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.

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