Additional effects of gepants on top of erenumab

Both rimegepant and olcegepant exert additional calcitonin gene-related peptide (CGRP) inhibiting effects on top of the maximum effect of erenumab in isolated human coronary arteries (HCA). This suggests that erenumab and gepants may have different mechanisms of action. This could imply that erenumab users might benefit from adding a gepant as an acute treatment.

Dr Tessa de Vries (Erasmus Medical Center, the Netherlands) explained that gepants and erenumab theoretically target the same receptor, CLR/RAMP1, so that no additional effects of a gepant on top of erenumab would be expected [1]. De Vries and colleagues put this to the test by studying the effect of erenumab in combination with rimegepant, olcegepant, or sumatriptan on CGRP-induced vasorelaxation in isolated human HCA. They used HCA segments from donors (11 women and 6 men; mean age 53 years).

The relaxation caused by CGRP in segments incubated with 3 µM erenumab was reversed by sumatriptan (134%), rimegepant (91%), and olcegepant (92%). The vasoconstrictive effects of sumatriptan were as expected, since it targets a different receptor: 5-HT18/1D(/1F). Unexpectedly, both rimegepant and olcegepant exerted additional CGRP-inhibiting effects on top of the maximum effect of erenumab. Olcegepant did not induce additional effects on top of erenumab for the agonists adrenomedullin and pramlintide. A possible explanation is that different receptor populations may mediate the effects of adrenomedullin, pramlintide, and CGRP.

Dr De Vries suggested 2 possible reasons why the 2 gepants exerted additional effects on top of erenumab. The first is that the mechanism of action of erenumab and gepants are not identical. “Maybe they target different receptors; for example, gepants may also target AMY1 or other receptors of the CGRP-receptor family that are not, or to a lesser extent, affected by erenumab.” It is known that rimegepant and olcegepant antagonism at the AMY1 receptor is 17-30 and about 150 times lower, respectively, compared with the CGRP receptor. The second explanation is that receptor internalisation is involved. “The CGRP receptor can still signal after internalisation, which plays a role in pain transmission. Maybe gepants can target the receptor even after internalisation, whereas the very large erenumab molecule cannot.”

The clinical relevance of these findings, said Dr De Vries, is that a patient taking erenumab as a prophylactic migraine treatment could benefit from taking a gepant as acute treatment, as gepants can induce additional receptor blockade on top of erenumab, regardless of the erenumab dosage. This might, however, result in additional safety concerns.

 

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   1. De Vries T. Differential mechanism of action of erenumab and gepants in human isolated coronary arteries. A11, EHC 2022, 07–10 December, Vienna, Austria.

 

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Posted on 5 January 20235 January 2023