Comparison of fesoterodine and tolterodine
`extended release for the treatment of
`
`BUI
`
`IJU INTERNATIONAL
`
`overactive bladder: a head-to-head
`placebo-controlled trial
`
`Sender Herschorn, Steven Swift“. Zhonghong Guani. Martin Car|sson*.
`Jon D. Morrow*. Marina Brodsky" and Jason Gongi
`Surmybrook Health Sciences Centre, Division of Urology, University of Toronto, Toronto, On tario, Canada,
`‘Department of Obstetrics and Gynecology Medical University of South Carolina, Charleston, SC, and *Ptizer inc,
`New York, NY, USA
`Accepted for publication 7 October 2009
`
`
`
`P<0.001}. Improvements in PPBC, UPS
`and OAB-q scale and domain scores at
`week 12 were all significantly better with
`fesoterodine than placebo [all P < 0.001} and
`tolterodine ER (all P< 0.05} except for the
`OAB-q Sleep domain vs tolterodine ER
`[P= 0.081). Dry mouth and constipation
`rates were 28% and 5% in the fesoterodine
`
`group, 16% and 4% in the tolterodine ER
`group. and 6% and 3% with placebo,
`respectively. Discontinuations due to
`treatment-emergent adverse events were
`8%, 401:: and 20/0 in the fesoterodine.
`tolterodine ER, and placebo groups,
`respectively.
`
`CONCLUSION
`
`In patients with OAB, fesoterodine 8 mg
`showed superior efficacy over tolterodine ER
`4 mg and placebo in reducing UUI episodes
`[primary endpoint] and in improving most
`patient-reported outcome measures. Both
`active treatments were well tolerated.
`
`KEYWORDS
`
`fesoterodine, tolterodine, head-to-head,
`patient-reported outcomes, efficacy, safety,
`quality of life
`
`
`voided volume per void (MVV); and the OAB
`questionnaire (DAB-q], Patient Perception of
`Bladder Condition [PPBC], and Urgency
`Perception Scale [UPS]. Safety and
`tolerability were assessed and summarized
`over the 12-week study period.
`
`RESULTS
`
`Fesoterodine [636 patients} significantly
`improved UUI episodes at week 12 [primary
`endpoint} compared with tolterodine ER
`[641 patients; P= 0.017} and placebo
`[313 patients; P< 0.001}. Fesoterodine
`also produced significantly greater
`improvements than tolterodine ER in MW
`IP= 0.005}. Fesoterodine significantly
`improved all diary endpoints compared with
`placebo [P< 0.001], except for nocturnal
`voids (P: 0.327}. Tolterodine ER
`significantly improved all diary endpoints vs
`placebo [P< 0.001], except for nocturnal
`voids (P: 0.506] and MW [P= 0.103}. Diary
`dry rates [the proportion of patients
`reporting no UUI episodes at endpoint
`among those with one or more UUI episodes
`at baseline} were significantly higher with
`fesoterodine [64010] than with tolterodine ER
`(57%; P= 0.015} and placebo [450/o;
`
`
`Study Type - Therapy [RCT}
`Level of Evidence
`lb
`
`OBJECTIVE
`
`To compare the efficacy and tolerability
`of fesoterodine 8 mg with tolterodine
`extended-release [ER] 4 mg and placebo in a
`randomized clinical trial of patients with an
`overactive bladder [0AB}.
`
`PATIENTS AND METHODS
`
`In this 12-week double-blind, double-
`durnmy, placebo-controlled, randomized
`clinical trial. eligible patients reported OAB
`symptoms for 23 months and recorded
`28 voids and 21 urgency urinary
`incontinence [UUI] episode per 24 h in 3-day
`bladder diaries at baseline. Patients were
`randomized in a 2:2:1 ratio to fesoterodine
`
`[4 mg for 1 week then 8 mg for 11 weeks);
`tolterodine ER 4 mg; or placebo [with sham
`dose escalation for tolterodine ER and
`
`placebo]. Endpoints were changes from
`baseline to week 12in UUI episodes [primary
`endpoint], total and nocturnal voids, urgency
`episodes, severe urgency episodes, and
`frequency-urgency sum per 24 h; mean
`
`
`
`
`INTRODUCTION
`
`Antimuscarinic agents are the first-line
`pharmacological treatment for overactive
`bladder IOABI [1]. Fesoterodine is a
`nonselective oral antimuscarinic agentforthe
`
`treatment of OAB symptoms that is rapidly
`and extensively converted by ubiquitous
`esterases to its active metabolite, 5-
`hydroxymethyl tolterodine (5-HMT]. As
`a result, fesoterodine is not detectable
`in plasma after oral dosing and its
`
`antimuscarinic effects are attributable to
`
`5—HMT [2,3]. The pharmacokinetic profile of
`5-HMT is dose-proportional at doses up to
`12 mg [4]. Tolterodine is also converted to
`5-HMT, although this occurs primarily in the
`liver via cytochrome P450 (CYP) 2D6. A
`
`58
`
`(O 2009 THE AUTHORS
`JOURNAL COMPILATION © 2005 BJU INTERNATIONAL I 105, 58-66 I dol:11'.l,111lIj.14E4-410X.200B.0BDE.6.x
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2087 - 0001
`
`

`
`HEAD-T0-HEAD COMPARISON OF FESOTERODINE AND TOLTERODINE Ea
`
`significant fraction of unconverted
`tolterodine is found in plasma [3]. Thus,
`both tolterodine and 5-HlVlT contribute to
`
`antimuscarinic effects in patients who take
`tolterodine [5], and the ratio of tolterodine to
`5-HMT varies depending on the CYP 2D6
`metabolizer status of the patient.
`
`By contrast with tolterodine extended-release
`[ER], for which 4 mg is the one approved dose
`for treatment in the general population of
`patients with OAB [6], fesoterodine is
`available in both 4- and 8-mg once-daily
`doses [7,8]. In two fixed-dose phase III studies,
`fesoterodine 4 and 8 mg significantly
`improved bladder diary variables, including
`micturition frequency, urgency episodes, and
`urgency urinary incontinence [UUI] episodes,
`compared with placebo [9,l0]; a pooled
`analysis showed that fesoterodine 4 and 8 mg
`also significantly improved measures of
`health-related quality of life (HRQL] vs
`placebo [11]. One of the two phase III trials of
`fesoterodine included tolterodine ER as an
`
`active control [9]. A post hoc analysis showed
`statistically significant differences in favour
`of fesoterodine 8 mg over tolterodine ER
`4 mg for UUI episodes as well as mean voided
`volume [MW] per void [12]. However, there
`are currently no data from studies designed
`primarilyto make a head-to-head comparison
`of fesoterodine vs tolterodine ER to assess
`
`whether the higher 8-mg dose of
`fesoterodine provides additional clinical
`benefit compared with the recommended 4-
`mg dose of tolterodine.
`
`Thus the primary objective of the present
`study was to assess whether the efficacy of
`fesoterodine 8 mg is superior to that of
`tolterodine ER 4 mg and placebo in improving
`symptoms of OAB and patient—reported
`outcomes.
`
`PATIENTS AND METHODS
`
`This was a 12-week, randomized, double-
`blind, double-dummy, placebo-controlled,
`parallel group, multicentre trial with a 2-week
`single-blind placebo run-in period. Upon
`completion of the placebo run-in, patients
`who met the entry criteria were randomized
`in a double-blind fashion to fesoterodine
`
`8 mg, tolterodine ER 4 mg, or placebo, in a
`2:2:l ratio. A simple randomization schedule
`with a block size of five was implemented
`using a centralized system. The randomization
`schedule was generated, secured. distributed
`
`and stored by Pfizer Global Clinical Data
`Services; neither the investigator nor the
`patient was aware of which treatment was
`administered.
`
`The USA and European fesoterodine product
`labels recommend a starting dose of
`fesoterodine of 4 mg once-daily, which can
`be increased to 8 mg once-daily based on
`individual response and tolerability [7,8]. In
`the present study, all patients in the
`fesoterodine group started on fesoterodine
`4 mg for 1 week, followed by fesoterodine
`8 mg for 11 weeks. All patients in the
`tolterodine ER group received tolterodine ER
`4 mg capsules for all 12 weeks. A double-
`dummy design was used, with all patients
`receiving one tablet [fesoterodine 4 or 8 mg,
`or matching placebo] and one capsule
`[tolterodine ER 4 mg, or matching placebo)
`daily. Throughout the trial, including the
`placebo run-in and double-blind treatments,
`all medications were taken once daily in the
`morning.
`
`The study was approved by the appropriate
`Institutional Review Boards and Independent
`Ethics Committees. All patients provided
`written informed consent, and the trial was
`conducted in accordance with the protocol,
`International Conference on Harmonization
`
`Good Clinical Practice guidelines, and
`applicable local regulatory requirements and
`laws.
`
`Eligible patients were men and women aged
`218 years, with symptoms of OAB (self-
`assessed] for 23 months before screening and
`a mean of one or more UUI episode,'24 h and
`28 voidsi'24 h reported in 3-day bladder
`diaries completed at baseline. Patients were
`excluded if they had: clinically significant
`hepatic or renal disease; lower genitourinary
`pathology or surgical treatment thereof
`responsible for voiding dysfunction;
`neurological conditions such as stroke,
`multiple sclerosis, spinal cord injury, or
`Parkinson's disease; previous history of acute
`urinary retention requiring catheterization;
`symptoms of incontinence being
`predominately stress Ul in the opinion of the
`investigator; treatment with antimuscarinic
`OAB medication within 2 weeks before
`
`screening; or use of any electrostimulation,
`bladder training, or pelvic floor exercises
`within 4 weeks of screening. Female patients
`of childbearing potential who were
`heterosexually active without using an
`adequate form of contraception, or who were
`
`(9 2009 THE AUTHORS
`JOURNAL COMPILATION © 2005 HJU INTERNATHJNAL
`
`pregnant, nursing, or with a positive urine
`pregnancy test were also excluded.
`
`Patients completed 3-day bladder diaries at
`baseline and week 12. Efficacy endpoints
`corresponded to changes from baseline to
`week 12 in UUI episodes/24 h [primary
`endpoint]; MW,’void; and voids, nocturnal
`voids, urgency episodes, severe urgency
`episodes, and frequency-urgency sum per
`24 h. Patients rated the sensation associated
`
`with each void using the 5-point Urinary
`Sensation Scale [USS; 1, no urgency; 2, mild
`urgency; 3, moderate urgency; 4, severe
`urgency; 5, UUI] [13]. Urgency episodes and
`severe urgency episodes were defined by a
`rating of 23 and 24, respectively, on the USS.
`Frequency-urgency sum, defined as the sum
`of USS ratings associated with all voids over
`the course of 24 h averaged over the diary
`period, is an integrated. validated measure
`reflecting both voiding frequency and
`urgency [14,15] that has been used in several
`recent studies [16—19].
`
`Patients also completed the Patient
`Perception of Bladder Condition (PPBC),
`Urgency Perception Scale [UPS], and DAB
`Questionnaire [DAB-q) at baseline and week
`12. The PPBC is a validated single-item
`questionnaire that asks patients to rate their
`overall bladder condition; lower scores
`indicate less-severe bladder-related problems
`[20]. The validated UPS is a single-item
`instrument with a 3-point, ordered,
`categorical response scale to assess patients’
`perception of urgency; higher scores indicate
`less urgency [21]. The validated OAB-q
`includes an eight-item Symptom Bother scale
`and a 25-item HROL scale [22]. Symptom
`Bother items address the level of bother
`
`associated with the patients bladder
`condition; lower scores indicate less symptom
`bother. The HROL scale comprises four
`domains (Concern, Coping, Sleep, and Social
`Interaction]; higher scores indicate better
`HROL. Each OAB-q scale or domain score is
`transformed so that scores range from 0 to
`‘I00 [22].
`
`Sample size determination was based on the
`previously observed mean {SD} treatment
`difference of 0.44 [2.36] between fesoterodine
`8 mg and tolterodine ER 4 mg groups for
`change in UUI episodesi'24 h from baseline to
`week 12 [9]. A sample size of 606 patients per
`active treatment group was required to detect
`a difference between fesoterodine and
`
`tolterodine ER in the change in UUI episodes
`
`59
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2087 - 0002
`
`

`
`E-IERSCHORN ETAL.
`
`from baseline to week 12 using a two-sided
`t-test at the 50/0 significance level with 90%
`power. Based on the previously observed
`mean [sol treatment differences of1.07 [285]
`between fesoterodine 8 mg and placebo
`groups, and 0.63 [2.81] between tolterodine
`ER 4 mg and placebo groups [9]. 303 patients
`were required in the placebo group for 288%
`power for each comparison. Thus, 1515
`patients were required. Assuming that
`approximately 90% of the randomized
`patients would contribute to the full-analysis
`set, it was planned to randomize 1675
`patients. Tolerability findings were analysed
`descriptively based on the safety-analysis
`set, which included all patients who were
`randomized and took one or more dose
`
`of double-blind study drug. Efficacy was
`analysed using the full-analysis set, which
`included randomized patients who took one
`or more dose of double-blind study drug and
`had one or more valid baseline or postbaseline
`efficacy assessment.
`
`Treatment differences in changes in UUI
`episodesl24 h from baseline to week 12
`(primary endpoint) 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 from placebo was significant. The
`tolterodine ER group was also compared with
`placebo. Numerical and percentage changes
`from baseline for each diary endpoint were
`considered in separate hierarchical order to
`preserve the oz-level of 5010 within each diary
`endpoint. Numerical changes were tested
`first, and percentage changes were tested
`only if the difference in numerical change was
`statistically significant.
`
`The statistical analysis plan specified that all
`bladder diary data were to be tested for
`whether they met the normality assumptions,
`and the appropriate [parametric or
`nonparametric] analytical methods were to be
`used. This assessment, based on whether the
`residuals derived from analysis of covariance
`(ANCOvA] were normally distributed [23],
`revealed that changes in UUI episodes,’24 h
`did not meet normality assumptions, whereas
`other diary endpoints did (Fig. 1]. Thus,
`baseline to week-12 differences in UUI
`
`episodesl24 h are presented as Winsorized
`means, which are less sensitive to outliers in
`the sample distribution tails. while still being a
`robust estimator of the sample mean. The
`Winsorized mean was calculated by replacing
`5% of the sample distribution tails with
`
`60
`
`I. Normality analyses for diary endpoints. Scatter plots of residuals yielded from fits of bladder diary
`FIG.
`data to an ANCOVA model vs quantlles: UUI episodes/24 h (A), MW/void (E), voids/24 h {C}, and urgency
`episodes/24 h (D). Data represent the full-analysis set {placebo 313,‘ tolterodine ER 641; fesoterodlne 636}.
`
`A
`
`UUI episodes
`
`12.5
`100
`15
`so
`25
`0
`-25
`-50
`-7.5
`1
`0
`-4 -3 -2 -1
`Normal Ouantiles
`
`residual
`
`2
`
`3
`
`4
`
`Mean Voided Volume
`
`500
`400
`300
`200
`100
`0
`-100
`-200
`-300
`1
`0
`-4 -3 -2 -1
`Normal Ouantiles
`
`
`
`2
`
`3
`
`4
`
`residual
`
`C
`
`Voids per 24h
`
`residual
`
`1
`0
`-4 -3 -2 -1
`Normal Ouantiles
`
`2
`
`3
`
`4
`
`D
`
`30
`
`Urgency Episodes per 24 h
`
`_
`I'D
`
`:E
`Q
`
`20
`
`10
`
`0
`
`-10
`
`-20
`1
`0
`-4 -3 -2 -1
`Normal Ouantiles
`
`2
`
`3
`
`4
`
`values at the 5th and 95th percentiles.
`respectively. The significance of changes in
`UUI episodes were assessed using the
`nonparametric Van Elteren's test, a stratified
`Wilcoxon-Mann-Whitney test [24,25].
`
`The statistical significance of baseline to
`week-12 changes in other diary endpoints,
`which met the normality assumptions, were
`determined based on an ANCOVA model
`
`including baseline value as a covariate with
`treatment and country as factors. Percentage
`changes from baseline in bladder diary
`endpoints were analysed using ANCOVA, except
`that a ranked score based on ranking of the
`percentage changes was used for the
`dependent variable and a ranked baseline
`value was used as a covariate. The Cochran-
`
`Mantel-Haenszel test stratified by country
`was used for PPBC and UPS data. An ANCOVA
`model was used to assess treatment
`
`differences in OAB-q scale and domain scores
`that included baseline value as a covariate
`
`for PPBC. UPS, and OAB-q data were not pre-
`specified and were conducted post hoc.
`Missing postbaseline data were imputed
`based on the last-observation-carried-
`
`forward principle using data from interim
`visits; baseline data were not carried forward.
`All tests were two-sided based on an or-level
`of 50/0.
`
`R ESU LTS
`
`Of 1712 patients randomized, 1897
`(fesoterodine 679; tolterodine ER 684;
`placebo 334) received one or more dose of
`study medication (Fig. 2). Among these
`patients, 91%, 92% and 88% in the placebo,
`tolterodine ER and fesoterodine groups,
`respectively, completed the study. Site audits
`conducted by an independent quality-
`assurance group revealed irregularities in
`bladder diary data obtained from two sites
`that were in violation of Good Clinical
`
`with treatment and country as factors.
`Statistical comparisons between the
`fesoterodine and tolterodine ER groups and
`between tolterodine ER and placebo groups
`
`Practice guidelines; the patients from these
`two sites [107] were not included in the
`efficacy analyses. This decision was made
`before the database unblinding and was
`
`(9 2009 THE AUTHORS
`JOURNAL COMPILATION © 2005 BJU INTERNATIONAL
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2087 - 0003
`
`

`
`HEAD-T0-HEAD COMPARISON OF FESOTERODINE AND TOLTERODINE Ea
`
`FIG. 2. Patient disposition. FA5 = full analysis set; TEAES {on y cause}. "lncluo‘es protocol violation, not meeting
`entrance criteria, and other reasons.
`
`documented in the final statistical analysis
`plan. A sensitivity analysis showed that
`excluding these patients from the analysis of
`the primary endpoint did not affect the result.
`
`Baseline demographic and clinical
`characteristics were similar among the
`placebo, tolterodine ER and fesoterodine
`groups (Table 1}. Overall, approximately 80%
`were women, 78% were white, and the mean
`age of patients was approximately 58 years.
`The mean OAB symptom duration was
`approximately 7 years, and about half of the
`patients had previously used antimuscarinics.
`Ofall patients, approximately 1% reported no
`UUI episodes during the 3-day diary period at
`baseline and were in violation of the study
`inclusion criterion. These patients were
`included in the safety and efficacy analyses
`with two relevant exceptions: they were
`excluded from the analyses of baseline to
`week 12 changes in UUI episodes,l24 h and of
`the diary-dry rates (see below).
`
`The mean reduction in the number UUI
`
`episodes;'24h (primary endpoint) was
`significantly greater from baseline to week
`12 in the fesoterodine group than with
`tolterodine ER [P= 0.017} or placebo
`(P< 0.001; Fig. 3A]. Tolterodine ER also
`
`produced a significantly greater improvement
`in UUI episodes than placebo [P= 0.011}.
`
`The median percentage reduction in UUI
`episodes in both the fesoterodine (100%)
`and tolterodine ER (100%) groups was
`significantly greaterthan the 82.1% reduction
`in the placebo group (both P< 0.001 ;Table 2].
`These data indicate that half or more of
`
`patients in the fesoterodine and tolterodine
`ER groups who had at least one UUI episode
`in the baseline diary reported no UUI episodes
`in bladder diaries at week 12; however, the
`statistically significant difference between
`these active treatment groups indicated that
`one group had a greater proportion of
`patients without UUI episodes at week
`12 [P= 0.022]. To assess the relative
`improvements in UUI episodes in the two
`active treatment groups, a post hoc analysis
`was used to determine the diary-dry rate,
`defined as the proportion of patients in each
`treatment group reporting one or more UUI
`episodes during the baseline diary period
`who reported no UUI episodes during the
`subsequent diary period; patients with
`no UUI episodes at baseline. constituting
`approximately 1% of study population. were
`not included in this analysis. The diary-dry
`rate at week 12 was significantly greater for
`patients receiving fesoterodine (64.0%, 396,’
`
`(9 2009 THE AUTHORS
`JOURNAL COMPILATION © 2005 BJU INTERNATHJNAL
`
`619] than for those receiving tolterodine ER
`(57.20/‘co, 358l626; P= 0.015) or placebo
`(45.00/o, 138l307; P< 0.001). The difference
`between tolterodine ER and placebo in diary-
`dry rate at week 12 was also significant
`(P< 0.001).
`
`Fesoterodine produced a significantly greater
`increase in MW/void from baseline to week
`12 than tolterodine ER (P= 0.005) or placebo
`(P<0.001; Fig. 3B). Compared with placebo,
`fesoterodine also significantly reduced voids
`(Fig. 3C], urgency episodes (Fig. 3E}, severe
`urgency episodes (Fig. 3F], and frequency-
`urgency sum (Fig. 3G; all P< 0.001] per 24 h
`vs placebo, but not nocturnal voids,l'24 h
`(Fig. 3D; P= 0.327]. The differences between
`fesoterodine and tolterodine ER on
`
`micturitions [P= 0.380), urgency episodes
`[P= 0.054], severe urgency episodes
`(P=0.139]. and frequency-urgency
`sum [P= 0.105] per 24 h were numerically
`in favour of fesoterodine but not statistically
`significant. Compared with placebo,
`tolterodine ER produced significantly greater
`baseline to week 12 improvements in voids
`(P< 0.001], urgency episodes (P< 0.001],
`severe urgency episodes (P< 0.001) and
`frequency-urgency sum (P< 0.001) per 24 h,
`but not MW [P= 0.103) or nocturnal voids,l
`24 h [P= 0.506]. Median percentage changes
`in bladder diary variables are presented in
`Table 2.
`
`The categorical change in PPBC score from
`baseline to week 12 [classified as a 22-point
`improvement. 1-point improvement, no
`change, or deterioration], was significantly
`more favourable in the fesoterodine group
`than in patients on placebo (P<0.001] and
`tolterodine ER (P< 0.001, post hoc statistical
`comparison]. Changes in the tolterodine ER
`group were also significantly more favourable
`than in the placebo group (P< 0.001, post hoc
`statistical comparison; Fig. 4). Consistent with
`this, the proportion of patients reporting
`‘some minor problems‘ or better on the PPBC
`at week 12 was higher in the fesoterodine
`group (55%) than in the tolterodine ER (45%,
`P< 0.001) and placebo (33%, P< 0.001]
`groups. The difference between the
`tolterodine ER and placebo groups was also
`statistically significant (P< 0.001].
`
`The categorical change in UPS score
`from baseline to week 12 (classified as
`improvement, no change, or deterioration)
`was significantly more favourable for
`fesoterodine than placebo (P< 0.001] and
`
`61
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2087 - 0004
`
`

`
`Placebo
`334
`
`269 [81]
`58.4 (13.7, 20435]
`
`251 (75)
`32 (10)
`11 (3)
`30 (9)
`7.3 (03-522)
`329 (99)
`
`Tolterodine ER
`684
`
`564 [E13]
`58.5 (13.2, 18—92)
`
`534 (75)
`71 (10)
`22(3)
`57(5)
`5.9 (02-505)
`572 (95)
`
`Fesoterodine
`679
`
`558 [82]
`518 (12.8, 19—8B)
`
`539 (79)
`57 (10)
`23 (3)
`50(7)
`7.1 (0.3—55.2)
`555 (95)
`
`2.6 (2.3]
`11.9 (3.5)
`2.3 (1.3l
`9.4 (4.21
`5.7 (3.6)
`147.9 [583]
`41.0 (14.3)
`
`2 (1)
`10(3)
`21 (7)
`97 (31)
`133 (43)
`50 [16]
`
`131 (42)
`159 (54)
`13 (4)
`
`55.9 (19.0)
`55.0 (22.5)
`52.4 (25.0)
`45.2 (25.3)
`55.0 (25.1)
`74.4 (24.4)
`
`2.5 (2.2)
`11.7 (3.4)
`2.2 (1.3)
`9.3 (3.7)
`5.9 (3.5)
`154.1 (54.5)
`40.5 (13.5)
`
`5(1)
`17 (3)
`35(5)
`235 (37)
`243 (351
`94 (15)
`
`233 (371
`351 (50)
`19 (3)
`
`55.5 (19.5)
`55.5 (22.2)
`51.5 (25.7)
`45.0 (25.2)
`54.4 (25.5)
`74.5 (23.5)
`
`2.4 (2.0)
`11.7 (3.1)
`2.2 (1.3)
`9.3 (3.9)
`5.9 (3.7)
`155.3 (51.5)
`40.4 (13.4)
`
`2 (<1)
`15(3)
`52 (5)
`225 (35)
`237 (35)
`95 (15)
`
`227 (35)
`371 (59)
`32 (5)
`
`57.5 (20.3)
`55.4 (22.1)
`54.5 (25.3)
`52.2 (25.1)
`55.5 (25.4)
`75.5 (23.1)
`
`EIERSCHORN ETAL.
`
`TABLE 1 Baseline demographic and clinical characteristics’
`
`Mean (SD), Mean (SD, range), or
`n ('3/0] variable
`No. of patients
`Gender; women
`Age, years
`Race
`White
`Asian
`Black
`Other
`OAB duration, years
`Patients with 21 UUI episode during the 3-day diary at baseline
`Bladder diary variables
`UUI episodes)'24 h
`Total voids,'24 h
`Nocturnal voids)'24 h
`Urgency episodesl24 l1
`Severe urgency episodes)'24 h
`MVVivoid, mL
`Frequency-urgency sum,'24 h
`PPBC
`
`Not many problems at all (1)
`Some very minor problems [2]
`Some minor problems [3]
`Some moderate problems (4)
`Severe problems (51
`Many severe problems (6)
`UPS+
`
`1 2 3
`
`OAB-q
`Symptom Bother
`Total HRCLL
`Concern
`
`Coping
`Sleep
`Social Interaction
`
`“Demographic data represent the safety set,‘ baseline diary variable data represent the full analysis set (placebo, 313,‘ tolterodine ER, 641,‘ fesoterodine, 636} for
`all patients reporting the symptom at baseline;patient-reported outcome data represent the full analysis set. fl, Notable to hold urine. 2, Able to hold urine
`(without leaking) untiil reach 0 toilet immediately: 3, Able to finish the ongoing work before going to the toilet (without leaking}.
`
`tolterodine ER [P= 0.014, post hoc statistical
`comparison} groups (Fig. 5); the difference
`between the tolterodine ER and placebo
`groups was not statistically significant
`(P= 0.167, post hoc statistical comparison).
`The proportion of patients who reported 'I am
`usually able to finish what I am doing before
`going to the toilet (without leaking)’ at week
`12 was higher in the fesoterodine group
`(31%) than with tolterodine ER (23%,
`P= 0.002] or placebo (15%, P< 0.001]
`groups. The difference between the
`
`tolterodine ER and placebo groups was also
`statistically significant (P= 0.003].
`
`Improvements in GAB-q scores from baseline
`to week 12 were significantly greater in the
`fesoterodine than the placebo group on the
`Symptom Bother scale, total HROL scale,
`and all four HRQL domains (all P<0.001].
`In a post hoc statistical comparison,
`improvementsfrom baseline to week 12 in the
`fesoterodine group were also significantly
`greater than in the tolterodine ER group on
`
`the Symptom Bother (P< 0.001) and total
`HROL (P= 0.006) scales and the Concern
`(P= 0.008], Coping (P= 0.002], and Social
`Interaction (P= 0.019] domains, but not
`on the Sleep domain (P= 0.081; Fig. 6].
`Also in a post hoc statistical comparison,
`improvements from baseline to week 12 in the
`tolterodine ER group were significantly
`greater than in the placebo group on the
`OAB-q Symptom Bother [P< 0.001} and total
`HROL (P= 0.002] scales, and the Concern
`(P<0.001l, Coping (P= 0.004) and Social
`
`62
`
`(9 2009 THE AUTHORS
`JOURNAL COMPILATION © 2005 BJU INTERNATIONAL
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2087 - 0005
`
`

`
`HEAD-T0-HEAD COMPARISON OF FESOTERODINE AND TOLTERODINE Ea
`
`FlG. 3. Change from baseline to week 12 in UUlepisodes/24 h {A}, MW/void (3), total voids/24 h {C}, nocturnal
`voids/24 h {D}, urgency episodes/24 h {E}, severe urgency episodes/24 h (F), and frequency—urgencysum/24 h
`(G). Error bars represent the SEM. Data represent the full-analysis set for patlen ts reporting symptoms at
`baseline (except for voids/24 h and frequency- urgencysum). ‘P < 0.05 vs placebo; tP < 0.05 fesoterodlne vs
`tolterodine ER.
`
`FlG. 4. Baseline to 1'2 week changes in PPBC‘.
`Data represent the full—analys1's set. ‘P < 0.001
`fesoterodine vs placebo; 1‘P < 0.007 fesoterodlne vs
`tolteraa'ine ER {post hoc comparison}; +P -: 0.001
`tolterodine vs placebo {post hoc comparison}.
`
`UUI Episodes per 24 h
`
`I Placebo
`I Tolterodine ER
`I Fesoterodine
`
`A
`
`0
`
`g
`5: -0.5
`E
`U
`
`E
`2 ‘l -0
`-5
`E
`E
`§
`
`
`-10
`307
`626
`6119
`|'l=
`
`B
`
`u
`3"
`
`35
`
`30
`
`25
`
`g 20
`.=
`E
`1 5
`2
`g 10
`5
`0
`n
`
`MW per void
`
`‘t
`
`=
`
`313
`
`633
`
`626
`
`‘I00
`
`80
`
`O
`5‘. so
`J5
`E 40
`E
`
`2o
`0
`
`I 22-point Improvement
`I 1-point Improvement
`I No Change
`I Deterioration
`
`1.
`
`*1-
`
`Placebo Tolterodine ER Fesoterodine
`
`C
`
`Voids per 24 h
`
`D
`
`0
`
`Nocturnal Voids per 24 h
`
`" = 313
`
`n = 641
`
`n = 636
`
`
`
`2 5
`- -
`n:
`
`313
`
`'
`534
`
`.
`523
`
`Urgency Episodes per 24 h
`
`U
`E
`5
`
`E 3
`
`E
`
`E
`
`0
`
`-0-5
`c
`g -1
`g -1-5
`=
`0
`‘2
`E
`Z.‘
`
`‘2-5
`_3
`
`*
`
`-3.5
`n=
`
`311
`
`531
`
`523
`
`G
`
`F'°°l”°”°V ‘ U'9°”°V 5”“ 9°’ 24 h
`0
`_2
`
`§ -4
`jg
`-6
`E _8
`g
`3]
`
`-10
`-12
`
`4::
`
`311
`
`_
`631
`
`553
`
`© 2on9 THE AUTHORS
`JOURNAL COMPILATION © 2005 BJU INTERNATIONAL
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2087 - 0006
`
`3
`E
`1'; .05
`E
`g
`
`FIG. 5. Baseline to l2 week changes in UPS scores.
`
`Data represent the full—analys1's set. ‘P < 0.001
`fesoterodine vs placebo; +P - 0.014 fesoterodlne
`vs tolterodine ER (past hac comparison). The
`tolterodine ER vs placebo comparison was not
`significant {P = 0. 167}.
`
`1 0
`- -
`n=
`
`293
`
`595
`
`501
`
`Severe Urgency Episodes per 24 h
`0
`
`F
`
`-0.5
`g -1.0
`g -1.5
`E
`3 -2.0
`2
`3 -2.5
`
`-10
`_3 5
`n:
`
`‘
`630
`
`.
`625
`
`311
`
`I Improvement
`I No change
`ID t
`'
`t‘
`E Ema '°"
`
`1*
`
`100
`
`so
`
`60
`
`E‘
`5‘: 40
`20
`
`Placebo Tolterodine ER Fesoterodine
`n=313
`n=64I
`n=536
`
`Interaction (P: 0.029) domains, but not on
`the Sleep domain [P= 0.052]. For all
`treatment groups. least squares mean
`changes in all scale and domain scores from
`baseline to week 12 exceeded the minimally
`important difference of 10 points. which is
`the smallest change in score that is clinically
`meaningful [26], except for Social Interaction
`domain scores forthe placebo [$3.8 pointsland
`tolterodine ER [9.4 points] groups.
`
`Both fesoterodine and tolterodine ER were
`well tolerated with few patients discontinuing
`
`63
`
`

`
`TABLE 2 Median percentage changes in bladder diary variables from baseline to week 12"
`
`Variable
`
`No. of patients
`UUI episodesi'24 h
`Total voidsl24 h
`Nocturnal voidsi'24 h1
`Urgency episodesi'24 h
`Severe urgency episodes.l24 h
`
`Placebo
`
`313
`-32.1
`-12.1
`-25.0
`-17.6
`-48.0
`
`Tolterodine ER
`641
`-1001‘
`- 1 6.2+
`-27.9
`—30.8+
`-63.4-+
`
`Fesoterodine
`636
`—100‘I"I'
`- 1 3.9+
`-28.6
`-3 7.9+
`-71.41-
`
`“Data represent the full analysis set. +P < 0.05 vs placebo; 1*P < 0.05 vs tolterodine ER. 1lnferential
`analysis was notdone because the differences in the mean numerical change from baseline to week 1'2
`were not statistically significant.
`
`FIG. 6. Baseline to 1'2 week changes in OAB—q scores. Data represent the full—ancrlysis set (placebo, 313,‘
`tolterodine ER, 541,- fesoterodine 535}. ‘P <0.00I fesoterodine vs placebo; tP <0.02 fesoterodine vs
`tolterodine ER {post hoc comparison); +P < 0.05 tolterodine ER vs placebo {post hoc comparison).
`
`Symptom Bother
`0
`
`-5
`
`.E
`U
`I
`E -10
`E
`3% -15
`
`§ -20
`w
`5 -25
`El
`
`
`
`-3° *
`
`*+
`
`I Placebo [r1 =313}
`*1. I Tolterodine ER [n = 641}
`Z Fesoterodine (11: 535)
`
`‘
`
`
`
`Total
`HROL
`
`Concern
`
`.
`Coping
`
`Sleep
`
`.
`Social
`Interaction
`
`25
`
`c
`D
`= 20
`E
`E
`0.!
`ft’ ‘5
`
`5 0
`E
`E 5
`9
`
`0
`
`Variable
`
`Placebo
`
`Tolterodine ER
`
`Fesoterodine
`
`TABLE 3
`
`No. of patients
`TEA}-j5_ qro
`Dry mouth
`Hgadachg
`constipation
`un
`Diarrhoea
`
`334
`
`684
`
`5.0
`2,4
`3,0
`(15
`1.2
`
`15.4
`3_4
`4,1
`1_5
`2.2
`
`579
`
`27.3
`5_5
`5,4.
`22
`2.1
`
`Tilt -‘"053-C0mm0m'V
`reported TEAES {all cause),
`reported by22%porientsin
`the safety set in either
`active treatmentgroup with
`higher incidence than
`placebo
`
`Interaction domains of the GAB-q. These
`findings are consistent with a post hoc
`analysis of data from a phase III trial of
`fesoterodine that included tolterodine ER as
`
`an active control [9], which showed that
`fesoterodine 8 mg was significantly more
`effective than tolterodine ER 4 mg on several
`endpoints, including UUI episodes, MW, and
`continent days,'week_ In the present study.
`improvements in voids, urgency episodes,
`
`severe urgency episodes, and frequency-
`urgency sum,'24 h did not differ significantly
`between fesoterodine and tolterodine ER
`
`groups. However, improvements in all ofthese
`variables were numerically in favour of the
`fesoterodine group. A possible explanation for
`the lack of statistically significant differences
`in these diary variables might be that the
`study was powered to assess differences
`between treatment groups in baseline to week
`
`(9 2009 THE AUTHORS
`JOURNAL COMPILATION © 2005 BJU INTERNATIONAL
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2087 - 0007
`
`E-IERSCHORN ETAL.
`
`during the study due to adverse events (AE5).
`Among these patients, six [2°io) receiving
`placebo, 28 [4010] receiving tolterodine ER, and
`42 l6%] receiving fesoterodine, discontinued
`due to treatment-emergent AES [TEAEs) of
`any cause. The most frequently reported
`TEAEs in the fesoterodine group were
`dry mouth (28%), headache (60/21) and
`constipation (5%; Table 3). These were also
`the most frequently reported TEAEs in the
`tolterodine ER group, with rates of 16%, 30/0
`and 4%, respectively. In the placebo group,
`the rates were 60/0, 20/0 and 3%, respectively.
`The large majority of all AEs, including
`dry mouth, were mild or moderate in all
`treatment groups. Dry mouth was reported as
`Severe by two [10io}. seven [1010] and 14 (2%)
`patients in the placebo, tolterodine ER, and
`fesoterodine groups, respectively.
`
`There were four fatal serious AES during the
`course of the study, including two in the
`placebo and two in the fesoterodine groups:
`these deaths were all reported as unrelated to
`study treatment. Non-fatal serious AEs
`occurring during treatment or within 30 days
`of the last dose were reported by six (2%),
`nine [1010] and 16 [20lo) of patients in the
`placebo, tolterodine ER and fesoterodine
`groups, respectively. None of the serious AEs
`reported in the placebo or tolterodine ER
`groups were considered to be treatment-
`related. Two serious AEs reported in the
`fesoterodine group were considered to be
`treatment-related. One of these patients, a
`70-year-old man with a history of benign
`prostatic enlargement and elevated PSA
`levels, developed urinary retention after
`6 days of treatment with fesoterodine 4 mg
`and required catheterization.
`
`DISCUSSION
`
`This is the first head-to-head trial with the
`
`primary objective of assessing the superiority
`of fesoterodine over tolterodine ER for the
`
`treatment of DAB symptoms. Compared
`with tolterodine ER, fesoterodine showed
`significantly greater efficacy in reducing UUI
`episodes, the primary endpoint, and in
`increasing bladder capaci