Download New Developments in the Treatment of Male OAB

Optimal dose of botulinum toxin A
for MS, Parkinson’s, and OAB
Sender Herschorn, MD, FRCSC
Division of Urology
University of Toronto
Botulinum Toxin
900kD complex
COOH
NH2
S-S
Light
Chain
NH2
S-S
Heavy
Chain
COOH
Local, temporary inhibition of vesicle-mediated neurotransmission
BoNT/A actions
Efferent nerve terminal
Afferent nerve
Urothelial cell
Kanai et al. N & U 2012, 31:300-8
Effect of BoNT/A
 Increase
 Bladder capacity
 Volume at first reflex detrusor contraction
 Compliance
 Decrease detrusor pressures
during filling and voiding
 Improvement in urgency – thought
to be afferently mediated
Apostolidis et al. Eur Urol 2006; 49:644-650
BoNT/A for refractory patients
Systematic review for NDO
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18 studies with 698 patients
3 retrospective with series with >75 patients
3 prospective studies
Majority were small open-label studies
Overall BoNT/A provides clinically significant
improvements in refractory NDO
Karsenty et al. Eur Urol 2008; 53:275-287
Herschorn et al. J Urol 2011; 185:2229-2235
Leakage episodes
Daily mean frequency of
leakage episodes
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
* P<0.05
*** P<0.001
***
***
*
§
BL
6
24
36
48
§
60
BoNT/A
Placebo
§ P<0.001
Compared to
baseline
Weeks afterWeeks
initial injection
after initial injection
Herschorn et al. J Urol 2011; 185:2229-2235
Adverse events
Botulinum toxin A
(n=28)
No. pts. (%)
Placebo
(n=29)
No. pts. (%)
Urinary tract infection
16 (57)
16 (55)
Voiding difficulty/retention
6 (21)
2 (7)
Headaches
6 (21)
5 (17)
Nausea +/- vomiting
6 (21)
2 (7)
Muscle weakness
3* (11)
* 1 unrelated
Herschorn et al. J Urol 2011; 185:2229-2235
Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50.
NDO study design

Multicentre (global), randomized, double-blind 52week study sponsored by Allergan, Inc

275 SCI or MS patients with UI due to NDO
 Not
adequately managed by
anticholinergics

Up to 2 treatments of 300 U, 200 U or placebo

Primary Endpoint: Number of UI episodes at week 6

Secondary Endpoints: Urodynamics, Incontinence
Quality of Life (I-QOL)
Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50.
Significant Decrease in Urinary
Incontinence
Change in urinary incontinence episodes/week
Baseline
*
*
*
*
*
*
* p= <0.001 in pairwise comparison versus placebo
Mean baselines:
Placebo = 36.7/wk, 200 U = 32.5/wk, 300 U = 31.2/wk
Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50.
Significant Increase in MCC
Change in MCC at 6 weeks
*
*
* p= <0.001 in pairwise
comparison versus placebo
MCC: Maximum cystometric capacity
Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50.
Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50.
Duration of Symptom Relief in Bladder Was
Approximately 9 Months
Based on time to patient request for re-treatment
300 U
Median
Median == 42.1
42.1 weeks
weeks
200 U
Median
Median == 42.1
42.1 weeks
weeks
29 weeks
Placebo
Median
Median==13.1
13.1weeks
weeks
0
10
20
Weeks
30
40
50
12 weeks was the earliest time
point when patients were
allowed to request treatment
6 months
9 months
1 year
Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50.
Adverse Events ≥ 5% in Any
Treatment Group
Adverse Events ≥ 5% (All of treatment cycle 1)
Placebo (N=90)
200 U (N=91)
300 U (N=89)
Overall
74.4 %
86.8 %
88.8 %
UTI
40.0 %
56.0 %
64.0 %
Urinary retention
3.3 %
19.8 %
31.5 %
Hematuria
4.4 %
5.5 %
10.1 %
Fatigue
1.1 %
8.8 %
3.4 %
Dysuria
2.2 %
5.5 %
7.9 %
Nasopharyngitis
3.3 %
6.6 %
6.7 %
Constipation
2.2 %
5.5 %
6.7%
Diarrhea
6.7 %
3.3 %
6.7 %
Muscle spasms
1.1 %
4.4 %
6.7%
Muscular weakness
1.1 %
6.6 %
4.5 %
Pyrexia
3.3 %
6.6 %
1.1 %
Arthralgia
5.6 %
3.3 %
1.1 %
Influenza
0
5.5 %
1.1 %
Urinary incontinence
2.2 %
5.5 %
1.1 %
Pain in extremity
3.3 %
5.5 %
2.2 %
Cruz F, et al. Eur Urol. 2011 Oct;60(4):742-50.
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416 pts. – 227 MS, 189 SCI and DO
14+ UI episodes/wk
1o endpoint – ΔUI episodes/wk,
2o endpoints – MMC, MDP, IQOL; AEs
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200U and 300U reduced UI episodes by 21 and 23/wk vs. 9 in placebo
(P<0.001)
Median time to retreatment was 256 and 254 days vs. 92 in placebo
Most common AEs were UTI and retention
IC initiated in 10% placebo, 35% 200U, and 42% 300U
®
BOTOX
Summary of
Phase 3 Trials

Studies demonstrated BOTOX® provided sustained benefits
to patients with NDO in terms of:


UI, urodynamic parameters, QOL
300 U dose provided no additional clinically relevant
benefits compared with 200 U, but:

300 U associated with increase in PVR and more
patients initiating catheterization

Mostly in MS patients who were not using CIC
 Higher incidence of UTI and retention in 300 U group
 Approved dose is 200 U
UTI: Urinary tract infection
PVR: Post-void residual
Long-term follow-up
Two 24-week,
randomised,
multicentre,
double-blind,
placebo-controlled
phase 3 studies
First patient in
2009
Protocol
amendment*
Aug 2012
Final patient out
Aug 2014
3-year, long-term follow-up study
OnabotA 100U*
OnabotA 100U vs
placebo
24 weeks
Up to 2 treatments
Up to 3 years
Multiple treatments, request for re-treatment initiated by patient
*Originally, a dose increase from 100U to 150U was permitted from treatment 3 onwards. Since the
150U dose did not provide additional efficacy, the protocol was amended to allow only the 100U
dose. The current analyses include data for the 100U dose only.
OnabotA = onabotulinumtoxinA.
Kennelly et al. Neurourol Urodyn epub 2015
Mean change from baseline in
daily UI episodes (week 6)
OnabotA consistently improved UI, volume/void, and QOL in patients with
UI, with no new safety signals
Kennelly et al. Neurourol Urodyn, 2015, epub
4-y efficacy and safety in
completers
 To assess year to year consistency of
outcomes in 227 pts.
 1.4-1.5 treatments per year
 Reduction of UI -3.4 to -3.9 episodes/d (BL 4.3)
 High proportion ≥50% and 100% reductions (88.694.1% and 43.6-57.4%)
 Median duration of effect ≥9 mo.
 ≥26% experienced effect ≥12 mo.
 Most common AE was UTI
Rovner et al. J Urol epub 2016
MS pilot study – 100U
 12 patients (11 women, 1 man)
 At 6–7weeks, sig. improvement in bladder capacity,
maximum detrusor pressure, urinary frequency urgency and
pad use.
 At 12-14 weeks sig. improvement in frequency, nocturia,
urgency and pad use.
 PVR sig. increased and reached 222 ml initially but
decreased over time for 12 weeks - 3 patients needed to
perform CIC
 No change in incontinence episodes
 10/12 pts. were satisfied; mean duration 8 mo.
Mehnert et al. J Urol, 2010; 184:1011-16
BoNT/A in Parkinson’s
Disease
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4 women with PD and 2 with MSA
200 U (OnabotA) in 20 sites
Questionnaires, micturition diary, UD assessments
At 1, 3, and 5 mo. all improved
No UTI, 3 with PD had to strain to void, 2 with MSA
needed daily CIC
 No systemic AEs
Giannantoni et al. J Urol 2009; 182:1453-7
BoNT/A in Parkinson’s
Disease
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10 women and 6 men with PD
500 U (AbobotA) in 30 sites
Questionnaire, Clinical, UD, Mict. Diary follow-up
Every 3 mo. until 1y
All parameters significantly better
At 9 mo.
 10 still improved, 12 prescribed medical therapy; 4 requested
reinjection
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No pt. needed IC
No neurological deterioration
Kulaksizoglu et al. Parkinsonism & RD 2010; 16:531-4
BoNT/A in Parkinson’s
Disease
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7 women and 1 man
100 U OnabotA in 10 sites
Clinical and UD assessments at 1, 3, and 6 mo.
All pts. had improved parameters
Increased PVR at 1 month but decreased at 3 and 6
months
 2 women with PVR of 300 mL
 2 women needed CIC
 No systemic AEs or PD deterioration
Giannantoni et al. J Urol 2011; 186:960-4
BoNT/A in Parkinson’s
Disease
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12 men, 8 women
100 U OnabotA in 10-20 sites including the trigone
At 3 months moderate to marked symptom relief
At 6 months 59% had ≥50% incontinence decrease
3 men had PVR at 1 month
2 men given α-blockers
2 women had UTIs
Anderson et al. Urology 2014; 83:22-7
Botulinum toxins
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OnabotulinumtoxinA (Botox/Botox Cosmetic),
AbobotulinumtoxinA (Dysport)
RimabotulinumtoxinB (Myobloc)
IncobotulinumtoxinA (Xeomin)
 All are different pharmacologically and are
not interchangeable
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/
DrugSafetyInformationforHeathcareProfessionals/ucm174949.htm
Conclusions - NDO
 BoNT/A intradetrusor injections are safe and
effective for patients with refractory UI from
NDO
 Patient selection on the basis of clinical and
UD parameters
 Dosing
 200 U for SCI and many MS patients
 100 U for PD and if concerned about retention
Systematic review for OAB
 Intravesical BoNT/A improves
refractory OAB symptoms
 Significant risk of increased PVR
and symptomatic urinary retention
 Optimal administration to be
determined
Anger et al. J Urol 2010; 183:2258
Phase 2 RCT for IOAB with
Onabot – Dose response
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RCT with 313 patients followed for 36 weeks; placebo and 5 doses
Primary efficacy variable at 12 weeks was weekly UUI episodes
UUI episode decrease

Doses ≥ 100 U durable efficacy; PVR increase related to dose
Dmochowski et al. J Urol 2010; 184:2416-22
Phase 2 RCT for IOAB with
Onabot - QoL


RCT 313 patients (288 females) with 36 week follow-up
50 – 300 U
King’s Health Questionnaire
>100U

Doses ≥ 100 U produced sig. QoL measurement
improvements
Fowler et al. Eur Urol 2012; 62:148-57
Objectives and Study Design
 To evaluate the efficacy and safety of onabotulinumtoxinA
in patients with OAB and urinary incontinence who have
been inadequately managed with anticholinergics
 Multicenter, randomized, placebo-controlled pivotal study
 Patients randomized to onabotulinumtoxinA 100 U or
placebo in 1:1 ratio
 N= 557 (onabotulinumtoxinA 100 U = 280; placebo =
277)
 Total number of clinical sites = 72
 24 weeks duration, primary timepoint week 12
Nitti et al. J. Urol 2013; 189:2186-93
Results: Percent Change from Baseline
in All OAB Symptoms
% Change at week 12
OAB symptom
OnabotA 100 U
Placebo
Urinary incontinence episodes
- 47.9 %
- 12.5 %
Micturition episodes
- 16.9 %
- 4.1 %
Urgency episodes
- 31.6 %
- 10.0 %
Nocturia episodes
- 20.2 %
+ 0.2 %
Nitti et al. J. Urol 2013; 189:2186-93
Results: Adverse Events ≥ 5%
First 12 weeks
Any time in treatment cycle 1
OnabotA 100 U
Placebo
OnabotA 100 U
Placebo
(N= 278)
(N= 272)
(N= 278)
(N= 272)
Urinary tract
infection1
43 (15.5%)
16 (5.9%)
68 (24.5%)
25 (9.2%)
Dysuria
34 (12.2%)
26 (9.6%)
40 (14.4%)
27 (9.9%)
Bacteriuria
14 (5.0%)
5
(1.8%)
23 (8.3%)
10 (3.7%)
Urinary retention2
15 (5.4%)
1
(0.4%)
16 (5.8%)
1
Hematuria
7
(2.5%)
15 (5.5%)
8
16 (5.9%)
For any reason
13 (4.6%)
21 (7.6%)
31 (11.1%)
34 (12.3%)
Due to adverse
events
4
2
5
4
Adverse event
(2.9%)
(0.4%)
Discontinuations
1 Defined
2 Defined
(1.4%)
(0.7%)
(1.8%)
(1.4%)
as positive urine culture with bacteriuria count of > 105 CFU/mL and leukocyturia of > 5/hpf
as PVR ≥ 200 mL with symptoms that required CIC, or PVR ≥ 350 mL with CIC regardless of symptoms
Nitti et al. J. Urol 2013; 189:2186-93
European and U.S. RCT
BL: PBO 5.7±3.9


BoNT/A 5.5±3.8
IQoL
548 pt. PBO 271, BoNT/A 277
239 vs. 250 completed
Chapple et al. Eur Urol 2013, 64:249-256
Adverse events
Chapple et al. Eur Urol 2013, 64:249-256
Systematic review and
meta-analysis
 8 studies (6 RCTs) with 1320
patients
 Sig. UI episodes, daily frequency,
MCC, voided volume
 29.2% vs. 7.95% became dry
 Only localized AEs - Sig. UTI and
retention vs. placebo
Cui et al. N&U, 2015; 34:413-9
Repeat BoNT/A
injections
 Review of multiple studies
 Overall objective and subjective
(patient reported) efficacy outcomes
after first injection sustained after
repeated injections
Dowson et al. Nat Rev Urol 2010; 7:661-667
Efficacy and safety at 3.5
years
 Pts. who completed either of two 24-wk trials entered
for 3.5 years
 Data analysed by treatment (up to 6) and by
treatment subgroup of 1-6 treatments
 74-83% reported improved or greatly improved symptoms after
each treatment
 Consistent reductions in daily UI episodes (3-4/day) and
urgency episodes (3-4/day)
 Median duration of effect 7.6 months
 No new safety signals: UTI (13.5%-17%), de novo IC (4% to
0.6%)
Nitti et al. J Urol, 2016; 196:791-800
Long-term use of BoNT/A

137 patients (idiopathic 104; neuropathic 33) followed for ≥36
months

Real life study, idiopathic dose was 200 or 300u, CIC started for
PVR 150 ml
Mohee A, et al BJUI 2013; 111:106-13
Durability of BoNT/A
 Retrospective review over a 7-year period in 136
patients
 Mean time for patients requesting additional
treatment:
 For first 5 cycles varied between 8.5 and 10.4 mo.
 Longest time between 3rd and 4th cycles
 Between 5th and 6th – 5.5mo. and between 6th and 7th –
5.25 mo. (p=0.015)
 80% discontinued treatment over time
Chohan et al. IUJ, 2015; 26:1605-12
Long-term patient
satisfaction
 First 100 patients treated from 2004-2010
 72 complete data for questionnaires
 49 continued; 23 discontinued
 High satisfaction among those who continued
 Discontinuation mainly for lack of efficacy
 44% no further treatment
 39% back to anti-muscarinics
 13% other
Malde et al. BJUI 2015; 116:443-9
Number of injections
sites and outcome
 Single blind RCT in 67 patients
 100U BoNT/A diluted in 10mL NS
injected in 10, 20, or 40 sub-urothelial
sites under GA
 At 1, 3, and 6 months
 No sig. difference in GRA, symptoms,
UDS findings and AEs
Liao et al. N&U 2016 Aug;35(6):717-23.
Retention rate
 Retrospective study in 160 patients (121
women and 39 men) treated with 100U or
200U of BoNT/A
 56(35%) had retention and needed CIC for
~16 weeks (1-40)
 After 1st injection associated with preop PVR
and bladder capacity
 After 2nd injection associated with preop PVR,
BoNT/A dose, and previous retention
Osborn et al. N&U, 2015; 34:675-8
OnabotA for OAB
 RCT evidence of efficacy in patients
refractory to or intolerant of oral medications
 Notable AEs are UTI and risk of retention
which is dose related
 Emerging data of long-term persistence of
efficacy and safety
 Limited comparisons to other therapies
 Currently recommended does is 100 U