Erenumab for headaches in idiopathic intracranial hypertension: A prospective open‐label evaluation

Abstract Objective To determine the effectiveness of erenumab in treating headaches in idiopathic intracranial hypertension (IIH) in whom papilledema had resolved. Background Disability in IIH is predominantly driven by debilitating headaches with no evidence for the use of preventative therapies. Headache therapy in IIH is an urgent unmet need. Methods A prospective, open‐label study in the United Kingdom was conducted. Adult females with confirmed diagnosis of IIH now in ocular remission (papilledema resolved) with chronic headaches (≥15 days a month) and failure of ≥3 preventative medications received erenumab 4‐weekly (assessments were 3‐monthly). The primary end point was change in monthly moderate/severe headache days (MmsHD) from baseline (30‐day pretreatment period) compared to 12 months. Results Fifty‐five patients, mean (SD) age 35.3 (9) years and mean duration of headaches 10.4 (8.4) years with 3.7 (0.9) preventative treatment failures, were enrolled. Mean baseline MmsHD was 16.1 (4.7) and total monthly headache days (MHD) was (29) 2.3. MmsHD reduced substantially at 12 months by mean (SD) [95% CI] 10.8 (4.0) [9.5, 11.9], p < 0.001 and MHD reduced by 13.0 (9.5) [10.2, 15.7], p < 0.001. Crystal clear days (days without any head pain) increased by 13.1 (9.5) [9.6, 15.3], p < 0.001, headache severity (scale 0–10) fell by 1.3 (1.7) [0.9, 1.9], p < 0.001, and monthly analgesic days reduced by 4.3 (9.2) [1.6, 6.9], p = 0.002. All these measures had improved significantly by 3 months, with a consistent significant response to 12 months. Headache impact test‐6 score and quality of life Short Form‐36 Health Survey significantly improved at 12 months. Sensitivity analysis revealed similar results for patients with and without a prior migraine diagnosis (28/55 (52%) patients) or those with or without medication overuse (27/55 (48%) patients). Conclusions This study provides evidence for the effectiveness of erenumab to treat headaches in IIH patients with resolution of papilledema. It provides mechanistic insights suggesting that calcitonin gene‐related peptide is likely a modulator driving headache and a useful therapeutic target.


INTRODUC TI ON
Idiopathic intracranial hypertension (IIH) is a chronic disease characterized by raised intracranial pressure (ICP) often associated with younger age, obesity, and females. 1,2 Disability in IIH is predominantly driven by debilitating headaches that significantly impact quality of life. 3,4 Reduction in ICP can improve headaches in IIH, 5,6 but headaches often persist despite normalization of ICP. 4,[7][8][9] Patients with prior IIH with resolved papilledema are termed "IIH in ocular remission" and frequently have a high long-term headache morbidity. 1 Headaches in IIH typically have migraine-like characteristics (approximately 80%). 8 There is no evidence for the use of headache preventative therapies for IIH headache with limited choices due to the risk of weight gain or mood disorders. 10 The incidence of IIH is increasing markedly (350% increase in 10 years) with increased economic burden as headaches drive frequent presentations to hospitals. 11,12 Headache therapy is consequently an urgent unmet need in IIH. 13 Calcitonin gene-related peptide (CGRP) is implicated in migraine etiology with elevated levels noted during migraine attacks, levels normalizing after therapeutic triptan administration, and exogenous administration of CGRP precipitating migraine-like headache in migraineurs. [14][15][16][17] Monoclonal antibodies targeting the CGRP signaling pathway are efficacious and well-tolerated therapies for both episodic and chronic migraine and are currently licensed for treatment. [18][19][20][21][22][23][24] Data are emerging supporting the role of CGRP in posttraumatic headache. 25 We hypothesized that CGRP would also have a role in driving IIH headaches.
This open-label prospective evaluation aimed to determine the effectiveness of erenumab in treating headaches in patients with IIH in ocular remission (resolved papilledema).

ME THODS
This study was approved and registered at University Hospitals The study was conducted from October 2018 to August 2020 with ongoing patient follow-up in routine care and analysis performed in August 2020. This was a prospective evaluation and we report the primary analysis of the data.

Study patients
Patients were recruited and data collected prospectively from a ter- Eligible patients had chronic moderate/severe headaches (≥15 per month). 26,27 All patients had IIH in ocular remission, defined as previous diagnosis of IIH with resolution of papilledema. 1 Study patients were adults (≥18 years) for whom ≥3 prior prophylactic treatments had failed. Treatment failure was defined as any of the following: inadequate efficacy with appropriate dosing and treatment duration; intolerable adverse effects; contraindications preventing use; safety concerns. 28 Drug treatment attempts were defined as: inadequate efficacy with appropriate dosing and treatment duration or intolerable adverse effects. Patients with a history of headache attributed to intracranial hypotension (apart from short-lasting post-lumbar puncture headache) were excluded. Patients were not on topiramate or acetazolamide at erenumab initiation.

Study design
An open-label, prospective cohort study was conducted to investigate use of erenumab in chronic headache in patients with IIH in ocular remission. Patients had access to a full range of advice from the Headache Centre as part of routine care. Patients with all degrees of medication overuse headache (MOH), including opiate overuse were included. 28 MOH was defined according to the International Classification of Headache Disorders 3b: "headache occurring on ≥15 days/month in a patient with a pre-existing primary headache and developing as a consequence of regular overuse of acute or Conclusions: This study provides evidence for the effectiveness of erenumab to treat headaches in IIH patients with resolution of papilledema. It provides mechanistic insights suggesting that calcitonin gene-related peptide is likely a modulator driving headache and a useful therapeutic target.

K E Y W O R D S
calcitonin gene-related peptide monoclonal antibody, headache, idiopathic intracranial hypertension, papilledema, raised intracranial pressure symptomatic headache medication (≥10 or ≥15 days/month, depending on the medication) for more than 3 months." 26 Following the baseline monthly headache diary, patients meeting the eligibility criteria were fully informed of the potential benefits and side effects and signed a written consent to proceed with subcutaneous erenumab (Aimovig ® , Novartis). A full neurological and ophthalmological review was performed by a neurologist and a neuro-ophthalmologist including optical coherence tomography (OCT) imaging (Heidelberg Engineering SPECTRALIS, Heidelberg, Germany) and dilated slit-lamp examination of the fundus to confirm resolution of papilledema.
Patients were taught erenumab self-administration and com-  (day without any head pain), days using analgesia, and symptoms associated with IIH (but not pathognomonic as they can also be reported in other headache conditions 34 ) were derived from the monthly headache diaries.
Dosing was determined from the change in MmsHD, MHD, headache severity, or HIT-6 score at the 3-monthly follow-up consultations. Where the response was ≤50% but ≥30% the dose was increased to 140 mg. Those with ≥50% response continued on erenumab at the 70 mg dose. Those with <30% response were discontinued from treatment.

Study outcomes
Primary end point was the mean change in MmsHD between the 30-day pretreatment period compared to 12 months. Data were also reported at 3, 6, and 9 months. A moderate/severe headache day was defined as a day with moderate or severe pain that last at least 4 hours or those requiring the use of abortive therapy. 28 Secondary end points included the MHD. MHD were all headache days, defined as those with an onset, continuation or recurrence any severity or phenotype of headache, lasting at least 30 minutes. 8 Other secondary end points were: crystal clear days (days with no headache), change in headache severity (headache severity was evaluated using a NRS; 0 [no pain] to 10 [most severe pain]), monthly analgesic days, responder rates (percentage of patients achieving at least 30%, 50%, and 75% reduction of MmsHD and MHD), and symptoms associated with IIH (double vision, blurred vision, pulsatile tinnitus, and visual obscurations). 1 Patient reported outcome measures included absenteeism (days off duty due to disability), presenteeism (days with loss of productive capacity during duties), 35 28 Patient reported outcomes are not specific to IIH (as these have not been yet developed) but have been used in previous IIH trials. [36][37][38]

Statistical analysis
Statistical analyses were undertaken on SPSS (Armonk, NY: IBM Corp. unless otherwise specified. End points were compared between the 30-day pretreatment period and 12 months, with secondary analyses at 3, 6, and 9 months, using a two-tailed paired t-test where data were normally distributed or Wilcoxon signed rank test where data were not normally distributed. A prespecified subgroup analyses was performed on those with and without MOH at baseline. 28 Additionally, we analyzed those with and without a preexisting diagnosis of migraine prior to being diagnosed with IIH. We have performed a further post hoc sensitivity analysis for key end points to account for the missing data for patients that erenumab was stopped through imputation by carrying forward the last observed values at the time-point that erenumab was stopped for the subsequent time-points. Statistical significance was considered at p < 0.05 level (two-tailed) unless otherwise stated and p-values were unadjusted. As this was a prospective service evaluation study, no power calculations were performed. All patients available for follow-up were included in the analysis. Missing data were noted in the results and all the authors had access to the study data.

RE SULTS Demographics
Fifty-five patients with IIH in ocular remission and chronic headaches were included in the study ( Figure 1). The headache phenotype was chronic migraine-like in 55/55 (100%) of the patients. All patients were female, with a mean (SD) age of 35.3 (9) years. The duration of chronic headaches since the papilledema had resolved

Baseline headache, medications, quality of life, and IIH characteristics
The population recruited had severe chronic resistant headache.
At baseline the mean duration of headaches was 10.4 (8.4) years.
Among the subgroup with migraine prior to IIH, the duration of headaches was 15.6 (8.2) years, and among those with no migraine prior to IIH diagnosis, the total duration of headaches was 5.1 (4.3) years.
The baseline frequency of moderate/severe headaches and total

Efficacy
There was a substantial improvement in the primary end point of  with significant improvement from 3 months which continued over the study period to 12 months.
However, quality of life, evaluated at 6 months and 12 months using the SF-36 score showed significant improvement in the PCS ( Figure 3A,B, Table 4). Additionally, 14 patients did not have a migraine diagnosis prior to IIH and no MOH and improvements were equivalent with the other groups (Table 4). The above subanalyses were performed for MHD with significant improvements at all time-points in all subgroups (Table 4).
A sensitivity analysis was conducted to account for missing data  Table 5).

DISCUSS ION
This prospective open-label study demonstrates the efficacy of erenumab to improve headaches in patients with IIH in whom the papilledema has resolved (ocular remission). The response was marked given that the population recruited had chronic, long duration, resistant headaches, and approximately half had MOH. also significantly improved. The majority of patients required an increased dose of erenumab to 140 mg monthly (87% at 3 months, 89% at 6 months, 90% at 9 months, and 94% by 12 months). The treatment was well tolerated with no patient withdrawals related to adverse effects and only six discontinuing due to lack of effect (by 12 months). Similar efficacy was seen in those without a diagnosis of previous migraine (48% of the cohort).

Mean (SD) [95% CI]
There are few pharmacotherapies in IIH although novel therapeutic approaches are being developed to target reduction in ICP. 36 44 and in line with IHS guidelines for chronic migraine trials. 28 MOH was common among this IIH cohort (48%) as has been noted in previous IIH populations. 8 This study demonstrates equivalent efficacy of erenumab to reduce headache in those with and without MOH at baseline. Additionally analgesic use reduced significantly over the study period, an outcome also noted in the erenumab chronic migraine trial. 22 The IIH patients had severely disabling headaches at baseline, as demonstrated by the HIT-6 score. 45 The reductions in the HIT-6 score by −7.6 at 12 months is both clinically and statistically significant (minimal important clinical difference in HIT-6 is 5). 45 The improvements in symptoms associated with IIH were only modest, with a fluctuating course through the duration of the study.
These symptoms are not pathognomonic for IIH and often asso-  previous medication trials. 33 The score did not change greatly during the study (15.3 (6.5) at baseline, decreasing to 15 (4.3) at 12 months).
There was a strong family history of migraine (24/55, 44%) among the IIH patients with resistant chronic headaches recruited into this study. We speculate that, as is noted among chronic posttraumatic headache patients, a family history of migraine may represent a poor prognostic marker for progression of chronic IIH headaches. [46][47][48] This study suggests that the CGRP pathway is likely a key modulator of headache in patients with IIH and that targeting CGRP may be a useful therapeutic strategy to manage headache. We hypothesize, as is suggested in other secondary headache disorders, that raised ICP drives trigeminovascular activation and CGRP release which continues even after the original insult of the raised ICP has subsided. 25,49,50 In support of the role of CGRP in driving headache mechanisms in the setting of raised ICP we evaluated the treatment response in IIH patients with and without a history of migraine headaches prior to the diagnosis of IIH. We noted a significant treatment response even in those with no prior migraine diagnosis, suggesting a role of CGRP in headache precipitated by raised ICP.
The open-label, prospective, study design is limited as there is no comparator group, thus, no ability to assess any potential placebo response which is known to be high with injectable headache therapies. 51 The placebo response in a randomized controlled trial of erenumab was 23% at 12 weeks. 22 However, the relatively long During this study, patients were not on a formal weight management program; however, we anticipate that all would have been aware of the importance of weight management in maintaining their IIH in ocular remission. As the majority of follow-up visits were by phone, weight was not formally assessed, but in those describing weight gain we formally assessed for recurrence of papilledema. 39 We cannot ex- Furthermore, a limitation of this study was that non-responders were not followed up and this could have inflated the outcomes. However very low numbers of patients were lost to follow-up by 12 months (five ineffective, one pregnant, and one noncompliant). The sensitivity analysis revealed similar significant improvements for key end points even when missing data were imputed (Table 5). Missing data for the primary end point were n = 7 but was higher for the patient reported outcome questionnaires as the majority of follow-up visits were by phone, enabling the majority of the data to be collected at the time of the visit, however, we required patients to post back the questionnaires which led to greater missing data.

CON CLUS ION
This prospective open-label study of erenumab in IIH patients with persistent headaches in whom their papilledema has resolved, demonstrates significant efficacy to reduce headaches. The moderate/ severe headaches days reflected migraine-like headaches in this IIH cohort. Erenumab had similar efficacy among the 48% who had no prior history of migraine. Targeting CGRP is likely to be a useful therapeutic strategy and worthy of evaluation in a future randomized controlled trial. The mechanisms driving headache in patients with IIH have not been previously evaluated or understood. These data provide important mechanistic insights suggesting that CGRP is likely a key modulator driving headache in patients with IIH.

E TH I C A L A PPROVA L
This study was approved and registered at University Hospitals Note: Imputation for missing data performed by carrying forward the last observed values at the time-point that erenumab was stopped for the relevant patients, for all the subsequent time-points for those patients. Statistical tests represent paired t-test for MmsHD and Wilcoxon signed ranks test for MHD for the 3, 6, 9, and 12 months end points compared to baseline.