Get aHEAD of the ACHE: Monoclonal Antibodies in Migraine ... Janisch 09042018.pdf · ©2018 MFMER | slide-2 Disclosures • No financial interest or conflicts of interest to disclose

©2018 MFMER | slide-1

Get aHEAD of the ACHE: Monoclonal Antibodies in Migraine Prevention

Amanda Janisch, PharmDPGY2 Ambulatory Care Pharmacy ResidentMCHS SWMN, Mankato, MN


Disclosures

• No financial interest or conflicts of interest to disclose

• Discussion of off-label use for the following in migraine prevention: metoprolol, atenolol, amitriptyline, venlafaxine, lisinopril, candesartan, carbamazepine, clonidine, and guanfacine


Objectives

• Explain the pathophysiology and epidemiology of migraines

• Describe treatment guidelines for management of migraines

• Discuss novel monoclonal antibodies for migraine prevention


Definitions

• Headache- head pain without neurologic symptoms

• Migraine- head pain with neurologic symptoms such as aura, nausea, vomiting, aversion to light, sound, or smell

• Episodic migraine (EM)- headache ≤14 days/month

• Chronic migraine (CM)- headache >15 days/month for at least 3 months, with ≥ 8 migraine days/month

Katsarava Z. Curr Pain Headache Rep. 2012.


Epidemiology• Migraine affects ~14% of the population

• More common in women• Highest prevalence in age range of 40 to 49

• Associated cost >$13 billion• Loss in productivity

• Studies suggest that ~30% of patients with migraine need preventative therapy

• 3-13% use preventative therapy

AAN/AHS. Am Fam Physician. 2013.Katsarava Z. Curr Pain Headache Rep. 2012.


Pathophysiology• COMPLEX

• Activation & sensitization of trigeminovascularpathways

• Dysregulation of sensory processing leading to neurologic symptoms

• Associations• Comorbidities: depression, anxiety, chronic pain

disorders• Medication over-use• Environmental factors: caffeine use, stress

Katsarava Z. Curr Pain Headache Rep. 2012.


TRUE or FALSE

Chronic Migraine (CM) occurs more commonly than Episodic Migraine (EM).


a. Trueb. False


Patient Case• MK a 42 year old female, is diagnosed with EM.• PMH: hypertension and s/p kidney excision

(donor)• She currently takes sumatriptan 50 mg as needed

and is using more frequently (~8x/month) • Other medications include: losartan and oral

contraceptive


Acute Treatment• Non-Steroidal Anti-inflammatory (NSAIDs)

• 1st line for mild-moderate migraines• Triptans

• 1st line for moderate-severe migraines• Dopamine antagonist antiemetics

• 2nd line for migraine treatment• Refractory Migraines

• May use parenteral dihydroergotamine, magnesium sulfate, valproate, and opioids

Mayans L, et al. Am Fam Physician. 2018.


Preventative Therapy• Consider when:

• ≥ 2 migraine days per month with disability lasting ≥ 3 days/month

• Acute treatment failure, adverse effects, or contraindication

• Use of abortive therapy ≥ 2 times/week• Patient preference and cost

• Goals:• Reduce frequency, intensity, and duration

Modi S, et al. Am Fam Physician. 2006.


FDA Approved for Migraine Prevention

Level of evidence A: ≥2 Class I trials

Silberstein SD,et al. Neurology. 2012.

Medication Dosage Rangedivalproex (Depakote®) IR: 250 mg twice daily up to 1000 mg/day

ER: 500 mg-1000 mg/day

topiramate (Topamax®) IR: 25 mg-100 mg in two divided dosesER: 25 mg-100 mg once daily

propranolol (Inderal®) IR: 80 mg/day divided every 6-8 hours, maximum of 160-240 mg/dayER: 80 mg once daily initially, Effective range 160-240 mg once daily

OnabotulinumtoxinA(Botox®)

5 units/0.1 mL per site with total dose of 155 units divided between 31 IM sites every 12 weeks.


Off-label use for Migraine Prevention

Medication Dosage Range Level of Evidence

metoprolol (Lopressor®, Toprol XL®)

n/a A

atenolol (Tenormin®) n/a B

amitriptyline (Elavil®) 10 mg-150 mg daily B

venlafaxine (Effexor®) ER: 37.5 mg- 150 mg daily B

Silberstein SD,et al. Neurology. 2012.Micromedex Database.


Off-label use for Migraine Prevention

Medication Level of Evidence

lisinopril (Zestril®, Prinivil®) C

candesartan (Atacand®) C

carbamazepine (Tegretol®) C

clonidine (Catapres®) C

guanfacine (Tenex®, Intuniv®) C



NOT Recommended or Effective for Migraine Prevention

• lamotrigine (Lamictal®)• clomipramine (Anafranil®)• clonazepam (Klonopin®)• nabumetone (Relafen®)• oxcarbazepine (Trileptal®)• telmisartan (Micardis®)



Drug Induced Headache

Mayo Clinic. 2018.

• Overuse of acute headache medications (>10 days/month)

• Butalbital products, acetaminophen, caffeine, NSAIDs, codeine, triptans

• Stimulants• Hormone therapy• Nitrates


Patient CaseWhich of the following products should NOT be recommended for MK as a first-line agent for migraine prevention?


a. topiramateb. butalbital/acetaminophen/caffeinec. propranolold. divalproex


Erenumab-aooe (Aimovig®)

Lauritsen CG, Silberstein SD. Pract Neurology. 2016.DailyMedGoodRx

Approval• Approved 5/17/2018 for EM and CM prevention

Mechanism

• Monoclonal antibody• Binds to calcitonin gene-related peptide (CGRP)

receptor

Product

• 70 mg monthly Sub-Q injection• Cost: $600- 700/carton of two SureClick®

Autoinjectors (8 week supply)


Erenumab-aooe Properties

• 4 letter abbreviation- naming convention for biologic agents

• “Fully Human” monoclonal antibody• ~90% human derived, ~10% murine

• IgG2 type antibody


Calcitonin Gene-Related Peptide (CGRP) Pathway

Edvinsson L. Headache. 2018.

• CGRP serum levels increase during migraine attack

• Trigeminal nerve stimulation increases CGRP

• CGRP concentration correlates to headache intensity


Efficacy and safety of erenumab (AMG334) in chronic migraine patients with prior preventive treatment failure: A subgroup analysis of a randomized, double-blind, placebo-controlled study

Ashina M, Tepper S, Brandes JL, et al. Cephalalgia. 2018.


Objectives• Primary Endpoint: Change from baseline in

monthly migraine days (MMD)

• Secondary Endpoints: • Achievement of ≥50% and ≥75% reduction from

baseline in MMD

• Change from baseline in monthly acute migraine-specific medication days (MSMD) based on use of acute medications (triptans/ergots)

Ashina M., et al. Cephalalgia. 2018.


Study Methods• Multicenter, randomized, double-blind, placebo-

controlled, 12-week, parallel-group study• Subgroup analysis in CM

• placebo• erenumab 70 mg monthly• erenumab 140 mg monthly



Enrollment


Inclusion

Adult patients with CM (≥ 15 headache days/month; ≥8 migraine days/month)

Exclusion

No therapeutic response to >3 preventative treatment categories


Subgroup Baseline Characteristics

Characteristic Placebon= 286

Erenumab70 mgn= 191

Erenumab140 mgn= 190

Age, years 41-42.9 40.7-42.9 41.4-44.2

Female, % 79 80-90 78-89

MMD 17.5-18.5 17.1-18.2 17.2-18.8

Monthly MSMD 6.3-11.4 6.9-10.5 6.2-12.4

Ashina M., et al. Cephalalgia. 2018.MMD- Monthly Migraine DaysMSMD- Migraine-Specific Medication Days


ResultsNo Prior Treatment

≥1 Prior Treatment Failure

≥2 Prior Treatment Failure

70 mg 140mg 70mg 140mg 70mg 140mgChange in MMD

-2.2 (-4.1,-0.3)*

-0.5 (-2.4, 1.5)

-2.5 (-3.8,-1.2)**

-3.3 (-4.6,-2.1)**

-2.7 (-4.2, -1.2)**

-4.3(-5.8, -2.8)**

≥ 50% reduction in MMD

1.8(0.9, 3.4)

1.3(0.7, 2.7)

2.6**(1.6, 4.5)

3.3**(2.0, 5.5)

3.5**(1.8, 6.6)

4.2** (2.2, 7.9)

≥ 75% reductionin MMD

2.0(0.8, 4.8)

1.9(0.8, 4.6)

3.1*(1.2, 10.9)

4.6**(2.1, 10.0)

3.6* (1.2, 10.9)

8.0** (2.8, 23.0)

Ashina M., et al. Cephalalgia. 2018.**p<0.001 *p<0.05 treatment groups compared to placebo


Results


38.1

17.3 14.2

50

34.7 35.641.9 40.8 41.3

0

10

20

30

40

50

60

No Prior Treatment >1 Prior Treatment Failure >2 Prior Treatment Failures

Proportion of Patients Reaching ≥50% Reduction in MMD over 3 Months

Placebo Erenumab 70mg Erenumab 140mg


Results

14.3

5.13.5

23.4

13.711.1

22.620

21.7

0

5

10

15

20

25

No Prior Treatment Failure > 1 Prior Treatment Failure >2 Prior Treatment Failures

Proportion of Patients Reaching ≥75% Reduction in MMD over 3 Months

Placebo Erenumab 70mg Erenumab 140mg



Strengths• 1st trial to evaluate

erenumab in CM in patients with prior preventative treatment failures

• Subgroup analysis• Not powered to detect

differences within each subgroup

• Statistical testing was not pre-specified or adjusted for multiplicity

• Exclusion criteria limited patients with higher treatment failures


Limitations


Conclusions• Erenumab was effective and well tolerated in

patients with previous treatment failures

• Further studies need for long-term safety/ efficacy and in patients exhibiting no therapeutic response to >3 classes of preventative therapy.


Treatment with erenumab resulted in ≥50% reduction in monthly migraine days in CM for ~_____% of patients.


a. 10-25%b. 35-50%c. 55-70%d. 75-90%


ARISE: A Phase 3 randomized trial of erenumab for episodic migraine

Dodick DW, Ashina M, Brandes JL, et al. Cephalalgia. 2018.


Objectives• Primary Endpoint: Change in monthly migraine days

(MMD)• Secondary Endpoints:

• ≥50% reduction in monthly migraine days (MMD)• Change in acute migraine-specific medication

treatment days (MSMD)• 5-point reduction in Physical Impairment and

Impact on Everyday Activities domain scores measured by the Migraine Physical Function Impact Diary (MPFID)

Dodick DW, et al. Cephalalgia. 2018.


Migraine Physical Function Impact Diary (MPFID)

13 item patient reported outcome measure

Demonstrated reliability and validity in two domains in prospective, observational study

Not used in clinical practice Developed by Amgen Inc.

Kawata AK, et al. Headache. 2017.


Study Methods

• Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial

• Randomized 1:1 to placebo or erenumab 70 mg monthly subcutaneous injection

• 577 patients randomized



Enrollment


Inclusion

Adults with EM (≥4 to 15 MMD and <15 headache days per month)

Exclusion

History of no therapeutic response to >2 preventative medication classes

Use of preventative medications during trial (washout period required)


Baseline CharacteristicsCharacteristic Placebo

n= 291Erenumab 70 mgn= 286

Age, years 42 ±12 42 ± 11Female sex, no (%) 247 (84.9) 245 (85.7)Age at migraine onset 22 ± 11 21 ± 10Prior Prophylactic Therapy, no (%) 125 (43) 123 (43)No Previous Prophylactic Therapy, no (%)

174 (59.8) 178 (62.2)

MMD 8.4 ± 2.6 8.1 ± 2.7MSMD 3.4 ± 3.6 3.7 ± 3.6MPFID impact on everyday activities score

13.2 ± 8.9 12.6 ± 8.6

MPFID physical impairment score 11.5 ± 9.2 10.8 ± 9.1Dodick DW, et al. Cephalalgia. 2018.MMD- Monthly Migraine Days

MSMD- Migraine-Specific Medication Days


Results

Endpoint Placebo Erenumab 70 mgChange in MMD -1.8 days -2.9 days

-1.0 (-1.6, -0.5) p< 0.001*≥50% reduction in MMD 29.5% 39.7%

OR: 1.59, (1.12,2.27) p=0.01*Change in MSMD -0.6 days -1.2 days

OR: -0.6, (-1.0,-0.2) p=0.002*MPFID impact on everyday activities score(≥5-point reduction)

35.8% 40.4%OR: 1.22, (0.87, 1.71) p=0.26

MPFID physical impairment score(≥5-point reduction)

27.1% 33.0%OR: 1.33, (0.92, 1.90) p=0.13

Dodick DW, et al. Cephalalgia. 2018.* statistically significantMMD- Monthly Migraine Days


Strengths• Endpoints measured • Excluded patients on

preventative treatment


Limitations


Conclusion• Erenumab reduced MMD and MSMD in patients

with EM

• Further studies in combination with other migraine preventative treatments and in cardiovascular disease


Safety• Adverse effects similar between treatment and

placebo groups within both studies• Common Adverse Effects (≥2%)

• injection site pain• influenza• fatigue• nausea• constipation

• sinusitis• upper respiratory

tract infection (URI)• nasopharyngitis


Place in Therapy-Erenumab-aooe (Aimovig®)

• May be appropriate for patients with CM or EM that have had prior treatment failures

• Cost will likely limit use until more market competition

• Reports of prior authorization and restricted prescribing


Patient Case• MK established care with a neurologist after

failing an adequate trial of divalproex, nortriptyline, and gabapentin. She developed flank pain with topiramate.

• Which of the following is an appropriate option for this patient?


a. erenumab (Aimovig®)b. onabotulinumtoxinA (Botox®)c. propranolol (Inderal®)d. all of the above


Future Considerations with CGRP Antagonists

Tso AR, Goadsby PJ. Curr Treat Options Neurol. 2017.

Phase III trials

completed

fremanezumab Phase II trials completed

eptinezumab

Phase II trials completed

glacanezumab telcagepant & MK-3207 Trials stopped due to hepatotoxicity

ubrogepant (oral) Phase III trial underway for acute treatment

atogepant (oral)Under development for prevention


Summary

• Migraine preventative medications are often underutilized

• First-line agents include divalproex, topiramate, propranolol, and onabotulinumtoxinA

• CGRP antagonists will likely find a place in treatment after patients have failed multiple first-line agents


Questions

Documents

Get aHEAD of the ACHE: Monoclonal Antibodies in Migraine ... Janisch 09042018.pdf · ©2018 MFMER | slide-2 Disclosures • No financial interest or conflicts of interest to disclose