New and Improved - The Facts and Hype about CGRP Antibodies - Part 2

In part 1 of this blog we learned about the new class of drugs for migraine prophylaxis or prevention – the CGRP monoclonal antibodies (CGRP-mAbs or CGRP inhibitors).
In summary CGRP is produced by irritated nerves as part of our inflammatory/healing pathway. With the trigeminal system being irritated in migraineurs, they have more CGRP, but this is a result of, not a cause of their underlying problem. This was proven when non-migraineurs are injected with CGRP – they don’t get migraines.
We looked at the results of clinical trials that have led to the first of these drugs being approved in the USA. Of the people on CGRP-mAbs, 30% achieve 50% or greater reduction in migraine days. The effect above placebo indicates that we need to treat about 6 people with the drug to find one that responds. At $575 (USD) per month that may pose a problem for people seeking it privately, or for public health systems already struggling for funding.
 
In light of these results and cost, the hype and excitement around these drugs hardly seems justified, but in part II I will talk about why the neurological community are excited, what to expect when CGRP-mAbs arrive in Australia, and what CGRP tells us about the underlying causes of migraine.

CGRP inhibitors (mAbs) compared to topiramate and amitriptyline

In the midst of growing hype, it was the absence of astounding results, which prompted my attending the recent American Headache Society (AHS) scientific meeting in San Francisco. My goal was to find out what the buzz was about. The clue to the excitement over these drugs came to me from two sources.
 
The first was a biochemist working for Amgen (co-producer of Erenumab, the first approved CGRP-mAb sold in US as Aimovig). I asked her why there was so much excitement about Aimovig given the modest clinical trial results.
 
Her response, with a grin was “it’s their baby”.
 
Neurologists and doctors have had to rely on anti-depressants, beta-blockers, anti-seizure medications and anti-histamines, all originally made for purposes other than migraine, and all stumbled upon when people with other illnesses reported their migraines improved on said medications. The preliminary research on CGRP, through to the development of the drugs, subsequent clinical trials and FDA approval, has been primarily driven by the neurological community in aid of migraine. Justifiably, there’s a degree of pride about this class of drugs.
 
The second, and most significant reason for excitement is the favorable side-effect profile. At the recent AHS scientific meeting a comment from the floor following a presentation on topiramate (brand name topamax) spoke to the frustration felt at the current group of medications:  ‘we know that a majority of our patients either can’t tolerate it enough to get a therapeutic dose, or if they do get there it either doesn’t help, or they can’t stay there long’.
 
The list of adverse reactions for the current list of preventive medications (including topiramate, amitriptyline, propranolol) includes paraesthesia (pins and needles), weight gain, weight loss, hair loss, nausea, dizziness, slowed thinking, sedation, renal calculi, acute angle closure glaucoma, headache, dry mouth, diarrhoea, constipation, loss of appetite, insomnia, weakness, lethargy. (1-3)
 
This can present patients with a predicament. Will the side effects of treatment be worse than the condition? A problem so eloquently recalled by Emma Larson in the movie ‘Out of my head’ (4)
Quoting her Neurologist:
 
‘I can give you one drug which will make you fat and your hair will fall out, or another that will make you thin and stupid’
 
Emma quipped sarcastically ‘I’ll take thin and stupid (I’ll be the perfect woman).’

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CGRP inhibitors (mAbs) side effects

​The excitement about the CGRP-mAbs is that based on the phase 3 clinical trial data, patients are far more likely to tolerate them to get a therapeutic dose, and likely to be able to stay there if they are effective. In a review of 5 clinical trials for CGRP-mAbs the only adverse event that showed a slightly higher incidence than placebo was dizziness.(5)
 
A word of caution needs to be read into this with regards to the stage of the drugs testing cycle. Clinical trials are conducted on very carefully targeted groups who don’t have any other co-morbidities (health conditions). This is common practice to minimise the variability amongst the treatment groups by not having other conditions or medications that can affect or interact with the test drug to get ‘cleaner’ results.
 
The problem is that the interactions with other conditions are unknown.
Aimovig now goes into phase 4 studies, which is closely monitored and reported ‘population’ based studies. In other words it starts getting prescribed and doctors monitor for any adverse events or interactions with other health conditions or medications, and to see the long-term effects of use.
 
There are some concerns about the effect of inhibiting CGRP.  As a part of our inflammatory response it plays an important role in helping us avoid damage in cardiovascular events such as stroke and myocardial infarction (heart attack). As David Dodick (Leading CGRP researcher, Director of the Headache Program, Mayo Clinic) observes on the actions of CGRP:
 
“One of the things it does is dilate blood vessels, and that may be particularly important when a blood vessel is blocked, as occurs in patients who are having a stroke, you could be potentially blocking the body’s ability to dilate a blood vessel when it’s needed.” (6)
The consequences in that case could be fatal, or lead to more severe impairment following stroke or heart attack.
 
A number of medications have failed the population-based test, and it can take decades for the problems to be apparent. A recent example is Vioxx, a medication that promised superior anti-inflammatory results without gastric upset. The results were equivocal to the old medications (NSAID’s) and serious cardiac problems occurred in 15 of every 1000 people on the drug. Both the drug company ‘Merck’ and American regulatory body FDA drew criticism for not acting more promptly. (7)
 
David Rind (MD, MSc, ICER's chief medical officer) offers a nice summary:
 
"CGRP inhibitors appear to offer modest improvements in outcomes for patients with chronic migraine and frequent episodic migraine. However, there are concerns remaining regarding unanticipated harms of the medication. So far, the medication has only been tested in short trials assessing outcomes by 12 or 24 weeks. There are some concerns about the long-term effects of continuous blocking of the CGRP or its receptor, but as these are the first inventions in the class, long-term effects remain unknown. In addition, since migraine is fairly common, there may be concerns about affordability and access.”(8)
 
 
Should you be excited about CGRP-mAbs? 
The short answer is yes, but temper your excitement. There will be a small ‘super-responder’ group in whom these are the ‘miracle’ they have been hoping for. Another group in whom these help decrease the frequency of migraines, and, sadly, a bigger group in whom they are ineffective. They are also likely to be more widely tolerated than the drugs they will be replacing, so the people in whom they are helping the most likely problem will be affordability rather than side-effects.

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CGRP inhibitors (mAbs) in Australia

​What can you expect when the drugs are approved by the Australian Therapeutic Goods Administration? Botox is probably the most recent and best comparison given the similarity in cost profile. It is most likely that initially CGRP-mAbs will be available privately through a neurologists prescription. Erenumab (the first CGRP-mAb approved in the USA) is a self-injected medication that is required to be injected monthly. In the USA the cost is approximately $575 (USD) per monthly injection. This is more than botox was before it was placed on the Pharmaceutical Benefits Scheme (PBS) at which time medicare covered the majority of the cost. This took several years after release as the drug goes through ‘phase IV’ testing. If CGRP-mAbs go onto the PBS, given the cost to taxpayers, it will most likely have the same restrictions as Botox, in that people will need to have trialed cheaper medications first, like topiramate and amitriptyline, for at least 3 months and failed before being approved to use the new medication.

The cause of migraine – what CGRP research tells us.

​I think the thing that excites me the most about the research in this area, is also, sadly, the one area that received absolutely no coverage at the AHS scientific meeting. It speaks to the underlying cause of migraine.
Constantly elevated CGRP is yet another indication of chronic irritation of the trigeminal system. Previously we have seen studies on hyper-excited nociceptive blink and trigemino-cervical reflexes(9-14)and elevated PET scan signals in all forms of primary headache. SO we have another biomarker, but this one is different – we know what creates CGRP.
 
The next question should be ‘why is the trigeminal system in a state of constant irritation?’
CGRP is a product of the problem, not the cause, as we have seen in the studies injecting CGRP into non-migraine sufferers. 

The simple fact remains that the nerves from the top three levels of the neck are the biggest input into the trigeminal nucleus, and remain the single most common source of irritation, and therefore, a likely source of increase CGRP levels.
We have already seen that techniques directed at the neck developed specifically to treat headache and migraine, ‘normalise’ elevated reflex responses. (17)
 
The logic is simple. Small faults at the top of the neck cause irritation of the trigeminal nerves in the brainstem. This irritation shows itself in constantly elevated reflex and CGRP responses. In susceptible people (i.e. headache sufferers) this irritation isn’t dampened but instead is allowed to build to the point of ‘exploding’ periodically, or constantly in some cases.
 
Drug therapy is focused on symptom suppression. A fire truck to put the fire out.
 
Treating the neck is targeting an underlying source of trigeminal irritation. This is fire prevention. 
 
So yes, be excited about a medication that won’t cause toxicity, tingling in your hands or make you feel like a zombie, but please continue to pursue the underlying problems contributing to the sensitivity so you don’t become a customer of big Pharma for life. 

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References

(1) Marmura, MJ (2014) Safety of topiramate for treating migraines.Expert Opinion Drug Safety, Sept 13 (9) 1241-7.
 
(2) Jasmer (2018) Endep side effects. Drugs.com
 
(3) Robbins, L and Phenicie, B (2018) Migraine Treatment A-Z. Practical Pain Management.com
 
(4) Ochs, J and Styron, S (2017) Out of my head. Eleventh Hour Film Production.
 
(5) Min Hou et al (2017) The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis.Journal of Headache and Pain
 
(6)Novak Jones, Diana New drugs in development may offer serious relief from migraines.  Chicago Suntimes, August 22, 2017
 
(7) Berenson et at (2004) Despite warnings drug giant took long path to vioxx recallNew York Times, November 14, 2014.
 
(8) Joszt, L (2018) Erenumab for migraine is cost-effective but long-term harms remain unclear. American Journalof Managed Care. June, 2018
 
(9) Nardone et al (2008) Trigemino-cervical reflex abnormalities in patients with migraine and cluster headacheHeadache, 48; pp 578-585.
 
(10) Nardone, R. and Tezzon, F. (2003) The trigemino-cervical reflex in tension-type headache. European Journal of Neurology, 10 (3), pp 307-312.
 
(11) Gantenbein, A.R. and Sandor, P.S. (2006) Physiological parameters as biomarkers of migraine. Headache, 48 (7); pp 1069-74.
 
(12) Varlibas, A. and Erdemoglu, A.K. (2009) Altered trigeminal system excitability in menstrual migraine patients. Journal of Headache and Pain, 10; pp 277-282.
 
(13) De Marinis, M.(2007) Blink reflex in cervicogenic headache. Blink reflex in cervicogenic headache. Cephalalgia, 27 (7); p 860.
 
(14) Sand, T. Moll-Nilsen, B. Zwart, J.A. (2006) Blink reflex R2 amplitudes in cervicogenic headache, chronic tension-type headache and migraine.Cephalalgia.26 (10); p.1186.
 
(15) Weiller C, May A Limmroth V, et al. (1995) Brainstem activation in spontaneous human migraine attacks. Nature Medicine. Jul;1(7):658–660.
 
(16) Afridi SK, Giffin NJ, et al. (2005) A positron emission tomographic study in spontaneous migraine.  Archives of Neurology; 62(8): 1270–5.
 
(17) Watson, D.H, and Drummond, P.D. (2014)  Cervical Referral of Head Pain in Migraineurs: Effect on the Nociceptive Blink Reflex. Headache: Journal of Head and Face Pain, June, 1035-1045