Migraine 09 Jul, 2024 Read Time: 5 mins

Ongoing studies of CGRP antagonists and monoclonal antibodies

In the past few years, acute and preventive migraine treatments have included the use of oral calcitonin gene-related protein (CGRP) receptor antagonists (gepants) and monoclonal antibodies (mAbs) targeting the calcitonin gene-related protein (CGRP) or its receptor. As with many treatments, response to such drugs varies. ‘Super responders’ to anti-CGRP mAbs can differ from ‘super non-responders’ in that they generally have experienced migraine for a shorter time and, when the drug is administered, they do not develop headaches following triggers or when experiencing prodromal symptoms. For patients whose anti-CGRP mAb treatment failed to rid them of migraine, case reports, safety studies, and pre-clinical research suggest adding a gepant may be of use. However, clinical trials of such combinations need to be carried out. Adequately powered head-to-head trials of migraine treatments are also lacking. Moreover, in response to findings such as sex-related differences in triptan response and side effects, analyses that stratify patients by characteristics such as sex, age, body weight, and genetics are needed. Professor Hans-Christoph Diener, from the Institute for Epidemiology at the University Duisburg-Essen in Germany, Rami Burstein, a Professor of Anaesthesia and Neuroscience at the Harvard Medical School in the US, and Antoinette Maassen van den Brink, an Associate Professor at the Erasmus University Medical Center Department of Pharmacology in The Netherlands, discussed these issues and more at the 2023 International Headache Congress.

CGRP ‘super responders’ and ‘super non-responders’

In recent years, monoclonal antibodies (mAbs) targeting the calcitonin gene-related protein (CGRP) or its receptor have been added to the migraine treatment armamentarium for preventive treatment.1 As shown in one study, while some patients may have no response to an anti-CGRP mAb, others can be categorised as ‘super-responders.’ These latter patients are typically those who have experienced migraine for fewer years than those who don’t respond. While prodromal symptoms following anti-CGRP mAb administration – including cognitive impairment, photophobia, fatigue, and aura – may still occur, they are significantly less likely to be followed by a headache in super-responders compared to ‘super non-responders.’ Triggers – including sleep problems, not drinking enough fluids, and being too hot – are also less likely to induce migraine in ‘super responders’ following anti-CGRP mAb administration.2 

While ‘super responders’ to migraine treatment can be identified, work is needed to provide treatment for ‘non-responders’

Non-responders to anti-CGRP mAbs have been shown in open-label observational studies to potentially benefit from switching to another anti-CGRP mAb, such as one with a slightly different mechanism.3 However, Professor Diener calls for proper randomized controlled trials to be carried out with regards to treatment switching. Similarly, there is a need for head-to-head studies of migraine treatments with regards to not only efficacy and safety, but also cost-effectiveness.

Drug-drug combinations

A case report suggests that adding acute migraine treatment with a CGRP receptor antagonist (gepant) to preventive treatment with an anti-CGRP mAb may be beneficial.4 Pharmacokinetic and safety studies, though small, suggest that this combination may be feasible from a drug-drug interaction point of view.5,6

To investigate how a gepant/anti-CGRP mAb combination may work, Professor van den Brink and her colleagues have used human coronary arteries. Work by Ms Tessa de Vries, from the Erasmus University Medical Center Department of Pharmacology and Vascular Medicine in The Netherlands, showed that anti-CGRP mAbs have a maximal effect on artery relaxation, such that administering higher doses once this has been achieved will not increase the effect. However, artery relaxation can be enhanced by the addition of a gepant.7 Professor van den Brink postulated that this may be due to the action of gepants on amylin 1 (AMY1) receptors,8 adding to the action of anti-CGRP mAbs on CGRP receptors, and/or it may be that gepants can function at internalised CGRP receptors, where anti-CGRP mAbs have no effect.

Randomized clinical trials are needed to assess gepant/anti-CGRP mAb combinations

Further work regarding anti-CGRP mAbs and gepants has been undertaken to elucidate their mechanisms of action. One finding is that anti-CGRP mAbs may block activation of thinly myelinated Ad meningeal nociceptors and, consequently, high threshold spinal trigeminal nucleus neurons.9 This is different from the mechanism of gepants, which, attenuate early activation of unmyelinated c-fibres (wide-dynamic range neurons) and show delayed attenuation of Ad fibre activity.10 

The need to stratify the effect and side effects of gepants and anti-CGRP mAbs 

Meta-analyses of clinical trial data show that there are differences in the efficacy of triptans when female and male patients are analysed separately.11 This may be due to differences in drug metabolism and also in drug distribution, due to factors such as body fat variances in female and male clinical trial participants. These differences can lead to variance not only in efficacy, but also in side-effect profile.12 Similarly, for gepants and anti-CGRP mAbs, there may be pharmacokinetic differences according to factors such as age, sex, body weight, and genetics.13 Despite this, Professor van den Brink believes that clinical trials of these treatments may not have stratified participants by these differences, or if a post-hoc analysis was carried out to examine these factors, it may not have been adequately powered. 

Investigations of migraine treatments need to take into account factors such as sex, genetics, and weight

Another finding regarding anti-CGRP mAbs is that, while treatment emergent adverse events and treatment termination typically show similarity between these drugs and placebo,14 one more rare adverse event to be aware of, as shown in one anti-CGRP mAb follow-up study, is blood pressure increases.15 Another potential adverse event following anti-CGRP mAb administration, found in case-studies, is non-serious alopecia.16

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

References

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  3. Lambru G, et al. Long-term effect of switching from an anti-CGRP receptor to an anti-CGRP ligand antibody in treatment-refractory chronic migraine: A prospective real-world analysis. Neurotherapeutics 2023;20:1284−93.
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