Dr. Falk Pharma GmbH
`Study Protocol SAG-19/BIO (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 1
`
`Version 1.1 - FINAL
`
`CLINICAL TRIAL REPORT
`
`A single-centre, controlled, randomised, cross-over study in healthy subjects to
`describe and compare the plasma pharmacokinetics and the urinary and faecal
`excretion of 5-aminosalicylic acid and N-acetyl-5-aminosalicylic acid after single
`oral doses of 500 mg 5-aminosalicylic acid (mesalazine):
`Effect of food and different batches of a pellet formulation
`
`Phase I
`
`Authors: (cid:9)
`
`Dr. D. Trenk, Prof. Dr. E. Jahnchen
`
`Principal Investigator: (cid:9)
`
`Prof. Dr. E. Jahnchen
`
`Co-Investigators: (cid:9)
`
`Dr. D. Trenk, Dr. J. Hajda, Dr. Dr. E. Stengele
`
`Centre: (cid:9)
`
`Abt. Klinische Pharmakologie, Herz-Zentrum Bad Krozingen,
`Sudring 15, D-79189 Bad Krozingen, Germany
`Tel: +49/7633-402 525, Fax: +49/7633-402 425
`
`Study phase: (cid:9)
`
`Clinical Phase I
`
`Trial dates: (cid:9)
`
`Sponsor: (cid:9)
`
`January 12, 2001 (screening of I 5t subject) –
`April 12, 2001 (end-of-trial in last subject)
`
`Dr. Falk Pharma GmbH
`Leinenweberstr. 5, D-79108 Freiburg, Germany
`Phone: +49/761-15141-0 Fax: +49/761-1514377
`
`Project managers (Sponsor): Dr. H.-D. Tauschel
`PD Dr. K. Dilger
`Tel: +49/761-1514-0, Fax: +49/761-1514377
`
`Version 1.1 - 21.06.2004
`
`Confidentiality statement:
`This material is the property of Dr. Falk Pharma GmbH. The information is confidential and is to be used only
`in connection with matters authorised by Dr. Falk Pharma GmbH and no part of it to be disclosed to others
`without prior written permission from Dr. Falk Pharma GmbH.
`
`SAG-19/BIO Final Study Report / Version 1.1 — 21.06.2004
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00377022
`Dr. Falk Ex. 2026
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG-19/BIO (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 2
`
`1.1 APPROVAL/SIGNATURE PAGE
`
`1 Author: (cid:9)
`Dr. D. Trenk
`
`Date (cid:9)
`
`signature
`
`2nd Author: (cid:9)
`Prof. Dr. E. J6hnchen
`
`Dr. Falk Pharma GmbH: (cid:9)
`PD Dr. K. Dilger
`
`Bloanalysis and Blostatistics: (cid:9)
`Dr. D. Trenk
`
`2 t, Juni 2004
`Date (cid:9)
`
`signal e
`
`3® (cid:9)
`Date (cid:9)
`
`2 ' (cid:9)
`signature
`
`6Z
`
`u D6a~
`
`Date (cid:9)
`
`signature
`
`
`
`,
`
`
`
`I hereby declare that I have read this Clinical Trial Report and that
`I agree with the presentation of the data and the conclusions
`drawn from them.
`
`Principal Investigator: (cid:9)
`Prof, Dr. E. J6hnchen
`
`21. Juni 2004
`Date (cid:9)
`
`signature
`
`~_-
`
`SAG-19/610 Final Study Report / Version 1.1 —21.06.2004
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00377023
`Dr. Falk Ex. 2026
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`(cid:9)
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG-19/BIO (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 3
`
`SYNOPSIS AND TRIAL ABSTRACT
`
`Name of Company: Dr. Falk Pharma GmbH
`
`TABULAR FORMAT
`
`Name of Finished Product: Salofalk o 500 mg granules
`
`Name of Active Substance(s): 5-Aminosalicylic acid
`
`REFERRING TO PART
`IV.A.2 OF THE DOSSIER
`
`Title:
`A single-centre, controlled, randomised, cross-over study in healthy subjects to describe and compare the
`plasma pharmacokinetics and the urinary and faecal excretion of 5-aminosalicylic acid and N-acetyl-5-
`aminosalicylic acid after single oral doses of 500 mg 5-aminosalicylic acid (mesalazine):
`Effect of food and different batches of a pellet formulation
`
`I nvestigator(s):
`Prof. Dr. E. Jahnchen (Principal investigator)
`Dr. D. Trenk, Dr. J. Hajda, Dr. Dr. E. Stengele (Co-investigators)
`
`Study centre(s):
`Abt. Klinische Pharmakologie, Herz-Zentrum Bad Krozingen
`D-79189 Bad Krozingen, Germany
`Phone: +49/7633-402 525, Fax: +49/7633-402 425
`Publication (reference):
`n. a.
`
`Study period:
`January 12, 2001 to April 17, 2001 (clinical phase)
`
`Clinical phase:
`Phase I
`
`conducted (cid:9)
`
`to (cid:9) describe (cid:9)
`
`and (cid:9)
`
`compare (cid:9)
`
`the (cid:9)
`
`systemic (cid:9) availability, (cid:9)
`
`the (cid:9) plasma
`
`Objectives:
`The (cid:9)
`study (cid:9) was (cid:9)
`pharmacokinetics
`and the urinary and the faecal excretion of 5-aminosalicylic acid (5-ASA) and N-acetyl-5-aminosalicylic
`acid (Ac-5-ASA) in healthy subjects after administration of single oral doses of 500 mg mesalazine
`granules without and with concomitant intake of food (standardized breakfast).
`In addition, two other batches from the production process with different in vitro-release profiles were
`investigated. These batches released in the appropriate settings for in vitro dissolution at 420 min. about
`85% (Batch no. G133 V060a) and 100% (Batch no. G133 V001) of 5-ASA, while the reference batch
`(G133 V040) released approximately 90% 5-ASA under the same conditions.
`To this end, three different batches of the granules formulation were used in a four-way cross-over
`/ study conditions on the systemic
`design, and the effects of the different in vitro release characteristics
`exposure with respect to 5-ASA and Ac-5-ASA was compared.
`Clinical and laboratory safety and tolerability after single oral administrations of 500 mg 5-aminosalicylic
`acid (mesalazine) was assessed as well.
`Methodology:
`The trial was carried out according to a single-centre, randomised, controlled, within-subject cross-over
`with a wash-out phase of at least 6 days between the administrations of the study medication,
`investigating the following single-dose treatments:
`
`A: 500 mg 5-aminosalicylic acid using granules (Batch-no.: G133 V040; 930 mg granules) with acid-
`resistant enteric coating administered under fasting conditions [Reference; n=24 subjects]
`
`e (cid:9)
`
`• (cid:9)
`
`B: 500 mg 5-aminosalicylic acid using granules (Batch-no.:G133 V040; 930 mg granules) with acid-
`resistant enteric coating administered 5 minutes after completion of a standardized breakfast [Test;
`n=24 subjects]
`• (cid:9) C: 500 mg 5-aminosalicylic acid using granules (Batch-no.:G133 V001; 930 mg granules) with acid-
`resistant enteric coating administered under fasting conditions [Test; n=12 subjects]
`
`o (cid:9)
`
`D: 500 mg 5-aminosalicylic acid using granules (Batch-no.: G1 33 V060a; 930 mg granules) with acid-
`resistant enteric coating administered under fasting conditions [Test; n=12 subjects]
`All treatments were administered after an in-house overnight fast and rest. Subjects remained fasted until
`4:00 h after dosing when a first meal was served (treatments A, C and D), respective 5 minutes after
`completion of a standardized high fat breakfast (treatment B).
`
`SAG-191810 Final Study Report / Version 1.1 —21.06.2004
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00377024
`Dr. Falk Ex. 2026
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG-19/BIO (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 4
`
`Name of Company: Dr. Falk Pharma GmbH
`
`TABULAR FORMAT
`
`Name of Finished Product: Salofalk® 500 mg granules
`
`Name of Active Substance(s): 5-Aminosalicylic acid
`
`REFERRING TO PART
`IV.A.2 OF THE DOSSIER
`
`Number of subiects:
`Twelve(12) subjects were investigated with evaluable pharmacokinetic data for the four treatment periods
`A, B, C and D, while twelve additional (12) subjects were investigated with evaluable pharmacokinetic
`data for the two treatment periods A and B only (i.e. 24 subjects in total for treatment periods A and B).
`Eight additional subjects were screened but not randomised.
`
`Diagnosis and criteria for inclusion:
`Male Caucasian subjects, aged 18 to 45 years, and found to be healthy on the basis of an extensive pre-
`study evaluation, while willing and able to provide informed consent
`
`Reference product, dose, mode of administration, batch Ne:
`• (cid:9)
`Treatment A: 930 mg mesalazine granules with acid-resistant enteric coating containing 500 mg 5-
`amino-salicylic acid — Batch Ns G133 V040 — p. o. administered dose: 500 mg mesalazine -
`administered under fasting conditions
`
`• (cid:9)
`
`Test products, dose, mode of administration, batch No:
`• (cid:9)
`Treatment B: 930 mg mesalazine granules with acid-resistant enteric coating containing 500 mg (cid:9) 5-
`amino-salicylic acid — Batch No G133 V040 — p. o. administered dose: 500 mg mesalazine -
`administered 5 minutes after completion of a standardized high fat breakfast
`Treatment C: 930 mg mesalazine granules with acid-resistant enteric coating containing 500 mg (cid:9) 5-
`amino-salicylic acid — Batch No G133 V001 — p. o. administered dose: 500 mg mesalazine -
`administered under fasting conditions
`Treatment D: 930 mg mesalazine granules with acid-resistant enteric coating containing 500 mg (cid:9) 5-
`amino-salicylic acid — Batch No G133 V060a — p. o. administered dose: 500 mg mesalazine -
`administered under fasting conditions
`
`• (cid:9)
`
`Duration of treatments:
`Single oral doses of 500 mg 5-aminosalicylic acid (treatments A, B, C and D) administered on four (n=12
`subjects) respective two occasions (n=12 subjects additional subjects; treatments A and B only) at least 6
`days apart
`
`Concomitant medication:
`The subjects were to abstain from any other medication during the entire course of the study.
`
`Criteria for evaluation:
`• Pharmacokinetics:
`Blood sampling: before dosing (blank), and then at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9,
`10, 12, 16, and 24 h after dosing (20 samples)
`Urine sampling: from -12 h before dosing up to time zero, and then at 0 - 12 h, 12- 24 h, 24 - 36 h,
`and 36 - 48 h after dosing (5 samples)
`Faeces sampling: from time of dosing up to at least 72 h after dosing (individual number of samples)
`- (cid:9) Concentrations of 5-ASA and Ac-5-ASA were determined by a specific HPLC-method with
`fluorescence detection after derivatization of 5-ASA
`- (cid:9) Time courses of the plasma concentrations were analysed non-compartmentally. Primary response
`variables were the plasma AUC0_m, C <, and tiag of 5-ASA as well as of Ac-5-ASA, and the sum of
`AUCam of 5-ASA + Ac-5-ASA. Secondary response variables were t„g<, and t1 12 of 5-ASA and Ac-5-
`ASA in plasma and the excretion of 5-ASA and Ac-5-ASA in urine and faeces.
`• (cid:9) Tolerability:
`Adverse events (throughout the study)
`Vital function (resting recumbent blood pressure and pulse rate)
`Standard (cid:9)
`laboratory evaluation (haematology, clinical chemistry, (cid:9) urinalysis) and (cid:9) 12-lead ECG;
`recorded upon recruitment and at the end-of-study evaluation
`
`SAG-19/BIG Final Study Report / Version 1.1 — 21.06.2004
`
`Confidential Information—Subject to Protective Order
`
`SALIX00377025
`Dr. Falk Ex. 2026
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
`
`(cid:9)
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG-19/BIO (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 5
`
`Name of Company: Dr. Falk Pharma GmbH
`Name of Finished Product: Salofalk® 500 mg granules
`Name of Active Substance(s): 5-Aminosalicylic acid
`
`TABULAR FORMAT
`
`REFERRING TO PART
`IV.A.2 OF THE DOSSIER
`
`(cid:9) period;
`
`Schedule:
`• Screening: assessment of eligibility within 14 to 1 day(s) before the l
`• N=12 subjects:
`Four study periods of at least 84 hours each, separated by a six days wash-out period between the study
`drug administrations; subjects were hospitalised from the evening before dosing until at least 72 h after
`morning dosing
`• N=12 subjects:
`Two study periods of at least 84 hours each, separated by a six days wash-out period between the study
`drug administrations; subjects were hospitalised from the evening before dosing until at least 72 h after
`morning dosing
`• End-of-trial (EOT) evaluation: within seven days after the last trial dose
`Statistical methods:
`• All study data were listed individually and summarised by suitable descriptive measures;
`• Ln-transformed C,,,a, and AUCa . were analysed. Treatments were contrasted by the point and interval
`estimates (95% confidence interval [Cl]) of the ratio of the treatment means (PT:PR) as back-transformed
`from In-transformed data.
`• The treatments were contrasted in terms of relative bioavailability (T vs R) by means of the point and
`95% Cl estimates of the ratios of the treatment means of Cme< and AUC0.,.
`SUMMARY - CONCLUSIONS:
`Subject Disposition :
`• Number: Thirty-two (32) subjects were screened. Twenty-four (24) out of these thirty-two subjects were
`enrolled. All twenty-four subjects completed the study in accordance with the protocol and are part of the
`pharmacokinetic and the safety analysis. Eight (8) subjects were only screened but not randomised.
`• Demographics: Twenty-four healthy, male, caucasian subjects aged 19 to 43 years (mean ± SD: 33.9 ± 7.1
`y), a body weight between from 61.0 to 92.4 kg ( 75.7 ± 8.1 kg), a height from 172 to 197 cm (180.8 ± 7.1
`cm) and a body mass index range between 18.8 and 25.8 kg-m 2 (23.1 ± 2.0 kg•m 2) were studied.
`
`SAG-19/B10 Final Study Report / Version 1.1 — 21.06.2004
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00377026
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`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
`
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG-19/610 (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 6
`
`Name of Company: Dr. Falk Pharma GmbH (cid:9)
`Name of Finished Product: Salofalk® 500 mg granules (cid:9)
`
`Name of Active Substance(s): 5-Aminosalicylic acid (cid:9)
`
`TABULAR FORMAT
`
`REFERRING TO PART
`IV.A.2 OF THE DOSSIER
`
`Clinical Pharmacology Criteria - Pharmacokinetics:
`Single administrations of the different granules formulations of 5-ASA produced the following plasma
`concentration - time profiles of parent drug 5-ASA and metabolite Ac-5-ASA:
`
`The time courses of the geometric mean plasma concentrations of 5-ASA and Ac-5-ASA after the
`administration of the three different batches of the granule formulations under fasting conditions (treatment
`A [n=24 subjects], treatment C [n=12] and treatment D [n=12]) and immediately after a standardized
`breakfast test (treatment B [n=24 subjects]) are shown here (linear concentration scale: left; log-linear
`concentration scale: right):
`
`5-ASA (cid:9)
`
`5-ASA
`
`300 (cid:9)
`
`c 200
`
`V (cid:9)
`U (cid:9)
`m (cid:9)
`m 100 (cid:9)
`
`0 (cid:9)
`0 (cid:9)
`
`800 (cid:9)
`
`_ (cid:9)
`E 600 (cid:9)
`m (cid:9)
`e (cid:9)
`
`0 400 (cid:9)
`
`a (cid:9)
`a 200 (cid:9)
`
`-e- Treatment A (cid:9)
`-A-Treatment B (cid:9)
`-®-TreatmentC (cid:9)
`-••4-` Treatment D (cid:9)
`
`8 (cid:9)
`4 (cid:9)
`Time, hours (cid:9)
`
`12 (cid:9)
`
`_ (cid:9)
`E (cid:9)
`
`ti (cid:9)
`V
`E (cid:9)
`
`U)
`
`500
`
`100
`
`50
`
`10
`0 (cid:9)
`
`-®- Treatment A
`-*-Treatment B
`- -TreatmentC
`•••°Treatment D
`
`8 (cid:9)
`4 (cid:9)
`Time, hours
`
`12
`
`Ac-5-ASA (cid:9)
`
`Ac-5-ASA
`
`r (cid:9)
`
`---- Treatment A
`—TreatmentB
`-4--TreatmentC
`--s--TreatmentD
`
`-C- Treatment A (cid:9)
`-A-TreatmentB (cid:9)
`-V-TreatmentC (cid:9)
`m, V•-TreatmentD (cid:9)
`
`1000
`
`500 (cid:9)
`
`~
`c
`
`0 100
`
`N 50
`
`n.
`
`0 (cid:9)
`0 (cid:9)
`
`4 (cid:9)
`
`16 (cid:9)
`12 (cid:9)
`8 (cid:9)
`Time, hours (cid:9)
`
`20 (cid:9)
`
`24 (cid:9)
`
`10
`0 (cid:9)
`
`4 (cid:9)
`
`16 (cid:9)
`12 (cid:9)
`8 (cid:9)
`Time, hours
`
`20 (cid:9)
`
`24
`
`SAG-19/810 Final Study Report / Version 1.1 -21.06.2004
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00377027
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`Page 6
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG-19/BlO (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 7
`
`Name of Company: Dr. Falk Pharma GmbH
`Name of Finished Product: Salofalk ® 500 mg granules
`Name of Active Substance(s): 5-Aminosalicylic acid
`
`TABULAR FORMAT
`
`REFERRING TO PART
`IV.A.2 OF THE DOSSIER
`
`Descriptive statistics of main plasma pharmacokinetics parameters:
`
`Treatment A: (cid:9) Administration of a single oral dose of 5-aminosalicylic acid 500 mg as granule
`[Reference] (cid:9)
`formulation with enteric coating under fasting conditions
`
`5-ASA
`
`Ac-5-ASA
`
`ArMean
`ArStd Dev
`ArStd Err
`ArCoefVar
`
`GeoMean
`Geo CoefVar
`
`Min
`Lo Quar
`Median
`Up Quar
`Max
`
`Valid N
`
`Cmax
`ng/ml
`
`333.393
`135.708
`27.701
`0.4071
`
`307.871
`0.4314
`
`123.27
`248.275
`307.555
`424.160
`622.76
`
`24
`
`AUCo-o,
`ng-h/ml
`
`954.77
`403.58
`82.38
`0.4227
`
`877.99
`0.4377
`
`426.2
`674.70
`807.90
`1331.55
`1889.7
`
`24
`
`Cmax
`ng/ml
`
`701.018
`218.391
`44.579
`0.3115
`
`669.018
`0.3211
`
`382.06
`530.195
`625.760
`921.815
`1158.74
`
`24
`
`AUCpb,
`ng•h/ml
`
`8798.71
`2669.03
`544.81
`0.3033
`
`8450.32
`0.2923
`
`5049.3
`6784.15
`8430.66
`10143.63
`16160.2
`
`24
`
`Treatment B: (cid:9) Administration of a single oral dose of 5-aminosalicylic acid 500 mg as granule
`formulation with enteric coating after a standardized high fat breakfast
`
`5-ASA
`
`Ac-5-ASA
`
`ArMean
`ArStd Dev
`ArStd Err
`ArCoefVar
`
`GeoMean
`Geo CoefVar
`
`Min
`Lo Quar
`Median
`Up Quar
`Max
`
`Valid N
`
`Cmax
`ng/ml
`
`182.892
`168.854
`35.209
`0.9232
`
`131.122
`0.9482
`
`43.07
`64.650
`106.890
`216.890
`579.36
`
`23
`
`AUC0
`ng•h/ml
`
`535.88
`432.88
`90.26
`0.8078
`
`410.47
`0.8371
`
`147.1
`245.88
`367.36
`599.62
`1633.5
`
`23
`
`Cmax
`ng/ml
`
`417.116
`232.598
`47.479
`0.5576
`
`369.961
`0.5058
`
`187.30
`251.385
`323.310
`457.500
`1022.02
`
`24
`
`AUC 0„
`ng•h/ml
`
`6143.84
`2125.62
`433.89
`0.3460
`
`5813.58
`0.3478
`
`3289.0
`4479.57
`5744.82
`7518.04
`10641.0
`
`24
`
`SAG-19/BIG Final Study Report / Version 1.1 - 21.06.2004
`
`Confidential Information-Subject to Protective Order
`
`SALIX00377028
`Dr. Falk Ex. 2026
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
`
`(cid:9)
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG- 19/B10 (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 8
`
`Name of Company: Dr. Falk Pharma GmbH
`Name of Finished Product: Salofalk® 500 mg granules
`Name of Active Substance(s): 5-Aminosalicylic acid
`
`TABULAR FORMAT
`
`REFERRING TO PART
`IV.A.2 OF THE DOSSIER
`
`Descriptive statistics of main plasma pharmacokinetics parameters (continued):
`
`Treatment C: (cid:9) Administration of a single oral dose of 5-aminosalicylic acid 500 mg as granule
`formulation with enteric coating under fasting conditions
`
`5-ASA
`
`Ac-5-ASA
`
`ArMean
`ArStd Dev
`ArStd Err
`ArCoefVar
`
`GeoMean
`Geo CoefVar
`
`Min
`Lo Quar
`Median
`Up Quar
`Max
`
`Valid N
`
`Cmax
`ng/ml
`
`556.503
`156.340
`45.132
`0.2809
`
`536.447
`0.2913
`
`312.62
`428.515
`547.485
`661.605
`847.33
`
`12
`
`AUC0.,,
`ng-h/ml
`
`1484.09
`641.63
`185.22
`0.4323
`
`1379.34
`0.4070
`
`677.4
`1172.53
`1321.37
`1676.66
`3176.9
`
`12
`
`Cmax
`ng/ml
`
`940.488
`227.483
`65.669
`0.2419
`
`916.929
`0.2360
`
`646.14
`782.265
`889.860
`1090.005
`1436.90
`
`12
`
`AUC0 . m
`ng•h/ml
`
`8261.87
`2135.13
`616.36
`0.2584
`
`8021.75
`0.2569
`
`5176.2
`7146.04
`7924.53
`9404.40
`12986.3
`
`12
`
`Treatment D: (cid:9) Administration of a single oral dose of 5-aminosalicylic acid 500 mg as granule
`formulation with enteric coating under fasting conditions
`
`5-ASA
`
`Ac-5-ASA
`
`ArMean
`ArStd Dev
`ArStd Err
`ArCoefVar
`
`GeoMean
`Geo CoefVar
`
`Min
`Lo Quar
`Median
`Up Quar
`Max
`
`Valid N
`
`Cmax
`ng/ml
`
`266.777
`176.345
`50.906
`0.6610
`
`211.734
`0.8613
`
`56.95
`114.135
`200.035
`421.770
`598.58
`
`12
`
`AUC0.,,
`ng , h/ml
`
`760.33
`464.43
`134.07
`0.6108
`
`623.90
`0.7917
`
`212.2
`388.41
`729.97
`913.25
`1713.7
`
`12
`
`Cmax
`ng/ml
`
`605.275
`305.365
`88.151
`0.5045
`
`532.486
`0.5926
`
`197.49
`352.115
`593.845
`744.640
`1177.00
`
`12
`
`AUC a„
`ng•h/ml
`
`7460.77
`2650.52
`765.14
`0.3553
`
`7039.58
`0.3732
`
`3583.7
`5852.69
`7280.60
`8923.10
`13528.0
`
`12
`
`SAG-191B10 Final Study Report / Version 1.1 - 21.06.2004
`
`Confidential Information-Subject to Protective Order (cid:9)
`
`SALIX00377029
`Dr. Falk Ex. 2026
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 8
`
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG-19/BIO (cid:9)
`
`BE Mesalazine 500 ma granules (cid:9)
`
`CR
`
`Name of Company: Dr. Falk Pharma GmbH
`
`TABULAR FORMAT
`
`Name of Finished Product: Salofalk® 500 mg granules
`
`Name of Active Substance(s): 5-Aminosalicylic acid
`
`REFERRING TO PART
`IV.A.2 OF THE DOSSIER
`
`This resulted in the following treatment contrasts (estimated mean treatment ratios):
`
`Contrasting Treatment A [Reference] vs. Treatment B [Test] with n=24 subjects:
`
`Estimated means
`
`Relative bioavailability
`
`Test
`
`130.59
`
` 411.82
`
`Reference
`
`309.02
`
`877.26
`
`
`
`PAc-5-ASA Test
`
`Reference
`
`AUC0_„
`
`369.96
`
`5813.58
`
`669.02
`
`8450.34
`
`T/R
`
`0.4226
`
`0.4694
`
`T/R
`
`0.5530
`
`0.6880
`
`0.3015
`
`0.3563
`
`0.4659
`
`0.6248
`
`95 % CI
`
`to
`
`to
`
`95%CI
`
`to
`
`to
`
`0.5923
`
`0.6185
`
`0.6564
`
`0.7575
`
`Ancillary PK-observations:
`If relative bioavailability of the test treatment was calculated based on the sum of the plasma exposures
`of 5-ASA and Ac-5-ASA, T/R ratios of 0.5158 (95 % Cl: 0.4122 to 0.6454) and 0.5724(95 % CI: 0.6115
`and AUCo_,respectively.
`to 0.7393) were obtained for the parameters C„ (cid:9)
`The lag-time of 5-ASA in plasma (t ag ) was 5.16 ± 1.86 hours for the test treatment and 2.13 ± 1.14 hours
`for the reference treatment. The lag-time of Ac-5-ASA was 2.80 ± 0.78 hours and 1.58 ± 0.60 hours for
`the test and for the reference treatment, respectively.
`The terminal half-lifes of elimination were 1.51 ± 1.15 and 1.69 ± 1.25 hours for 5-ASA and 13.50 ± 7.30
`hours and 14.26 ± 6.28 hours for Ac-5-ASA for the test and the reference treatment, respectively.
`
`Contrasting Treatment A [Reference] vs. Treatment C [Test] with n=12 subjects:
`
`5-ASA
`
`C„aX
`
`AUC0 ,,
`
`Ac-5-ASA
`
`CmaX
`
`AUC 0 .~
`
`Estimated means
`
`Test
`
`Reference
`
`536.45
`
`1379.34
`
`Test
`
`916.93
`
`8021.77
`
`321.95
`
`918.36
`
`Reference
`
`712.01
`
`8250.75
`
`T/R
`
`1.6662
`
`1.5019
`
`T/R
`
`1.2878
`
`0.9722
`
`Relative bioavailability
`
`1.3242
`
`1.3491
`
`1.1160
`
`0.8667
`
`95 % CI
`
`to
`
`to
`95 % CI
`
`to
`
`to
`
`2.0965
`
`1.6722
`
`1.4860
`
`1.0906
`
`Ancillary PK-observations:
`If relative bioavailability of the test formulation was calculated based on the sum of the plasma exposures
`of 5-ASA and Ac-5-ASA, T/R ratios of 1.4224(95 % CI: 1.1977 to 1.6892) and 1.0353(95% Cl: 0.9303
`to 1.1522) were obtained for the parameters C maX and AUCam,respectively.
`The lag -time of 5 -ASA in plasma (tag) was 1.92 ± 0.73 hours for the test formulation and 1.67 ± 0.49
`hours for the reference formulation. The lag-time of Ac-5-ASA was 1.58 ± 0.42 hours and 1.29 ± 0.33
`hours for the test and for the reference formulation, respectively.
`The terminal half-lifes of elimination were 1.54 ± 0.59 and 1.57 ± 1.42 hours for 5-ASA and 8.42 ± 2.42
`hours and 13.46 ± 6.08 hours for Ac-5-ASA for the test and the reference formulation, respectively.
`
`SAG-19/610 Final Study Report / Version 1.1 - 21.06.2004
`
`Confidential Information-Subject to Protective Order
`
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`GeneriCo v. Dr. Falk IPR2016-00297
`Page 9
`
`(cid:9)
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG-19/610 (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 10
`
`Name of Company: Dr. Falk Pharma GmbH
`Name of Finished Product: Salofalk ® 500 mg granules
`Name of Active Substance(s): 5-Aminosalicylic acid
`
`TABULAR FORMAT
`
`REFERRING TO PART
`IV.A.2 OF THE DOSSIER
`
`Contrasting Treatment A [Reference] vs. Treatment D [Test] with n=12 subjects:
`
`5-ASA
`C,'
`)(
`
`AUC0.,,
`Ac-5-ASA
`
`Estimated means
`Test
`Reference
`211.73
`321.95
`623.90
`918.36
`Test
`Reference
`532.49
`712.01
`
`T/R
`0.6577
`0.6794
`T/R
`0.7479
`
`7039.57
`
`8250.75
`
`0.8532
`
`Relative bioavailability
`95 % Cl
`to
`to
`95 % Cl
`to
`to
`
`0.4215
`0.4774
`
`0.5638
`
`0.7718
`
`1.0261
`0.9668
`
`0.9920
`
`0.9432
`
`AUC0_„
`Ancillary PK-observations :
`If relative bioavailability of the test formulation was calculated based on the sum of the plasma exposures
`of 5-ASA and Ac-5-ASA, T/R ratios of 0.7168 (95 % Cl: 0.5101 to 1.0072) and 0.8347 (95 % Cl: 0.7452
`and AU Co.„,respectively.
`to 0.9348) were obtained for the parameters C, (cid:9)
`The lag-time of 5-ASA in plasma (t iag ) was 2.96 ± 0.99 (cid:9) hours for the test formulation and 1.67 ± 0.49
`hours for the reference formulation. The lag-time of Ac-5-ASA was 2.80 ± 0.78 hours and 1.29 ± 0.33
`hours for the test and for the reference formulation, respectively.
`The terminal half-lifes of elimination were 1.82 ± 1.04 and 1.57 ± 1.42 hours for 5-ASA and 13.41 ± 6.47
`hours and 13.46 ± 6.08 hours for Ac-5-ASA for the test and the reference formulation, respectively.
`Urinary excretion of 5-ASA and Ac-5-ASA within 48 h after dosing (% of dose of 5-ASA):
`Treatment B
`Treatment A
`Ac-5-ASA Sum of 5-ASA
`Ac-5-ASA
`+ Ac-5-ASA
`12.476
`3.311
`0.676
`0.2654
`7.19
`10.433
`12.304
`13.662
`20.87
`24
`
`ArMean
`ArStdDev
`ArStdErrr
`ArCoefVar
`Min
`Lo Quar
`Median
`Up Quar
`Max
`Valid N
`
`5-ASA
`
`0.091
`0.083
`0.017
`0.9129
`0.00
`0.021
`0.080
`0.123
`0.30
`24
`
`Sum of 5-ASA
`+ Ac-5-ASA
`17.833
`3.521
`0.719
`0.1974
`13.44
`14.853
`16.898
`20.089
`26.13
`24
`
`5-ASA
`
`0.054
`0.065
`0.013
`1.2218
`0.00
`0.000
`0.035
`0.093
`0.26
`24
`
`17.742
`3.471
`0.709
`0.1956
`13.44
`14.813
`16.731
`20.047
`25.83
`24
`
`12.423
`3.277
`0.669
`0.2638
`7.13
`10.422
`12.229
`13.646
`20.60
`24
`
`5-ASA
`
`0.155
`0.161
`0.046
`1.0374
`0.00
`0.098
`0.115
`0.142
`0.64
`12
`
`Treatment C
`Ac-5-ASA Sum of 5-ASA
`+ Ac-5-ASA
`20.400
`4.644
`1.341
`0.2277
`14.14
`17.418
`20.173
`21.364
`30.45
`12
`
`20.246
`4.545
`1.312
`0.2245
`13.95
`17.299
`20.061
`21.236
`29.81
`12
`
`5-ASA
`
`0.060
`0.072
`0.021
`1.1918
`0.00
`0.000
`0.057
`0.083
`0.24
`12
`
`Treatment D
`Ac-5-ASA Sum of 5-ASA
`+ Ac-5-ASA
`15.759
`5.268
`1.521
`0.3343
`9.05
`11.201
`14.854
`20.418
`24.91
`12
`
`15.699
`5.215
`1.505
`0.3322
`9.05
`11.163
`14.798
`20.375
`24.67
`12
`
`ArMean
`ArStdDev
`ArStdErrr
`ArCoefVar
`Min
`Lo Quar
`Median
`Up Quar
`Max
`Valid N
`
`SAG-191810 Final Study Report / Version 1.1 - 21.06.2004
`
`Confidential Information-Subject to Protective Order (cid:9)
`
`SALIX00377031
`Dr. Falk Ex. 2026
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 10
`
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG-19/810 (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 11
`
`Only trace amounts (<1% of dose) of parent 5-ASA were recovered from urine collected within 48 hours
`after study drug administration. The highest recovery of 5-ASA from urine was obtained in treatment C
`which gave also the highest systemic exposure.
`Median recoveries with respect to the formed metabolite Ac-5-ASA were 16.7, 12.2, 20.1 and 14.8 % of
`the dose of 5-ASA administered in treatments A, B, C and D, respectively. The recovery of Ac-5-ASA was
`significantly lower in treatment B if compared with treatments A and C. Recoveries of the metabolite
`correlated also with the systemic exposures of 5-ASA in the different treatments.
`Faecal recovery of total 5-ASA and total Ac-5-ASA (% of dose of 5-ASA):
`
`Treatment A
`
`Treatment B
`
`Ac-5-ASA Sum of 5-ASA
`+ Ac-5-ASA
`48.79
`15.01
`3.06
`0.3077
`7.0
`43.04
`54.05
`58.38
`63.0
`24
`
`32.81
`13.60
`2.78
`0.4146
`5.1
`20.47
`32.45
`46.29
`52.6
`24
`
`5-ASA
`
`15.71
`11.59
`2.36
`0.7373
`1.1
`6.45
`12.98
`26.18
`36.1
`24
`
`Ac-5-ASA Sum of 5-ASA
`+ Ac-5-ASA
`48.03
`15.55
`3.17
`0.3238
`11.0
`34.64
`50.10
`61.11
`68.5
`24
`
`32.32
`12.60
`2.57
`0.3900
`9.9
`21.98
`32.51
`41.90
`52.6
`24
`
`Treatment C
`
`Treatment D
`
`ArMean
`ArStdDev
`ArStdErrr
`ArCoefVar
`Min
`Lo Quar
`Median
`Up Quar
`Max
`Valid N
`
`5-ASA
`
`15.98
`12.18
`2.49
`0.7623
`2.0
`5.58
`13.14
`21.43
`40.3
`24
`
`5-ASA
`
`Ac-5-ASA Sum of 5-ASA
`+ Ac-5-ASA
`46.49
`10.52
`3.17
`0.2262
`29.7
`37.35
`50.78
`53.58
`61.3
`11
`
`5-ASA
`
`14.91
`11.48
`3.46
`0.7700
`5.9
`7.33
`10.28
`16.54
`39.3
`11
`
`Ac-5-ASA Sum of 5-ASA
`+ Ac-5-ASA
`50.10
`10.85
`3.27
`0.2166
`31.9
`38.69
`53.22
`60.25
`62.1
`11
`
`35.18
`11.83
`3.57
`0.3362
`18.4
`22.46
`36.36
`45.51
`52.9
`11
`
`35.58
`10.91
`ArMean
`13.03
`9.65
`ArStdDev
`3.93
`2.91
`ArStdErrr
`0.3662
`0.8841
`ArCoefVar
`18.6
`2.0
`Min
`23.99
`4.87
`Lo Quar
`35.32
`6.38
`Median
`48.33
`11.45
`Up Quar
`54.9
`29.8
`Max
`11
`11
`Valid N
`Recovery of total 5-ASA from faeces extracts ranged from median figures of 6.4 % (treatment C) to 13.1
`% of the dose administered (treatment A) with marked interindividual variability within each treatment.
`Slightly less 5-ASA was recovered after administration of treatment C compared to the other treatments.
`Recovery of the metabolite Ac-5-ASA from faces extracts was markedly higher than the ones of parent 5-
`ASA with no significant differences between the different treatments investigated.
`Safety endpoints :
`Administrations of single oral doses of three different enteric coated granules formulations of 500 mg 5-
`ASA (cid:9) under fasting/non-fasting conditions (four treatment periods, n=72 administrations in total) were
`generally well tolerated by all subjects.
`There was a total of 21 AEs reported in the study: 18 AEs in 7/12 subjects receiving four treatments and 3
`AEs in 1/12 subjects with two treatment periods. None of the AEs was serious. Fifteen AEs were of mild,
`four AEs were of moderate and one AE was of severe intensity. One AE (splintering of the upper left
`canine) was not evaluated in terms of intensity by the investigator. More frequently reported AEs were
`headache/feeling of pressure on head (8/21 AEs) and gastrointestinal disturbances (4/21; nausea (2
`subjects), abdominal fullness, flatulence). The other AEs experienced comprised flickering of eyes (1/21),
`dryness of mouth (2/21) dizziness (1/21), herpes labialis (1/21), somnolence (1/21), common cold (1/21)
`an d thrombophlebitis at the right forearm (1/21) and splintering of the upper left canine (1/21).
`
`SAG-19/810 Final Study Report / Version 1.1 -21.06.2004
`
`Confidential Information-Subject to Protective Order (cid:9)
`
`SALIX00377032
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`GeneriCo v. Dr. Falk IPR2016-00297
`Page 11
`
`

`
`Dr. Falk Pharma GmbH
`Study Protocol SAG-19/BIO (cid:9)
`
`BE Mesalazine 500 mg granules (cid:9)
`
`CR page 12
`
`In terms of causality one AE was considered to be probably/likely related to the study medication, 15 AEs
`were possibly related and 5 AEs were unlikely to be related to the trial medication. Most of the AEs
`experienced resolved at latest at the following day after reporting. Thrombophlebitis, common cold and
`herpes labialis persisted after first reporting for 3, 8 and 16 days, respectively.
`There was no evidence or indication of clinically relevant individual or average effects on standard safety
`laboratory tests (haematology, clinical chemistry, urine analysis), vital signs and physical examination.
`
`Conclusions:
`• The oral administration of the granules formulation of 5-ASA five minutes after a standardized high fat
`breakfast led to an average relative bioavailability of 5-ASA of 47% (Cl: 35 to 62 %) compared with the
`reference administration where the same granules formulation was administered after an overnight
`fast. The estimated ratio of the treatment means of C m ,, of 5-ASA was 42% (Cl: 30 to 59%) relative to
`the reference formulation.
`• The oral administration of the granules formulation of 5-ASA after a standardized breakfast led to an
`average relative bioavailability of Ac-5-ASA of 69% (Cl: 62 to 76%) compared with the administration
`under fasting conditions (reference). The estimated ratio of the treatment means of Cmax of Ac-5-ASA
`was 55% (Cl: 46 to 66%) relative to the reference formulation.
`• The oral administration of the granules formulation with different release characteristics of 5-ASA
`affected relative bioavailability of the drug. Systemic availability of 5-ASA was increased after
`administration of the formulation with 100% in vitro release (Treatment C: Batch Na G133 V001). The
`average extent of relative bioavailability of 5-ASA was 150% (Cl: 134 to 167%) and the estimated ratio
`of the treatment means of Cmsx of 5-ASA was 166% (Cl: 132 to 210%) relative to the reference
`formulation. In contrast, systemic availability of 5-ASA was decreased after administration of the
`formulation with 85% in vitro release (Treatment D: Batch Na G133 V060a). The average extent of
`relative bioavailability of 5-ASA was 68% (Cl: 47 to 97%) and the estimated ratio of the treatment
`means of Cm , of 5-ASA was 65% (Cl: 42 to 103%) relative to the reference formulation. Similar
`findings were obtained with respect to the metabolite Ac-5-ASA.
`• Bioequivalence of 5-ASA/Ac-5-ASA could neither be demonstrated for treatment B (administration
`after a high fat breakfast) nor for Treatments C and D if compared with the reference formulation /
`treatment (Treatment A).
`• Substantial inter-individual variability in plasma concentrations of both 5-ASA and Ac-5-ASA were
`observed in all treatments.
`• Single oral dose administrations of mesalazine granule formulations with 500 mg 5-aminosalicylic acid
`were well tolerated by all subjects.
`
`SAG-19/610 Final Study Report / Version 1.1 — 21.06.2004
`
`Confidential Information—Subject to Protective Order (cid:9)
`
`SALIX00377033
`Dr. F