Get ahead of the ACHE: Monoclonal Antibodies in Migraine Prevention Amanda Janisch, PharmD PGY2 Ambulatory Care Pharmacy Resident MCHS SWMN, Mankato, MN 2018 MFMER slide-1
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 2018 MFMER slide-2
Objectives Explain the pathophysiology and epidemiology of migraines Describe treatment guidelines for management of migraines Discuss novel monoclonal antibodies for migraine prevention 2018 MFMER slide-3
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. 2018 MFMER slide-4
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. 2018 MFMER slide-5
Pathophysiology COMPLEX Activation & sensitization of trigeminovascular pathways 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. 2018 MFMER slide-6
TRUE or FALSE Chronic Migraine (CM) occurs more commonly than Episodic Migraine (EM). 2018 MFMER slide-7
a. True b. False 2018 MFMER slide-8
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 2018 MFMER slide-9
Acute Treatment Non-Steroidal Anti-inflammatory (NSAIDs) 1 st line for mild-moderate migraines Triptans 1 st line for moderate-severe migraines Dopamine antagonist antiemetics 2 nd line for migraine treatment Refractory Migraines May use parenteral dihydroergotamine, magnesium sulfate, valproate, and opioids Mayans L, et al. Am Fam Physician. 2018. 2018 MFMER slide-10
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. 2018 MFMER slide-11
FDA Approved for Migraine Prevention Medication divalproex (Depakote ) topiramate (Topamax ) propranolol (Inderal ) Level of evidence A: 2 Class I trials OnabotulinumtoxinA (Botox ) Dosage Range IR: 250 mg twice daily up to 1000 mg/day ER: 500 mg-1000 mg/day IR: 25 mg-100 mg in two divided doses ER: 25 mg-100 mg once daily IR: 80 mg/day divided every 6-8 hours, maximum of 160-240 mg/day ER: 80 mg once daily initially, Effective range 160-240 mg once daily 5 units/0.1 ml per site with total dose of 155 units divided between 31 IM sites every 12 weeks. Silberstein SD,et al. Neurology. 2012. 2018 MFMER slide-12
Off-label use for Migraine Prevention Medication Dosage Range Level of Evidence metoprolol (Lopressor, n/a A Toprol XL ) 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. 2018 MFMER slide-13
Off-label use for Migraine Prevention Medication lisinopril (Zestril, Prinivil ) candesartan (Atacand ) carbamazepine (Tegretol ) clonidine (Catapres ) guanfacine (Tenex, Intuniv ) Level of Evidence C C C C C Silberstein SD,et al. Neurology. 2012. 2018 MFMER slide-14
NOT Recommended or Effective for Migraine Prevention lamotrigine (Lamictal ) clomipramine (Anafranil ) clonazepam (Klonopin ) nabumetone (Relafen ) oxcarbazepine (Trileptal ) telmisartan (Micardis ) Silberstein SD,et al. Neurology. 2012. 2018 MFMER slide-15
Drug Induced Headache Overuse of acute headache medications (>10 days/month) Butalbital products, acetaminophen, caffeine, NSAIDs, codeine, triptans Stimulants Hormone therapy Nitrates Mayo Clinic. 2018. 2018 MFMER slide-16
Patient Case Which of the following products should NOT be recommended for MK as a first-line agent for migraine prevention? 2018 MFMER slide-17
a. topiramate b. butalbital/acetaminophen/caffeine c. propranolol d. divalproex 2018 MFMER slide-18
Erenumab-aooe (Aimovig ) 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) Lauritsen CG, Silberstein SD. Pract Neurology. 2016. DailyMed GoodRx 2018 MFMER slide-19
Erenumab-aooe Properties 4 letter abbreviation- naming convention for biologic agents Fully Human monoclonal antibody ~90% human derived, ~10% murine IgG2 type antibody 2018 MFMER slide-20
Calcitonin Gene-Related Peptide (CGRP) Pathway CGRP serum levels increase during migraine attack Trigeminal nerve stimulation increases CGRP CGRP concentration correlates to headache intensity Edvinsson L. Headache. 2018. 2018 MFMER slide-21
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. 2018 MFMER slide-22
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. 2018 MFMER slide-23
Study Methods Multicenter, randomized, double-blind, placebocontrolled, 12-week, parallel-group study Subgroup analysis in CM placebo erenumab 70 mg monthly erenumab 140 mg monthly Ashina M., et al. Cephalalgia. 2018. 2018 MFMER slide-24
Enrollment Inclusion Exclusion Adult patients with CM ( 15 headache days/month; 8 migraine days/month) No therapeutic response to >3 preventative treatment categories Ashina M., et al. Cephalalgia. 2018. 2018 MFMER slide-25
Subgroup Baseline Characteristics Characteristic Placebo n= 286 Erenumab 70 mg n= 191 Erenumab 140 mg n= 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 MMD- Monthly Migraine Days MSMD- Migraine-Specific Medication Days Ashina M., et al. Cephalalgia. 2018. 2018 MFMER slide-26
Change in MMD Results 50% reduction in MMD No Prior Treatment 1 Prior Treatment Failure 2 Prior Treatment Failure 70 mg 140mg 70mg 140mg 70mg 140mg -2.2 (-4.1, -0.3)* 1.8 (0.9, 3.4) -0.5 (-2.4, 1.5) 1.3 (0.7, 2.7) -2.5 (-3.8, -1.2)** 2.6** (1.6, 4.5) -3.3 (-4.6, -2.1)** 3.3** (2.0, 5.5) -2.7 (-4.2, -1.2)** 3.5** (1.8, 6.6) -4.3 (-5.8, -2.8)** 4.2** (2.2, 7.9) 75% reduction in 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) **p<0.001 *p<0.05 treatment groups compared to placebo Ashina M., et al. Cephalalgia. 2018. 2018 MFMER slide-27
60 50 40 Results 38.1 Proportion of Patients Reaching 50% Reduction in MMD over 3 Months 50 41.9 40.8 41.3 34.7 35.6 30 20 10 17.3 14.2 0 No Prior Treatment >1 Prior Treatment Failure >2 Prior Treatment Failures Placebo Erenumab 70mg Erenumab 140mg Ashina M., et al. Cephalalgia. 2018. 2018 MFMER slide-28
Results 25 20 23.4 Proportion of Patients Reaching 75% Reduction in MMD over 3 Months 22.6 21.7 20 15 10 14.3 13.7 11.1 5 5.1 3.5 0 No Prior Treatment Failure > 1 Prior Treatment Failure >2 Prior Treatment Failures Placebo Erenumab 70mg Erenumab 140mg Ashina M., et al. Cephalalgia. 2018. 2018 MFMER slide-29
Strengths 1 st trial to evaluate erenumab in CM in patients with prior preventative treatment failures Limitations 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 Ashina M., et al. Cephalalgia. 2018. 2018 MFMER slide-30
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. 2018 MFMER slide-31
Treatment with erenumab resulted in 50% reduction in monthly migraine days in CM for ~ % of patients. 2018 MFMER slide-32
a. 10-25% b. 35-50% c. 55-70% d. 75-90% 2018 MFMER slide-33
ARISE: A Phase 3 randomized trial of erenumab for episodic migraine Dodick DW, Ashina M, Brandes JL, et al. Cephalalgia. 2018. 2018 MFMER slide-34
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. 2018 MFMER slide-35
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. 2018 MFMER slide-36
Study Methods Multicenter, randomized, double-blind, placebocontrolled, parallel-group, phase 3 trial Randomized 1:1 to placebo or erenumab 70 mg monthly subcutaneous injection 577 patients randomized Dodick DW, et al. Cephalalgia. 2018. 2018 MFMER slide-37
Enrollment Inclusion Exclusion Adults with EM ( 4 to 15 MMD and <15 headache days per month) History of no therapeutic response to >2 preventative medication classes Use of preventative medications during trial (washout period required) Dodick DW, et al. Cephalalgia. 2018. 2018 MFMER slide-38
Baseline Characteristics Characteristic Placebo n= 291 Erenumab 70 mg n= 286 Age, years 42 ±12 42 ± 11 Female sex, no (%) 247 (84.9) 245 (85.7) Age at migraine onset 22 ± 11 21 ± 10 Prior 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 ± 2.7 MSMD 3.4 ± 3.6 3.7 ± 3.6 MPFID impact on everyday activities 13.2 ± 8.9 12.6 ± 8.6 score MPFID physical impairment score 11.5 ± 9.2 10.8 ± 9.1 MMD- Monthly Migraine Days MSMD- Migraine-Specific Medication Days Dodick DW, et al. Cephalalgia. 2018. 2018 MFMER slide-39
Results Endpoint Placebo Erenumab 70 mg Change 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) MPFID physical impairment score ( 5-point reduction) * statistically significant MMD- Monthly Migraine Days 35.8% 40.4% OR: 1.22, (0.87, 1.71) p=0.26 27.1% 33.0% OR: 1.33, (0.92, 1.90) p=0.13 Dodick DW, et al. Cephalalgia. 2018. 2018 MFMER slide-40
Strengths Endpoints measured Limitations Excluded patients on preventative treatment Dodick DW, et al. Cephalalgia. 2018. 2018 MFMER slide-41
Conclusion Erenumab reduced MMD and MSMD in patients with EM Further studies in combination with other migraine preventative treatments and in cardiovascular disease 2018 MFMER slide-42
Safety Adverse effects similar between treatment and placebo groups within both studies Common Adverse Effects ( 2%) injection site pain sinusitis influenza upper respiratory fatigue tract infection (URI) nausea nasopharyngitis constipation 2018 MFMER slide-43
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 2018 MFMER slide-44
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? 2018 MFMER slide-45
a. erenumab (Aimovig ) b. onabotulinumtoxina (Botox ) c. propranolol (Inderal ) d. all of the above 2018 MFMER slide-46
Future Considerations with CGRP Antagonists fremanezumab Phase III trials completed eptinezumab Phase II trials completed ubrogepant (oral) Phase III trial underway for acute treatment atogepant (oral) Under development for prevention glacanezumab Phase II trials completed telcagepant & MK-3207 Trials stopped due to hepatotoxicity Tso AR, Goadsby PJ. Curr Treat Options Neurol. 2017. 2018 MFMER slide-47
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 2018 MFMER slide-48
Questions 2018 MFMER slide-49