Fremanezumab for the Preventative Treatment of Chronic Migraine

Shawn Yee, Mercer University College of Pharmacy

Migraine headache is a neurological disorder that manifests as recurrent attacks of pulsating head pain, with or without visual disturbances. Migraines are moderate to severe in pain and can be debilitating, leading to a lower quality of life. [1] The current Neurology Guideline suggests divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, and timolol are effective for migraine prevention and can be used to reduce migraine frequency and severity. [2]

Chronic migraine is seen in about 2% of the general population, and in comparison with episodic migraine, it is associated with decreased quality of life and increased headache-related burden. Therefore, preventing the onset could reduce the burden of chronic migraine and is an ongoing area of research. [3]

Fremanezumab is a humanized IgG2a monoclonal antibody that binds to calcitonin gene-related peptide (CGRP). In a phase II trial, the number of migraine and headache days were significantly lower with fremanezumab treatment, and no serious treatment-related adverse events occurred. [4] Below is a summary of phase III trial. [5]

Fremanezumab for the Preventative Treatment of Chronic Migraine  
Design Randomized, double-blind, placebo-controlled, parallel-group phase III trial; N= 1,130  
Objective To evaluate the safety and efficacy of two dose regimens of fremanezumab in the preventive treatment of chronic migraine  
Study Groups ●       Fremanezumab 675 mg quarterly (n= 376)

●       Fremanezumab 225 mg monthly (n= 379)

●       Placebo; n= 375

 
Methods Patients were recruited from 132 sites in nine countries. All the patients received three abdominal subcutaneous injections at baseline and one injection at weeks four and eight, and patients were randomly assigned into one of three groups in a 1:1:1 ratio. The quarterly group received 675 mg of fremanezumab at baseline (three injections of 225 mg per 1.5 mL), followed at weeks four and eight by placebo (one 1.5-ml injection). The monthly group received 675 mg of fremanezumab at baseline and 225 mg of fremanezumab at weeks four and eight (one injection of 225 mg per 1.5 ml). Final evaluation was done at week 12 after 12 weeks of intervention. Patients were seen at five scheduled times: at screening, baseline, weeks four and eight, and week 12, or at the time of withdrawal.

 

Inclusion Criteria:

●       18 to 70 years old

●       ≥ 12 month history of migraine

●       fulfilled criteria for chronic migraine during the 28 day pre-intervention period (headache of any duration or severity on ≥15 days and headache meeting ICHD-3 beta criteria for migraine on ≥8 days)

●       allowed up to 30% of patients using a stable dose of one migraine-preventive medication for ≥ two months before the start of the pre-intervention period to continue these medications

 

Exclusion Criteria:

●       use of onabotulinumtoxinA four months before screening

●       use of nerve blocks and transcranial magnetic stimulation two months before screening

●       use of opioids or barbiturates > four days during the preintervention period

 
Duration March 2016 to January 2017  
Primary Outcome Measure Mean change in the average number of headache days per month

Headache days: days in which headache lasted at least four hours with a peak severity of at least moderate, or days in which acute migraine medication (triptans or ergots) were used.

 
Baseline Characteristics  

Characteristic

 

Fremanezumab quarterly (n= 376) Fremanezumab monthly (n= 379) Placebo (n= 375)
Age in years; mean ± standard deviation (SD) 42.0 ± 12.4 40.6 ± 12.0 41.4 ± 12.0
Female; n (%) 331 (88) 330 (87) 330 (88)
Disease History
Current use of prevention medication; n (%) 77 (20) 85 (22) 77 (21)
Current use of acute headache medication; n (%) 359 (95) 360 (95) 358 (95)
Disease characteristics during 28 day pre-intervention period; mean ± SD
Migraine days 16.2 ± 4.9 16.0 ± 5.2 16.4 ± 5.2
Days of use of any acute headache medications 13.1 ± 6.8 13.1 ± 7.2 13.0 ± 6.9
Days of use of any migraine-specific acute medications 11.3 ± 6.2 11.1 ± 6.0 10.7 ± 6.3
Headache Impact Test (HIT-6) ranging from 36 to 78, with higher values indicating greater disability 64.3 ± 4.7 64.6 ± 4.4 64.1 ± 4.8
 
Results  

All values are represented as mean ± standard deviation
End Point Fremanezumab quarterly (n= 375) Fremanezumab monthly (n= 375) Placebo (n= 371)
Primary endpoint: Average number of headache days per month
Mean value during 12 week period after 1st dose 8.5 ± 6.3 8.0 ± 6.3 10.4 ± 6.4
Least-squares mean change from baseline during 12 week period after 1st dose -4.3 ± 0.3 -4.6 ± 0.3 -2.5 ± 0.3
Difference versus placebo -1.8 ± 0.3 -2.1 ± 0.3 Not disclosed
Secondary endpoints: Average number of migraine days per month
Least-squares mean change from baseline during 12 week period after 1st dose -4.9 ± 0.4 -5.0 ± 0.4 -3.2 ± 0.4
Difference versus placebo -1.7 ± 0.4 -1.8 ± 0.4 Not disclosed
≥ 50% Reduction in average number of headache days per month; n (%) 141 (38) 153 (41) 67 (18)
Average number of days of use of any acute headache medication per month
Least-squares mean change from baseline during 12 week period after 1st dose -3.7 ± 0.3 -4.2 ± 0.3 -1.9 ± 0.3
Difference versus placebo -1.8 ± 0.3 -2.3 ± 0.3 Not disclosed
Average number of headache days per month
Least-squares mean change from baseline during four week period after 1st dose -4.4 ± 0.3 -4.5 ± 0.3 -2.1 ± 0.3
Difference versus placebo -2.3 ± 0.4 -2.4 ± 0.4 Not disclosed
Average number of headache days per month in patients not receiving concomitant preventative medications
Patients evaluated; n (%) 298 (79) 290 (77) 294 (79)
Least-squares mean change from baseline during 12 week period after 1st dose -4.6 ± 0.3 -4.8 ± 0.3 -2.6 ± 0.3
Difference versus placebo -1.9 ± 0.4 -2.2 ± 0.4 Not disclosed
HIT-6 Score
Least-squares mean change from baseline during four week period after last dose -6.4 ± 0.5 -6.8 ± 0.4 -4.5 ± 0.5
Difference versus placebo -1.9 ± 0.5 -2.4 ± 0.5 Not disclosed
 
Adverse Events  

All values are represented as number of patients (percent)
Event Fremanezumab quarterly (n= 376) Fremanezumab monthly (n= 379) Placebo (n= 375)
≥ 1 Adverse event 265 (70) 270 (71) 240 (64)
≥ 1 Adverse event related to the trial regimen 186 (49) 194 (51) 159 (42)
≥ 1 Serious adverse event 3 (< 1) 5 (1) 6 (2)
Adverse event leading to discontinuation 5 (1) 7 (2) 8 (2)
Death 1 (< 1) 0 0
Adverse events reported in > 2% of patients in any group
Injection site reactions
   Pain 114 (30) 99 (26) 104 (28)
   Induration 74 (20) 90 (24) 68 (18)
   Erythema 80 (21) 75 (20) 60 (16)
   Hemorrhage 7 (2) 8 (2) 10 (3)
Infections
   Nasopharyngitis 19 (5) 15 (4) 20 (5)
   Upper    respiratory tract infection 18 (5) 16 (4) 15 (4)
   Sinusitis 10 (3) 4 (1) 10 (3)
Dizziness 9 (2) 11 (3) 5 (1)
Nausea 4 (1) 6 (2) 11 (3)
Study Author Conclusions Fremanezumab subcutaneous injections given monthly or quarterly was shown to be more effective than placebo for preventing the number of headaches in chronic migraine patients.

 

Overall, this study provides useful insight into the potential use of fremanezumab in preventing headaches in patients diagnosed with chronic migraine, and affirms the findings of the previous phase II trial. In this phase III trial, two different dosage regimens were used in the treatment groups (675 mg initially, then 225 mg monthly versus 675 mg initially, then 675 mg every 3 months), which gives a greater understanding of duration of treatment effect. However, the investigators did not compare the two regimens, which may have been beneficial in determining a treatment plan for patients. The study also did not include patients with refractory diseases, which appears to be the population with the most unmet needs. Moreover, long-term data is yet to be determined.

Based on the results, fremanezumab may provide short-term benefits in chronic migraine patients that are not well controlled with triptans and ergot derivatives without increased risk of adverse events other than injection site reactions. Additionally, the lower administration frequency may provide convenience to patients, if they are willing to use injectables. However, it may be prudent to consider these benefits against the cost associated with fremanezumab prior to initiating the therapy.

 

References

[1] Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev 2017;97:553-622.

[2] S.D. Silberstein, S. Holland, F. Freitag, D.W. Dodick, C. Argoff, E. Ashman. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults. Neurology. 2012;78(17):1337-1345.

[3] Manack AN, Buse DC, Lipton RB. Chronic migraine: epidemiology and disease burden. Curr Pain Headache Rep 2011;15:70-78.

[4] Bigal ME, Edvinsson L, Rapoport AM, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015;14:1091-1100.

[5] Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 2017;377:2113-2122.

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