Superior efficacy of fesoterodine over
`tolterodine extended release with rapid
`onset: a prospective. head-to-head.
`placebo-controlled trial
`
`
`
`
` BUI
`
`
`IJU INTERNATIONAL
`
`Steven A. Kaplan, Tim Schneider*, Jenelle E. Footei, Zhonghong Guan*,
`Martin Car|sson* and Jason Gongi‘, on behalf of the Second Fesoterodine
`Assessment and Comparison versus Tolterodine (FACT 2) Study Group
`Department of Urology Weill Cornell Medical College, Cornell University, and iPfizer Inc, New York, Nlf USA,
`ill/lidtown Urology Er Midtown Urology Surgical Center, Atlanta, GA, USA, and “Praxisl<linik Urologie lihein/Ruhr,
`Mililheim, Germany
`Accepted for publication 18 June 2010
`
`Study Type — Therap‘/ lRCTl
`Level of Evidence
`1b
`
`OBJECTIVE
`
`0 To show the superior efficacy of
`fesoterodine over tolterodine extended
`
`release (ERJ in a placebo-controlled
`overactive bladder [OAB] trial with
`predefined treatment comparisons for both
`diary measures and patient-reported
`outcomes.
`
`MATERIALS AND METHODS
`
`0 In this 12-week, double-blind, double-
`dummy trial, subjects reporting >1 urgency
`urinary incontinence [UUI] episode and 28
`micturitions per 24 h at baseline were
`randomized to fesoterodine [4 mg for 1
`week, 8 mg for 11 weeks], tolterodine ER
`4 mg. or placebo.
`0 Subjects completed 3-day bladder diaries,
`the Patient Perception of Bladder Condition
`(PPBC) and the Urgency Perception Scale
`[UPS] at baseline and weeks 1, 4 and 12 and
`the DAB Questionnaire at baseline and week
`12.
`
`RESULTS
`
`What's known on the subject? and What does the study add?
`A previous trial found greater efficacy with the maximum available close of fesoterodine
`8 mg compared with the maximum available dose of tolterodine ER 4 mg and placebo for
`improving overactive bladder symptoms, and patient-reported outcomes were
`demonstrated by a recent placebo-controlled, head-to-head trial.
`
`The results of this trial, the largest to date to compare antimuscarinic efticacy, confirms
`the superior efficacy of fesoterodine 8 mg over tolterodine ER 4 mg for the treatment of
`OAB symptoms, and further emphasize the clinical advantage of the availability of an
`additional 8—mg dose over single-dose tolterodine ER 4 mg.
`
`placebo on UUI episodes [primary endpoint},
`micturitions, urgency and most other diary
`endpoints, and on the PPBC, UPS and all OAB
`Questionnaire scales and domains [all P<
`0.05}.
`' Superiority of fesoterodine 8 mg over
`tolterodine ER 4 mg was seen as early as
`week 4 (3 weeks after escalation to
`fesoterodine 8 mg]. At week 1, fesoterodine
`4 mg was superior to placebo on most diary
`variables, the PPBC and
`the UPS [all P< 0.05}. Dry mouth and
`constipation rates were 28% and 4% with
`fesoterodine, 13% and 30/0 with tolterodine
`ER, and 5% and 2% with placebo.
`' Discontinuation rates as a result of
`adverse events were 5%, 30/0 and 2% for
`fesoterodine. tolterodine ER and placebo,
`respectively.
`
`CONCLUSl0NS
`
`performed to date, fesoterodine 8 mg was
`superior to tolterodine ER 4 mg for UUI
`episodes, micturitions and urgency episodes,
`as well as for self-reported patient
`assessments of bladder—related problems.
`urgency. symptom bother and health-related
`quality of life.
`0 The superiority of fesoterodine 8 mg over
`tolterodine ER 4 mg was observed as early as
`3 weeks after escalation from fesoterodine
`
`4 mg for most outcomes. These data may
`have important implications for the clinical
`management of OAB patients previously
`treated with tolterodine ER.
`
`KEYWORDS
`
`antimuscarinic, fesoterodine, tolterodine.
`head-to-head, efficacy, quality of life
`
`0 A total of 2417 subjects were randomized.
`At week 12, fesoterodine 8 mg showed
`superiority over tolterodine ER 4 mg and
`
`0 In this randomized study, which is the
`largest to compare antimuscarinic efficacy
`
`1432
`
`BJU INTERNATIONAL © 2010 BJU lNTEHNA‘l|(.‘lNAL | 107, 1432-1440ldoi:1D.1111l'j.1464-410X.2D1[l.0BS4D.x
`
`2010 THE AUTHORS
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2088 - 0001
`
`

`
`HEAD-T0-HEAD COMPARISON OF FESOTERODINE AND TOLTERODINE Ea
`
`INTRDDUCTION
`
`With the emergence of comparative
`effectiveness research as a driver of
`
`healthcare policy and reform. there is
`currently an emphasis on establishing the
`clinical value of one treatment over another
`[1]. A number of randomized, double-blind,
`placebo-controlled trials have compared the
`efficacy of antimuscarinics for the treatment
`of overactive bladder IOAB} symptoms [2-9].
`The International Conference on
`Harmonisation Good Clinical Practice
`
`guidelines recommend the superiority design
`for comparisons between active treatments
`and with placebo [10]. However. most trials of
`antimuscarinic efficacy have been designed
`for comparison with placebo only; trials
`designed to compare the clinical efficacy of
`two antimuscarinics have either been based
`
`on a non-inferiority design or have lacked a
`placebo arm. Additionally, no placebo-
`controlled trials to date have reported
`predefined comparisons in both diary-based
`and patient-reported outcomes [PROS]
`measures.
`
`Fesoterodine is an antimuscarinic agent that
`is rapidly and extensively converted by
`ubiquitous esterases to its active metabolite,
`5-hydroxymethyl tolterodine (5-HMT];
`fesoterodine is not detectable in plasma after
`oral dosing, and all antimuscarinic effects are
`attributable to 5-HMT [11]. Tolterodine is also
`converted to 5-HMT. although this occurs
`primarily in the liver via cytochrome P450
`2%. A significant fraction of unconverted
`tolterodine is found in plasma. and both
`tolterodine and 5-HMT contribute to
`
`antimuscarinic effects [11]. After oral
`administration of tolterodine, there
`is considerable variability in the
`pharmacokinetic properties of 5-HMT and
`tolterodine between individuals with different
`
`cytochrome P450 2% phenotypes [12].
`There is much less variability in 5-HMT
`pharmacokinetics after oral administration of
`fesoterodine [13].
`
`By contrast to tolterodine extended release
`[ER], for which 4 mg is the one approved dose
`for treatment in the general population of
`patients with OAB [14]. fesoterodine is
`available in both 4 and 8 mg once-daily doses
`[15,16]. Notably, a posthoc analysis of a
`placebo-controlled phase III trial of
`fesoterodine that included tolterodine ER as
`
`voided volume [MVV] per micturition with
`fesoterodine 8 mg compared to tolterodine
`ER 4 mg [18]. Consistent with these findings,
`a recent placebo-controlled. head-to-head
`trial showed that reductions in UUI episodes
`at 12 weeks [the primary endpoint} and
`increases in MW per micturition and 3-day
`diary-dry rate [proportion of subjects with >0
`UUI episodes on baseline bladder diaries who
`reported 0 UUI episodes at week 12; post hoc
`analysis} were significantly greater in subjects
`treated with fesoterodine 8 mg than in
`subjects treated with tolterodine ER 4 mg [9].
`Subjects receiving fesoterodine 8 mg also had
`significantly greater improvements on the
`Patient-Perception of Bladder Condition
`[PPBC]. Urgency Perception Sale [UPS] and the
`Overactive Bladder questionnaire [OAB-q]
`compared to subjects receiving tolterodine ER
`4 mg (all posthocanalyses) [9].
`
`The present study, which is the largest
`placebo-controlled. randomized, head-to-
`head antimuscarinic study peformed to date,
`is the second study to prospectively assess the
`superiority of the maximum available dose of
`fesoterodine [8 mg) over the maximum
`available dose of tolterodine ER (4 mg}.
`Notably, all comparisons of diary-based
`endpoints and PROs in the present study were
`predefined, and this is the first placebo-
`controlled study for which the time course of
`the superiority of one antimuscarinic over
`another has been reported.
`
`MATERIALS AND METHODS
`
`STU DY DESIGN
`
`This was a 12-week. randomized, double-
`blind. double-dummy. placebo-controlled.
`parallel group. trial with a 2-week single-blind
`placebo run-in period. conducted at 210
`centres in North America, South America,
`Europe, Asia and Africa between February
`2008 and October 2009 [C|inica|Tria|s.gov
`Unique ID NCT00611026]. Eligible subjects
`were randomized to fesoterodine, tolterodine
`ER or placebo in a 2 :2 :1 ratio. A
`randomization schedule with a block size of
`
`five was implemented. which was generated.
`secured. distributed and stored by Pfizer
`Global Clinical Data Services. The trial was
`
`approved by the appropriate Institutional
`Review Boards and Independent Ethics
`Committees and conducted in accordance
`
`an active control [17] showed significantly
`greater improvements in urgency urinary
`incontinence [UUI] episodes and mean
`
`with the protocol, International Conference
`on Harmonisation Good Clinical Practice
`
`guidelines. and applicable local regulatory
`
`(9 2010 THE AUTHORS
`BJU INTERNATIONAL © 2010 BJU INTERNATIONAL
`
`requirements and laws. All subjects provided
`their written informed consent.
`
`The United States and European fesoterodine
`product labels recommend a starting dose of
`fesoterodine of 4 mg once daily, which may
`be increased to 8 mg once daily based on
`individual response and tolerability [15,16]. In
`the present study, all subjects in the
`fesoterodine group received fesoterodine
`4 mg for the first week followed by
`fesoterodine 8 mg for the next 11 weeks. All
`subjects in the tolterodine ER group received
`tolterodine ER 4 mg for all 12 weeks.
`Throughout the study. all subjects were
`instructed to take one tablet [fesoterodine 4
`or 8 mg. or matching placebo] and one
`capsule (tolterodine ER 4 mg. or matching
`placebo] daily in the morning.
`
`SUBJECTS
`
`Eligible men and women [218 years) self-
`reported OAB symptoms for 23 months and
`had a mean of at least one UUI episode and
`28 micturitions per 24 h in 3-day bladder
`diaries at baseline. Key exclusion criteria were:
`clinically significant hepatic or renal disease;
`voiding dysfunction attributable to lower
`genitourinary pathology or surgical
`treatment; neurological conditions lstroke.
`multiple sclerosis. spinal cord injury or
`Parkinson*s disease]; history of acute urinary
`retention requiring catheterization;
`symptoms of incontinence being
`predominately stress urinary incontinence
`in the opinion of the investigator;
`antimuscarinic treatment within 2 weeks
`
`before screening or electrostimulation,
`bladder training or pelvic floor exercises
`within 4 weeks of screening. Also excluded
`were female subjects who were pregnant.
`nursing or of childbearing potential. and who
`were heterosexually active without using
`adequate contraception measures.
`
`OUTCOME MEASURES
`
`Subjects completed 3-day diaries at baseline
`and weeks 1, 4 and 12; endpoints were
`changes from baseline in UUI episodes.
`micturitions. nocturnal micturitions. urgency
`episodes. severe urgency episodes and
`frequency—urgency sum per 24 h. 3-day
`diary-dry rate and MW per micturition. The
`primary endpoint was change in UUI episodes
`from baseline to week 12. Urgency episodes
`and severe urgency episodes were those rated
`23 and 24. respectively. on the five-point
`
`1433
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2088 - 0002
`
`

`
`[<APLAN ET AL.
`
`Urinary Sensation Scale (1 = no urgency,
`5 = UUI] [19]. The frequency—urgency sum
`was defined as the sum of Urinary Sensation
`Scale ratings associated with all micturitions
`over the course of 24 h averaged over the
`diary period. Three-day diary-dry rate was
`defined as the proportion of subjects with >0
`UUI episodes on baseline bladder diaries who
`reported 0 UUI episodes on post-baseline
`diary. Subjects also completed the PPBC [20]
`and UPS [21] at baseline and weeks 1, 4
`and 12, and the OAB-q [22] at baseline and
`week 12.
`
`STATISTICAL ANALYSIS
`
`On the basis of a previously observed mean
`(SD) difference of 0.44 (2.36) between
`fesoterodine 8 mg and tolterodine ER 4 mg
`groups for changes in UUI episodes per 24 h
`from baseline to week 12 [17]. 606 subjects
`per active treatment group were required for
`90% power for comparisons at the 5%
`significance level. On the basis of the
`previously observed mean (SD) differences of
`1.07 [285] between fesoterodine 8 mg and
`placebo groups and 0.63 (2.81] between
`tolterodine ER 4 mg and placebo groups [17],
`303 subjects were required in the placebo
`group for 28801:: power for each comparison.
`Thus, 1515 subjects were required; assuming
`that 90% of randomized subjects would
`contribute to the full analysis set [FAS], it was
`originally planned to randomize 1675
`subjects.
`On the basis of the results of the first head-
`
`to—head trial of fesoterodine 8 mg vs
`tolterodine ER 4 mg [9], it was determined
`that non-parametric methods may be
`required for statistical analysis of some
`endpoints in the present study. A blinded
`sample size re-estimation was performed in
`January 2009 to calculate the conditional
`power of the present study based on the
`originally planned sample size of 1675
`randomized subjects. The study wasjudged to
`be underpowered (68%] for non-parametric
`analysis as conducted in the previous study.
`To increase the power to 80%, the sample
`sizes were increased to 820, 820 and 410
`subjects in the fesoterodine, tolterodine ER
`and placebo groups, respectively [total n =
`2050]. It was assumed that 95% of the
`randomized subjects would contribute to the
`FAS [9]; thus, at least 2160 randomized
`subjects were required.
`
`Tolerability findings were assessed
`descriptively using the safety analysis set,
`
`‘I434
`
`which included all subjects who took one or
`more dose of double-blind study drug.
`Efficacy analyses were initially planned using
`the FAS. which included all subjects who took
`one or more dose of double-blind study drug
`and had at least one valid post-baseline
`efficacy assessment. Significant Good Clinical
`Practice violations and data irregularities
`were identified in theee study sites during a
`quality assurance audit conducted by the
`sponsor, during the study. All 77 subjects from
`these three sites were excluded from the FAS,
`although these subjects were included in
`the safety analysis set. This decision was
`documented in an amended statistical
`
`analysis plan and finalized before database
`unblinding. Sensitivity analyses of changes
`from baseline to week 12 for the primary
`endpoint [UUI episodes] and three secondary
`endpoints (MW, micturitions per 24 h, and
`urgency episodes per 24 h} were conducted
`based on a supporting FAS that included the
`77 subjects from these three sites. The
`sensitivity analyses showed that the results
`obtained for the primary and selected
`secondary endpoints based on the supporting
`FAS were consistent with those obtained
`based on the FAS.
`
`All comparisons reported in the present study
`were prespecified. Treatment differences in
`the primary endpoint [changes in UUI
`episodes per 24 h from baseline to week 12]
`and all secondary endpoints were assessed
`using a closed testing procedure: the
`fesoterodine group was first compared with
`placebo and then with the tolterodine ER
`group if the difference vs placebo was
`significant. The tolterodine ER group was also
`compared with placebo. Numeric and
`percentage changes from baseline for each
`diary endpoint were considered in separate
`hierarchical order to preserve the on-level of
`5% within each diary endpoint. Numeric
`changes were tested first, and percentage
`changes were tested only if the difference in
`numeric change was statistically significant.
`
`The statistical analysis plan specified testing
`whether diary data met normality
`assumptions [23]. It was found that changes
`in UUI episodes, MW and severe urgency
`episodes violated normality assumptions.
`Thus, changes in these variables were
`assessed using the non-parametric Van
`Elteren's test. a Stratified Wi|coxon—Mann—
`Whitney test [24]. Changes in these variables
`are presented as Winsorized means.
`comprising a robust estimator of the sample
`
`Discontinued
`= 47 [1096]
`TEAEs
`= 9 (2%)
`Lack of efficacy
`= 11 (2%)
`Lost to follow-
`up = B (1%)
`Consent
`withdrawn
`= 7' (2%)
`Other
`= 13 [3%)'
`
`Discontinued
`= 85 (SIWI
`TEAEs
`= 23 (3%)
`lack of efficacy
`= 10 (1%)
`Lost to follow-
`up = 1 1 (1%)
`Consent
`withdrawn
`=19 (2111:)
`Other
`= 20 (2%)'
`
`Discontinued
`= as (10%)
`TEAES
`= 45 (5%)
`Lack of efficaey
`= 4 [<1%]
`Lost to follow-
`up = 14 (2%)
`Consent
`withdrawn
`= 16 (2111)
`Other
`= 18 [2°la)'
`
`mean that is calculated by replacing 5% of
`the sample distribution tails with values at the
`5th and 95th percentiles, respectively.
`Changes in other diary endpoints and OAB-q
`scores were assessed using analysis of
`covariance (ANCoVA), with baseline value as a
`covariate and treatment and country as
`factors. Percentage changes from baseline in
`bladder diary endpoints were analyzed using
`ranked ANCOVA with terms for country,
`treatment and ranked baseline value as
`covariate. The Cochran—Mante|-Haenszel test
`
`stratified by country was used to assess
`treatment differences in 3-day diary-dry rate.
`four category changes in PPBC scores [22-
`point improvement, 1-point improvement, no
`change. deterioration), and three category
`changes in UPS scores (improvement, no
`change, deterioration).
`
`Missing post-baseline data were imputed
`based on the last-observation-carried-
`
`forward principle; baseline data were not
`carried forward. All tests were two-sided
`based on an ot-level of 5%.
`
`RESULTS
`
`SUBJECTS
`
`Among 2417 subjects who were randomized.
`2411 subjects received one or more dose of
`study medication (Fig. 1); 47 [10°Iol. 88 (9%]
`and 98 [10070] subjects in the placebo,
`
`2010 THE AUTHORS
`BJU INTERNATIONAL © 2010 BJU INTERNATIONAL
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2088 - 0003
`
`FIG. 1. Subject disposition. TEAE5, treatment-
`ernergent adverse events {any causality). “lnc1‘ua‘es
`protocol v.I'olatr'on, not meeting en trance cr1'terl'a,
`and other reasons.
`
`= 2417
`
` Randomized
`
`Treated with
`placebo
`= 478
`
`
`
`Treated with
`tolterodine
`
`ER = 973
`
`Treated with
`fesoterodine
`= 960
`
`
`
`

`
`HEAD-T0—HEAD COMPARISON OF FESOTERODINE AND TOLTERODINE Eli
`
`TABLE 1' Baseiine demographic and clinical characteristics
`
`Tolterodine ER
`
`Fesoterodine
`
`tolterodine ER, and fesoterodine groups,
`respectively, discontinued the study. Baseline
`demographic and clinical characteristics were
`similar among the treatment groups [Table 1).
`Approximately 2% of subjects reported a
`8 mg
`4mg
`Placebo
`.
`.
` mean of less than one UUI episode per 24 h
`Women, r1(0ra)
`410 (B6)
`818 (84)
`816 (85)
`d
`.
`_
`.
`.
`.
`uring the 3 day diary period at baseline and
`Age (years)
`were in violation of study inclusion criterion.
`Mean (so)
`These subjects were included in safety and
`R Rangel
`)
`efficacy analyses-
`ace, n 016
`white
`WEEK 12 OUTCOMES
`Asian
`
`595 (13.2)
`18.0-89.0
`384 (80)
`41(1o)
`
`513.1 (13.8)
`18.0-89.0
`153 (78)
`99 (101
`
`57.9 (4315)
`18.0-90.0
`144 (78)
`101 (11)
`
`Black
`other
`OAS duration [))em)
`LAM" (SD)
`_
`_
`_ange
`_
`Sub)ects with >0 UUI episodes,(24 h at baseline.
`,
`" W")
`_
`,
`,
`_
`,
`Number of sub)ects with previous antimuscannic
`
`20 (4)
`27 (6)
`
`53 )5)
`63 )7)
`
`6'3 R2)
`0'3'73'4
`472 (99)
`
`65 (73)
`0'3_63‘4
`963 [99]
`
`165 (34.5)
`
`314 (32.3)
`
`B""“‘)e’ “)3” "“")"""'°5* me)“ )5”)
`UUI episodes per 24 h
`MW per micturition (mt)
`Total micturitions per 24h
`Nocturnal micturitions per 24 h
`éjggglczfpfiodes Per 24 h
`gene)’ Epmdes per 24 h
`Ppgrcequeénciwurgency sum per 24 h
`,
`1'1 %
`No) man) pmmems at an )1)
`Some very minor problems (2)
`Some minor problems (3)
`Some moderate problems (4)
`Severe problems (5)
`Many severe prebiems (5)
`UPS,
`in (010)
`1
`2
`3
`0AB-q, mean (SD)
`symptom bother
`Total HROL
`Concern
`Coping
`Sleep
`Social Interaction
`
`2.4 (1.9)
`141.3 (54.9)
`11.7 (3.1)
`2.1 (1.3)
`9'5 (19)
`6'0 (15)
`40.3 (13.5)
`4 )1)
`9(2)
`28 (6)
`151 (33)
`203 (45)
`57 (13)
`
`170 (38)
`266 (59)
`15 (4)
`
`514 (13_1)
`54.9 (20.7)
`50.5 (23.5)
`432 (254)
`53.4 (24.7)
`13.1 (23.2)
`
`2.6 (2.1)
`142.1 (55.5)
`11.9 (3.0)
`2.3 (1.2)
`9'7 (35)
`6'3 (35)
`41.B (12.9)
`4 (<1)
`29(3)
`56 (6)
`295 (32)
`412 (44)
`134 (14)
`
`366 (39)
`526 (56)
`40 (4)
`
`593 (195)
`53.3 (22.6)
`49.1 (26.0)
`452 (2112)
`51.3 (26.3)
`12.4(2-1.3)
`
`55 (6)
`60 (6)
`
`5'6 (75))
`03-553
`950 [99]
`
`305 (31.6)
`
`2.6 (2.2)
`146.2 (54.5)
`11.7 (3.3)
`2.2 (1.3)
`9'7 H0)
`GA )4'0)
`41.7 (15.0)
`3 [<1]
`24 (3)
`57 (6)
`239 (32)
`393 (43)
`141 (15)
`
`364 (40)
`519 (57)
`30(3)
`
`5g_4 (19_1)
`53.4 (21.3)
`48.4 (24.9)
`46_1 [25]]
`52.2 (25.0)
`13.2 (23.2)
`
`ER, extended reieose,'HROL, health-related quaiityofi'ife,'Ml/1/, mean voided volume; (JAB-q, Overactive
`BiadderOuestionnairc,'PPBC PatientPerccptr'on of Bladder Condition,-PRO. patient-reported outcomes;
`UPS, Urgency Perception Scaie (T =not able to hold i.rrine,'2 =Abi'e to hold urine, withoutieoking, untiii
`reach a toii'etin1mediateiy,'3 =Abi'e to finish the ongoing workbefaregoing to the toiiet, withoutleaking};
`UUI, urgency urinary incontinence. Demographic data represent the safety set (placebo, n = 478;
`tolterodine ER, 11 = 973,‘ fesoterodine. n = 960}; baseline diary variable data represent fuii anal‘)/sis set
`(placebo, 11 = 462; tolterodine ER, n = 942,'fesoterodir1e, n = 930) for oii subjects reporting the symptom
`
`at basciine;PRO data represent the fair analysis set.
`
`(9 2010 THE AUTHORS
`BJU INTERNATIONAL © 2010 BJU lNTEHNAT|ClNAL
`
`At week 12 subjects receiving fesoterodine
`8 mg had significantly greater mean
`improvements in most diary variables than
`subjects receiving tolterodine ER, including
`UUI episodes (the primary endpoint, P=
`00072]! micmmions (F: 00016]. Urgency
`episodes [P< 0.0001), severe urgency
`.
`:i::°r::‘5:.%??°ii::::::;;:':::i“W
`micturitions (P: b.1551) or MW (P: 0.0525)
`.
`.
`3191'::r:i):ig:EJ$:::dr;ne:]E
`in alldiaryendpoints at Week nmmpared to
`placebo [all P< 0.0001‘ except P: 00134 for
`nocturnal micturitions), whereas the
`tolterodine ER group showed significantly
`greater improvements in UL“ Episodes
`il}1Jl:Il.)]il:)Il202l‘El3S]'(i):/|E\’b)(l:)J4:7[)'S:)2lil(fiCnbd0 but not
`in other wary V;_(a'b|eS (P > $051‘
`'
`
`The median percentage reduction in UU|
`episodes at week 12 was 100% in all groups
`(Table 2). However, the treatment differences
`between the fesoterodine group and the
`tolterodine ER (P: 0.0093) and placebo
`(P: 0.0001) groups were statistically
`significant, reflecting an overall difference in
`the distribution of percentage changes in UUI
`in favour of fesoterodine. Consistent with
`this. the 3-day diary-dry rate at week 12
`(proportion of subjects reporting no UUI
`episodes at endpoint among those with
`greater than zero UUI episodes at baseline)
`was significantly greater in the fesoterodine
`group vs tolterodine ER and placebo groups
`(P = 0-0159 and P = 0-0003} Fig. 23) Th?
`tffifltmfint dlffE|'€nCES b€iZWE€i’i
`U16
`t0ltE|’0dli'l€
`ER and Pl8CEb0 QFOUPS With
`in
`(65060? T0 F060 la 0 PEFCEMBQE Fed UCUOTI
`UUI episodes (P = 0.0805) and diary-dry rate
`(P: 0-0991) 3) Week )2 We”-‘ “Oi 5t3tl5lilC3llV
`S) g ni flcant.
`
`Categoricm Changes in PPBC and UPS Scores
`from baseline to week 12 were significantly
`better in the fesoterodine group compared
`
`1435
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2088 - 0004
`
`

`
`[<APLAN ET AL.
`
`FIG. 2. Change from baseline (Bl) to weeks 1, 4 and 12 in UUI episodes per 24 h {A}, MWper micturition {C}, totaln'u'cturitions per 24 h {D}, nocturnal micturitions per
`24 h (E), urgency episodes per 24 h (F), severe urgency episodes per 24 h (6) and frequency—urgency sum per 24 h {H}. Error bars represent the SEM. Also shown in (B)
`are the 3-day diary-dry rates at weeks 1, 4 and 12. Data represent the full analysis set for subjects reporting symptoms at baseline. Subjects in the fesoterodine group
`received fesoterodine 4 mg for the first week and then fesoterodine 8mg for the remaining 11 weeks. ER, extended release; Ml/V, mean voided volume,‘ UUI, urgency
`urinary incontinence. ‘P <0.05 tolterodine ER vs placebo,‘ +P <0.05 fesoterodine vs placebo,‘ tP < 0.05 fesoterodine vs tolterodine ER.
`
`A
`
`UUI Episodes per 24 h
`Week
`
`3
`
`Diary Dry-Rate
`
`c
`
`Mean Voided Volume per Micturition
`
`
`0-0 BL1
`4
`12
`---Placebo
`-'-Tolterodine ER 4 mg
`‘ Fesoterodine 4 or 8 mg
`_‘i'_;\\
`\
`xx;
`\§%,
`++
`
`M
`E‘
`16
`§ '05
`ru
`§ _1 O
`E -1 5
`§
`
`"2 O
`
`+i=
`
`69
`U;
`E
`‘_‘
`a
`
`70
`50
`50
`40
`so
`20
`10
`
`Week
`
`
`
`+
`U 4o_o
`i
`++j
`E 350
`/
`»
`I 30.0
`//..E___—-———-"I
`E 25-0
`ru
`E 20-0 +I,/
`I
`I
`-—"-'—_d_————F
`1/1
`‘E 10.0
`3 5'0
`M’ BL1
`
`12
`
`4
`Week
`
`Number of Subjects
`Placebo
`Tolterodine ER
`Fesoterodine
`
`442
`911
`B99
`
`448
`922
`908
`
`448
`926
`908
`
`Number of Subjects
`Placebo
`Tolterodine ER
`Fesoterodine
`
`442
`911
`899
`
`448
`922
`908
`
`448
`926
`908
`
`Number of Subjects
`Placebo
`Tolterodine ER
`Fesoterodine
`
`442
`911
`899
`
`452
`927
`909
`
`452
`930
`912
`
`D
`
`Micturitions per 24 h
`Week
`
`E
`
`F
`
`Urgency Episodes per 24 h
`Week
`
`0.0
`
`-0.5
`
`%
`E _1_[}
`J:
`‘E’
`-1 5
`3
`'
`E -2.0
`3
`
`'25
`-3.0
`
`
`
`5
`-:
`E
`‘Z
`5
`5
`2
`
`Nocturnal Nlicturitions per 24 h
`Week
`4
`
`Bl 1
`
`12
`
`0.0
`-0.1
`I
`a -0.2
`: \
`'
`g -0.3
`ti —o 4
`I
`3';
`' ml
`2 ‘"5
`5 _o_(-;
`-
`-0.7
`+3
`-0.3
`
`Number of Subjects
`Placebo
`Tolterodine ER
`Fesoterodine
`
`448
`921
`908
`
`454
`831
`916
`
`454
`835
`916
`
`Number of Subjects
`Placebo
`Tolterodine ER
`Fesoterodine
`
`432
`879
`B71
`
`437
`888
`879
`
`437
`882
`879
`
`Number of Subjects
`Placebo
`Tolterodine ER
`FESOtEr0dinC
`
`447
`918
`905
`
`453
`829
`915
`
`413
`833
`915
`
`G
`
`Severe Urgency Episodes per 24 h
`Week
`
`H
`
`Frequency - Urgency Sum per 24 h
`Week
`
`BL 1
`
`4
`
`12
`
`0-0 BL 1
`
`4
`
`12
`
`U E
`
`
`
`H
`
`3
`4
`-
`-5
`
`-2.5
`_1
`ll
`-5.0
`En
`6 “
`5 -7.5
`§
`*2
`\.
`I
`1::
`_
`- .
`E
`\.\X E:
`10 0
`E
`5
`++
`5 -12.5
`.2
`_
`3
`15.0
`-17.5
`
`Number of Subjects
`Placebo
`Tolterodine ER
`Fesoterodine
`
`446
`915
`902
`
`452
`926
`911
`
`452
`930
`911
`
`Number of Subjects
`Placebo
`Tolterodine ER
`Fesoterodine
`
`447
`918
`903
`
`453
`929
`915
`
`453
`933
`915
`
`with the tolterodine ER [P= 0.0005 and
`P: 0.0016] and placebo groups [P< 0.0001
`and P< 0.0001 ; Fig. 3). Categorical changes in
`PPBC and UPS scores were also significantly
`better in the tolterodine ER group vs placebo
`(P = 0.0107 and P = 0.0060].
`
`Compared with the tolterodine ER group, the
`fesoterodine 8 mg group had significantly
`greater improvements at week 12 on the
`OAB-q Symptom Bother scale [P< 0.0001),
`total health-related quality of life [HROL]
`scale [P= 0.0003] and the Concern [P <
`
`0.0001], Coping [P= 0.0004), Sleep [P=
`0.0180] and Social Interaction (P: 0.0117}
`domains [Fig. 4). The fesoterodine group also
`had significantly greater improvements vs
`placebo on the OAB-q Symptom Bother scale
`[P< 0.0001]. HROL scale [P< 0.0001] and the
`
`1436
`
`2510 THE AUTHORS
`EJU INTERNATIONAL © 2015 BJU INTERNATIONAL
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2088 - 0005
`
`

`
`HEAD-T0—HEAD COMPARISON OF FESOTERODINE AND TOLTERODINE Ea
`
`TABLE 2 Median percentage changes in bladder diary variables from baseline
`
`Bladder diary variable
`UUI episodes per 24 h
`Week
`1
`4
`12
`
`Micturitions per 24 h
`Week
`1
`4
`12
`
`Nocturnal micturitions per 24 h
`Week
`1
`4
`12
`
`Urgency episodes per 24 h
`Week
`1
`4
`12
`
`Severe urgency episodes per 24 h
`Week
`1
`4
`12
`
`Placebo
`(n = 462]
`
`-40.3
`-75.0
`-100.0
`
`-7.1
`-13.4
`-18.2
`
`-7.7
`-20.0
`-27.3
`
`-9.4
`-17.2
`-31.0
`
`-19.7
`-41.7
`-61.0
`
`Tolterodine
`
`ER 4 mg
`[n = 942]
`
`-50.0‘
`—38.9*
`—100.0
`
`Fesoterodine
`
`4 or 8 mg§
`(n = 930]
`
`-500+
`—100.0++
`-100.0l'+
`
`-9.4
`-16.7‘
`-20.8‘
`
`-14.3
`-25.0
`-33.3
`
`-12.0
`-26.3‘
`-37.5
`
`-24.1
`-55.6‘
`-69.2
`
`-9.01‘
`-1B.9‘l"l'
`-23.5H'
`
`-12.5
`-2 50+
`-313+
`
`-11.8
`—32.1'l'+
`—45.5H=
`
`-25.0
`-61.1‘l+
`-79.3‘H'
`
`‘P < 0.05 tolterodine vs placebo,‘ +P <0.05 fesoterodine vs placebo,‘ +P < 0.05 fesoterodine vs tolterodine
`ER .§Subjects in the fesoterodine group received fesoterodine 4 mg for the first week and then
`fesoterodine 8 mg for the remaining 11 weeks. ER, extended release; UUI, urgency urinary incontinence.
`Data represent the full analysis set for all subjects reporting the symptom at baseline. P values are based
`on a ranked analysis ofcovariance model, with terms for coun try; treatment and ranked baseline value as
`covariate.
`
`Concern [P< 0.0001], Coping [P< 0.0001].
`Sleep [P= 0.0003] and Social Interaction
`(P: 0.0011) domains. The tolterodine ER
`group reported significantly greater
`improvements vs placebo on the OAB-q
`Symptom Bother [P= 0.0458] and HROL
`[P= 0.0429] scales and the Coping
`(P: 0.0229] domain, but not on the Concern
`(P: 0.0795], Sleep (P: 0.0923] or Social
`Interaction (P: 0.2208] domains.
`
`WEEK 4 OUTCOMES
`
`At week 4. subjects receiving fesoterodine
`8 mg showed significantly greater mean
`improvements vs subjects receiving
`tolterodine ER in UUI episodes (P: 0.0148],
`MW (P: 0.0130], micturitions (P: 0.0186],
`urgency episodes (P: 0.0005). severe urgency
`episodes [P= 0.0071) and frequency-urgency
`
`sum (P: 0.0006], but not nocturnal
`micturitions [P= 0.5906; Fig. 2A—G]. Subjects
`receiving fesoterodine 8 mg also had
`significantly greater improvements in all diary
`endpoints compared to placebo [all P<
`0.0001, except P: 0.0286 for nocturnal
`micturitions]. In the tolterodine ER group,
`improvements in UUI episodes [P= 0.0019],
`MW [P : 0.0002], micturitions (P: 0.0043],
`urgency episodes (P= 0.0054}, severe urgency
`episodes (P: 0.0009] and freq uency-urgency
`sum (P: 0.0034], but not nocturnal
`micturitions (P: 0.0794], were significantly
`greater than in the placebo group.
`
`The median percentage reduction in UUI
`episodes from baseline to week 4 was
`significantly greater in the fesoterodine group
`[—1000io] compared to the tolterodine ER
`[—88.90io; P: 0.0219] and placebo groups
`
`© 2010 THE AUTHORS
`BJU INTERNATIONAL © 2010 BJU lNTEHNAT|ClNAL
`
`(-75.0070; P< 0.0001], as well as in the
`tolterodine ER group vs placebo (P: 0.0038;
`Table 2]. The 3-day diary-dry rates were
`significantly greater for fesoterodine vs
`tolterodine ER [P= 0.0494] and placebo
`[P< 0.0001] at week 4 [Fig. 2B].The difference
`between tolterodine ER and placebo in 3-day
`diary-dry rate was also significant at week 4
`(P: 0.0063].
`
`The categorical change in PPBC and UPS
`scores from baseline to week 4 was
`
`significantly better in the fesoterodine group
`compared to the tolterodine ER (P: 0.0177;
`P: 0.0040] and placebo groups [P< 0.0001
`and P: 0.0002; Fig. 3]. Changes in PPBC score
`in the tolterodine ER group were significantly
`better than in the placebo group (P: 0.0001],
`but the difference between tolterodine ER and
`
`placebo in change in UPS score was not
`significant [P = 0.1485].
`
`WEEK 1 OUTCOMES
`
`At week 1, there were no statistically
`significant differences between subjects
`receiving fesoterodine 4 mg and those
`receiving tolterodine ER for changes in any
`diary variable [all P> 0.05]. Compared to
`placebo, the fesoterodine group had
`significantly greater improvements in UUI
`episodes [P= 0.0006], diary-dry rate
`[P= 0.0008], MW [P = 0.0020]. micturitions
`(P: 0.0161], urgency episodes [P : 0.0374]
`and frequency-urgency sum (P: 0.0136] at
`week 1, but not in severe urgency episodes
`(P: 0.0576] or nocturnal micturitions
`(P: 0.3823]. Differences between the
`tolterodine ER and placebo groups were not
`statistically significant for any bladder diary
`variable (P> 0.05], except for UUI episodes
`(P: 0.0202] and diary-dry rate (P: 0.0024].
`
`Compared to the tolterodine ER group,
`categorical changes in PPBC and UPS scores
`from baseline to week 1
`in the fesoterodine
`
`group did not reach statistical significance
`(P: 0.2817 and P: 0.3713; Fig. 3). However,
`categorical changes in PPBC and UPS scores
`were significantly better in the fesoterodine
`(P: 0.0009 and P: 0.0011] and tolterodine
`ER [P=0.0279 and P: 0.0072] groups at week
`1 compared to placebo.
`
`SAFETY AND TOLERABILITY
`
`Both active treatments were well tolerated
`
`with nine (20r'n], 28 [3010] and 45 (50701 subjects
`in placebo. tolterodine ER and fesoterodine
`
`1437
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2088 - 0006
`
`

`
`[<APLAN ET AL.
`
`I 22-point improvement
`I 1-point improvement
`I No change
`I Deterioration
`A PPBC Week1
`
`Week 12
`
`
`
`PBO TOL ER FESO
`4 "'9 3 “"9
`455 937
`are
`
`
`
`PBO TOL ER FESO
`4mg 8mg
`938
`918
`
`455
`
`20
`0
`Number PBO TOL ER FESO
`°fb_
`4 "'9 4 “"9
`su jects 452
`931
`913
`I Improvement
`I No Change
`I Deterioration
`Week 1
`,,
`
`+
`
`I00
`§ 80
`E; 50
`9 40
`,3
`
`B UPS
`100
`
`69 30
`2:‘ B0
`.3‘;
`U1
`-g 40
`20
`
`
`
`.
`0
`Number PBO TOL ER FESO
`of
`4mg 4mg
`subjects 452
`932
`913
`
`3
`5
`PBO TOL ER FESO
`4mg Bmg
`455 938
`918
`
`.
`PBO TOL ER FESO
`4 ""9 3 “"9
`455 937
`913
`
`Week 4
`
`+ t
`
`‘"'
`
`46
`
`FIG. 3.
`Ca tegarical changes in from
`baseline to weeks 1', 4 and T2 in
`Patient Perception of Bladder
`Condition {A} and Urgency
`Perception Scale {3} scores. Data
`represent the full analysis set.
`Subjects in the Fesoterodine
`group received fesoterodine 4 mg
`for the first week and then
`.
`fesoterodrne 8mg for the
`remaining 17 weeks. FESO,
`fesoterodine;PBO, placebo; PPBC‘,
`Patlent—Perception of Biadder
`Condition,‘ TOL ER, tolteradine
`extended release‘, UPS Urgency
`Perception Scale. “P < 0.03
`tolteradine ER vs placebo,‘
`-rP < 0.002 fesoteradlne vs _
`pI::ceb:‘t-P 23.02 fesoterodme vs
`to tero rne
`.
`
`FIG. 4. Changes from baseline to i2 weeks in
`Overactive Bladder Questionnaire scores. Data
`
`represent the full analysis set. ER, extended release,‘
`HROL, health-related quality oflife; LS leastsquares.
`‘P < 0.05 tolteradine ER vs placebo,‘ +F < 0.007
`fesa teradine vs placebo,’ +P < 0.02 fesateradine vs
`tolteradine ER.
`
`u 30
`325
`E 20
`U
`s ‘5
`u 10
`a s
`
`- Placebo (n = 462]
`— Tolterodine ER [n = 942]
`— Fesoterodine [n = 930]
`‘H:
`+1‘
`*
`
`
`
`to
`\,
`\‘§9<>°& ($3?
`«O41;
`Q»
`
`as,
`
`0
`Q
`‘>212’ (Dan
`éke.
`. \
`8°66
`
`Sggmglrl
`u
`'5
`E‘
`2
`u -15
`s
`u _25
`a
`
`-
`
`during treatment or within 7 days at the
`last dose were reported by seven