The findings of the role of CGRP (calcitonin gene-related peptide) in migraine pathogenesis make anti-CGRP drugs fremanezumab, erenumab, galcanezumab, and eptinezumab potential as promising migraine treatments. These four drugs are monoclonal antibodies.

Anti-CGRP (Calcitonin Gene-Related Peptide) as The New Migraine Treatment
Fremanezumab
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Fremanezumab (TEV 48125), Galcanezumab (LY 2951742), and Eptinezumab (ALD 403) are drugs that have the potential to bond with calcitonin gene-related peptide (CGRP). Erenumab (AMG 334) is a drug that selectively has the potential to occupy the CGRP receptor. These drugs are monoclonal antibodies that have recently been found to treat migraines.

Headache is often complained of in daily practice, and one of the main causes is the migraine that is quite disruptive to a person's quality of life. Acute migraine treatment has options, including paracetamol, aspirin, ibuprofen, triptans (e.g., sumatriptan, eletriptan, naratriptan), ergotamine, or a combination thereof. In chronic migraine, the administration of drugs for prevention is considered. The first line of drugs for this prevention includes the beta-blocker class, the angiotensin blocker, the tricyclic class.

Several theories explaining the pathogenesis of migraine are:
  1. Vascular theory: vasodilation occurs resulting in activation of the trigeminal nerve associated with intracranial vessels
  2. Neurogenic inflammation theory: there is vasodilation, extravasation of protein, and release of inflammatory mediators
  3. Central neuron theory: certain genes are associated with migraines.
CGRP is a neuropeptide with 37 amino acids located in the trigeminal nerve tissue in intracranial blood vessels' walls. It was found that CGRP is released in migraine and cluster headache. The release of CGRP at the trigeminal nerve endings causes vasodilation and inflammation. Whereas at the central synapse, CGRP plays a role in modulation of pain.

Factors that can trigger migraines can lead to elevated CGRP levels. There is a possibility of involvement of the hypothalamus and amygdala. These factors include:
  • Hormonal fluctuations such as during menstruation (involving the hypothalamus-pituitary-adrenal axis)
  • Stress (involving the amygdala and hypothalamus)
  • Hunger or fasting state
  • Sleep disturbance
  • Physical activity
  • External factors (e.g., weather, smell, visual stimuli, heat)
Therefore, CGRP is a factor in migraine and central pain modulation. Discontinuation of the CGRP pathway is a potential migraine treatment.



a. Fremanezumab

In 3rd phase study, fremanezumab administered subcutaneously reduced the number of headache-related days per month by 4.3 to 4.6 days, and compared with placebo, this figure decreased by only 2.5 days (p <0.001). There was also a ≥50% reduction in headache-related days, a decrease in the number of drugs used for acute headaches, and an increase in quality of life associated with headaches, as calculated by the HIT-6 (Headache Impact Test) score in the fremanezumab group.
Furthermore, this study compared the administration of fremanezumab doses every month (675 mg followed by a dose of 225 mg in the next 2 months) with fremanezumab once (675 mg) followed by placebo administration in the next 2 months found comparable results.


b. Erenumab

In a 3rd phase study,  erenumab administered in doses of 70 mg and 140 mg subcutaneously reduced migraine-related days by 3.2 - 3.7 days compared with placebo, which fell by only 1.8 days (p <0.001). It also found that erenumab increased more than 50% decrease in migraine-related days each month, decreased days associated with drug use for acute migraine and improved daily quality of life (measured by Migraine Physical Function Impact Diary score or MPFID) compared to placebo. . administration at a dose of 70 mg compared with 140 mg also gave comparable results.


c. Galcanezumab

In the 2nd Phase study, it was found that administering galcanezumab reduced the number of migraine headache days per month compared to placebo (p = 0.003). There were also improvements in quality of life (based on HIT-6 and Migraine Specific Quality of Life or MSQL) in the galcanezumab group.


d. Eptinezumab

in the 2nd Phase study, it was found that intravenous administration of eptinezumab decreased migraine-related days compared with placebo (p = 0.306). Migraine-related QoL improvement (tested by HIT-6 and MSQL) was higher in the eptinezumab group, but this difference was not tested for significance.



Side effects

In research on anti-CGRP drugs such as fremanezumab, erenumab, galcanezumab, and eptinezumab, almost all patients were given either treatment or placebo were able to complete the study. The most common side effects of injection were found in subcutaneously administered regimens, such as pain and induration with the erythema. Serious events that occurred were found to be unrelated to treatment.
A small proportion of patients given fremanezumab (<2%) had elevated liver enzymes not more than 3-5 times the upper limit of normal values. They were reversible and considered by researchers as non-fatal, and did not lead to study discontinuation.

Blood chemistry tests, vital signs, and ECG results were not found to be significant differences in the erenumab, galcanezumab, eptinezumab, and placebo groups.

The effect of fremanezumab to "prevent" vasodilation of blood vessels that causes migraine is thought to have the potential for cardiovascular effects. However, in studies in experimental animals (monkeys) given fremanezumab for nearly 100 days at weekly doses, no cardiovascular disorders (systolic and diastolic blood pressure, heart rate, and ECG) were found.

Although it does not cause side effects relatively greater than the placebo, the safety for long-term use still needs further investigation.


Summary
  • Migraine is a type of headache and causes a decrease in the quality of life of the sufferer.
  • The theory explaining migraine's pathogenesis is vasodilation associated with intracranial blood vessels, neurogenic inflammation, and certain genes related to migraines.
  • CGRP (calcitonin gene-related peptide) is a factor in migraine, and the cutting of the CGRP process chain in the nervous system is a potential migraine treatment.
  • Fremanezumab (TEV 48125), Erenumab (AMG 334) Galcanezumab (LY 2951742), and Eptinezumab (ALD 403) are monoclonal antibodies that are potential anti-CGRP class drugs for migraine by blocking the CGRP pathway.
  • Fremanezumab, galcanezumab, and eptinezumab are drugs that can selectively bind to CGRP. Fremanezumab and galcanezumab are given via the subcutaneous route, and eptinezumab are given via the intravenous line.
  • Erenumab is a drug that selectively has the potential to occupy the CGRP receptor. Erenumab is given via the subcutaneous route.
  • The four anti-CGRP drugs, Fremanezumab, galcanezumab, eptinezumab, and erenumab, compared to placebo, reduced the number of days associated with migraine pain per month and improved quality of life.
  • Mild side effects of anti-CGRP drugs were observed during the study, one of which was related to the subcutaneous administration route, namely induration and erythema at the injection site. Serious incidents that occurred at the time of the study were also reported but not associated with the intervention's administration.
  • Although it does not cause side effects relatively greater than the placebo, the safety for long-term use still needs further investigation.