion that H3IA has alerting effects (alone and with donepezil) but do not show improvement in episodic memory, important for AD,
What to do next? Proof of concept studies considered for several indications include the following Excessive daytime sleepiness (EDS) in sleep apnea: supported by qeeg results But MK-0249 was less effective than Modafinil POC trial in subjects with sleep apnea feasible Adult ADHD: supported by qeeg, scopolamine results POC trials are relatively expensive Cognition in AD, schizophrenia: Other supported by scopolamine results Large unmet medical need but POC trials are relatively expensive and POS less certain Essential tremor (ET): preclinical support only Ph 1B study in essential tremor has good face validity, ETHOH as active comparator Obesity (OB): preclinical support only 4-week Ph IIA weight loss study: relatively inexpensive, good predictive validity compared to Ph 3 trials.
Daytime sleepiness in patients with obstructive sleep apnea: no beneficial effect of MK-0249 on sleep latency using Maintenance of Wakefulness Test Design: 3 period X over 2 week treatment Doses: 5-12 mg/d; adaptive allocation Primary outcome: sleep latency using Maintenance of Wakefulness Test Results: modafinil but not MK-0249 increased latency to sleep during daytime test of sleepiness vs placebo Conclusion: MK-0249 not effective in sleep apnea from J. Herring et al., unpublished Baseline Week 2 Change From Baseline Mean Mean at Week 2 Treatment N (SE) (SE) Mean (95% CI) Placebo 114 11.63 (0.61) MK-0249 5 mg MK-0249 8 mg MK-0249 10 mg MK-0249 12 mg MK-0249 (top 2 doses ) 10 11.63 (0.61) 22 11.63 (0.61) 38 11.63 (0.61) 35 11.63 (0.61) 73 11.63 (0.61) Modafinil 104 11.63 (0.61) 12.68 (0.75) 10.72 (2.00) 14.49 (1.39) 13.17 (1.09) 13.85 (1.13) 13.51 (0.85) 17.18 (0.75) 1.06 ( -0.22, 2.34) -0.90 ( -4.84, 3.03) 2.86 ( 0.15, 5.58) 1.54 ( -0.56, 3.65) 2.23 ( 0.04, 4.41) 1.88 ( 0.28, 3.49) 5.55 ( 4.08, 7.02)
Adult ADHD POC study: No effect of MK-0249 after 4 weeks of treatment on the ADHD Investigator Symptom Rating Scale Design: 2 period cross over incomplete block design Two 4 wk treatment periods with 1 wk washout Dose: 10 mg/d N= ~40/group Primary outcome : AISRC= ADHD Investigator Symptom Rating Scale Results AISRC at week 4: MK-0249 vs PBO p=0.341 Concerta vs PBO p=.001 Exploratory cognition measures: MK improved scores on the Stroop and CPT vs placebo, Concerta did not. Conclusion: MK-0249 not effective in adult ADHD Placebo MK-0249 Concerta from J. Herring et al., unpublished
Cognitive impairment in schizophrenia: no effect of MK-0129 on BACS cognition score after 4 weeks of treatment 50 MK-0249 / Placebo Placebo / MK-0249 45 Plac MK Mean BACS Total Score 40 35 MK Plac Period 1 Period 2 30 25 Practice effects over 1 st 3 administrations suggest assay sensitivity 1 2 3 6 7 10 Visit
Mild-moderate AD: no effect of MK-0129 on cognition score after 4 weeks of treatment Randomized, double-blind, placebo controlled, parallel-group, ~ 70/arm Dose: 5 mg/d (predicted r/o ~ 85%) Outcome measures: 1) CNTB summary score (RT, list learning, visual memory); 2) ADAS cog 11 2 CNTB summary score Deterioration Improvement 1 0-1 -2-3 MK-0249 Placebo p=.54 0 2 4 Week p=.28 N=52 N=62
MK-0249: Phase 2 Summary Excessive daytime sleepiness (EDS) Results : MK-0249 not effective (modafnil superior to placebo) Attention deficit hyperactivity disorder (ADHD ): Ph IIA study Results: MK-0249 not effective (Concerta superior to placebo) Trends for improvement in some cognitive domains insufficient to improve clinical outcome Dementia of the Alzheimer s type (DAT): Ph IIA study Results: MK-0249 not effective after 4 wks Rx @ ~85% r/o Questions re dose & duration, Cognition in Schizophrenia : Ph IIA study Results: MK-0249 not effective when added to atypical antipsychotics Essential tremor (ET): POC in single dose Ph IB model in patients with ET Results: ETOH effective, MK-0249 not effective Obesity (OB): 4-week Ph IIA weight loss study Results: Sibutramine effective, MK-0249 not effective,
Lessons learned by indication Excessive daytime sleepiness (EDS) & ADHD Good translational path but Biomarkers not predictive Active comparators: confirm trial validity Target validation: lacking AD study Scopolamine model not predictive. Target validation: lacking Cognition in Schizophrenia Study Protocol issues: crossover design, use of antipsychotics with H1 affinity. Clinical & preclinical models not predictive. Target validation: lacking Essential tremor & Obesity Models not predictive Target validation: lacking
Lessons learned regarding overall strategy Multiple POC studies using one compound and overlapping biomarker set was efficient and provided useful lessons learned for multiple indications Target validation: not good enough Future target selection criteria should be revised: stronger support needed for primary indications Animal models: poorly predictive of efficacy in humans clearly not sufficient; unclear if efficacy in animal models is necessary for human efficacy should not be used for target validation. Biomarker development: For CNS, showing target engagement is useful for dose selection and suggesting that hypotheses were adequately tested. Recommendation: pick one indication with best evidence for target validation.
Acknowledgments Strategy Darryle Schoepp Bill Potter David Michelson Richard Hargreaves Clinical Pharmacology Robert Iannone Keith Gottesdiener Gail Murphy Experimental medicine AJ Verma Bill Cho Gary Herman Sabrina Fox-Bosetti Basic John Renger Nicole Calder Kristine Cerchio Clinical Neuroscience Joe Herring Mike Egan Michael Ryan Christopher Lines Regina Gottwald Lyn Harper-Mozley David Michelson Basic John Renger Nicole Calder Kristine Cerchio Imaging Richard Hargreaves Statistics John Placza Cynthia Gargano Lian Liu Yahong Peng Xin Zhao Ying Zhang, Duane Snavely
Back up slides
Possible short term effect on ADAS-Cog Total Score Lack of effect @ 4 wks and failure on primary endpoint suggest lack of clinically relevant, persistent efficacy. Questions: Was 4 week treatment too short? Was dose too low? Was half life too long? Deterioration Improvement -3-2 -1 0 1 p=.004** p=.72 N=65 N=68 2 MK-0249 Placebo 0 2 4 Week
Phase 1B study in subjects with essential tremor after a single dose of MK-0249 compared to ETOH Single dose design, N = 18 subjects with > 18 years (mean) with ET 3-period crossover MK-0249 (25 mg), Pbo and IV EtOH Primary Endpoint: Accelerometry-based laboratory tremorography Conclusion: Single dose MK-0249 did not improve tremor in ET patients Max Power Glove B-F (uv) Kinetic (%) 70 60 50 40 30 20 10 0-10 -20-30 -40-50 0 120 240 360 480 600 Time (min) MK-0249 Pbo EtOH
Design of POC study in schizophrenia for cognitive impairment 2 period cross over with 1 wk washout & 1 wk placebo run in Dose: 10 mg/d 40 stable outpatients with schizophrenia Primary outcome measure: BACS
MK-0249 4-week Obesity Phase IIA Results 3 Mean Weight Change Over Time Change in Body Weight (kg) 2 1 0-1 -2-3 -4-5 -2 0 2 4 = Placebo = MK-0249 = Sibutramine Week
Summary of 3 EM qeeg studies with H3 Inverse agonists : Spectral ratios are shown comparing drug vs. placebo Data are shown for the highlighted electrodes. There was significant regional heterogeneity if spectral ratio pattern seem for different electrodes. Fitted mean value 95% CI
Target occupancy vs. qeeg pharmacodynamics for MK-3134 qeeg dose-response for MK-3134 (~6h post-dose) Predicted Brain H3 RO Following Single Oral MK-3134 Doses in Healthy Yong Male Subjects (Fast) 20mg 5mg 1mg Dark symbols on line indicate statistical significance, even after correcting for multiplicity (60 frequencies). Predicted Receptor Occupancy (%) 100 90 80 70 60 50 40 30 20 10 0 1-mg MK-3134 5-mg MK-3134 25-mg MK-3134 0 6 12 18 24 Time (hr)
Study Design Summary Design Double-blind, two period crossover study MK vs placebo Each arm=4 wks, one wk washout in between Single blind 8 day run in to allow practice test sessions (3 total) for cognitive battery to maximize practice effect. Patients: stable outpatients with mild-moderate sx, 6 th grade reading (or better). Concomitant antipsychotic medication: stable dose x 2mos or more. Dose: MK-0249: >85% RO at 10 mg/d, down titration (after 3 d) to 7mg (>80% RO). MK-0577: >90% RO at 10 mg/d, down titration (after 3 d) to 5mg (>90% RO). Increase back to 10 mg/d not permitted. Results for MK-0249: 6 MK and 3 placebo pts reduced dose. Screening Period: Days -30 to -14.
Outcome measures Primary: Global summary score from Brief Assessment of Cognition in Schizophrenia (BACS) Secondary (compiled from BACS and Penn s CNP) MK-0557 Working Memory Executive Function Episodic Memory MK-0249 Attention Episodic Memory Working Memory Tertiary Positive and Negative Syndrome Scale (PANSS) Clinical Global Impression Severity of Illness Scale (CGI-S)
MK-0249: Demographics MK-0249 10mg / PBO PBO / MK-0249 10mg Total Gender n (%) n (%) n (%) Male 20 (71.4) 20 (74.1) 40 (72.7) Female 8 (28.6) 7 (25.9) 15 (27.3) Age (YEARS) Mean 30.7 yr 32.5 yr 31.6 yr SD 7.5 8.4 7.9 Race n (%) n (%) n (%) ASIAN 10 (35.7) 10 (37.0) 20 (36.4) WHITE 18 (64.3) 17 (63.0) 35 (63.6)