Medically reviewed by Dr. Bronwyn Jenkins on 5 January 2019.
FEB 2019 LATEST NEWS: Read about PBS submission process.
WHAT IS CGRP
Calcitonin gene-related peptide (CGRP) is known to be closely involved in the cascade of events that lead to a migraine attack. Recently, positive results have arisen from Phase 3 clinical research studies showing that CGRP antibodies for migraine may offer an entirely new approach in the treatment and prevention of migraine.
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 in many other parts of the body and 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 nerves, including 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 nerves which leads to pain. (2)
CGRP levels have been shown to be elevated during a migraine attack. (9)
HOW DOES 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 sensitization. (2) Ordinary stimuli such as light, sound and smell can then cause pain.
The secret of this latest generation of CGRP treatment is inhibiting CGRP through use of monoclonal antibodies.
A monoclonal antibody is a protein that is used by the immune system to identify and neutralize harmful agents such as bacteria and viruses.
Monoclonal antibodies are designed to bind to a single specific substance.
CGRP monoclonal antibodies bind to CGRP to block the activation and sensitization 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 sensitized 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 available in Australia include Sumatriptan (Imitrex, Imigran), Rizatriptan (Maxalt), Eletriptan (Relpax), Zolmitriptan (Zomig) and Naratriptan (Naramig).
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 CGRP 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 late stage development. 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 signaling is blocked.
The 3 antibodies which are targeting the CGRP itself, allow for some CGRP signaling 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 long term damage as it is a more aggressive
intervention. Only time will tell as more comprehensive, long term studies are conducted.
In the meantime, all have been shown to be effective in the current trials to date.
The manufacturers and drug names involved in the research are:
- Amgen (Erenumab AMG 334) now marketed with brand name Aimovig, is approved by Therapeutic Goods Administration (TGA) with limited availability.
- Teva Pharmaceutical Industries (Fremanezumab TEV-48125) now marketed with brand name Ajovy, but awaiting approval by the TGA in Australia.
- Eli Lilly and Company (Galcanezumab LY2951742) now marketed with brand name Emgality, but awaiting approval by the Therapeutics Goods Administration (TGA) in Australiay.
- Alder Biopharmaceuticals (Eptinezumab ALD403) not yet available as at October, 2018.
None of the CGRP monoclonal antibodies are approved on the Pharmaceutical Benefits Scheme (PBS) yet.
The below chart shows the summarized results from published phase II clinical trials of the anti-CGRP antibodies.
It is important to note that each study was conducted differently. Therefore a head to head comparison can not be drawn from this chart. Instead, focus on the difference above placebo as a better indication of treatment efficacy.