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 an offer an entirely new approach to treat migraine headaches.
Today, most treatments for migraine are originally designed for other conditions for example epilepsy, hypertension and depression. CGRP is exciting as this would be the first treatment designed specifically for migraine.
What is CGRP?
To understand CGRP there are a few medical terms to define. These are:
- Amino acids
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 regulating 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 itself doesn’t 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)
How Does the CGRP treatment work?
Today there is now little dispute 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 now cause pain.
The secret of this latest generation of CGRP treatments are the 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 actually 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 migraineurs. (3)
Now they 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 come onto the scene.
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.
ALD403 was evaluated in a phase 2 trial over 24 weeks. Individuals with 5-14 migraine days per month were randomly assigned to receive 1000mg ALD403 or the placebo. There were 163 participants (roughly 80 each) who received a single intravenous infusion. (5)
Patients used a migraine diary to keep track of their condition throughout the study. The effectiveness of the treatment was evaluated to placebo between weeks 5-8.
Interestingly there was a strong placebo effect with 54% of migraineurs experiencing a 50% reduction in migraine frequency. However, 75% of those taking the real treatment experienced a 50% reduction in migraine frequency.
15% of placebo had no migraines whilst 26% with the treatment experienced no migraines during this period.
LY2951742 was also measured over 24 weeks. Participants had 4-14 migraine days per month and were randomly given a placebo or the 150mg LY2951742. In this trial the treatment was injected every 2 weeks during the 12 week period. (6)
Patients recorded information about their condition using an interactive voice response system. The effectiveness of the treatment was evaluated over 12 weeks where the average days in migraine frequency was reduced by 62% (or 4.2 days).
70% of participants halved their migraine frequency whilst almost a third experienced no migraines during the 12 week period. (6) These figures were both higher than placebo however placebo was still high (as well) in this treatment.
Researchers suspect placebo was high in these due to a heightened expectations, bi-weekly clinic visits and administration via injection.
Initial studies by Lillly & Alder were conducted separately but both showed very similar findings. When taken as a bi weekly dose for 3 months. After 2 months the patient’s days with migraine reduced by approximately 60%.
The new generation of CGRP monoclonal antibodies showed no findings of liver toxicity, cardiovascular or adverse events in the preliminary results. (5) So far in research, side effects appear to very low.
For both studies, around 10% of people had been migraine free in the 6 months of treatment.
Research Companies Involved
There are 4 monoclonal antibodies being developed. 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 unknown.
Which approach is best? We don’t know. A complete lock might be better for your immediate migraines 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 involved in research are:
- Teva Pharmaceutical Industries (TEV-48125)
- Eli Lilly and Company (bought LY2951742 from Arteaus Therapeutics)
- Alder Biopharmaceuticals (ALD403)
- Amgen (AMG 334)
At the time of writing in June 2015, most of them have recently completed phase 2 studies.
According to the US National Institutes of Health Clinical Trial Register, these are the following timings for the trials:
- Eli Lilly and Company (LY2951742) - Phase 2 completed
- Alder Biopharmaceuticals (ALD403) - Phase 2 completed
- Amgen (AMG 334) – Phase 2 estimated study completion Mar 2020.
- Teva Pharmaceutical Industries (TEV-48125) information not disclosed.
It is difficult to estimate how long it will be before the first product becomes publicly available for prescription. Phase 3 trials will occur where a larger group of people are trialled to confirm the earlier results and make sure no safety issues come up in larger and longer exposures.
Dr Peter Goadsby has been involved in the research estimates that it may be 3 to 4 years until the products become available.
To see if you’re eligible to participate in the studies being held in the US visit www.clinicaltrials.gov and search for “Migraine CGRP”.
Implications for you
This is the first treatment designed specifically for migraineurs which is very exciting. The positive results in preliminary studies should give you hope. 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 as 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 have powerful effects. The half life of ALD403 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. The preliminary results show a 60% reduction in migraine headache frequency across the two treatments studied (LY2951742 and ALD403) however notably the duration and severity for the migraines that did occur remain unchanged. Acute treatments were still required.
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 for own benefit.
Most importantly are the 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 migraineurs 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 migraineurs were currently taking preventatives. (8) The side effects of current medicinal preventatives are common and hard tolerate. There are many alternative preventative treatments like Botox and Cefaly TENS devices (both FDA approved treatments for chronic migraine) and a variety of complementary therapies and natural treatments which have been shown to benefit migraineurs.
Ultimately you’ll need to find what works for you in partnership with your doctor. Are you with the right doctor for your migraines? 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