Real-world experience with new migraine treatments in Brazil Preliminary results

Introduction Migraine is a highly prevalent disorder. Current treatments are far from desired regarding efficacy and tolerability. Recent knowledge has been indicating targets whose antagonism may improve outcomes. Blocking CGRP or its receptor with monoclonal antibodies (mAb) can interfere with migraine mechanisms and decrease the frequency of attacks. Erenumab, galcanezumab, fremanezumab and epitnezumab were recently approved for migraine treatment and the first three are available in Brazil. Although the figures of efficacy were not astonishing, tolerability and higher adherence were demonstrated. However, real-world experience is limited in Brazil, since these new therapies have been used for only a year. Objective We present a summary of pivotal studies with the four mAb and preliminary results of this short-term option for migraine in real-world Brazilian patients. Methods One hundred twelve episodic or chronic migraineurs received the prescription of a mAb during the last 12 months in a tertiary center. This initial study was performed with 83 patients who should have taken, at the time of this writing, at least three-monthly doses of a mAb, which was chosen by a neurologist with full time dedication to headache medicine. Results Sixty-four women (77.1%) and 19 men (22.9%), with episodic (n=49; 59%) or chronic migraine (n=34; 41%), mean age of 43.6 years and mean headache history of 26.2 years were retrospectively studied. Baseline frequency was 14.8 headache days/month in the three months prior to the mAb use. Erenumab was prescribed to 40 (48.2%) patients; galcanezumab was given to 37 (44.6%) patients and fremanezumab was prescribed to 6 (7.2%) migraineurs. The mean headache frequency among the 77 patients who returned was reduced to 5.6 headache days/month in the following three months. Considering the headache frequency reduction of ≥50%, 44 (57%) migraine sufferers achieved a meaningful decrease. Mild adverse events were presented by 24.6% of the patients. Conclusion The authors present the first Brazilian experience in real-world patients using different mAbs in migraineurs' preventive treatment.


Introduction
M igraine is a highly prevalent neurological disorder. 1 It causes substantial burden, but treatments, especially preventive, were chosen by serendipity. 1,2 Despite effectiveness, at least partial, of numerous drugs, outcomes were distant from the expected by patients and treating physicians. Poor adherence due to tolerability issues and limited efficacy were commonly seen. 2,3 The knowledge about migraine pathophysiology is still uncertain. 4,5 Peptides involved in the complex process of migraine attacks, such as calcitonin gene-related peptide (CGRP), have been implicated and identified as targets for migraine therapies. 4,5 CGRP is a 37-amino acid peptide densely present in the hypothalamus, thalamus and cerebellum as well as in sensory fibers and neurons involved in pain transmission at dorsal root ganglia and trigeminal ganglia. In addition, CGRP is also present in the peripheral nervous system. 4,5 The binding receptor of CGRP, described as a G-protein coupled receptor, has two subunits composed by a calcitonin receptor-like subunit (CLR) and an activity-modifying protein 1 subunit known as RAMP1. 6 The critical role of this peptide in migraine has been emphasized by the fact that its serum levels are elevated in episodic migraine attacks, the intravenous infusion of CGRP triggers attacks in migraineurs and CGRP concentrations in jugular veins blood rise during headache attacks of migraine. Additionally, CGRP serum level decreases with symptomatic relief of the headache. 6,7 There are different antagonists of the CGRP or its receptor.
The last 20 years of research have identified potential agents either for the acute treatment as well as for the prevention of migraine. 4,5,7,8,9 Specifically for migraine prevention, biological options such as monoclonal antibodies anti-CGRP or its receptor started to be developed and four were recently approved by the FDA and Anvisa. 7,8,10

New therapies
Four monoclonal antibodies (mAb) anti-CGRP were approved for migraine prevention during the last three years. Commercially, there are three already available in Brazil. Erenumab is the only monoclonal antibody against the CGRP receptor whereas galcanezumab, fremanezumab and epitnezumab act on the peptide CGRP itself. 8 The latter is likely to be launched in Brazil soon.
There is a body of excitement regarding these new treatment options. All four mAb have long half-lifes, restricted tissue penetrance and highly selective affinity for the CGRP itself or its receptor. Therefore, it has become the center of the upcoming arsenal, although CGRP nerve endings are extraluminal in most tissues, which may impair and limit its efficacy. 4,5 Two phase 3 pivotal registration trials were recently published with erenumab. 11,12 The STRIVE (Study to Evaluate the Efficacy and Safety of Erenumab in Migraine Prevention) trial evaluated subjects presenting 4-14 migraine days/month during 6 months in three arms. Among the 955 randomized patients, 319 received 140 mg, 317 received 70 mg and 319 received placebo in monthly subcutaneous injections. In the primary endpoint of reduction in mean migraine days per month, compared to the previous 3-month baseline period, the 140 mg group had a higher reduction of 3.7 days. The 70 mg dose group reduced headache frequency by 3.2 days and placebo group of 1.8 days (p<.001 for each dose vs. placebo). In the secondary endpoints of ≥50% responder rate in mean monthly migraine days, days with use of migraine-specific medications and changes of score for everyday activities and general physical impairment, both doses were significantly better than placebo. 11 The second phase 3 pivotal study included 570 patients who were treated for 3 months either with the 70 mg-dose or placebo. The change in mean monthly migraine days from weeks 9-12 compared to the baseline was also the primary endpoint.
Erenumab lead to a mean reduction of 2.9 days vs. 1.8 days of the placebo group (p<.001).
In both trials, no serious adverse events were observed, but injection-site reactions or local pain were presented by 3.2% to 6% of those having used erenumab. Mild arthralgia and bothersome constipation were also observed with erenumab in the STRIVE study. 12 Fremanezumab was the second mAb approved by the FDA, but the third launched in Brazil. The trials involved episodic migraine sufferers, high-frequency episodic migraineurs and chronic migraineurs. In high-frequency migraineurs, different doses were used in patients with 8-14 headache days during a 4-week baseline period, who were randomized to receive either 675 mg (followed by two placebo doses), 225 mg monthly doses or placebo every 4 weeks during the study timeframe of 12 weeks. 13 Efficacy endpoint was measured by the change in number of migraine days during the weeks 9-12 compared to the frequency baseline. Both doses promoted significantly greater reductions compared to placebo. 13 The monthly doses of 225 mg resulted in a reduction of -6.27 vs. -3.46 of the placebo and 675 mg resulted in a reduction of 6.09 vs. 3.46 days of the placebo (p<.0001). 13 In a pivotal phase 3 registration trial, the HALO study, the mean change in migraine days, was compared among 875 patients (742 women; 133 men) with mean age of 41.8 years.
The patients who received 225 mg per month (3 doses) had a reduction from 8.9 days to 4.9 days vs. 9. placebo group reduced migraine days from 9.1 days to 6.5 days (p<.001). 14 Tolerability issues were not different between placebo and treatment groups and erythema and induration at injection sites (n=3 and 2, respectively) were the most frequent adverse events presented by the studied patients. 14 Fremanezumab was also evaluated for the prevention of chronic or placebo (375 patients). 16 The change in headache days in which migraine-specific medications were used was one of the primary endpoints. 16 Baseline frequency of migraine days were 16.4 days for the placebo group, 16.2 days for the quarterly dose group and 16 days for the monthly dose group. Fremanezumab every month resulted in migraine days reduction of 4.6 ± 0.3. Fremanezumab quarterly showed a reduction of 4.3 ± 0.3 days and the placebo patients revealed a 2.5 ± 0.3 reduction in headache days (p<.001 for both comparisons with placebo).
Galcanezumab was studied in two phase 3 trials (EVOLVE1 and EVOLVE2) for the preventive treatment of migraine. 17,18 The EVOLVE1 trial was a randomized, double-blind, placebo-controlled comparison between galcanezumab 120 mg, 240 mg or placebo. The patients received monthly doses for 6 months. Patients (18-65 years) had a minimum of 1-year history of migraine and 4-14 migraine headache days per month. A total of 858 patients were included in the intention-to-treat population. Contrarily to other mAbs studies, no other preventive medications were allowed during the study. 17 Primary outcome was the mean change in number of monthly migraine headache days and secondary endpoints were a frequency reduction of at least 50%, of at least 75%, and of 100%. In addition, migraine headache days with acute medication utilization was also compared between goups. 17 The primary endpoint was achieved for both galcanezumab doses and the active treatment significantly reduced monthly migraine headache days by 4.7 days (120 mg) and by 4.6 days (240 mg) compared with placebo (2.8 days) (for both p<.001). Secondary endpoints were significantly superior to placebo either for galcanezumab 120 mg and 240 mg. 17 The EVOLVE 2 involved 915 intention-to-treat patients. They either received monthly subcutaneous injections of placebo (n = 461), galcanezumab 120 mg (n = 231) or 240 mg (n = 223) during 6 months. 18 The primary endpoint was the mean change in monthly migraine headache days and other key secondary endpoints were response rates of ≥50%, ≥75%, and 100% in addition to reduction of monthly migraine headache days with acute medication use. 18 At baseline, 66.9% of patients had ≥8 migraine headache days/month and most of the subjects (65.5%) had prior experience with migraine preventive medications. Interestingly, 14.3% had previously failed to two or more pharmacological agents. 18 Monthly migraine days were reduced by 4.3 and Responder rates of ≥75% and ≥50% were secondary end-points also evaluated and compared between groups for the weeks 1-4 and 1-12. As for the weeks 1-4, 31.5% of the 300 mg patients vs. 20.3% of the placebo group revealed a responder rate of higher than 75% (p=.0066). Additionally, 51% of those having received 300 mg achieved ≥75% reduction in days of migraine after the 3 rd and 4 th infusions. 19 Tolerability profile was similar among groups. Upper respiratory infection occurred in 11% of the 30-mg, 10% in the 100-mg, 10% in 300-mg and 7% of the placebo groups. Krynchantowski  The PROMISE-2 study was designed to evaluate the efficacy in the prevention of chronic migraine. 20 The patients had ≥15 to 26 headache days per month with at least 8 migraine days. They either received placebo or epitnezumab in the doses of 100 mg and 300 mg in intravenous quarterly injections. Baseline migraine frequency was 16.2 for the placebo group and 16.1 days for the active antibody groups. Changes in mean migraine days per month during weeks 1-12 was the primary endpoint. Reductions were, respectively, -8.2 days for 300-mg group, -7.7 for the 100-mg group and -5.6 days for the placebo group (p<.0001 for both doses vs. placebo). 20

Real-world experience in Brazil
In the Headache Center of Rio de Janeiro, during the period February 2020 to February 2021, anti-CGRP mAbs were prescribed to 112 migraine patients. The results and outcomes are being collected and tabulated. As of the writing of this initial review, we have data on 83 patients to whom a mAb prescribed before November the 1st, 2020 ( Table 1)  If the mAb prices are to be considered as a main stain for deciding the treatment, it becomes even worse in Brazil.
The higher percentage of patients presenting adverse events is also noteworthy in this study. Although no serious adverse were observed, constipation and injection site erythema were the most common complains; we also saw two patients with vertigo, two with insomnia and one with facial edema. A higher number of patients with adverse reactions after using a mAb was also described by Kanaa et al. 21 , who demonstrated nearly half of the patients with constipation or other mild symptoms as well as safety regarding cardiovascular effects. 21,22 More information and outcomes must be obtained so far and questions regarding when and why a monoclonal anti-CGRP antibody should be prescribed, whether it works better in patients already being treated with traditional pharmacological agents or starting a migraine treatment without previous use of medications is warranted and is on the way for real Brazilian sufferers.