Novel treatment agent of
overactive bladder syndrome
Fesoterodine
서울성모병원
김수진
2
Desired Profile of an Optimised Antimuscarinic:
Individualised Approach for OAB Treatment
• 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. 2006;296:2319-2328.
Rogers R et al. Int Urogynecol J. 2008;19:1551-1557.
Hegde SS. Br J Pharmacol. 2006;147(suppl 2):S80-S87.
Chapple CR et al. Eur Urol. 2008;54:543-562.
3
Introduction to Fesoterodine
• 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. 2007;52:1204-1212.
Detrusitol® SR SmPC. 2007. Pfizer Inc.
Toviaz® SmPC. 2008. Pfizer Inc.
4
What Links Fesoterodine to Tolterodine?
Tolterodine
Fesoterodine
O
O
HO
H
Rapid conversion
by ubiquitous
esterases
N
Both fesoterodine and
tolterodine form 5-HMT
(the active metabolite) via
different pathways
OH
HO
H
N
OH
H
N
Liver
metabolism
(CYP2D6)
The ratio between tolterodine
5-HMT alone is responsible
and 5-HMT depends on
for the antimuscarinic effects
the patient’s CYP2D6 status*
of fesoterodine 5-Hydroxymethyl tolterodine (5-HMT)†
*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. 2008;9:1787-1796.
Malhotra B et al. Int J Clin Pharmacol Ther. 2008;46:556-563.
Brynne N et al. Clin Pharmacol Ther. 1998;63:529-539.
Fesoterodine PK Is Simple and Predictable
Fesoterodine Conversion to 5-HMT Is Simple and Predictable
Fesoterodine
Esterases
Ubiquitous
5-HMT
Tolterodine Metabolism Is More Complex and Less Predictable
Tolterodine
CYP2D6
Liver, Gut
Tolt
Tolt
+
+
5-HMT
Extensive
Metabolisers
78%
5
Tolt
5-HMT
Intermediate
Metabolisers
Poor
Metabolisers
7%
Michel M. Expert Opin Pharmacother 2008;9:1787-1796.
Malhotra B et al. Int J Clin Pharmacol Ther. 2008 46:556-563.
Brynne N et al. Clin Pharmacol Ther. 1998;63:529-539.
Zanger UM et al. Naunyn-Schmiedebergs Arch Pharmacol. 2004;369:23-27.
Bradford LD et al. Int J Neuropsychopharmacol. 1998;1:173-185.
6
Key Pharmacokinetic Properties of
Fesoterodine
• 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. 2004;29:715-720.
Toviaz® SmPC. 2008.
Phase 3 Results
7
8
UUI Episodes/24 h†
Feso 4 mg
(n=427)
Feso 8 mg
(n=441)
Yes
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
Placebo
(n=416)
Treatment Response, %
-42.9%
-75.0%
*
-83.3%
*
P<0.05
Mean Voided Volume, mL
40
35
30
25
20
15
10
5
0
P<0.05
*
22.2
*
33.6
9.0
Placebo
(n=539)
Feso 4 mg
(n=531)
Feso 8 mg
(n=540)
LS Mean Change
LS Mean Change
Median % Change
Pooled Analysis of Phase 3 Data:
Key OAB Endpoints
90
80
70
60
50
40
30
20
10
0
*
69%
P<0.05
*
77%
49%
Placebo
(n=545)
Feso 4 mg
(n=532)
Feso 8 mg
(n=543)
Continent Days/wk†‡
3.5
*
2.6
3.0
P<0.05
*
3.1
2.5
2.0
1.8
1.5
1.0
0.5
0.0
Comparison of 8 mg vs 4 mg was a post-hoc analysis.
Placebo
(n=416)
Feso 4 mg
(n=427)
Feso 8 mg
(n=441)
*P<0.05 vs placebo; †Analysis includes only subjects with UUI at baseline;
‡Extrapolated from 3-day diary data.
LS = least square.
Khullar V et al. Urology. 2008;71:839-843.
Post Hoc Analysis of Int’l Trial Showed Statistically
Significant Difference Between Fesoterodine 8 mg and
Tolterodine ER 4 mg on Key OAB Endpoints
Tolt ER 4 mg
(n=290)
Feso 8 mg
(n=287)
-25
-50
-75
-100
P<0.001
*
LS Mean Change
Continent Days/wk‡§
4
P<0.05
*
3
2
1
0
Placebo
Tolt ER 4 mg
Feso 8 mg
(n=283)
(n=290)
(n=287)
*P<0.001 vs placebo; †P<0.05 vs placebo;
‡Analysis includes only subjects with UUI at baseline;
§3-day diary data extrapolated to 7 days.
Median % Change
0
Placebo
(n=283)
Micturition Frequency/24 h
LS Mean Change in MVV (mL)
Median % Change
UUI Episodes/24 h‡
0
-5
-10
-15
-20
-25
-30
Placebo
(n=283)
Tolt ER 4 mg Feso 8 mg
(n=290)
(n=287)
†
*
Mean Voided Volume, mL
P<0.05
40
*
30
†
20
10
0
Placebo
(n=283)
Tolt ER 4 mg
(n=290)
Feso 8 mg
(n=287)
Chapple C et al. BJU Int. 2008;102:1128-1132.
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Pooled, Post Hoc Analysis of Efficacy of
Fesoterodine in Subjects With Different Baseline
Severity of UUI
Moderate
(2 to <4 UUI episodes)
Mild
(>0 to <2 UUI episodes)
Placebo
Mean Change in UUI Episodes
BL=
1.1
0
-1
BL=
1.0
Feso
4 mg
BL=
1.1
*
-100%†
-2
Placebo
Feso
8 mg
*
Feso
4 mg
Severe
(≥4 UUI episodes)
Feso
8 mg
Placebo
BL=
2.7
BL=
2.8
BL=
7.0
BL=
2.7
BL=
7.3
Feso
4 mg
Feso
8 mg
BL=
7.0
-100%†
*
-68%†
*
-86%†
-3
P<0.05
-4
*
-62%†
*
-71%†
-5
P<0.05
*P<0.05 vs placebo;
†Median percent change.
Cardozo L et al. Int Urogyn J. 2008;19(Suppl 1):S38(#8).
10
Pooled Analysis: Patient-Reported Outcomes
Were Improved With Fesoterodine Treatment
Placebo
(n=545)
Feso 4 mg
(n=532)
Feso 8 mg
(n=543)
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
-2.2
-3.6*
-4.2*
Pooled Analysis of SP583 and SP584
King’s Health Questionnaire (KHQ)
ICIQ-SF
*P<0.05 vs placebo;
†P<0.05 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.
11
Kelleher CJ et al. BJU Int. 2008;102:56-61.
ICIQ-SF = International Consultation of Incontinence Questionnaire, Short Form.
Adverse Events Reported by 2% of Subjects*
and Exceeding Placebo Rate in Phase 3 Trials
Treatment-Emergent
Adverse Event
(all causality)
Placebo
(n=554)
%
Tolt 4 mg
(n=290)
%
Feso 4 mg
(n=554)
%
Feso 8 mg
(n=566)
%
Dry mouth
7
17
19
35
Constipation
2
3
4
6
UTI
3
1
3
4
Dry eyes
0
<1
1
4
Dyspepsia
<1
2
2
2
Dysuria
<1
1
1
2
Nausea
1
2
<1
2
Dry throat
<1
1
<1
2
• Urinary retention rate was 1% in the fesoterodine 4- and 8-mg groups
• Total discontinuations due to dry mouth in fesoterodine patients: <1%
*In at least 1 of the active treatment groups.
12
UTI = urinary tract infection.
Chapple C et al. Eur Urol. 2007;52:1204-1212.
Nitti VW et al. J Urol. 2007;178:2488-2494.
Khullar V et al. Urology. 2008;71:839-843.
Long-Term Open-Label Efficacy and
Safety Study
13
• 3-year, open-label extension study of one (Int’l) Phase 3 trial
• Of 417 subjects entering the extension study:
–
–
–
–
–
85%
79%
73%
59%
56%
remained
remained
remained
remained
remained
enrolled
enrolled
enrolled
enrolled
enrolled
at
at
at
at
at
4
8
1
2
3
months
months
year
years
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.
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
14
Van Kerrebroeck PEV et al. Abstract presented at EAU 2009.
Summary of the Phase 3 Study
•
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 (<1%)
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. 2007;52:1204-1212.
Nitti VW et al. J Urol. 2007;178:2488-2494.
Khullar V et al. Urology. 2008;71:839-843.
Chapple C et al. BJUI. 2008;102:1128-1132.
15