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Migraines and mAbs – is it time for compulsory phase 4 trials?

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Published: 24 Mar 2021

This article, written by Gabriella Santiago from Swansea University, was a runner up for our Pharmacology Matters Writing Competition for early career pharmacologists in 2020. If you are interested in entering this year’s competition, entries are now open, and all of the details are here.
Monoclonal antibodies (mAbs) are a special type of antibody, released by a particular type of white blood cells known as B-lymphocytes, or B-cells. While the discovery of mAbs dates back to 1890, it wasn’t until 1975 that scientists at Cambridge University made the ground breaking discovery that myeloma cells can be treated with specific antibodies released by something known as a hybridoma cell (a combination of both an antibody-producing spleen cell and a myeloma cell). This opened up a plethora of possibilities within both theoretical and applied biomedical research, allowing not only for precise diagnosis but also for the treatment of disease. The essential element of predetermined specificity enabled scientists to manipulate the immune system and use it therapeutically. At the time, the concept of hacking the immune system was unprecedented and it led to Köhler and Milstein not only being awarded the 1984 Lasker Award (alongside Potter) but also sharing the 1984 Nobel Prize in Physiology or Medicine (alongside Jerne).

If we fast forward 34 years, that discovery proved so important that it led to the growth of the therapeutic use of mAbs, which now ‘have an ever-increasing role and have generated a multibillion-dollar market’. Due to their versatility and specificity, mAbs have been used for everything from the prevention of kidney transplant rejection (in the case of muromonab-CD3), to the modification of the disease pathway of multiple sclerosis (e.g. natalizumab), to the prevention of migraine (e.g. fremanezumab (Ajovy)). Of course, this is not just good news for big pharma, it is also exciting for patients across the globe.

On 12 March 2020, NICE announced that this revolutionary new migraine drug, fremanezumab (Ajovy), was deemed cost-effective and could be made available through the NHS. Given the prevalence of mAb use this may sound unremarkable, but to put it into context, this one drug alone has the potential to benefit around 10,000 people in the UK. For some of those patients it holds enormous hope, particularly considering it may even help those who have previously been unresponsive to botox (also known as botulinum toxin A), which had previously been the last resort for many migraine patients, or those who have tried three or more unsuccessful preventive treatments. There is hope that this will also drive more research into the causes of migraine, so that better treatments can be developed.
There is just one problem, despite the successful use of mAbs to treat cancer and other diseases for the past 34 years, we still do not really have any data on the long-term effects of mAb therapies and what we do know, hardly seems encouraging. Not to mention that Calcitonin Gene-Related Peptide (CGRP) treatments are relatively new, which means that at this stage it simply is not possible to know the long-term effects. The list of known side effects differs from treatment to treatment; with only hypersensitivity listed for fremanezumab (the most recent addition), constipation, skin reactions and vertigo for galcanezumab and constipation, muscle spasms, skin reactions, oedema and swelling for erenumab.

So, how do we determine which drugs are safe enough for review? In the UK, once discovered, drugs are subjected both to rigorous pre-clinical testing along with three phases of clinical trials culminating in licensing and eventual prescription (if deemed safe and effective). But is it simply enough for a drug to work or should researchers be able to offer some information on the long-term consequences? And should drug companies be held accountable? Legally, pharmacovigilance (also known as phase 4 clinical trials) is not a requirement of all regulators, even though drug companies are required to report all adverse effects to the Medicines and Healthcare products Regulatory Agency (MHRA). So, to answer the question, it is currently enough for a drug to merely work in the UK, but drug companies should be held accountable not only for what happens following prescription, but also for ensuring that phase 4 clinical trials are conducted.

So why is this particularly important when considering new migraine drugs like fremanezumab? It boils down to one simple fact, although migraine attacks tend to gradually improve for most people, it takes many years, which means that the treatments tried during that time ought to be as safe as possible so that they can be prescribed responsibly and be of the maximum possible benefit to patients everywhere. Fortunately, in spite of a hiccup earlier in the year, the NICE appraisal was resumed and patients are now able to access CGRP treatments through their specialist headache clinic. mAbs have come a long way since 1975, but there is still more to be done, perhaps phase 4 trials will be the start.


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Published: 24 Mar 2021

About the author

Gabriella Santiago

Gabriella Santiago is a third year student studying Population Health and Medical Sciences (BSc) at Swansea University. She hopes to pursue a PhD after she graduates.

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