CONDUCTING THE “RIGHT” PROOF OF CONCEPT STUDY

Michael F. Egan, MD

Clinical Neuroscience, Merck

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

Introduction

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

Which indication to target: factors to consider

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

Background on histamine and H3 receptor: evidence for target validation

H3 receptor function

Esbenshade, 2006

H3 IA ↓ H3R signaling

and ↑ Histamine

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 Steady State RO between Dosing Interval

Time (hr)0 4 8 12 16 20 24

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qEEG pharmacodynamic measures -related to wake promoting effects- show dose response to H3 IA with receptor occupancy as low as 60%

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Predicted Brain H3 RO Following Single MK-3134 Dose

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.

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qEEG dose-response for MK-3134 (~6h post-dose)

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

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MK-0249 10 mg (n=24)MK-0249 50 mg (n=24)Modafinil 200 mg (n=24)Placebo (n=24)

8 am

Treatment Mean AUC (sd) MK-0249 10 mg 12784 (6181) MK-0249 50 mg 13502 (6333) Modafinil 200 mg 14624 (6350) Placebo 7846 (4331)

Scopolamine results: using Cogstate, 10 mg MK-0249 showed efficacy alone and combined with dopenezil (non-memory measures only)

Results support notion that H3IA has alerting effects (alone and with donepezil) but do not show improvement in episodic memory, important for AD,

Cho, Maruff, Verma et al., 2011

Reaction time (RT)

Choice RT

Exec function

Episodic memory

Learning & memory

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:

– supported by scopolamine results

– Large unmet medical need but POC trials are relatively expensive and POS less certain

– Other

– 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

Baseline Week 2 Change From Baseline

Mean Mean at Week 2

Treatment N (SE) (SE) Mean (95% CI)

Placebo 114 11.63 (0.61)

12.68 (0.75)

1.06 ( -0.22, 2.34)

MK-0249 5 mg

10 11.63 (0.61)

10.72 (2.00)

-0.90 ( -4.84, 3.03)

MK-0249 8 mg

22 11.63 (0.61)

14.49 (1.39)

2.86 ( 0.15, 5.58)

MK-0249 10 mg

38 11.63 (0.61)

13.17 (1.09)

1.54 ( -0.56, 3.65)

MK-0249 12 mg

35 11.63 (0.61)

13.85 (1.13)

2.23 ( 0.04, 4.41)

MK-0249 (top 2 doses‡ )

73 11.63 (0.61)

13.51 (0.85)

1.88 ( 0.28, 3.49)

Modafinil 104 11.63 (0.61)

17.18 (0.75)

5.55 ( 4.08, 7.02)

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

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

MK-0249

Placebo

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

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Practice effects over 1st 3 administrations suggest assay sensitivity

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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

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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

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p=.004** p=.72

• 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?

N=65

N=68

Phase 1B study in subjects with essential tremor after a single dose of MK-0249 compared to ETOH

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• 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

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

Mean Weight Change Over Time

= Placebo = MK-0249 = Sibutramine

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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

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Predicted Brain H3 RO Following Single Oral MK-3134 Doses in Healthy Yong Male Subjects (Fast)

Dark symbols on line indicate statistical significance, even after correcting for multiplicity (60 frequencies).

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qEEG dose-response for MK-3134 (~6h post-dose)

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, 6th 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)