CGRP: Early Results from Phase III Trials

Monoclonal antibodies that target calcitonin gene-related peptide (CGRP) or its receptor are emerging as preventive treatments for episodic and chronic migraine. Four agents are now in phase III trials. These trials and the early results are described here and presented in tables below. Please note: Results of monthly change in migraine days cannot be compared across the investigational products since each clinical trial was set up differently. All results showed a significant reduction in migraine days per month.

Table 1
Table 2

Erenumab (AMG 334)

Erenumab is being studied in several phase III trials: ARISE, STRIVE, and LIBERTY.1-3 Early results from ARISE and STRIVE, which enrolled patients with episodic migraine, have been presented.4 LIBERTY is currently recruiting participants with episodic migraine in whom other preventive treatments have not worked.3 A phase II study was conducted in patients with chronic migraine.5 The FDA accepted an application for erenumab in July 2017.6

ARISE and STRIVE: Erenumab for episodic migraine

Who participated in the study?
ARISE and STRIVE enrolled adults with a 12+ month history of episodic migraine with or without aura. Episodic migraine is defined as fewer than 15 headache days per month, with at least 4 migraine days.1,2

ARISE included 577 adults, who had an average of 8.3 migraine days per month before the study started.4 The patients were randomly assigned to treatment with erenumab 70 mg or placebo. The study lasted 40 weeks.1

STRIVE included 955 adults, who were randomly assigned to erenumab 70 mg or 140 mg, or placebo.4

How is erenumab taken?
Erenumab is taken once per month by injection under the skin (subcutaneous injection).4

What were the results?
To see how well erenumab works, researchers compared the frequency of migraine days per month before and after taking the drug. Results from ARISE showed that people taking erenumab 70 mg had 2.9 fewer migraine days per month from baseline (pre-study) to study weeks 9 through 12.4 In STRIVE, people taking 70 mg had 3.2 fewer migraine days per month during study weeks 13 to 24.4 The people taking 140 mg had 3.7 fewer migraine days per month in the same time period.

What side effects did participants report?
The most common adverse events were runny/stuffy nose, upper respiratory tract infection, and injection site pain.4 In ARISE, adverse events were reported by 48.1% of patients in the erenumab group.

Phase II: Erenumab for chronic migraine

Who participated in the study?
This phase II study included 667 adults with chronic migraine.5 Chronic migraine is defined as at least 15 headache days per month, including at least 8 migraine days. Participants were randomly assigned to erenumab 70 mg or 140 mg, or placebo. The study lasted 12 weeks.

What were the results?
To see how well erenumab works, researchers compared the frequency of migraine days per month before taking the drug and during the last month of the study (weeks 9-12). The results showed that at both doses, people taking erenumab had 6.6 fewer migraine days per month.5

What side effects did participants report?
The most common side effects were injection-site pain, upper respiratory tract infection, and nausea.5 Overall, 45% of patients receiving erenumab reported an adverse event.

Galcanezumab (LY2951742)

Galcanezumab has been studied in three phase III trials: EVOLVE-1, EVOLVE-2, and REGAIN.7-9 Early results from these trials have been reported.10 The manufacturer plans to apply for FDA approval in the second half of 2017.

EVOLVE-1 and EVOLVE-2: Galcanezumab for episodic migraine

Who participated in the study?
EVOLVE-1 and EVOLVE-2 enrolled adults with a 12+ month history of episodic migraine with or without aura.7,8 Participants had an average of 9.1 migraine headache days per month before the study started.10

Participants were randomly assigned to treatment with galcanezumab, 120 mg or 240 mg, or placebo. The studies lasted 6 months.10

How was galcanezumab given?
Galcanezumab is given by injection under the skin (subcutaneous injection) once per month. The first month, both galcanezumab groups received 240 mg. Afterward, patients received either 120 mg or 240 mg.

What were the results?
To see how well galcanezumab works, researchers compared the frequency of migraine days per month before taking the drug and over 6 months of taking it.

Results from EVOLVE-1 showed that:10

  • People taking 120 mg had 4.7 fewer migraine days per month
  • People taking 240 mg had 4.6 fewer migraine days per month

Results from EVOLVE-2 showed that:10

  • People taking 120 mg had 4.3 fewer migraine days per month
  • People taking 240 mg had 4.2 fewer migraine days per month

What side effects did participants report?
The most commonly reported adverse events in all 3 studies were reactions at the injection site, including pain. In phase II studies, the most common adverse events were pain or redness at the injection site, upper respiratory tract infections, and back, abdominal, or joint pain.11

REGAIN: Galcanezumab for chronic migraine

Who participated in the study?
REGAIN enrolled adults with a 12+ month history of chronic migraine with or without aura.9 Participants had an average of 19.4 migraine headache days per month before the study started.10

What were the results?
To see how well galcanezumab works, researchers compared the frequency of migraine days per month before taking the drug and for the first 3 months of taking it. The results showed that:10

    • People taking 120 mg had 4.8 fewer migraine days per month
    • People taking 240 mg had 4.6 fewer migraine days per month

REGAIN will continue for another 9 months. This extension allows researchers to collect information about long-term safety and efficacy.

Fremanezumab (TEV-48125)

Fremanezumab has been studied in the phase III HALO clinical trial program, which included a chronic migraine and an episodic migraine study. The manufacturer has announced early results, which are described below. The manufacturer plans to apply for FDA approval in 2017.12

HALO EM: Fremanezumab for episodic migraine

Who participated in the study?
HALO EM enrolled 873 adults with episodic migraine.12 Participants had a mean of 9.1 migraine days per month before the study started, and 39 days of functional impairment per 3 months. This study included patients who continued on a stable dose of a preventive medicine and patients who were not taking any other migraine medicines.

Participants were randomly assigned to one of three study groups: monthly fremanezumab (225 mg); quarterly fremanezumab (675 mg); or placebo.

How was fremanezumab given?
Fremanezumab is given as an injection under the skin (subcutaneous injection). Monthly and quarterly dosing have been studied for episodic migraine.

What were the results?
To see how well fremanezumab works, researchers compared the frequency of migraine days per month before taking the drug and during the trial. The results showed that:12

      • People taking monthly fremanezumab had 3.7 fewer migraine days per month
      • People taking quarterly fremanezumab had 3.4 fewer migraine days per month

What side effects did participants report?
The most common adverse effect was injection-site pain, which affected patients in the placebo and active treatment groups equally.12

HALO CM: Fremanezumab for chronic migraine

Who participated in the study?
HALO CM enrolled 1,130 adults with chronic migraine.12 Participants were randomly assigned to one of three study groups: monthly fremanezumab (675 mg first month, 225 mg subsequent months); quarterly fremanezumab (675 mg first month); or placebo. This study included patients that continued on a stable dose of a preventive medicine and patients who were not taking any other migraine medicines.

What were the results?
To see how well fremanezumab works, researchers compared the frequency of headache days of at least moderate severity per month before taking the drug and during the trial. The results showed that:13

      • People taking monthly fremanezumab had 4.6 fewer migraine days per month
      • People taking quarterly fremanezumab had 4.3 fewer migraine days per month

What side effects did participants report?
In the placebo and active groups, the most common adverse effect was injection-site pain.

Eptinezumab (ALD403)

Eptinezumab is being studied in three phase III trials: PROMISE 1, PROMISE 2, and a long-term safety study.14-17 The manufacturer has announced early results from PROMISE 1, a study of patients with episodic migraine.18 These results are described below. PROMISE 2 is currently enrolling chronic migraineurs.16 The manufacturer plans to apply for FDA approval in the second half of 2018.18

PROMISE 1: Eptinezumab for episodic migraine

Who participated in the study?
PROMISE-1 enrolled 888 adults with frequent episodic migraine.15,18 Patients had an average of 8.6 migraine days per month before the study started.18 The patients were randomly assigned to treatment with eptinezumab or placebo.18 Three doses of eptinezumab were studied: 30 mg, 100 mg, or 300 mg. The study lasted 1 year.18

How was eptinezumab given?
Eptinezumab was given by infusion into the vein (intravenous infusion) once every 12 weeks.18

What were the results?
To see how well eptinezumab works, researchers compared the frequency of migraine days per month before taking the drug and in the first 12 weeks of taking it. The results showed that:18

      • People taking 300 mg had 4.3 fewer migraine days per month
      • People taking 100 mg had 3.9 fewer migraine days per month

What side effects did participants report?
The full safety data will be reported when the PROMISE 1 study is finished. The early report states that the type and frequency of side effects were similar to earlier studies of eptinezumab.18

In a phase II study, the most frequent adverse events were upper respiratory tract infection, urinary tract infection, fatigue, back pain, nausea and vomiting, and joint pain.19 Overall, 55% percent of participants in the phase II study had an adverse event. The adverse events were split fairly evenly between the placebo group (52%) and treatment group (57%). Most adverse events were mild to moderate and lasted only a short time.

View References
  1. ClinicalTrials.gov. Study to Evaluate the Efficacy and Safety of AMG 334 Compared to Placebo in Migraine Prevention (ARISE). Trial identifier: NCT02483585
  2. ClinicalTrials.gov. Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention (STRIVE). Trial identifier: NCT02456740
  3. ClinicalTrials.gov. A Study Evaluating the Effectiveness of AMG 334 Injection in Preventing Migraines in Adults Having Failed Other Therapies (LIBERTY). Trial identifier: NCT03096834
  4. Phase 3 STRIVE and ARISE Trials Show Efficacy, Safety for Erenumab in Migraine Prevention. Medscape. April 26, 2017. Accessed July 18, 2017 at: http://wb.md/2gWxUYg [http://www.medscape.com/viewarticle/879161]
  5. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16:425-434.
  6. FDA Accepts Biologics License Application For Aimovig™ (erenumab) [press release]. July 20, 2017. Accessed July 24, 2017 at: http://prn.to/2gQfo3E [http://www.prnewswire.com/news-releases/fda-accepts-biologics-license-application-for-aimovig-erenumab-300491861.html]
  7. ClinicalTrials.gov. Evaluation of LY2951742 in the Prevention of Episodic Migraine- the EVOLVE-1 Study (EVOLVE-1). Trial identifier: NCT02614183
  8. ClinicalTrials.gov. Evaluation of LY2951742 in the Prevention of Episodic Migraine- the EVOLVE-2 Study (EVOLVE-2). Trial identifier: NCT02614196
  9. ClinicalTrials.gov. Evaluation of LY2951742 in the Prevention of Chronic Migraine (REGAIN). Trial identifier: NCT02614261
  10. Lilly Announces Positive Results for Three Phase 3 Studies of Galcanezumab for the Prevention of Episodic and Chronic Migraine [press release]. May 12, 2017. Accessed July 21, 2017 at: http://bit.ly/2rvEk4L [https://investor.lilly.com/releasedetail.cfm?ReleaseID=1026201]
  11. Dodick DW, Goadsby PJ, Spierings EL, et al. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2014;13:885-892. Abstract
  12. Teva's Fremanezumab Meets all Primary & Secondary Endpoints Across Both Monthly and Quarterly Dosing Regimens in Phase III Study in Episodic Migraine Prevention [press release]. June 7, 2017. Accessed July 19, 2017 at: http://bit.ly/2vEsDqS [http://www.tevapharm.com/news/teva_s_fremanezumab_meets_all_primary_secondary_endpoints_across_both_monthly_and_quarterly_dosing_regimens_in_phase_iii_study_in_episodic_migraine_prevention_06_17.aspx]
  13. Teva Announces Positive Results for Phase III Study of Fremanezumab for the Prevention of Chronic Migraine [press release]. May 31, 2017. Accessed July 19, 2017 at: http://bit.ly/2rHFY3F [http://www.tevapharm.com/news/teva_announces_positive_results_for_phase_iii_study_of_fremanezumab_for_the_prevention_of_chronic_migraine_05_17.aspx]
  14. Alder Pharmaceuticals. Pipeline. Accessed June 29, 2017 at: http://www.alderbio.com/therapeutics/pipeline/.
  15. ClinicalTrials.gov. A multicenter assessment of ALD403 in frequent episodic migraine (PROMISE 1). Trial identifier: NCT02559895.
  16. ClinicalTrials.gov. Evaluation of ALD403 (Eptinezumab) in the Prevention of Chronic Migraine (PROMISE 2). Trial identifier: NCT02974153.
  17. ClinicalTrials.gov. An Open Label Trial of ALD403 (Eptinezumab) in Chronic Migraine. Trial identifier: NCT02985398.
  18. Alder BioPharmaceuticals Announces Positive Eptinezumab Phase 3 Results for Prevention of Frequent Episodic Migraine [press release]. June 27, 2017. Accessed June 29, 2017 at: http://bit.ly/2tDphry [https://globenewswire.com/news-release/2017/06/27/1029420/0/en/Alder-BioPharmaceuticals-Announces-Positive-Eptinezumab-Phase-3-Results-for-Prevention-of-Frequent-Episodic-Migraine.html]
  19. Dodick DW, Goadsby PJ, Silberstein SD, et al; ALD403 study investigators. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014;13:1100-1107. Abstract

Comments

View Comments (4)
  • toniatch
    7 months ago

    Are hemiplegic migraines contraindicated for this type of treatment?

  • Marcia Kavulich moderator
    1 year ago

    Hi Nicci. Thank you so much for sharing! Unfortunately, we don’t have a way for you to edit your comments after submitting but you may send an email to contact@migraine.com to request any changes you’d like us to make on your behalf – though I think this reads just fine!

    Have you considered sharing more of your experiences in our story section? https://migraine.com/stories/ We would love to hear from you.

    We also have gathered information about CGRPs in this hub if you’re looking for more information. https://migraine.com/cgrp-new-direction-migraine-treatment/

    Thank you again for a being a part of our community!
    -Marcia (Migraine.com Team)

  • Nicci
    1 year ago

    I have many comments and updates for this as a CGRP-MABs study participant, but lost my post text right at the end! So, if you’d like my account, experience, thoughts, insights, I’ll try to remember and recompose in another program and repost. Editorial, please advise. I’d guest blog a follow on.

    Important: study results above do not include complied qualitative data gathered by oral interviews with study participants on reduction in severity, resilience to triggers, changes in severity of the other three phases of attacks, or comorbidilues that may have improved as well. The above presents quantitative data (measurable) only: frequency and side effects, which is only half the target goal of the preventives, which aim for 50% reduction in frequency and/or severity.. If a patient drops from 8 to 4 attacks monthly, yet 3 of those 4 are less severe, or more acute-med responsive, we’ve not got a fuller and more successful picture.

    I see self-injectables highly-likely to be studied. I could swear I might have been smim-read past a transdermal (DO NOT QUOTE ME, PLEASE!) I was skimming through who knows where and it could have been a whole different drug from one of these companies… but I love the idea!)

    More on this subject? Moderators, authors, I don’t know what all you’ve already written.

  • Nicci
    1 year ago

    Where’s the “edit” button for my embarrassing smartphone-typing errors?! GAH!

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