Novel treatment agent of overactive bladder syndrome Fesoterodine

1
Novel treatment agent of overactive bladder
syndrome Fesoterodine

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• ???

2
Desired Profile of an Optimised Antimuscarinic
Individualised Approach for OAB Treatment
2

• Consistent efficacy and good tolerability in
  improving OAB symptoms at therapeutic doses
• Consistent improvements in patient-reported
  outcomes, including HRQL
• Dose flexibility
• At least two doses, preferably with distinct
  dose-related efficacy yet similar safety and
  tolerability
• Dose flexibility allows for individual titration
  of therapy to produce a maximum efficacy versus
  tolerability in individual cases

Kaplan SA et al. JAMA. 20062962319-2328.Rogers
R et al. Int Urogynecol J. 2008191551-1557.Hegd
e SS. Br J Pharmacol. 2006147(suppl
2)S80-S87. Chapple CR et al. Eur Urol.
200854543-562.
3
Introduction to Fesoterodine
3

• Fesoterodine is a new once-daily antimuscarinic
  for the treatment of OAB symptoms
• Fesoterodine is structurally related to
  tolterodine
• Rapidly and extensively converted to
  5-hydroxymethyl tolterodine (5-HMT), which is
  also the active metabolite of tolterodine
• Fesoterodine has been developed in two strengths
• 4 mg once daily and 8 mg once daily
• Tolterodine ER has one recommended strength (4 mg
  once daily)

Chapple C et al. Eur Urol. 2007521204-1212.
Detrusitol SR SmPC. 2007. Pfizer Inc. Toviaz
SmPC. 2008. Pfizer Inc.
4
What Links Fesoterodine to Tolterodine?
4
Fesoterodine
Both fesoterodine and tolterodine form 5-HMT
(the active metabolite) via different pathways
The ratio between tolterodine and 5-HMT depends
on the patients CYP2D6 status
5-HMT alone is responsible for the
antimuscarinic effects of fesoterodine
The metabolic capacity in individuals can differ
from ultrarapid and extensive to poor
metabolisers (EMs or PMs), based on genotype or
drug interactions. Also known as SPM 7605 and
DD01.
Michel M. Expert Opin Pharmacother.
200891787-1796. Malhotra B et al. Int J Clin
Pharmacol Ther. 200846556-563. Brynne N et al.
Clin Pharmacol Ther. 199863529-539.
5
Fesoterodine PK Is Simple and Predictable
Fesoterodine Conversion to 5-HMT Is Simple and
Predictable
5-HMT
Esterases
Fesoterodine
Ubiquitous
Tolterodine Metabolism Is More Complex and Less
Predictable
Tolt
Tolt
Tolt


CYP2D6
Tolterodine
5-HMT
5-HMT
Liver, Gut
PoorMetabolisers ?7
ExtensiveMetabolisers ?78
Intermediate Metabolisers
Michel M. Expert Opin Pharmacother
200891787-1796. Malhotra B et al. Int J Clin
Pharmacol Ther. 2008 46556-563. Brynne N et al.
Clin Pharmacol Ther. 199863529-539.Zanger UM
et al. Naunyn-Schmiedebergs Arch Pharmacol.
200436923-27. Bradford LD et al. Int J
Neuropsychopharmacol. 19981173-185.
6
Key Pharmacokinetic Properties of Fesoterodine
6

• Fesoterodine acts like a prodrug of 5-HMT, to
  which it is
• rapidly and extensively converted
• 5-HMT has a favourable pharmacokinetic profile
• Linear, dose-proportional pharmacokinetics
• Terminal half-life is about 7 hours, allowing for
  once-daily dosing with little drug accumulation
• No clinically relevant food effect
• No gender, age, or racial differences
• No effect on QTc interval in thorough QT study
• No clinically significant variation in PK with
  morning and evening dosing

Malhotra B et al. Presented at Br Pharmacol Soc
Winter Meeting 2007. Cole P. Drugs Future.
200429715-720.Toviaz SmPC. 2008.
7
Phase 3 Results
8
Pooled Analysis of Phase 3 Data Key OAB
Endpoints
8
Treatment Response,
UUI Episodes/24 h
Placebo
Feso 4 mg
Feso 8 mg

Plt0.05
(n416)
(n427)
(n441)

90
0
77
69
80
-10
-20
70
-30
60
49
-40
50
Yes
-42.9
-50
40
Median Change
-60
30
-70
20
-80
-75.0

10
-83.3
-90

0
Placebo
Feso 4 mg
Feso 8 mg
Plt0.05
(n545)
(n532)
(n543)
Continent Days/wk
Mean Voided Volume, mL


Plt0.05
3.5
Plt0.05
3.1

40
33.6
35

3.0
2.6
30
2.5
22.2
25
1.8
2.0
LS Mean Change
20
LS Mean Change
1.5
15
9.0
1.0
10
5
0.5
0
0.0
Placebo
Feso 4 mg
Feso 8 mg
Placebo
Feso 4 mg
Feso 8 mg
(n539)
(n531)
(n540)
(n416)
(n427)
(n441)
Comparison of 8 mg vs 4 mg was a post-hoc
analysis. Plt0.05 vs placebo Analysis includes
only subjects with UUI at baseline
Extrapolated from 3-day diary data. LS least
square.
Khullar V et al. Urology. 200871839-843.
9
Post Hoc Analysis of Intl Trial Showed
Statistically Significant Difference Between
Fesoterodine 8 mg and Tolterodine ER 4 mg on Key
OAB Endpoints
9
Plt0.001 vs placebo Plt0.05 vs
placeboAnalysis includes only subjects with
UUI at baseline 3-day diary data extrapolated
to 7 days.
Chapple C et al. BJU Int. 20081021128-1132.
10
Pooled, Post Hoc Analysis of Efficacy of
Fesoterodine in Subjects With Different Baseline
Severity of UUI
10
Moderate (2 to lt4 UUI episodes)
Mild (gt0 to lt2 UUI episodes)
Severe (4 UUI episodes)
BL2.8
BL1.1
BL1.0
BL1.1
BL7.0
BL2.7
BL2.7
BL7.0
BL7.3


-100
-100

-68

Mean Change in UUI Episodes
-86
Plt0.05

-62

-71
Plt0.05
Plt0.05 vs placeboMedian percent change.
Cardozo L et al. Int Urogyn J. 200819(Suppl
1)S38(8).
11
Pooled Analysis Patient-Reported Outcomes Were
Improved With Fesoterodine Treatment
Pooled Analysis of SP583 and SP584 Placebo (n545) Feso 4 mg (n532) Feso 8 mg (n543)
Kings Health Questionnaire (KHQ)
Severity (coping) -7.4 -11.3 -13.7
Emotions -9.1 -12.4 -15.3
Role limitations -12.5 -18.5 -21.4
Physical limitations -11.4 -17.2 -19.6
Social limitations -7.9 -11.6 -13.8
Sleep/energy -7.8 -10.7 -12.3
Personal relationship -5.9 -7.8 -9.6
Impact on life -14.2 -19.6 -22.5
General health -2.4 -2.9 -2.6
ICIQ-SF -2.2 -3.6 -4.2
Plt0.05 vs placebo Plt0.05 vs Feso 4 mg
(post hoc analysis). Least-squares mean
change from baseline at Week 12 shown for KHQ and
ICIQ-SF.Minimally important difference (MID) 5
for KHQ and its domains. ICIQ-SF International
Consultation of Incontinence Questionnaire, Short
Form.
Kelleher CJ et al. BJU Int. 200810256-61.
12
Adverse Events Reported by ?2 of Subjects and
Exceeding Placebo Rate in Phase 3 Trials
Treatment-Emergent Adverse Event (all causality) Placebo (n554) Tolt 4 mg (n290) Feso 4 mg (n554) Feso 8 mg (n566)
Dry mouth 7 17 19 35
Constipation 2 3 4 6
UTI 3 1 3 4
Dry eyes 0 lt1 1 4
Dyspepsia lt1 2 2 2
Dysuria lt1 1 1 2
Nausea 1 2 lt1 2
Dry throat lt1 1 lt1 2
Dry throat lt1 1 lt1 2

• Urinary retention rate was 1 in the fesoterodine
  4- and 8-mg groups
• Total discontinuations due to dry mouth in
  fesoterodine patients lt1

Chapple C et al. Eur Urol. 2007521204-1212. Nitt
i VW et al. J Urol. 20071782488-2494.Khullar V
et al. Urology. 200871839-843.
In at least 1 of the active treatment groups.
UTI urinary tract infection.
13
Long-Term Open-Label Efficacy and Safety Study
13

• 3-year, open-label extension study of one (Intl)
  Phase 3 trial
• Of 417 subjects entering the extension study
• 85 remained enrolled at 4 months
• 79 remained enrolled at 8 months
• 73 remained enrolled at 1 year
• 59 remained enrolled at 2 years
• 56 remained enrolled at 3 years
• All 417 subjects started on 8 mg, with an
  opportunity to reduce dose after 1 month of
  treatment and at later visits
• 19 of subjects chose to decrease dose to 4 mg at
  1 month
• Long-term (3 y) treatment with fesoterodine was
  safe and well tolerated, with 75 to 80 of
  patients remaining on 8 mg

Van Kerrebroeck PEV et al. Abstract presented at
EAU 2009.
14
Long-Term Open-Label Efficacy and Safety Study
Results

• Safety and Tolerability
• Over the 3 years, discontinuations due to adverse
  events occurred in 12 of subjects
• Due to dry mouth 2.0
• Due to constipation 1.0
• There were no unexpected adverse events
• There were no clinically relevant changes in
  vital signs, ECG, or laboratory parameters
• Efficacy
• Long-term treatment with fesoterodine resulted in
  maintained or continued improvement in all
  efficacy and health-related quality of life
  measures
• Results for long-term US study were similar

Van Kerrebroeck PEV et al. Abstract presented at
EAU 2009.
15
Summary of the Phase 3 Study
15

• Robust efficacy on diary endpoints and
  patient-reported outcomes with both the 4-mg and
  8-mg doses of fesoterodine
• Pooled analyses showed that fesoterodine 8 mg
  resulted in significantly larger improvements vs
  fesoterodine 4 mg on key OAB symptoms
• The earliest on-treatment assessment of efficacy
  was at 2 weeks by then, statistically
  significant improvements were seen vs placebo on
  key OAB symptoms
• Fesoterodine 8 mg resulted in significantly
  larger improvements vs tolterodine ER on key OAB
  symptoms
• Good tolerability profile at both the 4 and 8 mg
  doses
• Overall discontinuations due to dry mouth were
  low (lt1)
• Constipation remained relatively low even with
  the higher, 8 mg dose of fesoterodine
• Placebo (2), fesoterodine 4 mg (4),
  fesoterodine 8 mg (6)

Chapple C et al. Eur Urol. 2007521204-1212. Nitt
i VW et al. J Urol. 20071782488-2494. Khullar V
et al. Urology. 200871839-843. Chapple C et al.
BJUI. 20081021128-1132.