A Ret ro spec tive Anal y sis of Mi graine Pro phy laxis with Anti-CGRP Monoclonal An ti bod ies at the Hos pi tal of Lith u a nian Uni ver sity of Health Sci ences Kaunas Clin ics

for both mi graine types. It was ob served that more than half of the pa tients re quired a dose in crease when treated with erenumab 70 mg, es pe cially in CM group.

role in find ing spe cific ther a peu tics med i ca tion for migraine pre ven tion.
The calcitonin gene-re lated pep tide (CGRP) an tag onists were ap proved in 2018 by the United States Food and Drug Ad min is tra tion and the Eu ro pean Med i cines Agency.The re cent in tro duc tion of monoclonal an ti bod ies against the CGRP path way has wid ened the spec trum of treat ment op tions avail able for pa tients with CM and ep isodic mi graine (EM) [4,5].Anti-CGRP monoclonal an tibod ies (mAbs) for mi graine pre ven tion reached the Lith ua nian mar ket in De cem ber 2018.Re im burse ment of the first drug in this class, erenumab, started in May 2020.The sec ond med i ca tion, fremanezumab, has been re im bursed since Jan u ary 2021.In Lith u a nia, anti-CGRP mAbs (erenumab, fremanezumab) is usu ally given once a month and is ad min is tered sub cu ta ne ously.Pri mary ef fi cacy should be eval u ated at 3 and 6 months.It is rec om mended to con sider the need to con tinue treat ment af ter 12 months [6].Erenumab can be ad min is tered at a dose of 70 mg or 140 mg, but if a suf fi cient clin i cal ef fect is not ob tained, a lower dose can be in creased to 140 mg [7].Fremanezumab can be given as a monthly dose of 225 mg or quar terly at three times higher dose (675 mg) [8].
The pro phy lac tic treat ment of mi graine with anti-CGRP mAbs has only re cently been in tro duced, and there is a grow ing body of ev i dence dem on strat ing their ef fi cacy both in clin i cal tri als and in daily prac tice.How ever, there are few stud ies eval u at ing the ef fec tive ness of erenumab and fremanezumab in Lith u a nia.

AIM
To eval u ate and com pare the ef fi cacy and side-ef fects of treatment with anti-CGRP mAbs (erenumab, fremanezumab) in pa tients with CM and EM.

MA TE RI ALS AND METH ODS
A to tal of 85 mi graine pa tients who at tended the Neu rology Clinic of the Hos pi tal of Lith u a nian Uni ver sity of Health Sci ences Kaunas Clin ics be tween Sep tem ber 2019 and De cem ber 2021 were in cluded in the anal y sis.The study was au tho rized by the Bioethics Cen tre un der No BEC-MF-84.
De mo graphic and clin i cal data were col lected by review ing out pa tient visit re cords: gen der and age of the patient, du ra tion of ill ness, symp toms of aura, prior preventive treat ment, anti-CGRP mAbs (erenumab, fremanezumab), monthly head ache days (MHDs) be fore anti-CGRP mAbs and at 3 and 6 months, the dose of erenumab (70 or 140 mg), dose change and rea sons for the change of anti-CGRP mAbs, ad verse ef fects of anti-CGRP mAbs.No data were col lected on med i ca tion over use, num ber of mi graine days, monthly mi graine-spe cific med i ca tion days, tran si tion from CM to EM.The sub jects were di vided into two groups de pend ing on the course of the dis ease: EM or CM.CM group con sisted of pa tients with head aches last ing ³15 days/month, 3 months or more.EM group in cluded pa tients who ex pe ri enced headaches for 0-14 days/month [9].The sub jects were also divided into groups ac cord ing to the type of anti-CGRP mAbs used for pro phy lac tic treat ment of mi graine (erenumab or fremanezumab).The ef fi cacy of pre ven tive mi graine treat ment with anti-CGRP mAbs was as sessed 3 and 6 months af ter the start of treat ment.MHDs re duction of ³50% was con sid ered a good re sponse to treat ment.If MHDs de creased by <50%, a suf fi cient re sponse was not achieved.Cases where treat ment was dis con tin ued due to ad verse med i ca tions re ac tions were in cluded sep arately.

In clu sion cri te ria:
Sub jects aged 18 years or older who had re ceived pro phylac tic mi graine treat ment with anti-CGRP mAbs for at least 6 months and whose de tailed med i cal re cords were found at base line of anti-CGRP mAbs at 3 and 6 months after the start of treat ment.Cases where treat ment was discon tin ued ear lier than 6 months due to an ad verse event or in suf fi cient re sponse were also in cluded.

Ex clu sion cri te ria:
Pa tients were ex cluded if they were un der 18 years of age and it was not pos si ble to eval u ate the ef fect of treat ment af ter 3 and 6 months.

Sta tis ti cal anal y sis
Sta tis ti cal anal y sis of the data was per formed us ing SPSS (Sta tis ti cal Pack age for the So cial Sci ences) Sta tis tics 27.0 soft ware.The re sults are pre sented as per cent ages, mean with stan dard de vi a tion (±SD), me dian with interquartile range (IQR).Anal y sis of qual i ta tive data was per formed us ing c 2 test of ho mo ge ne ity and Fisher's ex act test.Quanti ta tive data were an a lyzed us ing Stu dent's t-test and Mann-Whit ney U-test.The dif fer ence was con sid ered statis ti cally sig nif i cant at p<0.05.

RE SULTS
A to tal of 85 mi graine pa tients were in cluded in the study; 75 (88.2%)were women and 10 (11.8%) were men.The mean age of migraineurs was 43.4 years (±11.8).Over all, the dis ease du ra tion me dian was 19 years (IQR: 8-32).A detailed com par i son of ma jor pa tient char ac ter is tics between EM and CM is shown in Table .Be fore treat ment with anti-CGRP mAbs, 63.5% of pa tients re ceived other pro phy lac tic treat ment (31.8% of pa tients were treated with topiramate, 20.0% with propranolol, 20.0% with amitriptyline, 9.4% with pregabalin, 7.1% with valproic acid, and 5.9% with escitalopram).Pro phy lac tic treat ment with sin gle drug was tried by 32.9% of pa tients, two or more drugs by 30.6% of pa tients.30 (55.6%) pa tients had no response and 13 (24.1%)pa tients ex pe ri enced ad verse ef fects (drows i ness, diz zi ness, bradycardia, hypotension, sleep dis tur bances, joint pains) that led to the with drawal of pre vi ously used drugs.
When com par ing MHDs between EM and CM pa tients before anti-CGRP mAbs and af ter start ing anti-CGRP mAbs at 3 and 6 months, the num ber of MHDs re mained sig nif i cantly higher in CM pa tients (p<0.001,p<0.001, and p=0.020, re spectively), but the de crease was propor tion ally sim i lar in both groups (Fig. 1).As dem on strated in Figure 2, al though slightly better treat ment out comes were observed in the EM group (84.8% of pa tients achiev ing a good response to anti-CGRP mAbs at 3 months af ter start ing treat ment) than in the CM group (69.2%), the dif fer ence was not sta tis tically sig nif i cant (p=0.319).Af ter 6 months of treat ment, the dif ference be tween the groups decreased (75.8% vs. 65.4%,p=0.727) (Fig. 2).Over the en tire fol low-up pe riod, the re sponse rate in the CM group (-3.8%) decreased less than in the EM group (-9%).
A to tal of 67 (78.8%) pa tients re ceived erenumab as the first anti-CGRP mAbs for mi graine pro phy laxis, and 18 (21.2%)patients re ceived fremanezumab (monthly).In terms of MHDs before start ing anti-CGRP mAbs, Fig. 1.Changes of MHDs be fore treat ment, at 3 and 6 months Mann-Whit ney U-test was used to com pare monthly head ache days (MHDs) be tween chronic mi graine (CM) and ep i sodic mi graine (EM) groups, fremanezumab and erenumab.All bars rep re sent me dian (interquartile range (IQR)), min i mal and max i mal val ues.***p<0.001com par ing MHDs be tween CM and EM groups be fore anti-calcitonin gene-related pep tide monoclonal an ti bod ies (anti-CGRP mAbs), at 3 months, **p=0.020com par ing MHDs be tween CM and EM groups us ing anti-CGRP mAbs at 6 months.

Fig. 2. Com par i of re duc tion of 50% or greater at 3 and 6 months
The c 2 test of ho mo ge ne ity was used to com pare monthly head ache days (MHDs) re duc tion of 50% or greater be tween fremanezumab and erenumab groups.All col umns rep re sent per centage of the re sponse (p>0.05).Ab bre vi a tions: CM -chronic mi graine; EM -ep i sodic mi graine.there was no sig nif i cant dif fer ence be tween erenumab and fremanezumab groups (me dian 15 days, p=0.883).Sim ilarly, the groups did not dif fer in to tal du ra tion of dis ease (me dian 18 (IQR 7-30.75) vs. 27 (IQR 10-31.75),p=0.528) and pres ence of aura symp toms (37.3 vs. 33.3%,p=0.755).As to anti-CGRP mAbs ef fi cacy at 3 months, the re sponse rate was slightly better in the fremanezumab group than in the erenumab group (83.3% vs. 73.1% of patients, re spec tively), but the dif fer ence was not sig nif i cant (p=0.541) (Fig. 2).At 6 months af ter ini ti a tion of treatment, the re sponse rate to fremanezumab re mained the same (83.3%),while a de crease was ob served in the erenumab group (65.7%); how ever, the dif fer ence between the groups did not reach a sta tis ti cally sig nif i cant level (p=0.149)(Fig. 2).Erenumab was ini ti ated at a dose of 70 mg in 41 patients and 140 mg in 26 pa tients.In 24 (58.5%)pa tients initially treated with 70 mg erenumab, af ter 2-6 months (median: 3 months (IQR: 2-6)), it was de cided to in crease the dose to 140 mg due to in suf fi cient ef fect.In 12 (50%) of these pa tients, the ef fect was achieved af ter in creas ing the dose, and in 4 pa tients who did not re spond to treat ment, it was de cided to switch from erenumab to fremanezumab.When com par ing CM and EM groups, the ini tial dose was in creased more of ten in pa tients with CM (14 (77.8%) vs. 10 (43.5%), p=0.027).De tailed in for ma tion about erenumab dose changes and ef fect as sess ment is shown in Fig ure 3.
Treat ment with erenumab was dis con tin ued in a to tal of 10 (14.9%) pa tients, two af ter 3 months and eight af ter 6 months.The main rea son for dis con tinu a tion was med ica tion in ef fec tive ness or sec ond ary loss of re sponse.Adverse events such as con sti pa tion, weight gain, and hair loss led to the dis con tinu a tion of erenumab in only one patient (with con com i tant ob ser va tion of lack of ef fi cacy).Fremanezumab was dis con tin ued in a to tal of 3 (16.7%)pa tients, two af ter 3 months and one af ter 6 months; the main rea sons for dis con tinu a tion were ad verse events such as lo cal al ler gic re ac tions/al ler gic der ma ti tis and hair loss; fremanezumab was not dis con tin ued due to lack of ef ficacy.As sess ing the over all in ci dence of ad verse events, it was found that fremanezumab (22.2%) had a slightly higher in ci dence of ad verse ef fects than erenumab (3%, p=0.017).

DIS CUS SION
A re cent study showed that the ef fi cacy of erenumab treatment be tween CM and EM was sim i lar, with slightly better re sults ob served in the EM group.Sim i lar re sults for erenumab treat ment were re ported by Schoenen et al. [10], a sig nif i cant dif fer ence be tween EM and CM was observed only at 3 months, af ter wards the dif fer ence dis appeared (at 6, 9 and 12 months).How ever, there is cur rently grow ing ev i dence that out come of treat ment also de pends on the se lec tion of dose [5,11].Our study found that 58.5% of pa tients who started erenumab at 70 mg needed a dose in crease, es pe cially pa tients with CM.How ever, we were un able to as sess the ef fect of drug dose on ef fi cacy due to the small num ber of pa tients.Al though at least 3 months af ter the ini ti a tion of erenumab for mi graine preven tion are rec om mended be fore the as sess ment of response [12], in our clinic the dose was some times changed af ter 2 months.Tal bot et al. [13] ob tained sim i lar re sults in their study: of 98 sub jects, 57% re ceived a dose es ca la tion af ter 2 months.How ever, ac cord ing to dif fer ent au thors, 30-74.1% of pa tients re quire a dose in crease [13][14][15][16][17]. Also, pre vi ous stud ies re ported a higher ef fi cacy of erenumab at a dose of 140 mg com pared to 70 mg [18,19].The choice be tween erenumab 70 mg and 140 mg may be based on fac tors that in di cate dif fi cult-to-treat dis ease.These in clude pa tients in whom prior pre ven tive treat ment were un suc cess ful and pa tients with acute med i ca tion over use [20][21][22].Ac cord ing to other re search ers, erenumab 140 mg may be better for pre vent ing dis ease pro gres sion by re duc ing the po ten tial of con ver sion from EM to CM, for in creas ing the like li hood of re ver sion from CM to EM, and for in creas ing the prob a bil ity of re vers ing acute med i ca tion over use to non-over use of acute med i cation [22,23].Erenumab 140 mg is the start ing dose for some pa tients with dif fi cult-to-treat dis ease, prior treatment fail ures, and for those most at of con ver sion from EM to CM [7].
Our study shows that when com par ing the ef fi cacy of fremanezumab be tween CM and EM, slightly better results were ob served in the EM group, but there was no statis ti cally sig nif i cant dif fer ence be tween the groups.Goadsby et al. [24] found a lower ef fi cacy of fremanezumab, but in our study, the ef fect was slightly better in the EM group.The pre ci sion of our re sults may have been in flu enced by a small num ber of subjects (n=18).When com par ing the ef fi cacy of erenumab and fremanezumab, a slightly better re sponse was achieved in the fremanezumab group.A meta-anal y sis by Soni et al. [25] showed that fremanezumab is slightly more ef fec tive than erenumab in the treat ment of CM, but no statis ti cally sig nif i cant dif fer ence was ob tained in their study ei ther.
When com par ing the in ci dence of ad verse events between fremanezumab and erenumab, a sta tis ti cally sig nifi cant dif fer ence was found, and fremanezumab dis continu a tion due to ad verse events was more com mon.How -ever, the lit er a ture shows that fremanezumab does not have a dif fer ent rate of ad verse re ac tions than pla cebo or erenumab [25,26].A study con ducted in Ja pan and Ko rea [26] showed that fremanezumab was well tol er ated and the in ci dence of ad verse events, in clud ing in jec tion site re ac tions, was sim i lar to pla cebo (at least one ad verse event oc curred in 61.4% (n=232) of fremanezumab treated pa tients and 61.8% (n=118) of pla cebo treated patients).The dis crep ancy in our study may be due to the method used (ret ro spec tive data anal y sis), as pa tients who ex pe ri enced mi nor side ef fects may not have re ported this to their phy si cian.Al ter na tively, the re sults can be explained by the fact that the de ci sion to dis con tinue tak ing fremanezumab could have been made by the pa tient without an ob jec tive as sess ment of the se ver ity of the side-effects and the ben e fit-risk ra tio (in the study, fremanezumab treat ment was stopped due to lo cal ized aller gic re ac tions and hair loss).
The main lim i ta tions of our study are that the data were col lected from med i cal re cords, a small sam ple size, es pe cially in pa tients treated with fremanezumab.Also, pa tients were con sulted by dif fer ent doc tors, so there may be dif fer ent in ter pre ta tions of the clin i cal effect, and due to fre quent and het er o ge neous dose changes (es ca la tion and de-es ca la tion), com par i sons be tween 70 mg and 140 mg were not pos si ble.The ad van tage of our study is its nov elty; this is the first study as sess ing the ef fec tive ness of anti-CGRP moncolonal an ti bod ies in our clinic, al though this is not the first study on this topic in Lith u a nia.Data of mi graine treat ment with erenumab from an other Lith u a nian head ache cen ter have al ready been pub lished [27].All the data col lected will be use ful in daily clin i cal prac tice, as anti-CGRP moncolonal an tibod ies have re cently been in tro duced for mi graine preven tion.

CON CLU SIONS
1.Both anti-CGRP mAbs, erenumab and fremanezumab, are ef fec tive and equiv a lent in the treat ment of chronic and ep i sodic mi graine.2. The ef fi cacy of anti-CGRP mAbs is not sig nif i cantly af fected by dis ease phe no type.3.More than half of the pa tients who started treat ment with erenumab 70 mg re quired dose es ca la tion, es pecially in CM group.4. Erenumab and fremanezumab are safe in adults, adverse re ac tions are rare but more com mon with fremanezumab.

Ac knowl edg ments
We would like to thank all the doc tors who have worked with mi graine pa tients in our clinic for us ing the med i cal re cords they have col lected.Rink ti ir ana li zuo ti de mo gra finiai bei kli ni ki niai li gos duo me nys.Ti ria mie ji su skirs ty ti á gru pes pa gal mig re nos ei gà -LM ir epi zodi nae mig re nà (EM), bei pa gal mig re nos pro fi lak ti niam gy dy mui skir tà vais tà -ere nu ma bà ar ba fre ma ne zu ma bà.Gy dy mo efek tyvu mas ver tin tas pra ëjus 3 ir 6 mën.nuo gy dy mo pra dþios.Ge ru at sa ku lai ky tas gal vos skaus mo (GS) die nø skai èiaus su ma þë jimas ³50 %.Sta tis ti në duo me nø ana li zë at lik ta nau do jant SPSS Sta tis tics 27.0 pro gra mà, c 2 ho mo ge nið ku mo, Fi ðe rio, Stju den to t ir Ma no-Vit nio kri te ri jus.