Female Urology
`
`Randomized, Double-blind, Placebo-controlled
`Trial of Flexible-dose Fesoterodine
`
`in Subjects With Overactive Bladder
`
`Roger R. Dmochowski, Kenneth M. Peters, Jon D. Morrow, Zhonghong Guan,
`Jason Gong, Franklin Sun, Paul Siami, and David R. Staskin
`
`OBJECTIVES
`
`METHODS
`
`RESULTS
`
`CONCLUSIONS
`
`To evaluate the efficacy and tolerability of flexible-dose fesoterodine vs placebo in subjects with
`overactive bladder (OAB).
`ln a I2—week double-blind trial, subjects were randomized to fesoterodine 4 mg or placebo once
`daily. taken within 4 hours of bedtime. At week 2, subjects could increase the fesoterodine dose
`to 8 mg (sham escalation for placebo). Subjects completed 3-day bladder diaries, Patient
`Perception of Bladder Condition, and Urgency Perception Scale at baseline and weeks 2, 6, and
`12 as well as OAB Questionnaire at baseline and week 12.
`Of 883 subjects, 63% and 73% of the fesoterodine (n = 438) and placebo (n = 445) groups,
`respectively, opted for dose escalation. Week 12 improvements from baseline in total micturi«
`tions, urgency episodes, urgency urinary incontinence episodes, frequency-urgency sum, and all
`OAB Questionnaire scales and domains, but not nocturnal micturitions or nocturnal urgency
`episodes, were significantly greater with fesoterodine than placebo (all P <05). Treatment
`differences in micturitions and frequencymrgency sum were significant by week 2 and in urgency
`urinary incontinence and urgency episodes by week 6. Significantly greater percentages of
`subjects taking fesoterodine had improved Patient Perception of Bladder Condition and Urgency
`Perception Scale scores at weeks 2, 6, and 12 (P <.O5). Dry mouth (fesoterodine, 26%; placebo,
`8%) and constipation (fesoterodine, 11%; placebo, 6%) were the most common adverse events.
`In both groups, 87% of the subjects completed the trial; 8% and 5% of the fesoterodine and
`placebo groups, respectively, discontinued because of an adverse event.
`Flexible-dose fesoterodine was efficacious and generally well tolerated for treatment of OAB
`symptoms. UROLOGY 75: 62-68. 2010. © 2010 Elsevier Inc.
`
`veractive bladder (OAB) is defined as urgency,
`
`Owith or without urgency incontinence. usually
`
`with increased daytime frequency and nocturiad
`Approximately 13%—17% of adults have OAB, with
`prevalence increasing with age.“ OAB can considerably
`impair health—related quality of life (HRQL).5
`Antimuscarinics are the principal pharmacologic tneatment
`for DAB, but patient response and ability to tolerate these
`drugs can vary.6 Fesoterodine is an antimuscarinic developed
`for treating OAB symptoms and is available as 4- or 8-mg
`tablets given once daily. Fesoterodine is rapidly and extensively
`converted by ubiquitous esterases to its primary metabolite,
`
`Pfizer, inc. Roger R. Dmochowski, Kenneth M. Peters, Paul
`This study was‘ fumled
`Simni. and DLll'i£i R, Sluikiii rm’ fluid t'miml:Ln1:s for Pfizer.
`lnc. mid Jon Morrow,
`Zhnnghong Gum. and Franklin Sun are empioyees of Pfizer, inc.
`From lire Vuriderbili L'niversiiy Medicai Center, Nashville, Tennessee; Wiiiirirn
`Beaumont Hospitrii, Royal Oak, Michigan; Pfizer inc, New Yrrrk, New Yorlc: Den»
`coness Clinic, Evansville, Indiana; and Tufts l_.li"li1.'L'TSll“)' School of Medicine, Boston,
`Nl(LV.\‘a&‘f1v£.\‘(‘li.\‘
`Reprint requests: Roger Dmocliowski, M.D., Department of Urology, Vumierlziit
`lfiniuers-in‘ Mciiicul Center, Rmnn A #302, Medical Center Nm‘[l1, Niishviile, TN
`57232. E—mo::'l: mger.dn1ochowski@vanderbi!t.edu
`Sul')1'nirir:aUuiy Z, 2009, u.cL'eplecl (with reuisitins): Sr:j>re1nlar:r 5, 2009
`
`62
`
`© 2010 Elsevier Inc.
`
`All Rights Reserved
`
`5—l’1yClt'oxymetl'1yl tolterodine (5-1-IMT); 5—HMT alone is re-
`sponsible for the antimuscarinic effects of fesoterodine.
`Tolterodine is also converted to 5—l-IMT, albeit by cytochrome
`P450 (CYP) ZD6, primarily in the liver.-" In patients taking
`tolterodine, both tolterodine and 5-HMT produce antimusca-
`rinic effects.
`
`The efficacy and safety of fesoterodine 4 and 8 mg were
`demonstrated in 2 fixed-dose 12-week phase III trials.8‘9
`Pooled data from these studies indicate that treatment of
`
`OAB symptoms with fesoterodine improves HRQL out-
`comes.” However, flexible closing reflects clinical prac«
`tice better than fixed closing. The recommended starting
`dose of fesoterodine is 4 mg once daily, which can be
`increased to 8 mg based on patient response and toleraa
`bility.” This phase Illb study assessed the efficacy, safety,
`and tolerability of a flexible—dose regimen of fesoterodine
`in subjects with OAB.
`
`MATERIAL AND METHODS
`
`flexible-
`This randomized, double-blind, placebo-controlled.
`dose trial of fesoterodine was conducted from August 2007 to
`
`0090-4295/10/$34.00
`doi:10.1016/j.urology.2009.09.018
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2079 - 0001
`
`

`
`April 2008 at 88 sites in the United States. The study protocol
`was approved by the appropriate institutional review boards,
`and all subjects provided written informed consent. The study
`was conducted in accordance with the Declaration of Helsinki
`
`and the International Conference on Harmonisation guidelines
`on Good Clinical Practice.
`
`Men and women aged 218 years were eligible if they re-
`ported OAB symptoms for 23 months before screening, re-
`corded a mean of 28 micturitions per 24 hours and 23 urgency
`episodes per 24 hours in a 3—day bladder diary at baseline, and
`rated their bladder condition at baseline as causing at least some
`moderate problems using the Patient Perception of Bladder
`Condition (PPBC).” Key exclusion criteria were a history of
`acute urinary retention requiring catheterization, severe voiding
`difficulties in the judgment of the investigator, urinary incon-
`tinence symptoms attributed by the investigator primarily to
`stress urinary incontinence, significant pelvic organ prolapse or
`lower urinary tract surgery within the preceding 6 months,
`clinically significant hepatic or renal diseases. neurologic dis-
`ease that significantly affected bladder function. treatment with
`an antimuscarinic OAB medication or potent CYP3A4 inhib-
`itor within 2 weeks of screening, and any contraindication to
`fesoterodine. Also excluded were men with intermittent or
`
`unstable use of alpha blockers or 5—alpha reductase inhibitors
`(consistent use was permitted) or who started such treatment
`within 4 weeks of screening.
`On the basis of previous studies,8'9 it was calculated that a
`sample size of 350 subjects per arm would provide 285% power
`to detect a difference between fesoterodine and placebo in
`24-hour micturitions using a 2-sided E test with a .05 signifi-
`cance level.
`
`Subjects completed a 2-week screening period during which
`no treatment was given, followed by 12 weeks of treatment.
`Subjects meeting eligibility criteria were randomized in a 1:1
`ratio, with no blocking, to fesoterodine 4 mg or placebo taken
`once daily within 4 hours of bedtime. Randomization was
`implemented using a centralized system accessed by phone or
`Internet that generated single subject identification and ran-
`domization numbers, both of which were to be entered on the
`electronic case report form. The randomization schedule was
`generated, secured, distributed, and stored by Pfizer Global
`Clinical Data Services; neither the investigator not subject was
`aware of the treatment administered.
`
`At the end of week 2, after subjective consultation with the
`investigator regarding efficacy and tolerability, subjects could
`Choose to increase the fesoterodine dose to 8 mg once daily for
`the remaining 10 weeks (for placebo, sham dose escalation). No
`dose adjustments were permitted after week 2.
`
`Efflcacy Assessments
`Subjects completed bladder diaries for 3 consecutive days im-
`mediately before the baseline visit and each subsequent visit
`(weeks 2, 6, and 12). Subjects recorded all micturitions, includ—
`ing incontinence episodes, and rated the sensation associated
`with each micturition using the Urinary Sensation Scale, with
`ratings ranging from 1 (no feeling of urgency) to 5 (unable to
`hold; leaked urine)” Urgency episodes were those rated 23;
`severe urgency episodes were those rated 24. Frequency—ur—
`gency sum (a composite measurement of urgency and fre-
`quency) was defined as the total of Urinary Sensation Scale
`ratings for all micturitions.
`Subjects completed the validated PPBC” and urgency per—
`ception scale (UPS)l4 at baseline and weeks 2, 6, and 12. On
`
`the PPBC, subjects rate their bladder—related problems on a
`scale from 1 (does not cause me any problems at all) to 6 (causes
`me many severe problems). On the UPS, subjects rate the
`urgency associated with their typical urination experience as 1
`(usually not able to hold urine), 2 (usually able to hold urine
`until reaching a toilet if I go immediately), or 3 (usually able to
`finish what l am doing before going to the toilet). Subjects
`completed the validated Overactive Bladder Questionnaire
`(OAB—q)15 at baseline and week 12. lncreases in OAB—q total
`HRQL and domain scores indicate improved HRQL; increases
`in Symptom Bother scores indicate increased bother. The min-
`imally important difference (the least change considered clin-
`ically meaningful) is lO points for all OAB—q scales and do-
`mains. 1 6
`
`Safety Assessments
`All adverse events (AE5). either reported by the subject or
`observed by the investigator, were recorded, as was the inves-
`tigator's opinion of whether the event was treatment related.
`Blood pressure and heart rate were recorded at each visit.
`
`Statistical Analysis
`Efficacy analyses were performed using data from the full anal-
`ysis set (subjects who took Bl dose of study drug and had 21
`baseline or postbaseline efficacy assessment). Safety analyses
`were performed using data from the safety analysis set
`(all
`subjects who took 21 close of study drug). Data from all subjects
`given fesoterodine were compared as a group with data from all
`subjects given placebo;
`the statistical analysis plan did not
`provide for stratification of subjects by final dose.
`The primary endpoint was the change from baseline to week
`12 in mean number of micturitions per 24 hours; analysis of
`covariance (ANCOVA) was used to assess treatment differ-
`ences. The ANCOVA model included treatment, center, and
`baseline value as a covariate. Changes from baseline in be-
`tween—treatment differences were estimated using least squares
`means, and treatments were compared using a Z—sided F test at
`the 5% significance level. Missing data at weeks 6 and 12 were
`inputed using last observation carried forward.
`Secondary endpoints included changes in other bladder diary
`variables and the OAB—q as well as the proportion of subjects
`reporting improvement on the PPBC and UPS. Bladder diary
`variables, with the exception of nocturnal micturitions and
`nocturnal urgency episodes, and OAB—q data were analyzed
`using an ANCOVA model similar to that used for the primary
`endpoint. Treatment differences for nocturnal micturitions and
`nocturnal urgency episodes were analyzed using analysis of
`variance because there was a significant qualitative baseline by
`treatment interaction (ie, the treatment effect reversed direc-
`tion at a given baseline value); the ANCOVA model is not
`valid in this situation. Percentage change for bladder diary
`variables was analyzed using ranked ANCOVA, with ranked
`percentage change as the response and terms for treatment,
`center, and ranked baseline value in the model. Categorical
`analyses for PPBC and UPS data were conducted using the
`Cochran—Mantel—Haenszel test adjusting for center. The PPBC
`data were categorized as a 22-point
`improvement, 1-point
`improvement, no change, or deterioration from baseline. The
`UPS data were categorized as improvement, no change, or
`deterioration from baseline.
`
`UROLOGY 75 (1), 2010
`
`63
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2079 - 0002
`
`

`
`RESULTS
`
`Table 1. Baseline demographic and clinical characteristics*
`
`Placebo
`(n = 445)
`
`Fesoterodine
`(n = 438)
`
`368 (83)
`77 (17)
`
`364(83)
`74(17)
`
`60.1 (12.9)
`22-88
`
`59.7 (13.7)
`22-100
`
`389 (87)
`40 (9)
`4 (1)
`12 (3)
`312 (85)
`260 (58)
`234 (64)
`26 (34)
`
`388 (89)
`38 (9)
`3(1)
`9 (2)
`281 (77)
`257 (59)
`231 (64)
`26 (35)
`
`13.0 (3.8)
`9.2 (4.3)
`2.2 (2.7)
`39.9 (15.0)
`2.7 (1.5)
`2.2 (1.4)
`
`12.8(3.8)
`9.2 (3.8)
`2.0(1.9)
`39.4 (13.4)
`2.6 (1.5)
`2.2 (1.4)
`
`O 0
`
`1 (<1)
`211 (49)
`
`164 (38)
`59 (14)
`
`0
`0
`
`1 (<1)
`207 (47)
`
`170 (39)
`64 (15)
`
`128 (29)
`298 (67)
`17 (4)
`
`126 (29)
`286 (66)
`23 (5)
`
`58.5 (18.2)
`54.7 (22.0)
`49.0 (25.2)
`50.3 (26.0)
`47.0 (27.4)
`76.9 (23.9)
`
`58.9 (18.3)
`53.3 (21.6)
`46.9 (24.3)
`43.7 (25.5)
`47.6 (26.7)
`75.4 (24.1)
`
`Sex, n (%)
`Female
`Male
`Age. 3!
`Mean (SD)
`Range
`Race, n (%)
`White
`Black
`Asian
`Other
`Postmenopausal, n (%)1
`UUI episodes >0, n (%)
`Female
`Male
`Bladder diary variables,
`mean (SD)/24 h
`Micturitions
`Urgency episodes
`UUI episodes
`Frequency—urgency sum
`Nocturnal micturitions
`Nocturnal urgency
`episodes
`PPBC, n (%)
`1 (No problems at all)
`2 (Some very minor
`problems)
`3 (Some minor problems)
`4 (Some moderate
`problems)
`5 (Severe problems)
`6 (Many severe
`problems)
`UPS, n (%)
`1 (Not able to hold urine)
`2 (Able to hold urine)
`3 (Able to finish what I
`am doing)
`OAB-q, mean (SD)
`Symptom bother
`Total HRQL
`Concern
`Coping
`Sleep
`Social interaction
`
`HRQL : health-related quality of life; OAB-q : Overactive Bladder
`Questionnaire; PPBC = Patient Perception of Bladder Condition;
`SD = standard deviation: UPS = Urgency Perception Scale:
`UUI = urgency urinary incontinence.
`* Demographic characteristics and percentage of subjects with
`UUI at baseline are based on the safety set (placebo. n = 445;
`fesoterodine, n = 438). Baseline mean number of UUI episodes
`are based on the full analysis set and include only subjects with
`UUI at baseline (placebo, n = 257; fesoterodine, n = 251). other
`baseline bladder diary variables are based on the full analysis set
`(placebo, n = 434; fesoterodine, n = 428).
`* Percentage of female subjects.
`
`mean change in scores from baseline to week 12 was signif-
`icantly better with fesoterodine than placebo for the OAB—q
`Symptom Bother scale (treatment difference = -7.8;
`P <.000l); total HRQL score (treatment difference =
`6.2; P <.0001); and Concern (treatment difference ‘
`
`Of the 1338 subjects screened, 896 were enrolled and
`randomly assigned to treatment (n = 448 each for fe-
`soterodine and placebo). Of the 438 and 445 subjects
`who took 3:1 dose of fesoterodine and placebo, respec-
`tively, 382 and 385 subjects (87% for both groups),
`respectively, completed the trial. Demographic and clin-
`ical characteristics were similar between groups, with a
`slightly higher proportion of postmenopausal women in
`the placebo group (Table 1). During the 3—day bladder
`diary period at baseline. 59% and 58% of subjects in the
`fesoterodine and placebo groups, respectively, reported
`urgency urinary incontinence (UUI). Approximately
`40% of subjects in both groups had been previously
`treated with an antimuscarinic for OAB. After 2 weeks of
`
`treatment, 274 of 438 subjects (63%) treated with fe-
`soterodine and 325 of 445 subjects (73%) given placebo
`opted to increase study drug dose.
`
`Efficacy
`in mean number of micturitions per 24
`Improvement
`hours at week 12 (primary endpoint) was significantly
`greater with fesoterodine than placebo (Fig. 1). At week
`12, the least squares mean (standard error) change from
`baseline was -2.9 (0.1) for fesoterodine and -2.1 (0.1)
`
`for placebo (P = .0002); median percentage change was
`—22.2% and -14.4%, respectively (P = .002).
`At week 12, improvements in urgency episodes (P =
`.0003), UUI episodes (P = .022), and frequency—urgency
`sum (P <.0001) were also significantly greater with fe-
`soterodine vs placebo (Fig. 1). Between«group differences
`at week 12 in nocturnal rnicturitions (P = .32) and
`nocturnal urgency episodes (P : .08) were not statisti-
`cally significant. Improvements in number of micturi—
`tions (P = .014) and frequency—urgency sum (P = .020)
`were significantly greater in the Fesoterodine group com-
`pared with the placebo group by week 2; improvements
`in urgency (P = .034) and UUI episodes (P = .023) were
`significantly greater with fesoterodine vs placebo by week
`6 (Fig. 1).
`The median percentage change at week 12 for urgency
`episodes was -49.4% for fesoterodine and -32.1% for
`placebo (P = .0001). The median percentage change in
`number of UUI episodes at week 12 was - 100% in both
`groups in subjects with UUI at baseline, indicating that
`more than half of such subjects reported no UUI at the
`end of treatment. To illuminate this finding, a post hoc
`analysis of the UUI data was conducted; among subjects
`reporting >0 UUI episodes at baseline, 63% of the fe-
`soterodine group and 51% of the placebo group recorded
`no UUI episodes in their 3-day bladder diaries at week 12
`(P <.01).
`The categorical distribution of changes in PPBC scores
`at week 2 (P = .011), week 6 (P = .0008), and week 12
`(P = .0006) and UPS scores at week 2 (P = .013), week
`6 (P = .010), and week 12 (P = .0009) was significantly
`better with fesoterodine than placebo (Fig. 2). In addition,
`
`64
`
`UROLOGY 75 (1), 2010
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2079 - 0003
`
`

`
`i Placebo (n=434)
`-L— Fesoierodhe (n =428)
`
`Time, weeks
`6
`
`2
`
`12
`
`i Placebo (n=434)
`-1- Fesoierodhe (n =428)
`
`LSMeanChangeFromBaselineinMictuntionsper24Hours 1. on
`
`
`FromBaselineinUrgencyEpisodesper24Hours
`LSMeanChange
`
`.1;
`
`0-0
`
`0
`.5 E
`§ 3
`B :|:
`E 3 -0.5
`D ..
`~= 3D
`23 -1.0
`5 _g
`'3 E
`g 3 -1.5
`up .5
`_I
`
`
`L5MeanChange
`
`FromBaselineinFrequency-UrgencySumper24Hours
`
`-5
`
`_1 0
`
`—15
`
`
`
`
`& Placebo (n=257)
`—L— Fesoiemdine (n=251}
`
`-1.2
`-15
`4
`
`12
`
`TIme,waeks
`6
`
`2
`
`# Placebo (n =434}
`—L— Fesoierodine (n=428}
`
`-_1o.3
`-13.6
`
`Figure 1. Least squares (LS) mean change from baseline in number of micturitions, urgency episodes, urgency urinary
`incontinence (UUI) episodes, and frequency-urgency sum per 24 hours. * P <.05 vs placebo.
`
`8.4; P <.OOOl), Coping (treatment difference = 7.1;
`P <.O0O1), Sleep (treatment difference = 4.7; P =
`.0044), and Social Interaction (treatment difference =
`3.7; P <.O007) domains (Fig. 2). All mean improvements
`on all OAB-q scales and domains in both the fesoterod-
`ine and placebo groups exceeded the 10-point minimally
`important difference.”
`
`Tolerabillty and Safety
`Dry mouth and constipation were the most common
`treatment-emergent AES (Table 2). Most AES were mild
`or moderate. No serious treatment-related AEs or deaths
`
`occurred in either group. Subjective urinary retention
`occurred in 3 subjects (all women) taking fesoterodine,
`1 of whom discontinued; none of the cases of urinary
`retention were classified as a serious AH by the investi-
`gators, and none of these subjects required catheteriza-
`tion. No clinically significant changes in blood pressure
`or heart rate occurred in either group.
`Thirteen percent of subjects in the fesoterodine and
`placebo groups discontinued the study, with 8% from the
`fesoterodine group and 5% from the placebo group with-
`drawing because of an AB (Table 2).
`
`COMMENT
`
`This study is the first to report on the use of a flexible-
`dose regimen of fesoterodine in a double-blind, placebo-
`controlled design.
`It
`is also the first
`to evaluate the
`efficacy and safety of night-time dosing of fesoterodine in
`subjects with OAB. In this population, fesoterodine 4 or
`8 mg given once daily within 4 hours of bedtime signif-
`icantly decreased the number of micturitions by week 2
`
`(first evaluation) and urgency and UUI episodes by week
`6, with all improvements maintained through week 12.
`Subjects treated with fesoterodine also had significantly
`greater improvement in OAB-q Symptom Bother and
`I-IRQL scores compared with placebo, and subjects in the
`fesoterodine group reported better improvement than the
`placebo group on the PPBC and UPS. These data,
`in
`conjunction with previous reports, suggest that fesotero-
`dine is effective when taken either in the morning or
`evening.
`To approximate clinical practice, the flexible-dosing de-
`sign of the study allowed subjects to decide whether to
`increase the drug dose at week 2. In the fesoterodine group,
`63% of subjects increased the drug dose, suggesting that the
`4 mg dose was sufficiently well tolerated to allow subjects to
`seek greater improvement
`in symptoms. Discussions be-
`tween subjects and investigators regarding efficacy and tol-
`erability at week 2 were unstructured and not recorded;
`thus,
`the reasons why subjects did or did not choose to
`increase the dose are not known. However, as in real-world
`
`clinical practice, subjects may have chosen to optimize the
`balance between efficacy and tolerability.
`Our results are similar to those of the 2 fixed-dose
`
`phase III trials,” with expected variations based on study
`design and Variations in the definition of specific metrics.
`The median percentage change at week 12 in micturi-
`tions per 24 hours was -22% in the fesoterodine group in
`the current study vs -16% for the fesoterodine 4-mg
`group and -17% for the fesoterodine 8-mg group in the
`fixed-dose phase Ill trials.” For urgency episodes, median
`percentage change was -49% with fesoterodine in our
`study and -17% and -19% for the fesoterodine 4- and
`
`UROLOGY 75 (1), 2010
`
`65
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2079 - 0004
`
`

`
`I 22-point improvement
`D 1-point improvement
`[I No change
`|:| Deterioration
`
`I improvement
`I] No change
`D Deterioration
`
`Symptom
`Bother
`
`23
`*
`
`O
`
`-10
`
`-20
`
`-30
`
`§
`
`U1‘-40O1
`
`25
`
`0
`
`
`
`SubjectsFieportlng
`
`ImprovementonPPBC,%
`
`ImprovementonUPS,°/e
`
`
`
`SubjectsReporting
`
`in
`
`5 §
`u. .55’
`{ID
`
`5 2
`g .—
`g 2
`3
`to
`
`
`
`FESO
`P80
`(n=4a4)
`(n=44o)
`Week 2
`
`FESO
`PBO
`(n=4-42) (n:-435)
`Week 6
`
`FESO
`PBO
`(n:435)
`(n:422)
`Week 12
`
`FESO
`PBO
`(n=434)
`(n=441)
`Week 2
`
`FESO
`PBO
`(n=443) [n=435)
`Week 6
`
`FESO
`PBO
`(n=435)
`(n=443)
`Week 12
`
`El Placebo (n=380)
`I Fesoterodine (n:372)
`
`Total
`HFIQL
`
`Concern
`
`Coping
`
`Sleep
`
`Social
`Interaction
`
`Figure 2. Percentage of subjects with improvement on the Patient Perception of Bladder Condition (PPBC) and Urgency
`Perception Scale (UPS) and least squares (LS) mean change from baseline to week 12 in Overactive Bladder Questionnaire
`(OAB—q) scales and domains. FESO = fesoterodine; PBO = placebo. * P <.O1 vs placebo; '1' P <.05 vs placebo.
`
`in the fixed—dose trials,” al-
`8—mg groups, respectively,
`though the definition of urgency and the scale used to
`measure it in the current study differed from that in the
`fixed—dose trials. The median percentage change in UU1
`episodes at week 12 was - 100% with fesoterodine in the
`current study and -75% and -83% in the fesoterodine
`4- and 8-mg groups, respectively,
`in the fixed-dose tri-
`als.” However, a smaller proportion of fesoterodine sub-
`jects in the current
`trial had UUI at baseline (59%)
`compared with the fesoterodine 4—mg group (80%) and
`8—mg group (81%) in the fixed—dose trials, and the mean
`reduction in UUI episodes per 24 hours was greater in the
`fesoterodine 4—mg group (-1.9) and 8—mg group (-2.3)
`in the fixed—dose trials” than in the fesoterodine group in
`the current study (-1.5).
`
`In the current study, significantly greater improve—
`ments were noted in subjects’ assessment of symptom
`bother, HRQL, and bladder-related problems with flexi-
`ble-dose fesoterodine vs placebo. Although different in-
`struments were used in the fixed-dose trials, subjects in
`those studies treated with fesoterodine 4 and 8 mg
`showed significantly greater improvements in HRQL and
`in bladder-related problems, and significantly greater
`treatment response than subjects who received placebo. 10
`The findings from the current study are also similar to
`those of an open-label, flexible—dose study of fesoterod—
`me,“ in which subjects could increase the dose from 4 to
`8 mg at week 4. In that study,
`there were significant
`improvements compared with baseline values in the
`number of 24-hour micturitions, urgency episodes and
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2079 - 0005
`
`

`
`Table 2. Summary of treatment-emergent adverse events*
`and discontinuations
`
`Subjects, n (%)
`Placebo
`Fesoterodine
`(n = 445)
`(n = 438)
`
`Adverse event
`Dry mouth
`Mild
`Moderate
`Severe
`Constipation
`Mild
`Moderate
`Severe
`Headache
`Dry eye
`Insomnia
`Fatigue
`Dry throat
`Cough
`Discontinuations
`Adverse eve-ntl
`Voluntary withdrawal
`Lost to follow-up
`Lack of efficacy
`Other
`
`34 (8)
`23 (5)
`9 (2)
`2 (0.4)
`25 (6)
`19 (4)
`5 (1)
`1 (0.2)
`15 (3)
`8 (2)
`2 (<1)
`2 (<1)
`1 (<1)
`2 (<1)
`60 (13)
`21 (5)
`11 (3)
`8 (2)
`16(4)
`4 (1)
`
`113 (26)
`66 (15)
`40 (9)
`7 (2)
`48 (11)
`26 (6)
`18 (4)
`4(1)
`19(4)
`13 (3)
`11 (3)
`11(3)
`9(2)
`9(2)
`56 (13)
`34(8)
`11 (3)
`6 (1)
`5(1)
`O
`
`* Adverse events. of any causality. occurring in 22% of subjects
`in the fesoterodine group and exceeding placebo incidence are
`shown.
`* Regardless of causality.
`
`severe urgency episodes, UUI episodes, and nocturnal
`micturitions, as well as in all OAB-q scales and domains.
`Fifty percent of subjects opted for dose escalation at week
`4 in the open—label study, compared with 63% of subjects
`who opted for dose escalation at week 2 in the current
`study; the difference may be related to the earlier esca-
`lation decision point in our study.
`Treatmenpemergent AEs reported with fesoterodine
`in the current study were generally mild or moderate and
`led to treatment discontinuation in 8% of subjects com-
`pared with 5% for placebo. Dry mouth and constipation
`were the most commonly reported AES and are typical of
`the antimuscarinic drug class.]9 The incidence of dry
`mouth (26%) with fesoterodine in the current flexible-
`dose study was higher than that for fesoterodine 4 mg
`(19%) but lower than that for fesoterodine 8 mg (35%)
`in the pooled results of the 2 f1xed—dose trials.” In the
`current study,
`in which subjects took doses in the
`evening, the constipation rate in the fesoterodine group
`(11%) was higher than that in the fixed—doses trials (4%
`for fesoterodine 4 mg; 6% for fesoterodine 8 mg),
`in
`which subjects took doses in the morning.” The consti-
`pation rate for placebo (6%) in the current study was also
`higher than in the fixed-dose trials (2"/0).” In the open-
`label, flexible—dose fesoterodine study,18 which also used
`morning dosing, the rates of dry mouth (23%) and con-
`stipation (5%) were somewhat lower than in the current
`study. This may also be due in part to the difference in
`dose—escalation timing; some subjects who chose to in-
`crease the dose to 8 mg at week 2 in the current study
`
`might have remained on 4 mg, with fewer AEs. had the
`decision been made at week 4 as in the open—label study.
`Results from the current flexible—dose study are not
`unexpected, given the findings in the fixed—dose trials.”
`However, subjects in the flexible—dose study were not
`randomly assigned to a fesoterodine 4- or 8-mg—dose
`group as in the fixed—dose trials. In the current study,
`subjects who desired greater efficacy and had acceptable
`tolerability with fesoterodine 4 mg could increase the
`dose to 8 mg. Subjects satisfied with efficacy or reluctant
`to increase dose because of tolerability concerns could
`remain at the 4—mg dose. This study design reflects how
`OAB might be managed in clinical practice, with pa»
`tients and clinicians consulting on appropriate dosing.
`Our study was not designed a priori to compare results
`by dose, so we cannot draw primary conclusions regarding
`the relative efficacy and tolerability of the individual 4
`and 8 mg doses of fesoterodine in the flexible—dose set-
`ting. Analyses of data by dose will be perfonned post hoc
`and reported separately. An additional study limitation is
`the absence of data on the reasons for subjects’ decisions
`regarding optional dose escalation.
`
`CONCLUSION
`
`In this study, a flexible—dose regimen of fesoterodine 4 or
`8 mg given once daily in the evening was effective for the
`treatment of OAB symptoms and was generally well
`tolerated. The availability of 2 doses of fesoterodine al«
`lows clinicians to tailor the dosing regimen to meet
`individual patient needs.
`
`Acknowledgments. Editorial assistance was provided by Karen
`Zimmermann and Colin P. Mitchell, Ph.D.,
`from Complete
`Healthcare Communications Inc, and was funded by Pfizer lnc.
`
`References
`
`l. Abrams P, Artibani W, Cardozo L, et al. Reviewing the ICS 2002
`terminology report: the ongoing debate. Neurourol Uroclyn. 2006;25:
`293.
`2. Milsom l, Abrams P. Cardozo L, et al. How widespread are the
`symptoms of an overactive bladder and how are they managed? A
`population-based prevalence study. BJU int. 2001;87:760»766.
`3. Irwin DE. Milsom I, Hunskaar 5. er al. l"opulation—b-ascd survey of
`urinary incontinence, overactive bladder, and other lower urinary
`tract symptoms in five countries: results of the EPIC study. Eur
`Urol. 20Ci6;50:l 306-1 31 5.
`4. Stewart WF, Van Rooyen ]B, Cundiff GW, et al. Prevalence and
`burden of overactive bladder in the United States. Wmid} Uml.
`2003;20:327-336.
`5. Abrams P. Kelleher C, Lerr L, et al. Overactive bladder signifi-
`cantly affects quality of life. Am] Manag Care. 2000;6:S580-S590.
`6. Cart LK. Ovcractivc bladder. Cari] Urol. 2008;l5(suppl 1):32-36;
`discussion 36.
`7. Michel MC. Fesoterodine: -.1 novel muscarinic receptor antagonist
`for the treatment of overactive bladder syndrome. Expert Opin
`Plmnnacotlier. 2008;9:l787-1796.
`8. Nirri VW, Dinochowski R, Sand PK, er al. Efficacy, safety and
`tolerability of fesoterodine for overactive bladder syndrome. J Urol.
`2007;178:2488-2494.
`9. Chapplc C, Van Kcrrcbrocck P, Tubaro A, ct al. Clinical cfficacy,
`safety, and tolerability of once—daily fesoterodine in subjects with
`overactive bladder. Eur Uml. 2007;52:l204-1212.
`
`UROLOGY 75 (1), 2010
`
`67
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2079 - 0006
`
`

`
`10.
`
`ll.
`
`12.
`
`13.
`
`14.
`
`Kelleher C]. Tubaro A, Wz1ng]T. er ‘.11. Impact of fesoterodine on
`quality of life: pooled data from two randomized trials. BJU Int.
`2008;l02:56-61.
`Toviaz® (Fesoterodine fumarate). Full Prescribing Information.
`New York, NY: Pfizer Inc; 2008.
`Coyne KS. Matzu LS, Kopp 2. et al. The validation of the patient
`perception of bladder condition (PPBC): 21 single—item global mea-
`sure for patients with overactive bladder. Eur Urol. 2006;419:1079-
`I086.
`Coyne KS, Tubaro A, Brubaker L, et al. Development and valida-
`[IIUFI ()fpB1:len['Tep()l'[f.'3d ULHCUFIIES lT1e'd5Lll'e§ fill’ UVEl'&:lC[lVe blflddflfl
`a review of concepts. Urology. 2006;68:9-16.
`Cardozo L, Coyne KS, Versi E. Validation of the urgency percep-
`tion scale. BJU lnt. 2005;95:591-596.
`
`15.
`
`16.
`
`17.
`
`18.
`
`19.
`
`Coyne K, Revicki D, Hunt T, et al. Psychometric validation of an
`overactive bladder symptom and health-related quality of life ques-
`tionnaire: the OAB-q. Qual Life Res. 2002;11:563-574.
`Coyne KS, Matza LS. Thompson CL, et al. Determining the
`importance of change in the overactive bladder questionnaire.
`J] Ural. 2006;176:627-632.
`Khullar V, Rovner ES, Dmochowski R, et al. Fesoterodine dose
`response in subjects with overactive bladder syndrome. Urology.
`2008;71:839-843.
`Wvndaele ]], Goldfischer ER. Morrow ]D. et al. Effects of flexible-
`dose fesoterodine on overactive bladder symptoms and treatment
`satisfaction: an open-label study. lnt_ICl:'11 PTQCL 2009;63:560-567.
`Abrams P, Andersson KE. Muscarinic receptor antagonists for
`overactive bladder. BJU lm. 2007;100:987-1006.
`
`68
`
`UROLOGY 75 (1), 2010
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2079 - 0007