mk-0633, a potent 5-lipoxygenase inhibitor, in chronic obstructive pulmonary disease

Respiratory Medicine (2011) 105, 392e401

ava i lab le at www.sc iencedi rect .com

journal homepage : www.e lsev ie r . com/ loca te / rmed

MK-0633, a potent 5-lipoxygenase inhibitor,in chronic obstructive pulmonary disease

Jonathan A. Bernstein a,*, Nancy Liu b, Barbara A. Knorr b,Steven S. Smugar b, William D. Hanley b, Theodore F. Reiss b,1,Steven Greenberg b

aBernstein Allergy Group, Bernstein Clinical Research Center, Inc. 8444 Winton Rd, Cincinnati, OH 45231, USAbMerck & Co., Inc., PO Box 100, Whitehouse Station, NJ 08889, USA

Received 2 August 2010; accepted 29 September 2010Available online 13 November 2010

KEYWORDS5-Lipoxygenase;Chronic obstructivepulmonary disease;Forced expiratoryvolume in 1 s;Lung function

* Corresponding author. Tel.: þ1 51E-mail address: jonathan.bernstei

1 Current employer: Covance, Inc.,

0954-6111/$ - see front matter ª 201doi:10.1016/j.rmed.2010.09.021

Summary

Chronic obstructive pulmonary disease (COPD) is associated with neutrophil-mediated inflam-mation, a potential target for treatment in COPD. We evaluated MK-0633, a 5-lipoxygenaseinhibitor in patients with COPD.

This was a 12 week, randomized, double-blind, multicenter study comparing MK-0633 100 mg and placebo in patients 40e75 years of age (N Z 266) with COPD, post-b-agonistforced expiratory volume in 1 s (FEV1) 25%e75% predicted, and an FEV1/forced vital capacityratio (FVC) �70%. Long-acting inhaled bronchodilators were permitted for approximately 50%of patients. The primary efficacy endpoint was the change from baseline in pre-dose (trough)FEV1 measured over the last 2 weeks of the 12 week treatment period.

The change in FEV1 over the last 2 weeks of the 12 weeks treatment period compared tobaseline was 0.015 L for MK-0633 and 0.0002 for placebo (p Z 0.556). For COPD Global Eval-uation, 75.4% of patients receiving MK-0633 reported feeling better vs. 59.8% of patientsreceiving placebo (p Z 0.032). There were no other significant differences between treat-ments. MK-0633 was well-tolerated and comparable to placebo.

The 5-LO inhibitor MK-0633 was not significantly more effective than placebo in improvingFEV1 from baseline in patients with COPD, although more patients reported feeling improvedwith MK-0633.

Clinicaltrials.gov identifier: NCT00418613.ª 2010 Elsevier Ltd. All rights reserved.

3 558 5533; fax: þ1 513 931 [email protected] (J.A. Bernstein).Princeton, NJ.

0 Elsevier Ltd. All rights reserved.

mailto:[email protected]

http://www.elsevier.com/locate/rmed

http://dx.doi.org/10.1016/j.rmed.2010.09.021



MK-0633, a potent 5-LO inhibitor, in COPD 393

Introduction

Chronic obstructive pulmonary disease (COPD) is the 4thleading cause of death worldwide1 and a source ofsubstantial economic and social burden that has beensteadily increasing. COPD is characterized by inflammation,parenchymal tissue destruction, mucus hypersecretion, andairflow limitation that is not fully reversible.2 The under-lying inflammation seen with COPD, particularly the smallairways, includes macrophages, neutrophils, CD4 and CD8-positive T-cells, and B-cells.3 Leukotriene B4 (LTB4),a potent chemoattractant of both neutrophils and T-cells,4

is thought to be an important mediator of neutrophilrecruitment and survival in COPD,5, 6 and increased levelshave been shown in serum,7 induced sputum,8 and exhaledbreath condensates9 in patients with COPD. Therefore,drugs that target LTB4 production could potentially reduceinflammation in COPD.

Indeed, a trial of a 5-lipoxygenase activating protein(FLAP) inhibitor led to trends in decreased concentrationsof LTB4 and myeloperoxidase, a marker of neutrophils, anddecreased neutrophil chemotactic activity in sputa obtainedfrom COPD patients.10 In addition, antibiotic treatment ofpatients with acute bacterial exacerbation of COPD reducedsputum LTB4, which was accompanied by a reduction ofw30% of sputum chemotactic activity attributed to LTB4.

11

Zileuton, a 5-LO inhibitor, and the only commercially avail-able agent that acts on the LTB4 pathway, has been shown todecrease LTB4 levels in patients with asthma, and signifi-cantly increase exercise capacity and quality of life inpatients with COPD.12 However, results directly implicatingLTB4 in COPD pathogenesis have been somewhat inconsis-tent.13 The purpose of this study was to evaluate MK-0633,a 5-LO inhibitor, in patients with COPD.

Methods

Patients

Men and postmenopausal women age 40e75 years witha history consistent with COPD for at least 1 year wereeligible. Eligible patients had a post-b-agonist forcedexpiratory volume in 1 s (FEV1)/forced vital capacity (FVC)ratio �70% and FEV1 25e75% of the predicted value,smoking history of �10 pack-years, and a body mass indexof 19e40 kg/m2.

Pertinent exclusion criteria included a clinically signifi-cant active pulmonary disorder (other than COPD); emer-gency room treatment or hospitalization for COPD withinthe previous 2 months; oxygen saturation on room air<88% while withholding b-agonist for at least 6 h; continuous(>16 h/day) oxygen therapy; uncontrolled hypertension(>160/100 mmHg); or myocardial infarction, congestiveheart failure, or uncontrolled cardiac arrhythmia within 3months. Excluded COPDmedications included oral or inhaledshort-acting anticholinergic agents within 2 weeks; oralor inhaled long-acting bronchodilators within 2 weeks(if patient is not within the 50% of patients permitted per siteto receive long-acting bronchodilators); antileukotrienemedications, intravenous or intramuscular corticosteroidswithin 3 weeks; xanthine derivatives or combinations within

2weeks; or oral or inhaled corticosteroids within 2weeks. Anaction plan for worsening COPD was provided.

To assess whether MK-0633 may have an additive benefitto long-acting bronchodilators, as well as to ensure that thesample population was representative of the COPD pop-ulation, up to 50% of patients randomized at each site wereallowed to receive chronic stable doses of long-actingbronchodilators (e.g., tiotropium, salmeterol) during thetrial. All patients were permitted to use an inhaled short-acting b-agonist throughout the study on an “as needed”basis for relief of COPD symptoms.

Study Design

This study (Merck protocol 009) was a 12 week, multicenter,randomized, double-blind, placebo-controlled, parallelgroup study of the efficacy of MK-0633 in COPD, conductedat 36 sites from January 2008 to March 2009. The conduct ofthis study was consistent with the standards of the Decla-ration of Helsinki. The protocol was approved by localinstitutional review boards or ethics committees, andpatients provided written informed consent prior toparticipation.

During a 2-week, single-blind placebo run-in period,patients were required to have daytime and nighttimeb-agonist administration weekly average �5 puffs per weekand an average overall daytime symptoms score of �1.2(based on symptom frequency, scored from 0Z “none of thetime” to 5Z “all of the time”), and demonstrate at least 80%compliance with test drug. After the run-in, eligible patientswere randomized to receive once-daily MK-0633 100 mg ormatching placebo eachmorning for 12 weeks. Allocation wasdetermined according to a computer-generated allocationschedule. Numbered packaging was used to implementallocation. All studypersonnel, including investigators, studysite personnel, patients, monitors, and central laboratorypersonnel remained blinded to treatment allocationthroughout the study. The code was revealed to theresearchers once recruitment, data collection, and labora-tory analyses were complete.

Efficacy and Tolerability Assessments

Spirometry was performed at baseline/randomization andat weeks 2, 4, 8, 10, and 12 between 6 AM and 10:30 AMafter withholding the morning dose of study medication andshort-acting b-agonists for at least 6 h, LABA for at least12 h, and long-acting anticholinergic agents for 24 h.Reversibility was measured by administering two puffs ofa short-acting b-agonist and performing spirometry20e30 min afterward. A daily patient diary was used tocapture daytime and nighttime symptoms, b-agonist use,peak expiratory flow rate (PEFR), and daytime COPDresource utilization. Daytime symptoms were assessed with6 questions, all scored on a 6-point Likert scale: 1) Overalldaytime symptom frequency; 2) Shortness of breathfrequency; and 3) Cough frequency, all scored from0 Z “None of the time” to 5 Z “All of the time”; 4) Mucusproduction, scored from 0Z “None” to 5Z “A very large ormassive amount”; 5) Difficulty performing routine activitiesrequiring light physical movement (e.g., bathing); and 6)

394 J.A. Bernstein et al.

Difficulty performing moderate or high physical movement(e.g., walking up stairs), both scored 0 Z “No difficulty” to5 Z “So difficult, couldn’t do it at all”. Nighttime symp-toms were assessed by quantitating awakenings due to lungsymptoms (0, 1, 2, 3 or more). PEFR was measured imme-diately before bedtime and immediately upon awakeningbefore taking study medication or concomitant medica-tions. COPD resource utilization was recorded in the diaryby asking the question “In the past 24 h, did you calla doctor; or visit a doctor, emergency room or hospital; ortake additional medications (including corticosteroid pills)due to a worsening of your lung disease?” Patients alsocompleted a global COPD evaluation at 12 weeks (ordiscontinuation) consisting of a single question describingpatients’ perception of the change in their COPD over thecourse of the study (“Very much better,” “Moderatelybetter,” “A little better,” “Unchanged,” “A little worse,”“Moderately worse,” “Very much worse”). Patientscompleted the self-assessed standardized version of thechronic respiratory disease questionnaire (CRQ-SAS)14, 15 atbaseline and at Weeks 8 and 12.

The primary efficacy endpoint was change from base-line (i.e., randomization) in pre-dose (trough) FEV1measured over the last two weeks of the 12 week activetreatment period. The rationale for analyzing the lasttwo weeks was because of the limited data available forMK-0633 and 5-LO inhibitors in general regarding whenthe maximal effect of a 5-LO inhibitor would be achievedin COPD. Secondary endpoints were overall daytimesymptoms scores, post-dose FEV1, total daily b-agonistuse, dyspnea, and CRQ score, measured over a 12 weektreatment period. Exploratory endpoints included AM andPM PEFR, individual daytime COPD symptom scores,nocturnal awakenings, and COPD exacerbations (definedaccording to resource utilization, including the need foradditional rescue medications [systemic corticosteroidsand/or antibiotics] or unscheduled COPD-related doctorvisits, emergency department visits or hospitalizations).Other exploratory endpoints were patient Global Evalua-tion, COPD symptom-free days (overall symptom score of0 or 1), pre-dose (trough) FVC, and post-b-agonist FEV1and FVC. A portion of patients at participating sites werealso enrolled in a whole body plethysmography lungvolume sub-study, with measurements made at baselineand 12 weeks.

Tolerability was assessed by physical and laboratoryexaminations, vital signs, and incidence of adverse expe-riences (AEs). Because of a suggestion of renal tubulardamage in mice in acute toxicity studies, an internal datasafety monitoring committee reviewed results of aninterim blinded safety analysis of urine N-acetyl-b-gluco-saminidase (NAG), a sensitive marker of acute tubularinjury,16 as well as other markers of renal function, after50% of patients completed the main study. Patientswith NAG >3x baseline value on 2 consecutive measure-ments were discontinued. The committee also evaluatedpatients with significant increases NAG or urinary micro-albumin that did not achieve the 2- or 3-fold levelsfor discontinuation to determine if elevations met pre-specified criteria for study termination. Patients with ALTor AST �3 ULN or on 2 consecutive occasions were alsodiscontinued.

Pharmacokinetic (PK) measurements

Plasma samples were collected for MK-0633 assay at pre-study and at week 8, pre-dose and at 4 h post-dose. Ifpossible, patients fasted over-night, or at least 8 h prior tothese visits. The analytical method for determination ofMK-0633 in human plasma involved isolation, via 96-wellprotein precipitation, of the analyte and internal standardin plasma, followed by reverse phase high pressure liquidchromatography tandem mass spectrometry analysis. Thelower limit of quantitation (LLOQ) for the plasma assay was5 nM and the linear calibration range was 5e5000 nM. Thepre-dose and 4 h post-dose MK-0633 concentrations at week6 were assessed from plasma concentrations at nominalsampling times and not corrected based on when the dosewas administered or when the samples were actuallycollected. Urinary LTE4 samples were collected at baselineand Week 8.

Statistical methods

The primary hypothesis was that MK-0633, compared withplacebo, would result in significant improvement in FEV1

measured over the last 2 weeks of a 12 week treatmentperiod in patients with COPD. The primary efficacy analysiswas based on the Full Analysis Set population, whichincluded all randomized patients with a baselinemeasurement and at least one post-treatment measure-ment. A per-protocol analysis was also performed. Theprimary endpoint was analyzed using a longitudinal linearmodel, with change from baseline in FEV1 at each visit asthe dependent variable and treatment, study country,concomitant long-acting bronchodilator use, smokingstatus, baseline FEV1 reversibility, baseline FEV1, andtreatment-by-visit interaction as independent variables.The covariance across visits within each subject wasmodeled using a general unstructured covariance matrix.The primary analyses were based on observed data, andmissing data were not imputed. Pre-specified subgroupanalyses of the primary endpoint included long-actingbronchodilator use, gender, age group (�40 to <50, �50 to<65, �65e75 years), ethnicity (white, black, Hispanic,other), smoking history (current smoker, ex-smoker), region(US/Canada, Central/South America, Europe, Japan,other), baseline severity based on baseline FEV1% predicted(�50% Z moderate; <50% Z severe); and baseline FEV1

reversibility to b-agonist (low reversibility Z �12%; highreversibility >12%). Additional post-hoc analyses ofsecondary and exploratory endpoints were performed forthese same pre-specified subgroups.

Between-group comparisons of the proportion of patientswith at least one COPDexacerbationwere analyzed using theFisher Exact test. The KaplaneMeier procedure was used toestimate and the log-rank testwas used to compare the time-to-first COPD exacerbation curves. The percentage of COPDsymptom-free days over the last 2 weeks of treatment wasanalyzed using an analysis of covariance (ANCOVA) modelwith factors for treatment, study country, concomitant log-acting bronchodilator use, smoking status, baseline FEV1

reversibility, and baseline percentage of COPD symptom-free days. The proportion of patients in each category of

Screened N=431

Enrollment N= 266

165 Screening Failures 136 Did not meet eligibility requirements 14 Withdrawal by subject 8 Adverse experience 6 Protocol violation 1 Lost to follow-up

Randomized to Placebo N=133

Randomized to MK-0633 100 mg N=133

15 Discontinued 5 Adverse experience* 2 Lost to follow-up 1 Progressive disease 2 Protocol violation 1 Study terminated by Sponsor 4 Withdrawal by subject

Completed 118 (88.7%)

Completed 121 (91.0%)

12 Discontinued 5 Adverse experience 1 Lost to follow-up 2 Protocol violation 4 Withdrawal by subject

129 (97.0%) Included in primary efficacy analysis

132 (99.3%) Received study drug and were included in safety analysis

131 (98.5%) Included in primary efficacy analysis

133 (100.0%) Received study drug and were included in safety analysis

Figure 1 Patient flow through the study. )Two patients dis-continued due to AEs that began prior to randomization. A totalof three patients receiving MK-0633 discontinued due to post-randomization AEs.


patient COPD Global Evaluation was tested using theCochraneManteleHaenszel test.

Tolerability analyses were based on the All Patients asTreated population, which included all randomized patientswho received at least one dose of study medication.Patients were included in the treatment group corre-sponding to the study medication actually received, irre-spective of the group to which they were randomized.Between-group differences in AEs were determined by theMiettinen and Nurminen method.17 Formal statisticaltesting (i.e., p-values) was performed only for urinary NAGand microalbumin endpoints. For other AEs, the incidenceand 95% confidence intervals were calculated.

It was expected that the difference between groupswould be approximately 80 mL in the subgroup of patientsnot receiving long-acting bronchodilators (approximately50% of patients) and 48 mL in the subgroup receivingbronchodilators. With 100 evaluable patients per group, thestudy had 80% power (a Z 0.05, two-sided t-test) to detectan overall difference of 64 mL between MK-0633 andplacebo in the change from baseline in FEV1, assuminga standard deviation of 160 mL. Secondary results were onlytested if the primary endpoint was significant at the 0.05level. However, because the secondary results weresupportive in nature, no adjustments for p-values weremade.

After results unblinding, data revealed two outliers,both in the MK-0633 group, whose improvement in FEV1

greatly exceeded that of all other patients. Based onreview of spirometry data, it was concluded that these twopatients were experiencing acute COPD exacerbations atbaseline (FEV1: 1.67 L and 1.96 L) and that their clinicalimprovements (1.62 and 2.18 L, respectively) were due toresolution of their exacerbations. Thus, these two patientshave been excluded from the efficacy analyses.

Results

Patients

Approximately 90% of patients in each group completedthe study; the most common reason for discontinuationwas an adverse experience (Fig. 1). Approximately 98% ofpatients in each group were included in the primary effi-cacy analysis, and all but one patient (in the MK-0633group) were included in the safety analyses. Most patientswere white and male, and the mean age was approxi-mately 63 years (Table 1). Although there were somenumerical differences in baseline characteristics (e.g.,age), patients in both treatment groups were generallysimilar.

Efficacy

For the primary efficacy endpoint of change from baselinein pre-dose (trough) FEV1 over the last two weeks of the12 week treatment period, there was no statisticallysignificantly difference between MK-0633 and placebo(least squares (LS) means 0.015 L vs. 0.002 L; p Z 0.556)(Table 2), although there were numerical improvementsover the entire 12 week period (Fig. 2). Results for the full

analysis population including the two outlier patientsshowed a larger treatment effect for MK-0633 comparedwith placebo, but the difference was not statisticallysignificant (0.038 L vs. 0.005 L; p Z 0.205).

The pre-specified subgroup analyses of the primaryendpoint showed trends toward greater improvements withMK-0633 vs. placebo in patients receiving long-actingbronchodilators, patients from Central/South America,patients between 50 and 65 years of age, and in patientswith reversibility >12% (Fig. 3), although none of thesefactors had a significant effect on the main outcome asdetermined by the ANCOVA model.

There were no significant differences in the secondaryendpoints of overall daytime symptoms scores, averagetotal daily b-agonist use, overall CRQ, individual CRQdomains (data not shown), or in the exploratory endpointsof AM or PM PEFR, nocturnal awakenings, COPD symptom-free days, (Table 2) or COPD exacerbations or time to firstCOPD exacerbation (Fig. 4). There were no significantdifferences for the change from baseline in the individualdaytime symptoms scores (data not shown), although thechanges for MK-0633 vs. placebo approached significancefor patient-reported amount of time coughed (LS mean�0.21 vs. �0.07; p Z 0.087), and patient-reported amountof mucus (LS mean �0.25 vs. �0.08; p Z 0.054).

Patients receiving MK-0633 reported significantly greaterCOPD Global Evaluation scores at Week 12 than thosereceiving placebo (p Z 0.001) (Table 3). There wasa significant (p Z 0.032) shift in the distribution of patientstoward better response for MK-0633 vs. placebo.

There were no significant differences in changes in pre-dose FVC, or post-b-agonist FEV1 or FVC (Table 2), andserial spirometry at 1, 2, and 4 h post-dose showed no

Table 1 Baseline patient characteristics.

MK-0633 100 mg Placebo

N Z 132 N Z 133

Age (years)Mean (SD) 63.3 (7.2) 62.9 (7.6)Range 45.0 to 75.0 40.0 to 75.0

Age group, n (%)�40 to <50 6 (4.5) 7 (5.3)�50 to <65 59 (44.4) 67 (50.4)�65 to �75 68 (51.1) 59 (44.4)

Gender, n (%)Female 45 (33.8) 33 (24.8)Male 88 (66.2) 100 (75.2)

Race, n (%)Asian 15 (11.3) 17 (12.8)Black 5 (3.8) 3 (2.3)Native American 1 (0.8) 0 (0.0)White 112 (84.2) 113 (85.0)

Smoking history, n(%)Current smoker 63 (47.4) 60 (45.1)Ex-smoker 70 (52.6) 73 (54.9)Pack-years, mean (SD) 50.2 (24.6) 48.8 (26.3)

FEV1

L, mean (SD) 1.31 (0.45) 1.38 (0.54)% predicted, mean (SD) 44.37 (13.45) 44.53 (14.49)Post-b-agonist (L), mean (SD) 1.46 (0.49) 1.53 (0.58)

FVC (L), mean (SD) 2.66 (0.72) 2.72 (0.80)FEV1/FVC ratio (%), mean (SD) 49.98 (11.02) 51.25 (12.17)Concomitant chronic long-acting bronchodilator use, n (%) 58 (43.6) 57 (42.9)Reversibility at screening, n (%)

�12% 79 (59.4) 83 (62.4)>12% 54 (40.6) 50 (37.6)Mean (SD) 10.58 (12.16) 10.59 (11.30)

Reversiblea patients, n (%) 41 (30.8) 37 (27.8)a Reversible defined as reversibility >12% and an increase >0.2 L.


significant differences between MK-0633 and placebo forpost-dose FEV1 or FVC (data not shown).

Post-hoc subgroup analyses

Additional post-hoc analyses were carried out for the pre-specified subgroup based on concomitant long-actingbronchodilator use. Differences between MK-0633 andplacebo were substantially greater in patients receivinglong-acting bronchodilators than in those not receivinglong-acting bronchodilators, for patient-reported shortnessof breath (�0.11 vs. �0.01), patient-reported amount ofmucus (�0.24 vs. �0.13), patient-reported difficulty inperforming light physical activity (�0.15 vs. �0.05),patient-reported difficulty in performing moderate/highphysical activity (�0.36, vs. 0.03), and CRQ (0.24 vs.�0.13).

Lung volume sub-study

A total of 134 patients participated in the sub-study, 71 inthe MK-0633 group and 63 in the placebo group. Of these,only 100 patients (51 in the MK-0633 group and 40 in the

placebo group) had both baseline and at least one post-randomization measurement. Only these patients wereincluded in the sub-study. There were no significantdifferences from baseline in total lung capacity, thoracicgas volume at functional residual capacity, expiratoryreserve volume, inspiratory capacity, residual volume,slow vital capacity, and airway resistance (data notshown).

Pharmacokinetic-pharmacodynamic analyses

Mean MK-0633 plasma levels at week 6 were approximately1935.5 nM pre-dose and 3773.1 nM at 4 h post-dose.Urinary LTE4/creatinine ratio was reduced by �90% frombaseline, from a mean of 96.98 pg/mg to 8.80 pg/mg whilethe mean change in urinary LTE4/creatinine in the placebogroup increased from 85.16 pg/mg to 93.90 pg/mg.Maximal inhibition of LTE4 (�90%) was associated with MK-0633 trough plasma levels of approximately 1200 nM andhigher (Fig. 5a). However, drug plasma levels of MK-0633associated with maximal inhibition of LTE4 were notassociated with greater improvements in FEV1 at Week 8(Fig. 5b).

Table 2 Efficacy results.

N Baseline(mean [SD])

Change from baseline(LS mean [95% CI])

Difference(LS mean [95% CI])

P

PRIMARY ENDPOINTAverage change from baseline in pre-dose (trough) FEV1 (L)

MK-0633 127 1.30 (0.45) 0.015 (�0.017, 0.048) 0.013 (�0.030, 0.056) 0.556Placebo 131 1.37 (0.53) 0.002 (�0.030, 0.034)

SECONDARY ENDPOINTSAverage change in overall daytime symptoms score

MK-0633 117 2.10 (0.66) �0.17(�0.28,�0.06) �0.04(�0.19,0.11) 0.592Placebo 121 2.05 (0.57) �0.13(�0.24,�0.02)

Average change in total daily b-agonist use (puffs/day)MK-0633 117 4.76 (3.34) �0.44(�0.94,0.07) �0.12(�0.81,0.56) 0.721Placebo 122 4.36 (3.89) �0.31(�0.80,0.18)

Average change in CRQ score (all domains) at Week 12MK-0633 118 4.77 (0.98) 0.19 (0.04, 0.35) 0.05 (�0.16, 0.25) 0.653Placebo 118 4.80 (0.98) 0.15 (�0.01, 0.30)

EXPLORATORY ENDPOINTSAverage change in AM PEFR (L/min)

MK-0633 117 220.96 (73.02) 8.73 (3.03, 14.43) 7.09 (�0.68, 14.86) 0.074Placebo 122 237.37 (86.04) 1.64 (�3.94, 7.21)

Average change in PM PEFR (L/min)MK-0633 117 233.94 (75.88) 8.85 (2.64, 15.05) 5.21 (�3.26, 13.68) 0.227Placebo 122 244.09 (86.94) 3.64 (�2.44, 9.72)

Nocturnal awakenings in patients who had at least 1 night with awakening per weekMK-0633 78 0.96 (0.85) �0.29(�0.41,�0.18) �0.06(�0.21,0.09) 0.450Placebo 81 0.94 (0.71) �0.23(�0.34,�0.12)

COPD symptom-free days (%) over 12 weeksMK-0633 128 19.44 (27.61) 8.206 (1.895, 14.518) 2.982 (�5.205, 11.169) 0.474Placebo 132 20.07 (26.90) 5.225 (�0.952, 11.402)

Pre-dose FVC (L)MK-0633 127 2.63 (0.69) 0.013 (�0.063, 0.089) 0.031 (�0.070, 0.133) 0.548Placebo 131 2.71 (0.80) �0.018(�0.092,0.057)

Post-b-agonist FEV1 (L)MK-0633 117 1.44 (0.50) 0.004 (�0.033, 0.040) 0.021 (�0.028, 0.069) 0.400Placebo 118 1.50 (0.56) �0.017(�0.053,0.019)

Post-b-agonist FVC (L)MK-0633 117 2.84 (0.83) �0.016(�0.097,0.065) 0.010 (�0.097, 0.116) 0.857Placebo 118 2.94 (0.84) �0.025(�0.104,0.053)

Unless noted otherwise, all endpoints are measured over the last 2 weeks of the 12 week treatment period unless otherwise noted. Allanalyses exclude the two outlier patients.

Baseline 2 4 8 10 12

e n i l e s a B m

o r F

e g n a h C

-0.06

-0.04

-0.02

0.00

0.02

0.04

0.06

0.08

Weeks on Treatment


Figure 2 Primary endpoint: Change from baseline in pre-dose (trough) FEV1 (L).


Tolerability

MK-0633 was well-tolerated and there were no significant orclinically meaningful differences in the rates of AEscompared with placebo (Table 4). The most common AEswere nasopharyngitis, pneumonia, and COPD. There werea total of 10 patients experiencing 13 serious AEs; 6patients in the MK-0633 group (hypoxemia, coronary arterydisease, cataract, ileus, acute pharyngitis, pneumonia,urinary retention, COPD exacerbation) and 4 in the placebogroup (gastrointestinal arteriovenous malformation, chestdiscomfort, chest pain, pneumonia, sepsis). None of theserious AEs were considered by the investigator to be drug-related. One patient receiving MK-0633 died while partici-pating in study due to a COPD exacerbation and multilobarpneumonia, which were determined by the investigator notto be drug-related.

Treatment Difference and 95% CI

-0.3 0.0 0.3

Baseline Reversibility: >12%Baseline Reversibility: <=12%

Baseline Severity: % predict FEV1>=50%Baseline Severity: % predict FEV1<50%

Region: JapanRegion: EuropeRegion: Central/South AmericaRegion: US/Canada

Smoking History: EX-SMOKERSmoking History: CURRENT SMOKER

Gender: FemaleGender: Male

Age: 65<= age <=75Age: 50<= age <65

Race: ASIANRace: WHITE

Concomitant Stratum: Patient not on LABDConcomitant Stratum: Patient on LABD

Figure 3 Prespecified subgroup analysis of the change frombaseline in trough FEV1(L).


There were no significant differences between MK-0633and placebo for NAG discontinuations (0 discontinuations inboth groups) (Table 4), or the absolute change or distributionof percentage change frombaseline in urinary NAG or urinarymicroalbumin (data not shown). However, there wasa borderline significant difference for MK-0633 compared

Patients at Risk MK-0633 100 mg 130 128 119 116 113 111 107 107 102 20

Placebo 133 129 124 118 115 110 109 106 98 8

0 10 20 30 40 50 60 70 80 90

t n e v E n a t u o h t i

w

s t n e i t a P f o e g a t n e c r e P

80

85

90

95

100

Study Days


Figure 4 KaplaneMeier plot of time to first COPD exacer-bation. A total of 17 (13.1%) of patients in the MK-0633 groupand 20 (15.0%) in the placebo group had COPD exacerbations.The KaplaneMeier estimates (% [95% CI)]) at Week 12 were12.3% (7.2, 18.8) and 15.9% (10.1, 22.8), respectively. Thedifference was �3.6 (�12.2, 5.1); p Z 0.425 vs. placebo basedon Log Rank Test. 95% confidence intervals based on thelogelog transformation.

with placebo in the percent change from baseline inurinary NAG (LS mean change 14.4% vs. 2.3%, respectively;p Z 0.074). There were no significant differences betweenMK-0633 and placebo for changes frombaseline in blood ureanitrogen or creatinine. In addition, there were no significantor clinically meaningful differences between MK-0633 andplacebo for elevations in AST or ALT.

Discussion

In this Phase IIa proof-of-concept study, MK-0633, a 5-LOinhibitor, was not significantly more effective than placeboin improving pre-dose, pre-bronchodilator FEV1 from base-line after 12 weeks of treatment in patients with COPD.There were numerical differences in some of the pre-speci-fied subgroup analyses of the primary endpoint. Notably,differences from placebo with MK-0633 were larger inpatients with baseline reversibility >12%, patients fromCentral/South America, and patients on concomitant long-acting bronchodilators. It was previously shown in studies ofLABAs that lung function response is greater in COPD patientswith greater reversibility,18 which may account for thegreater response to MK-0633 in this subgroup. Of note is that60% of patients from Central/South America had a baselinereversibility >12%, which likely accounts for the greaterresponse vs. placebo in that subgroup. In addition, a greaterpercentage of patients using concomitant long-acting bron-chodilators compared with non-users had a high degree ofreversibility (42% vs. 36%), which might have partiallycontributed to the apparently greater improvement inmultiple endpoints in this subgroup.

We did not observe significant differences betweenMK-0633 and placebo for any of the secondary and explor-atory endpoints, with the exception of patient Global Eval-uation. The greater percentage of patients reporting overallimprovement in the MK-0633 group may have reflectednumerical improvements in the individual daytime symptomsof amount of time coughed and amount of mucus in thissubgroup. Both cough and mucus have been shown to beassociatedwithworsequality of life in COPD19,20 andboth arehighly tangible measures of disease activity that patientsmay perceive more readily than changes in lung functionmeasures. These findings would need to be confirmed ina prospective study.

We also did not observe any between-treatmentdifferences in the lung function sub-study, which isconsistent with the spirometry results in the main study.However, it is nonetheless worth noting that 84% ofparticipants were from Europe, only 35% of whom hadbaseline reversibility �12%. Thus, the disproportionatelylow reversibility in these patients may have accounted, inpart, for the apparent lack of efficacy of MK-0633 in thesub-study.

The inflammatory pattern and findings in COPD airways(i.e., neutrophilic, and associated with increased LTB4

4e6)provided a pathophysiologic basis for targeting LTB4activity in COPD.21 In Phase I data of MK-0633 in healthyadult subjects, doses of �100 mg/day provided continuousand complete LTB4 inhibition in ex vivo whole-bloodassays, and reduced urinary LTE4 levels to <10 pg/mgcreatinine, which correlated with an LTE4 inhibition ofapproximately 90% or higher (data on file). In the present

Table 3 Patient Global Evaluation at Week 12.

Overall Score N LS Mean (95% CI) Difference(LS mean [95% CI]) P

MK-0633 115 1.45 (1.22, 1.68) 0.50 (0.20, 0.80) 0.001Placebo 122 0.95 (0.72, 1.17)

Evaluation Category Better N (%) Unchanged N (%)

MK-0633 122 92 (75.4) 22 (18.0) 0.032*Placebo 127 76 (59.8) 36 (28.3)

*p-value for pairwise comparison based on CochraneManteleHaenszel test.


study, the mean trough plasma level of MK-0633 was1935.5 nM, which was sufficient to inhibit mean urinaryLTE4/Cr by >90%. Despite this marked decrease in anaccepted biomarker of 5-LO activity, there were nogreater increases in change from baseline in FEV1 over therange of drug exposures evaluated here. It is possible thatMK-0633 plasma levels, and the corresponding extent ofenzymatic inhibition observed in this study were insuffi-cient to achieve maximal clinical efficacy. For example,the urinary concentration of LTE4 reflects total bodyproduction and metabolism of LTE4. It is possible, if notlikely, that concentrations of products of the 5-LOpathway are much higher at sites of inflammation, such asthe small airways, implying that urinary LTE4/Cr is a poor

oitaR

eninitaerC/4ETL

0

10

20

30

40

50

60

70

80

Plasma Concentration0 1000 2000 3000 4000 5000 6000 7000

1VEFni

enilesaBmorf

egnahC

-1

0

1

2

Plasma Concentration0 1000 2000 3000 4000 5000 6000 7000

A

B

Figure 5 Relationship of pre-dose plasma concentration ofMK-0633 (nM) to urinary LTE4/creatinine ratio (pg/mg) (A) andchange from baseline in FEV1 (B) at Week 8.

surrogate biomarker for lung LTE4 concentrations.It is alsopossible that in COPD patients, only some aspects ofdisease (e.g., mucus production, but not bronchocon-striction) are driven by either LTE4 or other metabolites ofthe 5-LO pathway, such as LTB4. Indeed, the greaterapparent responses to MK-0633 in patients withgreater reversibility at baseline may reflect not onlya greater intrinsic capacity for bronchodilation, but alsoa greater dependency on the 5-LO pathway for airwayinflammation in this subgroup.

We are aware of only two studies of drugs that act onLTB4 that assessed clinical endpoints in patients withCOPD. Gronke and colleagues evaluated LTB019, an LTB4receptor antagonist, in 24 patients with COPD, andfound no significant difference from placebo in sputumneutrophils or related cytokines, use of rescue medica-tion, or FEV1 or FVC.13 The authors hypothesized thatbased on the lack of effect on neutrophils, mediatorsother than LTB4 may have been primarily responsible forneutrophil recruitment in the lungs of their patients,and/or other cytokines compensated for LTB4 viaparallel pathways. Berger and colleagues reported ona trial of 8 patients with COPD, in which the 5-LOinhibitor zileuton significantly improved exercisecapacity as measured by the 6-min walk test comparedwith placebo, as well as quality of life and COPD ques-tionnaire scores. However, spirometric endpoints such asFEV1 were not reported.12

There have been few prospective trials of other anti-leukotriene agents in COPD. Cazzola and colleagues eval-uated double-blinded zafirlukast and placebo in 16patients with COPD, and found a significant improvementin bronchodilation with zafirlukast 30 min to 4 h afteradministration, with a mean maximum increase in FEV1 of0.14 L.22 In a randomized, single-blind non-placebocontrolled trial of 117 patients, the addition of mon-telukast to ipratropium and formoterol resulted in signifi-cant changes from baseline in FEV1, FVC, oxygensaturation, and quality of life, but there were no suchchanges in patients receiving ipratropium and formoterolonly.23 The sum of the available clinical evidence of anti-leukotrienes in COPD has been inconsistent and based onsmall trials, with at best modest effects on symptoms andlung function that have yet to be confirmed in largerandomized clinical trials. A possible explanation for theapparent limited efficacy of leukotriene antagonists inCOPD is that by the time COPD has become clinicallyapparent, the disease is already moderately advanced,24

with irreversible parenchymal damage, thus limiting the

Table 4 Adverse experiences (clinical and laboratory).

MK-0633 Placebo

N Z 132 N Z 133

Any adverse experience 56 (42.4) 63 (47.4)Drug-related adverseexperience

12 (9.1) 14 (10.5)

Serious adverse experience 6 (4.5) 4 (3.0)Discontinuation due to adverseexperience

3 (2.3) 5 (3.8)

Discontinuations due to NAGcriteriona

0 (0.0) 0 (0.0)

a Levels >3x upper limit of normal on 2 consecutive occasions; NAG Z N-acetyl-b-glucosaminidase.


benefits of anti-inflammatory treatments alone, particu-larly with respect to lung function. These results furtheremphasize both the difficulty in effectively managingCOPD and, perhaps, the need to move beyond the asthmatreatment paradigm in targeting COPD treatment. Giventhe findings of montelukast add-on in COPD23 and thetrends we observed in the present study in patientsreceiving long-acting bronchodilators, particularly withrespect to mucus production and physical activity, it ispossible that agents such as 5-LO inhibitors could havea role as adjunctive therapy in this disease. However,further prospective studies are required.

A limitation of this study is that we did not assessmarkers of airway inflammation. As noted above, previousstudies of other compounds targeting the LTB4 receptorhave shown improvements in such markers,10,11 althoughresults were not consistent.13 Preclinical research with MK-0633 suggested that urinary LTE4 was a reasonable surro-gate endpoint for LTB4 production, but as discussed, thismay not accurately reflect cysteinyl leukotrienes in thelung. Assessing sputum inflammatory markers may haveprovided important additional information regarding notonly the efficacy of MK-0633 in COPD, but also the rela-tionship between such markers and clinical severity ofCOPD. However, such an analysis was beyond the scope ofthis Phase II study.

In conclusion, the 5-LO inhibitor MK-0633 was notsignificantly more effective than placebo in improving FEV1from baseline in patients with COPD, although morepatients reported feeling improved with MK-0633.

Conflict of interest statement

This study was supported by Merck & Co., Inc. Drs. Liu,Knorr, Smugar, Hanley, and Greenberg are employees ofMerck & Co., Inc. who may potentially own stock and/orhold stock options in the Company. Dr. Reiss was employedby Merck at the time of the conduct of this study, and iscurrently employed by Covance, Inc., Princeton, NJ.Dr. Bernstein is a Principal investigator for Merck, BI, Meda,GSK, AZ, Forest, Novartis, Dyax, Shire, CSL-Behring, Dynovaand MediciNOVA. He consults for Dynova laboratories, FlintHills Resources and Dyax. He is the Editor in Chief forJournal of Asthma. He has served as a paid lecturer forAlcon and AZ.

Acknowledgments

The authors thank Susan Lu, PhD for her interpretationof the data, and Jennifer Pawlowski for her assistance withthe preparation of this manuscript.

Protocol 009 Investigators:

Canada: D McCormack, J Hebert, A Nayar. Chile: MChahuan, I M Leiva; Colombia: C E Matiz, J M Pardo,F O Serrano; Israel: R Breuer, G Fink; Japan: Y Naka-tani, K Ogurusu, T Saito, H Sekino, A Tada, Lithuania:K Malakauskas. R Zablockis; Puerto Rico: W Rodriguez;United States: J A Bernstein, A J Cagino, J J Condemi,G I Greenwald, G D Hammond, T F Hartley, J D Hoyt,S G Kelsen, R F Lockey, J E Pappas, S J Pollard,S Spangenthal, J R Taylor, M S Villareal.

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mk-0633, a potent 5-lipoxygenase inhibitor, in chronic obstructive pulmonary disease

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