Looking at CGRP-Related Medications for Migraine, April 2023

Since 2018, the field of headache medicine has changed significantly. The development of calcitonin gene-related peptide (CGRP)-targeting preventive medications has led to the ability to treat migraine in a much more specific manner. The development of CGRP acute oral medications over the past 2 years has allowed people with migraine the ability to use well-tolerated, migraine-specific, abortive treatments. Triptan medications were the first migraine-specific acute treatments developed, some of which were nonoral, such as injectable sumatriptan and intranasal sumatriptan and zolmitriptan. The study by Lipton and colleagues assesses the safety and tolerability of a novel acute CGRP antagonist nonoral treatment, zavegepant.

In this double-blind, randomized, multicentered trial, nearly 2000 participants were enrolled with a diagnosis of episodic migraine with or without aura; they were excluded if they had previously used another CGRP antagonist, either an injectable or oral medication, before enrolling in this study. In addition to assessing migraine pain, participants were asked to identify their otherwise most bothersome symptom, specifically photophobia, phonophobia, or nausea. They were given a nasal spray to self-administer and were assessed at 15 minutes after treatment and at multiple additional intervals, up to 48 hours after the initial dosing. The primary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 hours after treatment onset. There were 17 secondary endpoints.

At 2 hours after treatment onset, a statistically significant group had achieved freedom from pain. The percentage, however, did remain somewhat low: 24%. Freedom from the most bothersome symptom was also statistically significant but was up to 40%. For 13 of the 17 endpoints, the results were also statistically significant, including pain relief at 2 hours, sustained pain relief at 2-24 hours and 48 hours, functional improvement, and freedom from photophobia and phonophobia. The most common adverse effects were poor taste, nasal discomfort, and throat irritation. No serious adverse events were noted.

Zavegepant has been FDA approved for the acute treatment of migraine on the basis of these data. This is a novel, well-tolerated, nonoral acute treatment for migraine. We can now treat patients with very severe nausea or more sudden-onset pain with a CGRP option that can potentially treat their attacks more quickly.

One early finding in many of the CGRP studies was that a certain subpopulation of migraine patients have a robust and rapid preventive response to monoclonal antibody treatment. Raffaelli and colleagues sought to evaluate potential characteristics that would better predict the efficacy of CGRP antagonist monoclonal antibodies for the prevention of migraine.

In this study, the definition of a superresponse to CGRP antagonist treatment was a >75% reduction in monthly headache days after 3 months of treatment. Nonresponse was defined as <25% reduction over this same period. This was a retrospective cohort study at one headache center in Berlin, Germany. A total of 260 patients were enrolled, all with a diagnosis of migraine and all given a preventive CGRP monoclonal antibody.

There was no significant difference between nonresponders and superresponders when compared for sex, age, or time since migraine diagnosis. Erenumab was the most commonly prescribed CGRP antagonist medication, but all CGRP antagonists were included. There was no significant difference when CGRP receptor or ligand targeting antibodies were compared. Nonresponders were seen as more likely to have chronic migraine and higher monthly headache day and monthly migraine day frequencies. Superresponders were seen to have more "typical" migraine characteristics, such as unilateral or localized migraines or migraines with pulsating/throbbing characteristics, as well as the presence of photophobia and nausea; however, this was not statistically significant. Of note, superresponders were also significantly more likely to report improvement of their acute migraine attacks with triptan medications as compared with nonresponders.

Patients with less frequent migraine attacks and more classic migraine attacks appear to be much more likely to respond quickly and effectively to many preventive options; this appears to be most robust with the CGRP antibody class. Although the reason for this robust response is not entirely clear, it would certainly be best for providers to consider the initiation of CGRP antagonist preventive treatment in patients with these characteristics.

The newest generation of migraine-specific medications targets either the inflammatory neurotransmitter CGRP or the CGRP receptor. Erenumab is a CGRP receptor blocker, whereas both fremanezumab and galcanezumab block the CGRP ligand. Erenumab has been associated with constipation and high blood pressure, whereas the other CGRP antagonist medications are not associated with these side effects. Whether this is due to the difference in mechanism of action, and specifically whether the antibodies block the CGRP receptor or are an antagonist, is under consideration. Schiano di Cola and colleagues specifically sought to investigate the subtle differences between these two subclasses of treatment.

Patients with high-frequency episodic and chronic migraine were enrolled in this retrospective study; 6 months of data were included. The researchers here specifically looked at efficacy after 1, 3, and 6 months of treatment. They examined, as a primary outcome, monthly headache and migraine days, and migraine disability as based on the Migraine Disability Assessment Scale (MIDAS) and Headache Impact Test (HIT-6) score. Concomitant analgesic medication consumption and response rate relative to baseline were also compared.

A total of 152 patients were enrolled, 68 with CGRP ligand-targeting therapy and 84 with CGRP receptor-blocking therapy. Medication overuse was present in 73% of patients. Although a significant improvement from baseline was noted in monthly headache days, monthly migraine days, severity, analgesic consumption, and disability, MIDAS scores were significantly lower in the CGRP ligand-blocking group compared with the CGRP receptor group at 1 and 3 months. Number of monthly migraine days was also lower in the CGRP ligand-blocking group, but only after 3 months. The other variables, including monthly headache days per month, analgesic consumption, severity, and disability, were not statistically different.

Adverse events were not compared between the two groups, even though this was a prior noted difference between these two classes of medications. Although there are some slight differences in efficacy, the majority of outcome metrics did not appear to be significantly different in either group. One would be hard-pressed to choose a specific CGRP medication on the basis of these data.

Since 2018, the field of headache medicine has changed significantly. The development of calcitonin gene-related peptide (CGRP)-targeting preventive medications has led to the ability to treat migraine in a much more specific manner. The development of CGRP acute oral medications over the past 2 years has allowed people with migraine the ability to use well-tolerated, migraine-specific, abortive treatments. Triptan medications were the first migraine-specific acute treatments developed, some of which were nonoral, such as injectable sumatriptan and intranasal sumatriptan and zolmitriptan. The study by Lipton and colleagues assesses the safety and tolerability of a novel acute CGRP antagonist nonoral treatment, zavegepant.

In this double-blind, randomized, multicentered trial, nearly 2000 participants were enrolled with a diagnosis of episodic migraine with or without aura; they were excluded if they had previously used another CGRP antagonist, either an injectable or oral medication, before enrolling in this study. In addition to assessing migraine pain, participants were asked to identify their otherwise most bothersome symptom, specifically photophobia, phonophobia, or nausea. They were given a nasal spray to self-administer and were assessed at 15 minutes after treatment and at multiple additional intervals, up to 48 hours after the initial dosing. The primary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 hours after treatment onset. There were 17 secondary endpoints.

At 2 hours after treatment onset, a statistically significant group had achieved freedom from pain. The percentage, however, did remain somewhat low: 24%. Freedom from the most bothersome symptom was also statistically significant but was up to 40%. For 13 of the 17 endpoints, the results were also statistically significant, including pain relief at 2 hours, sustained pain relief at 2-24 hours and 48 hours, functional improvement, and freedom from photophobia and phonophobia. The most common adverse effects were poor taste, nasal discomfort, and throat irritation. No serious adverse events were noted.

Zavegepant has been FDA approved for the acute treatment of migraine on the basis of these data. This is a novel, well-tolerated, nonoral acute treatment for migraine. We can now treat patients with very severe nausea or more sudden-onset pain with a CGRP option that can potentially treat their attacks more quickly.

One early finding in many of the CGRP studies was that a certain subpopulation of migraine patients have a robust and rapid preventive response to monoclonal antibody treatment. Raffaelli and colleagues sought to evaluate potential characteristics that would better predict the efficacy of CGRP antagonist monoclonal antibodies for the prevention of migraine.

In this study, the definition of a superresponse to CGRP antagonist treatment was a >75% reduction in monthly headache days after 3 months of treatment. Nonresponse was defined as <25% reduction over this same period. This was a retrospective cohort study at one headache center in Berlin, Germany. A total of 260 patients were enrolled, all with a diagnosis of migraine and all given a preventive CGRP monoclonal antibody.

There was no significant difference between nonresponders and superresponders when compared for sex, age, or time since migraine diagnosis. Erenumab was the most commonly prescribed CGRP antagonist medication, but all CGRP antagonists were included. There was no significant difference when CGRP receptor or ligand targeting antibodies were compared. Nonresponders were seen as more likely to have chronic migraine and higher monthly headache day and monthly migraine day frequencies. Superresponders were seen to have more "typical" migraine characteristics, such as unilateral or localized migraines or migraines with pulsating/throbbing characteristics, as well as the presence of photophobia and nausea; however, this was not statistically significant. Of note, superresponders were also significantly more likely to report improvement of their acute migraine attacks with triptan medications as compared with nonresponders.

Patients with less frequent migraine attacks and more classic migraine attacks appear to be much more likely to respond quickly and effectively to many preventive options; this appears to be most robust with the CGRP antibody class. Although the reason for this robust response is not entirely clear, it would certainly be best for providers to consider the initiation of CGRP antagonist preventive treatment in patients with these characteristics.

The newest generation of migraine-specific medications targets either the inflammatory neurotransmitter CGRP or the CGRP receptor. Erenumab is a CGRP receptor blocker, whereas both fremanezumab and galcanezumab block the CGRP ligand. Erenumab has been associated with constipation and high blood pressure, whereas the other CGRP antagonist medications are not associated with these side effects. Whether this is due to the difference in mechanism of action, and specifically whether the antibodies block the CGRP receptor or are an antagonist, is under consideration. Schiano di Cola and colleagues specifically sought to investigate the subtle differences between these two subclasses of treatment.

Patients with high-frequency episodic and chronic migraine were enrolled in this retrospective study; 6 months of data were included. The researchers here specifically looked at efficacy after 1, 3, and 6 months of treatment. They examined, as a primary outcome, monthly headache and migraine days, and migraine disability as based on the Migraine Disability Assessment Scale (MIDAS) and Headache Impact Test (HIT-6) score. Concomitant analgesic medication consumption and response rate relative to baseline were also compared.

A total of 152 patients were enrolled, 68 with CGRP ligand-targeting therapy and 84 with CGRP receptor-blocking therapy. Medication overuse was present in 73% of patients. Although a significant improvement from baseline was noted in monthly headache days, monthly migraine days, severity, analgesic consumption, and disability, MIDAS scores were significantly lower in the CGRP ligand-blocking group compared with the CGRP receptor group at 1 and 3 months. Number of monthly migraine days was also lower in the CGRP ligand-blocking group, but only after 3 months. The other variables, including monthly headache days per month, analgesic consumption, severity, and disability, were not statistically different.

Adverse events were not compared between the two groups, even though this was a prior noted difference between these two classes of medications. Although there are some slight differences in efficacy, the majority of outcome metrics did not appear to be significantly different in either group. One would be hard-pressed to choose a specific CGRP medication on the basis of these data.

Since 2018, the field of headache medicine has changed significantly. The development of calcitonin gene-related peptide (CGRP)-targeting preventive medications has led to the ability to treat migraine in a much more specific manner. The development of CGRP acute oral medications over the past 2 years has allowed people with migraine the ability to use well-tolerated, migraine-specific, abortive treatments. Triptan medications were the first migraine-specific acute treatments developed, some of which were nonoral, such as injectable sumatriptan and intranasal sumatriptan and zolmitriptan. The study by Lipton and colleagues assesses the safety and tolerability of a novel acute CGRP antagonist nonoral treatment, zavegepant.

In this double-blind, randomized, multicentered trial, nearly 2000 participants were enrolled with a diagnosis of episodic migraine with or without aura; they were excluded if they had previously used another CGRP antagonist, either an injectable or oral medication, before enrolling in this study. In addition to assessing migraine pain, participants were asked to identify their otherwise most bothersome symptom, specifically photophobia, phonophobia, or nausea. They were given a nasal spray to self-administer and were assessed at 15 minutes after treatment and at multiple additional intervals, up to 48 hours after the initial dosing. The primary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 hours after treatment onset. There were 17 secondary endpoints.

At 2 hours after treatment onset, a statistically significant group had achieved freedom from pain. The percentage, however, did remain somewhat low: 24%. Freedom from the most bothersome symptom was also statistically significant but was up to 40%. For 13 of the 17 endpoints, the results were also statistically significant, including pain relief at 2 hours, sustained pain relief at 2-24 hours and 48 hours, functional improvement, and freedom from photophobia and phonophobia. The most common adverse effects were poor taste, nasal discomfort, and throat irritation. No serious adverse events were noted.

Zavegepant has been FDA approved for the acute treatment of migraine on the basis of these data. This is a novel, well-tolerated, nonoral acute treatment for migraine. We can now treat patients with very severe nausea or more sudden-onset pain with a CGRP option that can potentially treat their attacks more quickly.

One early finding in many of the CGRP studies was that a certain subpopulation of migraine patients have a robust and rapid preventive response to monoclonal antibody treatment. Raffaelli and colleagues sought to evaluate potential characteristics that would better predict the efficacy of CGRP antagonist monoclonal antibodies for the prevention of migraine.

In this study, the definition of a superresponse to CGRP antagonist treatment was a >75% reduction in monthly headache days after 3 months of treatment. Nonresponse was defined as <25% reduction over this same period. This was a retrospective cohort study at one headache center in Berlin, Germany. A total of 260 patients were enrolled, all with a diagnosis of migraine and all given a preventive CGRP monoclonal antibody.

There was no significant difference between nonresponders and superresponders when compared for sex, age, or time since migraine diagnosis. Erenumab was the most commonly prescribed CGRP antagonist medication, but all CGRP antagonists were included. There was no significant difference when CGRP receptor or ligand targeting antibodies were compared. Nonresponders were seen as more likely to have chronic migraine and higher monthly headache day and monthly migraine day frequencies. Superresponders were seen to have more "typical" migraine characteristics, such as unilateral or localized migraines or migraines with pulsating/throbbing characteristics, as well as the presence of photophobia and nausea; however, this was not statistically significant. Of note, superresponders were also significantly more likely to report improvement of their acute migraine attacks with triptan medications as compared with nonresponders.

Patients with less frequent migraine attacks and more classic migraine attacks appear to be much more likely to respond quickly and effectively to many preventive options; this appears to be most robust with the CGRP antibody class. Although the reason for this robust response is not entirely clear, it would certainly be best for providers to consider the initiation of CGRP antagonist preventive treatment in patients with these characteristics.

The newest generation of migraine-specific medications targets either the inflammatory neurotransmitter CGRP or the CGRP receptor. Erenumab is a CGRP receptor blocker, whereas both fremanezumab and galcanezumab block the CGRP ligand. Erenumab has been associated with constipation and high blood pressure, whereas the other CGRP antagonist medications are not associated with these side effects. Whether this is due to the difference in mechanism of action, and specifically whether the antibodies block the CGRP receptor or are an antagonist, is under consideration. Schiano di Cola and colleagues specifically sought to investigate the subtle differences between these two subclasses of treatment.

Patients with high-frequency episodic and chronic migraine were enrolled in this retrospective study; 6 months of data were included. The researchers here specifically looked at efficacy after 1, 3, and 6 months of treatment. They examined, as a primary outcome, monthly headache and migraine days, and migraine disability as based on the Migraine Disability Assessment Scale (MIDAS) and Headache Impact Test (HIT-6) score. Concomitant analgesic medication consumption and response rate relative to baseline were also compared.

A total of 152 patients were enrolled, 68 with CGRP ligand-targeting therapy and 84 with CGRP receptor-blocking therapy. Medication overuse was present in 73% of patients. Although a significant improvement from baseline was noted in monthly headache days, monthly migraine days, severity, analgesic consumption, and disability, MIDAS scores were significantly lower in the CGRP ligand-blocking group compared with the CGRP receptor group at 1 and 3 months. Number of monthly migraine days was also lower in the CGRP ligand-blocking group, but only after 3 months. The other variables, including monthly headache days per month, analgesic consumption, severity, and disability, were not statistically different.

Adverse events were not compared between the two groups, even though this was a prior noted difference between these two classes of medications. Although there are some slight differences in efficacy, the majority of outcome metrics did not appear to be significantly different in either group. One would be hard-pressed to choose a specific CGRP medication on the basis of these data.