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CE: Review of Calcitonin Gene-Related Peptide (CGRP) Inhibitors for Migraine Treatment

13 Apr 2022 12:45 PM | Anonymous

Authors: Lauren McCulley, PharmD, Center for Behavioral Medicine - Kansas City, MO And Mary Beth Dameron, PharmD, BCACP, University Health - Kansas City, MO

Program Number: 2022-02-02
Approved Dates:   April 1, 2022-October 1, 2022
Approved Contact Hours:  One Hour(s) (1) CE(s) per session

Learning Objectives:

  • Identify the pathophysiology for migraines
  • Describe the role of CGRP inhibitors in migraine therapy
  • Differentiate dosing and mechanism of action between the different CGRP inhibitors
  • Analyze the relevant studies looking at the safety and efficacy of CGRP inhibitors in migraine treatment
  • Determine the place in therapy for CGRP inhibitors


Background:

Migraine is a chronic neurologic disease that affects more than 10% of the population worldwide.1 It is often associated with significant distress in a person’s life, which can lead to an inability to perform daily tasks, financial burden, and an increased risk for comorbid mental health diagnoses (such as anxiety and depression).2 The prevalence of migraine and severe headache in the US adult population is 9.7% in males and 20.7% in females.3 According to the National Institutes of Health, migraine-associated pain involves an intense pulsing or throbbing pain in one area of the head. It is often accompanied by nausea, vomiting, phonophobia, and/or photophobia. Common migraine triggers include stress, anxiety, hormonal changes, weather changes, bright or flashing lights, lack of food or sleep, and dietary substances.1 Identification and avoidance of patient-specific triggers may reduce or prevent migraine attacks.

There are many proposed mechanisms that likely play a pivotal role in the pathophysiology of migraines. Migraine pain is thought to happen after stimulation of the trigeminal sensory nervous pain pathways from vasodilation of local intracranial blood vessels.4 As the trigeminovascular pain pathway is stimulated, vasoactive peptides such as substance P and calcitonin gene-related peptide (CGRP) are released. This leads to an exacerbation of vasodilation, which results in inflammation and pain.5 Due to knowledge regarding the role of CGRP in migraine pathophysiology, new medications specifically targeting CGRP or its receptor have been developed. CGRP antagonists are thought to alleviate migraines through the following processes6:

  • Blocking neurogenic inflammation: CGRP antagonists bind to CGRP receptors present on mast cells, which inhibits inflammation caused by the trigeminal nerve release of CGRP onto mast cells within the meninges of the brain
  • Decreasing artery dilation: CGRP antagonists inhibit dilation of intracranial arteries by blocking CGRP receptors present in smooth muscle cells
  • Inhibiting pain transmission: CGRP antagonists bind to CGRP or its receptors, which results in suppression of pain through inhibition of the central relay of pain signals

According to the International Classification of Headache Disorders (ICHD-3), a diagnosis of migraine is based on the frequency of monthly migraine days (MMDs), monthly headache days (MHDs), duration of headache attack, and symptom presentation.7 Migraines can be categorized as episodic or chronic and can be treated with preventive and abortive therapies. There are many preventive and abortive treatments approved for migraine. Preventative treatments are used to reduce attack frequency, severity, duration, and disability. Based on patient preference, use of prophylactic therapy is indicated in patients whose migraine attacks interfere with their daily routines despite abortive treatment, have frequent attacks, and have contraindications to or fail abortive treatments.2 Before CGRP inhibitors were studied and approved for preventative treatment, people with migraines were trialed on many oral medications including beta blockers, tricyclic antidepressants, and antiepileptics.  According to the consensus statement in 2021 from the American Headache Society, CGRP inhibitors are indicated for preventative treatment in migraines when persons with migraines have an intolerance or an inadequate response to an 8-week trial of two or more oral preventative treatment options.2

With CGRP inhibitors playing a larger role in treatment for preventative migraines, this article will discuss CGRP inhibitors and the evidence behind each agent.

CGRP inhibitors:

Four CGRP monoclonal antibodies (mAbs) have been approved by the U.S. Food and Drug Administration (FDA) for migraine prophylaxis: eptinezumab, erenumab, fremanezumab, and galcanezumab. Erenumab is the only CGRP mAb that targets the CGRP receptor, whereas the others target the CGRP ligand. Small molecule CGRP antagonists are oral options approved for the preventive treatment of episodic migraine and include atogepant and rimegepant. Additional details outlining medication-specific characteristics can be found in Table 1 below.


Literature Review:

Several efficacy and safety trials have been performed to investigate CGRP agents for episodic and chronic migraines and for abortive and preventative treatment. There are no head-to-head trials of CRGP inhibitors in patients with migraines but most of these trials had similar designs and primary endpoints. Each of these trials will be discussed below.

Erenumab (Aimovig)

Erenumab has been studied for preventative treatment for both episodic and chronic migraines. There were 2 trials performed for efficacy and safety in episodic migraines. Study 1, known as the STRIVE trial, included 955 patients who were randomized to a subcutaneous injection of erenumab 70mg, 140mg, or placebo once monthly for 6 months. Individuals were included in the trial if they had a history of migraine (with or without aura) for at least 12 months and had at least 4 but no more than 15 migraine days a month across the 3 months prior to screening and during baseline. The primary endpoint was to assess the change from baseline in mean monthly migraine days over months 4 to 6. Researchers found that both erenumab 70mg and 140mg significantly reduced monthly migraine days and use of acute migraine-specific medications when compared to placebo, as outlined in table 2 below.8


Like the STRIVE trial, study 2 aimed to assess efficacy and safety in episodic migraine preventative treatment. The trial included 546 patients randomized to either erenumab 70mg or placebo subcutaneously once monthly for 3 months. The inclusion criteria was the same as the STRIVE trial. The primary endpoint was the change from baseline in monthly migraine days at month 3. Similar to the STRIVE trial discussed above, this trial found that erenumab 70mg once monthly significantly reduced monthly migraine days and use of acute migraine-specific medications when compared to placebo. Additional details regarding results of efficacy endpoints can be found in table 3.8


The last trial assessed erenumab for prevention of chronic migraines. This was a 3 month trial with 667 patients randomized to erenumab 70mg, 140mg or placebo given as a subcutaneous injection once monthly. This trial included those with a history of at least 5 attacks of migraine without aura or migraine with visual sensory, speech, language, retinal, or brainstem aura. Participants had to have at least 15 headache days and a minimum of 8 migraine days per month as reported by the participant. The primary endpoint was similar to trials 1 and 2, change from baseline in monthly migraine days at month 3. Consistent with previous studies discussed, both erenumab 70mg and 140mg demonstrated statistically significant improvements in monthly migraine days compared to placebo. A summary of key efficacy endpoints can be found in table 4.8


Galcanezumab (Emgality)

Trials for galcanezumab have been performed to assess safety and efficacy in episodic and chronic migraines. Study 1 (EVOLVE-1) and Study 2 (EVOLVE-2) had similar trial designs and included adults with a history of episodic migraine (4 to 14 migraine days per month). The primary endpoint for both studies was the mean change from baseline in the number of monthly migraine headache days over a 6 month treatment period. Patients in EVOLVE-1 and EVOLVE-2 were randomized to receive once monthly injections of galcanezumab 120mg, 240mg, or placebo. Those randomized to the 120mg group received a 240mg galcanezumab loading dose as well. EVOLVE-1 had a total of 858 patients randomized and EVOLVE-2 had a total of 915 patients randomized all 18 to 65 years of age. Overall, these trials demonstrated statistically significant improvements in monthly migraine days with galcanezumab 120mg once monthly dose. The 240mg once monthly dose showed no additional benefit over the 120mg dose. Results of the primary efficacy endpoint are summarized in table 5.9


The third trial, REGAIN, included adults ages 18 to 65 years old who had a history of chronic migraines (≥15 headache days per month with ≥8 migraine days per month). Patients were randomized to the same doses as trialed in the EVOLVE studies over a 3 month treatment period. The primary endpoint was the mean change from baseline in the number of monthly migraine headache days over the 3 month treatment period. REGAIN had a total of 1113 patients randomized and 1037 individuals completed the 3-month study. Galcanezumab 120mg demonstrated statistically significant improvement in mean change from baseline in the monthly migraine headache days, which is consistent with findings of the EVOLVE trials as discussed above. Galcanezumab 240mg once monthly showed no additional benefit compared to galcanezumab 120mg once monthly. See table 6 for additional details.9


Fremanezumab (Ajovy)

The efficacy of fremanezumab was demonstrated in 2 randomized, 3 month, placebo-controlled studies. Study 1 included adults with a history of episodic migraine (<15 headache days per month) who were randomized to receive subcutaneous injections of fremanezumab 675mg every 3 months, fremanezumab 225mg once monthly, or placebo once monthly. Additionally, patients had to have 85% compliance with a headache e-diary and a total body weight between 99 and 265 pounds for study inclusion. The primary endpoint was the mean change from baseline in the monthly average number of migraine days during the 3 month treatment period. A total of 791 patients completed the trial and the trial found that the quarterly (every 3 month) injection and the monthly injection demonstrated statistically significant improvements in migraine days compared to placebo. Results of the primary efficacy endpoint are summarized in table 7.10


Much like the other trials involving CGRP inhibitors, fremanezumab was also studied in those with chronic migraines (at least 15 headache days per month). In study 2, patients were randomized to fremanezumab 675mg initially, followed by 225 mg once monthly, 675 mg every 3 month, or placebo once monthly for a 3 month treatment period. This study had the same inclusion criteria as study 1 with the exception of the number of headache days per month. A total of 1034 patients completed the trial, and the primary efficacy endpoint was the mean change from baseline in the monthly average number of headache days of at least moderate severity during the 3-month treatment period. Both the monthly and quarterly dosing provided statistically significant improvement in migraine days compared to placebo as outlined in table 8 below.10


Eptinezumab (Vyepti)

Eptinezumab has been evaluated for efficacy in two randomized placebo-controlled trials. Study 1 included adults with a history of episodic migraines, which was defined as 4 to 14 headache days with at least 4 migraine days per month. A total of 665 patients were randomized to receive eptinezumab 100mg, 300mg, or placebo every 3 months for 12 months. The primary endpoint was change from baseline in mean monthly migraine days over months 1 through 3. Treatment with eptinezumab 100mg and 300mg demonstrated statistically significant improvements in migraine days compared to placebo. Refer to table 9 for results of the primary efficacy endpoint.11


The second eptinezumab study included patients with a history of chronic migraine defined as 15 to 26 headache days per month of which at least 8 were migraine days. A total of 1073 patients were randomized to receive eptinezumab 100mg, 300mg, or placebo every 3 months for 6 months total. This study also included those who had a diagnosis of chronic migraine and medication overuse headache. The primary endpoint was the same as study 1 and eptinezumab 100mg and 300mg demonstrated statistically significant improvements in monthly migraine days compared to placebo. Table 10 includes details of the primary efficacy endpoint for this trial.11


Rimegepant (Nurtec ODT)

The efficacy of rimegepant was evaluated for the preventive treatment of episodic migraine in adults in a randomized, double-blind, placebo-controlled trial. Individuals with at least a 1-year history of migraine (with or without aura) were randomized to receive every other day dosing of rimegepant 75mg or placebo for 12 weeks. Trial participants had a history of 4 to 18 moderate or severe monthly migraine attacks. Those who experienced ≥6 migraine days and ≤18 headache days during the observation phase were eligible for the study. The primary efficacy endpoint was change from baseline in the mean number of monthly migraine days during weeks 9-12. Results of the trial showed statistically significant improvements for the primary efficacy endpoint in those given rimegepant 75mg every other day compared to placebo, as further described in table 11.12


Atogepant (Qulipta)

The efficacy of atogepant was evaluated for the preventive treatment of episodic migraine in adults in two randomized, multicenter, double-blind, placebo-controlled studies. In study 1, 910 participants were randomized to atogepant 10mg, 30mg, 60mg, or placebo once daily for 12 weeks. The primary efficacy endpoint was the change from baseline in mean monthly migraine days across the 12-week treatment period. A total of 805 (88%) of individuals completed the study and atogepant showed statistically significant improvements for the primary efficacy endpoint in those receiving atogepant at any dose when compared to placebo. Key results are included in Table 12.13


In study 2, 652 participants were randomized to receive atogepant 10mg, 30mg, 60mg, or placebo once daily for 12 weeks. The primary efficacy endpoint evaluated was the same as study 1 and as demonstrated in study 1, there was a significantly larger reduction in mean monthly migraine days across the 12-week treatment period in those receiving atogepant at any dose compared to placebo. Refer to Table 13 for additional details regarding results of the primary efficacy endpoint.13


Conclusion:

Migraines can be extremely disabling and may lead to significant distress regarding ability to function or complete daily activities. Preventative migraine treatment is indicated when someone experiences frequent and prolonged severe attacks. Many oral options are available for patients for preventative treatment. However, the emergence of CGRP inhibitors have allowed for yet another treatment option for people who suffer from migraines. Guidelines suggest CGRP inhibitors are indicated after failure of at least two oral preventative treatments. The choice of which CGRP inhibitor to use in a patient is dependent on several factors such as insurance status, patient preference, and tolerability.

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References:

  1. Migraine Information Page. National Institute of Neurological Disorders and Stroke. U.S. Dep. Health Hum. Serv. Updated online December 31, 2019. Accessed January 9, 2021. https://www.ninds.nih.gov/Disorders/All-Disorders/Migraine-Information-Page
  2. Ailani J, Burch RC, Robbins MS; Board of Directors of the American Headache Society. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache. 2021 Jul;61(7):1021-1039. doi: 10.1111/head.14153. Epub 2021 Jun 23. PMID: 34160823.
  3. Burch R, Rizzoli P, Loder E. The Prevalence and Impact of Migraine and Severe Headache in the United States: Figures and Trends From Government Health Studies. Headache. 2018 Apr;58(4):496-505. doi: 10.1111/head.13281. Epub 2018 Mar 12. PMID: 29527677.
  4. Hargreaves RJ, Shepheard SL. Pathophysiology of migraine--new insights. Can J Neurol Sci. 1999 Nov;26 Suppl 3:S12-9. doi: 10.1017/s0317167100000147. PMID: 10563228.
  5. Durham P. Calcitonin Gene-Related Peptide (CGRP) and Migraine. Headache. 2006 June;46 Suppl 1:S3-S8.
  6. Durham PL. CGRP-receptor antagonists--a fresh approach to migraine therapy? N. Engl. J. Med. 2004;350(11):1073-1075. doi:10.1056/NEJMp048016.
  7. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018; 38(1):1-211.
  8. Aimovig [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.
  9. Emgality [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.
  10. Ajovy [package insert]. North Wales, PA: Teva Pharmaceuticals Inc.;2020.
  11. Vyepti [package insert]. Bothell, WA: Lundbeck Seattle BioPharmaceuticals; 2021.
  12. Nurtec [package insert]. New Haven, CT: Biohaven Pharmaceuticals, Inc.; 2020.
  13. Qulipta [package insert]. Dublin, Ireland: Forest Laboratories Ireland Ltd.;2021.

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