Superiority of fesoterodine 8 mg vs 4 mg in
`reducing urgency urinary incontinence episodes
`in patients with overactive bladder: results of the
`
`randomised. double-blind, placebo-controlled
`EIGHT trial
`
`Christopher Chapple, Tim Schneider*, Francois Haabl, Franklin Suni.
`Laurence Whelanfi, David Scholfieldfi, Erika Dragon“ and Erin Mangani
`
`The Royal Hallamshlre Hospital, Sheffield, 5Pfizer Ltd, Walton Oaks, UK, *Praxlskllnlk Urologle Rheln/Ruhr, A/lcllhelm,
`Germany, ’H<’5pltal Tenon, "Pfizer PIO, Paris, France, and ‘Pfizer lnc., New York, NY, USA
`
`Objective
`
`To assess the superiority of fesoterodine 8 mg vs 4 mg for
`improvement in urgency urinary incontinence (UUI) episodes
`and other diary variables, diary-dry rate (proportion of
`patients with >0 UUI episodes on baseline diary and 0 UUI
`episodes on post-baseline diary), and improvements in
`measures of symptom bother, health-related quality of life
`(HRQL), and other patient—reported outcomes (PROs).
`
`Patients and Methods
`
`This was a 12-week, randomised, double-blind,
`
`placebo-controlled, multinational trial of men and women
`aged 218 years with overactive bladder (OAB) symptoms
`including UUI (ClinicalTrials.gov ID NCT01302067). Patients
`were randomised (2:2:l) to receive fesoterodine 8 mg,
`fesoterodine 4 mg, or placebo once daily; those randomised to
`fesoterodine 8 mg started with fesoterodine 4 mg once daily
`for 1 week, then 8 mg once daily for the remaining 11 weeks.
`Patients completed bladder diaries at baseline and weeks 4 and
`12 and the Patient Perception of Bladder Condition (PPBC),
`Urgency Perception Scale (UPS), and Overactive Bladder
`Questionnaire (OAB-q) at baseline and week 12. The primary
`endpoint was change from baseline to week 12 in UUI
`episodes per 24 h.
`
`Results
`
`At week 12, patients receiving fesoterodine 8 mg (779 patients)
`had significantly greater reductions from baseline in UUI
`episodes, micturitions, and urgency episodes than patients
`receiving fesoterodine 4 mg (790) or placebo (386); diary-dry
`rate was significantly higher in the fesoterodine 8-mg group vs
`the fesoterodine 4-mg and placebo groups (all P < 0.05). At
`week 12, patients receiving fesoterodine 8 mg also had
`significantly greater improvements in scores on the PPBC, UPS,
`
`and all OAB-q scales and domains than patients receiving
`fesoterodine 4 mg or placebo (all P < 0.01). Patients receiving
`fesoterodine 4 mg had significantly greater improvements in
`UUI episodes, urgency episodes, and micturitions; significantly
`higher diary-dry rates; and significantly greater improvement in
`PPBC scores and OAB-q scores than patients receiving placebo
`(all P < 0.05). Dry mouth was the most commonly reported
`adverse event (AE) in the fesoterodine groups (placebo group,
`3.4%; fesoterodine 4-mg group, 12.9%; fesoterodine 8-mg
`group, 26.1%); most cases were mild or moderate in all
`treatment groups. Rates of serious AEs and discontinuations
`clue to AEs were low in all groups.
`
`Conclusions
`
`In a 12-week, prospectively designed, superiority trial,
`fesoterodine 8 mg showed statistically significantly superior
`eflicacy vs fesoterodine 4 mg and placebo, as measured by
`reductions in UUI episodes and other diary variables,
`diary-dry dry rate, and improvements in measures of
`symptom bother, HRQL, and other PROS; clear evidence of
`dose-dependent efficacy is unique to fesoterodine among
`antimuscarinics and other oral agents for the treatment of
`OAB_ Fesoterodine 4 mg was significantly more effective than
`placebo on all outcomes except for improvements in UPS
`scores. These data support the benefit of having two doses of
`fesoterodine in clinical practice, with the recommended
`starting dose of 4 mg for all patients and the fesoterodine
`8-mg dose available for patients who require a higher close to
`achieve optimal symptom relief.
`
`Keywords
`
`fesoterodine, dose comparison, urgency urinary incontinence,
`overactive bladder, dose response, dose titration
`
`BJU int 2014: I 14: 418-426
`wileyonlinelibrarycom
`
`© 2014 The Authors
`| doi:10.I 1 I 1/biu.1267B
`BJU International © 2014 BJU International
`Published by John Wiley Sc Sons Ltd. www.bjui.org
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2085 - 0001
`
`

`
`Introduction
`
`While urinary urgency is the defining symptom of overactive
`bladder (OAB) syndrome, urgency urinary incontinence
`(UUI) episodes may be the OAB symptom that causes the
`greatest personal and economic burden [1,2]. Fesoterodine,
`an antimuscarinic for the treatment of OAB symptoms, was
`developed in two once-daily doses, 4 and 8 mg, thus offering
`dose flexibility for treatment individualisation [3,4]. Based on
`each patient’s treatment response, the dosage can be adjusted
`to optimise the therapeutic balance between efficacy and
`tolerability [5].
`
`Flexible-dosing strategies are based on the assumption that
`increasing dosage will result in increased efficacy [5].
`However, fixed-dose studies of various pharmacological OAB
`treatments have typically not shown a statistically significant
`dose—response effect for the reduction of OAB symptoms
`[6—8] or have shown a dose—response effect only over
`a short (4-week) period
`In two phase III pivotal
`trials, fesoterodine 4 and 8 mg demonstrated significant
`improvements in OAB symptoms and health—related quality of
`life (HRQL) compared with placebo in patients with OAB
`[10,11]. A post hoc analysis of data pooled from these phase
`III trials showed that fesoterodine 8 mg significantly reduced
`UUI episodes and significantly increased the number of
`continent days/week and mean voided volume/micturition
`compared with fesoterodine 4 mg, suggesting significant
`additional benefit of the higher dose [12]. A significantly
`higher percentage of patients receiving fesoterodine 8 mg
`self-reported a treatment response vs patients receiving
`fesoterodine 4 mg [12]. Models based on phase II and phase
`III data also support a fesoterodine dose response [13].
`
`The objective of the present double-blind, placebo-controlled
`study was to prospectively assess the superiority of
`fesoterodine 8 mg compared with fesoterodine 4 mg and
`placebo in improving UUI episodes and other bladder diary
`endpoints and measures of symptom bother, HRQL, and other
`patient-reported outcomes (PROS) after 12 weeks of treatment
`in patients with OAB.
`
`Patients and Methods
`
`Study Design
`
`The EIGHT (Evaluation of urinary urge Incontinence
`patients Given fesoterodine 8 mg vs fesoterodine 4 mg in a
`Head-to-head efficacy Trial) trial was a 12-week, randomised,
`double-blind, placebo-controlled, parallel-group, multicentre
`study of treatment with fesoterodine 8 mg, fesoterodine 4 mg,
`or placebo (ClinicalTrials.gov ID: NCT01302067). The
`proportion of patients in the study was monitored to ensure
`that a maximum of =65% were antimuscarinic naive. The
`EIGHT trial was conducted at 241 centres in 27 countries
`
`between May 2011 and November 2012. The trial was
`
`Fesoterodine 8 mg vs 4 mg for OAB patients with UUI
`
`approved by the appropriate Institutional Review Boards
`and Independent Ethics Committees and conducted in
`accordance with the protocol, the International Conference on
`Harmonisation of Technical Requirements for Registration of
`Pharmaceuticals for Human Use (ICH) Good Clinical Practice
`guidelines, and applicable local regulatory requirements and
`laws. All patients provided written informed consent.
`
`At the end of a 2—week, single—blind, placebo run—in phase,
`eligible patients were randomised (2:2:1) to receive
`double-blind fesoterodine 8 mg, fesoterodine 4 mg, or placebo
`once daily via a centralised randomisation system. In
`accordance with labelling, a starting dose of 4 mg was used in
`the fesoterodine groups; patients randomised to fesoterodine
`8 mg started with fesoterodine 4 mg for 1 week, followed by a
`dose increase to 8 mg for the remaining 11 weeks of the study.
`The study medications and placebo were identical in
`appearance to preserve blinding.
`
`Patients
`
`Eligible patients were men and women aged 218 years with
`self—reported OAB symptoms for 26 months before screening
`and a mean of 28 micturitions and 22 and S15 UUI
`
`episodes/24 h (Urinary Sensation Scale [USS] rating of
`5 [l4]) captured in a 3-day diary at baseline who reported that
`their bladder caused at least some moderate problems on the
`Patient Perception of Bladder Condition (PPBC) [15]. Patients
`were required to be able to complete micturition diaries
`and study related questionnaires and comply with study
`procedures. Female patients who were pregnant, nursing, or
`had a positive urine pregnancy test or intended to become
`pregnant during the trial or within 3 months after the
`completion of the trial were not eligible, and female patients
`of childbearing potential who were heterosexually active
`were required to use an adequate form of contraception.
`Other exclusion criteria were: any condition that would
`contraindicate use of fesoterodine; conditions that may affect
`bladder function, including predominant stress UI, significant
`pelvic organ prolapse, clinically significant BOO (evidenced
`by previous history of acute urinary retention requiring
`catheterisation, use of an indwelling catheter or an
`intermittent selficatheterisation programme, urodynamic
`evidence of obstruction, or severe voiding symptoms
`including a previously measured post-void residual urine
`volume of 2200 mL) that was not being appropriately
`managed, and neurological conditions that are known or
`suspected of influencing bladder function; current or
`recurrent UTI; treatment with other anticholinergic
`medications within 2-3 weeks of screening; new or unstable
`use of certain medications, including diuretics, 0t—blockers,
`tricyclic antidepressants, and oestrogens; treatment with
`potent CYP3A4 inhibitors within 2 weeks of screening,
`CYP3A4 inducers within 30 days of screening, or botulinum
`toxin within 6 months of screening; or initiation of
`
`© 2014 The Authors
`BJU International © 2014 BJU International 419
`
`
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2085 - 0002
`
`

`
`Chapple er al.
`
`electrostimulation, bladder training, or pelvic floor exercises
`within 4 weeks of screening (patients on stable therapy were
`permitted).
`
`Outcome Measures
`
`Patients completed 3-day diaries at baseline and after 4 and
`12 weeks. The primary endpoint was change from baseline
`to week 12 in UUI episodes/24 h (USS rating of 5) for
`fesoterodine 8 mg vs fesoterodine 4 mg and placebo.
`Secondary endpoints, including changes in micturitions and
`urgency episodesf24 h, were also assessed.
`
`Patients also completed the PPBC [15], Urgency Perception
`Scale (UPS) [16], and Overactive Bladder Questionnaire
`(OAB-q) [17] at baseline and week 12. The PPBC is a
`validated single-item instrument used by patients to rate
`the severity of their bladder-related problems on a scale from
`1 to 6 (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) [15]. The UPS is a
`validated single-item instrument with a 3-point scale used by
`patients to rate their typical sensation of urgency (l,I am
`usually not able to hold urine; 2, I am usually able to hold
`urine [without leaking] until I reach a toilet if I go to the toilet
`immediately; 3, I am usually able to finish what I am doing
`before going to the toilet [without 1eaking]) [16]. The
`validated OAB-q contains an eight-item Symptom Bother
`Scale and a 25-item HRQL Scale with four domains (Concern,
`Coping, Sleep, and Social Interaction); scores on each scale
`and domain are normalised to a scale of 0-100. Higher scores
`on the Symptom Bother Scale reflect greater bother, and
`higher scores on the HRQL scale and domains reflect better
`HRQL [17].
`
`Adverse events (AE5) were monitored throughout the study,
`with severity and causal relationship to study drug assessed by
`the study investigator. A physical examination was conducted
`at the screening visit; blood pressure and heart rate
`measurements and laboratory testing were assessed at all clinic
`visits.
`
`Statistical Analysis
`
`Sample size was calculated based on an 85% power to detect a
`mean (SD) difference of -0.43 (2.71) in UUI episodes/24 h at
`5% significance level (two-sided). The Safety Analysis Set
`(SAS) included all patients who took at least one dose of the
`study drug. The Full Analysis Set (FAS) included all patients
`who took at least one dose of the assigned study drug and had
`at least one baseline or post—baseline elficacy assessment.
`Efficacy analyses were based on the PAS. For the primary
`efficacy endpoint, an analysis of covariance (ANCOVA) model
`was used to compare the fesoterodine 8 mg, 4 mg, and
`placebo arms for the change in the mean number of UUI
`episodes/'24 h at week 12 relative to baseline in patients with
`
`© 2014 The Authors
`420 BJU International © 2014 BJU International
`
`>0 UUI episodes at baseline (i.e. protocol violators with UUI
`= 0 were excluded). The ANCOVA model included terms for
`
`treatment, country, and baseline UUI as a covariate. The
`secondary interaction terms, treatment by baseline and
`treatment by country, were assessed at the 10% level of
`significance. Treatment comparisons were performed with a
`two-sided test at a 5% significance level and conducted using a
`step-down procedure in order to preserve the Type I error at
`5%. For each outcome, fesoterodine 8 mg was compared with
`placebo; the primary comparison of fesoterodine 8 mg vs 4 mg
`was performed only if there was a statistically significant
`treatment effect of 8 mg vs placebo. The comparison of
`fesoterodine 4 mg vs placebo also was performed. Treatment
`differences in change from baseline were estimated by least
`squares (LS) means and 95% C15. The interaction terms
`(treatment X baseline and treatment X country) were assessed
`at the 10% level of significance. Similar to the analysis
`of the primary endpoint, ANCOVA models were performed
`for changes in secondary bladder diary endpoints
`and OAB-q scores. Diary-dry rate was analysed using a
`Cochran-Mantel-Haenszel general association test and
`controlling for country. Changes in PPBC and UPS scores
`were analysed using a Cochran-Mantel-Haenszel test with
`modified ridit scoring controlling for country. Missing data
`were imputed with last-observation-carried-forward (LOCF)
`method.
`
`Results
`
`Of 2012 randomised patients (placebo, 402; fesoterodine
`4 mg, 806; fesoterodine 8 mg, 804), 1955 received 21 close of
`double-blind study drug (placebo, 386; fesoterodine 4 mg, 790;
`fesoterodine 8 mg, 779) (Fig. 1). Baseline demographic and
`clinical characteristics were similar in patients randomised to
`fesoterodine 8 mg, fesoterodine 4 mg, and placebo (Table 1).
`
`Fesoterodine 8 mg treatment resulted in significantly
`greater improvements in the change from baseline in UUI
`episodes.v'24 h (primary outcome) at week 12 compared with
`placebo (P < 0.001) and compared with fesoterodine 4 mg
`(P = 0.011; Fig. 2). There was a significant baseline by
`treatment interaction (P < 0.1) that was quantitative,
`indicating a larger treatment difference for patients with
`larger baseline values. The diary-dry rate was significantly
`higher with fesoterodine 8 mg vs placebo (P < 0.001) and
`fesoterodine 4 mg (P < 0.001) at week 12. Patients receiving
`fesoterodine 8 mg also had significantly greater improvements
`in micturition frequency and urgency episodes/24 h than
`patients receiving placebo (both P < 0.001) or fesoterodine
`4 mg (both P < 0.001) (Fig. 2). Improvements in scores on the
`PPBC, UPS, and all OAB-q scales and domains at week 12
`were significantly greater with fesoterodine 8 mg compared
`with placebo (all P < 0.001) and fesoterodine 4 mg (all
`P < 0.01) (Figs 3,4).
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2085 - 0003
`
`

`
`Fig. ‘I Patient disposition. FESO. fesoterodine: FAS, Full Analysis Set; SAS, Safety Analysis Set.
`
`Fesoterodine 8 mg vs 4 mg for OAB patients with UUI
`
`Screened (n = 4326)
`
`Randomised (n = 2012)
`
`
`
`FESO 8 mg {n = 804)
`
`Treated (n = 779)
`
`SAS (n = 779)
`
`FAS (n = 779)
`
`
`
`SAS (n = 790)
`
`FAS (n = 790)
`
`SAS (n = 386)
`
`FAS (n = 335)
`
`
`
`Discontinued (n = 34; 8.8%)
`All causality AES: n = 14
`lnsufl’. response: 11 = 4
`Consent withdrawn: n = 6
`Other: 11 = 10
`
`Discontinued (n = 78; 9.9%)
`All causality AEs: n = 27
`Insuff. response: 11 = 8
`Consent withdrawn: n = 13
`Other: 11 = 30
`
`Discontinued (n = 98; 12.6%)
`All causality AEs: n = 45
`lnsufl". response: 11 = 2
`Consent withdrawn: n = 10
`Other: 11 = 41
`
`
`
`Completed (11 = 712) 90.1%
`
`Completed (n= 352) 91.2%
`
`Completed (11 = 681) 87.4%
`
`
`
`Changes in micturitions (P = 0.008) and urgency episodes
`(P = 0.012) were significantly greater in patients receiving
`fesoterodine 8 mg than in patients receiving fesoterodine
`4 mg at week 4; the difference in the change in UUI episodes
`(P = 0.066) and difference in diary—dry rate (P = 0.812) were
`not statistically significant at week 4 (Fig. 2). UUI episodes,
`micturitions, and urgency episodes were significantly
`improved and diary-dry rate was significantly higher with
`fesoterodine 8 mg vs placebo at week 4 (all P < 0.01).
`
`Fesoterodine 4 mg also significantly improved all outcomes
`and produced a higher diary-dry rate vs placebo (all P < 0.05),
`with the exception of UPS scores (P = 0.39) at week 12.
`Fesoterodine 4 mg significantly improved all diary variables
`and produced a higher diary-dry rate (all P < 0.05) vs placebo
`at week 4 (Figs 2-4).
`
`Dry mouth was the most commonly reported
`treatment-emergent AE (TEAE; Table 2). Most TEAES were of
`mild or moderate intensity in all treatment groups. The rate of
`discontinuations due to TEAEs was 3.4% (13 patients) in the
`placebo group, 3.4% (27) in the fesoterodine 4-mg group. and
`5.4% (42) in the fesoterodine 8-mg group. The rate of serious
`TEAES was 2.8% (11 patients) in the placebo group, 1.3%
`(10) in the fesoterodine 4—mg group, and 1.3% (10) in the
`fesoterodine 8—mg group. Two patients receiving fesoterodine
`8 mg died during the study (one due to hypertensive heart
`disease and pulmonary embolism; one due to bladder cancer);
`both deaths were considered unrelated to study treatment.
`Urinary retention was reported in two patients receiving
`
`fesoterodine 8 mg and two receiving fesoterodine 4 mg; one
`patient in the fesoterodine 4—mg group was catheterised.
`
`Discussion
`
`The present study shows that fesoterodine 8 mg is significantly
`more effective than fesoterodine 4 mg in reducing UUI
`episodes and increasing diary-dry rate in patients with OAB
`symptoms including UUI. Fesoterodine 8 mg also produced
`significantly greater reductions in micturitions and urgency
`episodes than fesoterodine 4 mg. Significantly greater
`reductions in symptom bother and significantly greater
`improvements in HRQL, PPBC, and UPS scores show that
`the difference in symptom reduction between 8 and 4 mg
`fesoterodine is meaningful to patients. The changes in OAB-q
`Symptom Bother and HRQL scores exceeded the minimally
`important difference in all groups [18]. Both 8 and 4 mg
`fesoterodine were significantly more effective than placebo,
`with the exception of UPS scores for fesoterodine 4 mg vs
`placebo. The incidence of TEAES appeared higher in the
`fesoterodine 8-mg group than in the 4-mg group, particularly
`for dry mouth and constipation, although there was no
`increase in the incidence of serious TEAES and the rate of
`
`discontinuations clue to TEAES was low in all groups. The
`results of the present prospective, fixed—dose trial comparing
`fesoterodine 8 mg vs fesoterodine 4 mg and placebo are
`consistent with a post hoc analysis of data pooled from two
`fixed-dose trials [12] and models using data from phase II and
`phase III trials [13].
`
`
`
`© 2014 The Authors
`BJU International © 2014 BJU International 421
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2085 - 0004
`
`
`
`
`Treated (n = 386)
`
`Placebo (n = 402}
`
`FESO 4 mg (n = 806}
`
`Treated (n = 790)
`
`

`
`Chopple el at.
`
`Table 1 Baseline demographic and clinical chorocteristios*.
`
` Fesoterodine 4 mg
`
`Fesoterodine 8 mg
`(n = 779)
`
`(n = 790)
`
`Mean (range) age,years
`Gender, :1 (96)
`Men
`Women
`Race, n (96)
`White
`Black
`Asian
`Other
`Mean (range) weight, kg
`Mean (range) BMI. kg/m2
`Mean (range) duration since
`OAB diagnosis, years
`Mean (SD) diary variables:
`UUI episodeslI'24 h
`Mictu.ritionsl24 1'1
`Urgency episodes)'24 1'1
`Mean (SD) OAB—q scores:
`Symptom Bother
`HRQL
`Coping
`Concern
`Sleep
`Social lnteraction
`PPBC, n (96)
`Not many problems at all (1)
`Some very minor problems (2)
`Some minor problems (3)
`Some moderate problems (4)
`Severe problems (5)
`Many severe problems (6)
`UPS. n (941)
`1
`2
`3
`
`59.6 (19-85)
`
`53.3 (18-89)
`
`70 (18)
`316 (82)
`
`305 (30)
`52 (14)
`18 (5)
`3 (2)
`53.3 (35.0-172.4)
`30.7 (17.9—51.3)
`8.4 (0.0—6l.8)
`
`143 (13)
`647 (82)
`
`550 (52)
`92 (12)
`34 (4)
`14 (2)
`32.5 (42.2-197.0)
`30.5 (15.9—55.s)
`7.1 (0.1—48.5)
`
`59.8 (21-94)
`
`152 (20)
`627 (80)
`
`535 (32)
`as (11)
`47 (6)
`9 (1)
`32.4 (43.1—153.5)
`30.3 (17.1—50.s)
`7.3 (0.5—69.3)
`
`4.1 (2.4)
`12.8 (3.9)
`11.2 (4.2)
`
`70.1 (18.3)
`44.4 (22.8)
`37.2 (26.3)
`40.0 (25.4)
`41.6 (26.5)
`64.3 (27.2)
`
`0 (0)
`3 (0.9)
`3 (0.9)
`85 (24.4)
`175 (50.3)
`82 (23.6)
`
`150 (51.7)
`154 (47.1)
`4 (1.1)
`
`3.9 (2.1)
`12.6 (3.7)
`11.1 (3.9)
`
`6B.6{18.7)
`46.6 (23.3)
`39.7 (26.7)
`42.3 (26.3)
`43.6 (26.3)
`66.8 (27.4)
`
`1 (0.1)
`0(0)
`10 (1.4)
`178 (25.4)
`340 (48.6)
`171 (24.4)
`
`333 (47.5)
`349 (49.9)
`18 (2.6)
`
`3.9 (2.3)
`12.7 (3.5)
`11.0 (3.9)
`
`68.8 (18.6)
`45.2 (22.3)
`37.8 (26.0)
`40.9 (24.9)
`43.9 (27.5)
`64.5 (27.7)
`
`3 (0.4)
`3 (0.4)
`9 (1.3)
`164 (24.2)
`337 (49.8)
`161 (23.8)
`
`329 (45.5)
`332 (49.0)
`16 (2.4)
`
`BMI. body mass index; UPS: 1. Notable to hold urine; 2, Able to hold urine [without leaking} until I reach a toilet
`immediately; 3, Able to finish the ongoing work before going to the toilet [without leaking]. ‘Demographic data represent
`the safety set; baseline diary variable and PRO data representfull analysis set.
`
`Table 2 Most commonly reported TEAES‘.
`
`Event. n (96)
`
`Fesoterodine 4 or 8 mgl (n : 790)
`
`Placebo (n = 386)
`
`Fesoterodine 4 mg
`
`(n : 779)
`
`Dry mouth:
`Mild
`Moderate
`Severe
`Constipation:
`Mild
`Moderate
`Severe
`UT]:
`Mild
`Moderate
`Severe
`
`13 (3.4)
`12 (3.1)
`1 (0.2)
`0
`7 (1.8)
`7 (1.3)
`0
`0
`5 (1.3)
`2 (0.5)
`3 (0.3)
`0
`
`192 (12.9)
`77 (9.7)
`23 (2.9)
`2 (0.2)
`12 (1.5)
`8 (1.0)
`3 (0.4)
`1 (0.1)
`15 (2.0)
`12 (1.5)
`4 (0.5)
`D
`
`203 (26.1)
`144 (18.5)
`50 (6.4)
`9 (1.2)
`31 (4.0)
`19 (2.4)
`11 (1.4)
`1 (0.1)
`17 (2.2)
`9 (1.2)
`8 (1.0)
`0
`
`’*AIl—causah'ty adverse events reported by >296 subjects in the safety set in either active treatment group with higher
`incidence than placebo. The severity of adverse events was assessed by the investigator. with adverse events that did ‘not
`interfere with subject’: usualfunction’ rated as mild, adverse events that interfered “to some extent with subject’: usual
`fimcrion” rated as moderate. and adverse events that interfered significantily with subjects usualfunction'rated as
`severe; (Subjects in thefaoterodine 8—mg group receivedfesoterocline 4 mgfor the first week and then fesntemcline 8 mg
`for the remaining 11 weeks.
`
`© 2014 The Authors
`422 BJU International © 2014 BJU International
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2085 - 0005
`
`

`
`Fig. 2 Change from baseline to weeks 4 and 12 in UUI episodes, micturitions, and urgency episodes/24 h. *P< 0.01 vs placebo; ‘P < 0.05 vs
`fesoterodine 4 mg. FESO. fesoterodine: PBO. placebo.
`
`Week-I
`
`Weeklz
`
`Fesoterodine 8 mg vs 4 mg for OAB patients with UUI
`
`,.
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`The findings of the present study have important clinical
`implications. Availability of multiple doses is an important
`therapeutic consideration for many conditions, including
`OAB [5,19]. The utility of multiple doses is predicated on
`the concept that the dose-response curve diifers between
`individual patients [5]. That is, patients with high drug
`sensitivity may have sufficient efficacy on a lower dose of
`drug but experience unacceptable tolerability on a higher
`dose, whereas patients with low drug sensitivity may have
`insuflicient eflicacy on a lower close but achieve increased
`benefit with acceptable tolerability on a higher dose [5].
`These differences in drug response may be due to a
`combination of pharmacodynamic and pharmacokinetic
`differences resulting from variations in genotype, age,
`comorbidity, concomitant medications, or other factors. The
`utility of multiple doses is based on the assumption of a
`dose-response elfect.
`
`In flexible-dose trials of fesoterodine, approximately 50-63%
`of patients opted for dose escalation from fesoterodine 4 to
`8 mg [20—25]. In a long-term, open-label extension trial,
`patients who completed a phase III trial were treated with
`open-label fesoterodine 8 mg but could reduce their dose to
`4 mg and increase back to the 8-mg dose once per year; 71%
`of patients remained on the 8-mg dose throughout treatment
`[26]. Fesoterodine treatment was continued for 224 months by
`61% of 417 patients, and statistically significant improvements
`in diary variables and PROs were achieved and maintained
`across this period. Collectively, these findings suggest that
`about half of the patients treated with fesoterodine derive
`adequate efficacy and!or achieve a favourable balance of
`eflicacy and tolerability with the 4-mg dose, but at least half of
`the patients treated with fesoterodine may opt for the higher
`dose, suggesting a desire for greater eflicacy with acceptable
`tolerability after treatment with fesoterodine 4 mg. The
`
`
`
`© 2014 The Authors
`BJU International © 2014 BJU International 423
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2085 - 0006
`
`

`
`Chapple er at.
`
`present study, which prospectively compared the efficacy of
`fesoterodine 4 and 8 mg, confirm that the 8—mg dose produces
`superior improvements in diary variables, as well as a higher
`diary-dry rate in patients with OAB symptoms including UUI.
`The differences in improving bladder diary variables appear to
`be clinically meaningful, as evidenced by significantly greater
`improvements in measures of symptom bother, HRQL, and
`other PROs in patients treated with fesoterodine 8 mg vs those
`who received fesoterodine 4 mg or placebo. These data suggest
`that dose escalation should be attempted in patients who do
`not achieve optimal eflicacy with the initial 4—mg dose, rather
`
`Fig. 3 Change from baseline to weeks 4 and 12 in PPBC scores and UPS
`scores. ‘P < 0.001 vs placebo: IP < 0.01 vs fesoterodine 4 mg. FESO.
`fesoterodine.
`
`100
`
`»=
`
`=i= ~r
`
`than switching to another agent. Notably, solid evidence of
`increased efficacy with higher approved doses has not been
`shown with other agents used in the treatment of OAB [6—8]
`or have only been demonstrated over a short (4-week)
`period [9].
`
`The results of the present study should be interpreted within
`the context of its limitations. The present study used a
`fixed-dose design. However, in clinical practice patients have
`the option of choosing the dose of fesoterodine that provides
`them with the best balance between eflicacy and tolerability.
`For example, the rate of AES among the fesoterodine 8-mg
`group in the present study may be higher than would be seen
`in clinical practice, as some patients randomised to the 8-mg
`group may have opted for the 4-mg dose as their best
`treatment option if given the choice. The use of a fixed—dose
`design was necessary to demonstrate the superiority of the
`higher dose, which suggests that patients in clinical practice
`who show good tolerability and need additional efficacy
`should be tried at the higher close before considering other
`treatment options for OAB symptoms.
`'
`_
`_
`_
`_
`study population, both fesoterodine
`In conclusion, in this
`4 and 8 mg were effective in improving OAB symptoms
`compared with placebo, including UUI. Fesoterodine 8 mg
`showed statistically significantly superior eflicacy vs
`fesoterodine 4 mg in reducing the mean number of UUI
`episodes.’ 24 h from baseline to week 12. Patients treated
`with fesoterodine 8 mg also had significantly superior
`improvements vs those treated with fesoterodine 4 mg in the
`mean number of micturitions and urgency episodes/24 h, and
`in PPBC, UPS, and OAB-q scores at week 12, as well as a
`higher diary-dry rate. Fesoterodine 4 and 8 mg were generally
`well tolerated and showed a comparable safety profile to
`that reported in other studies. The data from the EIGHT
`study, together with data from phase III studies, provide
`confirmation that fesoterodine 8 mg demonstrates superior
`efficac for im rovin OAB s m toms includin UUI and
`Y
`P
`g
`Y p
`’
`g
`’
`
`I 2 Lpoimlmpmvemem
`I 1-point Improvement
`I No Change
`I Deterioration
`
`. Improvement
`I No Change
`I Dotoooroooo
`
` 3 3
`is)5 Change
`FromBaselinetoWeek12inUPSScores
`
`Pl““b°
`
`FES0 4 mg FESO 3 mg
`
`Placebo
`
`FESO 4 mg FESO 8 mg
`
`E E 30
`E g 60
`5 E
`E
`go 3
`g 3 20
`U 3
`
`40
`
`0
`
`100
`W3
`
`ChC
`
`J3-G
`
`0
`
`I Placebo (n = 347) I FESO 4 mg (n = 701) I FESO 3 mg (n = 577)
`
`
`
`0
`.5
`‘Ti
`3an
`
`Ein
`31:
`54:
`
`UE SE{
`
`O
`..i
`
`Symptom
`Bother
`
`Fi9- 4 Change from boseline T0 Wee|<Tl2 in
`OAB—q scores. P < 0.001 vs placebo; P < 0.01
`vs fesoterodine 4 mg: *P< 0.05 vs placebo.
`
`HRQL
`Total
`
`Concern
`
`Coping
`
`Sleep
`
`Social
`Interaction
`
`© 2014 The Authors
`424 BJU International © 2014 BJU International
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2085 - 0007
`
`

`
`PROS compared with fesoterodine 4 mg. The demonstrations
`of statistically significant dose—dependent eflicacy effects for
`fesoterodine are unique among antimuscarinics and other
`oral agents for the treatment of OAB. The greater efficacy of
`fesoterodine 8 mg supports the benefit of having two doses of
`fesoterodine and the recommended starting dose of 4 mg with
`dose escalation for patients in clinical practice who require a
`higher dose to achieve optimal symptom relief. The variability
`in treatment response supports the clinical utility of having
`two approved doses of fesoterodine to optimise symptom
`control for patients who desire greater efficacy and can
`tolerate the higher dose.
`
`Acknowledgments
`The authors gratefully acknowledge the contributions of Dr
`Pamela Ellsworth. This study was sponsored by Pfizer Inc.
`Medical writing assistance was provided by Patricia B. Leinen,
`PhD, and Colin P. Mitchell, PhD, from Complete Healthcare
`Communications, Inc., and was funded by Pfizer Inc.
`
`Conflict of interest
`
`C.C.: Pfizer — Consultant, Researcher, Speaker and Trial
`Participation.
`Allergan — Consultant, Researcher, Speaker and Trial
`Participation.
`American Medical Systems — Consultant.
`Astellas - Consultant, Researcher, Speaker and Trial
`Participation.
`Lilly — Consultant.
`ONO — Consultant.
`
`Ranbaxy — Speaker.
`Recordati — Consultant, Researcher, Speaker and Trial
`Participation.
`T.S.: No conflicts of interest.
`F.H.: Astellas — Consultant and Lecturer.
`
`Allergan — Consultant and Lecturer.
`Pfizer — Consultant and Lecturer.
`
`F.S., L.‘/V., D.S., E.D., and E.M. are all employees of Pfizer.
`
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`3 Michel MC. Fesoterodine: a novel muscarinic receptor antagonist for the
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`4 Malhotra B, Gandelman K, Sachse R, Wood N, Michel MC. The design
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`Fesoterodine 8 mg vs 4 mg for OAB patients with UUI
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