Meeting Diverse Acute Migraine Treatment Needs Through...
Transcript of Meeting Diverse Acute Migraine Treatment Needs Through...
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.