Therapeutic Uses of Botulinum Toxin in Neuro-ophthalmology

JanetteJanette I. Lindley, MD FRCSC I. Lindley, MD FRCSC

St. Paul’s HospitalSt. Paul’s Hospital

University of British ColumbiaUniversity of British Columbia

Overview

1.On label uses:1.On label uses:hemifacial spasmhemifacial spasm blepharospasmblepharospasm

injection techniquesinjection techniquesother:other: cervical dystoniacervical dystonia

strabismusstrabismus

wrinkles (glabella)wrinkles (glabella)

Overview2. Off label uses:2. Off label uses: headache (chronic daily)headache (chronic daily)

Phase II Trial ResultsPhase II Trial Resultsinjection technique injection technique

crocodile tears, protective ptosiscrocodile tears, protective ptosis other: writer’s cramp, hyperhydrosis, other: writer’s cramp, hyperhydrosis, head tremor, focal spasticity, head tremor, focal spasticity, droolingdrooling

Botulinum Toxin in Neuro-ophthalmology

neurotransmission inhibition (ACH, other) neurotransmission inhibition (ACH, other) at NMJat NMJ

chemical denervation striated muscle chemical denervation striated muscle peaks @ 2 weekspeaks @ 2 weeks

Neuronal sprouting heralds return of Neuronal sprouting heralds return of function @ 3 – 6 mos.function @ 3 – 6 mos.

Botulinum Toxin

Serotype A (Botox Serotype A (Botox , Dysport), Dysport)

Serotype B (Myobloc)Serotype B (Myobloc)

Hemifacial spasm

UnilateralUnilateral Periocular and lower facialPeriocular and lower facial

+/-platysma+/-platysma stapedius (clicking at hs) stapedius (clicking at hs)

R/O facial nerve compression R/O facial nerve compression

(MRI)(MRI)

Hemifacial spasm movie

Click here

Blepharospasm

tonic/ clonic lid closuretonic/ clonic lid closure may present unilaterallymay present unilaterally uncontrollableuncontrollable functional cause for visual lossfunctional cause for visual loss (apraxia of lid opening)(apraxia of lid opening)

Blepharospasm movie

(Click here)

Blepharospasm

Pathological Pain Inhibition

observed (Binder et al) after Rx observed (Binder et al) after Rx hyperfunctional facial lineshyperfunctional facial lines

inhibition of neuromuscular activityinhibition of neuromuscular activity andand substance P, glutamate, & calcitonin substance P, glutamate, & calcitonin

peptide releasepeptide release results in analgesic effectresults in analgesic effect

Headache Disorders

heterogeneous group of conditionsheterogeneous group of conditions recent results Phase II trials inrecent results Phase II trials in

chronic daily headache (CDH)/chronic daily headache (CDH)/

transformed migrainetransformed migraine randomized, double blindrandomized, double blind placebo controlledplacebo controlled 75% completion at 11 mos.75% completion at 11 mos.

CDH or Transformed Migraine

HAHA15 d/m > 1(3)m 15 d/m > 1(3)m each HA each HA 4 h/d4 h/d no primary causeno primary cause H/O episodic migraine (>50% pr migr)H/O episodic migraine (>50% pr migr) 4% of pop ~1.2-1.5 million in Canada4% of pop ~1.2-1.5 million in Canada significant disability/resource usesignificant disability/resource use

Baseline

Placebo

BoNTA*

BoNTA*

Placebo

Placebo

BoNTA*BoNTA*

BoNTA* BoNTA*

Placebo Placebo

Placebo Placebo

Final analysis

Placebo Non-Responder

(PNR)

Placebo Responder

(pr)

-60 -30 0 Day 90 180 270

Chronic Daily Headache Studies -Common Design

Primary analysis

*Allergan, Botox®, USA

Chronic Daily Headache Injection Patterns: Fixed Site-Fixed Dose (FSFD) 75,150,225 UModified Follow-the-Pain (mFTP) 105-260 U. 190

XX X

X

X

XX

X

Procerus, Corrugator, Frontalis, Temporalis, Masseter (optional),Occipitalis

Trapezius, Semispinalis, Splenius capitis

Chronic Daily Headache Studies - DesignSilberstein et al, Headache 2005. Mathew et al, Headache 2005.

Silberstein Silberstein (n=702)(n=702)

Mathew Mathew (n=355)(n=355)

Concurrent HA Concurrent HA ProphylaxisProphylaxis

AllowedAllowed

Randomization to Randomization to Active TreatmentActive Treatment

3:13:1 1:11:1

Injection Injection ParadigmParadigm

FSFDFSFD mFTPmFTP

DoseDose 0, 75, 150, 225U0, 75, 150, 225U 0, 105 – 260U0, 105 – 260U

SafetySafety Safe and well-toleratedSafe and well-tolerated Safe and well-toleratedSafe and well-tolerated

ResultsResults 11°° - HA-Free Days – N.S - HA-Free Days – N.S.. 22°° - Responder Rate – N.S.- Responder Rate – N.S.

11°° - HA-Free Days – N.S - HA-Free Days – N.S.. 22°° - Responder Rate – - Responder Rate –

P<0.05P<0.05 % % 50% 50% HA d/m HA d/m

*Allergan, Botox®, USA

Chronic Daily Headache – Efficacy MeasuresMathew et al, Headache 2005.

Efficacy MeasuresEfficacy Measures Outcome MeasureOutcome Measure Day 180Day 180

11oo Number of HA-Free Days/monthNumber of HA-Free Days/monthNot Not

significantsignificant

22oo

Responder Rate Responder Rate

(% Patients with ≥ 50% decrease HA-(% Patients with ≥ 50% decrease HA-days/month)days/month)

p p << 0.05 0.05

AdditionalAdditional Number of Headaches/monthNumber of Headaches/month p p << 0.05 0.05

AdditionalAdditional

Proportion of patients with Proportion of patients with ≥50% ≥50% decrease in HA frequency decrease in HA frequency

Number of days of acute HA med useNumber of days of acute HA med use Number of intakes of acute medsNumber of intakes of acute meds MIDASMIDAS Headache Specific QOLHeadache Specific QOL

Not Not significantsignificant

*Allergan, Botox®, USA

Chronic Daily Headache – Adverse EventsMathew et al, Headache 2005.

Treatment-Related Adverse EventTreatment-Related Adverse Event BoNTA*BoNTA* PlaceboPlacebo p-valuep-value

Neck PainNeck Pain 23 (13.3%)23 (13.3%) 1 (0.5%)1 (0.5%) <0.001<0.001

Arm PainArm Pain 7 (4%)7 (4%) 1 (0.5%)1 (0.5%) 0.0330.033

Injection Site HemorrhageInjection Site Hemorrhage 2 (1.2%)2 (1.2%) 9 (4.9%)9 (4.9%) 0.0390.039

Muscular WeaknessMuscular Weakness 38 (22%)38 (22%) 0 (0%)0 (0%) <0.001<0.001

Skin TightnessSkin Tightness 8 (4.6%)8 (4.6%) 0 (0%)0 (0%) 0.0030.003

BlepharoptosisBlepharoptosis 12 (6.9%)12 (6.9%) 1 (0.5%)1 (0.5%) <0.001<0.001

No significant difference: Headache, neck rigidity, pain, face pain, dysphagia, hypertonia, hyperesthesia, dizziness, pharyngitis, visual disturbanceMajority of AE's were mild to moderate in severity and transient in nature

*Allergan, Botox®, USA

Repeat treatment (up to 3 treatment cycles) with BoNTA* is Repeat treatment (up to 3 treatment cycles) with BoNTA* is safe and well-tolerated at doses up to 260Usafe and well-tolerated at doses up to 260U

No neutralizing antibodiesNo neutralizing antibodies No benefit of placebo run-in No benefit of placebo run-in pool PNR and PR groups pool PNR and PR groups Although the 1Although the 1° endpoint was not met, s° endpoint was not met, significant & clinically ignificant & clinically

meaningful improvements were seen following BoNTA* vs meaningful improvements were seen following BoNTA* vs placebo:placebo:

Responder ratesResponder rates Headache frequencyHeadache frequency

No significant change in proportion of patients with No significant change in proportion of patients with ≥50% ≥50% Decrease in HA Frequency, Number of Days of Acute HA Med Decrease in HA Frequency, Number of Days of Acute HA Med Use, Number of Uses of Acute Meds, MIDAS, Headache Use, Number of Uses of Acute Meds, MIDAS, Headache Specific QOLSpecific QOL

Chronic Daily Headache – Safety & Results Mathew et al, Headache 2005.

*Allergan, Botox®, USA

CDH – 1° Outcome MeasureMathew et al, Headache 2005.

0

2

4

6

8

10

12

14

16

0 30 60 90 120 150 180 210 240 270

Mean Change in Number of Days

PNR BoNTA*(n=134)

PNR PBO(n=145)

PR BoNTA*(n=39)

PR PBO(n=37)

Days After Placebo Run - In

Blinded Treatment

Number of Headache-Free Days

Δ = 1.5 HA-free days at Day 180

*Allergan, Botox®, USA

CDH – 2° Outcome Measure Mathew et al, Headache 2005.

*

*p<0.027

Days After Placebo Run - In

Blinded Treatment

Responder Rate% Patients with > 50% Decrease Headache Days

33

15

*Allergan, Botox®, USA

0

25

50

75

100

0 30 60 90 120 150 180 210 240 270

% of Patients

PNR BoNTA*(n=134)

PNR Placebo(N=145)

-12

-10

-8

-6

-4

-2

0

0 30 60 90 120 150 180 210 240 270

Mean Change in

Number of Headaches

per Month

BoNTA*(n=173)

Placebo(n=182)

**

*p<0.05

* * *

*

*§

§ p=0.001

3.4

Days After Placebo Run - In

Blinded Treatment

Baseline

BoNTA* = 13.5

Placebo = 12.7

CDH – Number of HA’s Mathew et al, Headache 2005.

Number of Headaches – Change from Baseline

Pooled(PNR + pr)

*Allergan, Botox®, USA

CDH – % Decrease HA FrequencyDodick et al, Headache 2005. Subgroup Analysis - No Concomitant Prophylaxis

*p<0.05

Days After Placebo Run - In

Blinded Treatment

% Decrease in Number of Headaches≥30% ≥50%

0

10

20

30

40

50

60

70

80

90

100

0 30 60 90 120 150 180 210 240 270

BoNTA* Placebo

Days After Placebo Run - In

* ** ** * *

0

10

20

30

40

50

60

70

80

90

100

0 30 60 90 120 150 180 210 240 270

% of Patients

*p<0.05

*Allergan, Botox®, USA

Chronic Daily Headache

mFTPmFTP HA free days - NSHA free days - NS 50% 50% in HA d/m - S in HA d/m - S #HA/mo - S#HA/mo - S

Protective ptosis

15 – 20 units15 – 20 units into levatorinto levator

ab externoab externo

via flipped upper lidvia flipped upper lid

Autonomic Nerve Inhibition – Ach Release Blocked

glandsglands lumen post injection (Swartling)lumen post injection (Swartling) smooth musclesmooth muscle

Injection of BTX-A

Conclusions

Onset of effect occurred within 2 – 3 days Onset of effect occurred within 2 – 3 days following injection and lasted for 3 - 4 months.following injection and lasted for 3 - 4 months.

Side effects are infrequent, mild and transient.Side effects are infrequent, mild and transient.

Subjective and objective evidence for reduction in Subjective and objective evidence for reduction in tear production.tear production.

Effectiveness needs to be established with a Effectiveness needs to be established with a randomised clinical trial.randomised clinical trial.

Thanks to:

SPH Staff:SPH Staff: Cynchia, Maureen, KathyCynchia, Maureen, Kathy

Residents:Residents:Leah, Paul, BriarLeah, Paul, Briar

Allergan: Botox Therapeutic DivAllergan: Botox Therapeutic DivG. DavidovicG. DavidovicD. HoppenbrouwerD. Hoppenbrouwer