CGRP is a 37 amino acid neuropeptide secreted by the nervous system of the central nervous system and the peripheral nervous system. It is widely distributed in the sensory nerves of the peripheral nervous system and the central nervous system and exhibits a large number of different biological activities. When released from trigeminal nerve fibers and other nerve fibers, CGRP is thought to mediate its biological response by binding to specific cell surface receptors. Elevated levels of CGRP play a role in several conditions, including migraine, cluster headache, and osteoarthritis pain.


The medical community has limited understanding of the mechanism of migraine attack, which seriously hinders the development of effective treatment methods. It was previously thought to be caused by the expansion of the blood vessels in the head, which is the basis for early drug design. It is now slowly believed that migraine is a neurological disease associated with changes in the nervous pathways and chemicals in the brain. At present, the treatment of migraine is divided into episode drug therapy, interstitial prophylactic drug therapy and adjuvant therapy/non-drug therapy.


First, the treatment of the attack


The treatment drugs during the attack period can be divided into non-specific drugs and specific drugs. Non-specific drugs include non-steroidal anti-inflammatory drugs (ibuprofen, acetaminophen, aspirin, naproxen, etc. and their combination preparations), barbiturate sedatives and opioids. Non-steroidal anti-inflammatory drugs have a certain effect on early migraine and mild to moderate migraine. In this case, it is recommended as a first-line treatment. Because barbiturate sedatives and opioids have certain addiction and overdose headaches (MOH), they are generally not recommended. Non-steroidal anti-inflammatory drugs have gastrointestinal side effects and bleeding risks, limiting their long-term and high-dose use.


Second, gap period preventive treatment


Prophylactic treatments include beta blockers (propranolol, metoprolol, etc.), calcium channel blockers (flunarizine, etc.), antiepileptic drugs (sodium valproate, topiramate, etc.), antibiotics Depressive drugs (amimetiline, etc.) and botulinum toxin type A (protective). Topiramate (topiramate) and botulinum toxin type A (protective) are the two most effective drugs, but the effective rate is less than 50%. Safeguard is the only drug approved by the FDA for the prophylactic treatment of chronic migraine.


Third, adjuvant therapy / non-medication


There are three main non-pharmacological treatments: lifestyle adjustment, physical therapy, and exercise. Lifestyle adjustments include a headache diary, remembering the environmental factors that cause headaches; maintaining regular diet, drinking water, sleep habits, and losing weight. Physical therapies include acupuncture, massage, stress management, biofeedback, and hypnotherapy. Exercise includes yoga, Tai Chi, running, swimming and more. The effect of non-pharmacological treatment of migraine varies from person to person, varies greatly, and is difficult to assess. The effect on chronic migraine is worse than episodic migraine.


CGRP and its receptor antagonist


Calcitonin-related peptide (CGRP) is a neuropeptide consisting of 37 amino acid residues released from the end of the primary sensory neurons of the trigeminal ganglion. Its content is significantly increased during migraine. The role of triggering, regulating, transmitting migraine signals and enhancing sensitivity. The CGRP target is the most popular target for the treatment of migraine today. David Dodick, the president of the International Headache Association and a neuroscientist at the Mayo Clinic, believes that CGRP is the best target to date for migraine.


1. Small molecule CGRP receptor antagonist


The development of small molecule antagonists (Gepant) of CGRP receptors around 2010 is very hot, is a well-validated target, can be compared with triptans, and has no triptans because it does not contract blood vessels. The use of taboos.


Second, CGRP and its receptor antibodies


Early in the development of CGRP receptor antagonists, there is no conclusive comment on the distribution of CGRP receptors and whether anti-migraine effects are required to cross the blood-brain barrier (BBB). Telcagepant passes through the BBB with few, but still has a good anti-migraine effect. In addition, the ability of sumatriptan to cross the BBB is limited, and the ability of the second-generation triptan to pass through the BBB does not show a better effect than sumatriptan. Therefore, it is currently believed that the CGRP receptor is outside the central nervous system, and the trigeminal ganglion is located outside the BBB. The drug does not pass through the BBB and exerts an anti-migraine effect mainly outside the central nervous system. These evidences provide a theoretical basis for the development of cdh17 antibody and CGRP receptor antibodies, and these antibodies have shown efficacy to further enhance this inference.


Safety and patient compliance


CGRP is a potential vasodilation factor, so inhibition of CGRP has the potential to cause cardiovascular risk due to vasoconstriction, especially when combined with the onset treatment drug triptan. In a Phase 264 clinical trial involving 264 participants, Teva found that CGRP alone (ie, TEV-48125) or in combination with triptans did not alter hemodynamics and ruled out concerns about cardiovascular and cerebrovascular risk.




CGRP and its receptor antibodies are currently the best drugs for the prevention of migraine. There are no suspense in the market, and it may be listed as early as 2018. It may become the first new mechanism drug for migraine treatment in the past half century. There are currently a number of clinical trials in progress for four drug candidates, and competition is heating up. Evaluate Pharma predicts that sales of such antibodies will exceed $2.5 billion by 2020. In addition, CGRP antibody may become a biomarker of migraine, and it is expected to open the era of precise treatment of migraine.