Optimising anti-CGRP treatment response in migraine by studying predictors of response

Alicia AlpuenteMultiple randomised controlled trials support the safety and efficacy of CGRP mAbs as the first target-driven treatment for migraine prevention,1-9 and a growing body of real world evidence supports these findings and provides key information about the use of CGRP mAbs in a more heterogeneous population. However, as Dr Alicia Alpuente from Vall d’Hebron University Hospital, Barcelona, Spain, explains, the variability of patient response to CGRP mAbs10 and cost considerations make it important to optimise the use of these agents in clinical practice by studying predictors of response.


Clinical predictors of response to CGRP mAbs

The most affordable types of predictors of CGRP mAb response in clinical practice are based on clinical parameters, though factors related to demographic and clinical features are very diverse. For example, some studies have focused on predictors of negative or incomplete response to treatment, such as medication overuse, higher acute medication intake, a higher number of prior preventive treatment failures,11-13, presence of allodynia,14 psychiatric comorbidities15, or daily headache.16 Other studies have identified predictors of positive response to preventive treatment such as response to triptans,17 presence of unilateral localisation of pain, allodynia, osmophobia, unilateral autonomic symptoms, and so-called dopaminergic symptoms.16 However, it is interesting to know which patients with more typical migraine characteristics respond better to treatment. In this regard, it seems that symptoms related to peripheral sensitisation such as unilateral pain and unilateral cranial autonomic symptoms are predictors of ≥50% and ≥75%responses to CGRP-mAbs in high frequency episodic migraine (HFEM), whereas a combination of symptoms related to both peripheral sensitisation and central sensitisation (allodynia) are predictive in chronic migraine (CM).18


CGRP as a molecular predictor of response to CGRP mAbs

Although there is currently no reliable biomarker of migraine disease, the study of CGRP as a molecular predictor of response to CGRP therapies has started. In the first published study, salivary CGRP-like immunoreactivity (CGRP-LI) at baseline and the interaction of salivary CGRP and headache frequency at baseline were independent statistically significant predictors associated with response to erenumab.19 In patients with episodic migraine, higher basal salivary CGRP-LI levels were statistically significantly associated with a greater probability of ≥50% reduction in headache frequency. However, this was not seen in patients with CM. Interestingly, CGRP levels after three months of treatment with erenumab 140 mg were associated with the interaction between time of treatment, presence of depressive symptoms and headache frequency at baseline. After treatment, salivary CGRP-LI levels in patients across the spectrum of migraine frequency converged to similar CGRP-LI values in the absence of depressive symptoms. No statistically significant differences were found in CGRP-LI levels pre- and post-treatment. A further study found no statistically significant differences in serum CGRP-LI between baseline and after two to four weeks of treatment with erenumab 70 mg.20 Absolute reduction in monthly migraine days in the third month after treatment with erenumab 70 mg was associated with serum CGRP-LI levels at two to four weeks after starting treatment, but not with serum CGRP-LI levels at baseline.

Contradictory results between studies may be due to methodological differences, and the absence of standardised methods hampers comparisons between studies. Many factors concerning sample collection and processing can affect results, including heterogeneity of study population, type of biofluid collected, type of assay and methodology used, or the time of the migraine phase in which samples were collected. It is therefore essential to take into account all these factors when interpreting results.


Future perspectives

The possibility of measuring salivary CGRP in clinical practice is highly engaging. To develop CGRP as a reliable molecular predictor in clinical practice, it will be necessary to do further studies expanding the number and type of patients and collect long-term longitudinal samples. It will also be important to rigorously describe the methodology used in these studies.

Unfortunately, due to the complexity and heterogeneity of migraine, it is unlikely that a single parameter such as CGRP level will be sufficient to predict treatment response. However, studies investigating predictors of response represent a step forward in the development of both precision and personalised medicine for migraine, with potential for treatment optimisation, improvements in clinical outcomes, and reduction of costs.



Dr Alpuente has received honoraria as a speaker from AbbVie and for education from Novartis and Eli Lilly.




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