Save migraines! The path to discovery of CGRP inhibitors

Monoclonal antibodies and small molecule antagonists that target CGRP or its receptors have had a significant impact on migraines, but they have the potential to do more.
June 1985, Australian medical student Peter Goadsby came to Lund, Sweden, for a conference.
in a panel discussion about trigemodes, neural networks connected to blood vessels in the head, something hit him in the heart.
he was studying migraines and suddenly realized that the system might be a way to overcome migraines.
he introduced himself to the speaker, Lars Edvinsson, a doctor at the local hospital.
the two discussed potential biomarkers of migraines in trigemical vascular systems over coffee, including a molecule called the calcitonin gene-related peptide (CGRP) discovered a few years ago.
CGRP is a powerful vascular esophotosis neuropeptide whose release causes local vascular dilation.
Edvinsson suspects it plays a key role in migraines.
the conversation, laying the groundwork for a remission drug for migraine sufferers after 35 years.
, now a neuroscientist at King's College London, said: "Initially we were just looking for a marker to see what pain might be about, and the end result was much more than that.
2018, the FDA has approved six drugs that block CGRP or its receptors.
these drugs are as effective as current treatments, but they have a huge impact because they have relatively small side effects and are effective for many people who do not respond to other medications.
Figure 1. Researchers at six FDA-approved migraine drugs targeting CGRP/CGRP receptors (Photo: NextPharma®) are now trying to treat other types of headaches with the same CGRP-targeted drug.
but despite the success of these drugs, the role of CGRP in migraines is not fully understood.
by studying how the molecule causes migraine-specific hypersensitive responses to sensory input, researchers are shed light on the complex basis of the disease, which could lead to more migraine therapies.
- Ordinary but complex migraines are a common trigemist vascular headache that can last between 4 and 72 hours.
it is characterized by throbbing or beating pain on one or both sides of the head, nausea, vomiting, and sensitivity to light, sound, odor and touch, which seriously affects the daily life of the patient.
estimated that migraines affect 14 percent of the world's population, with about one-in seven people in the U.S. (about 33 million) suffering from migraines, 8 million in Japan and about 13 million in China.
cost of medical care and productivity caused by migraines is estimated at about $80 billion a year in the United States.
think the migraine problem hasn't been taken seriously enough, " says Goadsby, a police official.
unfortunately, because migraines are so complex, it has proven to be a difficult disease to treat, " he said.
many migraine therapies are drugs for other diseases, such as antidepressants, anticonvulsants, anti-depressants, anti-depressants, and type A botulinum toxins (also known as pyrethroids) are used to prevent migraines.
the 1990s, a trot-like migraine-specific drug emerged.
these drugs treat migraine seizures by activating 5-serotonin- and provide pain relief for at least two hours for up to half of migraine patients.
diagram of the effects of qutan-type drugs.
picture source: D. W. Dodick Headache 58 (Suppl.1), 4-16 (2018); Graphic: Alisdair Macdonald and Denis MalletCGRP targeted drugs are equally effective.
Edvinsson noted that about 25 percent of those who took the drug to prevent migraines almost completely stopped the seizures.
another 50 percent reported moderate improvement, fewer episodes, and the rest did not respond to them.
, a neuroscientist at the University of Copenhagen, said: "In general, these drugs are no more effective than the drugs we have.
but new drugs have huge advantages.
" early drugs are at risk of side effects, and even migraine-specific trotin can cause nausea, heart rate and fatigue.
, CGRP targeted drugs used to treat acute migraine attacks appear to cause only minor side effects such as constipation in a small number of people.
advantage of CGRP-targeted drugs is that their mechanism of action is different from that of previous therapies.
a lot of different drugs because one drug doesn't work for everyone," olsen said.
CGRP blockers can provide much-needed relief for those who have tried other migraine medications that have not worked," he said.
the discovery of CGRP in 1982, Edvinsson and other researchers found that CGRP was present in half of the nerves of the Trident nerve section, a cellular structure located behind the face that is the center of sensation in the face and head.
, migraines were thought to be associated with the regulation of cerebral blood flow.
given that CGRP is known to dilation blood vessels, Edvinsson reasoned that the molecule may be associated with migraines.
although current studies suggest migraines originate in the nervous system, CGRP still plays a key role in migraines.
meeting in Lund, Goadsby teamed up with Edvinsson to transfer samples from animal models and tissues to patients.
two took blood samples from the neck veins of patients with migraine attacks and again after the pain subsided.
found that CGRP levels increased during the onset and then dropped to normal levels after the attack.
published their findings in 1990.
study three years later showed that the new quarry-like migraine drug, Schumacher, lowered CGRP levels, reinforcing the link between CGRP and migraines.
2002, a team of researchers further cemented this link by injecting CGRP to trigger the onset of the disease in migraine-prone populations.
, Olesen led a proof-of-concept study that showed that blocking small molecules in CGRP subjects can reduce the symptoms of migraine attacks.
later discovered other similar, more effective molecules, known as gepant drugs.
two of these drugs were approved by the FDA in December 2019 and February 2020, respectively, for the treatment of acute migraines, which are available oral at the onset of an attack.
FDA also approved four anti-CGRP monoclonal antibodies for migraine prevention, three in 2018 and one in February 2020, that must be injected monthly or quarterly (Figure 1).
decryption mechanism All of these drugs are designed to block CGRP contact by blocking or binding to CGRP.
exactly how it affects migraines is uncertain.
, for example, there is no conclusive evidence that these drugs block CGRP in the central nervous system or in the peripheral nervous system.
the basic mechanisms of a complex disease such as migraines seem unlikely to exist only in the outer nerves, says Goadsby, a government official.
rodent experiments have shown that CGRP does work in the brain.
but the central nervous system is protected by a blood-brain barrier that blocks the entry of large particles such as CGRP antibodies.
the gepant class of drugs is much smaller, Edvinsson likens it to the fact that if the antibody is as big as American football, the gepant class is small like a grain of rice.
, however, only a small fraction of gepant drugs pass through the blood-brain barrier.
As a result, most migraine researchers suspect that these drugs interfere with CGRP outside the central nervous system, such as the possible "origin" of migraines in trigeminal nerves or CGRP in the meninges (a layer of membrane between the brain and skull).
perhaps the simplest theory is that CGRP makes these peripheral nerves sensitive, which in turn send signals to the central nervous system, inducing pain and sensitivity to migraine-related sensory stimuli.
s question now is how exactly it does it," said Andrew Russo, a neuroscientist at the University of Iowa in Washington.
possibility is that when CGRP binds to a subject, it makes the nerve sensitive by increasing the rate at which the nerve is discharged.
, as Russo and others have pointed out, CGRP can trigger an inflammatory response.
, for example, CGRP can cause glial cells (non-neuron cells in the nervous system) and nearby immune cells to release inflammatory substances such as cytokines.
these compounds can alter the environment around nerve endings, making them more sensitive to sensory inputs.
CGRP may also induce vascular cells to release these compounds.
addition, CGRP may activate pain receptors by dilated blood vessels.
russo says that when blood vessels dilate in the trigemuscul section, they stimulate pain receptors in the adjacent nerves.
these subjects respond to pressure and release pain signals, triggering more release of CGRP in the feedback loop.
even the gastrointestinal tract may be involved in the role of CGRP in migraines.
in some people, certain foods can cause migraine attacks.
CGRP antibody erenumab can cause constipation, and a study co-authored by Olesen suggests that injecting CGRP can cause gastrointestinal problems such as diarrhea.
CGRP may play a role in the gastrointestinal tract, which is the cause of some people's illness," said Greg Dussor, a neuroscientist at the University of Texas in New York.
" beyond migraines Although it is uncertain how the CGRP-targeted drug will relieve migraines, researchers and clinicians are still exploring whether it can play a broader role.
, for example, CGRP antibodies are used to prevent migraine attacks, gepant is used to treat acute seizures, is there a drug that can balance two effects? In March, Biohaven Pharmaceuticals, based in Connecticut, announced promising results for a Phase III trial of migraine prevention with Rimegepant, a gepant-type drug that has been approved for the treatment of acute migraines.
antibodies that must be injected, Rimegepant is a pill that is easier to take.
" is beginning to blur the distinction between acute and preventive treatment.
," said Andrew Charles, a neuroscientist at the University of California, Los Angeles.
are also exploring the use of CGRP-targeted drugs in migraine children.
are currently being recruited for clinical trials in children.
, Charles had treated some children with medication.
's real experience with children is that they're very effective, but we haven't systematically proven that yet," he said.
" these drugs are also used to relieve other disabling headaches, such as congrus headaches, severe pain that occurs several times a day and lasts for weeks or even months.
2018, a study showed that injecting CGRP into people experiencing congeal headaches induced the onset of the disease.
the following year, after clinical trials, the FDA approved the use of CGRP antibody galcanezumab to treat plexual plexus headaches.
CGRP can also be shown to be an effective target for treating headaches after head injuries.
said: "It's very likely that a post-injury headache will help.
" concussion symptoms, such as dizziness and light sensitivity, are similar to migraines, and researchers have shown that CGRP antibodies can prevent these symptoms from appearing in concussion rodents.
, researchers published the results of the first clinical trial to show that CGRP antibodies help reduce the frequency of post-trauma headaches.
, however, is less optimistic about tension headaches.
goadsby says it's fundamentally different from migraines.
people with stress headaches tend to have only pain, no hypersensitivity, and focusing on a task can relieve pain, contrary to the effect of migraines.
some researchers are slightly more likely to see this.
, for example, Russo points out that some migraine episodes start with tension headaches, suggesting that there may be some biological overlap.
stress headaches may be associated with muscle tightening in the neck and head, which affects the peripheral sensational nerve fibers and releases CGRP, according to Dussor.
it is not clear what important role CGRP may play.
I don't think it's going to work for tension headaches, but it's going to be fun to find out," Russo said.
" A success story CGRP story is a success story.
, according to migraine researchers, migraines had previously been treated with contempt because there was no specific data to quantify or define them.
"CGRP's involvement in the discovery of migraines is important, as this is the first step in establishing the bio-chemical mechanism behind migraines.
," Russo said.
this journey is particularly gratifying for Edvinsson and Goddsby, who have spent their careers leading the transformation of basic research into drugs they now use to treat patients.
I never thought I'd live to see myself drive," said Goadsby, a police source