Renewal Evaluation

Renewal of Target Agent(s) may be considered medically necessary when ALL of the following are met:

I.                 The patient has been previously approved for the requested agent through the plan’s Prior Authorization process [Note: patients not previously approved for the requested agent will require initial evaluation review]  AND

II.                The patient has had clinical benefit with the requested agent (e.g., decreased requirement of RBC transfusions, stabilization/improvement of hemoglobin, reduction of lactate dehydrogenase (LDH), stabilization/improvement of symptoms) (medical records required) AND

III.              The patient is not using requested agent with botulinum toxin for headache prophylaxis or will not be initiating botulinum toxin for headache prophylaxis while treated with requested agent AND

IV.              The patient has been evaluated for medication overuse headache AND

V.               The requested dose is within FDA approved dosage limits AND

VI.              The patient does NOT have any FDA labeled contraindications to the requested agent.

Length of Approval: 12 months

The calcitonin gene-related peptide (CGRP) is a therapeutic target in migraine because of its hypothesized role in mediating trigeminovascular pain transmission and the vasodilatory component of neurogenic inflammation.⁴

The diagnostic criteria for chronic migraine requires the inclusion of all of the following:¹⁰

1. Headache (migraine-like or tension-like) on ≥15 days per month for >3 months and fulfilling criteria B and C

2. Occurring in a patient who has had at least five attacks fulfilling of migraine without aura and/or migraine with aura

3. On ≥8 days per month for >3 months, fulfilling any of the following:

   1. Migraine without aura

   2. Migraine with aura

   3. Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative

4. Not better accounted for by another ICHD-3 diagnosis.

Preventative pharmacotherapy for chronic migraine is less well studied than for episodic migraine.  However, use of recommended episodic prevention agents is also recommended in chronic migraine. Clinical trials suggest efficacy is often first noted at four weeks and can continue to increase for three months.⁴

The American Headache Society and the American Academy of Neurology suggest the following agents for the prevention of migraine:⁹

• Established as effective

  • Antiepileptic drugs (AEDs)

    • Divalproex

    • Valproate

    • Topiramate

  • Beta blockers

    • Metoprolol

    • Propranolol

    • Timolol

  • Triptans

    • Frovatriptan for short term menstrually associated migraines (MAMs) prevention

• Probably effective

  • Antidepressants

    • Amitriptyline

    • Venlafaxine

  • Beta blockers

    • Atenolol

    • Nadolol
      

• Triptans

  • Naratriptan, zolmitriptan for short term MAMs prevention
    

Erenumab

Erenumab was studied in chronic migraine in a randomized, double-blind, placebo-controlled, phase 2 study.  656 men and women aged 18-65 years with a history of chronic migraine (with or without aura) were enrolled.  In each of the 3 months before screening, patients had to have had 15 or more headache days per month, of which 8 or more of those days were migraine days.  Patients were also required to be 80% compliant with their headache logs. Patients were excluded if they were older than 50 years at migraine onset and if they had a history of cluster headache or hemiplegic migraine, or chronic migraine with continuous pain.  Patients were also excluded from the study if they had no therapeutic response (reduction in frequency, duration, or severity of headache) with prophylaxis of more than three treatment categories after an adequate trial (at least 6 weeks of treatment at generally accepted doses). Migraine preventive drugs were prohibited during the study and 2 months before the start of the baseline phase. Botulinum toxin injections in the head or neck region were prohibited during the study and for at least 4 months before the start of the baseline phase.  At baseline, the monthly migraine days was 18.2 (SD 4.7) for the placebo group, 17.9 (SD 4.4) for the erenumab 70 mg group, and 17.8 (SD 4.7) for the 140 mg erenumab group. Monthly headache days was 21.1 (SD 3.9) for placebo, 20.5 (SD 3.8) for 70 mg erenumab group, and 20.7 (SD 3.8) mg for 140 erenumab group.  Monthly acute migraine-specific drug use days was 9.6 (SD 7.6) for placebo, 8.8 (SD 7.2 for erenumab 70 mg, and 9.7 (SD 7.0) for erenumab 140 mg. Study outcomes were assessed after 12 weeks:⁵ 

• Monthly migraine days reduction was -4.2 (SE 0.4) days for placebo, 6.6 (SE 0.4) days for erenumab 70 mg and 140 mg.

• Both doses of erenumab showed a statistically significant difference in reduction of -2.5 (CI -3.5 to -1.4) days in monthly migraine days vs. placebo. 

• Erenumab also exhibited statistically significant higher number of patients who were 50% responders (decrease of at least 50% migraine days vs. baseline) vs placebo.  However, the percentage of 50% responders in both dosage strengths was in the minority (40% for 70 mg, 41% for 140 mg, 23% for placebo). 

• There was a statistically significant difference in reduction of monthly acute migraine-specific drug treatment days for erenumab vs. placebo (-1.9 days vs placebo for 70 mg, -2.6 days vs placebo for 140 mg). 

• There was not a statistically significant difference in cumulative monthly headache hours vs. placebo.  
  

Erenumab was studied in 955 adult patients 18-65 years of age for use in episodic migraines.  Patients were randomly assigned to either placebo, 70 mg of erenumab, or 140 mg erenumab.  Patients were required to have a history of migraine with or without aura for at least 12 months.  Patients had to have at 4 and fewer than 15 migraine days per month and fewer than 15 headache days per month on average during at the 3 month screening period.  Patients were excluded if they were older than 50 years of age at migraine onset, had a history of hemiplegic migraine or cluster headache, had received botulinum toxin within 4 months before or during the baseline phase, used devices or procedures for migraine prevention within 2 months before the baseline phase, or had had no therapeutic response to more than two migraine-preventive treatment categories.  The study allowed enrollment of patients with concomitant use of 1 migraine preventative medication at a stable dose. Study outcomes were assessed after 24 weeks.  Baseline and outcomes results are presented in Table 1 below.⁶

Table 1.

MPFID - Migraine Physical Function 

Fremanezumab

Fremanezumab was studied in a double-blind, randomized, placebo-controlled, phase 3 trial with 1130 patients.  Individuals were randomized to receive placebo, fremanezumab quarterly, or fremanezumab monthly.  Inclusion criteria included an age of 18-70 years, a history of migraine for at least 12 months, history of chronic migraine (headache of any duration or severity on ≥15 days and migraine headache on ≥8 days) during the 28 days prior to intervention. Up to 30% of patients using a stable dose of one migraine-preventive medication for at least 2 months were allowed to continue these medications.  Key exclusion criteria were the use of onabotulinum toxin A during the 4 months before screening, the use of interventions or devices for migraine such as nerve blocks and transcranial magnetic stimulation during the 2 months before screening, the use of opioids or barbiturates on more than 4 days prior to intervention, and lack of efficacy of at least two or four clusters of preventative medications after an adequate therapeutic trial. Study outcomes were assessed after 12 weeks:⁷

• The primary endpoint of least squares mean change from baseline of average number of headache days per month was -4.3 (SE0.3) for fremanezumab administered quarterly, -4.6 (SE 0.3) for fremanezumab administered monthly, and -2.5 (SE 0.3) for placebo.  The difference between placebo and the two fremanezumab arms were statistically significant.

• The least squares mean change from baseline in average number of migraine headache days per month was -4.9 (SE 0.4) for fremanezumab administered quarterly, -5.0 (SE 0.4) for fremanezumab administered monthly, and -3.2 (SE0.4) for placebo.  The difference between placebo and the two fremanezumab arms were statistically significant.

• The percentage of patients with ≥50% reduction in average number of headache days per month was 38% for fremanezumab administered quarterly, 41% for fremanezumab administered monthly, and 18% for placebo

• The least squares mean change from baseline in average number of days of use of any acute headache medication per month was -3.7 (SE 0.3) for fremanezumab administered quarterly, -4.2 (SE 0.3) for fremanezumab administered monthly, and -1.9 (SE 0.3) for placebo.  The difference between placebo and the two fremanezumab arms were statistically significant

• 79% of the fremanezumab administered quarterly, 77% of the fremanezumab administered monthly, and 79% of placebo arms were not receiving concomitant preventative medications.  The least squares mean change from baseline in average number of headache days per month for these patients was -4.6 (SE 0.3) for fremanezumab administered quarterly, -4.8 (SE0.3) for fremanezumab administered monthly, and 2.6 (SE 0.3) for placebo.  The difference between placebo and the two fremanezumab arms were statistically significant.

• The average number of headache days per month showed statistically significant differences between the two fremanezumab arms and placebo during the 4 weeks period after the first dose.

Galcanezumab

Galcanezumab was studied in a phase 2b trial in patients with episodic migraine.  936 patients were randomized to 1 of 5 treatment groups (2:1:1:1:1 ratio) to receive either placebo or 1  galcanezumab dose level (5, 50, 120, or 300mg), respectively. The study was separated into 4 study periods (SP). SP 1 (4-45 days) was for screening and washout. SP 2 (28-38 days) was the prospective baseline period for evaluating the frequency of migraine headache days (MHDs).  SP 3 (3 months) was the double-blinded treatment period. And SP 4 (3 months) was the post-treatment period. Galcanezumab or placebo was administered by subcutaneous (SC) injection once monthly during office visits. Patients were required to track daily headache information starting in SP2. During the study, acute migraine treatments were allowed as needed (opioids or barbiturates were not permitted). Concomitant medications allowed included acetaminophen, nonsteroidal anti-inflammatory drugs, aspirin, triptans, corticosteroids (periodic topical or inhaled but not oral or injected), and ergotamines and their derivatives. Preventive treatments were permitted only during SP 4 at the discretion of the investigator. Patients were men and women 18 to 65 years of age with a history of migraine, with or without aura, for at least 1 year prior to enrollment. For inclusion, patients had to experience a frequency of 4 to 14 MHDs and at least 2 migraine attacks in a 28-day period during SP 2.  Migraine onset must have occurred prior to age 50 years. Use of botulinum toxin A and B administered in the head or neck area must have been discontinued at least 4 months prior to SP 2. Patients were excluded from study participation for any of the following reasons: currently enrolled in or discontinued within the last 30 days from a clinical trial using any investigational drug or device; any current or previous exposure to a CGRP or nerve growth factor antibody; history of hemiplegic, ophthalmoplegic, or basilar-type migraine; history or presence of other medical illness indicating a medical problem that would preclude study participation; failure to respond to more than 2 effective migraine preventive treatments; evidence of significant active psychiatric disease; and pregnancy or lactation. Patients should have completed at least 80% of daily headache log entries during SP 2. The mean (SD) MHDs per month at baseline was 6.6 (2.7) and 6.7 (2.6) for placebo and galcanezumab respectively.  The mean (SD) migraine attacks per month was 4.7 (1.5) and 4.7 (1.6) for placebo and galcanezumab respectively. The primary objective was to assess whether at least 1 dose of galcanezumab was superior to placebo in the prevention of migraine.  The posterior probability of greater improvement in MHDs with galcanezumab, 120 mg (99.6%; −4.8 MHDs, 90% BCI, −5.4 to −4.2 MHDs) compared with placebo (−3.7 MHDs, 90% BCI, −4.1 to −3.2 MHDs) was greater than the specified threshold (95%)for the mean change from baseline in the number of MHDs at month 3.  Least square (LS) mean change from baseline for secondary outcomes was statistically significantly different between galcanezumab, 120mg, and placebo at month 3 except for headache days: migraine plus probable MHDs (−5.9; 95% CI,−6.7 to−5.1;P < .001) vs placebo (−4.0;95%CI,−4.6to−3.4), probable MHD (−0.9; 95% CI, −1.3 to −0.6; P = .049) vs placebo (−0.5; 95%CI, −0.8 to −0.3), migraine attacks (−3.5; 95% CI, −3.9 to −3.0;P = .003) vs placebo (−2.7; 95%CI,−3.0to−2.3), 50% response rate (47/62 [75.8%]; P = .03) vs placebo (78/126 [61.9%], and 100% response rate (22/62 [35.5%]; P = 0.04) vs. placebo (29/126 [23.0%]).⁸

Safety

Contraindications to erenumab include:¹

• None
  

Erenumab contains the following black box warnings:¹

• None
  

Contraindications to fremanezumab include:²

• TBD
  

Fremanezumab contains the following black box warnings:²

• TBD
  

Contraindications to galcanezumab include:³

• TBD
  

Galcanezumab contains the following black box warnings:³

• TBD