A Controlled Trial of Erenumab for Episodic Migraine

Shawn Yee, Mercer University College of Pharmacy

Migraine is a common neurological disorder that is ranked top 10 in terms of global disease burden. [1] The term migraine can be categorized into either episodic (< 15 migraine or headache days per month) or chronic (≥ 15 headache days per month, with ≥ eight days of migraine days). [2] Patients with debilitating or frequent migraines are eligible for preventative treatment; however, none of these options target the pathophysiologic pathways involved in migraines. [3]

Erenumab is a fully human monoclonal antibody that binds to the calcitonin gene-related peptide (CGRP) receptor, which is involved in migraine pathophysiology of the trigeminovascular system. [3] There are other monoclonal antibodies targeting CGRP, such as fremanezumb that have shown safety and efficacy in migraine prevention. Erenumab in particular, has also demonstrated efficacy in reducing the number of migraine days per month at doses ranging from 70 mg to 140 mg per month in a prior phase II trial. [3,4] Below is the summary of a phase III trial. [3]

A controlled trial of erenumab for episodic migraine
Design Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III trial; N= 955
Objective Analyze if erenumab is effective for the prevention of episodic migraines
Study Groups
  • Erenumab 70 mg subcutaneous injection monthly (n= 317)
  • Erenumab 140 mg subcutaneous injection monthly (n= 319)
  • Placebo (n= 319)
Methods The trial had a screening phase (≤ three weeks), a baseline phase (four weeks), a double-blind treatment phase (24 weeks), an active-treatment phase with 70 mg or 140 mg of erenumab (28 weeks), and follow-up phase for safety (12 weeks). A total of 955 patients were randomized to receive subcutaneous injections of erenumab 70 mg/month, erenumab 140 mg/month, or placebo during the double-blind treatment phase. A Migraine Physical Function Impact Diary (MPFID) was used to assess the overall effect and burden of migraine, which scores up to 100, and higher scores indicate increased patient burden on functioning.
Inclusion Criteria:

  • Ages 18 to 65 with ≥ one year history of migraine with or without aura
  • Have ≥ four migraine days per month three months prior to screening
  • Have < 15 migraine days and headache days per month three months prior to screening
  • Handheld electronic diary (ERT) completed daily with ≥ 80% adherence during baseline phase (four weeks)

Exclusion Criteria:

  • > 50 years of age at migraine onset
  • History of hemiplegic migraine or cluster headache
  • Botulinum toxin treatment ≤ four months before baseline
  • Use of devices or procedures for migraine prevention ≤ two months prior to baseline
  • No therapeutic response with > two migraine-preventive treatment categories (not detailed)
Duration July 2015 to September 2016
Primary Outcome Measure Change in the average number of migraine days per month from baseline during months four through six
Baseline Characteristics
Values are mean ± standard deviation (SD) unless stated otherwise
Characteristic Placebo (n= 319) Erenumab 70 mg (n= 317) Erenumab 140 mg (n= 319)
Age in years (range) 41.3 ± 11.2 (18-65) 41.1 ± 11.3 (18-63) 40.4 ± 11.1 (19-65)
Female, n (%) 274 (85.9) 268 (84.5) 272 (85.3)
Geographic region, n (%)
North America 158 (49.5) 159 (50.2) 160 (50.2)
Other 161 (50.5) 158 (49.8) 159 (49.8)
Age of migraine onset 21.2 ± 10.2 21.4 ± 11.0 20.7 ± 9.9
Acute headache medication use, n (%)
Migraine-specific 191 (59.9) 179 (56.5) 192 (60.2)
Non-migraine-specific 244 (76.5) 243 (76.7) 256 (80.8)
Migraine-prevention medication use, n (%)
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 preventative treatment failure, n (%) 127 (39.8) 127 (40.1) 116 (36.4)
Lack of efficacy, n (%) 90 (28.2) 89 (28.1) 83 (26.0)
Unacceptable side effects, n (%) 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 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
Clinical responses over the final three months of the double-blind treatment phase (months 4, 5, and 6)*:
Outcome 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 versus 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
n (%) 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 versus 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 versus 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 versus placebo (95% CI) -1.9 (-3.0 to -0.8) -2.4 (-3.5 to -1.4)
* = All values represented as least squares mean ± standard error (SE)
Adverse Events Common Adverse Events: Not disclosed
Serious adverse events Placebo (n= 319) Erenumab 70 mg (n= 314) Erenumab 140 mg (n= 319)
Number of patients reporting serious adverse events, n (%) 7 (2.2) 8 (2.5) 6 (1.9)
Noncardiac chest pain 1 (<1) 1 (<1) 1 (<1)
Cholelithiasis 0 2 (<1) 0
Ankle fracture 0 0 (<1)
Cerebral venous thrombosis 0 0 (<1)
Clostridium difficile colitis 0 0 (<1)
Viral gastroenteritis 0 0 (<1)
Kidney infection 0 0 (<1)
Pyelonephritis 0 0 (<1)
Sepsis 0 0 (<1)
Spinal pain 0 0 (<1)
Vestibular neuronitis 0 0 (<1)
Back pain 0 (<1) 0
Migraine 0 (<1) 0
Ovarian cyst 0 (<1) 0
Post-traumatic neck syndrome 0 (<1) 0
Acute pyelonephritis 0 (<1) 0
Arthralgia (<1) 0 0
Endometriosis (<1) 0 0
Fall (<1) 0 0
Hypersensitivity (<1) 0 0
Intentional overdose (<1) 0 0
Osteoarthritis (<1) 0 0
Percentage that Discontinued due to Adverse Events: Less than 3% discontinued erenumab
Study Author Conclusions Monthly doses of erenumab 70 mg SQ or 140 mg SQ significantly reduced migraine frequency, reduced the use of acute migraine medications, and improved quality of daily activities for patients.

 

This study affirms the findings of erenumab’s efficacy from the previous phase II trial, which also tested the same dosage regimens of 70 mg or 140 mg subcutaneously every month. The results of this phase III trial indicate that both doses of erenumab may be effective in reducing migraine frequency, reducing acute migraine medications, and improving overall quality of life for patients. In the future, studies comparing the different doses directly may provide more insight into the dose effects of erenumab. The safety data for this study is also promising, with fewer than 3% of patients discontinuing erenumab and similar number of serious adverse events in comparison to placebo. However, long-term safety and efficacy still needs to be evaluated.

Based on the results, erenumab may be a treatment option to consider in patients with severe migraine attacks or patients who are refractory to other preventative treatments. To note, this study only included patients diagnosed with episodic migraines (< 15 migraine or headache days per month), and erenumab efficacy in chronic migraine patients remains to be seen. With erenumab monthly injection formulation, patient preference and adherence will have to be addressed as well as the cost associated with erenumab treatment.

 

References

[1] Hershey, AD. CGRP-the next frontier for migraine. N Engl J Med 2017; 377:2190-2191.

[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;377:2123-2132.

[4] Sun H, Dodick DW, Silberstein S, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016;15:382-390.

 

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