What is CGRP?
CGRP (calcitonin gene-related peptide) is known to be closely involved in the cascade of events that lead to a migraine attack. Recently, positive results have arisen from Phase 2 clinical research studies showing that CGRP may offer an entirely new approach to treat migraine headaches.
Today, most treatments for migraine were originally designed for other conditions such as epilepsy, hypertension or depression. This class of CGRP treatments are exciting as they are the first preventative treatment designed specifically for migraine.
To understand CGRP we need to understand a few terms. These are:
- Amino acids
- Trigeminal nerve
Amino acids are essentially the building blocks of proteins in our body. They are responsible for the transport and storage nutrients.
A peptide is a type of amino acid.
It is a naturally occurring biological molecule found in every cell and tissue. It performs a wide range of functions in the body including the regulation of hormones.
The difference between a peptide and a protein is the number of amino acids it contains. Generally speaking when a molecule contains 2-50 amino acids it is considered a peptide. If there are more than 50 amino acids it’s classified as a protein. (1)
CGRP stands for calcitonin gene-related peptide (CGRP). CGRP is known to be involved at the molecular level in the migraine process. It is also one of the strongest vasodilators in our body.
Contrary to popular opinion, vasodilatation is not believed to cause migraine pain.
Our brain does not have the ability to feel pain. Instead, the trigeminal nerve passes the sensation of pain on the brain’s behalf. The trigeminal nerves are the nerves around the head which are responsible for sensations in the face, head and motor functions such as chewing.
During a migraine headache, CGRP is released and binds to receptors in the trigeminal nerve which leads to pain. (2)
CGRP levels have been shown to be elevated during a migraine attack. (9)
How does the CGRP treatment work?
Today most experts believe that migraine is a neurological disorder that begins inside the brain, occurring primarily in the brainstem with the activation of certain brain structures.
These same brain structures cause peptides including CGRP, to be released.
CGRP then binds to receptors which leads to vasodilation and muscle relaxation which leads to inflammation and pain.
The released peptides bind to specific receptors which cause sensitisation. (2) Ordinary stimuli such as light, sound and smell can then cause pain.
The secret of this latest generation of CGRP treatments are inhibiting CGRP through use of monoclonal antibodies.
An antibody is a protein that is used by the immune system to identify and neutralise harmful agents such as bacteria and viruses.
Monoclonal antibodies are designed to bind to a specific substance. They can detect or purify that substance.
CGRP monoclonal antibodies bind to CGRP to prevent the activation and sensitisation of trigeminal nerves.
CGRP monoclonal antibodies prevent migraine by:
- binding with the CGRP released from trigeminal sensory nerve fibers
- preventing activation of trigeminal nerves
- preventing CGRP induced activation of sensitised central trigeminal pathways
- preventing attacks in migraine susceptible individuals
Research to date
In the 1990s, CGRP was discovered by one of the most effective treatment classes currently available, the triptans. Common triptans include Sumatriptan (Imitrex, Imigran), Rizatriptan (Maxalt), Zolmitriptan (Zomig) etc.
During studies to understand what role the triptans performed in preventing the migraine it was discovered that CGRP was inhibited by the triptans. Triptans cause vasoconstriction.
The early studies showed that if you inhibit CGRP you could do what the triptans are doing but without causing vasoconstriction.
The aim was to block CGRP without causing the vasoconstriction that the triptans caused. (2)
Interestingly, tests showed that if CGRP is injected via IV it delivered a migraine attack in migraine patients. (3)
Researchers wanted to know if the reverse was true.
If they blocked CGRP, could they block migraine? In medical terms this is called an antagonist. An antagonist is something which interferes with or inhibits the physiological action of something else.
Early results showed that it did indeed work. In fact, it delivered the same efficacy or effectiveness as the triptans in the use of acute migraine treatment. (4)
Telcagepant was one of the key drugs developed in these initial trials. However it was associated with serious liver toxicity side effects. Therefore treatment with Telcagepant was stopped.
This is where the monoclonal antibodies began.
The monoclonal antibodies specifically targeted CGRP. This development also shifted the focus of CGRP treatment from acute treatment of a migraine attack to a preventative solution. For monoclonal antibodies to be effective they would need to be regularly topped up.
There are 4 monoclonal antibodies either available or in developement. Three target CGRP itself whilst one antibody targets the receptor (AMG 334).
There is a functional difference between a CGRP antagonist which targets the receptors versus one which targets the CGRP itself.
When the receptor is targeted it causes a complete lockout. All CGRP signalling is blocked.
The 3 antibodies which are targeting the CGRP itself, allow for some CGRP signalling during therapy. This avoids the potential effects of a long-term total disruption to the normal physiological functions of the CGRP system which are currently unknown.
Which approach is best? We don’t know. A complete lock might be better for your immediate migraine attacks but it could do longer term damage as it is a more aggressive intervention. Only time will tell as more comprehensive, long term studies are conducted.
The companies and drug names involved in research are:
- Teva Pharmaceutical Industries (Fremanezumab TEV-48125)
- Eli Lilly and Company (Galcanezumab LY2951742)
- Alder Biopharmaceuticals (Eptinezumab ALD403)
- Amgen (Erenumab AMG 334) now marketed as Aimovig.
The below chart shows the summarized results from published phase II clinical trials of the anti-CGRP antibodies.
Fremanezumab from Teva found that 53% of patients reduced the frequency of their days with migraine by 50% or more. Those given the placebo experienced a 28% reduction. Teva also looked at a subgroup of patients who reduced their days with migraine by 75% or more. 33% patients experienced a reduction of 75% days with migraine whilst 11% on placebo also experienced the same result. (10)
Galcanezumab from Lilly found that 70% of patients reduced the frequency of their days with migraine by 50% or more. Those given the placebo experienced at 45% reduction. Lilly also looked at a subgroup of patients who reduced their days with migraine by 75% or more. 49% patients experienced a reduction of 75% days with migraine whilst 27% on placebo also experienced the same result. Lilly also had a subgroup of patients who experienced a complete remission with 100% of days measured free from migraine during the trial period. 32% of patients experienced freedom from migraine whilst 17% on placebo also experienced no days with migraine. (5)
Eptinezumab from Alder found that 61% of patients reduced the frequency of their days with migraine by 50% or more. Those given the placebo experienced at 33% reduction. Alder also looked at a subgroup of patients who reduced their days with migraine by 75% or more. 33% patients experienced a reduction of 75% days with migraine whilst 9% on placebo also experienced the same result. Lilly also had a subgroup of patients who experienced a complete remission with 100% of days measured free from migraine during the trial period. 16% of patients experienced freedom from migraine whilst 0% on placebo experienced no days with migraine. (6)
Erenumab from Amgen (Aimovig) found that 46% of patients reduced the frequency of their days with migraine by 50% or more. Those given the placebo experienced a 30% reduction. (11)
Why is the placebo effect so strong?
Researchers suspect placebo was high in these due to a heightened expectations, bi-weekly clinic visits and administration via injection.
Side effects are minimal
Fortunately the new generation of CGRP monoclonal antibodies showed no findings of liver toxicity, cardiovascular or adverse events in the studies. (5) So far in research reports, side effects appear to very low.
Minor skin reddness, pain or irritation can occur around the injection site but was not common or significant.
At the time of writing in May 22, 2018:
- Aimovig has been approved.
- Lilly and Teva have filed for approval with the FDA.
- Alder is in Phase 3 Clinical Trials.
Aimovig is now available in US pharmacies with a prescription. Patients can now self-administer Aimovig 70mg or 140mg once a month via a SureClick autoinjector. Aimovig will cost $575 for once-monthly or $6,900 annually. Co-Pay is available as well as a free 2 month trial for eligible patients at the time of writing at https://www.aimovig.com/
It is difficult to estimate how long it will be before the remaining anti-CGRP antibodies are available as they each have their own unique evidence, results and costs. One industry observer speculates that Lilly will be close behind with a decision due late in the US summer of 2018. According to company sales forecasts, Teva may follow potentially at the very end of 2018 or 2019. Alder is not expected to become available until 2020.
Fortunately, even after the launch of the CGRP antibodies, trials are still expected to continue to evaluate all the usage, marketing and safety data. To see if you’re eligible to participate in the current studies being held visit www.clinicaltrials.gov and search for “Migraine CGRP”. Another very easy clinical search tool where you can set reminders to be notified if a study opens up near you is at https://findmecure.com/
This is the first preventative treatment designed specifically for migraine patients which is very exciting. The positive results in the studies should give hope to many. There are however a few important things to note:
- It’s going to be expensive: Dr Peter Goadsby, one of the researchers on the projects has already been quoted saying that his will not be a cheap treatment. Monoclonal antibodies are the same type of treatment used in cancer and can be very expensive. Monthly injections in a clinic may also come with a cost.
- They are delivered by injection. Which doesn’t suit many people and is not the easiest format to administer.
- They are strong. The half life of ALD403 for example is 31 days. That means after 31 days after you’ve taken the treatment, 50% of the drug is still circulating and taking effect in your system.
- This is not a final cure. Phase 2 clinical trials show between 50-70% of patients experiencing a 50% or greater reduction in migraine days. It's not a cure and acute treatments will still be required for many.
Overall, the fact that we are getting the first wave of treatments specifically for migraine has many people rightly excited.
For the medical community, migraine has traditionally been the black sheep of the family with historically little progress or promise in the field. Now, that’s changing. With more progress comes further research, funding and publicity which is sorely needed.
Most importantly are these strides towards better care and treatment for all of us out there suffering. If you’re struggling at the moment hold on, there is more hope than ever for a better future.
What to do in the meantime?
Patients are encouraged to find the right doctor. (7)
There are over 14 million people with migraine who meet the criteria for preventative treatment. That’s 40% of the of the total migraine population in the US (37 million). (8)
However only 13% or 4.7 million people are taking preventatives. (8) The side effects of current medicinal preventatives are common and hard tolerate. There are many alternative preventative treatments like Botox and devices such as the Cefaly TENS unit (both FDA approved treatments for chronic migraine) and a variety of complementary therapies and natural treatments which have been shown to benefit those with migraine.
Ultimately you’ll need to find what works for you in partnership with your doctor. Are you happy with your current migraine treatment or looking for something new? Let me know in the comments below.
- 'What Are Peptides' Zealand Pharma. Archived from the original on 6 Apr 2014.
- Bigal, M. Burstein R. et.al. Targeting Calcitonin Gene-Related Peptide (CGRP) for Prevention of Migraine. Webinar. 12 Feb 2015.
- Hasen, JM. Hauge, AW. et.al. ‘Calcitonin gene-related peptide triggers migraine-like attacks in pateints with migraine with aura’. Cephalalgia 2010 Oct;30(10):1179-86. doi: 10.1177/0333102410368444.
- Connor KM, Shapiro RE, Diener H-C, et al. Randomized, controlled trial of telcagepant for the acute treatment of migraine. Neurology. 2009;73(12):970-977. doi:10.1212/WNL.0b013e3181b87942.
- Dodick, David W et al. ‘Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study.’ The Lancet Neurology , Volume 13 , Issue 9 , 885 – 892
- Dodick, David W et al. ‘Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial’ The Lancet Neurology , Volume 13 , Issue 11 , 1100 – 1107
- Dumas, PK. ‘Free at last? New CGRP Drugs To Prevent Migraine Attacks For Most’. MigraineAgain.com June 23, 2015
- Lipton, R.B., Bigal, M.E., Diamond M., et. Al. (2007), Migraine prevalence, disease burden, and the need for preventive therapy, Neurology, 68:343-349, doi: 10.1212/01.wnl.000025280897649.21
- Goadsby, P. J., L. Edvinsson, and R. Ekman. "Vasoactive peptide release in the extracerebral circulation of humans during migraine headache." Annals of neurology 28.2 (1990): 183-187.
- Sun, Hong, et al. "Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial." The Lancet Neurology 15.4 (2016): 382-390.
- Bigal, Marcelo E., et al. "Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study." The Lancet Neurology14.11 (2015): 1081-1090.