A lack of specific chemical targets related to migraine pathophysiology has led to limited efficacious treatments for migraine headaches. Therefore, the approach to migraine prophylaxis has been to investigate medications with primary indications other than migraines. Examples include beta-blockers; centrally acting alpha agonists; certain atypicals; selective serotonin reuptake inhibitors; various antidepressants, including serotonin-norepinephrine reuptake inhibitors, anticonvulsants, and tricyclic antidepressants; and others that have been used with variable efficacy. These medications have unique adverse effect (AE) profiles and toxicities that often result in poor compliance, further contributing to reduced treatment efficacy.

The 2012 American Academy of Neurology (AAN) guidelines for episodic migraine prevention in adults categorize medications by likelihood of effectiveness and evidence of ineffectiveness.1 These guidelines were reaffirmed by AAN in 2015, with a guideline update in progress.

An ideal migraine medication would target a chemical or receptor specific to the pathophysiology of migraines, with the ability to prevent and/or reduce active symptoms of the disease. The overall benefit to be obtained from the triptan medication class suffers from a stringent monthly dosing limit because of the risk for potentially serious AEs. Development of abortive medications that offer an improved safety profile would be useful to those who suffer from migraines. Many patients are also in need of effective preventive therapies that may be used on a regular basis to decrease their need for abortive medications. Not all patients with migraines benefit substantially from or require regular use of prophylactic migraine medication. Some indications for their use include contraindication, failure of, or intolerance to acute therapies; long-lasting or recurring migraines; or migraines that cause a decrease in quality of life or interfere with daily routine, despite the use of acute therapy.2 Calcitonin gene-related peptide (CGRP) inhibitors were developed to address the issue of inadequate preventive therapy.

WHAT ARE CGRPS?
A search of studies for biomarkers of migraine activity found that CGRP levels are elevated in individuals who experience migraines.3 CGRP is a neuropeptide that is released from and synthesized in trigeminal neurons as a potent vasodilator, facilitating increased intracranial pressures and nociceptive pain transmission due to excessive cerebral blood flow.4 Additional studies have tested the relationship between CGRP and migraines by assessing intravenous infusion of CGRP in humans, which produced lasting headaches in healthy individuals and migraine headaches in patients already suffering from the condition.5

Three monoclonal antibodies targeting CGRP were released to the market recently—erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality)—and approved by the FDA in 2018 for preventive treatment of migraines in adults.6-8



OVERVIEW AND COMPARISON
Erenumab came to market on May 17, 2018, as the first CGRP available for use and the first medication approved for migraine headaches since onabotulinum-toxin A in 2010.9 It is a human immunoglobulin G2 (IgG2) that binds to the CGRP receptor and inhibits the action of CGRP. Erenumab is a monthly subcutaneous (SC) injection available as an auto-injector pen or syringe at a starting dose of 70 mg that can be tried at an increased dose of 140 mg in select patients. The medication is stored under refrigeration; must be left at room temperature for 30 minutes prior to administration into the abdomen, thigh, or upper arm; and is very well tolerated, with the most common AEs being injection-site reactions, constipation, and muscle cramp/spasm incidence of 6%, 1%, and less than 1%, respectively, in a study of 787 patients receiving the 70-mg dose.

Neutralizing antibodies produced by the human immune system can occur during treatment with monoclonal antibody drug products. Although 6.2% and 2.6% of patients experienced an emergence of anti-erenumab antibodies with either the 70- or 140-mg dose, respectively, just 2 of 1282 patients had neutralizing activity in vitro.10 However, at this time it cannot be inferred that neutralizing antibodies would affect the efficacy, pharmacokinetics, or safety of the medication until further studied.

Geriatric populations and those with creatinine clearance less than 30 mL/min were not sufficiently represented in trials, and there are no specific recommendations about how to treat these patients. Peak serum concentration is reached within 6 days, and the effective half-life of erenumab is about 28 days, reaching steady state concentration within 3 months using once-monthly dosing. The 2 main routes of elimination are nonsaturable proteolytic activity that results in cleavage of the antibody and saturable binding to the CGRP receptor.6

Fremanezumab was approved on September 14, 2018, and is the only CGRP inhibitor that allows the flexibility of both monthly (225 mg) and every-3-month (675 mg) dosing options.7,9 Similar to erenumab, this medication is also a SC injection available in a prefilled syringe, which must be removed from the refrigerator 30 minutes prior to administration into the thigh, abdomen, or upper arm. Although erenumab is a fully human monoclonal antibody, it is humanized, meaning that it contains a small portion of murine protein in its structure. Another minor distinction between the 2 medications is that erenumab binds to the CGRP receptor and fremanezumab binds to the CGRP ligand, with the prevention of interaction between the 2 entities as a result in both cases. The only AE to occur at an incidence of 2% or greater was injection-site reactions (43% - 45% in fremanezumab vs 38% in a placebo).

Antifremanezumab antibodies were detected in 1.6% of patients in an ongoing open-label study and 0.4% of patients in a 3-month study. Within the open-label study, 17 of 30 patients with antidrug antibodies demonstrated neutralizing activity. However, because of differences in immunoassays and other factors in the analysis, comparing this statistic across CGRP inhibitors may not be accurate or appropriate. Time to max concentration after a single dose is about 5 to 7 days, and steady state is achieved after about 6 months in both monthly and quarterly dosingregimens.Themedicationisalsoeliminatedviaproteolytic cleavage activity.7

Galcanezumab came to market on September 27, 2018.9 It is a human immunoglobulin G4 antibody also available as a single-dose prefilled pen or syringe that must be refrigerated and placed at room temperature 30 minutes prior to administering. This medication is the only one in the class with an initial loading dose of 240 mg followed by monthly SC doses of 120 mg administered in the abdomen, back of the upper arm, buttocks, or thigh. The loading dose allows for attainment of steady state concentration after just 1 dose. The time to max concentration is 5 days, with an elimination half-life of 27 days and a mechanism of elimination similar to erenumab. Geriatric patients with renal impairment did not have a large enough representation in trials to make definitive conclusions about efficacy and safety.8

Eptinezumab by Alder Biopharmaceuticals is a fourth CGRP inhibitor, and it is on its way to market. There is no prescribing information available to the public at this time, as the medication is in investigational drug status. The biological license application was under review by the FDA as of April 22, 2019, with a decision regarding its approval expected in February 2020.

CGRP EFFICACY
All 3 CGRP inhibitors on the market display similar efficacy in trials, with a reduction in migraine days per month by about 3 to 5 days compared with no therapy at baseline for patients with chronic migraines (15 or more migraine days per month) or episodic migraines (4-14 migraine days per month). Of note, the CGRP inhibitor mentioned have not been directly compared with one another within a trial, and limitations in interpretation of results between studies should be acknowledged.

Erenumab was the first to demonstrate the efficacy of CGRP inhibitors in 1 study of patients with chronic migraines and 2 studies of those with episodic migraines. In a 2017 study for episodic migraines conducted by Goadsby et al, the primary efficacy endpoint was change from baseline in mean monthly migraine days over months 4 to 6. The trial included 317 and 319 patients in the 70-mg and 140-mg erenumab groups, respectively, and 319 patients in the placebo group. Mean migraine frequency at baseline was 8.3 migraine days per month, which changed from baseline in the erenumab groups by –3.2 and –3.7 days per month, respectively. A change of –1.8 migraine days per month was observed for the placebo, resulting in a difference of –1.4 and –1.9 migraine days per month for the 70-mg and 140-mg doses (P <.001 for both erenumab groups compared with the placebo).10

In the second study for episodic migraines, the primary endpoint was change from baseline in monthly migraine days as measured at month 3. Patients had a mean of 8 migraine days per month at baseline, with the 70-mg erenumab group experiencing a change of –2.9 migraine days compared with the baseline, which was a reduction of 1.0 day compared with the placebo (P <.001).6

A third study of erenumab in episodic migraines, authored by Reuter et al and known as the LIBERTY trial, was a double-blind, multicenter, phase 3b, placebo-controlled randomized trial. It included patients who had failed 2 to 4 prophylactic therapies because of lack of efficacy, tolerability, or both. The trial period was 12 weeks, and an elderly subset of patients was not included. Patients in the erenumab arm received only the higher 140-mg monthly dose compared with the placebo. The primary endpoint was the proportion of patients achieving a 50% or greater reduction in mean monthly migraine days during weeks 9 to 12 of active treatment. With 121 participants in the erenumab group and 125 assigned to the placebo, 30% of erenumab patients met the primary endpoint compared with 14% in the placebo group (odds ratio, 2.7; CI, 1.4-5.2; P = .002). Safety and tolerability were statistically similar between the groups.11 These study results show that erenumab may provide benefit in patients with multiple treatment failures.

In a separate study for patients with chronic migraines, the primary endpoint was also the mean change in monthly migraine days at month 3. Mean migraine frequency was 18 days per month at baseline, with a change of –6.6 migraine days per month in the 70-mg and 140-mg treatment arms, with a difference of –2.5 days (P <.001) for both erenumab groups compared with the placebo.6

To demonstrate efficacy with fremanezumab, a 3-month study was conducted in patients with chronic migraines, with a reduction in monthly migraine days of at least moderate severity from 12.8 to 8.2 in the 225-mg monthly group and from 13.2 to 8.9 in the 675-mg quarterly group. This was statistically significant compared with the placebo, which reduced migraines from 13.3 to 10.8 days.12 In 2018, Dodick et al published a 3-month study of 791 patients with episodic migraines, comparing fremanezumab 225-mg monthly and 675 mg quarterly. Fremanezumab 225 mg monthly resulted in a reduction of mean monthly migraine days from 8.9 to 4.9, and 675 mg every 3 months reduced monthly migraine days from 9.2 to 5.3. These were statistically significant compared with a reduction from 9.1 to 6.5 migraine days with the placebo.13 Of note, in the Dodick study, fremanezumab was being studied in patients suffering from cluster headaches. The manufacturer of fremanezumab analyzed early results and projected that the study would be unable to meet the primary endpoint, so it was suspended in April 2019.14

Initial data available for galcanezumab included 1 study in patients with chronic migraines and 2 studies in patients with episodic migraines. Both episodic migraine studies were 6 months in length, with about 9.1 to 9.2 migraine days per month at the baseline for the active treatment and placebo arms. The mean change in migraine days from baseline for galcanezumab 120 mg in both studies were –4.7 and –4.3 days compared with –2.8 and –2.3 with placebo.15,16 In patients with chronic migraines, baseline monthly migraine days were 19.4 and 19.6 in the placebo and treatment groups, respectively. Over a 3-month period, galcanezumab showed a reduction in migraine days per month of 4.8 compared with the placebo group. All comparisons mentioned between the placebo and treatment were statistically significant.

COSTS
Although CGRP inhibitors have displayed acceptable efficacy and safety, medication costs may result in delayed widespread use. Analysts originally projected that CGRP inhibitors would cost $8000 to $20,000 per year. However, likely in an effort to expand access, erenumab was brought to market at a wholesale acquisition cost of $6900 per year.

The Institute for Clinical and Economic Review (ICER) conducted a cost-effectiveness analysis for erenumab in April 2018 based on a price of $8500 per year. The institute calculated that it would cost $135,000 for 1 patient to gain 1 quality-adjusted life year compared with no treatment for migraines and that using erenumab would result in an additional $6000 in costs per patient to the health care system.17 With knowledge of the official pricing set below initial projections, ICER has since made a statement that erenumab is cost-effective once less expensive options have been trialed with data to support this price point.18

ICER is a nonprofit, private organization without regulation by government entities and has a portion of its funding provided in connection with various third-party payers.19 Although ICER has been criticized for flaws in methodology and difficulty in applying results to the unique situations of some stakeholders based on assumptions used in the modeling,20-22 ICER addresses an unmet need for price and value transparency in the United States. The analyses that it produces allow manufacturers, payers, the public, and other stakeholders to gain another perspective on value, with a primary goal of keeping the cost of US health care down while using efficacious therapy.

As patients exhaust options for preventive therapy and continue to have debilitating events, patients may consider the out-of-pocket cost of CGRP inhibitors to be worth the relief of their symptoms. In line with ICER recommendations, CGRP inhibitor use likely will be supported by payers for use in patients who have been refractory to full trials of standard-of-care preventive medications or in those who are contraindicated to the use of standard-of-care medications.

CONCLUSION
Pharmacists should familiarize themselves with counseling on administration and storage, the indications for use of preventive migraine therapy, pharmacokinetics of CGRP inhibitors (see table23), the possibility of development of antidrug antibodies, and the uncertainty of how that affects efficacy and safety, being aware of the cost both to the health care system and patients.

CGRP inhibitors offer a unique mechanism that is more targeted to the pathophysiology of migraines than any guideline-recommended medication preceding them. The short-term AE profile of CGRPs is relatively benign in comparison to nonspecific treatments for migraine. Dose adjustments for hepatic or renal impairment are not required, and drug interactions are generally nonexistent with injected monoclonal antibodies, as they are not metabolized through the cytochrome P450 enzyme system.

Although CGRPs have their own limitations, most notably cost, lack of long-term safety data, and lack of robust head-to-head trials with current standard of care, they are a long-awaited class that may only be the tip of the iceberg for breakthrough migraine treatments. The development of CGRP inhibitors may prove to be a catalyst in encouraging pharmaceutical companies to invest in the further development of medications that will provide great advances in the quality of life of those with migraines.
 
Nicholas Trotta, PharmD, recently completed a PGY-1 pharmacy practice residency at the New Mexico Veterans Affairs Health Care System in Albuquerque and has accepted a position as an outpatient clinical pharmacist for the Veterans Affairs Greater Los Angeles Healthcare System in California.

Jeffrey Fudin, PharmD, FCCP, FASHP, FFSMB, is CEO and founder of Remitigate LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at Western New England College of Pharmacy and Health Sciences, an adjunct associate professor of pharmacy practice and pain management at Albany College of Pharmacy and Health Sciences, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center in New York.


REFERENCES
  1. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345. doi: 10.1212/WNL.0b013e3182535d20.
  2. 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;55(6):754-762.
  3. Bellamy JL, Cady RK, Durham PL. Salivary levels of CGRP and VIP in rhinosinusitis and migraine patients. Headache. 2006;46(1):24-33.
  4. Durham PL, Dong PX, Belasco KT, et al. Neuronal expression and regulation of CGRP promoter activity following viral gene transfer into cultured trigeminal ganglia neurons. Brain Res. 2004;997(1):103-110.
  5. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(1):54-61.
  6. Aimovig (erenumab-aooe) [prescribing information]. Thousand Oaks, CA: Amgen Inc; 2018. pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/aimovig/aimovig_pi_hcp_english.ashx. Accessed August 27, 2019.
  7. Ajovy (fremanezumab-vfrm) [prescribing information]. North Wales, PA: Teva Pharmaceuticals; 2018. accessdata.fda.gov/drugsatfda_docs/label/2018/761089s000lbl.pdf. Accessed August 27, 2019.
  8. Emgality (galcanezumab-gnlm) [prescribing information]. Indianapolis, IN: Eli Lilly and Co; 2018. pi.lilly.com/us/emgality-uspi.pdf. Accessed August 27, 2019.
  9. FDA. Novel drug approvals for 2018. fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm592464.htm. Updated September 27, 2018. Accessed August 27, 2019.
  10. Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):2123. doi: 10.1056/NEJMoa1705848.
  11. Reuter U, Goadsby PJ, Lanteri-Minet M, et al. Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study. Lancet. 2018;392(10161):2280-2287. doi: 10.1016/S0140-6736(18)32534-0.
  12. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377(22):2113-2122. doi: 10.1056/NEJMoa1709038.
  13. Dodick DW, Silberstein SD, Bigal ME, et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018;319(19):1999-2008. doi: 10.1001/jama.2018.4853.
  14. Teva announces update on fremanezumab clinical development for use in episodic cluster headache [news release]. Jerusalem, Israel: Teva Pharmaceuticals; ; April 23, 2019. ir.tevapharm.com/investors/press-releases/press-release-details/2019/Teva-Announces-Update-on-Fremanezumab-Clinical-Development-for-use-in-Episodic-Cluster-Headache/default.aspx. Accessed August 28, 2019.
  15. Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442-1454. doi: 10.1177/0333102418779543.
  16. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018;75(9):1080-1088. doi: 10.1001/jamaneurol.2018.1212.
  17. Calcitonin gene-related peptide (CGRP) inhibitors as preventive treatments for patients with episodic or chronic migraine: effectiveness and value. Institute for Clinical and Economic Review website. icer-review.org/wp-content/uploads/2017/11/ICER_Migraine_Draft_Report_041118.pdf. Published April 11, 2018. Accessed August 28, 2019.
  18. Institute for Clinical and Economic Review finds price of erenumab aligns with clinical benefit in patients for whom other therapies have failed to prevent migraines [news release]. Boston, MA: Institute for Clinical and Economic Review; May 31, 2018. icer-review.org/announcements/cgrp-evidence-report/. Accessed August 29, 2019.
  19. Sources of funding. Institute for Clinical and Economic Review website. icer-review.org/about/support/. Updated January 2019. Accessed August 29, 2019.
  20. The utility of ICER reports for private payer drug coverage decision-making: cost-effectiveness assessments. Milliman Inc website. phrma-docs.phrma.org/files/dmfile/Milliman-Critique-of-ICER-CEA-Report-09-19-18.pdf. Published September 19, 2019. Accessed August 29, 2019.
  21. Kennedy B. Re: input for ICER’s 2020 Value Assessment Framework. Institute for Patient Access website. instituteforpatientaccess.org/wp-content/uploads/2019/06/Institute-for-Patient-Access_ICER-Value-Assessment_June-2019.pdf. Published June 10, 2019. Accessed August 29, 2019.
  22. Burkholder R. Re: call for public input on ICER Value Framework. Pharmaceutical Research and Manufacturers of America website. phrma-docs.phrma.org/files/dmfile/PhRMA_Response_to_2020-Open_Call_for_Feedback_on_ICER_Value_Framework.pdf. June 10, 2019. Accessed August 29, 2019.
  23. Comparison of CGRP medication products currently available in the United States. PainDr website. paindr.com/wp-content/uploads/2019/08/Comparison-of-CGRP-medication-products-currently-available-in-the-United-States.pdf. Updated August 2019. Accessed August 29, 2019.