Erenumab for the Treatment of Episodic Migraine

Achal Patel, Mercer University College of Pharmacy

It is reported that migraines are the third most prevalent illness in the world, prominently affecting women. [1] Symptoms include visual disturbances, extreme sensitivity to sound, light, touch, and smell, and tingling or numbness in the extremities and face. [1] Migraines can be classified as either episodic (< 15 headache days/month) or chronic (≤ 15 headache days/month). [2]

Erenumab is a fully human monoclonal antibody that inhibits the calcitonin gene-related peptide (CGRP) receptor that is involved in migraine pathophysiology through nociceptive mechanisms in the trigeminovascular system. [3] In a prior phase two trial, erenumab has shown a reduction in the number of episodic migraines at monthly doses of 70 mg and 140 mg. [3]

A controlled trial of erenumab for episodic migraine
Design Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial; N= 955
Objective To test erenumab for the prevention of episodic migraine
Study Groups Erenumab 70 mg (n= 317), Erenumab 140 mg (n= 319), and Placebo (n= 319)
Methods Patients were randomly assigned in a 1:1:1 ratio to receive monthly subcutaneous injections of 70 mg of erenumab, 140 mg of erenumab, or placebo at day 1 and weeks 4, 8, 12, 16, and 20

During baseline and double-blind treatment phases, patients completed an electronic diary daily with information about their migraine and non-migraine headaches, including the date and time of onset and resolution, pain severity and features, associated symptoms, and the use of migraine-specific abortive therapies and analgesic medications. Patients also completed the Migraine Physical Function Impact Diary (MPFID), a 13-item self-administered tool that measures physical functioning in the past 24 hours, on migraine and non-migraine days using the electronic diary.

Inclusion criteria:

–        Adults 18 to 65 years of age

–        History of migraine with or without aura for at least 12 months before screening

–        Patients had to have at least 4 and fewer than 15 migraine days per month and fewer than 15 headache days per month on average during the 3-month period before screening

–        During a 4-week baseline phase that was assessed with the use of a handheld electronic diary (ERT) completed daily by the patient and had to demonstrate at least 80% adherence to reporting with the electronic diary during the baseline phase

Exclusion criteria:

–        Patients were excluded if they had no therapeutic response in migraine prevention after an adequate therapeutic trial of >2 of the following medication categories:

o   Category 1: Divalproex sodium, sodium valproate

o   Category 2: Topiramate

o   Category 3: Beta blockers

o   Category 4: Tricyclic antidepressants

o   Category 5: Serotonin-norepinephrine reuptake inhibitors

o   Category 6: Flunarizine, verapamil

o   Category 7: Lisinopril, candesartan

–        The following medications, devices, or procedures were excluded:

o   Botulinum toxin

o   Ergotamine derivatives, steroids, and triptans

o   Devices and procedures used for migraine prophylaxis

o   Investigational medications and devices

o   Patients also must not have used investigational medications or devices for at least 90 days prior to screening

Duration July 2015 – September  2016
Primary Outcome Measure Change from baseline to four months through six in the mean number of migraine days per month
Baseline Characteristics  

Placebo (n = 319) Erenumab, 70 mg (n = 317) Erenumab, 140 mg (n = 319)
Age (range) 41.3±11.2 (18–65) 41.1±11.3 (18–63) 40.4±11.1 (19–65)
Female sex 274 (85.9) 268 (84.5) 272 (85.3)
Geographic region
North America 158 (49.5) 159 (50.2) 160 (50.2)
Other 161 (50.5) 158 (49.8) 159 (49.8)
Age at migraine onset 21.2±10.2 21.4±11.0 20.7±9.9
Acute headache medication use
Migraine-specific 191 (59.9) 179 (56.5) 192 (60.2)
Non–migraine-specific 244 (76.5) 243 (76.7) 256 (80.3)
Migraine-preventive medication use
No current or previous use 178 (55.8) 175 (55.2) 187 (58.6)
Previous use only 131 (41.1) 133 (42.0) 124 (38.9)
Current use 10 (3.1) 9 (2.8) 8 (2.5)
History of preventive treatment failure 127 (39.8) 127 (40.1) 116 (36.4)
Lack of efficacy 90 (28.2) 89 (28.1) 83 (26.0)
Unacceptable side effects 78 (24.5) 65 (20.5) 62 (19.4)
Assessment of migraine during baseline phase
Migraine days per month 8.2±2.5 8.3±2.5 8.3±2.5
Headache days per month 9.3±2.6 9.1±2.6 9.3±2.5
Migraine attacks per month 5.1±1.5 5.2±1.5 5.2±1.4
Days of use of acute migraine–specific medication per month 3.4±3.4 3.2±3.4 3.4±3.5
Monthly MPFID everyday-activities score 13.7±9.1 14.0±8.9 13.1±8.3
Monthly MPFID physical-impairment score 12.2±9.4 12.6±9.6 12.0±9.0
Results  

Placebo (n = 316) Erenumab, 70 mg (n = 312) Erenumab, 140 mg (n = 318)
Migraine days per month
Change from baseline −1.8±0.2 −3.2±0.2 −3.7±0.2
Difference vs. placebo (95% CI) −1.4 (−1.9 to −0.9) −1.9 (−2.3 to −1.4)
≥50% Reduction from baseline in migraine days per month
No. of patients (%) 84 (26.6) 135 (43.3) 159 (50.0)
Odds ratio (95% CI) 2.13 (1.52 to 2.98) 2.81 (2.01 to 3.94)
Days of use of acute migraine–specific medication per month
Change from baseline −0.2±0.1 −1.1±0.1 −1.6±0.1
Difference vs. placebo (95% CI) −0.9 (−1.2 to −0.6) −1.4 (−1.7 to −1.1)
Monthly MPFID everyday-activities score
Change from baseline −3.3±0.4 −5.5±0.4 −5.9±0.4
Difference vs. placebo (95% CI) −2.2 (−3.3 to −1.2) −2.6 (−3.6 to −1.5)
Monthly MPFID physical-impairment score
Change from baseline −2.4±0.4 −4.2±0.4 −4.8±0.4
Difference vs. placebo (95% CI) −1.9 (−3.0 to −0.8) −2.4 (−3.5 to −1.4)
Adverse Events  

Placebo (n= 319) Erenumab, 70 mg (n= 314) Erenumab , 140 mg (n= 319)
Adverse event 201 (63.0) 180 (57.3) 177 (55.5)
Adverse events reported by ≥2% of patients in any trial group
Nasopharyngitis 32 (10.0) 31 (9.9) 35 (11.0)
Upper respiratory tract infection 18 (5.6) 21 (6.7) 15 (4.7)
Sinusitis 7 (2.2) 7 (2.2) 11 (3.4)
Constipation 4 (1.3) 5 (1.6) 11 (3.4)
Arthralgia 6 (1.9) 7 (2.2) 7 (2.2)
Fatigue 8 (2.5) 6 (1.9) 7 (2.2)
Nausea 6 (1.9) 7 (2.2) 6 (1.9)
Influenza 6 (1.9) 4 (1.3) 8 (2.5)
Urinary tract infection 7 (2.2) 5 (1.6) 7 (2.2)
Back pain 7 (2.2) 6 (1.9) 6 (1.9)
Injection-site pain 1 (0.3) 10 (3.2) 1 (0.3)
Migraine 10 (3.1) 4 (1.3) 3 (0.9)
Hypertension 8 (2.5) 5 (1.6) 0
Adverse event leading to discontinuation of trial regimen 8 (2.5) 7 (2.2) 7 (2.2)
Serious adverse event 7 (2.2) 8 (2.5) 6 (1.9)
Study Author Conclusions Erenumab significantly reduced migraine frequency, effects of migraine on daily activities, and the use of acute migraine-specific medication over a six-month period.

Although erenumab demonstrated efficacy in the study, baseline suggests patients had mild migraine and >50% of patients have never used preventative medications. Moreover, it shows a small number of patients failed previous treatment due to lack of efficacy. Together, it is reasonable to question whether these patients may have also responded to other currently recommended first-line treatments (i.e. beta-blockers, triptans, and antiepileptic drugs). In addition, despite being monthly injection, it is expected that the cost of erenumab may be high similar to other drugs in the same class (monoclonal antibodies). Considering these limitations, even if the drug is approved, its use may be limited to mild migraines, and without other significant benefits (e.g. improved quality of life), it may be considered a second-line therapy.

References

[1] Migraine facts. Migraine research foundation. http://migraineresearchfoundation.org/about-migraine/migraine-facts/. Accessed January 25, 2018.

[2] Headache classification committee of the international headache Society (IHS). The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 2013;33:629-808

[3] Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):2123-2132.

[4] Silberstein SD, Holland S, Freitag F. et. al. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults. American Headache Society.

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