PTX-145
`
`Clinical Study Report- PN400-104
`
`POZENinc.
`
`PN 400
`(NAPROXEN AND ESOMEPRAZOLE)
`PN400-104
`A RANDOMIZED, OPEN-LABEL, 4-WAY CROSS-OVER STUDY TO
`EVALUATE THE EFFECT OF TWICE DAILY ORAL
`ADMINISTRATION OF THREE PN 400 DOSE COMBINATIONS
`(NAPROXEN 500 MG COMBINED WITH ESOMEPRAZOLE 10, 20,
`OR 30 MG) VS. TWICE DAILY ORAL ADMINISTRATION OF
`500 MG NAPROXEN AND ONCE DAILY ORAL ADMINISTRATION
`OF EC ESOMEPRAZOLE (20 MG) ON THE DAY 9 24-HOUR
`INTRAGASTRIC PH IN HEAL THY VOLUNTEERS
`
`FINAL CLINICAL STUDY REPORT
`
`Product:
`
`IND Number:
`
`PN 400 (naproxen and esomeprazole)
`
`76,301
`
`Developmental phase of study:
`
`Phase 1
`
`Study Sponsor:
`
`POZEN Inc.
`1414 Raleigh Rd. Suite 400
`Chapel Hill, NC 27517
`(919) 913-1030
`
`Study Initiation Date:
`
`Study Completion Date:
`
`03 April 2007
`
`25 June 2007
`
`Release date of report:
`
`26 September 2008
`
`Sponsor's Medical Officer:
`
`Joseph De Vaugh-Geiss, MD
`
`Sponsor Signatory:
`
`Everardus Orlemans, PhD
`
`GCP STATEMENT:
`
`This study was performed in compliance with Good Clinical Practice (GCP), including
`the archiving of essential documents.
`
`CONFIDENTIALITY:
`
`This document is confidential property of POZEN Inc. No part of it may be reproduced,
`published, or transmitted by other persons without permission of PO ZEN Inc.
`
`ATTORNEY CONFIDENTIAL
`
`1
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`PZ00034117
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`Page 1 of 81
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`Patent Owner Ex. 2017
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Clinical Study Report - PN400-104
`
`POZEN Inc.
`
`SIGNATURE PAGE
`Study Title: A Randomized, Open-Label, 4-Way Cross-Over Study to Evaluate the
`Effect of Twice Daily Oral Administration of Three PN 400 Dose Combinations
`(Naproxen 500 mg combined with Esomeprazole 10, 20, or 30 mg) vs. Twice Daily Oral
`Administration of 500 mg Naproxen and Once Daily Oral Administration of EC
`Esomeprazole (20 mg) on the Day 9 24-Hour Intragastric pH in Healthy Volunteers
`
`Protocol Number: PN400-104
`
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`
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`
`Approved By:
`
`)?':~~~ Orlen\ans, Ph~ .
`.c: •• Semor Vice President, Chmcal Research
`POZEN Inc.
`
`ATTORNEY CONFIDENTIAL
`
`2
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`IPR2017-01995
`
`

`

`Clinical Study Report- PN400-104
`
`POZENinc.
`
`2.
`
`SYNOPSIS
`
`Name of Sponsor/Company:
`Individual Study Table
`Referring to Part of the
`POZEN Inc.
`,1 - - - - - - - - - - - - - - - -< Dossier
`Name of Finished Product:
`Volume:
`PN 400
`11-----------------, Page:
`Name of Active Ingredients:
`naproxen and esomeprazole
`
`(For National Authority Use
`Only)
`
`Title of Study: A Randomized, Open-Label, 4-Way Cross-Over Study to Evaluate the Effect
`of Twice Daily Oral Administration of Three PN 400 Dose Combinations (Naproxen 500 mg
`combined with Esomeprazole 10, 20, or 30 mg) vs. Twice Daily Oral Administration of
`500 mg Naproxen and Once Daily Oral Administration of EC Esomeprazole (20 mg) on the
`Day 9 24-Hour Intragastric pH in Healthy Volunteers
`
`Investigator: Philip Miner, Jr., MD
`
`Study center: Oklahoma Foundation for Digestive Disease Research, 1000 N. Lincoln Blvd.
`Suite 210, Oklahoma City, OK 73104
`
`Publications: none
`
`Study period:
`Date first subject enrolled: April 3, 2007
`Date last subject completed: June 25, 2007
`
`Phase of development:
`Phase 1
`
`•
`
`Objectives:
`Primary: To compare the pharmacodynamic (PD) measurements of intragastric pH (percent
`time of pH> 4.0) on Day 9 of three PN 400 dose combinations following twice daily (bid)
`administration versus a combination of enteric-coated (EC) naproxen taken bid and EC
`esomeprazole (20 mg) taken once daily.
`Secondary:
`•
`To compare the PD measurement ofintragastric pH (percent time of pH> 4.0) on Day 1
`of three PN 400 dose combinations following bid administration versus a combination
`of EC naproxen taken bid and EC esomeprazole taken once daily
`To assess the pharmacokinetics of esomeprazole and naproxen on Day 1 and Day 9 in
`each of the treatment groups
`To evaluate the safety of each of the treatment groups
`•
`A non-EC naproxen formulation was inadvertently used instead of the protocol-planned
`EC naproxen.
`Methodology: This was a randomized, open-label, 4-way crossover, single-center study in
`28 healthy adults designed to compare the effect of three formulations of PN 400 (delayed(cid:173)
`release naproxen 500 mg combined with immediate-release esomeprazole 10, 20 or 30 mg)
`with co-administration of enteric-coated (EC) naproxen and esomeprazole on intragastric pH
`All other study medications were verified to be correct. The study consisted of four 9-day
`treatment periods, with a washout period of at least 12 days between treatment periods. Clinical
`laboratory tests, physical examination, and measurement of vital signs were performed at
`Screening and the Final Visit. A 12-lead electrocardiogram (ECG) and 13C-urea breath test to
`
`3
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`ATTORNEY CONFIDENTIAL
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`Patent Owner Ex. 2017
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`IPR2017-01995
`
`

`

`Clinical Study Report- PN400-104
`
`POZENinc.
`
`screen for possible Helicobacter pylori infection were performed at Screening. A urine drug
`screen for all subjects and a urine pregnancy test for women of childbearing potential were
`performed at Screening and on Days O and 8 of each treatment period. On Days 1 and 9 of each
`treatment period, 24-hour blood sampling was performed for pharmacokinetic (PK)
`assessments.
`
`At any time during Screening, subjects had their lower esophageal sphincter (LES) located to
`determine accurate placement of the pH probe.
`Subjects were randomized on Day 1 of the first treatment period into 1 of 4 dosing sequences
`to receive a 9-day course of each one of the following daily treatment regimens in a crossover
`fashion:
`• Treatment A: 1 tablet PN 400 (naproxen 500 mg/esomeprazole 30 mg) bid (PN 400/E30)
`• Treatment B: 1 tablet PN 400 (naproxen 500 mg/esomeprazole 20 mg) bid (PN 400/E20)
`• Treatment C: 1 tablet PN 400 (naproxen 500 mg/esomeprazole 10 mg) bid (PN 400/ElO)
`• Treatment D: 1 tablet of naproxen 500 mg and 1 tablet EC esomeprazole 20 mg in the
`AM and 1 tablet ofnaproxen 500 mg in the PM (EC E20 + naproxen)
`All treatments were administered 60 minutes prior to meals by study personnel.
`Prior to administration of the Day 1 AM dose of study drug, the pH probe was placed to
`monitor intragastric pH for a period of 24 hours. In addition, a pre-AM dose blood sample and
`serial post-AM blood samples were obtained over the next 24 hours. The pH probe was
`removed in the morning on Day 2 prior to AM dosing. After AM dosing on Day 2, subjects
`were discharged from the Phase 1 unit and instructed to return for the next dosing in the PM of
`Day 2 and on Days 3-8 to receive the AM and PM doses. Subjects were again confined to the
`Phase 1 unit in the PM of Day 8 in preparation for the 24-hour PK and pH assessments on
`Day 9. The pH probe was removed in the AM on Day 10. Final PK samples were collected in
`the AM of Day 10.
`In each subsequent treatment period, the same procedures were performed as during the first
`period, and final study procedures were performed on Day 10 of the last treatment period or
`whenever a subject discontinued from the study.
`
`Number of subjects (planned and analyzed): 28 subjects were planned, randomized and
`treated, and data for 25 subjects were analyzed as the Per-Protocol (PP) population; the Intent(cid:173)
`to-Treat (ITT), Safety and PK populations included all 28 subjects.
`
`Diagnosis and main criteria for inclusion: Subjects were healthy males or non-lactating,
`non-pregnant females 18 to 55 years of age with a body mass index of 19-32 kg/m2
`, were
`Helicobacter pylori (H. pylori) negative, and were generally in good health with no history of
`peptic ulcer disease or other acid-related gastrointestinal (GI) symptoms.
`
`Test product, dose and mode of administration, batch number: PN 400 (combination
`tablets of delayed-release naproxen 500 mg/immediate-release esomeprazole 10, 20 or 30 mg),
`Batch numbers
`,
` and
` respectively, given by mouth bid for 9
`days
`
`Duration of treatment: 4 treatment periods of 9 days each
`
`Reference therapy, dose and mode of administration, batch number: Naproxen 500 mg
`tablets (Lot# HA08607, Glenmark Pharmaceuticals, Ltd., expiration date 12/2010) given by
`mouth bid for 9 days along with EC esomeprazole 20 mg tablets (Lot# U4149, AstraZeneca,
`expiration date 09/2009) given by mouth once daily for 9 days. A non-EC naproxen
`formulation was inadvertently used instead of the protocol-planned EC naproxen.
`
`ATTORNEY CONFIDENTIAL
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`Patent Owner Ex. 2017
`Mylan v. Pozen
`IPR2017-01995
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`

`Clinical Study Report- PN400-104
`
`POZENinc.
`
`Criteria for evaluation:
`Pharmacodynamics: Intragastric pH monitoring
`Pharmacokinetics: Full plasma profiles of naproxen and esomeprazole over the 24-hour post(cid:173)
`AM dose period on Day 1 and Day 9.
`Safety: Adverse event assessment, clinical laboratory tests (hematology, chemistry, urinalysis,
`urine drug screen, and pregnancy test for women of childbearing potential), vital signs,
`physical examination, 12-lead ECG.
`
`Endpoints and statistical methods:
`Sample size: From a previous AstraZeneca study, the within-subject standard deviation (SD)
`of percent time of pH> 4.0 was 10%. The current study planned to enroll 28 subjects with the
`aim to have 24 evaluable subjects for analysis. A total of 24 subjects provides 80% power to
`reject the null hypothesis that the difference between each of the PN 400 treatments and the
`active control in percent time of pH> 4.0 over 24 hours is S: -8% using a pairwise t-test with a
`one-sided significance level of0.05.
`Pharmacodynamics:
`Primary Endpoint: Percent time intragastric pH> 4.0 on Day 9
`Secondary Endpoint: Percent time intragastric pH> 4.0 on Day 1
`Endpoints were summarized by treatment and analyzed by Analysis of Variance (ANOV A).
`The ANOV A model included sequence, period, and treatment as fixed effects, and subject
`within sequence as a random effect. The least square (LS) means for each treatment, the
`difference of LS means between each of the PN 400 treatments and the active control, and 95%
`confidence intervals (Cls) for all treatment differences were calculated. The PP population was
`the primary analysis population.
`Pharmacokinetics:
`PK parameters for esomeprazole were determined following the three different PN 400
`treatments and PK parameters for naproxen were determined following each of the 4
`treatments included peak plasma concentration (Cmax) on Days 1 and 9, time to peak plasma
`concentration (tmax) on Days 1 and 9, area under the plasma concentration vs. time curve from
`time zero to the last time point with measurable drug concentration (AUC0_1) on Days 1 and 9,
`and the terminal half-life (tYz), if possible, following both the AM and PM doses on Days 1 and
`9. In addition, the AUC from time zero (time of dosing) to 10 hours post-AM dose (AUC0_10_am)
`and AUC from time zero (time of dosing) to 14 hours post-PM dose (AUCo.14,pm) and a total
`daily AUC (AUC0_24) were determined on Days 1 and 9. PK parameters for esomeprazole
`following EC E20 + naproxen included Cmax. !max. AUCo.1. tYz, and AUCo.24 following the AM
`dose on both Days 1 and 9. Statistical analysis was performed using Analysis of Variance
`(ANOV A) to determine the point estimate and 90% CI of the Day 9 to Day 1 ratios for the
`following parameters for both naproxen and esomeprazole Cmax,am, Cmax. rm, AUC0_10_ am, AUC0_
`14,pm, and AUCo.24.
`Safety:
`Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA)
`for system organ class (SOC) and preferred term. Adverse events were summarized by
`treatments, SOC and preferred term. Tabulations and listings of values for vital signs, clinical
`laboratory tests, and abnormal physical examination findings were prepared. Laboratory values
`for each subject were listed with abnormal values flagged.
`
`ATTORNEY CONFIDENTIAL
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`Page 5 of 81
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`Patent Owner Ex. 2017
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Clinical Study Report- PN400-104
`
`POZENinc.
`
`SUMMARY
`PHARMACODYNAMIC RESULTS:
`Primary Pharmacodynamic Endpoint
`On Day 9, both PN 400/E30 and PN 400/E20 treatments resulted in a greater percent time with
`intragastric pH> 4.0 than treatment with EC E20 + naproxen. PN 400/ElO had the lowest
`percent time with intragastric pH> 4.0 and was also the most variable treatment as evidenced
`by the high %CV in the in-text table below.
`Percent Time of pH Greater than 4.0 - Day 9 - Per-Protocol Population
`
`A
`PN 400/E30
`
`C
`B
`PN 400/E20 PN 400/ElO
`
`N=25
`
`N=25
`
`N=25
`
`D
`ECE20+
`naproxen
`N=25
`
`% Time of pH > 4.0
`Mean (SD)
`Median
`% Coefficient of variation
`Range
`LSMean(SD)
`LS Mean Difference (SE)
`
`56.85 (10.06)
`55.14
`18
`40.63 - 75.51
`57.23 (3.02)
`
`40.85 (22.51)
`35.76
`55
`10.30 - 85.26
`41.09 (3.02)
`Cvs.D
`-16.14 (3.25)
`-22.26- -9.66
`
`71.35 (13.01)
`76.50 (12.26)
`70.42
`78.79
`18
`16
`51.76 - 97.61
`49.79 - 95.32
`71.46 (3.02)
`76.75 (3.02)
`Avs. D
`Bvs. D
`14.23 (3.25)
`19.52 (3.25)
`7.75 - 20.71
`13.04- 26.01
`95% Confidence Interval
`PN 400/E30 = naproxen 500 mg/esomeprazole 30 mg bid
`PN 400/E20 = naproxen 500 mg/esomeprazole 20 mg bid
`PN 400/ElO = naproxen 500 mg/esomeprazole 10 mg bid
`EC E20 + naproxen = EC esomeprazole 20 mg+ naproxen 500 mg in AM, naproxen 500 mg in PM.
`SD= standard deviation; LS= least-squares; SE= standard error; CV= coefficient of variation
`Source: Table 14.2.1.1
`Secondary Phannacodynamic Endpoint
`On Day 1, the LS mean percent time intragastric pH> 4.0 ranged from 13% with PN 400/ElO
`to 28% with PN 400/E30. Treatment differences compared to EC E20 + naproxen were small.
`Only PN 400/E30 (28%) had a statistically significant, greater percent time with pH > 4.0
`compared to EC E20 + naproxen (21 %).
`PHARMACOKINETIC RESULTS
`PK analysis was performed for esomeprazole and naproxen plasma concentration vs. time data
`from 28 subjects completing PN 400/E30 and EC E20 + naproxen treatments and 27 subjects
`completing PN 400/ElO treatment on Days 1 and 9; and 28 and 27 subjects completing PN
`400/E20 treatment on Day 1 and Day 9, respectively.
`Esomeprazole Pharmacokinetic Parameters
`Day/
`Dose
`Time
`1
`AM
`1
`PM
`9
`AM
`9
`PM
`
`Treatment
`A
`
`PN 400/E30
`
`Cmax
`(ng/mL)
`487
`(82)
`187
`(132)
`1584
`(39)
`810
`(59)
`
`tmax
`(hr)
`0.50
`(0.33-1.50)
`1.50
`(0.33-4.00)
`0.50
`(0.17-1.50)
`1.00
`(0.33-8.00)
`
`AUCo-10,am or
`AUCo.14,rm
`(hr*ng/mL)
`591
`(108)
`388
`(137)
`2779
`(45)
`2066
`(53)
`
`AUCo.24
`(hr*ng/mL)
`
`978
`(115)
`
`4911
`(42)
`
`tYi
`(hr)
`0.892
`(35)
`1.11
`(62)
`1.26
`(25)
`1.46
`(34)
`
`ATTORNEY CONFIDENTIAL
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`Patent Owner Ex. 2017
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Clinical Study Report- PN400-104
`
`POZENinc.
`
`C
`
`PN 400/ElO
`
`B
`
`PN 400/E20
`
`350
`0.50
`292
`1
`(77)
`(113)
`(0.20-1.50)
`AM
`206
`1.49
`96.6
`1
`PM
`(104)
`(141)
`(0.33-3.00)
`1216
`0.50
`715
`9
`(69)
`(52)
`(0.17-1.50)
`AM
`919
`0.75
`428
`9
`PM
`(84)
`(73)
`(0.33-3.00)
`148
`0.33
`138
`1
`(111)
`(0.17-3.10)
`AM
`(71)
`85.7
`35.3
`1.50
`1
`PM
`(179)
`(0.33-3.00)
`(84)
`368
`0.33
`278
`9
`(89)
`(0.17-1.00)
`(57)
`AM
`223
`1.00
`97.6
`9
`PM
`(0.33-2.002
`(1342
`(1362
`540
`1.50
`282
`1
`D
`AM
`(60)
`(1.00-16.0)
`(66)
`ECE20
`+
`1046
`1.50
`435
`9
`(54)
`(1.00-14.0)
`(48)
`AM
`na2roxen
`Values are mean(% CV) for all parameters, except for tmax, which are median (range).
`Source: Table 14.2.6
`
`0.846
`(42)
`0.994
`(55)
`1.12
`(33)
`1.31
`(42)
`0.810
`(48)
`0.878
`(50)
`0.860
`(41)
`1.09
`(472
`1.09
`(44)
`1.27
`(36)
`
`556
`(119)
`
`2134
`(74)
`
`237
`(133)
`
`602
`(1032
`580
`(67)
`1212
`(47)
`
`Following oral administration of PN 400, esomeprazole was rapidly absorbed with plasma
`esomeprazole concentrations measurable at 10 minutes after the AM dose, and at 20-30
`minutes after the PM dose. Plasma esomeprazole concentrations after the PM dose were lower
`than those after the AM dose on both days. Cmax and AU Cs of esomeprazole increased nearly
`dose proportionally after the AM dose on Day 1, but more than dose proportionally after the
`PM dose on Day 1 and both the AM and PM doses on Day 9. Esomeprazole concentrations
`were much higher on Day 9 than on Day 1 for each PN 400 treatment, presumably reflecting
`the increased intragastric pH and concurrent reduced gastric acid degradation of esomeprazole
`after repeat dosing. The geometric least-squares mean AUC0_24 ratios, Day 9 to Day 1, were
`7.13, 4.10, and 2.26 for treatment with PN 400/E30, PN 400/E20, and PN 400/ElO,
`respective 1 y.
`Following EC E20 + naproxen treatment, esomeprazole absorption was delayed, as expected
`from an EC formulation, with the first measurable concentration at 0.5 to 1.5 hrs. post dose.
`To evaluate the effect of the immediate-release formulation of esomeprazole from PN 400 with
`EC E20, the PK parameters from PN 400/E20 and EC E20 + naproxen treatments were
`compared. On Day 1, esomeprazole Cmax,am mean values were approximately equal for the PN
`400/E20 and EC E20 + naproxen treatments (292 and 282 ng/ml, respectively). In line with the
`expectation that the immediate-release esomeprazole would be more susceptible to gastric acid
`degradation than the EC formulation, the AUC0_10 mean values on Day 1 from the PN 400/E20
`treatment were approximately two-thirds that of EC E20 + naproxen treatment (350 vs. 520
`hr·ng/ml, respectively). By Day 9 however, the esomeprazole AUC0_10 from the immediate(cid:173)
`release formulation was greater than that from EC formulation (1216 vs. 1046 hrng/ml,
`respectively) and Cmax,am from the immediate-release formulation was almost double that from
`the EC formulation (715 vs. 435 ng/ml, respectively). These data demonstrate that, following
`repeat PN 400 dosing, its immediate-release esomeprazole may not be as susceptible to gastric
`acid degradation as was originally believed.
`
`ATTORNEY CONFIDENTIAL
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`IPR2017-01995
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`

`

`Clinical Study Report- PN400-104
`
`POZENinc.
`
`Treatment
`A
`
`PN 400/E30
`
`B
`
`PN 400/E20
`
`C
`
`PN 400/ElO
`
`D
`
`ECE20
`+
`naproxen
`
`Naproxen Pharmacokinetic Parameters
`Day/
`AUCo-10,am or
`Dose
`Cmax
`AUCo.14,pm
`tmax
`(hr)
`(uv'mL)
`(hr*uv'mL)
`Time
`259
`4.00
`48.1
`1
`(56)
`(53)
`(2.00-10.0)
`AM
`471
`14.0
`68.9
`1
`PM
`(30)
`(0.50-14.0)
`(28)
`603
`3.00
`80.9
`9
`(21)
`(0.00-8.00)
`(23)
`AM
`648
`10.4
`76.2
`9
`PM
`{0.00-14.02
`{202
`{232
`231
`4.00
`44.4
`1
`(70)
`(2. 00-10. 0)
`(68)
`AM
`450
`14.0
`71.5
`1
`PM
`(33)
`(0.00-14.0)
`(26)
`607
`3.00
`86.2
`9
`(19)
`(0.00-8.05)
`(22)
`AM
`678
`10.0
`76.8
`9
`PM
`(16)
`(0.00-14.0)
`(18)
`310
`4.00
`57.0
`1
`(35)
`(2.00-10.0)
`(31)
`AM
`508
`10.0
`68.6
`1
`PM
`(29)
`(0.00-14.0)
`(26)
`637
`2.50
`87.1
`9
`(17)
`(0.00-8.00)
`(21)
`AM
`672
`14.0
`78.6
`9
`PM
`{1.50-14.02
`{192
`(172
`409
`1.50
`65.5
`1
`(16)
`(0. 75-6.00)
`(25)
`AM
`685
`1.50
`81.5
`1
`PM
`(10)
`(14)
`(0.50-2.50)
`617
`1.50
`90.0
`9
`(12)
`(0.50-4.00)
`(19)
`AM
`1387
`769
`1.50
`86.5
`9
`PM
`(10)
`(10)
`(0. 75-4.00)
`(13)
`Values are mean (%CV) for all parameters, except for tmax, which are median (range).
`Source: Table 14.2.11
`
`AUCo.24
`(hr*uv'mL)
`
`730
`(32)
`
`1251
`{162
`
`680
`(36)
`
`1275
`(15)
`
`819
`(21)
`
`1309
`{152
`
`1094
`(12)
`
`tVz
`(hr)
`8.52
`(25)
`12.1
`(30)
`9.17
`(21)
`12.3
`{272
`8.75
`(33)
`11.8
`(28)
`9.42
`(23)
`11.3
`(28)
`9.24
`(42)
`12.7
`(23)
`9.91
`(26)
`10.5
`{232
`8.85
`(22)
`15.4
`(31)
`9.32
`(23)
`14.4
`(17)
`
`Following oral administration of PN 400, the first measurable naproxen concentrations
`occurred at about 2 hrs. post AM dose on Day 1. Plasma exposure to naproxen was
`comparable among the three PN 400 treatments. Following repeated doses of PN 400, the Day
`9 to Day 1 naproxen concentration ratio was consistent with the expected accumulation based
`on the half-life estimates ofnaproxen. The variability in naproxen AUC between AM and PM
`doses was less on Day 9 than on Day 1, reflecting that naproxen levels are approximately at
`steady state with repeat dosing. Cmax values were somewhat more variable between the AM
`and PM doses on Day 1 compared to Day 9, with mean AM levels being lower than mean PM
`levels for all treatments on Day 1 and mean AM levels slightly higher than mean PM levels for
`all treatments on Day 9.
`
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`Mylan v. Pozen
`IPR2017-01995
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`

`Clinical Study Report- PN400-104
`
`POZENinc.
`
`SAFETY RESULTS:
`No serious adverse events were reported. The incidence of all adverse events ranged from 29%
`with EC E20 + naproxen to 50% with PN 400/E30 and PN 400/E20. GI events occurred in
`29-32% of subjects with PN 400 treatments and 18% of subjects with EC E20 + naproxen
`treatment. Iron deficiency, due to frequent blood sampling, was reported as an adverse event in
`11 % of subjects while on PN 400/E30, 18% with PN 400/E20, and 4% each with PN 400/ElO
`and EC E20 + naproxen. Most of the adverse events were mild, and no subjects withdrew from
`the study due to adverse events.
`Most laboratory abnormalities were small deviations from the normal range; however, there
`was a notable decrease in hematocrit, hemoglobin, and/or red blood cell counts at the end of
`each treatment period for all subjects, likely reflective of frequent blood sampling. Vital sign
`measurements and physical examination findings were similar at Screening and the Final Visit.
`CONCLUSIONS:
`
`• PN 400/E30 and PN 400/E20 treatments resulted in a higher percent time intragastric
`pH> 4.0 compared to EC E20 + naproxen given separately, after 9 days of treatment
`PN 400/E30, PN 400/E20 and EC E20 + naproxen treatments were similar in percent time
`intragastric pH> 4.0 after 1 day of treatment
`
`•
`
`• PN 400/ElO had the lowest percent time with intragastric pH > 4.0 and the highest
`variability in this response on both Days 1 and 9
`
`•
`
`Immediate-release esomeprazole was absorbed rapidly from the PN 400 tablets with
`plasma concentrations measurable at 10 minutes post dose on Day 1. The AM dose
`following an overnight fast was absorbed faster and to a greater extent than the PM dose;
`
`increased
`• After repeat bid PN 400 doses, plasma esomeprazole concentrations
`substantially as compared to those after the first day of dosing. The magnitude of this
`increased exposure to esomeprazole after repeat doses was dose dependent
`
`• At steady state (Day 9), esomeprazole AUC0_10 was higher for PN 400/E20 than for EC
`E20 + naproxen and Cmax.am values following the AM dose of PN 400/E20 on Day 9 were
`twice as high as EC esomeprazole 20 mg
`
`•
`
`Steady-state naproxen plasma profiles were comparable among the three PN 400 dosages,
`indicating that esomeprazole in PN 400 did not affect the PK ofnaproxen; plasma profiles
`of naproxen following PN 400 exhibited delayed absorption characteristics, consistent
`with the formulation design
`
`• The Day 9 PK and PD profiles of esomeprazole and naproxen demonstrated that
`immediate-release esomeprazole can be combined with delayed-release naproxen in a
`dosage form that produces an early onset of increased intragastric pH before naproxen is
`absorbed
`PN 400 and EC E20 + naproxen treatments were generally well tolerated in 9-day bid
`treatment periods in healthy subjects
`
`•
`
`•
`
`Based on pH control and low inter-subject variability, PN 400/E20 was selected for
`studies in subjects at risk for NSAID-associated gastric ulcers
`
`Date of the report: September 26, 2008
`
`ATTORNEY CONFIDENTIAL
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`Patent Owner Ex. 2017
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Clinical Study Report- PN400-104
`
`POZENinc.
`
`3.
`
`TABLE OF CONTENTS FOR THE INDIVIDUAL
`CLINICAL STUDY REPORT
`TABLE OF CONTENTS
`TITLE PAGE ..................................................................................................................... 1
`
`SIGNATURE PAGE ........................................................................................................... 2
`
`2.
`
`3.
`
`4.
`
`5.
`
`5 .1
`
`5 .2
`
`5. 3
`
`6.
`
`7.
`
`8.
`
`9.
`
`9 .1
`9.2
`
`9.3
`
`9.3.1
`9.3.2
`
`9.3.3
`
`9 .4
`
`9.4.1
`
`9.4.2
`
`9.4.3
`
`9.4.4
`9.4.5
`
`9.4.6
`
`SYNOPSIS .................................................................................... .
`
`. ........... 2
`
`TABLE OF CONTENTS FOR THE INDIVIDUAL CLINICAL
`STUDY REPORT .......................................................................................... 10
`
`LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................. 17
`
`ETHICS ......................................................................................................... 19
`
`Independent Ethics Committee or Institutional Review Board ..................... 19
`
`Ethical Conduct of the Study .......................................................................... 19
`
`Subject Information and Consent ................................................................... 19
`
`INVESTIGATORS AND STUDY ADMINISTRATIVE
`STRUCTURE ................................................................................................. 20
`
`INTRODUCTION .......................................................................................... 21
`
`STUDY OBJECTIVES ................................................................................ 22
`
`INVESTIGATIONAL PLAN ....................................................................... 23
`
`Overall Study Design and Plan: Description ................................................. 23
`Discussion of the Study Design, Including the Choice of Control
`Groups............................................................................................
`
`. ........ .24
`
`Selection of Study Population ...................................................................... 24
`
`Inclusion Criteria .......................................................................................... 24
`Exclusion Criteria ......................................................................................... 25
`
`Removal of Patients from Therapy or Assessment.. ...................................... 26
`
`Treatments ..................................................................................................... 26
`
`Treatments Administered ................................................................................ 26
`
`Identity of Investigational Products ............................................................... 27
`
`Method of Assigning Subjects to Treatment Groups....
`
`. .............. 28
`
`Selection of Doses in the Study ..................................................................... 28
`Timing of Dose and Meal Schedule for Each Subject.. .................................. 28
`
`Blinding .......................................................................................................... 29
`
`ATTORNEY CONFIDENTIAL
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`10
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`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Clinical Study Report- PN400-104
`
`POZENinc.
`
`9.4.7
`
`9.4.8
`
`9.5
`
`9.5.1
`
`9.5.2
`
`9.5.3
`
`9.5.4
`
`9.5.5
`
`9.5.6
`
`9.5.7
`
`9.5.7.1
`
`9.5.7.2
`
`9.5.8
`
`9.5.8.1
`
`9.5.8.2
`
`9.5.8.3
`
`9.5.8.4
`
`9.5.9
`
`9.5.9.1
`
`9.5.9.2
`
`9.5.9.3
`
`9.6
`
`9.7
`
`9.7.1
`
`9.7.1.1
`
`9.7.1.2
`
`9.7.1.3
`
`9.7.1.4
`
`9.7.2
`
`9. 8
`
`10.
`
`Prior and Concomitant Therapy .................................................................... 29
`
`Treatment Compliance .................................................................................. 29
`
`Pharmacodynamic, Pharmacokinetic and Safety Variables ........................... 30
`
`Pharmacodynamic, Pharmacokinetic and Safety Measurements
`Assessed and Flow Chart ................................................................................ 30
`
`Screening Period (Day -14 - Day -1) ............................................................. 32
`
`Day 0 ............................................................................................................. 32
`
`Treatment Period (Days 1-10) ...................................................................... 32
`
`Final Visit ...................................................................................................... 33
`
`Appropriateness of Measurements ................................................................. 34
`
`Evaluation of Pharmacodynamics .................................................................. 34
`
`Intragastric pH ............................................................................................... 34
`
`Primary Pharmacodynamic Variable ............................................................. 34
`
`Evaluation of Safety ....................................................................................... 34
`
`Physical Examination and Vital Signs .......................................................... .34
`
`12-Lead ECG ................................................................................................ 34
`
`Clinical Laboratory Tests ............................................................................... 34
`
`Clinical Adverse Event Assessments .............................................................. 35
`
`Evaluation of Pharmacokinetics - Drug Concentration Measurements ........ .36
`
`Collection of Samples ..................................................................................... 36
`
`Assay Methods ............................................................................................... .37
`
`Assay Performance ....................................................................................... 38
`
`Data Quality Assurance ................................................................................ 39
`
`Statistical Methods Planned in the Protocol and Determination of
`Sample Size .................................................................................................... 39
`
`Statistical and Analytical Plans .................................................................... 39
`
`Analysis Populations .................................................................................... 39
`
`Analysis of Pharmacodynamics .................................................................... 39
`
`Analysis of Safety ......................................................................................... 40
`
`Analysis of Pharmacokinetics ...................................................................... .41
`
`Determination of Sample Size.................
`
`.. ............................................. .43
`
`Changes in the Conduct of the Study or Planned Analyses ........................... .43
`
`STUDY SUBJECTS ....................................................................................... 44
`
`ATTORNEY CONFIDENTIAL
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`Patent Owner Ex. 2017
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Clinical Study Report- PN400-104
`
`POZENinc.
`
`10.1
`
`10.2
`
`11.
`
`11.1
`
`11.2
`
`11.3
`
`11.4
`
`DispositionofSubjects .................................................................................. .44
`
`Protocol Violations ........................................................................................ .44
`
`PHARMACODYNAMIC AND PHARMACOKINETIC
`EVALUATION .............................................................................................. 45
`
`Data Sets Analyzed ........................................................................................ .45
`
`Demographic and Other Baseline Characteristics ........................................ .45
`
`Measurements of Treatment Compliance ..................................................... .47
`
`Pharmacodynamic Results and Tabulations oflndividual Subject
`Data .............................................................................................................. .47
`
`11.4.1
`
`Analysis of Pharmacodynamics ................................................................... .4 7
`
`11.4.1.1
`
`Primary Pharmacodynamic Measure ........................................................... .47
`
`11.4.1.2.
`
`Secondary Pharmacodynamic Measure ........................................................ 50
`
`11.4.1.3
`
`Other Pharmacodynamic Measures ............................................................... 51
`
`11.4.1.4
`
`Exploratory Pharmacodynamic Measures .................................................... 52
`
`11.4.2
`
`Statistical/ Analytical Issues ........................................................................... 52
`
`11.4.2.1
`
`Adjustments for Covariates ..................................