Discontinuing monoclonal antibodies targeting CGRP pathway after one-year treatment: an observational longitudinal cohort study

BackgroundMonoclonal antibodies anti-calcitonin gene-related peptide (mAbs anti-CGRP) pathway are effective and safe on migraine prevention. However, some drug agencies limited these treatments to one year due to their high costs. This study aimed at evaluating the effect of discontinuing mAbs anti-CGRP on monthly migraine days (MMDs) and disability in high-frequency episodic (HFEM) and chronic migraine (CM) patients.MethodsThis observational longitudinal cohort study was conducted at 10 Italian headache centres. Consecutive adult patients were followed-up for three months (F-UP1–3) after discontinuation of a one-year erenumab/galcanezumab treatment. The primary endpoint was the change in F-UP MMDs. Secondary endpoints included variation in pain intensity (Numerical Rating Scale, NRS), monthly acute medication intake (MAMI), and HIT-6 scores. We also assessed from F-UP1 to 3 the ≥50% response rate, relapse rate to CM, and recurrence of Medication Overuse (MO).ResultsWe enrolled 154 patients (72.1% female, 48.2 ± 11.1 years, 107 CM, 47 HFEM); 91 were treated with erenumab, 63 with galcanezumab. From F-UP1 to F-UP3, MMDs, MAMI, NRS, and HIT-6 progressively increased but were still lower at F-UP3 than baseline (Friedman’s analysis of rank, p < .001). In the F-UP1–3 visits, ≥50% response rate frequency did not differ significantly between CM and HFEM patients. However, the median reduction in response rate at F-UP3 was higher in HFEM (− 47.7% [25th, − 79.5; 75th,-17.0]) than in CM patients (− 25.5% [25th, − 47.1; 75th, − 3.3]; Mann-Whitney U test; p = .032). Of the 84 baseline CM patients who had reverted to episodic migraine, 28 (33.3%) relapsed to CM at F-UP1, 35 (41.7%) at F-UP2, 39 (46.4%) at F-UP3. Of the 64 baseline patients suffering of medication overuse headache ceasing MO, 15 (18.3%) relapsed to MO at F-UP1, 26 (31.6%) at F-UP2, and 30 (42.3%, 11 missing data) at F-UP3. Lower MMDs, MAMI, NRS, and HIT-6 and higher response rate in the last month of therapy characterized patients with ≥50% response rate at F-UP1 and F-UP3 (Mann-Whitney U test; consistently p < .01).ConclusionMigraine frequency and disability gradually increased after mAbs anti-CGRP interruption. Most patients did not relapse to MO or CM despite the increase in MMDs. Our data suggest to reconsider mAbs anti-CGRP discontinuation.     

Galcanezumab for the prevention of cluster headache

ABSTRACT

Introduction

Cluster headache (CH) is among the worst painful conditions. The available therapies are scarce and not specific, leaving many patients unsatisfied because of poor efficacy and/or tolerability. Patients not responding to common treatments are offered semi-invasive and invasive procedures with uncertain results. Based on the current understanding of CH pathophysiology, new possible therapeutic approaches come from drugs interfering with Calcitonin Gene Related Peptide (CGRP).     

Galcanezumab in episodic migraine: the phase 3, randomized,double-blind,placebo-controlled PERSIST study

BackgroundGalcanezumab, a humanized monoclonal antibody that binds calcitonin gene-related peptide, has demonstrated efficacy and good tolerability in patients with episodic migraine in previous phase 3 trials. We report results from the PERSIST study, which was designed to assess the efficacy and safety of galcanezumab in patients with episodic migraine from China, India, and Russia.MethodsThis phase 3 study was conducted at 40 centers in China (n = 26), India (n = 10), and Russia (n = 4). Eligible adult patients with episodic migraine were randomized in a 1:1 ratio to receive monthly galcanezumab 120 mg (with 240 mg loading dose) or placebo during a double-blind, 3-month treatment period. The primary endpoint was the overall mean change from baseline in monthly migraine headache days (MHDs). Key secondary endpoints were the mean proportion of patients with ≥ 50%, ≥ 75%, and 100% reductions from baseline in MHDs and mean change in the Migraine-Specific Quality of Life Questionnaire (MSQ) Role Function-Restrictive domain score.ResultsIn total, 520 patients were randomized and received at least one dose of galcanezumab (N = 261) or placebo (N = 259). The least squares (LS) mean reduction from baseline in monthly MHDs over 3 months was significantly greater with galcanezumab compared with placebo (-3.81 days vs. -1.99 days; p < 0.0001). Significantly greater mean proportions of patients with galcanezumab versus placebo had ≥ 50%, ≥ 75%, and 100% reductions from baseline in MHDs (all p < 0.0001). The overall mean improvement from baseline in MSQ Role Function-Restrictive score over 3 months was significantly greater with galcanezumab versus placebo (p < 0.0001). There were no clinically meaningful differences between the galcanezumab and placebo group on any safety parameters except for a higher incidence of injection site pruritus (5.0% vs. 0.0%), injection site reaction (3.8% vs. 0.4%), and injection site discomfort (2.3% vs. 0.0%). TEAEs related to injection sites were mild in severity, except in 1 patient who had a moderate injection site reaction. Six serious adverse events were reported by 6 patients (2 galcanezumab, 4 placebo).ConclusionsGalcanezumab 120 mg once monthly was effective and well tolerated in patients with episodic migraine from China, India, and Russia.Trial registrationClinicalTrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT03963232","term_id":"NCT03963232"}}NCT03963232 (PERSIST), registered May 24, 2019.     

Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week,multicenter, real-life,cohort study (the FRIEND study)

BackgroundFremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8–14 days/month) or CM.MethodsThis is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9–12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥ 50%, ≥ 75% and 100% responder rates at the same time intervals.ResultsSixty-seventh number migraine patients had received ≥ 1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p < 0.05), MHDs (-9.4, p < 0.001), MAI (-5.7, p < 0.05; -11.1, p < 0.001), NRS (-3.1, p < 0.001; -2.5, p < 0.001), and MIDAS scores (-58.3, p < 0.05; -43.7; p < 0.001). HIT-6 was significantly reduced only in HFEM patients (-18.1, p < 0.001). Remission from CM to episodic migraine and from MO to no-MO occurred in 75% and 67.7% of the patients. The ≥ 50%, ≥ 75% and 100% responder rates at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM. Younger age emerged as a positive response predictor (OR = 0.91; 95% CI 0.85–0.98, p = 0.013). Treatment-emergent adverse events were uncommon (5.7%) and mild. No patient discontinued fremanezumab for any reason.ConclusionsFremanezumab seems more effective in real-life than in RCTs. Younger age emerges as a potential response predictor.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01396-x.     

Efficacy of erenumab and factors predicting response after 3 months in treatment resistant chronic migraine: a clinical service evaluation

BackgroundCalcitonin gene-related peptide (CGRP) inhibitors have been developed as options for treatment of chronic and episodic migraine. We present our experience of the use of erenumab in a tertiary headache centre.MethodsThis was a prospective clinical audit of all patients commenced on erenumab following a locally agreed pathway and criteria over a consecutive period. Patients received monthly erenumab 140 mg for 3 months. Data were collected prospectively at baseline and 3 months follow up.ResultsOne hundred three patients were commenced on erenumab during the study period. Patients had tried a median of 7 previous prophylactics, including onabotulinum toxin A in 94%. At 3 months there was a reduction in median total (28 to 20, 29% reduction, p < 0.0001) and severe (15 to 5, 67% reduction, p < 0.0001) headache days. 39.8% of patients achieved at least a 30% reduction in total headache days; 61.8% of patients achieved at least a 50% reduction in severe headache days. Meeting either of these thresholds was considered a positive response, 68% of patients achieved this. Presence of daily headache pattern was negatively associated with response, (56% response vs. 90% without daily headache, p = 0.0003). There was no association between age, gender, presence of medication overuse or number of previously tried prophylactic treatments and response to erenumab. 43% of patients reported at least one adverse effect, most commonly constipation (26%); treatment was discontinued in 3 patients due to adverse effects.ConclusionsErenumab was an effective treatment for chronic migraine in this treatment resistant population over 3 months of follow up. Presence of daily headache predicted poorer response but there was still a significant positive response rate in this group.     

European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update

BackgroundA previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments.MethodsThe guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided.ResultsWe found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts’ opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives.ConclusionMonoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01431-x.     

Efficacy and safety of fremanezumab in patients with episodic and chronic migraine with documented inadequate response to 2 to 4 classes of migraine preventive medications over 6 months of treatment in the phase 3b FOCUS study

BackgroundFremanezumab, a fully humanized monoclonal antibody (IgG2Δa) selectively targets the calcitonin gene-related peptide and has proven efficacy for the preventive treatment of migraine. In this study, we evaluated the long-term efficacy, safety, and tolerability of monthly and quarterly fremanezumab.MethodsEpisodic migraine and chronic migraine patients completing the 12-week double-blind period of the FOCUS trial entered the 12-week open-label extension and received 3 monthly doses of fremanezumab (225 mg). Changes from baseline in monthly migraine days, monthly headache days of at least moderate severity, days of acute headache medication use, days with photophobia/phonophobia, days with nausea or vomiting, disability scores, and proportion of patients achieving a ≥50% or  ≥75% reduction in monthly migraine days were evaluated.ResultsOf the 807 patients who completed the 12-week double-blind treatment period and entered the open-label extension, 772 patients completed the study. In the placebo, quarterly fremanezumab, and monthly fremanezumab dosing regimens, respectively, patients had fewer average monthly migraine days (mean [standard deviation] change from baseline: − 4.7 [5.4]; − 5.1 [4.7]; − 5.5 [5.0]), monthly headache days of at least moderate severity (− 4.5 [5.0]; − 4.8 [4.5]; − 5.2 [4.9]), days per month of acute headache medication use (− 4.3 [5.2]; − 4.9 [4.6]; − 4.8 [4.9]), days with photophobia/phonophobia (− 3.1 [5.3]; − 3.4 [5.3]; − 4.0 [5.2]), and days with nausea or vomiting (− 2.3 [4.6]; − 3.1 [4.5]; − 3.0 [4.4]). During the 12-week open-label extension, 38%, 45%, and 46% of patients, respectively, achieved a ≥50% reduction and 16%, 15%, and 20%, respectively, achieved a ≥75% reduction in monthly migraine days. Disability scores were substantially improved in all 3 treatment groups. There were low rates of adverse events leading to discontinuation (<1%).ConclusionFremanezumab demonstrated sustained efficacy up to 6 months and was well tolerated in patients with episodic migraine or chronic migraine and documented inadequate response to multiple migraine preventive medication classes.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03308968","term_id":"NCT03308968"}}NCT03308968 (FOCUS).     

Impact of age and sex on the efficacy of fremanezumab in patients with difficult-to-treat migraine: results of the randomized,placebo-controlled,phase 3b FOCUS study

BackgroundMigraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages. Thus, understanding this burden and the efficacy of migraine preventive medications in both sexes and across age groups is critical. The randomized, placebo-controlled, double-blind, phase 3b FOCUS study demonstrated the safety and efficacy of fremanezumab, a fully humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide as a migraine preventive treatment for individuals with migraine and prior inadequate response to 2 to 4 migraine preventive medication classes. Here, we assessed the efficacy of fremanezumab in participants from FOCUS subgrouped by age (18–45 years and > 45 years) and sex.MethodsIn the FOCUS study, eligible participants were randomized (1:1:1) to 12 weeks of double-blind treatment with quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. In this post hoc analysis, we evaluated changes from baseline in monthly migraine days (primary endpoint of FOCUS) and other secondary and exploratory efficacy outcomes in prespecified age (18–45 and > 45 years) and sex subgroups.ResultsThe modified intention-to-treat population (received ≥ 1 dose of study drug and had ≥ 10 days of postbaseline efficacy assessments for the primary endpoint) totaled 837 participants (18–45 years, n = 373; > 45 years, n = 464; male, n = 138; female, n = 699). Consistent reductions in monthly average number of migraine days during 12 weeks were observed, regardless of age (18–45 years: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.7 days; placebo, − 0.9 days; P < 0.001; > 45 years: quarterly fremanezumab, − 3.6 days; monthly fremanezumab, − 3.7 days; placebo, − 0.3 days; P < 0.001) and sex (male: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.6 days; placebo, − 0.3 days; P < 0.001; female: quarterly fremanezumab, − 3.6 days; monthly fremanezumab, − 3.9 days; placebo, − 0.6 days; P < 0.001). Fremanezumab also reduced monthly headache days of at least moderate severity, monthly days of acute medication use, and improved Migraine Disability Assessment scores across subgroups.ConclusionsThese results demonstrate the efficacy of fremanezumab in patients with difficult-to-treat migraine for reducing migraine and headache days, acute medication use, and disability, regardless of age or sex.Trial registrationClinicalTrials.gov Identifier {"type":"clinical-trial","attrs":{"text":"NCT03308968","term_id":"NCT03308968"}}NCT03308968 (FOCUS), registered October 13, 2017.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01336-1.     

Real-world long-term efficacy and safety of erenumab in adults with chronic migraine: a 52-week,single-center,prospective, observational study

BackgroundClinical trials have shown that erenumab is effective and well-tolerated for the preventive treatment of chronic migraine. To extend the results from clinical trials, we assessed the real-world efficacy and safety of erenumab in patients with chronic migraine from the outpatient clinic at the Danish Headache Center.MethodsA 52-week, single-center, prospective, observation study of erenumab in adults with chronic migraine who are eligible for treatment with monoclonal antibodies against CGRP or its receptor in Denmark. The primary outcome was defined as proportion of patients who achieved ≥ 30% reduction in monthly migraine days (MMDs) from baseline to weeks 9–12.ResultsA total of 300 adult patients with chronic migraine were enrolled and received at least one dose of erenumab. At baseline, the mean (SD) number of monthly headache days was 23 ± 4.9 and mean number of MMDs was 16.8 ± 6.4. Of 300 enrolled patients, 273 (91.0%) patients completed 12 weeks of treatment, and 119 (39.7%) completed 52 weeks of treatment. The number of patients who achieved ≥ 30% reduction in MMDs from baseline to weeks 9–12 was 195 (71.4%) of 273 patients. Sustained ≥ 30% reduction in MMDs at all assessment periods throughout the 52-week treatment period was achieved by 102 (34%) of 300 patients. Adverse events occurred in 220 (73.3%) out of 300 patients. The most common adverse event was constipation. Treatment discontinuation due to lack of tolerability occurred in 41 (13.7%) patients.ConclusionsAmong adult patients with chronic migraine and previous failure of medications for migraine prevention, erenumab was found to be effective and well-tolerated.     

Preventive treatment with CGRP monoclonal antibodies restores brain stem habituation deficits and excitability to painful stimuli in migraine: results from a prospective case-control study

Background & ObjectivesCalcitonin gene-related peptide ligand/receptor (CGRP) antibodies effectively reduce headache frequency in migraine. It is understood that they act peripherally, which raises the question whether treatment merely interferes with the last stage of headache generation or, alternatively, causes secondary adaptations in the central nervous system and might thus possess disease modifying potential. This study addresses this question by investigating the nociceptive blink reflex (nBR), which is closely tied to central disease activity, before and after treatment with CGRP antibodies.MethodsWe enrolled 22 patients suffering episodic migraine (21 female, 46.2 ± 13.8 years of age) and 22 age-/gender-matched controls. Patients received assessments of the nBR (R2 component, 10 trials, 6 stimuli/trial) before (V0) and three months (V3) after treatment with CGRP antibodies started, controls were assessed once. The R2 area (R2a) and habituation (R2h; gradient of R2a against stimulus order) of the stimulated/non-stimulated side (_s/_ns) following repeated supraorbital stimulation provide a direct readout of brainstem excitability and habituation as key mechanisms in migraine.ResultsAll patients showed a substantial reduction of headache days/month (V0: 12.4±3.3, V3: 6.6 ± 4.9). R2a_s (F_global=5.86, p<0.001; block 1: R2a_s: -28%, p<0.001) and R2a_ns (F_global=8.22, p<0.001, block 1: R2a_ns: -22%, p=0.003) were significantly decreased, and R2h_ns was significantly enhanced (F_global=3.07, p<0.001; block 6: R2h_ns: r=-1.36, p=0.007) from V0 to V3. The global test for changes of R2h_s was non-significant (F_global=1.46, p=0.095). Changes of R2h significantly correlated with improvement of headache frequency (R2h_s, r=0.56, p=0.010; R2h_ns: r=0.45, p=0.045). None of the nBR parameters assessed at baseline predicted treatment response.DiscussionWe provide evidence that three months of treatment with CGRP antibodies restores brain stem responses to painful stimuli and thus might be considered disease modifying. The nociceptive blink reflex may provide a biomarker to monitor central disease activity. Future studies should evaluate the blink reflex as a clinical biomarker to predict treatment response at baseline and to establish the risk of relapse after treatment discontinuation.Trial registrationThis trial was prospectively registered at clinicaltrials.gov (ID: {"type":"clinical-trial","attrs":{"text":"NCT04019496","term_id":"NCT04019496"}}NCT04019496, date of registration: July 15, 2019).     

Calcitonin gene-related peptide in blood: is it increased in the external jugular vein during migraine and cluster headache? A review

The involvement of calcitonin gene-related peptide (CGRP) in migraine pathophysiological mechanisms is shown by the facts that CGRP can induce migraine and that two CGRP antagonists, olcegepant and telcagepant, are effective in the treatment of migraine attacks. Increase of the neuropeptide CGRP during migraine and cluster headache attacks in the extracerebral circulation as measured in the external jugular vein (EJV) has been regarded as an established fact. Then in 2005, a study, using the migraine patients as their own controls, showed; however, no changes of CGRP in EJV. For migraine there is thus some uncertainty as to whether CGRP is increased in all migraine patients and more research is needed. In contrast, there are three ‘positive’ studies in cluster headache in which both sumatriptan, O₂ and spontaneous resolution normalized CGRP. The source of an increase of CGRP in EJV is most likely a ‘nervous vasodilatory drive’ in the extracranial vascular bed. It remains an enigma how the observed increase of CGRP in the EJV fits into the mechanisms of migraine and cluster headache.     

Galcanezumab effect on “whole pain burden” and multidimensional outcomes in migraine patients with previous unsuccessful treatments: a real-world experience

BackgroundClinical trials have demonstrated galcanezumab as safe and effective in migraine prevention. However, real-life data are still lacking and overlook the impact of galcanezumab on those different migraine facets strongly contributing to migraine burden. Herein we report the clinical experience from an Italian real-world setting using galcanezumab in patients with migraine experiencing previous unsuccessful preventive treatments.MethodsForty-three patients with migraine and failure of at least 3 migraine preventive medication classes received monthly galcanezumab 120 mg s.c. At the first administration and after 3 and 6 months, patients underwent extensive interviews to assess clinical parameters of disease severity. Furthermore, validated questionnaires were administered to explore migraine-related disability, impact, and quality of life as well as symptoms of depression or anxiety, pain catastrophizing, sleep quality and the ictal cutaneous allodynia.ResultsAfter the third and the sixth administration of monthly galcanezumab 120 mg s.c., headache attacks frequency reduced from 20.56 to 7.44 and 6.37 headache days per month, respectively. Moreover, a significant improvement in headache pain intensity (from 8.95 to 6.84 and 6.21) and duration (from 9.03 to 3.75 and 2.38) as well as in scores assessing migraine related disability and impact, depressive and anxious symptoms, and pain catastrophizing was observed. Furthermore, we demonstrated a significant reduction in the values of “whole pain burden”, a composite score derived from the product of the average of headache frequency, intensity, and duration in the last three months.ConclusionReal-world data support monthly galcanezumab 120 mg s.c. as a safe and effective preventive treatment in reducing headache frequency, intensity, and duration as well as comorbid depressive or anxious symptoms, pain catastrophizing and quality of life in both episodic and chronic migraine patients with previous unsuccessful preventive treatments. Furthermore, we demonstrated that monthly galcanezumab 120 mg s.c. is able to induce a significant improvement in the scores of “whole pain burden”. The latter is a reliable and easy-to-handle tool to be employed in clinical setting to evaluate the effectiveness of preventive drugs (in this case, galcanezumab) or when the decision of continuing the treatment with anti-CGRP mAbs is mandatory.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01436-6.     

Safety and tolerability of erenumab in individuals with episodic or chronic migraine across age groups: a pooled analysis of placebo-controlled trials

BackgroundErenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, has demonstrated efficacy and safety in the prevention of episodic and chronic migraine. There exists an unmet need to establish the safety of erenumab in older individuals, in view of existing multiple comorbidities, polypharmacy, and age-related physiological changes. This pooled analysis of five large migraine-prevention studies examined the safety of erenumab stratified across age groups, particularly in older populations.MethodsPooled and age-stratified analysis of safety data from the 12-week double-blind treatment phase (DBTP) of five randomized, placebo-controlled Phase 2 and 3 studies of erenumab in participants with episodic or chronic migraine across the age groups < 40 years, 40–49 years, 50–59 years, and ≥ 60 years was completed. The safety of erenumab across age groups was determined by assessing safety endpoints including treatment-emergent adverse events (AEs), serious AEs, and events leading to study drug discontinuation.ResultsOverall, 3345 participants across five studies were randomized to receive either placebo (n = 1359), erenumab 70 mg (n = 1132) or erenumab 140 mg (n = 854); 3176 (94.9%) completed the DBTP, and 169 (5.1%) discontinued, mainly due to participant decision (110; 3.3%). Overall, 1349 (40.6%), 1122 (33.8%), and 850 (25.6%) participants received at least one dose of placebo, erenumab 70 mg, and erenumab 140 mg, respectively.Incidence of treatment-emergent AEs was similar across all age groups for both doses of erenumab (70 mg or 140 mg) and placebo (< 40 years, 44.0% vs 44.4%; 40–49 years, 42.5% vs 49.2%; 50–59 years, 46.5% vs 41.6%; ≥ 60 years, 43.8% vs 59.4%). Incidence of treatment-emergent serious AEs overall, and stratified by age groups for both doses and placebo was low (< 40 years, 0.9% vs 1.2%; 40–49 years, 1.7% vs 1.9%; and 50–59 years, 1.6% vs 1.1%), with no serious AEs reported in participants aged ≥ 60 years. No deaths were reported.ConclusionsErenumab (70 mg or 140 mg) exhibited a similar safety profile compared with placebo across age groups in individuals with episodic or chronic migraine, with no increased emergence of events due to age. Erenumab was well tolerated in older participants with multiple comorbidities, polypharmacy, and age-related physiological changes.Trial registration numberClinicalTrials.gov Identifiers: {"type":"clinical-trial","attrs":{"text":"NCT02066415","term_id":"NCT02066415"}}NCT02066415, {"type":"clinical-trial","attrs":{"text":"NCT02456740","term_id":"NCT02456740"}}NCT02456740, {"type":"clinical-trial","attrs":{"text":"NCT02483585","term_id":"NCT02483585"}}NCT02483585, {"type":"clinical-trial","attrs":{"text":"NCT03096834","term_id":"NCT03096834"}}NCT03096834, {"type":"clinical-trial","attrs":{"text":"NCT03333109","term_id":"NCT03333109"}}NCT03333109.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01470-4.     

Efficacy of galcanezumab in patients with migraine and history of failure to 3–4 preventive medication categories: subgroup analysis from CONQUER study

BackgroundChronic migraine (CM) and episodic migraine (EM) are associated with substantial headache-related disability, poor quality of life and global societal burden. In this subgroup analysis from the CONQUER study, we report efficacy outcomes from a pre-specified analysis of galcanezumab versus placebo in patients with CM or EM and 3–4 prior preventive medication category failures due to inadequate efficacy (after at least 2 months at maximum tolerated dose), or safety or tolerability reasons. The patient population is of particular interest due to evidence of decreased quality of life and increased economic burden among patients with migraine that is inadequately managed and is of interest to decision-makers globally.MethodsKey outcomes included overall mean change from baseline in monthly migraine headache days and proportions of patients achieving ≥30% (CM), ≥50%, and ≥ 75% reduction (response rates) in monthly migraine headache days across Months 1–3. Patient functioning and disability were evaluated at Month 3.ResultsOf the 462 randomized patients, 186 (40.3%) had a history of 3–4 preventive category failures. Galcanezumab versus placebo resulted in significantly (P ≤ .001) larger overall mean reduction in monthly migraine headache days (total: − 5.49 versus − 1.03; CM: − 6.70 versus − 1.56; EM: − 3.64 versus − 0.65). Similarly, the ≥50% response rate was significantly (P ≤ .001) higher with galcanezumab versus placebo (total: 41.0 versus 12.7; CM: 41.5 versus 8.4; EM: 41.1 versus 16.5). In the CM group, the ≥30% response rate was significantly higher in the galcanezumab group than the placebo group (CM, 57.5 versus 19.8, P ≤ .0001) as was the ≥75% response rate (13.3 versus 2.6, P ≤ .05). Galcanezumab also resulted in significant (P < .0001) improvements in patient functioning and reductions in disability.ConclusionsGalcanezumab was effective in a difficult-to-treat population of patients with CM or EM who had failed 3–4 prior preventive medication categories.Trial registrationCONQUER. Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT03559257","term_id":"NCT03559257"}}NCT03559257.     

MAB-MIG: registry of the spanish neurological society of erenumab for migraine prevention

BackgroundErenumab was approved in Europe for migraine prevention in patients with ≥ 4 monthly migraine days (MMDs). In Spain, Novartis started a personalized managed access program, which allowed free access to erenumab before official reimbursement. The Spanish Neurological Society started a prospective registry to evaluate real-world effectiveness and tolerability, and all Spanish headache experts were invited to participate. We present their first results.MethodsPatients fulfilled the ICHD-3 criteria for migraine and had ≥ 4 MMDs. Sociodemographic and clinical data were registered as well as MMDs, monthly headache days, MHDs, prior and concomitant preventive treatment, medication overuse headache (MOH), migraine evolution, adverse events, and patient-reported outcomes (PROs): headache impact test (HIT-6), migraine disability assessment questionnaire (MIDAS), and patient global improvement change (PGIC). A > 50% reduction of MMDs after 12 weeks was considered as a response.ResultsWe included 210 patients (female 86.7%, mean age 46.4 years old) from 22 Spanish hospitals from February 2019 to June 2020. Most patients (89.5%) suffered from chronic migraine with a mean evolution of 8.6 years. MOH was present in 70% of patients, and 17.1% had migraine with aura. Patients had failed a mean of 7.8 preventive treatments at baseline (botulinum toxin type A—BoNT/A—had been used by 95.2% of patients). Most patients (67.6%) started with erenumab 70 mg. Sixty-one percent of patients were also simultaneously taking oral preventive drugs and 27.6% were getting simultaneous BoNT/A. Responder rate was 37.1% and the mean reduction of MMDs and MHDs was -6.28 and -8.6, respectively. Changes in PROs were: MIDAS: -35 points, HIT-6: -11.6 points, PIGC: 4.7 points. Predictors of good response were prior HIT-6 score < 80 points (p = 0.01), ≤ 5 prior preventive treatment failures (p = 0.026), absence of MOH (p = 0.039), and simultaneous BoNT/A treatment (p < 0.001). Twenty percent of patients had an adverse event, but only two of them were severe (0.9%), which led to treatment discontinuation. Mild constipation was the most frequent adverse event (8.1%).ConclusionsIn real-life, in a personalized managed access program, erenumab shows a good effectiveness profile and an excellent tolerability in migraine prevention in our cohort of refractory patients.