Acute Migraine Treatment Novel Formulations

MAA AGM 26TH September 2009

Dr Andrew DowsonChairman MAA Medical Advisory Board

News of cGRP

• Telagepant MSD• Back up compound MSD

• Boehringer Ingelheim

Traditional Versus Novel Delivery

– Traditional• Injections• Intranasal • Oral• Sublingual • Rectal

– Novel• Needle-free injections• Inhalation• Intranasal Dry Powder• Lingual Spray/ Transmucosal• Topical/ Transdermal• Novel oral formulations• Stimulators

• Acute-migraine drugs need rapid onset and sustained efficacy

• Patients often prefer oral therapies, but efficacy is limited by gastric absorption and emptying

Gastric Stasis Limits Oral Delivery

• Gastric emptying was evaluated with scintigraphy in 3 migraineurs versus normative data

Perc

enta

ge

Aurora et al. Headache. 2007;47(10):1443-1446.

112 124

182

243

44 51 63 64

0

100

200

300

Controls Spontaneousmigraine

Inducedmigraine

Interictal

Min

utes

Gastric half-emptying time (minutes)% radioactive material remaining after 2 hours

New Formulations of Sumatriptan

Injectable: DOSE-PRO/ SUMAVEL Needle-Free Sumatriptan – FDA Approved 2009

• Advantage: improved patient acceptance over injection with needles

• Needle-free injectable sumatriptan– Approved for acute migraine and cluster

headache– SC delivery of sumatriptan 6 mg– Compressed nitrogen gas pushes

sumatriptan subcutaneously

Injectable: Needle-Free Sumatriptan

• PK similar to sumatriptan traditional injection1

– Rapid absorption and distribution with slow elimination– Tmax 2 minutes sooner with needle-free injectable sumatriptan

compared with sumatriptan traditional injection – Because of comparable bioequivalence, efficacy data assumed

to be comparable to sumatriptan traditional injection • Patients able to successfully use this technology2

• Safety and tolerability generally similar to sumatriptan traditional injection1

– Local site reactions (immediate, nonpersistent bleeding; transient swelling; transient erythema2) more frequent and persisted slightly longer after needle-free injectable sumatriptan than after sumatriptan traditional injection

1. Farr et al. Poster presented at: 50th Annual Scientific Meeting of the American Headache Society; June 26-29, 2008; Boston, MA. Abstract S7. 2. Brandes et al. Headache. 2008;48(suppl 1):S39. Abstract S2.

Transdermal: ZELRIXSumatriptan Iontophoresis, Phase III

• Advantages: avoids GI; sustained delivery

• Sumatriptan iontophoresis patch– Low electrical

current facilitates transdermal delivery

– Linear relationship between applied current and sumatriptan delivery

– PK data• AUC ≈ SC suma• Cmax < SC suma• Consistent and

predictable PK

Pierce et al. Headache. 2009;49(6):817-825.

Printed with permission from Pierce M, Marbury T, O’Neill C, Siegel S, Du W, Sebree T. Zelrix: a novel transdermal formulation of sumatriptan. Headache. 2009;49(6):817-825.

Sumatriptan Iontophoresis

• Phase 3• N = 530

– Mean age = 41 years– 84% female

Significant difference between sumatriptan and placebo:* P < .001.† P < .01.

29

63

21

40

53*

84*

34†

60†

0

25

50

75

100

2-h painrelief

2-h nausearelief

24-hsustained

relief

No rescuemeds

Patie

nts

(%)

Sumatriptan Placebo

Sumatriptan Iontophoresis

AE Sumatriptan PlaceboApplication site reaction

Pain 23% 15%

Tingling 12% 19%

Itching 8% 7%

Site reaction 7% 6%

Triptan AEs 2% 0

Data being presented at the 2009 International Headache Congress/American Headache Society meeting.

Docekal and Djupesland. Data being presented at the 2009 International Headache Congress/American Headache Society meeting. Abstract PO10.

Intranasal Dry Powder: OPTINOSESumatriptan – Phase II

• Nasal drug delivery device– Delivers sumatriptan powder– Tmax = 20 minutes– Most common AE

• Bitter taste in 10% with 7.5 mg of sumatriptan and 13% with 15 mg of sumatriptan

– Sustained pain-free (SPF) AND no AEs (SNAE) SNAE = SPF (1-AE)• 37% (15 mg) and 39% (7.5 mg)

with sumatriptan powder• 6% to 22% with oral triptans• 18% with sumatriptan plus

naproxen• 13% with oral CGRP antagonist

47.4

17.9

48.6

23.1

0

20

40

60

Sustained pain-free at48 hours

Incidence of AEs

Patie

nts

(%)

7.5 mg sumatriptan 15 mg sumatriptan

Lingual Spray: Sumatriptan – Phase II

• Sumatriptan lingual spray (LS)– Advantages: rapid

absorption and avoids GI system

– Sprayed over the tongue– PK in 10 normal males – Crossover comparison

with sumatriptan 50-mg tablets

– Sumatriptan LS absorption was biphasic

• Lower mean peak concentration compared with oral sumatriptan tablets

– There were no reports of unpleasant taste

Dilone et al. Published online ahead of print June 22, 2009. Headache. doi: 10.1111/j.1526-4610.2009.01475.x.

30

Time (min)

Con

cent

ratio

n (n

g/m

L)

25

22

15

10

5

00 100 200 300 400

Suma-LS 20-mg fastedSuma-LS 20-mg fedTablet 50-mg fasted

Lingual Spray: Sumatriptan –Phase II

The P values shown are for comparison with 50-mg sumatriptan tablet.

Dilone et al. Published online ahead of print June 22, 2009. Headache. doi: 10.1111/j.1526-4610.2009.01475.x.

* P < .01.† P ≤ .05.

0

20

40

60

80

Patie

nts

Res

pond

ing

(%)

60 minutes120 minutes

P = .11P = .12†

P = .08

50PO

20LS

30LS

100PO

2 x 20LS

50PO

100PO

20LS

30LS

2 x 20LS

* **

†

(n = 53) (n = 38) (n = 34) (n = 31) (n = 22) (n = 53) (n = 38) (n = 34) (n = 22)(n = 31)

Oral Inhalational Delivery

Oral Inhalational Delivery

• Alveoli provide a large, absorptive surface– Advantages1,2

• Painless• High permeability• Rapid access to systemic circulation

– Lung deposition of drug depends on particle size and properties and the health of the respiratory system1

– Small, lipophilic molecules delivered to the deep lung affords rapid onset of action1

• Advantages of inhalation administration3

– Noninvasive systemic drug delivery– Fast, predictable, effective plasma concentration

1. Gonda. J Aerosol Med. 2006;19(1):47-53. 2. Siekmeier and Scheuch. J Physiol Pharmacol. 2008;59(suppl 6):53-79. 3. Patton and Byron. Nat Rev Drug Discov. 2007;6(1):67-74.

Orally Inhaled DHE (MAP0004) – Phase III

Significant IV plasma ‘spike’- ↑ Potential for side effects

Suppressed inhaled plasma Cmax- ↓ Potential for side effects

Cook. Presented at: European Headache and Migraine Trust International Congress (EHMTIC); September 4-7, 2008; London, UK.

Plas

ma

[DH

E] p

g/m

L

100,000

0

10,000

1000

100

1 2 3

Time (h)

4 5 6

1 mg IV

0.89 mg inhaled (4 inhalations)

0.44 mg inhaled (2 inhalations)

Orally Inhaled DHE: LEVADEX (MAP0004)

* Differences between MAP0004 and placebo: P ≤ .05.

Aurora et al. Headache. 2009;49(6):826-837.

• Adults with active migraine (N = 86)

• Randomized to MAP0004 0.5 or 1 mg systemic equivalent dose or placebo

10 15 30 60 90 120 240

32

41

54

22

40

7 7 7

27

44*

9

35*

28*

66

12

0

20

40

60

Minutes After Dose

Pain

-Fre

e Pa

tient

s (%

)

MAP0004 0.5 mg MAP0004 1 mg Placebo

Orally Inhaled DHE (MAP0004)

Significant difference from placebo:* P < .05.† P < .0001.

Primary data from phase 3 studies are being presented by S. Silberstein September 12 at the Late-Breaking Session at the 2009 International Headache Congress/American Headache Society meeting.

AE MAP0004

Placebo

Nausea 4.5% 2.0%

Cough 2.5% 1.2%

Bad Taste 6.4% 1.7%

28.8*

47.8†

58.7†

64.6†

43.7†

35.6†

8.5

16.519.6

36.834.5

28.121.6

6.7

0

25

50

75

10 min 30 min 1 h 2 h 4 h 24 h 48 h

Time Posttreatment

Patie

nts

With

Pai

n R

elie

f (%

)

MAP0004 (n = 395) Placebo (n = 397)

Thermally Generated–Aerosol (TGA) Prochlorperazine – Phase II

Route Tmax(minutes)

Cmax(ng/mL)

IV Over 5 Seconds 3.50 ± 2.88 1.06 ± 0.84

Single-Breath Inhalation 2.00 ± 0.76 1.38 ± 0.56

Between-Treatment Difference (P value)a .13 .30

Avram et al. Clin Pharmacol Ther. 2009;85(1):71-77.

Data are listed as mean ± SD (n = 8).a Difference between IV and aerosol by paired t test.

TGA Prochlorperazine in Migraine

• Phase 2b, randomized study• Single migraine

– 3 doses: 5 mg; 7.5 mg; 10 mg– Placebo

• N = 400• Aerosol prochlorperazine

better than placebo after– 15 minutes with 7.5 mg

(P = .02)– 30 minutes with 5 and 10 mg

(P = .006)• Phase 2b migraine trial with

loxapine has been initiated Pain relief at 2 hoursfrom moderate-severe to mild or none;

all doses versus placebo: * P = .001.

Cassella et al. Presented at: 59th Annual Meeting of the American Academy of Neurology; April 28-May 5, 2007; Boston, MA.

40.8

60.2* 63.7* 66.0*

0

25

50

75

Placebo 5 mg 7.5 mg 10 mg

Dose of Inhaled ProchlorperazinePa

tient

s W

ith 2

-h P

ain

Rel

ief (

%)

Effervescent

• Effervescent diclofenac1

– More rapid absorption than traditional pills with 30-minute Tmax

• Diclofenac potassium powder2

– Onset of analgesia 15 minutes for powder versus 60 minutes for tablets

– FDA approved

Diclofenac powder

Diclofenac tablet

Placebo

1. Terhaag et al. Int J Clin Pharmacol Ther. 2000;38(11):546-551. 2. Diener et al. Cephalalgia. 2005;26(5):537-547.

* P ≤ .05 for diclofenac powder versus placebo. † P ≤ .05 for diclofenac powder versus diclofenac tablet. ‡ P ≤ .05 for diclofenac tablet versus placebo.

Effervescent Diclofenac – CAMBIAFDA Approved 2009

70

Minutes

Mea

n H

eada

che

Inte

nsity

(mm

)

65

60

55

50

45

40

350 30 60 90 120

†‡

*

‡

†‡

†

†† *

* **

*

Effervescent Diclofenac

Diener et al. Cephalalgia. 2005;26(5):537-547.

• Adverse events (AEs) were typical of those seen with oral diclofenac

46.0

24.7

41.6

18.524.1

11.7

0

10

20

30

40

50

Pain relief Pain free

Patie

nts

(%)

50 mg diclofenac powder50-mg diclofenac tabletPlacebo

Other Intranasal Delivery Systems

Intranasal: Ketorolac – Phase III (for postoperative pain)

• Phase 3 clinical trials– Postoperative pain– N = 300– Greater pain reduction

with ketorolac– Morphine use reduced

by 34% with ketorolac versus placebo

– AEs were typical of those seen with oral ketorolac; nasal irritation occurred for 24% with intranasal ketorolac versus 2% with placebo

Brown et al. Published online ahead of print July 6, 2009. Pain Med. doi:10.1111/j.1526-4637.2009.00647.x.

* Significant between-treatment difference: P ≤ .05.

28

Time (h)

Pain

Inte

nsity

Diff

eren

ces

(PID

)

262422201816141210

86420

0 1 2 3 4 5 6

Intranasal ketorolacPlacebo

*

*

*

**

Intranasal: Carbon Dioxide (CO2) – Phase II

• CO2 inhibits sensory nerve activation and neuropeptide release1

• Intranasal CO2 in migraine pilot study2

– Randomized, double-blind, placebo-controlled, parallel-group

– N = 132– 2-hour pain free in 9% with placebo versus 30%

with intranasal CO2 (P < .01)• Phase 2 trials are ongoing

1. Vause et al. Headache. 2007;47(10):1385-1397. 2. Spierings. Headache. 2005;45(6):809. Abstract S78.

Other Transdermal Delivery Systems

Transdermal: Liposomal Formulations

• Traditional liposomes are vesicles made with phospholipid membranes– May be filled with drugs for drug delivery

• Drug carrier: elastic liposomes– Noninvasive drug delivery across skin– Highly deformable to permit squeezing through pores smaller than

own diameter– Achieves more rapid onset and sustained effect

• Migraine– Diclofenac

• Topical-delivery diclofenac limited by poor skin permeability and rapid elimination because of its hydrophilic properties

– Rizatriptan

Elastic Liposome Diclofenac –Preclinical

• Biological activity twice that of traditional formulations

• Prolonged duration of action– Elastic

liposome: 24 h – Topical

hydrogel: 6 h – Plain drug:

3 h

Jain et al. Curr Drug Deliv. 2005;2(3):223-233.

100

Time (h)

Inhi

bitio

n of

Paw

Ede

ma

(%) 90

70

50

40

10

00 3 9

80

60

30

20

6 12 1815 21 24

Elastic liposomeLiposomeHydrogelPlain drug

Elastic Liposome Rizatriptan –Preclinical

• Tested in rodent model– Transdermal

permeation better with elastic liposome

• Sustained 24 hours

– Effect on pain response greater with elastic liposome

• Sustained action

Formulation Transdermal Flux

(mcg/cm2/h)

Drug Deposited

(%)

Elastic Liposome 18-43 20-40

Conventional Liposome 7 7

Solution 2 4

Garg et al. Drug Dev Ind Pharm. 2008;34(10):1100-1110.

Stimulators

Transcranial Magnetic Stimulation

• Low frequency TMS effective in acute treatment of migraine with aura regardless of presence or absence of prophylaxis

Almaraz, Dilli and Dodick. Data being presented at the 2009 International Headache Congress/American Headache Society meeting. Abstract PO18.

Sphenopalatine Ganglion

Triggers:alcohol, smells

Triggers:Photoperiod stress

Sleep-wake cycle alteration

VIPGCRP

Post/Inferiorhypothalamus

SSN

Trigeminalganglion

Sphenopalatine ganglion [SPG]

Superior cervical ganglion

Edvinsson and Goadsby. Cephalalgia. 1994;14(5):320-327.

Infraorbital

Infraorbital nerve

Stimulator: Sphenopalatine GanglionStimulation for Chronic Migraine

• 10 women, 1 man

• Mean age: 44 y (range: 35-57)

• Diagnosis– 9 medication overuse– 2 refractory episodic migraine

Tepper et al. Headache. 2009;49(7):983-989.

N = 11

n = 11

Goodn = 8

Poorn = 3

Goodn = 3

(1, 3, 5)

Fairn = 1(7)

Poorn = 4

(4, 8, 9, 11)

Fairn = 1(6)

Poorn = 1(2)

NA, no stimn = 1(10)

Completen = 2(1, 5)

Reductionn = 3

(3, 7, 11)

Nonen = 5

(2, 10, 4, 6, 8, 9)

Total number of patients

Total number of evaluations

Electrode placement

Physiologic response(patient ID #)

Pain relief(patient ID #)

News on Preventative Migraine Treatments

• Tonabersat• Botox

• Gabapentin

Novel Acute Migraine Formulations—1Delivery Route

Advantages Over Traditional Formulation

Examples

Needle-Free Injection

Improved patient acceptanceRapid absorption and distribution Slow eliminationTmax 2 minutes sooner than traditional

injection

Needle-free injectable sumatriptana

TransdermalIontophoresis

Noninvasive drug delivery across skinControlled delivery with sustained effectReduced side effects

Sumatriptana

InhalationNoninvasive systemic drug deliveryFast, predictable, effective plasma concentration

DHE MAP0004b

TGA prochlorperazine

Intranasal

Blood levels achieved quicker than PO

Bypass GI systemDry Powder SumatriptanCO2

Ketorolac

a Currently available.b Completed phase 3 clinical trials.

Novel Acute Migraine Formulations—2 Delivery Route

Advantages Over Traditional Formulation

Examples

Novel Oral

ConvenienceMore rapid and complete absorption

Sumatriptan RT Effervescentdiclofenacb

Lingual SprayRapid onset and sustained effectBypass GI systemAvoid bitter taste with nasal sprays

Sumatriptan LS

Transdermal Elastic Liposomes

Noninvasive drug delivery across skinRapid onset and sustained effect

DiclofenacRizatriptan

Stimulators

Appears effective in migraine with auraShows promise in refractory cluster and medication overuse headaches

TMSSphenopalatine ganglion

aCompleted phase 3 clinical trials.b Currently available.