CLINICAL FOCUS: UROLOGICAL DISORDERS: CAUSES. EFFECTS. AND MANAGEMENT
`
`Evaluation of Cognitive Function in Healthy Older
`Subjects Treated with Fesoterodine
`
`Gary G. Kay, PhD'
`Paul Maruff. PhD’
`
`David Scholfield. MBBS3
`
`Bimal Malhotra. PhD‘
`Laurence Whelan. PhD5
`
`Amanda Darekar. MSc"
`
`Diane L. Martire, MD. MPH’
`
`‘President. Cognitive Research
`Corporation. Saint Petersburg. FL:
`‘Chief Scientific Officer. Cogstate Ltd.
`Me|bourne.Australia and Professor,
`Center for Neuroscience. University
`of Melbourne. Melbourne.Austra|ia;
`3Executive Director. Pfizer Ltd,Walton
`Oaks. UK: ‘Senior Director. Pfizer
`Inc, New York. NY; 5Clinical Scientist.
`Pfizer Ltd.Walton Oaks. UK; ‘Principal
`Statistician. Pfizer Ltd.Walton Oaks.
`UK; 7Senior Medical Director. Pfizer
`Inc. New York. NY
`
`Correspondence: Gary (3. Kay, Ph D.
`Cognitive Research Corporation.
`200 Central Ave..
`Suite I230.
`Saint Petersburg. FL 3370 I.
`Tel: 727-897-9000
`Fax: 727-897-9009
`E-mail: gkay@cogres.corn
`
`DOI: pgrn.20|2.05.2543
`
`Abstract
`
`Objective: To evaluate the cognitive effects offesoterodine 4 and 8 mg versus placebo in healthy
`older adults. Methods: This was an active- and placebo-controlled, double-blind. double-dummy
`
`crossover study conducted using healthy volunteers (aged 65-85 years) with baseline Mini-
`Mental State Examination score 2 26. The study comprised 4 treatment periods: fesoterodine
`4 mg for 6 days; fesoterodine 4 mg for 3 days followed by fesoterodine 8 mg for 3 days; placebo
`for 6 days; and placebo for 6 days with alprazolam 1 mg on day 6. The treatment sequence was
`randomized, with a 3- to 6-day washout between periods. Subjects completed computer-based
`cognitive assessments and the Rey Auditory Verbal Learning Test on day 1 (before dosing) and
`day 6 ("after dosing") of each period. The primary endpoint was the Detection task; secondary
`endpoints were the Identification task, 1-card learning task, Continuous Paired Associate Learning
`task, Groton Maze Learning Task, and the Rey Auditory Verbal Learning Test. Results: Among
`18 subjects in the per protocol set, changes from baseline to day 6 with fesoterodine 4 and 8 mg
`were not significantly different from placebo for any endpoint (P > 0.05); alprazolam produced
`significant impairment in all endpoints versus placebo (P < 0.05). No serious adverse events
`were reported; the most common adverse events were dry mouth for fesoterodine and sedation
`for alprazolam. No sedation was reported with fesoterodine. Conclusion: In healthy older
`adults, fesoterodine 4 and 8 mg once daily had no statistically significant effects versus placebo
`on any cognitive function assessed, including memory; alprazolam 1 mg produced statistically
`significant deterioration.
`
`Keywords: fesoterodine; antimuscarinic; elderly; cognition; memory
`
`Introduction
`
`Overactive bladder (OAB) is a syndrome characterized by urinary urgency, with or
`
`without urgency incontinence, usually accompanied by frequency and nocturia.”
`
`Overactive bladder is a prevalent condition that affects approximately 11% of men
`
`and 13% of women; its prevalence increases with advancing age.’ Overactive bladder
`symptoms are associated with increased rates of institutionalization and mortality in
`older individuals,“ as well as with comorbidities (cg, falls and fractures) that are a
`
`concern in older individuals who may have to rush to the bathroom?
`
`Muscarinic antagonists are first-line pharrnacologic treatment for OAB.5 Individual
`
`antimuscarinic agents vary in the muscarinic receptor subtypes with which they interact
`
`and in their propensity to cross the blood—brain barrier (BBB), which may affect the
`
`agent’s safety and tolerability profile.’ Muscarinic M1 and M2 receptor subtypes are
`
`expressed at the highest levels in the prefrontal cortex and hippocampus, which are
`
`important for memory, attention, and executive function.“ Therefore, interaction of an
`antimuscarinic agent with M1 and M2 receptors in these brain regions could produce
`
`impairment of cognitive functions?
`
`(9 Postgraduate Medicine. Volume I24. Issue 3. May 20|2. ISSN — 0032-548i. e-ISSN — l94|-9260
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`7
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2084 - 0001
`
`

`
`Kay et al
`
`Safety and tolerability are particularly important
`considerations in older individuals with OAB due to
`
`increased permeability of the BBB, changes in hepatic
`
`metabolite, S—hydroxymethyl tolterodine (5-HMT)? 5-HMT
`
`has been shown to have low lipophilicity, which limits the
`propensity of 5-HMT to cross the BBB, and is a substrate
`
`and renal function, and the presence of comorbidities.‘°
`
`of the P-glycoprotein (P-gp) efflux transporter, which may
`
`Additionally, older individuals may be more likely to
`
`limit CNS penetration through active removal of molecules
`
`receive concomitant administration of drugs that may have
`
`that do cross the BBB.7~25 Although the low degree of CNS
`
`additive antimuscarinic effects or compete for metabolic
`
`resources.““2 For example, there is evidence that cumulative
`
`penetration of 5-HMT has been confirmed in vivo in rats”
`and via observation that the incidence of CNS AEs in human
`
`anticholinergic effects of multiple drugs may impair short-
`
`subjects with OAB in fesoterodine clinical trials has been
`
`term memory, executive function, and psychomotor function,
`“"5 and concomitant administration of
`in older individuals,
`
`no greater than placebo,2°'22 the potential of fesoterodine to
`impair cognitive fimctioning in older populations has not
`
`antimuscarinics with drugs that enhance cholingeric activity
`
`been assessed. The objective of the present 6-week study
`
`(cholinesterase inhibitors) may also have a negative impact
`
`was to assess cognitive function using sensitive, specific,
`
`on activities of daily living.” Notably, older individuals
`
`validated methodology in healthy older volunteers after oral
`
`with OAB symptoms may have clinically recognizable or
`
`administration of fesoterodine 4 and 8 mg compared with
`
`even occult neurologic diseases characterized by reduc-
`
`placebo. Because 5-HMT does not cross the BBB and no
`
`tions in cognitive function (eg, Alzheimer’s disease) that
`
`cognitive impairment or CNS AEs have been observed pre-
`
`could be exacerbated by antimuscarinic drugs.“ Even in the
`
`viously after treatment with fesoterodine, we hypothesized
`
`absence of neurological disease, the deleterious effects of
`
`that fesoterodine would not induce impairment in attention,
`
`drugs acting on the central nervous system (CNS), such as
`anticholinergics and benzodiazepines, are greater in people
`
`memory, or executive function in this psychopharmacological
`challenge. To ensure the experiment was sufficiently sensitive
`
`aged > 60 years compared with healthy young adults. '9 Thus,
`
`to cognitive change in the older adults, we included a positive-
`
`there is concern regarding potential CNS adverse events
`
`control treatment (alprazolam 1 mg) that is often prescribed
`
`(AE5) in older individuals being treated with antimuscarinics
`
`for use in older adults and known to reliably induce acute
`
`for OAB symptoms?
`
`and reversible impairment in cognitive domains known to be
`
`Fesoterodine is an antimuscarinic agent approved for
`
`impacted by anticholinergics in adults at the recommended
`
`the treatment of OAB symptoms that is available in 2 doses
`
`therapeutic doses.“
`
`(4 and 8 mg). Both fixed— and flexible—dose studies have
`
`shown that fesoterodine 4 and 8 mg significantly improve
`bladder diary variables, including micturition frequency,
`
`urgency episodes, and urgency urinary incontinence epi-
`
`Materials and Methods
`
`Study Design and Subjects
`In this randomized, positive— and placebo-controlled, double-
`
`sodes and measures of health-related quality of life (HRQL)
`
`blind, double-dummy, 4-way crossover study, healthy vol-
`
`compared with placebo.“‘‘“ A pooled analysis of data from
`
`unteers aged 65 to 85 years who scored 2 26 on the MMSE
`
`2 fixed-dose phase 3 studies stratified by subjects’ age showed
`
`at baseline were enrolled at 1 site in the United States (Clini-
`
`that both fesoterodine 4 and 8 mg effectively treated OAB
`
`calTrials.gov ID NCT0l 161472). Subjects with cognitive
`
`symptoms and improved HRQL in subjects aged < 7'5 years,
`
`impairment due to any concurrent condition or who were
`
`and fesoterodine 8 mg was effective in those aged 2 75 years.
`
`taking concomitant medications that may cause cognitive
`
`Fesoterodine was generally well tolerated in both younger
`and older subjects.” Similarly, a randomized, double-blind,
`
`impairment were excluded. The cognitive effect of alpra-
`zolam 1 mg compared with placebo was used as a positive
`
`placebo-controlled, flexible-dose trial of subjects aged
`
`control to assess the sensitivity of the methodology used.”'13
`
`2 65 years reported significant improvements in most diary
`
`The study comprised 4 treatment periods: fesoterodine
`
`variables, symptom bother, and HRQL and significantly
`
`4 mg for 6 days with matching alprazolam placebo on day 6;
`
`higher treatment response rates in the fesoterodine group
`
`fesoterodine 4 mg for 3 days followed by fesoterodine 8 mg
`
`versus placebo; flexible—dose fesoterodine was well tolerated,
`
`for 3 days with matching alprazolam placebo on day 6; match-
`
`with no change in Mini-Mental State Examination (MMSE)
`
`ing fesoterodine placebo for 6 days with matching alprazo-
`
`score in either group.“
`
`lam placebo on day 6; and matching fesoterodine placebo
`
`After oral administration, fesoterodine is rapidly and
`
`for 6 days with alprazolam l mg on day 6. Subjects were
`
`extensively converted by ubiquitous esterases to its active
`
`randomized in a l : l : l : 1 ratio to one of 4 cross-over sequences,
`
`3
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`
`

`
`Lack of Fesoterodine Cognitive Effects
`
`with 4 treatment periods in each sequence arranged in a
`
`locations), and the Groton Maze Learning Task (GMLT; a
`
`Williams’ square. There was a 3- to 6-day washout period
`
`between each treatment period.2°‘-" Total study duration
`
`measure of executive function in which the subject must
`locate and learn a pathway hidden beneath a 10 X 10 grid)
`
`was 6 weeks. All treatments were administered once daily;
`
`and the Rey Auditory Verbal Learning Test (RAVLT; a test
`
`subjects were confined to the study site for the night prior to
`
`in which the subject must learn a set of 15 unrelated spoken
`
`cognitive assessment. Compliance with the dosing regimen
`
`words on 5 learning trials). Previous studies suggest that the
`
`was evaluated at each cognitive assessment via collection of
`
`practice effects should be minimal for these tests under the
`
`unused study drug.
`
`Measures
`
`Subjects were administered a validated computer-based
`
`cognitive test battery (CogState)32 and the Rey Auditory
`
`design employed in the current study.“ Safety was monitored
`
`throughout the study based on treatment—emergent adverse
`
`events (TEAES), assessments of vital signs, and physical
`examination.
`
`Verbal Learning Test (RAVLT)33 on day 1 (before dosing)
`
`Statistical Methods
`
`and day 6 (after dosing) of each treatment period (Table 1).
`
`The sample size estimation to ensure that the study had
`
`The primary endpoint was performance on the Detection
`
`sufficient statistical power to detect statistically significant
`
`task, a test of psychomotor function and processing speed
`
`differences between active treatment and placebo was
`
`in which a subject must respond as quickly as they can to
`
`based on data from previous crossover studies using the
`
`the presence of a visual stimulus. Secondary endpoints were
`
`CogState cognitive testing battery in healthy volunteers.
`
`performance on the Identification task (a test of visual atten-
`
`Approximately 20 subjects were to be enrolled in the study.
`
`tion or vigilance in which the subject must decide whether
`a card presented is red), One Card Learning task (a test
`
`Subjects who withdrew from the study before completing all
`4 study periods could be replaced with a mirror replacement.
`
`of visual learning and memory in which the subject must
`
`To show a clinically meaningful difference in the Detection
`
`decide whether or not they have seen each card before),
`
`task endpoint (change from baseline to end of treatment)
`
`Continuous Paired Associate Learning (CPAL) task (a
`
`of 0.06 (log'° ms) between active treatment and placebo,
`
`test of visual learning and memory in which subjects must
`
`a sample size of 17 subjects was needed for the statistical
`
`learn a set of 6 associations between abstract patterns and
`
`test to have a power of 90% to detect a difference between
`
`Table I. Cognitive Function Outcomes Measures
`Cognitive Domain
`
`Detection task (primary endpoint)
`
`Identification task
`
`One-card learning task
`
`CPAL task
`
`GMLT
`
`o Psychomotor function or processing speed
`I Measures subject's speed of response to a card being turned over on the computer screen
`I Data are presented as mean |og|0 with a lower score corresponding to better performance
`I Visual attention or vigilance
`I Measures subject's speed of deciding ifa card turned over on the screen is red or not
`I Data are presented as mean |og|0 with a lower score corresponding to better performance
`I Visual learning and memory
`I Measures subject's accuracy of remembering which cards have been shown before in the task
`I Data are presented as an arcsine transformation of proportion of correct responses with a higher score
`corresponding to a better performance
`
`I Visual kearning and memory
`I Measures subject's error rate in learning and remembering pictures hidden beneath different locations on the
`COFFIPUIEF SCl'EBl'|
`I Lower scores correspond to better performance
`
`I Executive functionfspatial problem solving
`I Measures subject's error rate in finding a hidden pathway across a grid
`I Lower scores correspond to better performance
`
`RAVLT
`
`n Verbal learning and memory
`I Measures subject's ability to recall words
`I Higher scores correspond to better performance
`Abbreviations: CPAL. Continuous Paired Associate Learning task: GMLT. Groton Maze LearningTasl<: RAVLT. Rey Auditory)/erbal LearningTest.
`
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`
`Patent Owner, UCB Pharma GmbH — Exhibit 2084 - 0003
`
`

`
`Kay et al
`
`treatment means, at a significance level of 0.05 (2—sided).
`
`Similarly, baseline to day 6 changes in the Identification
`
`This was rounded up to the nearest multiple of 4 to ensure
`an equal number of subjects in each sequence, giving a total
`
`task, One Card Learning task, CPAL task, GMLT, and
`RAVLT with fesoterodine 4 and 8 mg were not statistically
`
`sample size of 20. This calculation assumes an estimate of
`
`significant compared with placebo, (all P > 0.05); the 95%
`
`the within-subject standard deviation (SD) to be 0.05 for
`
`Cls associated with the differences versus placebo included
`
`change in the Detection task endpoint at the end oftreatment
`
`zero (Figure 2). In contrast, in the alprazolam treatment
`
`observed in previous studies.
`
`period, baseline to day 6 changes in all the secondary end-
`
`Analysis of primary and secondary endpoints was based
`
`points were statistically significantly different when com-
`
`on the Per Protocol Analysis Set (PPAS), which includes all
`
`pared with placebo (all P < 0.05); the 95% Cls associated
`
`subjects who completed the study, and who did not violate any
`
`with the differences versus placebo did not include zero
`
`of the inclusion/exclusion criteria or deviate from the protocol
`
`(Figure 2).
`
`in a way that could affect the outcome ofthe study. The Safety
`
`Among the safety set, 7 (35%), 6 (30%), ll (58%), and
`
`Analysis Set consists of all subjects who received study drug,
`
`18 (95%), subjects receiving placebo, fesoterodine 4 mg,
`
`regardless of whether they completed the study.
`
`fesoterodine 8 mg, and alprazolam, respectively, reported
`
`Change from baseline to day 6 for all endpoints was
`
`any AEs, among whom 4 (20%), 5 (25%), 8 (42%), and
`
`analyzed using an analysis of covariance (ANCOVA) model
`
`17 (89%) subjects reported AEs related to treatment. No
`
`with period and treatment as fixed effects, subject as a random
`
`serious AEs were reported and no AEs were considered to be
`
`effect, and between and within subject baseline values as
`
`severe. As expected, the most common AEs were dry mouth
`
`covariates. The least squares (LS) mean change in scores
`
`for fesoterodine 4 mg (10%) and fesoterodine 8 mg (32%)
`
`from baseline to day 6 and corresponding standard errors
`for active treatments and placebo are presented, along with
`the 95% Cls and P values for the differences in LS means
`
`for active treatments versus placebo. Statistical significance
`was tested based on P < 0.05.
`
`Results
`
`and sedation for alprazolam (53%; Table 2). There was no
`reported sedation with fesoterodine.
`
`Discussion
`
`The current study examined the effects of fesoterodine 4 mg,
`
`fesoterodine 8 mg, and alprazolam versus placebo across a
`
`wide range of tests assessing different elements of cognitive
`
`A total of 20 healthy volunteers were randomized and treated,
`
`function, including psychomotor function, visual atten-
`
`among whom 1 discontinued for personal reasons and 1 was
`
`tion, visual learning, visual associative learning, executive
`
`excluded from the PPAS for a violation of the study protocol
`(receiving a prohibited medication). The 2 subjects who were
`not included in the PPAS were not from the same treatment
`
`sequence group. No subjects were excluded for lack of
`
`function, verbal learning, and memory. Both the CogState
`test battery and the RAVLT have demonstrated validity and
`
`sensitivity to cognitive change in clinical research settings
`and are known to be sensitive to antimuscarinic treatment.-”'-‘‘‘
`
`compliance with the dosing regimen. The safety set (all sub-
`
`In the current study, there was no observed improvement
`
`jects who received study drug) consisted of 12 men and
`
`in performance for any of the cognitive tests during admin-
`
`8 women with a mean (SD, range) age of 72.2 (5.2, 65-84)
`
`istration of placebo. This finding suggests that repeated
`
`years, who had a mean (SD, range) 15.4 (2.4, 12-20) years
`
`administration of the tests does not give rise to practice effects
`
`of education, and a mean (SD, range) MMSE score of 29.05
`
`and is consistent with the results ofprevious studies in which
`
`(1.15, 26-30).
`Least-square mean changes in all endpoints are shown
`
`the CogState battery has also been given repeatedly without
`inducing practice effects.“
`
`in Figure 1. Differences in LS mean changes in Detection
`
`The results show that at steady state, fesoterodine 4 or
`
`task scores from baseline to day 6 (primary endpoint) for
`
`8 mg were not associated with impairment of cognitive fitne-
`
`fesoterodine 4 or 8 mg versus placebo were not statistically
`
`tioning in healthy older subjects versus placebo. In contrast,
`
`significant (P > 0.05); the 95% Cls for the differences versus
`
`an acute l—mg dose of alprazolam gave rise to statistically
`
`placebo included zero (Figure 2). In contrast, in a secondary
`
`significant worsening in all cognitive function scores. The
`
`comparison, alprazolam demonstrated statistically signifi-
`
`magnitude and consistency of the decline in cognitive func-
`
`cant changes in Detection task scores from baseline to day
`
`tion observed following alprazolam in the current sample of
`
`6 compared with placebo (P = 0.0013); the 95% Cls for the
`
`healthy older adults indicates that the current experimental
`
`difference versus placebo did not include zero (Figure 2).
`
`design had sufficient sensitivity and power to detect impairing
`
`I0
`
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`
`

`
`Figure I. Least-squares mean (SEM) change from baseline to day 6 in Cogstate Subtest [Detection Task (A). Identification Task (B), One-card Learning Task (C). CPAL (D).
`GMLT {E)] and RAVLT (F) scores. Data represent the PPAS (n = I8).
`
`Lack of Fesoterodine Cognitive Effects
`
`Detectmn Task
`
`Identification Task
`
`
`
`cPA|_ Task
`
`F°5°“"9
`2.'rs(0.05)
`
`F°5°3"‘9 A"‘"'z°'“'"
`2.TT(0.06)
`2.76(0.06l
`
`3 °"°°
`3 0075
`E
`C
`g 0.050
`E
`0.025
`E
`$_ 0.000
`5
`g -0.025
`2
`
`-0.050
`
`MeanlSD)
`baseline Vague
`
`0.04
`
`0.02
`
`3;
`5 __ 0.00
`J: 55'
`_<-_3_ '._-._.'
`-0.02
`2 °'
`LlJ
`-4'1
`-0 04
`-_— C
`an "
`'
`q,
`..
`5 3 -0.05
`5 N -0.00
`3?
`
`-0.10
`-0.12
`
`Placebo
`2.5B(O.D9]
`
`Feso 4 mg
`2.63 (0.10)
`
`Feso 8 mg
`2.s0(0.09)
`
`Alprazolam
`2.s1(0.11)
`
`One Card Learning Task
`
`m 0.100
`E
`E, 0015
`D!
`:-
`'
`5
`S 0050
`'2‘
`3
`‘E 0.025
`3
`5
`_| Mon
`
`Mean(SDl
`baseline value
`
`P'“°°b°
`2.75 (0.06)
`
`70
`
`In
`5°
`"
`50
`E
`‘D.
`5, 40
`5
`30
`5
`U 20
`5
`..
`5 1°
`E
`0
`g -10
`2 _m
`-30
`
`Mean (SD)
`ba93""° Val‘-'9
`
`Placebo
`0.93(0.0-3)
`
`Fesotlmg
`0.96(0.09l
`
`Fesosmg
`09410-09)
`
`Alprazelam
`I195 (0-11)
`
`Mean (50)
`baseline value
`
`Placebo
`107.4(53.-4.)
`
`Faso4mg
`96.3(5T.1]
`
`Fesos mg
`99.a(55.3)
`
`Alprazolam
`s9.5(5s.2)
`
`ll!
`
`30
`25
`29
`15
`
`'§
`5
`"7
`°‘
`‘:
`“"
`A
`5 1°
`E
`5
`.0
`E 0
`=
`-5
`3
`‘3 "°
`-15
`
`Mean (SD)
`baseline value
`
`GMLT
`
`
`
`Placebo
`s2.3(15.7)
`
`Feso 4 mg
`53.7(17.1)
`
`Fest: 8 mg
`53.4(15.2)
`
`Alprazolarn
`56.8(15.0)
`
`0
`
`B
`g 1
`§
`II;
`E
`3 -1
`_
`aa
`El
`.:
`5 -2
`3
`E ‘3
`e
`‘-' _,
`2
`3 '5
`M30950
`6.33 (3.30)
`Mean (SD)
`baseline value
`
`RAVLT
`
`F950 4 "19
`6.50 (3.00)
`
`F950 3 01!!
`6.6'l'(3.63)
`
`ND''3Z°|3''"
`7.22 (3.59)
`
`Abbreviations: CPAL. Continuous Paired Associate Learning task; Feso, fesoterodine; GMLT. Gnoton Maze Learning Task; LS, least-squares; PPAS, per-protocol analysis set;
`RAVLT. Rey Auditory Verbal Learning Test.
`
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`I
`
`I
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2084 - 0005
`
`

`
`Kay et al
`
`Figure 2. Least-squares mean (95%C|) difference between placebo and active treatments for changes from baseline to Day 6 in Cogstate Subtest [Detection Task (A).
`Identification Task (B),One-card LearningTask (C),CFAL (D). GMLT (E)] and RAVLT (F) scores. Data represent the FPAS (n = IS).
`
`Detection Task
`
`.
`
`D
`
`CPAL
`
`Z’
`
`2E E:
`
`9
`
`Fesoterodine
`4mg vs. Placebo
`
`Fesoterodine
`Bmg vs. Placebo
`
`Alprazolarn
`1mg vs. Placebo
`
`Identification Task
`
`.
`
`l
`
`Faaoterodmo
`4mg vs. Placebo
`
`Fosoterodina
`Bmg vs. Placebo
`
`Alprazolam
`1rng vs. Placebo
`
`One Card Leamlng Task
`
`Fosaterodina
`4mg vs Placebo
`
`Fasnterodina
`Bmg vs Placebo
`
`'
`Alprazolam
`1mg vs. Placebo
`
`0 1
`
`A
`8 Tc.‘
`5 E 0 05
`E 8’
`-
`D -1
`6 §
`§ 2g D.
`5 g -0.05
`8 ._S (D
`> -0.1
`
`0
`
`In
`E
`S.’
`S’_l
`
`01
`
`0.05
`
`0
`
`-0.05
`
`-0.1
`
`0.1
`
`0.05
`
`O
`
`-0.05
`-0.1
`
`-0.15
`
`E1:
`
`E E
`
`2
`
`3
`
`C
`
`
`
`Fesolerodine
`4mg vs Pleebo
`
`Fesoierodlne
`Bmg va. Placebo
`
`Alprazoiarn
`1mg vs Placebo
`
`GMLT
`
`'
`
`£
`
`Fasotarodine
`4mg vs Placebo
`
`Fasotarodina
`Bmg vs Placebo
`
`Alprazolarn
`1mg vs Placebo
`
`RAVLT
`
`E
`
`50
`
`40
`
`30
`20
`IE
`l-
`E 10
`0
`
`-10
`-20
`
`3 2
`
`F
`
`Fesolerodlne
`4mg vs Placebo
`
`Fesoterodlne
`Brng vs Placebo
`
`.
`Alprazolam
`1mg vs Placebo
`
`1
`E
`0
`§
`g -1
`D _
`E
`2
`
`3 T
`
`-3
`!
`-9 -4
`-5
`_6
`
`*P < 0.05.
`Abbreviations: CPAL, Continuous Paired Associate Learning task; Feso,fesoterodine:(3ML'|'. Groton Maze Learning Task; L5, least-squares; PPAS. per-protocol analysis set;
`RAVLT. Rey Auditorylferbal LearningTest.
`
`drug effects, particularly given that the statistically significant
`
`sizes observed for change from baseline under the fesotero-
`
`difference in the primary endpoint between alprazolam and
`
`dine and placebo conditions also indicate that the absence of
`
`placebo was identical to the clinically meaningful difference
`the study was powered on. Figure 1 shows the magnitude of
`
`any statistical significance between these conditions reflected
`true non-differences rather than lack of power.
`
`decline associated with alprazolam and the absence of any
`
`Although concern has been expressed regarding potential
`
`decline associated with fesoterodine or placebo for each
`
`CNS effects of antimuscarinic agents in older individuals,
`
`of the cognitive tasks. The magnitude of efi'ect sizes, when
`
`the likelihood of these efi'ects occurring may difi'er widely
`
`expressed as Cohen’s d with a negative value representing
`
`across the medications in this class.” The propensity for
`
`deterioration in performance, were generally close to zero
`
`an antimuscarinic agent to cause CNS effects depends on
`
`with placebo, fesoterodine 4 mg, and fesoterodine 8 mg, but
`
`its physicochemical properties, including molecular size,
`
`this was not the case for alprazolam, demonstrating a true lack
`
`charge, structure, and lipophilicity, which determine its
`
`of effect between placebo and fesoterodine 4 and 8 mg, and
`
`potential to cross the BBB and its muscarinic receptor
`
`the converse for alprazolam. The small and equivalent effect
`
`subtype selectivity? Agents that have higher lipophilicity,
`
`I 2
`
`© Postgraduate Medicine. Volume I24, Issue 3, May 20|2. ISSN — 0032-54B| , e-ISSN — I94 I -9260
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`
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`
`

`
`Table 2. Most Frequently Reported TEAES‘
`
`TEAE, n (%)
`
`Dry mouth
`Ataxia
`Dizziness
`Headache
`Sedation
`Sornnolence
`
`Placebo
`(N = 20)
`
`0 (0)
`o (0)
`I (5)
`3(|5)
`I (5)
`0 (0)
`
`Fesoterodine
`4 mg
`(N=20)
`2 (I0)
`o (0)
`2 (I0)
`I(5)
`o (0)
`0 (0)
`
`Lack of Fesoterodine Cognitive Effects
`
`Fesoterodine
`8 mg
`(N=I9)
`6 (32)
`o (0)
`I (5)
`2(|l)
`o (0)
`0 (0)
`
`Alprazolam
`I mg
`(N=I9)
`0 (0)
`2 (I I)
`4 (2|)
`2(|l)
`I0 (53)
`2 (I I)
`
`‘Data represenI:TEAEs occurring in 2 2 subietts in a treatment condition in the safety set (all subjects who received study drug).
`Abbreviation: TEAE, treatment-emergent adverse event.
`
`smaller size, neutral polarity, and are not substrates of the
`
`investigating the CNS effects of darifenacin, solifenacin,
`
`P-gp efflux transporter are most likely to penetrate and
`
`tolterodine extended release, and trospium.3-39-4° Currently,
`
`remain within the CNS.25~” Agents that have high affinity
`
`the evidence suggests lack of effect on cognitive function
`
`for muscarinic M1 and M2 receptors, which are abundant
`
`with darifenacin, solifenacin, tolterodine, and trospium.3”-“'45
`
`in hippocampus and prefrontal cortex and known to be
`
`It has been reported that the quarternary amine trospium is
`
`important for memory, may also be more likely to produce
`
`cognitive effects.”
`
`undetectable in the cerebrospinal fluid of older individuals
`after oral administration.“
`
`The present results, showing an apparent lack of effect of
`
`Inclusion in this study required that the older adults have
`
`fesoterodine 4 and 8 mg on cognitive fimction, are consistent
`with data suggesting that 5-HMT, the active metabolite of
`
`no cognitive impairment; therefore, the current results do
`not extend to circumstances where antimuscarinic drugs are
`
`fesoterodine, has a relatively low lipophilicity at physiologic
`
`used to treat OAB in older adults with cognitive impairment
`
`pH and a low potential for penetration into the CNS? After
`
`(eg, in Alzheimer's disease or after stroke). In addition,
`
`oral dosing, fesoterodine is rapidly and extensively converted
`
`this study population had a relatively high level of educa-
`
`by ubiquitous esterases to 5-HMT, and fesoterodine, the
`
`tion compared with the general population of the United
`
`parent compound, is not detectable. Thus, antimuscarinic
`
`States.“ It is possible that older adults with higher levels of
`
`activity after oral fesoterodine administration is primarily
`attributable to 5—HMT.7 Tolterodine is also converted to
`
`education are less prone to cognitive impairment with anti-
`
`muscarinics, perhaps due to higher brain reserve. Lastly, the
`
`5—HMT; however, in contrast to fesoterodine, this occurs
`
`primarily in the liver via cytochrome P450 (CYP) 2D6. For
`
`number of concomitant medications, and thus the potential
`for cumulative anticholinergic effects, may have been lower
`
`this compound a significant fraction of unconverted tolt-
`
`in this population of healthy older adults than in the general
`
`erodine is found in plasma.“ Tolterodine is relatively lipo-
`
`population of older adults. These limitations should be con-
`
`philic compared with 5-HMT and has a relatively increased
`
`sidered when interpreting the observed treatment effects in
`
`potential for crossing the BBB? Although tolterodine has
`
`the context of the overall population.
`
`not been associated with significant CNS adverse events in
`
`clinical trials,” the potential for such effects is increased in
`
`Conclusion
`
`the approximately 7% of white and 2% of black individuals
`
`In these healthy older adults, fesoterodine 4 and 8 mg had
`
`in the population who are referred to as CYP 2D6 poor
`metabolizers. Among other antimuscarinics, oxybutynin is
`
`no statistically significant effects compared with placebo on
`any of the cognitive functions assessed, including memory.
`
`relatively lipophilicl and is associated with significant cogni-
`
`in contrast,
`
`in the same adults, alprazolam resulted in a
`
`tive effects. Additionally, antimuscarinics that are substrates
`
`large, generalized, and statistically significant deterioration
`
`of the P-gp efflux transporter, such as 5-HMT, darifenacin,
`
`in cognitive functioning compared with placebo.
`
`and trospium, have been shown to exhibit lower levels of
`
`brain penetration than agents that are not P—gp substrates,
`
`such as oxybutynin, solifenacin, and tolterodine.” In clinical
`
`Acknowledgments
`Funding for this study was provided by Pfizer Inc, and
`
`studies, oxybutynin has been associated with deterioration
`
`employees of Pfizer Inc and Pfizer Ltd were involved in the
`
`in cognitive function in older individuals.”'3°'4' In fact,
`
`study design, data collection, data analysis, and manuscript
`
`oxybutynin has been used as an active-comparator in studies
`
`preparation for this study. Medical writing assistance was
`
`© Postgraduate Medicine, Volume I24. Issue 3, May 20|2, ISSN — 0032-543i, e-ISSN — I94!-9260
`Researchsharem: l1ttp:.0'www.research-share.com1'Get|t - Copyright Clearance Center: l1ttp:n'n’www.copyright.corn
`
`I 3
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2084 - 0007
`
`

`
`Kay et al
`
`provided by Simon J. Slater, PhD, and Colin P. Mitchell,
`
`PhD, of Complete Healthcare Communications, Inc., and
`was funded by Pfizer Inc.
`
`Conflict of Interest Statement
`
`Gary G. Kay, PhD discloses a conflict of interest with
`
`Allergan, Novartis, Pfizer Inc, and Watson. Paul Maruff,
`
`PhD discloses a confiict of interest with Cogstate Ltd. David
`Scholfield, MBBS discloses a conflict of interest with Pfizer
`
`Inc. Birnal Malhotra, PhD discloses a conflict of interest
`
`with Pfizer Inc. Laurence Whelan, PhD discloses a confiict
`
`of interest with Pfizer Inc. Amanda Darekar, MSc a confiict
`
`of interest with Pfizer Inc. Diane L. Martire, MD discloses
`a conflict of interest with Pfizer Inc.
`
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