Description
Eptinezumab-jjmr (Vyepti^™) is a calcitonin gene-related peptide (CGRP) antagonist indicated for the preventative treatment of migraine in adult patients. Eptinezumab is a humanized monoclonal antibody that was approved by the U.S. Food and Drug Administration (FDA) in February 2020. It works by binding to CGRP ligand and blocking its binding to the receptor.  

Migraine is a common disabling headache disorder characterized by recurrent moderate to severe headaches with associated symptoms. The typical migraine headache is throbbing, unilateral, and aggravated by motion. Migraines are frequently associated with nausea, vomiting, photophobia, and phonophobia, although other neurological symptoms may occur. Migraine attacks can last from several hours to several days and are often preceded by transient neurological symptoms (e.g., visual disturbance) known as migraine aura. Migraines are categorized as episodic or chronic depending on the frequency of attacks. Episodic migraine is defined as migraine or headache for less than 15 days per month and accounts for more than 90% of cases of migraine. Chronic migraine is defined as 15 or more headache days each month, of which at least 8 are migraine days. Migraine was previously thought to be primarily vascular, but recent evidence suggests that sensitization of pain pathways in the central nervous system may be involved. At least three messenger molecules are thought to be involved during migraine attacks: nitric oxide, 5-hydroxytryptamine and calcitonin gene-related peptide (CGRP). CGRP is produced in both peripheral and central neurons and is a potent vasodilator. Some preclinical studies suggest that during a migraine, sensory neurons in the trigeminal ganglion release CGRP from their peripherally projecting nerve endings in the meninges.

Symptomatic treatment is available for migraine attacks. Initial treatment for migraine is the use of oral pain relievers, but those with severe disease typically try multiple therapies, including both non-drug (e.g., exercise, diet, relaxation techniques) and drug therapies. Acute drug therapies, such as triptans, treat symptoms after they have begun. For patients who experience more than four migraine days per month, preventive treatment may be recommended and includes certain antidepressants, anti-seizure medications, beta-blockers, and, for those with chronic migraine, onabotulinum toxin A. Oral medications approved by the FDA for migraine prophylaxis include topiramate, propranolol, timolol, and valproate. All of these medications have contraindications and side effects that limit their use. For many people, preventive therapies are not effective or have intolerable side effects.

Policy
Vyepti is considered MEDICALLY NECESSARY when the following criteria is met:

1. One of the following:
   1. Both of the following:
      1. Diagnosis of episodic migraines AND
      2. Patient has 4 to 14 migraine days per month, but no more than 14 headache days per month OR
   2. All of the following:
      1. Diagnosis of chronic migraines AND
      2. Patient has greater than or equal to 15 headache days per month, of which at least 8 must be migraine days for at least 3 months AND
      3. Medication overuse headache has been considered and potentially offending medication(s) have been discontinued AND
2. Patient is 18 years of age or older AND
3. Two of the following:
   1. One of the following:
      1. History of failure (after at least a two-month trial) or intolerance to Elavil (amitriptyline) or Effexor (venlafaxine). Patient has a contraindication to both Elavil (amitriptyline) and Effexor (venlafaxine)  OR
   2. One of the following:
      1. History of failure (after at least a two-month trial) or intolerance to Depakote/Depakote ER (divalproex sodium) or Topamax (topiramate). OR Patient has a contraindication to both Depakote/Depakote ER (divalproex sodium) and Topamax (topiramate) OR
   3. One of the following:
      1. History of failure (after at least a two-month trial) or intolerance to one of the following beta blockers: atenolol, propranolol, nadolol, timolol, or metoprolol. OR Patient has a contraindication to all of the following beta blockers: atenolol, propranolol, nadolol, timolol, or metoprolol AND
4. Trial and failure (after a trial of at least three months), contraindication, or intolerance to formulary approved CGRP self-injectable migraine therapies. AND
5. Medication will not be used in combination with another injectable CGRP inhibitor.
6. All other uses of Vyepti are considered NOT  MEDICALLY NECESSARY.

Rationale
The efficacy of eptinezumab was assessed for the prevention of episodic (PROMISE-1;NCT02559895) and chronic (PROMISE-2; NCT02974153) migraine in two randomized, placebo- controlled, multicenter clinical trials, each with 6-month double-blind periods. In each trial, eptinezumab was administered as an intravenous infusion every 3 months, with the primary endpoint measured at 12 weeks.

Episodic Migraine:
Adult patients with a history of episodic migraine (4 to 14 headache days per month, of which at least 4 were migraine days) were included in the PROMISE-1 trial. A total of 665 patients were randomized 1:1:1 to receive eptinezumab 100mg (n = 221), eptinezumab 300mg (n = 222), or placebo (n = 222) every 3 months for 12 months. Patients enrolled in the study were permitted to use concurrent acute migraine or headache medications during the trial, to include migraine-specific medications (i.e., triptans, ergot derivatives). Patients were excluded with a history of cardiovascular disease (hypertension, ischemic heart disease), neurological disease, or cerebrovascular disease. The mean migraine frequency at baseline was approximately 8.6 migraine days per month across treatment groups. The primary efficacy endpoint was the change from baseline in mean monthly migraine days over 3 months with eptinezumab 100 mg and 300 mg compared to placebo (100mg, -3.9 days, p = 0.0182; 300mg, -4.3 days; placebo, -3.2 days, p = 0.0001). In adult patients with episodic migraine, eptinezumab 100 mg and 300 mg significantly decreased monthly migraine days at 12 weeks compared with placebo in adults with episodic migraine.

Chronic Migraine:
Adult patients with a history of chronic migraine (15 to 26 headache days per month, of which at least 8 were migraine days) were included in the PROMISE-2 trial. A total of 1,072 patients were randomized 1:1:1 to received eptinezumab 100mg (n = 356), eptinezumab 300mg (n = 350), or placebo (n = 366) every 3 months for 6 months. Patients enrolled in the study were permitted to use and continue an established stable acute migraine or headache preventative medication regimen (except onabotulinumtoxin A). Patients with a dual diagnosis of chronic migraine and medication overuse headache attributable to acute medication overuse (triptans, ergot derivatives, or combination analgesics > 10 days per month) were also permitted. However, patients using opioids or butalbital-containing products for greater than 4 days per month were not allowed in the study. Patients were excluded with a history of cardiovascular disease (hypertension, ischemic heart disease), neurological disease, or cerebrovascular disease. The mean migraine frequency at baseline was approximately 16.1 migraine days per month across treatment groups. The primary efficacy endpoint was the change from baseline in mean monthly migraine days over 3 months with eptinezumab 100mg and 300mg compared to placebo (100 mg, -7.7 days, p < 0.0001 vs placebo; 300 mg, -8.2 days, p < 0.0001 vs placebo; placebo, -5.6 days). In adults with chronic migraine, eptinezumab 100 mg and 300 mg significantly decreased the mean monthly migraine days (MMDs) at 12 weeks compared with placebo.

References

1. Lundbeck Seattle BioPharmaceuticals, Inc. Vyepti (eptinezumab-jjmr) injection for intravenous use. Highlights of prescribing information. February 2020. Available at: https://www.lundbeck.com/upload/us/files/pdf/Products/Vyepti_PI_US_EN.pdf. Last accessed May 2020.
2. Ashina M, Saper J, Cady R, et al. Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study: PROMISE-1. Cephalalgia. 2020 Mar; 40(3): 241-254. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066477/pdf/10.1177_0333102420905132.pdf. Last accessed May 2020.
3. Lipton RB, Goadsby PJ, Smith J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology. 2020 Mar 31;94(13):e1365-e1377. doi: 10.1212/WNL.0000000000009169. Available at: https://n.neurology.org/content/94/13/e1365.long. Last accessed May 2020.
4. Katsarava Z, Buse DC, Manack AN, et al. Defining the differences between episodic migraine and chronic migraine. Curr Pain Headache Rep (2012) 16:86-92. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3258393/pdf/11916_2011_Article_233.pdf. Last accessed May 2020.
5. Headache Classification Committee of the International Headache Society (HIS). The International Classification of Headache Disorders; 3^rd edition. Cephalalgia. 2018 Jan;38(1):1-211. Available at: https://journals.sagepub.com/doi/pdf/10.1177/0333102417738202. Last accessed May 2020.
6. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards
7. Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012 Apr 24;78(17):1337-45. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335452/. Last accessed May 2020.
8. Silberstein SD. Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000 Sep 26;55(6):754-62. Available at: https://n.neurology.org/content/55/6/754.long. Last accessed May 2020.
9. Evers S, Afra J, Frese A, et al. EFNS guideline on the drug treatment of migraine – revised report of an EFNS task force. Eur J Neurol. 2009 Sep;16(9):968-81. Available at: https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1468-1331.2009.02748.x. Last accessed May 2020.
10. Medical Director review 6/2020 Medical Director review 7/2020
11. Specialty Matched Consultant Advisory Panel 10/2020

Dosing
The recommended dose for Vyepti is 100 mg administered as an intravenous infusion over approximately 30 minutes every 3 months. Some patients may benefit from a dose of 300 mg every 3 months.

According to the manufacturer’s safety labeling, Vyepti can cause hypersensitivity reactions to include angioedema, urticaria, facial flushing, and rash. Discontinuation of Vyepti should be considered if a hypersensitivity reaction occurs and appropriate treatment is initiated.

Coding

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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