E)_(p_ert
`Opinion
`
`1. Overview of the market
`
`.”"F'E“!"
`
`Introduction to the compound
`
`Chemistry
`
`Pharmacodynamics
`Pharmacokinetics
`and metabolism
`
`Clinical efficacy
`
`5-°.°°."'.°" Conclusions
`
`Safety and tolera bility
`
`Regulatory affairs
`
`10. Expert opinion
`
`Drug Evaluation
`
`Fesoterodine: a novel muscarinic
`
`receptor antagonist for
`the treatment of overactive
`
`bladder syndrome
`
`Martin C Michel
`
`Urziversity ofA msrerdam. Department afPImrmrzml'ogy zmd Pbarmmxotlaempy,
`Academic Medical Center, Meibergdreqff 5, I I 05 .A.ZAm5reralam, The Netherlands
`
`Background: Fesoterodine is a newly approved drug for the treatment
`of overactive bladder syndrome. Objective: The aim of this study was
`to review the preclinical and clinical data on fesoterodine. Methods:
`The study involved a search of the Medline database and the proceedings
`volumes
`of
`urological
`congresses. Results/conclusions:
`Fesoterodine
`functions as an orally active prodrug that
`is converted to the active
`metabolite
`5-hydroxymethyltolterodine
`by
`non-specific
`esterases.
`5-Hydroxymethyltolterodine is a muscarinic receptor antagonist. Fesoterodine
`is primarily eliminated as inactive metabolites along with significant renal
`excretion as the unchanged active metabolite 5—hydroxymethyltolterodine.
`Fesoterodine is indicated for use at doses of 4 and 8 mg once daily.
`In
`clinical studies both doses of fesoterodine were consistently superior to
`placebo in improving the symptoms of overactive bladder syndrome, with
`8 mglday having significantly greater effects than 4 mglday.
`
`Keywords: blood~brain barrier, Cytochrome P450 ZDG, fesoterodine,
`5-hydroxymetliyltolterodine, muscarinic receptor antagonist, overactive bladder syndrome
`
`Expert Ofiifi. P/mrrmlrat/Jar: (2008) 9U 0).'I787-I796
`
`1. Overview of the market
`
`Overactive bladder syndrome (OAB) is present in ~ 16% of the adult population
`and muscarinic receptor antagonists are the standard of care in its treatment |l].
`More recently they have also been considered for
`the treatment of male
`lower urinary tract
`symptoms, which historically have been attributed to
`benign prostatic hyperplasia [2]. Several representatives of this class are available,
`including darifenacin, oxybutynin, propiverine.
`solifenacin,
`tolterodine and
`trospiurn, with tolterodine being the global market leader. While generally well
`tolerated, their efficacy relative to placebo is only moderate [1,5]. While several of
`these drugs have multiple registered doses, close dependency is only poorly
`established. Moreover, many of these drugs have usage restrictions in special
`patient populations. Other drug classes have not been approved for use in OAB,
`but botulinum toxin and fiyadrcnoceptor agonists are currently in advanced
`clinical development.
`
`2. Introduction to the compound
`
`informa
`healthcare
`
`Fesoterodine functions as an orally active prodrug that is converted to its active
`metabolite 5-hydroxymethyltolterodine
`(5-HMT)
`by non-specific
`esterases.
`5—Hydro)-tymethyltolterodine is a competitive muscarinic receptor antagonist.
`
`10.1 51 7‘.’146S5560802l66944 © 2008 Informa UK Ltd ISSN 1465-6566
`
`1787
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2073 - 0001
`
`

`
`Fesote rodine
`
`HO
`
`Fesoterodine
`
`Nonspecific
`esterases
`
`l
`
`OH YN
`H
`
`Tolterodine
`
`iCYP3A4
`
`T»
`CYP2D6
`
`Ho
`
`°” Y
`H
`
`I
`
`5-HMT
`
`J CYP3A4
`
`C
`
`OH
`
`H
`
`H
`
`N
`
`.
`
`O
`
`OH
`
`H
`
`T.
`CYF'2D6
`
`H0
`
`H
`
`N
`
`'
`
`T»
`CYP2D6
`
`Ho
`
`°” Y
`H Y
`
`5-CM
`
`X CYP3A4
`
`OH
`
`0 0 N
`T
`., Y
`
`HO
`
`Z.
`
`CYP2D6
`
`N-dealkylated metabolite
`(Tolterodine-specific)
`
`N-dealkylated 5-HMT
`
`N-dealkylated 5—CM
`
`Figure 1. Schematic depiction of the metabolism of tolterodine and fesoterodine.
`Courtesy of Pfizer Inc.
`S-CM: 5-Carboxy metabolite of 5-HMT.
`
`3. Chemistry
`
`The structures of fesoterodine and 5-HMT are shown in
`
`Figure 1. S-Hydroxymethyltolterodine is chemically identical
`to an active metabolite of tolterodine, which has also been
`
`mentioned in previous reports under the code names DD01,
`I’NU—200577 or SPM 7605.
`
`4. Pharmacodynamics
`
`rapidly and
`Following oral administration fesoterodine is
`completely metabolised to 5-HMT and the parent compound
`fesoterodine is not detected in the peripheral blood (see
`below). Therefore, most of the preclinical and clinical
`pharmacology of fesoterodine is
`relevant and discussed
`in relation to the active metabolite 5-HMT rather than
`
`The pharmacological properties of 5-HMT have been
`investigated in radioligand binding studies with cloned
`human muscarinic receptor subtypes and with endogenously
`expressed receptors in the urinary bladder, salivary glands
`and other tissues. An early study reported 5-HMT affinities
`values) of 2.3, 2.0, 2.5, 2.8 and 2.9 nM at cloned M1,
`M2, M3, M4
`and M5
`receptors,
`respectively, whereas
`tolterodine exhibited slightly but consistently lower affinities
`of 3.0, 3.8, 3.4, 5.0 and 3.4 nM, respectively [4]. A later
`study largely confirmed these findings and additionally
`reported that
`the parent drug fesoterodine had much
`lower affinities at all muscarinic receptor subtypes (631,
`501, > 1000, 158 and > 1000 nM,
`respectively)
`[5]. The
`affinities of 5-HMT, as determined in studies in the urinary
`bladder, salivary glands and other tissues of guinea-pigs [4],
`mice [6,7] and humans [8], are consistent with the data
`
`the parent compound fesoterodine
`
`from the cloned human receptor subtypes (Table 1). Thus,
`
`1 788
`
`Expert Opin. Pharmacother. (2008) 9(10)
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2073 - 0002
`
`

`
`Table 1. Affinities of tolterodine, fesoterodine and 5-HMT in radioligand binding studies and functional
`experiments.
`
`Tolterodine
`
`Fesoterodine
`
`5-HMT
`
`Ref.
`
`Michel
`
`Binding to cloned human muscarinic receptors (-log Ki)
`
`M2
`
`M2
`
`M3
`
`M3
`
`8.4
`
`8.2
`
`8.5
`
`7.9
`
`Binding to muscarinic receptors in tissues (-log Ki)
`
`Guinea pig bladder
`Mouse bladder
`
`Mouse bladder
`
`Human bladder (detrusor)
`
`Human bladder (urothelium)
`
`Guinea pig salivary gland
`
`Mouse salivary gland
`
`Guinea pig heart
`Mouse heart
`
`8.6
`8.9
`
`8.9
`
`ND
`
`ND
`
`8.3
`
`8.9
`
`8.8
`8.7
`
`Functional in vitro antagonism in the bladder (pKB)
`Rat
`ND
`
`Guinea pig
`Human
`
`ND: Not determined.
`
`8.5
`9.0
`
`ND
`
`6.3
`
`ND
`
`< 6.0
`
`ND
`ND
`
`ND
`
`8.6
`
`8.6
`
`ND
`
`ND
`
`ND
`ND
`
`8.7
`
`ND
`ND
`
`8.7
`
`8.8
`
`8.6
`
`8.2
`
`8.5
`9.1
`
`9.1
`
`ND
`
`ND
`
`8.3
`
`8.9
`
`9.0
`9.1
`
`8.8
`
`9.1
`9.0
`
`[4]
`
`[5]
`
`[4]
`
`[5]
`
`[4]
`[5]
`
`[7]
`
`[5]
`
`[8]
`
`[4]
`
`[5]
`
`[4]
`[5]
`
`[5]
`
`[11]
`[12]
`
`based on pharmacological characterisation combined with
`undetectable systemic exposure of fesoterodine after its oral
`administration to humans,
`the parent drug fesoterodine at
`its therapeutic doses is considered pharmacologically inactive
`and its clinical effects appear
`to be fully mediated by
`5—HMT [9]. Furthermore, 5-HMT lacks relevant affinity for
`a range of more than 50 other molecular targets [I0]. These
`data demonstrate that 5-HMT, as the active metabolite of
`
`fesoterodine, has a high selectivity for muscarinic receptors
`and recognises all of their subtypes with similar affinity.
`Nevertheless,
`a
`slightly higher
`affinity for muscarinic
`receptors in the bladder as compared to those in the salivary
`glands has been reported consistently across several studies
`(Table 1): this tissue selectivity can most likely be explained
`by differential tissue penetration [6].
`Functional in virro studies on the effects of 5-HMT have
`
`been reported from isolated bladder strips of rats [5], guinea-
`pigs
`[11]
`and humans
`[12]. 5-Hydroxymethyltolterodine
`caused a concentration-dependent parallel right shift of the
`concentration—response curve of the muscarinic receptor
`agonist carbachol
`in rats without affecting the maximal
`carbachol response: based upon this competitive antagonism
`an affinity (KB value) of 1.6 nM was calculated [S], which
`is
`in good agreement with the radioligand binding data.
`
`the
`fesoterodine under
`A similar apparent potency of
`same experimental conditions indicated rapid conversion
`of
`fesoterodine
`to
`5-HMT by
`the
`bladder
`strips.
`5-Hydroxymethyltolterodine
`also
`inhibited
`contraction
`of the rat bladder upon electrical field stimulation,
`that is
`due to the release of endogenous agonist, in a concentration-
`dependent manner
`and a
`concentration of 0.]
`].1M
`was
`sufficient
`for maximal
`inhibition [5]. Competitive
`antagonism with a similarly high potency was demonstrated
`for 5-HMT in bladder strips from guinea—pigs
`[4] and
`humans (Table 1)
`[12].
`In the latter study 5-HMT also
`inhibited the contraction induced by field stimulation but not
`the receptor-independent contraction evoked by KCI, confirming
`the specificity of this drug for muscarinic receptors.
`In cystometric in vivo studies in female rats intravenous
`5-HMT at a dose of 0.01 mglkg significantly increased
`bladder capacity by 10% and contraction intervals by 11%
`and reduced micturition pressure by 63% [5]: similar findings
`were also obtained with intravenous administration of
`fesoterodine.
`In similar
`studies with anaesthetised cats
`
`5-HMT inhibited bladder contraction with an lD50 of
`15 nmollkg, whereas a 50% inhibition of salivary secretion
`required a close of 40 nmollkg (p < 0.05 versus the bladder),
`while in parallel experiments the potency of tolterodine
`
`Expert Opin. Pharmacother. (2008) 9(10)
`
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`Patent Owner, UCB Pharma GmbH — Exhibit 2073 - 0003
`
`

`
`Fesote rodine
`
`(ID50 values 101
`
`for both effects
`was consistently lower
`and 257 nmolfkg, respectively) [41,11].
`Oral fesoterodine or 5-1-IMT at doses of 30 mg/kg did
`not increase the gastrointestinal transit time in mice, whereas
`atropine (20 mgfkg), darifenacin (10 and 30 mg/kg) and
`solifenacin (10 and 30 mg/kg) inhibited the transit
`time
`by 33, 18 — 25 and 20 — 29%, respectively [13].
`Dedicated clinical studies on the possible adverse effects
`of 5-HMT on the CNS have not been reported yet.
`However, the CNS penetration of a drug depends largely on
`its lipophilicity [14].
`In this regard 5-HMT has a much
`lower
`lipophilicity than tolterodine
`(the octanol:water
`coefficient expressed as log D values was 0.74 versus 1.83)
`or other clinically used muscarinic receptor antagonists
`except for trospium [15,16]. Following oral administration of
`radiolabelled tolterodine only a
`small
`fraction of the
`radioactivity reaches the CNS and a CNS:blood ratio of
`radioactivity of 0.1 — 0.3 was
`reported in mice [15].
`Consistent with the lower lipophilicity of S-HMT relative
`to tolterodine,
`the CNS penetration of 5-HMT (assessed
`following oral administration of radiolabellcd fesoterodine)
`was even lower and a CNS:blood ratio of only 0.04 — 0.07
`was reported in mice [19]. These data indicate that, due to
`its
`low lipophilicity, 5-HMT exhibits a very low CNS
`penetration. This
`is
`consistent with data from mice,
`where > 80% of circulating active drug following tolterodine
`dosing was S-HMT and even considerably supratherapeutic
`doses did not affect memory [17]. Whether this translates
`into a clinically relevant advantage cannot be decided
`definitively
`based
`upon
`the
`presently available
`data,
`as
`tolterodine in doses up to 0.3 mg/kg also did not
`affect memory formation in rats under conditions where
`the same dose of oxybutynin or scopolamine significantly
`impaired it [18]. In non-selected groups of patients, including
`specific studies in the elderly [19], CNS-related adverse
`effects have typically not been reported with the use of
`tolterodine, but case reports have indicated that tolterodine
`may induce memory impairment or hallucinations in some
`individuals
`[20-23]. A recently reported dedicated study
`in VUlU.I1[CCl'S
`dC[f.‘C[Cd HO 3dVCfSC CFFCCKS Of
`[Ul[Cl'Od1Ilf.‘
`
`in a subgroup analysis
`on cognitive function [24]. However,
`of this
`study the phenotype for drug metabolism by
`CYPZDG [25] appeared to play a relevant role in adverse
`effects on rapid eye movement
`sleep. Thus, volunteers
`with the more frequently expressed ‘extensive metaboliser’
`(EM) phenotype, who can effectively convert tolterodine to
`S-HMT, exhibited no impairment of their REM sleep. In
`contrast, volunteers with the ‘intermediate metaboliser' (IM)
`or ‘poor metaboliser’
`(PM) phenotype, who produce little
`S-HMT from tolterodine [26], showed impaired REM sleep
`upon tolterodine treatment, that is the relative contribution
`of REM sleep declined significantly from 21.8 to 17.4% [24].
`These data indicate that
`the risk of CNS adverse events
`
`could be even lower with fesoterodine than with tolterodine,
`
`particularly in patients with the IM or PM phenotype with
`
`regard to CYPZDG: however, this remains to be confirmed
`in dedicated clinical studies.
`
`the available preclinical pharmacology
`Taken together,
`data demonstrate that S-HMT is a high-affinity, competitive
`antagonist of muscarinic receptors in the urinary bladder of
`several species, including humans and its potency is in good
`agreement with data from radioligand binding studies. Starting
`at
`low doses S-HMT affects bladder function in viva in
`
`experimental animals, as is to be expected from a muscarinic
`receptor antagonist. In direct comparative studies 5—HMT
`has an antagonist potency that is similar to or slightly higher
`than tolterodine. Consistent with
`its
`physicochemical
`difference to tolterodine,
`that
`is hydroxylation, 5-HMT
`exhibits less CNS penetration and, in patients with the IM
`or PM phenotype,
`this could translate into an even lower
`risk of CNS adverse events with fesoterodine.
`
`5. Pharmacokinetics and metabolism
`
`Following oral administration fesoterodine is not detected in
`the peripheral blood, thereby indicating a rapid and complete
`conversion to 5-1-IMT by non—specific esterases [9]. Although
`5-HMT is also a metabolite of tolterodine,
`there is an
`
`tolterodine
`fesoterodine,
`unlike
`distinction:
`important
`metabolism to 5-HMT is mediated by CYPZDG (Figure 1)
`and is subject
`to the CYPZDG phenotype of the patient.
`Accordingly, subjects with the EM phenotype of CYPZDG
`exhibit roughly similar serum concentrations of tolterodine
`and 5-I-IMT [11,27]. However,
`in subjects with the PM
`phenotype their plasma concentrations of tolterodine are
`considerably higher, with low or even undetectable levels of
`5-HMT [27]. Accordingly, the mean Cm” value and AUC of
`tolterodine can be five and 10 times higher,
`respectively,
`in subjects with the PM phenotype as compared to the
`EM phenotype with regard to CYPZDG [28]. Individual Cm“
`and AUC values span a range of over 100-fold across
`the genotypes [28]. In contrast, average plasma concentrations
`of 5-I-IMT following oral administration of fesoterodine
`differ by less than a factor of 2 in subjects with the PM
`and EM phenotypes, for example the values are 1.89 versus
`3.45 ng/ml, respectively, following a single dose of 4 mg
`of fesoterodine [29].
`
`A significant proportion of 5—HMT is excreted renally
`without additional metabolism and the renal clearance of
`5—I-IMT is ~ 250 ml/min, with > 15% of the administered
`
`fesoterodine dose excreted as unchanged S-HMT [30]. This
`raises the possibility that 5-HMT also could work from the
`luminal side of the bladder, an effect that may be clinically
`relevant based upon current discussions around the role of
`muscarinic receptors in the urothelium [31,32].
`pathways
`In
`addition
`to
`renal
`excretion, multiple
`exist for the metabolism of 5—HMT to inactive metabolites.
`
`are
`regard CYP2D6 and CYP3A4
`this
`In
`alternative and equally prominent pathways
`its carboxy and N-desisopropyl metabolites,
`
`two
`the
`form
`that
`respectively:
`
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`
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`
`

`
`each
`
`in
`
`turn
`
`is
`
`further metabolised
`
`to
`
`the
`
`final
`
`these
`[11]. Each of
`carboxy-N-desisopropyl metabolite
`three secondary metabolites is pharmacologically inactive.
`In
`addition to S-HMT,
`the
`inactive metabolites
`are
`also common between fesoterodine and tolterodine. The
`
`metabolic pathways of tolterodine and fesoterodine are
`shown schematically in Figure 1
`(the enzymes
`involved
`in the formation of the secondary metabolites have not
`been experimentally confirmed in all cases).
`The prodrug fesoterodine is absorbed almost completely
`from the gut, but non-specific esterases rnetabolise it rapidly
`and completely so that only S-HMT is detectable in the
`peripheral blood after oral administration of fesoterodine [9].
`This is also consistent with undetectable fesoterodine not
`
`only in the blood but also an absence of any appreciable
`fesoterodine being excreted in the urine or faeces. Although
`fesoterodine is completely converted to form 5—IcIMT,
`some of the converted 5-HMT is metabolised presystemically:
`nevertheless,
`the absolute bioavailability of 5-HMT from
`orally administered fesoterodine remains high, averaging
`~ 52% [33]. The pharmacokinetics of 5-I-IMT were found
`to be dose linear with the
`administered fesoterodine
`
`dose [29]. The appearance of 5-HMT in the blood is food
`independent
`[34], which allows
`fesoterodine to be taken
`with or without a meal. Specific Phase I studies have not
`demonstrated any evidence for clinically relevant pharmaco-
`kinetic differences between the genders or age groups [35]
`or between ethnic groups [56].
`Fesoterodine has been developed using a sustained release
`formulation for which the maximal plasma concentrations
`of S-HMT are reached after ~ 5 h with a terminal half-life
`
`of ~ 7 — 9 h across multiple studies in different populations
`with single and repeated dosing [9,29.3o,34.39]. In line with the
`half-life, no evidence of accumulation was
`seen upon
`fesoterodine treatment for multiple days in those studies.
`Taken fogffthef PIICSC ph3fInaCOl(lnC[lC data Suppflft Ofl.CC'd.3.lly
`administration of fesoterodine.
`
`With regard to special patient populations apart from
`gender, age [35] and ethnicity [36] the standard studies have
`been performed in patients with impaired kidney or liver
`function. In this regard one study compared subjects with
`normal
`renal
`function (glomerular
`filtration rate (GFR)
`> 80 ml/min) and those with a GFR of 50 — 80,
`
`30 — 50 and < 30 mlfmin [39]. Following log-transformation
`the
`5—HMT peak plasma concentrations
`in the renal
`impairment groups relative to those in healthy subjects were
`1.35, 1.48 and 2.03-fold, respectively: similar findings were
`obtained for
`the AUC values. These findings
`suggest
`that
`the starting dose of 4 mg/day of fesoterodine can
`also be used in patients with impaired renal
`function
`and can be titrated, with caution, to 8 mg/day in subjects
`with mild—to—moderate renal
`impairment.
`In contrast,
`the
`package inserts of tolterodine and tolterodine extended
`release (ER) require dose adjustment, at
`least for patients
`with severe renal impairment (GFR < 30 ml/min).
`
`Michel
`
`In another study the pharmacokinetics of fesoterodine
`were compared between healthy subjects and patients with
`moderate impairment of liver function (Child—Pugh B)
`[33].
`In the liver-impaired patients the Cm“ and AUC values were
`approximately twice the values of the healthy controls,
`whereas the terminal half—life was not significantly affected.
`These data indicate that the Starting dose of 4 mgfday can
`also be used in patients with mild-to-moderate hepatic
`impairment and can be titrated, with caution, to 8 mg/day
`in subjects with mild hepatic impairment. No data are
`currently available for patients with severe impairments of
`liver function and, thus, fesoterodine use is not recommended
`
`for
`the package inserts
`In contrast,
`in these patients.
`tolterodine and tolterodine ER require dose adjustment in
`all patients with impaired liver function.
`Finally, an interaction study with the potent CYP3A4
`inhibitor ketoconazol (200 mg) was performed,
`in which
`subjects with the EM and PM phenotypes with regard to
`CYPZD6 were analysed separately [37]. The maximal plasma
`concentrations of 5-HMT during ketoconazol administration
`in the EM and PM phenotype subjects were 2.2 and
`1.5
`times
`as high as
`in the absence of ketoconazol,
`respectively:
`the AUC value was affected similarly. These
`data suggest that the standard fesoterodine dose of 4 mg.’day
`can also be used in patients concomitantly receiving
`potent CYP3A4 inhibitors,
`regardless of their CYPZDG
`phenotype. In contrast,
`the package inserts for tolterodine
`and tolterodine ER do not
`recommend their use upon
`concomitant treatment with potent CYP3A4 inhibitors.
`Formulations allowing once-daily dosing are available for
`most of the muscarinic receptor antagonists used clinically
`for OAB treatment. In some cases this is achieved by specific
`formulations (e.g. oxybutynin, propiverine and tolterodine),
`while in other cases this is due to the intrinsic phatmacokinetic
`properties of the drug (darifenacin and solifenacin)
`[40].
`In this regard the very long elimination half-life of ~ 60 h
`for solifenacin deserves Consideration, as it may theoretically
`lead to accumulation [41].
`
`While some muscarinic receptor antagonists are primarily
`excreted Via the kidneys (e.g. trospium), others are intensively
`metabolised by the liver
`(e.g. darifenacin, oxybutynin,
`propiverine, solifenacin and tolterodine)
`[42]. Based upon
`these excretion pathways, dose adjustments are required in
`patients with impaired kidney or liver function as described
`in the respective package inserts. In contrast,
`the standard
`starting fesoterodine dose can be used in patients with
`impaired renal or hepatic function due to the combination
`of renal excretion and hepatic metabolism of 5~HMT.
`It
`is
`an
`intriguing observation from the
`available
`pharmacokinetic studies with fesoterodine administration
`that
`the interindividual variability in drug exposure is
`relatively small as compared to that reported, for example,
`for
`tolterodine (Figure 2). Obviously,
`such comparisons
`involve various processes, such as absorption, which is highly
`variable with trospium, metabolism and excretion [40]. In
`
`Expert Opin. Pharmacother. (2008) 9(10)
`
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`
`doses but lasted 12 weeks and involved 173 — 186 patients
`per group [43],
`that
`is
`it had a design and size similar
`to many previous Phase III studies in this indication. This
`study also demonstrated significant
`improvements of both
`primary efficacy variables relative to placebo. Based on these
`data on efficacy and tolerability, fesoterodine doses of 4 and
`8 mg/day were selected for the pivotal Phase III studies.
`As the OAB definition by the International Continence
`Society does not
`require urodynamic proof of detrusor
`overactivity [46], one of the Phase II studies had also involved
`pressure—flow investigations
`[45]. Their
`analysis
`showed
`similar clinical improvements in patients with and without
`detrusor overactivity at each fesoterodine dose tested.
`The design of the two Phase III studies was in line
`with the regulatory recommendations by the EMEA and
`FDA,
`that
`is
`these were placebo-controlled,
`randomised,
`double-blind multicentre studies of 12 weeks duration
`
`with > 250 patients per treatment group. The inclusion and
`exclusion criteria were similar to those of studies with other
`
`muscarinic receptor antagonists that have been submitted
`for
`registration in recent years. One of the two studies
`(performed in the US) had three arms and compared
`fesoterodine doses of 4 and 8 mg/day with placebo [47].
`The other study (largely performed in Europe) had a very
`similar design but additionally included a fourth group of
`patients who received 4 mg/day of tolterodine ER as active
`control
`[48]. Secondary analyses of the pooled data from
`both Phase III studies have also been reported [49,50].
`The patients in both Phase III studies had rather similar
`baseline characteristics and also exhibited rather similar
`
`[47.48]. Therefore,
`symptom improvements upon treatment
`they are described together. Both doses of fesoterodine were
`significantly more effective than placebo for
`the three
`co-primary efficacy variables of urinary frequency, urgency
`incontinence
`episodes
`and the percentage of patients
`reporting a treatment
`response (Figure 3), as well as for
`many secondary efficacy variables including the number of
`urgency episodes. The extent of symptom improvement was
`in a range similar to that reported with other muscarinic
`receptor antagonists
`in studies of a similar design [1].
`Only the symptom of nocturia was not consistently improved
`by fesoterodine. This is not surprising based upon the
`low baseline
`level of nocturia
`in these
`studies,
`the
`causes of nocturia and the observations
`multifactorial
`
`that other muscarinic receptor antagonists also did not
`yield consistent nocturia improvements in OAB patients [5]].
`An efficacy parameter, which has
`rarely been used in
`other studies but which may have direct
`relevance for
`patients, was
`the extrapolated number of incontinence-
`free days per week:
`this was consistently improved by
`both fesoterodine doses in both studies.
`
`Although several doses are available for most muscarinic
`receptor antagonists
`for OAB treatment,
`a significantly
`greater benefit with higher doses has typically not been
`reported [1]. In contrast, the fesoterodine dose of 8 mg/day
`
`Fesote rodine
`
`l
`
`_. C)O
`
`
`
`Coefficientofvariation(°/o)
`
`Figure 2. Variability (expressed as coefficients of variation)
`in maximal plasma concentrations upon oral treatment
`with fesoterodine (assessed as 5-HMT)
`in comparison
`with published data on tolterodine. The figure is based
`upon published data [9,25,27,29,34—35,3a—4o,55]. Note that data
`from both genders and different age and ethnic groups were
`included, whereas data from diseased subjects (other than OAB)
`were excluded.
`
`the case of fesoterodine the CYPZDG-independent generation
`of the active drug moiety appears to be a key explanation
`for
`the relatively small variability in 5-HMT exposure.
`Irrespective of such mechanistic considerations, a relatively
`small variability in exposure may be therapeutically beneficial,
`as it may lead to a greater predictability in clinical response.
`However, whether
`this indeed translates into a clinically
`relevant benefit cannot be determined from the presently
`available data.
`
`5. Clinical efficacy
`
`The clinical efficacy and tolerability of fesoterodine has been
`explored in 20 Phase I (partly described above), three Phase
`II and two Phase III studies. This includes a thorough study
`on the possible effects on QT intervals (see the section on
`clinical
`tolerability). Fesoterodine doses of 2, 4,
`8 and
`I2 mgfday were tested in placebo-controlled, randomised,
`double—blind multicentre
`trials
`during
`the Phase
`II
`studies [43.44|. One of these studies also involved urodynamic
`pressute—flow investigations
`[45]. The primary efficacy
`parameter of the Phase II studies was the number of daily
`micturition and urgency incontinence episodes. In the study
`performed in the US, which involved an 3-week treatment
`of only 38 — 47 patients per group, significant improvements
`relative to placebo were observed for both efficacy parameters,
`despite the small numbers of subjects, at fesoterodine doses
`of 4, 8 and 12 mg/day [44]. The second trial, performed
`in Europe,
`Israel and South-Africa,
`involved the same
`
`1792
`
`Expert Opin. Pharmacother. (2008) 9(10)
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2073 - 0006
`
`

`
`Michel
`
`was significantly more effective for most efficacy parameters
`than 4 mgfday in the pooled analysis of both Phase III
`studies [30]. Given the adverse effects of OAB on quality of
`life it also appears
`important
`that significant symptom
`l.IiIl.pl'OVCII1C1'lt5 HIE delfflctablff
`35 Carly 35 2 WeEk5 after
`initiation of fesoterodine treatment, that is the earliest time
`
`point of assessment after randomisation [50]. In this context
`it is also relevant that several rating scales assessing patient
`reported
`outcomes
`and
`quality of
`life
`have
`shown
`dose—dependent
`and significantly greater
`improvements
`with fesoterodine than with placebo [52].
`overall
`the
`in
`With regard
`to
`clinical
`end-points
`OAB population, comparisons among data sets obtained
`from different
`studies are problematic and only direct
`comparative studies
`allow reliable conclusions
`[1,3]. At
`present, one direct comparative study between fesoterodine
`and another muscarinic receptor antagonist exists, which is
`the four—armed Phase III study also including a patient
`group receiving tolterodine ER at 4 mg/day [48].
`In that
`study 8 mg/day of fesoterodine was numerically superior to
`both 4 mg/day of fesoterodine and 4 mg/day of tolterodine
`ER with regard to efficacy, but also had more adverse events
`(primarily dry mouth). A subsequent post /90: analysis of
`this study, comparing maximum registered doses of both
`agents,
`reported that fesoterodine at 8 mg/day was also
`statistically superior to tolterodine ER at 4 mg/day for the
`primary end-point
`(the number of urgency incontinence
`episodes) as well as for several secondary end-points [53].
`In contrast,
`the incidence of adverse events was almost
`
`identical with 4 mglday of fesoterodine and tolterodine ER,
`allowing for a direct comparison of their efficacy. Fesoterodine
`at 4 mg/day performed numerically better than tolterodine
`ER at 4 mg/day across all efficacy parameters, but a
`statistical analysis of this comparison has not been reported.
`Therefore,
`the present data only allow the conclusion
`that, at a similar adverse event
`incidence,
`the efficacy
`of 4 mg of fesoterodine is at
`least as good as that of
`tolterodine ER.
`
`7. Safety and tolerability
`
`In the Phase III trials, adverse events were noted in 55% of
`
`in the US study,
`the patients during placebo treatment
`whereas the corresponding incidences were 61 and 69%
`with 4 and 8 mglday of fesoterodine, respectively [47]. In the
`mainly European study these incidences were 38% with
`placebo and 50 and 58°43 with 4 and 8 mg/day of
`fesoterodine, respectively [43]. As expected for a muscarinic
`receptor antagonist, dry mouth was the most
`frequently
`reported adverse event but was rated as mild to moderate
`in most cases. In one Phase III study it was seen in 7, 16
`and 36% of patients receiving placebo, 4 and 8 mgfday
`of
`fesoterodine,
`respectively [47], whereas
`in the other
`Phase III study it was seen in 7.1, 21.7 and 33.8% in
`the same groups (16.9% for 4 mg/day of tolterodine) [43].
`
`20
`
`ski
`
`Micturitions
`
`it
`
`¢,v°
`\9°
`<2
`
`569
`
`<9
`us‘?
`0%
`o
`K\-
`(<56:
`{<69
`«o
`Urgency urinary incontinence
`
`”
`
`029°
`Q\@-
`
`40*
`
`bxég
`
`QQCQO
`Treatment response
`
`b-dig
`
`‘bioq
`Q00
`
`15
`
`E
`.9
`‘G
`.3 10
`
`E3
`
`9
`
`5
`
`0
`
`100
`
`so
`
`r:
`u3
`-3 so
`
`E 4
`B2
`
`0
`
`20
`
`0
`
`100
`
`so
`
`60
`
`40
`
`20
`
`0
`
`E1::
`I:
`.In
`E
`39
`
`on
`
`o°°°
`Q\%
`
`b-‘iii
`45‘
`
`D-($5
`
`«Q-3°
`
`QFQ
`(<9ro°
`
`Figure 3. Efficacy of 4 and 8 mglday of fesoterodine in
`comparison to that of placebo and 4 mglday of tolterodine
`ER in the European Phase III study for the three co-primary
`end-points: number of micturitions (baseline 11.5 — 12.0I24 h
`across all groups), number of urgency incontinence episodes
`(baseline 3.7 — 3.8/24 h across all groups) and treatment
`responders (defined as ‘greatly improved’ or 'improved').
`Adapted from [48].
`
`Expert Opin. Pharmacother. (2008) 9(10)
`
`1793
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2073 - 0007
`
`

`
`Fesote rodine
`
`reported adverse events during fesoterodine
`The other
`treatment were also qualitatively and quantitatively in the
`range of what has been reported with other modern
`muscarinic receptor antagonists [I].
`Based upon recent concerns regarding the cardiovascular
`safety of drugs in general, a thorough study of the possible
`effects on QT intervals was performed [33]. This included
`parallel groups of 64 — 68 subjects each, who were treated
`for 3 days with 4 mg/day of fesoterodine,
`the highly
`supratherapeutic dose of 28 mgfday of fesoterodine,
`the
`active control moxifloxacin at 400 mgfday or placebo. Both
`the standard dose of 4 mg.’day and the highly supratherapeutic
`dose of 28 mg/day did not provide any evidence of QT
`prolongation (e.g. QTC for 28 mg/day from 404.5 i 16.7 to
`400.] i 14.0 ms. with delta: -5.0 i 7.9 ms). In comparison
`a similar study with tolterodine showed no effect on QTC at
`the recommended doses (2 X 2 mg/day) whereas a modest
`QTC prolongation (5.6 i 2.1 ms) was
`seen at
`the
`supratherapeutic dose of 2 X 4 mg/day: while the authors
`considered that
`to be clinically irrelevant
`[27], others have
`questioned this interpretation [54].
`
`8. Regulatory affairs
`
`Based upon the accumulated preclinical and clinical data
`the EMEA granted marketing authorisation approval
`for
`fesoterodine in April 2007. A registration procedure with
`the US authorities is under way.
`
`9. Conclusions
`
`Taken together, the available Phase II and III data show that
`fesoterodine at 4 and 8 mg/day is effective in the treatment
`of OAB symptoms. The overall efficacy and tolerability are
`in the range of what has been reported with other muscarinic
`receptor antagonists. A major difference as compared to
`other drugs is a significant dose dependency of its efficacy.
`This could be related to the smaller variability in exposure
`to active drug (see above), which facilitates the detection of
`
`dose differences due to a smaller data scatter. Moreover,
`
`based upon its pharmacokinetic and metabolic profile, only
`small restrictions