Effectiveness of Switching CGRP Monoclonal Antibodies in Non-Responder Patients in the UAE: A Retrospective Study

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The present retrospective, exploratory study focused on patients with episodic/chronic migraine who were treated with two or more GCRP mAbs. The primary focus was on the safety and effectiveness of switching between CGRP classes.

 

I believe the biggest limitation is the sample size (n=53, 20 chronic migraine patients). Because of this issue, the authors should emphasize (in the Abstract as well as in the main text – maybe in the Title) that this is preliminary data. 

 

Overall, the Results section and the Tables, Figures also need to be improved.

 

Abstract:

 

I believe the Abstract misses some important information which need to be included:

o   Galcanezumab, Eptinezumab targets the CGRP ligand and Erenumab targets CGRP receptors 

o   Fremanezumab is currently not available in the UAE (hence not part of the present study)

o   Please clarify what “CGRP/R CGRP/L” mean even in the Abstract

o  Add more information on the Methods and report the main Results with numbers and statistical tests 

         Please add all the information above (at least in parentheses).

 

Introduction:

 

-       “Thus, numerous studies have emerged within the past decade investigating the effectiveness of monoclonal antibodies (mAbs) as CGRP receptor antagonists in migraine treatment” – Is there any review paper/metanalysis? If yes, please add as a reference here

-       “One real-world analysis study demonstrated that one-third of Erenumab non-responders achieved >30%  response after switching to another CGRP-mAb [19].” – Based on the Introduction, Erenumab seems to be the first choice of treatment in general (Is this the case?), but this needs to be clearly stated and explained in the text. If not, please consider rewriting this section. 

-       The study does not have clear hypotheses which need to be included. (Although the author did write one in the Discussion. That should be stated here as well)

 

 Methods:

 

-       Was the intensity of headache pain recorded? How? This should be added to the Methods (and Results).

-       Why is switching allowed after 3-month treatment (and not after e.g., 6-month, 1-year)? What is the rationale behind this decision? Is there a protocol to follow? Please, clarify in the text (with refences if possible). 

-       Please add the reference for ICHD-3

-       “who had a diagnosis of either EM or CM” – With or without aura? Please clarify.

-       This section needs a separate Statistical analysis section.

 

Results:

-       Table 2/Migraine features: Please add aura symptoms, pain intensity, associated symptoms etc. if possible.

-       Figure 2 and Table 3: The titles need to be changed (please do not use short forms in the titles of the Tables and Figures) and include more information about the Results in the Figure 2 legend (and in all the other Figures). 

-       Clarify what CGRP/R and /L mean in the Note section under the Table and in all the Figure legends

-       Please add error bars representing standard error of mean to the figures (where applicable)

-       It would be interesting to see a Summary table about the reasons the switched happened for all the patients (even if some data are missing) 

-       Table 3: some patients seem to have 1 MMD at baseline. Was CGRP mAbs therapy necessary for them? Please discuss in the manuscript what the protocol is for episodic migraine in the present patient group/population.

-       Please add the number of patients to Figure 2 and Table 3 (n=). Maybe I misunderstood but it seems that not everyone was followed 6 months after the first treatment (Pre-switch M6 MMD): According to the Methods section, patients received the first treatment for a minimum of 3 months. Please clarify. 

-       How much time did the patients have between switching? 1 month? Please clarify in the text. Based on Table 3, the baseline went up after switching. Please include this information in the Figure legend or the Note section under Table 3.

-       Please correct 0.000 p values (it should be < 0.001)

 

In general, Figure legends, titles of the Tables, and Notes under the Tables should describe and summarize the results.

 

Discussion:

 

-       “Indeed, prior to conducting the study, we expected switching between different classes of CGRP mAbs could yield improved results, especially for those switching from L to R or vice versa.” – Is this the hypotheses of the study? Then this should be stated in the Introduction/Aim of the study. The Introduction should also support this hypothesis. 

 

-       “patients included in the analysis completed at least 3 months of treatment before switching” – What do the authors think about the possibility that 6-month or 1-year treatment could be more effective? And maybe use that as an exclusion criteria. 
Again, I think this should be discussed with some references. There are also late responders:

 

E.g., 

Barbanti P, Aurilia C, Egeo G, Torelli P, Proietti S, Cevoli S, Bonassi S (2023) Italian Migraine Registry study group. Late response to Anti-CGRP monoclonal antibodies in migraine: a multicenter prospective observational study. Neurology 101(11):482–488 

 

Vernieri F, Brunelli N, Messina R, Costa CM, Colombo B, Torelli P, et al. Discontinuing monoclonal antibodies targeting CGRP pathway after one-year treatment: an observational longitudinal cohort study. J Headache Pain.

Comments on the Quality of English Language

There are some typos in the text and Figures, please check.

E.g., 4c: Swithced, GGRP

 

Author Response

Please see the attachment. Thank you.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

I find the methods and results difficult to follow.

It seems that the patients included in this study were considered to have failed their initial CGRP Ab treatment. Yet from figure 2 and table 2, there seems to have been a very substantial reduction in MMDs at 3 and 6 months after the initial treatment. However, by the second baseline period MMDs had deteriorated again.  Were patients withdrawn from their first treatment to measure a second baseline or were they continued on the first treatment until a decision was made to switch and then put straight onto the second agent? In other words, was the deterioration between 6 months after first treatment and second baseline due to withdrawal of treatment or declining efficacy.

The authors should indicate why patients with apparently good results for the first 6 months were considered treatment failures. The duration of the first treatment should be stated (there will be a range); was there reduction in efficacy over time in a large group of patients? Or were the patients who elected to switch partial responders who were hoping to be better still after switching?

The response in the ligand to ligand group may be attributable to switching from S/C to I/V, either because of pharmacokinetic reasons or from enhanced placebo effect. This should be discussed.

Suboptimal response to CGRP Ab treatment in an individual may theoretically result from:
1. Intrinsic inadequate responsiveness to all CGRP treatments
2. Idiosyncratic better response to ligand blockers than to receptor blockers
3. Idiosyncratic better response to receptor blockers than to ligand blockers
4. Idiosyncratic better response to I/V than to S/C treatment
5. Idiosyncratic better response to S/C than to I/V treatment

On this basis, it would be helpful to know what proportions of those switching in each category regarded the second treatment as better than, worse than or no different from the first. In real life, patients with a partial response face this decision frequently and, if for example a third were in each group (better, worse, no change) the overall results (when analysed by mean MMDs or some other aggregated statistic) would on average suggest that there was no net benefit in switching, while in fact a third of patients would clearly benefit and the other two thirds would be no worse off (as they could revert to the original treatment).

This issue could be usefully addressed by tabulating the patients' global impression of change from switching.

Comments on the Quality of English Language

Some minor glitches. For example in line 35, "intrigue" is an unusual choice of word: "interest" is probably better.

Author Response

Please see the attachment. Thank You.

Author Response File: Author Response.pdf