Current M'('a'r'('r'mt1'Clwiirfslry, 2009, 16, 4481-4489
`
`4481
`
`The Design and Development of Fesoterodine as a Prodrug of 5-
`Hydroxymethyl Tolterodine (5-HMT), the Active Metabolite of Tolterodine
`
`B. Malhotra*‘], K. Gandelrnan], R. Sachsez, N. Wood3, M.C. Miehel4
`
`iffizer Inc’, New Yorlr, NY, USA.‘ 2SCHl/VARZ Bi'0Sei'eriCes, M0m’1ei'm, Ger'mcm_v,' 3Pfizer Global Re.rear'c’l1 and
`Development, S(II’1i$lWlCl’t, Kent, UK,‘ 4Urilversl{v of/lmsterdam, Amsterdam, The Netherlands
`
`Abstract: This review highlights the design and development of fesoterodine (Toviazo) as a prodrug of5—hydi'oxymetliy1
`tolterodine (5-11MT). which is also the active metabolite oftolterodine. for the treatment of overactive bladder (OAB).
`Tolterodine and 5-HMT are both potent antimusearinic agents. A prodrug approach was necessary for systemic bioavail-
`ability of 5—HMT after oral administration. Fesoterodine was selected amongst a series of ester analogues of 5—HMT to
`develop an advanced OAB treatment with an optimum hiopharmaeeutics profile. while maintaining a pharmacological
`link to tolterodinc.
`
`the logD value. a determinaiit of lipophilieity and
`While tolterodinc and 5-l-{MT have similar antimusearinie activity.
`permeability across biological interfaces such as the gut wall and blood-brain barrier. is eonsidembly lower for 5-llMT
`(0.74) versus tolterodinc (1.83). In contrast to the cytochrome P450 (CYP) 2D6-mediated metabolism of tolterodinc. 5-
`HMT formation from fesoterodine occurs via ubiquitous nonspecific esterases. Consequently, treatment with fesoterodine
`results in consistent. genotype-independent exposure to a singular active moiety (5-HMT): treatment with tolterodinc re-
`sults in CYPZDO genotype-dependent exposure to varying proportions of two active moieties (5-HMT and tolterodinc). At
`least partially due to the avoidance ofvariations in pliarmaeokinetie exposures observed with tolterodinc. it was possible
`to develop fesoterodine with the flexibility oftwo efficacious and well-tolerated dosage regimens of4 and 8 mg daily.
`
`Keywords: Fesoterodine. prodrug. 5-HMT. tolterodinc. metabolite. lipophilicity. CNS.
`
`INTRODUCTION
`
`Overactive bladder (OAB) is defined by the lnternational
`Continence Society as urgency, with or without urgency in-
`continence. usually accompanied by increased daytime fre-
`quency and nocturia [l]. The etiology of OAB remains un-
`clear, although it
`is generally accepted that OAB is often
`associated with detrusor overactivity. which may result from
`inappropriate levels of cholinergic activation of muscarinic
`receptors on the detrusor muscle or afferent nerves [2]. An-
`timuscarinic agents are the mainstay of pharmacologic
`treatment for OAB;
`their therapeutic effect
`is presumably
`mediated via blockade of muscarinic receptors on detrusor
`smooth muscle cells. urothelium, and/or sensory afferents,
`thereby inhibiting detrusor contractions [3, 4].
`
`tolterodinc, and
`solifcnacin,
`Darifenacin, oxybutynin,
`trospium are among the antimuscarinic drugs approved for
`the treatment of urgency urinary incontinence (UUI) and
`other symptoms related to OAB. The effectiveness of oxybu-
`tynin has been demonstrated in several clinical studies. but
`the clinical usefulness of oxybutynin is limited due to an-
`timuscarinic side effects. Dryness of the mouth is the most
`common experienced side effect which may be severe
`enough to result in poor compliance or discontinuation of
`treatment [5-7]. Tolterodine. a potent and competitive an-
`timuscarinic agent. was the first drug specifically developed
`for OAB treatment. Preclinical pharmacological data show
`that tolterodinc exhibits more potent antimusearinic receptor
`activity in vivo in the urinary bladder over the effect on the
`salivation, whereas oxybutynin exhibits the reverse selectiv-
`ity [8]. The favorable bladder selectivity of tolterodinc dem-
`onstrated in preclinical studies has been confirmed in clinical
`
`’’‘Address correspondence to this author at the Clinical Sciences. Pfizer Inc.
`(:85 3rd Avenue. New York. NY 10017. USA: Tel: 1-212-733-4723:
`Fax: 1-212-441-4490: E-mail: himal.k.ma1hotraaflpfizer.com
`
`studies [6]. Tolterodine being a tertiary amine, combined
`with other physicochemical attributes such as low lipophilie-
`ity and positive charge. has relatively low central nervous
`system (CNS) penetration in animal models and a low inci-
`dence of CNS adverse events in clinical trials [9-l 1]. Thus
`good clinical efficacy combined with low incidences of dry
`mouth and other antimuscarinic side effects makes tol-
`
`terodinc a treatment ofehoiee for OAB [12, 13]. However.
`clinicians and patients are not completely satisfied with OAB
`therapy despite the availability of tolterodinc and the newer
`antimuscarinic agents, solifenacin and darifenacin. because
`of a suboptimal efficacy/tolcrability balance or the inability
`to achieve optimal efficacy in difficult-to-treat patients.
`The clinical effects of tolterodinc are derived from the
`
`combined exposure to two active moieties, the parent drug
`(tolterodinc)
`and
`its
`equipotent
`active metabolite
`(5-
`hydroxymethyl tolterodinc; 5-HMT). which is formed via a
`major pathway involving the cytochrome P450 (CYP) 2D6
`enzyme [14]. Since CYPZD6 is genetically polymorphic
`there is considerable variability among patients in the pro-
`portion of these moieties, with higher exposures to tol-
`terodinc in CYPZD6 poor metabolizers (PMs) compared
`with extensive metabolizers (EMs) [l4.
`l5].
`ln a multiple-
`dose study of tolterodinc, the tolterodinc area under the con-
`centration-timc curve (AUC) values varied over a 130-fold
`range across CYPZD6 EMs and PMs whereas those for 5-
`HMT varied over a 5-fold range in EMs (5-HMT was not
`formed in PMs) [15]. Likely dLIe to the high variability of
`tolterodinc exposures.
`the development of tolterodinc was
`limited to only a single dosage of4 mg daily, although the
`dose may be lowered to 2 mg daily based on individual re-
`sponse and tolerability.
`
`involving
`Delivery of 5-HMT as a new drug without
`CYPZD6-mediated metabolism of tolterodinc has advantages
`compared to tolterodinc because only one active principle
`would be handled by the patients with less variability. which
`
`U929-8673/09 $55.0[l+.ll[l
`
`(0 2009 Beiitliam Science Publisliers Ltd.
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2074 - 0001
`
`

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`4482 Current M'('a'r'cr'naI CII('nn'.I‘(ry, 2009 V01. I6, N0. 33
`
`M'aHm.rra at :11.
`
`should result in a lower variation in efficacy and fewer side
`effects. The introduction of an additional hydroxyl group in
`the toltcrodine molecule, however, results in reduced lipo-
`philicity, which could produce a side effect profile with CNS
`penetration even lower than that of toltcrodine but would
`also result
`in lower absorptionfbioavailability.
`In order to
`overcome the absorption disadvantage, different prodrugs of
`5-IIMT have been synthesized and tested for their antimus-
`carinic activity, potential
`absorption through biological
`membranes. and enzymatic cleavage.
`
`Fesoterodine (Toviaza) is the isobutyric acid ester of 5-
`11MT which, based on its optimum biopharmaceutical attrib-
`utes, was selected amongst a series of carboxylic acid ester
`analogs for development as a treatment for OAB at dosages
`of 4-mg and 8-mg daily. Fesoterodine is rapidly and exten-
`sively converted to 5-HMT, such that
`the pharmacologic
`activity appears to be primarily attributable to 5-HMT [16,
`17]. The physieoehemieal, pharmacologic, and metabolic
`properties of fesoterodine,
`in relation to toltcrodine, and the
`rationale for the development of fesoterodine are the subject
`of this review.
`
`1. Antimuscarinic Pharmacology of Tolterodine and 5-
`HMT
`
`The antimuscarinic activities of fesoterodine, tolterodine
`and 5-IIMT have been evaluated in membrane preparations
`of Chinese hamster ovary cells expressing the five mus-
`carinic receptor subtypes (M1—M5);
`the functional activities
`were determined in organ-bath studies using the rat bladder
`in vifm and in eystometry studies in rats in vivo [18]. These
`studies demonstrated that 5-HMT is the main active principle
`of fesoterodine, which acts as a prodrug, and that both to]-
`tcrodine and 5-HMT are specific muscarinic receptor an-
`tagonists at the M1 through M5 subtypes [18]. The potencies
`of various antimuscarinic agents, expressed
`Ki values for
`each muscarinic receptor subtype, are summarized in Table 1
`[19—24]. Across different studies reported in the literature,
`the absolute values of the in vitm affinity estimates vary
`somewhat, however,
`the relative affinities for the receptor
`subtypes are consistent for each antimuscarinic drug. Feso—
`terodine, being a prodrug, has very low but similar affinity
`across the five musearinie receptor subtypes.
`
`2. Biopharmaceutics and Preclinical Pharmacologic As-
`sessment: Selection of Fesoterodine
`
`A comprehensive evaluation of the absorption, distribu-
`tion, metabolism, and excretion (ADME) properties in pre-
`
`clinical models and in Phase 1 clinical pharmacology studies
`forms the biopharmaceutics-related determination of the de-
`velopment potential of therapeutic drug molecules. An inte-
`gration of the knowledge of the biopharmaceutics and pre-
`clinical pharmacological properties of a drug along with
`anatomic distribution of receptors can become useful
`in a
`qualitative prediction of the beneficial and adverse effects of
`the drug.
`
`Lipophilkity and CNS Penetration af5-HMT
`
`Muscarinie receptors are not only located in the target
`organ responsible for efficacy (bladder) but also in other
`tissues and organs (gastrointestinal
`tract, salivary glands,
`heart, and brain) that can affect the tolerability and safety of
`an antimuscarinic drug. For example, antimuscarinic drugs
`with greater M3 receptor occupation may cause greater inci-
`dence of dry mouth and constipation [25]. Relevant to the
`antimuscarinic pharmacology in the CNS, physicochemical
`properties such as lipophilicity and permeability are impor-
`tant predictors of the ability of a molecule to penetrate the
`blood-brain barrier (BBB), such that those with higher lipo-
`philicity at physiologic pH are more likely to exert pharma-
`cologic adverse effects (AEs) in the CNS. The logD values at
`the physiologic pH 7.4, determined from the oetanolzwater
`distribution coefficient [26], are commonly used to compare
`the lipophilicity of drugs as an indicator of their ability to
`cross the BBB and their propensity to cause CNS AEs. A
`significant and positive correlation between logD and CNS
`AEs has been demonstrated across the class of triptan drugs
`for the treatment of migraines [27].
`
`The logD for 5-HMT [14], toltcrodine [14], and other an-
`timuscarinic agents [14, 28-30] is shown in Table 2. 5-H MT
`has demonstrated low lipophilicity at acidic pH and higher
`lipophilicity at more basic pH [31], as expected for a com-
`pound with a pKa value of 9.28. The logD values of tol-
`tcrodine and 5-HMT have been reported to be 1.83 and 0.74,
`respectively (Table 2) [14]. In addition,
`the lipophilicity of
`several antimuscarinic agents used for treatment of OAB has
`been reported previously [14, 29, 32, 33]. Tolterodine has
`low lipophilicity and low CNS penetration (brain/blood ratio,
`0.1-0.3 for radioactivity) in mice [14] with no significant
`CNS AEs observed in patients [34]. LogD values for solifen-
`acin and oxybutynin are reported to be 1.69 and >3.3, re-
`spectively, suggesting that both of these compounds are
`more lipophilic than 5-HMT (Table 2) [24, 35]. Trospium
`chloride is a quaternary ammonium compound and, as such,
`would not cross the BBB because of its low lipophilicity
`(Table 2) [32]. The small logD for 5-HMT suggests that it is
`
`Table 1.
`
`Affinity of Various Antimusearinic Drugs for Human Muscarinie Receptor Subtypes
`
`Muscarinic
`Receptor
`
`Tolterodine
`|2 1, 22, 24]
`3.0, 3.0, 2.7
`3.8, 6.4, 4.2
`3.4. 12, 4.4
`5.0, 1.9, 6.6
`3.4, 4.6, 2.5
`
` ‘).U, 8.2
`
`5-HMT
`|2l , 22]
`
`Fesoterodine
`|22]
`
`Ki. nM
`
`Trospium
`|23]
`
`Oxybutynin
`|22, 24]
`
`Solifenacin
`|24]
`
`Darifenacin
`| 1'9, 24]
`35,3]
`56, 100
`1.2, 2.0
`13,52
`
`ND: Not f)ele1‘min'.1b|e ("S1J‘?=I. bintling at
`
`I
`
`|.IM),
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2074 - 0002
`
`

`
`Dm'i'gr: and Dvvdripriwrrf 0f'F:*.\'riterridirrc’
`
`C'urrw1t ."Wt’df£'fl!fl[ Clrwuiiflry, 2009 Vol. M. Na. 33
`
`4483
`
`Table 2. Lipophilieity of Various Antimusearinie Agents for Overactive Bladder
`
`Antimusearinie
`Agent
`Lngl)
`
`Truspium -I .22
`|28]
`
`5-HMT 0.74
`H4]
`
`Tulterorline L83
`H4]
`
`Lil 6
`
`@,.®
`
`O
`U 0 OH
`
`0
`
`Antimuscarinic
`Agent
`L0gD
`
`Solifenacin 1.69
`
`Darifenacin 2.7
`I30]
`
`() xyhutynin >-3.3
`I14]
`
`unlikely to cross the BBB and cause CNS effects. The low
`CNS penetration potential of 5-HMT is of particular clinical
`relevance in elderly patients. who may be taking a number of
`concomitant medications and are vulnerable to CNS Alis.
`
`A study comparing changes in quantitative-topographical
`clcctrocncephalogram (qEEG) activity following administra-
`tion of antimuscarinic agents demonstrated that oxybutynin.
`a tertiary amine, caused significant changes in four fre-
`quency bands compared with placebo and produced the
`highest number of CNS-related effects [34]. Neither
`tol-
`terodine. also a tertiary amine. or trospium chloride. a quar-
`ternary amine, produced significant changes in qEE(} activ-
`ity compared with placebo.
`
`The brain/plasma ratios of fesoterodine-related radioac-
`tivity have been reported to be approximately 0.04 and 0.07
`for maximal drug concentration (C.,,.‘,_..) and AUC, respec-
`tively. after single oral doses of MC-fesoterodine given to
`mice (data on file. Pfizer Inc). Similarly. permeability studies
`in a porcine model demonstrated that the BBB permeability
`eoeflieient of 5-H MT is 6.5x l()‘° em/s compared with per-
`meability coefficients of 23><l0'° cm/s
`for oxybutynin,
`solifenacin, and darifenacin (data on file: Pfizer Inc). Lower
`brain/plasma ratio and permeability with fesoterodine com-
`pared with tolterodine suggest an even lower risk of CNS
`AEs with fesoterodine than with tolterodine.
`In Phase 3
`
`following once-daily ad-
`trials with fesoterodine,
`clinical
`ministration of fesoterodine 4 or 8 mg or tolterodine 4 mg,
`there were no CNS AEs with an incidence rate greater than
`2% or exceeding that following placebo administration [9,
`ll), 36, 37]. Similarly,
`in a Phase 3 study of tolterodine, the
`incidence of CNS AEs ofsomnolenee and dizziness was low
`
`(3% and 2%, respectively) but slightly higher than that for
`placebo (2% and 1%, respectively) [3 8].
`
`Permeability 0f5-H1141} Improving Absorbubility by Pro-
`drug Apprmtrch
`
`While the lower lipophilicity of 5-HMT favors its CNS
`tolerability through lower CNS penetration. it also affects the
`ability of 5-IIMT to permeate other biological barriers, such
`as gut wall or skin for oral or transdermal delivery, respec-
`tively. Therefore. a prodrug approach was considered to
`structurally modify 5-llMT for enhanced permeability across
`human skin to facilitate the delivery of 5-HMT into the sys-
`temic circulation. Ester derivatives were considered as the
`
`choice for developing the prodrug of 5-HMT (Table 3), be-
`cause esterases are known to be ubiquitous and are not
`known to be subject to genetic polymorphism or drug inter-
`actions of clinical significance [39-41]. As a result of rapid
`and eflieient hydrolysis of an ester prodrug immediately af-
`ter permeability aeross the gut wall or skin. only 5-HMT
`would be available in the systemic circulation.
`
`To investigate the feasibility of nonsystemic delivery, the
`biological membrane permeability of 5-HMT along with its
`various ester analogues was assessed using flux rates across
`human skin in the flow-through cell model
`in vitro [42].
`Substitution of both the hydroxy groups of 5-l-IMT leads to
`approximately a 20-fold increase in skin permeation in rela-
`tion to 5-HMT. Surprisingly, monosubstitution of the pheno-
`lic hydroxy group resulted in even higher. about 50-fold in-
`creased, penetration rate through human skin. The in virr-0
`metabolism ofdifferent ester prodrugs to generate the active
`metabolite. 5-IIMT, by enzymatic process was evaluated in
`pooled human liver S9-preparation. The formation of the
`active metabolite depended on the substituents both at the
`benzylic and phenolic side of the respective compounds,
`with turnover rates ranging from 96% to 63%. Similar to
`permeability. monosubstitution of the phenolic hydroxy
`group resulted in highest
`turnover to form 5-IIMT [42].
`Overall, based on its optimized permeability (Table 3) and
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2074 - 0003
`
`

`
`4484 Current M'('a'r't'r'r:a1' CII('nn'.I‘(ry, 2009 V01. I6, N0. 33
`
`M'aHm.rra at al.
`
`Table 3. In Vitm Permeability of Various Structural Analogs of 5-HMT [42|
`
`(RHO 6
`
`O-R2
`HY
`\“\/N\‘/
`
`5-HMT Ester Derivatives
`
`Chemical designation (name)
`
`Permeation Rate (pg/em3l24 hours)
`
`
`
`Hydroxy
`
`Hydroxy
`
`lsobutyrate
`
`Propionate
`
`Hydroxy
`
`lsobutyrate
`
`lsobutyrate
`
`Propion-ate
`
`HO-/-OH (5 -hydroxymethyl tolterodine)
`
`HO-/-(')BL1t(fesoterodine)
`
`But()-/-()But
`
`|’rop(J-/-()|’rop
`
`rapid hydrolytic conversion, the isobutyrate monoester (feso-
`terodine) was considered to be the best candidate for bio-
`pharmaceutical development. Furthermore,
`the results ob-
`tained in the receptor binding and tissue assays demonstrated
`that the anticholinergic activity of the compounds decreases
`with increased derivatization, such that the ester derivatives
`were significantly less potent
`than 5-HMT:
`therefore, an
`ester such as fesoterodine. which has optimum permeability
`and efficient hydrolysis, would act effectively as prodrug of
`5-HMT.
`
`3. Elimination Pathways of Tolterodine, Fesoterodine,
`and 5-HMT
`
`it was demonstrated
`Based on pharmacokinetie studies,
`that fesoterodine is rapidly and extensively converted by
`nonspecific, ubiquitous esterases to 5-HMT, such that feso-
`terodine is undetectable in plasma after oral dosing [16, 17].
`Furthermore, compared with 5-HMT, fesoterodine is 2 or
`more orders of magnitude less potent at muscarinie receptors
`[22]. Further biotransformation of 5-HMT results in inactive
`metabolites, making 5-llMT the principal active moiety of
`fesoterodine after oral administration [l6, l7, 22] 5-HMT is
`also an active metabolite of tolterodine. but
`in contrast to
`fesoterodine,
`the metabolism of tolterodine to 5-llMT is
`more complex; it undergoes oxidation via CYPZD6 primarily
`in the liver (Fig. 1) [14]. Both tolterodine and 5-HMT con-
`tribute to the pharmacologic activity observed following
`administration of tolterodine, but the proportion of plasma
`tolterodine/5-H MT varies according to a patient’s CYP2D6
`genotype [15, 43]. Because the CYP2Do pathway is subject
`to genetic polymorphism,
`the efficiency with which indi-
`viduals can metabolize tolterodine to 5-HMT varies across
`
`the population [44]. Overall, CYP2D6 metabolizer status can
`be broken down into EMs, intermediate metabolizers (IMs),
`or PMs [44]. Approximately 7—l0"o of the Caucasian popu-
`lation are devoid of CYP2D6 (ie, PMs) and are unable to
`metabolize tolterodine efficiently and do not form 5-HMT.
`The CYP2D6 EMs can efficiently metabolize tolterodine to
`5-HMT, resulting in approximately similar exposures to tol-
`terodine and 5-HMT. IMs are less efficient at metabolizing
`tolterodine, resulting in a smaller proportion of5-HMT. This
`
`genetic variability in metabolic status, as well as variability
`arising from drug interactions with CYP2D6. leads to highly
`variable ratios of tolterodine and 5-llMT in different patients
`(Fig.1) [15, 45, 46]. As highlighted in Fig. (1), because feso-
`terodine functions as a prodrug and due to the involvement
`of esterases in the formation of 5-llMT, all patients are ex-
`posed to a single active moiety when fesoterodine is admin-
`istered. On the contrary. tolterodine itself is also active and
`due to CYPZD6-mediated metabolism of tolterodine to 5-
`
`HMT, depending on patient’s CYP2D6 genotype, varying
`proportions of two different active moieties are involved
`when tolterodine is administered.
`
`Whether formed after tolterodine or fesoterodine admini-
`
`stration, 5-HMT is subsequently metabolized to inactive ear-
`boxy. carboxy-N-desisopropyl. and N-desisopropyl metabo-
`lites, with CYP2D6 and CYP3A4 identified as likely to con-
`tribute
`to
`the
`formation of
`the
`earboxy and
`the N-
`desisopropyl metabolites.
`respectively,
`following incuba-
`tions with heterologously expressed human CYP isoforms
`and CYP chemical
`inhibitors (Fig. 2) [20]. Thus, CYP ac-
`tivity appears to be responsible for the further metabolism of
`5-HMT after administration of fesoterodine or tolterodine.
`
`The apparent oral clearance of 5-HMT is reduced by ap-
`proximately 40% in CYPZD6 PMs compared with EMs. A
`similar reduction in the apparent oral clearance of5-HMT is
`also noted; during concomitant administration of
`feso-
`terodine and the potent CYP3A4 inhibitor ketoconazole [47,
`48]. The observation that the magnitude of the increase in 5-
`llMT exposure was similar when either of the 2 pathways
`was absent/inhibited indicates
`that both CYP2D6 and
`
`CYP3A4 may play equally important roles in the elimination
`of5-llMT [47]. In addition to metabolic inactivation via two
`major pathways involving CYP3A4 and CY P2D6 enzymes,
`5-HMT is also excreted unchanged in the urine. accounting
`tor about 16% of the orally administered dose offesoterodine.
`Because of the availability of multiple metabolic and renal
`pathways for the elimination of 5-HMT. patient
`intrinsic
`(hepatic or renal impairment) or extrinsic (drug interactions
`with potent CYP3A4 or CYPZD6 inhibitors) factors have
`only a modest effect of about 2.5—fold increase in 5-HMT
`exposures [36]. These modest increases in 5-HMT exposures
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2074 - 0004
`
`

`
`Desigrr and Develapmem 0f'Fe.\'rJterrJdr'r:e
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`C'ur'reut :'l4'eal'i::'imu' Clrerrtixtry, 2009 Vol. M. Na. 33
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`4485
`
`Fesoterodine Conversion to 5-HMT Is Sim la and Predictable
`Esterases
`
`Fesoterodine
`
`/ 5-HMT
`Ubiquitous
`
`Tolterodine Metabolism is More Com [ex and Less Predictable
`
`Tolterodine
`
`CYP2 D6
`
`Z
`Liver, gut
`
`Tolt
`
`+
`
`Tolt
`
`"'
`@
`
`Tolt
`
`Extensive
`Melabolizers
`-78%
`
`Interm ediate
`Metabolizers
`-1 5%
`
`Poor
`Metabolizers
`-7%
`
`Fig. (1). l:'ste1‘ase-Mediated vs. CYP2D6-Mediated Forination of5-HMT; Tolt: Tolterodine; 5-HMT: 5-hydroxymethyl tolterodine.
`
`after fesoterodine administration are managed through sim-
`ple dosing recommendations in the product label that require
`fesoterodinc doses not exceeding the initial dose of4 mg/day
`under the aforesaid situations [36]. On the other hand, since
`CYP2D6 is the single predominant pathway involved in the
`elimination of tolterodine. potent inhibition of CYPZD6 ac-
`tivity by iluoxetine results in marked reduction in clearance
`(up to 93%) and increase in exposure (up to 14-fold) of tol-
`terodine. where as 5-HMT was undetectable [49]. Therefore,
`as a result of variations in patient-intrinsic and -extrinsic
`factors, relatively low inter-patient or inter-occasion variabil-
`ity in active moiety exposures is expected following feso-
`terodine administration compared with tolterodine.
`
`Fesolerodlne
`
`The antimusearinic effects of drugs used for OAB treat-
`ment [50] can potentially be attributed to the presence ofMg
`and M3 receptors (with a predominance of M3 receptors) on
`the detrusor muscle and the urothelium [2]. As shown in
`Table 4, some antimusearinic agents have an appreciable
`urinary excretion of unchanged parent drug (trospium [51,
`52] and solifenaein [53]) or an active metabolite (toltcrodine
`[10] and fcsoterodinc [36]), providing exposure to the active
`moiety locally in the bladder. The bladder exposure to the
`antimusearinic active moieties in these cases may have an
`effect on the afferent nerves located near the urothelium
`
`[54], which could impart additional efficacy in reducing
`OAB symptoms.
`
`J\‘¢°
`
`Tolterodine
`
`Tollblndlno-Spetifif mclabnlllt‘ N—dea||<ylated 5—HMT
`
`Nrdealkylaled metabolite
`
`OHY
`Hr
`
`Carboxyrmerabolire
`
`X CYFEA4
`
`Neealkylaled S—CM
`
`Fig. (2). Biotransfiarmation Pzttllwztys of Fesoterodine and Tolterodine: 5-HMT: 5-hydroxymcthyl tolterodinc
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2074 - 0005
`
`

`
`4486 Current M'('a'r'cr'nat' CIrt'rm'.rrry, 2009 Vol. 16, No. 33
`
`M'aHm.rra at al.
`
`Table 4. Systemic Bioavailability & Urinary Excretion of Various Antimuscarinic Drugs for Overactive Bladder
`
`4 mg
`(once-daily)
`
`toltcrodine
`
`|7"xi. (EM)
`(15% [ PM)
`
`Sanctura®
`|51|
`ttrnspiunl)
`
`20 mg
`(twice-daily)
`
`trnspiurn
`
`Sanctura®
`XR|52|
`ttrnspiunl)
`
`60 mg
`(once-daily)
`
`trnspiurn
`
`Vesica rc®
`|53|
`(snlifcnacin)
`
`10 mg
`(once-daily)
`
`snlifcnacin
`
`Enal)|ex® I5ll|
`(darifcnacin)
`
`Ditropan XL® [35|
`(nxyhutynin)
`
`15 mg
`(once-daily)
`
`darifcnacin
`
`20 mg
`(once-daily)
`
`nx_vhut_vnin
`
`dcscth_vl-
`mryhutynin
`
`60% of urinary
`L‘.\L‘1‘L‘tit)1t
`
`60% of urinary
`
`L‘.\L‘1‘L‘tit)1t
`
`Trade Name
`(generic
`name)
`
`Dose
`(regimen)
`
`Toviaz® I36|
`
`Detrol L/\® [1ll|
`
`(fesoterodine)
`
`(toltcrodine)
`
`8 mg
`(once-daily)
`
`Active Mnicty
`
`5-HMT
`
`Systemic
`Bioavailability
`ol'Active
`Mnicty
`
`Dose Excretecl
`as Active
`Moicty in
`Urine
`
`Active Moiety
`li.\c1'ctcd in
`Urine. mg**
`
`*Based on absolute bioavailability of'Sanctura® and the plasma area under the curve of tmspium following of Sanctura® XR vs. Sanctura®.
`*“L‘o1nputet.i based on highest dose and ‘A. ol't.iose e,~.ereted in urine (dose. hioavailability and ‘A. of urinary excretion l'o1'Sanctu1'a®).
`NR=not reported.
`
`4. Clinical Pharmacokinetic Studies of Fesoterodine
`Versus Tolterodine
`
`From an overall safety, tolerability and efficacy perspec-
`tive, following administration of therapeutic doses ofa drug,
`it becomes desirable to achieve a narrower and more predict-
`able range of systemic concentrations of the drug and/or its
`active mctabolite(s) across patients. This allows the physi-
`eian to use the drug in different patient types with a reason-
`able expectation of the effects in individual patients based on
`the results of controlled clinical trials.
`
`Findings from studies assessing the pharmacokinetics
`(PK) of toltcrodine and fesoterodine suggest
`that
`the PK
`variability observed after dosing with toltcrodine appears to
`be attributable to the toltcrodine molecule rather than 5-
`
`llMT. In an open-label, multiple-dose study, the PK of tol-
`tcrodine extended release (ER) were investigated in healthy
`volunteers [15]. Because CYPZD6 is the predominant elimi-
`nation pathway for toltcrodine and results in the formation of
`5-HMT. both toltcrodine and 5-HMT are active. Therefore
`the sum of both active moieties is relevant to the effects of
`
`toltcrodine. Fig. (3) demonstrates the serum concentration
`versus time profiles of the 2 active moieties separately and
`also combined following oral administration of toltcrodine
`ER, with each plot line representing individual subjects in a
`heterogeneous population of CYPZD6 EMs and PMs.
`In
`patients with normal CYP2D6 activity (EMs). roughly equal
`concentrations of toltcrodine and 5-HMT are seen. However,
`in patients with CYPZD6 activity absent
`(PMs),
`the tol-
`tcrodine concentrations are several-fold higher than those in
`EMs (Panel A) whilst 5-HMT is not quantifiable (Panel B).
`As a consequence, when toltcrodine was administered to a
`group of CYP2D6 EMs and PMs, the active moiety concen-
`trations varied over a wide range (almost 2 orders of magni-
`tude) as apparent in Panel C [15].
`
`When we separate the active moiety concentrations into
`individual contributions from toltcrodine and 5-HMT.
`it
`is
`
`apparent that unchanged toltcrodine is the primary source of
`variability. whereas 5-HMT exposures are maintained within
`a relatively narrow range (Fig. 3). For instance, examination
`of peak exposures indicates that the lowest and highest val-
`ues are 6-fold apart for toltcrodine but only 4-fold apart for
`5-HMT. The C.,,,,,, of toltcrodine varies between 1-60 nM
`[15], whereas the Cum of 5-HMT only varies between 3-13
`nM [55]. This is primarily related to CYP2D6 activity. as
`PMs have the highest toltcrodine concentrations. Since tol-
`tcrodine and 5—HMT are similar antimusearinie agents,
`the
`less variable pharmacokinetics of 5-HMT makes it a more
`desirable therapeutic molecule.
`
`Based on these data, it would be ideal to deliver 5-HMT
`without reliance on toltcrodine or CYP2D6, which is pre-
`cisely what has been accomplished by developing feso-
`terodine as a prodrug of 5-HMT. Fesoterodine itself is inac-
`tive and is converted rapidly and extensively by esterases to
`form 5-HMT,
`the singular active moiety in case of feso-
`terodine. In a separate open-label. single-dose study. the PK
`and dose proportionality investigation of fesoterodine sus-
`tained release (SR) were investigated in healthy volunteers
`[55]. In this study of fesoterodine in CYP2D6 PMs and EMS.
`each subject- whether EM or PM- has exposure to 5-llMT
`because its formation does not depend on CYPZD6. After
`fesoterodine administration. the inherent lower variability of
`5-llMT is maintained
`was seen with toltcrodine, without
`the high variability associated with toltcrodine.
`
`Although these data were obtained from 2 separate stud-
`ies in which toltcrodine or fesoterodine were administered to
`
`a heterogeneous group of EMs and PMs, comparisons of
`active moieties are of interest and valid, given the objective
`nature of PK measurements and the inclusion of subjects
`genotyped as EMs and PMs in both studies [15, 55, 56].
`While the fesoterodine study was single-dose, these data are
`representative of steady state because fesoterodine does not
`accumulate and the PK are time invariant. The individual
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2074 - 0006
`
`

`
`Desigrr and Drwralrlpnirarn‘ 0fFe.mt‘errJdiur3
`
`Current MediciIraICI:eI:1i.v1ry, 2009 V01. 16. Na. 33
`
`4487
`
`A
`
`100
`
`Toltorodlne ER 4 mg
`
`B
`
`100
`
`Tollerodine ER 4 mg
`
`u‘:
`
`E3:
`
`5 3
`
`oDEE
`
`10
`
`«E
`::
`
`1
`
`10
`
`1
`
`3 E‘
`
`.5’
`
`8 E E
`
`EO
`
`i-
`
`
`
`Tolterodine+5—HMTSerumCone(ng!mL)‘-7
`
`Time (hours)
`
`Time (hours)
`
`Tolterodlne EH 4 mg
`
`_. O0
`
`‘I0
`
`DI
`
`
`
`12
`Tlme (hours)
`
`IE
`
`24
`
`Fig. (3). Serum Concentrations of Active Moictics following Administration of Toltcrodinc 4 mg: (A) Toltcrodinc; (B) 5—HMT; (C) Sum of
`Active Moieties [15]. Solid curves represent CYP2D6 PMs and dashed curves represent CYP2D6 EMs; EMs: Extensive Metabolizers; PMs;
`Poor Mctabolizers.
`
`profiles in the graph for fesoterodine (Fig. 4) fall within a
`much narrower range than the profiles for tolterodine ER.
`This indicates that the range of exposures to active moiety
`(i.e., PK variability) across subjects is considerably less vari-
`able for fesoterodine than it is for tolterodine ER. When the
`
`dose of fesoterodine is increased to 8 mg, the resulting expo-
`sure range from fesoterodine remains similarly narrow. At
`higher exposures, efficacy generally reaches a ceiling due to
`receptor saturation but the incidence of some adverse events
`may increase. it is because of the lower PK variability that
`more patients are likely to fall within the therapeutic range
`after either dose of fesoterodine. Therefore,
`it may be con-
`cluded that fesoterodine delivers markedly reduced variabil-
`ity in total active moieties relative to toltcrodinc,
`in part al-
`lowing for the development of a higher dose of fesoterodine.
`Higher drug exposures with fesoterodine 8 mg combined
`with lower variability may improve consistency and predict-
`ability of symptom response, allowing individualization of
`therapy in patients treated for OAB.
`
`In various Phase 1 studies in healthy volunteers, feso-
`terodine doses from 4 to 28 mg exhibited dose-proportional
`increase in 5—HMT exposures, without significant changes in
`
`time to maximal concentration or half life across doses [16,
`55, 56]. Following fesoterodine administration, both C...“
`and AUC of 5—HMT showed low coefficient of variation,
`suggesting reproducibility.
`in two Phase 2 studies,
`feso-
`terodine has been administered to OAB patients without sig-
`nificant safety concerns up to the supratherapeutic dose of 12
`mg;
`the efficacy analyses showed that the l2-mg dose of
`fesoterodine provided no further appreciable incremental
`benefit compared with the 8—mg dose [57, 58].
`
`5. Clinical Efficacy of Fcsotcrodinc
`
`it was demon-
`In a pooled analysis of two phase 3 trials,
`strated that fesoterodine has the ability to significantly re-
`duce OAB symptoms, including urgency and UUI, in a dose-
`dependent fashion [59]. The 8-mg dose provides significant
`additional benefit in improving most bladder diary variables
`compared with the lower dose and allows for dose escalation
`and individualization in subjects with OAB. This allows sub-
`jects to achieve a better balance between treatment efficacy
`and tolerability.
`In a Phase 3 trial, fesoterodine 4 mg pro-
`vided numerically greater symptom relief in nearly all effi-
`
`Patent Owner, UCB Pharma GmbH — Exhibit 2074 - 0007
`
`

`
`4488 Current fl/Iea'r'cr'uaI C'Irt:rm'.u'!ry, 2009 VIII. 16, N0. 33
`
`A
`
`100
`
`Fesoterodine 4 mg
`
`U3
`
`Fesoterodine 8 mg
`
`Mkrflmtra at al.
`
`10
`
`r
`
`
`
`Tlme (hours)
`
`
`
`
`
`5-HMTPlasmaCan