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Long-term safety and tolerability of erenumab: Three-plus year results from a five-year open-label extension study in episodic migraine

Long-term safety and tolerability of erenumab: Three-plus year results from a five-year... Background: Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab. Methods: Interim analysis was undertaken from an ongoing five-year open-label treatment phase after all patients completed three years in the open-label treatment phase or discontinued the study. Adult patients with episodic migraine enrolled in the open-label treatment phase initially received 70 mg erenumab monthly. A protocol amendment increased the dosage to 140 mg monthly to assess long-term safety of the higher dose. Safety and tolerability were assessed by monitoring adverse events, electrocardiograms, laboratory assessments, and vital signs. Results: Of 383 patients enrolled in the open-label treatment phase, at data cutoff 235 (61.3%) remained in the study, all received 140 mg for 1 year. Median (Q1, Q3) exposure (70 or 140 mg) for all patients enrolled was 3.2 (1.3, 3.4) years. The most frequent adverse events (4.0/100 patient-years) were reported as viral upper respiratory tract infection, sinusitis, influenza, and back pain. Exposure-adjusted serious adverse event rates were 4.2/100 patient-years. There was no increase in cardiovascular events over time. Conclusions: In this long-term study of a CGRP-receptor antibody, erenumab was found to be safe and well-tolerated with a spectrum and rate of adverse events consistent with shorter-term placebo-controlled studies. Trial registration: ClinicalTrials.gov NCT01952574 Keywords Erenumab, safety, migraine Date received: 6 December 2018; revised: 18 April 2019; 9 May 2019; accepted: 10 May 2019 Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, London, UK Introduction Department of Neurology, Charite ´ Universita ¨tsmedizin Berlin, Berlin, Migraine is a long-lasting disorder whose attack fre- Germany Jefferson Headache Center, Thomas Jefferson University, Philadelphia, quency fluctuates in the individual patient (1,2). Some PA, USA patients need to be on preventive therapy for many Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA years, requiring that treatments have favorable long- Amgen Inc., Thousand Oaks, CA, USA term risk benefit profiles (1,2). Multiple studies have Novartis Pharma AG, Basel, Switzerland provided clinical evidence on the efficacy and safety Corresponding author: of investigational monoclonal antibodies targeting the Messoud Ashina, Danish Headache Center and Department of calcitonin gene-related peptide (CGRP) receptor (3–7) Neurology, Faculty of Health and Medical Sciences, Glostrup Hospital, or the ligand itself (8–10), but to date there have been University of Copenhagen, Nordre Ringvej, Glostrup, DK-2600, no studies assessing long-term tolerability and safety of Denmark. these treatments beyond one year. Email: [email protected] 1456 Cephalalgia 39(11) Erenumab (in the US, erenumab-aooe) is a fully Patients human anti-CGRP receptor monoclonal antibody approved in the US and EU for migraine prevention Eligibility criteria for enrollment in the parent study (11). Across four registrational studies, the safety of have been previously reported (6). In brief, key inclu- erenumab has been evaluated in 2537 patients with sion criteria included age 18 and 60 years with his- migraine, representing 2310 patient-years of exposure tory of migraine based on International Classification (11). One study has an ongoing five-year open-label of Headache Disorders second edition (ICHD-2) (14) extension (6). Among these studies, the most common for 12 months prior to screening, with at least 4 adverse events (incidence  3% for either 70 mg or and 14 migraine days per month and< 15 headache 140 mg and more often than placebo) were injection (migraine and non-migraine) days per month. To be site reactions and constipation (11). Here, we present eligible to continue in the OLTP, patients had to com- extended interim safety data after over 3 years of a 5- plete the double-blind treatment phase, not discontinue year open-label erenumab treatment of patients with the investigational product early, and continue to pro- episodic migraine who completed a 12-week double vide informed consent; continuation of treatment had blind treatment phase. Efficacy and safety results to be considered appropriate by the investigator. from the double-blind treatment phase (6) and a pre- planned 1-year open-label interim analysis (12) have Study outcomes been previously published. Data from this interim safety analysis have been presented in abstract form Safety and tolerability were assessed by monitoring (13). adverse events (AEs), electrocardiograms, laboratory assessments, and blood pressure/heart rate and other vital signs. AEs were coded according to the Medical Methods Dictionary for Regulatory Activities (MedDRA) ver- sion 20.0, and severity was graded using the Common Study design Terminology Criteria for Adverse Events (CTCAE) The 12-week double-blind treatment phase (DBTP) for version 4.03. Dose level was classified based on the this study (6) included patients with episodic migraine dose at which the AE occurred. Cardiovascular and (EM) who received placebo or erenumab at 7 mg, cerebrovascular adverse events were identified based 21 mg, or 70 mg administered subcutaneously (SC) on a search strategy composed of events from a monthly. Patients who entered the open-label treatment Standardized MedDRA Query (SMQ) for ischemic phase (OLTP) initially received erenumab at 70 mg SC central nervous system vascular conditions and ische- monthly (Figure 1). A protocol amendment increased mic heart disease, and an internal validated search the dosage to 140 mg monthly to assess long-term safety strategy for peripheral arterial disease. of the higher dose. This was a preplanned safety ana- We compared incidence rates to those observed lysis of data from all patients who completed at least during the DBTP and to those expected in the patient three years in the OLTP or discontinued the study population based on an analysis of secondary data during the OLTP before the data cutoff date. No new from the MarketScan Research Databases in migraine efficacy data are reported here because efficacy end- patients with an age and sex distribution comparable to points were not assessed during years 2 and 3 of this study to estimate incidence rates of cardiovascular OLTP (Figure 1). and cerebrovascular events. This retrospective cohort Efficacy Evaluation Double-blind Open-label Treatment Phase Over 4 Weeks Treatment phase Placebo Study year 1 Study year 2 Study year 3 Study year 4 Study year 5 N = 160 XXXXXXXXXXXXX X X X X Erenumab 7 mg N = 108 70 mg (N = 383) 140 mg (N = 250) Erenumab 21 mg N = 108 Erenumab 70 mg Current interim analysis through ≥ Year 3 of OLTP (to date) Ongoing safety and efficacy assessments N = 107 12 Weeks 5 Years Figure 1. Study design. Safety Follow-up (8–12 weeks) 12 weeks after last dose Ashina et al. 1457 study (n¼ 741,007) included adult patients with Patients provided written informed consent. Qualified migraine, ages 18–65 years, identified from January researchers may request data from Amgen clinical stu- 2010 through December 2011 using a combination of dies. Complete details are available at the following: ICD-9 diagnosis codes (34i6.xx) and prescription claims http://www.amgen.com/datasharing for acute migraine medications (e.g. triptans or ergots) and followed through September 30, 2015 for cardio- vascular and cerebrovascular events in view of the fact Results that CGRP can mediate vasodilation and given that Patients the background rates of vascular disease are increased in individuals with migraine (15–17). Patients were The open-label treatment phase (OLTP) enrolled 383 required to have at least 12 months of continuous patients. The demographics and baseline disease char- enrollment in MarketScan to be included, and no car- acteristics of these patients are presented in Table 1. diovascular or cerebrovascular events in the one year After a median of 2.0 years exposure to 70 mg monthly prior to the start of follow-up; the one-year cutoff was in the OLTP, all remaining 250 patients increased the selected to be consistent with the inclusion/exclusion dose to 140 mg monthly following a protocol amend- criteria of the erenumab double-blind clinical trials ment. At the time of this interim analysis, 236 patients (4–7,12). Cardiovascular events were defined as diag- were continuing in the study (Table 2). Median noses of myocardial ischemia, acute myocardial infarc- (Q1, Q3) erenumab exposure (70 or 140 mg) for all tion, unstable angina, Prinzmetal angina, coronary patients enrolled was 3.2 (1.3, 3.4) years and median revascularization, and other and unspecified angina exposure to 140 mg was 1.2 (1.1, 1.3) years. One hun- pectoris; cerebrovascular events were defined as ische- dred and thirty-two patients discontinued erenumab mic stroke, transient ischemic attack (TIA), other acute treatment prior to the dose increase and 14 discontin- cerebrovascular events, and other ischemic cerebrovas- ued erenumab treatment while receiving 140 mg after cular events. Patient incidence rates (per 100 person- the dose increase (Table 2). Very few discontinuations years) of new cardiovascular or cerebrovascular were due to adverse events or lack of efficacy and most events (along with 95% confidence intervals, CI) were estimated based on person counts within a particular event category and corresponding person-time. A Table 1. Demographics and clinical characteristics at baseline patient with multiple cardiovascular or cerebrovascular of the parent study for patients who entered the OLTP . events was only counted once within the category. All patients (n¼ 383) Statistical considerations Age, mean years (SD) 41.3 (10.9) All patients who received at least one dose of erenumab Sex, n female (%) 303 (79) in the OLTP were included in the analysis. AEs are Race, n white (%) 354 (92) summarized as exposure-adjusted patient incidence Age at migraine onset, mean years (SD) 20.9 (11.3) rates, defined as the total number of patients who Duration of disease, mean years (SD) 20.9 (11.9) reported that event in a given time period of follow- History of migraine with aura, n (%) 137 (36) up divided by total patient-years of exposure in that period. Total patient-years of exposure was defined as Monthly migraine days, mean (SD) 8.7 (2.7) the sum of the duration of exposure from first erenu- Monthly headache days, mean (SD) 9.8 (2.7) mab dose to the earliest of end-of-study date, data Monthly migraine-specific 4.3 (3.7) cutoff date, or first report of event across all patients medication days , mean (SD) during the OLTP. Change from baseline values for Prior prophylactic history, n (%) safety endpoints were calculated based on OLTP base- Naı¨ve 214 (56) line. OLTP baseline was defined as the last non-missing Prior use 169 (44) measurement for the endpoint of interest taken before Treatment failure 138 (36) the first dose of OLTP treatment. Other 31 (8) Baseline was prior to the parent study double-blind phase. Standard protocol approvals, registrations, and Migraine-specific medications were triptans and ergot amine-derivative. patient consents Two hundred and fifty-nine patients (68%) received triptans and four (1%) patients received ergotamine derivatives during the baseline period. This trial is registered with ClinicalTrials.gov Treatment failure included discontinuation due to lack of efficacy and/or (NCT #01952574). All procedures were approved by side effects. institutional review boards at all participating sites. Q1, first quartile; Q3, third quartile; SD, standard deviation. 1458 Cephalalgia 39(11) Table 2. Patient disposition during the OLTP at time of interim analysis. Erenumab 70 mg Erenumab 140 mg* n (%) n (%) Received erenumab during the OLTP 383 (100.0) 250 (100.0) Continuing open-label erenumab 140 mg NA 236 (94.4) Discontinued open-label erenumab 132 (34.5) 14 (5.6) Ineligibility determined 1 (0.3) 0 (0.0) Protocol deviation 1 (0.3) 0 (0.0) Non-compliance 6 (1.6) 0 (0.0) Adverse event 16 (4.2) 1 (0.4) Patient request 68 (17.8) 8 (3.2) Decision by sponsor 1 (0.3) 1 (0.4) Lost to follow up 13 (3.4) 1 (0.4) Death 1 (0.3) 0 (0.0) Requirement for alternative therapy 3 (0.8) 1 (0.4) Pregnancy 5 (1.3) 0 (0.0) Lack of efficacy 12 (3.1) 0 (0.0) Other 5 (1.3) 2 (0.8) OLTP: open-label treatment phase. *Following an amendment, patients were required to increase erenumab dose to 140 mg. yAdverse events leading to discontinuation are detailed in Table 3. zFatality, previously reported, due to arteriosclerosis, occurring in patient with prior history of hypertension and left anterior hemiblock (ECG), who on autopsy showed evidence of severe coronary artery disease and presence of cardiac stimulants (liver tissue) – considered not related to the investigational product by the investigator (12). were driven by patient request (Table 2); however, were each reported in two patients (Table 4). The further detail on reasons for patient request were not types and nature of AEs and the patient incidence captured, such that additional information cannot be rates and severity (usually non-serious and Grade 2) provided for these patients. were comparable with previous observations and did not reveal any new safety concerns. Safety Serious adverse events. Exposure-adjusted serious AE Adverse events. The exposure-adjusted AE patient inci- (SAE) patient incidence rates were 4.2 per 100 dence rate was 132.0 per 100 patient-years (142.0 prior patient-years; the exposure-adjusted patient incidence to and 128.1 following dosage increase). The most fre- rates in the OLTP were similar to the placebo rates quent AEs ( 4.0 per 100 patient-years) were reported from the DBTP (Table 3). SAEs were in general iso- as viral upper respiratory tract infection, upper respira- lated events without a clear treatment-related pattern. tory tract infection, sinusitis, influenza, and back pain The most frequent SAEs (occurring in two patients (Table 3). Based on pooled results from four completed each) were adjustment disorder, syncope, uterine leio- placebo-controlled trials (3–5,7), none of these events myoma, and breast cancer. One death, which occurred have been found to be increased in erenumab-treated during the first year of the OLTP at 70 mg, was con- patients relative to placebo, and in fact these events founded by comorbidities, as previously reported (12). were similar to the common events occurring in the double-blind placebo-controlled portion of this and Cardiovascular and cerebrovascular safety. There were only other studies. Furthermore, the exposure-adjusted two patients reporting a cardiovascular event in the patient incidence rates of AE during the OLTP were OLTP, and no patient reported a cerebrovascular lower than the placebo incidence rates from the event (Table 5). An event of myocardial ischemia was DBTP. Sixteen patients discontinued erenumab treat- reported during the first year of the OLTP (12) based ment due to AEs; one patient experienced an AE during on results of an exercise treadmill test confounded by the DBTP that led to treatment discontinuation during sumatriptan administration 4 hours prior to the event. the OLTP (Table 4). None of the AEs leading to treat- Since then, one additional event was reported, which ment discontinuation occurred in more than was increased blood creatine phosphokinase MB that one patient except for rash and depression, which was noted during an evaluation for myocarditis based Ashina et al. 1459 Table 3. Exposure-adjusted patient incidence rates of adverse events. Double-blind treatment phase Open-label treatment phase Erenumab Erenumab Erenumab Erenumab Placebo 70 mg 70 mg 140 mg 70/140 mg (n¼ 153) (n¼ 106) (n¼ 383) (n¼ 250) (n¼ 383) n (r) n (r) n (r) n (r) n (r) All AEs 82 (350.1) 57 (326.2) 323 (142.0) 179 (128.1) 335 (132.0) Grade 2 37 (117.1) 23 (98.0) 245 (66.9) 133 (70.2) 273 (63.6) Grade 3 2 (5.3) 3 (11.5) 55 (8.8) 18 (6.3) 67 (7.7) Serious AEs 0 (0.0) 1 (3.8) 29 (4.4) 14 (4.9) 39 (4.2) AEs leading to discontinuation of IP 2 (5.3) 3 (11.5) 15 (2.2) 1 (0.3) 16 (1.6) Fatal* 0 (0.0) 0 (0.0) 1 (0.1) 0 (0.0) 1 (0.1) Most frequent AEs (>4.0/100 patient-years) Viral upper respiratory tract infection 12 (33.9) 6 (22.3) 85 (14.8) 40 (15.1) 100 (12.9) Upper respiratory tract infection 3 (8.0) 3 (11.4) 52 (8.3) 29 (10.6) 62 (7.2) Sinusitis 2 (5.3) 2 (7.5) 30 (4.6) 15 (5.3) 42 (4.6) Influenza 5 (13.5) 1 (3.8) 36 (5.5) 7 (2.4) 38 (4.2) Back pain 4 (10.8) 1 (3.8) 30 (4.6) 10 (3.5) 38 (4.2) Serious AEs occurring in >1 patient Adjustment disorder 1 (0.1) 1 (0.3) 2 (0.2) Syncope 2 (0.3) 0 (0.0) 2 (0.2) Uterine leiomyoma 1 (0.1) 1 (0.3) 2 (0.2) Breast cancer 2 (0.3) 0 (0.0) 2 (0.2) AEs: adverse events; IP: investigational product; n: number of patients reporting at least one occurrence of event; r: exposure-adjusted patient incidence rate per 100 patient-years (n/e*100). *Fatality, previously reported, due to arteriosclerosis, occurring in patient with prior history of hypertension and left anterior hemiblock (ECG), who on autopsy showed evidence of severe coronary artery disease and presence of cardiac stimulants (liver tissue) – considered not related to the investigational product by the investigator. Note: Each column includes adverse events that occurred while receiving the open-label erenumab at that dose level. Table 4. Exposure-adjusted patient incidence rates of adverse events leading to discontinuation of erenumab during the OLTP. Erenumab 70 mg Erenumab 140 mg Erenumab 70/140 mg (n¼ 383) (n¼ 250) (n¼ 383) n (r) n (r) n (r) AEs leading to discontinuation 15 (2.2) 1 (0.3) 16 (1.6) of investigational product Rash 2 (0.3) 0 (0.0) 2 (0.2) Depression 2 (0.3) 0 (0.0) 2 (0.2) Pancreatic cyst 1 (0.1) 0 (0.0) 1 (0.1) Febrile convulsion 1 (0.1) 0 (0.0) 1 (0.1) Breast cancer 1 (0.1) 0 (0.0) 1 (0.1) Dyspnoea exertional 1 (0.1) 0 (0.0) 1 (0.1) Oedema peripheral 1 (0.1) 0 (0.0) 1 (0.1) Biliary cirrhosis primary 1 (0.1) 0 (0.0) 1 (0.1) Headache 1 (0.1) 0 (0.0) 1 (0.1) Invasive lobular breast carcinoma 1 (0.1) 0 (0.0) 1 (0.1) Syncope 1 (0.1) 0 (0.0) 1 (0.1) Myocardial ischaemia 1 (0.1) 0 (0.0) 1 (0.1) Influenza-like illness 1 (0.1) 0 (0.0) 1 (0.1) Suicide attempt 0 (0.0) 1 (0.3) 1 (0.1) Lung adenocarcinoma stage III 1 (0.1) 0 (0.0) 1 (0.1) n: number of patients reporting at least one occurrence of event; r: exposure-adjusted patient incidence rate per 100 patient-years (n/e*100). 1460 Cephalalgia 39(11) Table 5. Exposure-adjusted patient rates of cardio- and cerebrovascular disorder events during the OLTP. Erenumab 70 mg Erenumab 140 mg Erenumab 70/140 mg (n¼ 383) (n¼ 250) (n¼ 383) n (r) n (r) n (r) Cardiovascular adverse events 2 (0.3) 0 (0.0) 2 (0.2) Ischemic heart disease 2 (0.3) 0 (0.0) 2 (0.2) Cardiac disorders 1 (0.1) 0 (0.0) 1 (0.1) Myocardial ischemia 1 (0.1) 0 (0.0) 1 (0.1) Investigations 1 (0.1) 0 (0.0) 1 (0.1) Blood creatine 1 (0.1) 0 (0.0) 1 (0.1) phosphokinase MB increased Cerebrovascular adverse events 0 (0.0) 0 (0.0) 0 (0.0) n: number of patients reporting at least one occurrence of event; r: exposure-adjusted rate per 100 patient-years. Note: Table based on the following search criteria: Ischemic central nervous system vascular conditions SMQ (narrow), ischemic heart disease SMQ (narrow) and peripheral arterial disease (PAD) AMQ (narrow). Coded using MedDRA version 20.0. Table 6. Incidence of cardiovascular and cerebrovascular events in persons with migraine. # Patients with event Person-years (PY) of Rate (95% CI) (n¼ 741,007 persons) follow-up per 100 PY Cardiovascular events 8,250 1,981,899 0.42 (0.41, 0.43) Cerebrovascular events 11,591 1,978,926 0.59 (0.58, 0.60) Data are incidence rates from MarketScan database of adult patients with migraine identified from January 2010 through December 2011 followed through 30 September, 2015. on symptoms of feeling listless and tired, and intermit- related hepatotoxicity (Table 8). There were eight tent inability to take a full breath after having severe patients with ALT or AST increases greater than three laryngitis for two weeks. This event was adjudicated by times the upper limit of normal (only one with ALT an independent clinical endpoint committee as not greater than five times the upper limit of normal) over being an event of myocardial infarction or hospitaliza- this long-term observation period, corresponding to tion for unstable angina. Given the lack of a placebo 1.8% and 0.8% of patients receiving 70 mg and 140 mg arm, a large claims database of migraine patients was (Table 8). Among the eight patients with ALT or analyzed to establish background rates for cardiovas- AST> 3ULN, one had ALT and AST decreased to cular and cerebrovascular events. The background >1ULN to 3 ULN and the other seven decreased patient incidence rate of cardiovascular events was to< 1 ULN by the latest assessment. The patients with 0.42 per 100 person-years and 0.59 per 100 person- total bilirubin> 2 ULN had total bilirubin reduced years for cerebrovascular events, which are both to> 1 ULN to 1.5 ULN by the latest assessment. higher than the exposure-adjusted cardiovascular and cerebrovascular patient incidence rates in this long- Anti-drug antibodies. No patients in any group had pre- term interim analysis (0.2 per 100 patient-years, and existing antibodies prior to the first erenumab dose. 0.0 per 100 patient-years, respectively) (Table 6). Among 400 subjects with postbaseline results after There were no meaningful changes in systolic/diastolic receiving 70 mg or 140 mg during DBTP or OLTP, 38 blood pressure or heart rate up to 3.3 years of follow- (9.5%) developed non-neutralizing binding antibodies, up (Table 7 and Figure 2). 29 of whom had a transient response (negative result at last time point tested), and three (0.8%) developed neu- Liver function. There were no cases of suspected Hy’s law tralizing antibodies, two of whom had a transient (alanine aminotransferase (ALT) or aspartate amino- response. Since the interim analysis after 52 weeks of transferase (AST)> 3 upper limit of normal (ULN) the OLTP, only two patients have newly developed a and total bilirubin> 2 ULN and alkaline phosphatase positive non-neutralizing binding antibody, both of (ALP)< 2 ULN) predictive of potential for drug- which were transient. Ashina et al. 1461 Table 7. Blood pressure and heart rate at Year 3 during the discontinuation due to constipation. During the pla- OLTP. cebo-controlled studies, constipation events were mild and tended to dissipate over time, so it is unsurprising Erenumab that it is not observed over longer treatment. 70/140 mg Retention rates in long-term clinical trials provide an (n¼ 240) indication of the long-term efficacy and tolerability of Systolic blood pressure, mmHg therapies, and hence are of particular importance in OLTP baseline 118.4 (12.3) chronic conditions. Of 383 patients who entered into Year 3 120.7 (13.1) the OLTP, patient retention rates at year 3 were rela- tively high (62%), highlighting the favorable long-term Patients with increase from OLTP baseline of20 mmHg, n (%) tolerability profile of erenumab and patient satisfaction with treatment, in contrast to those observed in long- <120 mmHg at Year 3 2 (0.8) term studies with other migraine preventatives (18). In 120–129 mmHg at Year 3 7 (2.9) the 8-month open-label extension of the pivotal topir- 130–139 mmHg at Year 3 6 (2.5) amate trials, 29% of participants withdrew and of those 140 mmHg at Year 3 10 (4.2) withdrawing 42% withdrew due to an adverse event Diastolic blood pressure, mmHg (18). The observed discontinuation rate due to reported OLTP baseline 74.9 (9.5) lack of efficacy or adverse events with erenumab in this Year 3 77.7 (9.3) analysis was low (<5%). This is in contrast to the high Patients with increase from discontinuation rates for commonly used migraine OLTP baseline of10 mmHg, n (%) prophylactics (18–20). <80 mmHg at Year 3 11 (4.6) In short-term phase 1 and phase 2 clinical trials of 80–99 mmHg at Year 3 23 (9.6) erenumab (including the double-blind treatment period 100 mmHg at Year 3 18 (7.5) of the study reported here), there was a low incidence of Heart rate, beats/min binding and neutralizing anti-erenumab antibodies. OLTP baseline 70.1 (9.6) The incidence of anti-erenumab antibodies remained low throughout the OLTP, and only two patients devel- Year 3 71.7 (10.2) oped positive non-neutralizing binding antibodies since Note: Data represent mean (SD) unless otherwise indicated. the 52-week interim analysis of the OLTP, indicating n: number of patients with observed results at Year 3. that late development of anti-erenumab antibodies occurs infrequently. The development of anti-erenumab antibodies has not been associated with any clinical Discussion finding or safety events. This three-year interim safety update of a five-year Long-term safety assessments are often complicated long-term open label study confirms the favorable tol- by lack of placebo comparison, which makes it difficult erability and safety profile of erenumab seen in short- to distinguish spontaneously occurring AEs or labora- term and one-year OLE trials (3,4,6,7,12). This tory abnormalities from those due to treatment. In the publication represents the longest-term data for a absence of a placebo comparison, context can be added CGRP pathway-targeted therapy to date and allows to events observed during open-label treatment by for an assessment of the risk-benefit profile of erenu- comparing with background rates observed in real- mab treatment over 3 years of treatment. The safety world settings. Given that CGRP can mediate vaso- profile of erenumab remained in line with that observed dilation, at least in theory inhibition of CGRP’s effects during the DBTP, with no increase in the rate of AEs might pose a vascular risk, though this has not been over time or following the dose increase, and no evi- observed in short-term placebo-controlled erenumab dence of cardiovascular or cerebrovascular risk. studies (3–7). Previously published epidemiological stu- Safety and tolerability profiles during the OLTP dies have shown an increased risk of cardiovascular (total exposure 961 patient-years) were similar to and cerebrovascular events in patients with migraine those observed for erenumab 70 mg in the double- compared to those without migraine, particularly blind parent study (total exposure 23.9 patient-years) among patients who experience migraine with aura and overall were similar to placebo (34.1 patient-years) (15–17). Overall, migraine is significantly associated in the parent study. Although constipation was identi- with myocardial infarction (Odds Ratio (OR)¼ 2.2, fied as a common AE in the pooled analysis of the 95% CI¼ 1.7–2.8) and stroke (OR¼ 1.5, 95% double-blind studies (11), patient incidence rates for CI¼ 1.2–2.1) (21). In the Nurses’ Health Study II, constipation were low in this OLTP (1.8 per 100 adjusted for CV risk factors, the hazard ratios (95% patient-years) and there were no cases of treatment CIs) for women with migraine were 1.50 (1.33–1.69) for 1462 Cephalalgia 39(11) Systolic blood pressure Diastolic blood pressure 150 100 120 75 Year 1 Year 2 Year 3 Year 1 Year 2 Year 3 90 50 BL1234567891011121316192225 28313437 BL12345678910111213 1619 222528 31 34 37 Months Months Heart rate Year 1 Year 2 Year 3 BL12345678910111213 1619 22252831 3437 Months Figure 2. Blood pressure and heart rate over time during the OLTP. BL: Open-label treatment phase baseline; study month: four weeks. Table 8. Incidence of liver function test abnormalities during the OLTP. Erenumab 70 mg Erenumab 140 mg (n¼ 383) (n¼ 250) n (%) n (%) ALT or AST> 3 ULN* 7 (1.8) 2 (0.8) Total bilirubin> 2 ULN 0 (0.0) 1 (0.4) ALT or AST> 3 ULN and total 0 (0.0) 0 (0.0) bilirubin> 2 ULN and ALP< 2 ULN ULN: Upper limit of normal; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase. *Only one case was> 5 ULN for ALT in erenumab 140 mg group. major CV events, 1.39 (1.18–1.64) for MI, 1.62 (1.37– incidence rates. The cardiovascular background rates 1.92) for stroke, and 1.37 (1.02–1.83) for CV mortality (0.42/100 person-years) were higher than those when compared to study participants without migraine observed in the OLTP of this study (0.2/100 patient- (22). In women, migraine with aura was the second years), consistent with the preclinical (23) and clinical strongest single contributor to major cardiovascular observations (24,25) to date that erenumab does not disease risk with an incidence rate of 7.9 per 1000 increase the risk of adverse cardiovascular/cerebrovas- women per year (17). Therefore, in order to context- cular events. ualize cardiovascular/cerebrovascular patient incidence The frequency of elevated ALT or AST> 3 ULN rates in our study, a cohort of patients with migraine during the OLTP with 3 years of exposure was low from the MarketScan claims database of 741,007 per- given the long duration of follow-up. For each of sons over a similar follow-up period as this interim these cases, elevation was< 5 ULN. For context, analysis was analyzed to establish background patient the frequency of ALT or AST elevation> 3 ULN Systolic blood pressure (mmHg) Mean (SD) Heart rate (beats/minute) Mean (SD) Diastolic blood pressure (mmHg) Mean (SD) Ashina et al. 1463 over 12 weeks in the pooled placebo groups of four In this three-plus years, long-term study of an anti- completed studies (3,4,6,7) was 0.5%. Given the much body targeting the CGRP receptor, erenumab was longer period of observation in the OLTP, the low level found to be safe and well-tolerated with a spectrum (> 3 but< 5 ) of AST or ALT elevation in few and rate of AEs consistent with shorter-term placebo- patients supports that long-term treatment with erenu- controlled studies. The favorable tolerability and safety mab does not increase liver function tests. More profile, and the low discontinuation rates, suggest that importantly there were no cases of Hy’s law, which adherence is favorable with erenumab and may result in predicts the potential for severe liver toxicity. positive long-term outcomes. Clinical implications . Erenumab (in the US, erenumab-aooe) is a fully human anti-CGRP receptor monoclonal antibody approved in the US and EU for migraine prevention. . In this three-year, long-term study, erenumab was found to be safe and well-tolerated with a spectrum and rate of adverse events consistent with shorter-term placebo-controlled studies. . The favorable tolerability and safety profile, and the low discontinuation rates, suggest that adherence is favorable with erenumab and may result in positive long-term outcomes. Electrocore LLC, Eli Lilly, eNeura, Neurolief, Novartis, Acknowledgements Ipsen, Impel, Satsuma, Supernus, Sun Pharma (India), This study was fully funded by Amgen Inc. Erenumab is co- Theranica, Teva, Vedanta, WL Gore, Nocira, PSL Group developed in partnership with Amgen Inc. and Novartis. Jon Services, University of British Columbia, Zosano, ZP Opco, Nilsen (Amgen Inc.) provided medical writing support for Foresite Capital, Oppenheimer. CME fees or royalty payments: this manuscript. Healthlogix, Medicom Worldwide, Medlogix Communications, Mednet, Miller Medical, PeerView, WebMD Health/ Declaration of conflicting interests Medscape, Chameleon, Academy for Continued Healthcare The authors declared the following potential conflicts of inter- Learning, Universal meeting management, Haymarket, est with respect to the research, authorship, and/or publica- Global Scientific Communications, Global Life Sciences, tion of this article: MA reports research grants from Global Access Meetings, UpToDate (Elsevier), Oxford Lundbeck Foundation, Research Foundation of the Capital University Press, Cambridge University Press, Wolters Region of Copenhagen, and Novo Nordisk Foundation; con- Kluwer Health; Stock options: Aural analytics, Healint, sulting from Allergan, Amgen Inc., Alder, Eli Lilly, Novartis Theranica, Second Opinon/Mobile Health, Epien, GBS/ and Teva. Nocira, Matterhorn/Ontologics, King-Devick Technologies. PJG reports grants and personal fees from Amgen and Eli- Consulting without fee: Aural Analytics, Healint, Second Lilly and Company, and personal fees from Alder Opinion/Mobile Health, Epien; Board of Directors: Epien, Biopharmaceuticals, Allergan, Autonomic Technologies Matterhorn/Ontologics, King-Devick Technologies. Patent: Inc., Dr Reddy’s Laboratories, Electrocore LLC, eNeura, 17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen Novartis, Scion, Teva Pharmaceuticals, and Trigemina Inc., for Chronic Migraine Prophylaxis without fee. Professional and personal fees from MedicoLegal work, NEJM Journal society fees or reimbursement for travel: American Academy Watch, Up-to-Date, Oxford University Press, and Wolters of Neurology, American Brain Foundation, American Kluwer; and a patent Magnetic stimulation for headache Headache Society, American Migraine Foundation, assigned to eNeura without fee. International Headache Society, Canadian Headache Society. UR reports consulting fees, speaking/teaching fees, and/or Other: Use agreement through employer: Myndshft. research grants – Allergan, Amgen, Autonomic JK reports employee and stock/stock options: Novartis Technologies, Eli Lilly and Co, Medscape, Novartis, Pharma AG. CoLucid, StreaMedUp, Teva. GR, FZ, SC, and DM report: Employees and stock/stock SS reports consultant/ad board fees: Alder Biopharmaceuticals; options, Amgen Inc. Allergan, Inc.; Amgen; Avanir Pharmaceuticals, Inc.; Curelator, Inc.; Dr. Reddy’s Laboratories; eNeura Inc.; electroCore Medical, LLC; Lilly USA, LLC; Medscape, Funding LLC.; NINDS; Supernus Pharmaceuticals, Inc.; Teva The authors disclosed receipt of the following financial sup- Pharmaceuticals; Theranica; and Trigemina, Inc. port for the research, authorship, and/or publication of this DWD reports the following conflicts: Personal fees: Amgen, article: This study was sponsored by Amgen Inc. Association of Translational Medicine, University Health Network, Daniel Edelman Inc., Autonomic technologies, ORCID iD Axsome, Aural Analytics, Allergan, Alder, Biohaven, Charleston Laboratories, Dr Reddy’s Laboratories/Promius, Peter J Goadsby https://orcid.org/0000-0003-3260-5904 1464 Cephalalgia 39(11) results from an ongoing open-label extension study in References episodic migraine. Headache 2018; 58: 18–19. 1. Serrano D, Lipton RB, Scher AI, et al. Fluctuations in 14. Headache Classification Subcommittee of the episodic and chronic migraine status over the course of International Headache Society. The International Clas- 1 year: Implications for diagnosis, treatment and clinical sification of Headache Disorders, 2nd ed. ICHD-II Clas- trial design. J Headache Pain 2017; 18: 101. sification: Parts 1–3: Primary, secondary and other. 2. Lipton RB, Bigal ME, Diamond M, et al. Migraine Cephalalgia 2004; 24: 23–136. prevalence, disease burden, and the need for preventive 15. 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Aimovig (erenumab-aooe) (US package 25. de Hoon J, Van Hecken A, Vandermeulen C, et al. Phase insert). Thousand Oaks, CA: Amgen Inc., 2018. 1, randomized, parallel-group, double-blind, placebo- 12. Ashina M, Dodick D, Goadsby PJ, et al. Erenumab controlled trial to evaluate the effects of erenumab (AMG 334) in episodic migraine: Interim analysis of an (AMG 334) and concomitant sumatriptan on blood ongoing open-label study. Neurology 2017; 89: pressure in healthy volunteers. Cephalalgia 2019; 39: 1237–1243. 100–110. 13. Ashina M, Goadsby P, Silberstein S, et al. Long-term safety and tolerability of erenumab: Three-plus year http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cephalalgia Pubmed Central

Long-term safety and tolerability of erenumab: Three-plus year results from a five-year open-label extension study in episodic migraine

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Pubmed Central
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© International Headache Society 2019
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0333-1024
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1468-2982
DOI
10.1177/0333102419854082
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Abstract

Background: Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab. Methods: Interim analysis was undertaken from an ongoing five-year open-label treatment phase after all patients completed three years in the open-label treatment phase or discontinued the study. Adult patients with episodic migraine enrolled in the open-label treatment phase initially received 70 mg erenumab monthly. A protocol amendment increased the dosage to 140 mg monthly to assess long-term safety of the higher dose. Safety and tolerability were assessed by monitoring adverse events, electrocardiograms, laboratory assessments, and vital signs. Results: Of 383 patients enrolled in the open-label treatment phase, at data cutoff 235 (61.3%) remained in the study, all received 140 mg for 1 year. Median (Q1, Q3) exposure (70 or 140 mg) for all patients enrolled was 3.2 (1.3, 3.4) years. The most frequent adverse events (4.0/100 patient-years) were reported as viral upper respiratory tract infection, sinusitis, influenza, and back pain. Exposure-adjusted serious adverse event rates were 4.2/100 patient-years. There was no increase in cardiovascular events over time. Conclusions: In this long-term study of a CGRP-receptor antibody, erenumab was found to be safe and well-tolerated with a spectrum and rate of adverse events consistent with shorter-term placebo-controlled studies. Trial registration: ClinicalTrials.gov NCT01952574 Keywords Erenumab, safety, migraine Date received: 6 December 2018; revised: 18 April 2019; 9 May 2019; accepted: 10 May 2019 Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark NIHR-Wellcome Trust King’s Clinical Research Facility, King’s College London, London, UK Introduction Department of Neurology, Charite ´ Universita ¨tsmedizin Berlin, Berlin, Migraine is a long-lasting disorder whose attack fre- Germany Jefferson Headache Center, Thomas Jefferson University, Philadelphia, quency fluctuates in the individual patient (1,2). Some PA, USA patients need to be on preventive therapy for many Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA years, requiring that treatments have favorable long- Amgen Inc., Thousand Oaks, CA, USA term risk benefit profiles (1,2). Multiple studies have Novartis Pharma AG, Basel, Switzerland provided clinical evidence on the efficacy and safety Corresponding author: of investigational monoclonal antibodies targeting the Messoud Ashina, Danish Headache Center and Department of calcitonin gene-related peptide (CGRP) receptor (3–7) Neurology, Faculty of Health and Medical Sciences, Glostrup Hospital, or the ligand itself (8–10), but to date there have been University of Copenhagen, Nordre Ringvej, Glostrup, DK-2600, no studies assessing long-term tolerability and safety of Denmark. these treatments beyond one year. Email: [email protected] 1456 Cephalalgia 39(11) Erenumab (in the US, erenumab-aooe) is a fully Patients human anti-CGRP receptor monoclonal antibody approved in the US and EU for migraine prevention Eligibility criteria for enrollment in the parent study (11). Across four registrational studies, the safety of have been previously reported (6). In brief, key inclu- erenumab has been evaluated in 2537 patients with sion criteria included age 18 and 60 years with his- migraine, representing 2310 patient-years of exposure tory of migraine based on International Classification (11). One study has an ongoing five-year open-label of Headache Disorders second edition (ICHD-2) (14) extension (6). Among these studies, the most common for 12 months prior to screening, with at least 4 adverse events (incidence  3% for either 70 mg or and 14 migraine days per month and< 15 headache 140 mg and more often than placebo) were injection (migraine and non-migraine) days per month. To be site reactions and constipation (11). Here, we present eligible to continue in the OLTP, patients had to com- extended interim safety data after over 3 years of a 5- plete the double-blind treatment phase, not discontinue year open-label erenumab treatment of patients with the investigational product early, and continue to pro- episodic migraine who completed a 12-week double vide informed consent; continuation of treatment had blind treatment phase. Efficacy and safety results to be considered appropriate by the investigator. from the double-blind treatment phase (6) and a pre- planned 1-year open-label interim analysis (12) have Study outcomes been previously published. Data from this interim safety analysis have been presented in abstract form Safety and tolerability were assessed by monitoring (13). adverse events (AEs), electrocardiograms, laboratory assessments, and blood pressure/heart rate and other vital signs. AEs were coded according to the Medical Methods Dictionary for Regulatory Activities (MedDRA) ver- sion 20.0, and severity was graded using the Common Study design Terminology Criteria for Adverse Events (CTCAE) The 12-week double-blind treatment phase (DBTP) for version 4.03. Dose level was classified based on the this study (6) included patients with episodic migraine dose at which the AE occurred. Cardiovascular and (EM) who received placebo or erenumab at 7 mg, cerebrovascular adverse events were identified based 21 mg, or 70 mg administered subcutaneously (SC) on a search strategy composed of events from a monthly. Patients who entered the open-label treatment Standardized MedDRA Query (SMQ) for ischemic phase (OLTP) initially received erenumab at 70 mg SC central nervous system vascular conditions and ische- monthly (Figure 1). A protocol amendment increased mic heart disease, and an internal validated search the dosage to 140 mg monthly to assess long-term safety strategy for peripheral arterial disease. of the higher dose. This was a preplanned safety ana- We compared incidence rates to those observed lysis of data from all patients who completed at least during the DBTP and to those expected in the patient three years in the OLTP or discontinued the study population based on an analysis of secondary data during the OLTP before the data cutoff date. No new from the MarketScan Research Databases in migraine efficacy data are reported here because efficacy end- patients with an age and sex distribution comparable to points were not assessed during years 2 and 3 of this study to estimate incidence rates of cardiovascular OLTP (Figure 1). and cerebrovascular events. This retrospective cohort Efficacy Evaluation Double-blind Open-label Treatment Phase Over 4 Weeks Treatment phase Placebo Study year 1 Study year 2 Study year 3 Study year 4 Study year 5 N = 160 XXXXXXXXXXXXX X X X X Erenumab 7 mg N = 108 70 mg (N = 383) 140 mg (N = 250) Erenumab 21 mg N = 108 Erenumab 70 mg Current interim analysis through ≥ Year 3 of OLTP (to date) Ongoing safety and efficacy assessments N = 107 12 Weeks 5 Years Figure 1. Study design. Safety Follow-up (8–12 weeks) 12 weeks after last dose Ashina et al. 1457 study (n¼ 741,007) included adult patients with Patients provided written informed consent. Qualified migraine, ages 18–65 years, identified from January researchers may request data from Amgen clinical stu- 2010 through December 2011 using a combination of dies. Complete details are available at the following: ICD-9 diagnosis codes (34i6.xx) and prescription claims http://www.amgen.com/datasharing for acute migraine medications (e.g. triptans or ergots) and followed through September 30, 2015 for cardio- vascular and cerebrovascular events in view of the fact Results that CGRP can mediate vasodilation and given that Patients the background rates of vascular disease are increased in individuals with migraine (15–17). Patients were The open-label treatment phase (OLTP) enrolled 383 required to have at least 12 months of continuous patients. The demographics and baseline disease char- enrollment in MarketScan to be included, and no car- acteristics of these patients are presented in Table 1. diovascular or cerebrovascular events in the one year After a median of 2.0 years exposure to 70 mg monthly prior to the start of follow-up; the one-year cutoff was in the OLTP, all remaining 250 patients increased the selected to be consistent with the inclusion/exclusion dose to 140 mg monthly following a protocol amend- criteria of the erenumab double-blind clinical trials ment. At the time of this interim analysis, 236 patients (4–7,12). Cardiovascular events were defined as diag- were continuing in the study (Table 2). Median noses of myocardial ischemia, acute myocardial infarc- (Q1, Q3) erenumab exposure (70 or 140 mg) for all tion, unstable angina, Prinzmetal angina, coronary patients enrolled was 3.2 (1.3, 3.4) years and median revascularization, and other and unspecified angina exposure to 140 mg was 1.2 (1.1, 1.3) years. One hun- pectoris; cerebrovascular events were defined as ische- dred and thirty-two patients discontinued erenumab mic stroke, transient ischemic attack (TIA), other acute treatment prior to the dose increase and 14 discontin- cerebrovascular events, and other ischemic cerebrovas- ued erenumab treatment while receiving 140 mg after cular events. Patient incidence rates (per 100 person- the dose increase (Table 2). Very few discontinuations years) of new cardiovascular or cerebrovascular were due to adverse events or lack of efficacy and most events (along with 95% confidence intervals, CI) were estimated based on person counts within a particular event category and corresponding person-time. A Table 1. Demographics and clinical characteristics at baseline patient with multiple cardiovascular or cerebrovascular of the parent study for patients who entered the OLTP . events was only counted once within the category. All patients (n¼ 383) Statistical considerations Age, mean years (SD) 41.3 (10.9) All patients who received at least one dose of erenumab Sex, n female (%) 303 (79) in the OLTP were included in the analysis. AEs are Race, n white (%) 354 (92) summarized as exposure-adjusted patient incidence Age at migraine onset, mean years (SD) 20.9 (11.3) rates, defined as the total number of patients who Duration of disease, mean years (SD) 20.9 (11.9) reported that event in a given time period of follow- History of migraine with aura, n (%) 137 (36) up divided by total patient-years of exposure in that period. Total patient-years of exposure was defined as Monthly migraine days, mean (SD) 8.7 (2.7) the sum of the duration of exposure from first erenu- Monthly headache days, mean (SD) 9.8 (2.7) mab dose to the earliest of end-of-study date, data Monthly migraine-specific 4.3 (3.7) cutoff date, or first report of event across all patients medication days , mean (SD) during the OLTP. Change from baseline values for Prior prophylactic history, n (%) safety endpoints were calculated based on OLTP base- Naı¨ve 214 (56) line. OLTP baseline was defined as the last non-missing Prior use 169 (44) measurement for the endpoint of interest taken before Treatment failure 138 (36) the first dose of OLTP treatment. Other 31 (8) Baseline was prior to the parent study double-blind phase. Standard protocol approvals, registrations, and Migraine-specific medications were triptans and ergot amine-derivative. patient consents Two hundred and fifty-nine patients (68%) received triptans and four (1%) patients received ergotamine derivatives during the baseline period. This trial is registered with ClinicalTrials.gov Treatment failure included discontinuation due to lack of efficacy and/or (NCT #01952574). All procedures were approved by side effects. institutional review boards at all participating sites. Q1, first quartile; Q3, third quartile; SD, standard deviation. 1458 Cephalalgia 39(11) Table 2. Patient disposition during the OLTP at time of interim analysis. Erenumab 70 mg Erenumab 140 mg* n (%) n (%) Received erenumab during the OLTP 383 (100.0) 250 (100.0) Continuing open-label erenumab 140 mg NA 236 (94.4) Discontinued open-label erenumab 132 (34.5) 14 (5.6) Ineligibility determined 1 (0.3) 0 (0.0) Protocol deviation 1 (0.3) 0 (0.0) Non-compliance 6 (1.6) 0 (0.0) Adverse event 16 (4.2) 1 (0.4) Patient request 68 (17.8) 8 (3.2) Decision by sponsor 1 (0.3) 1 (0.4) Lost to follow up 13 (3.4) 1 (0.4) Death 1 (0.3) 0 (0.0) Requirement for alternative therapy 3 (0.8) 1 (0.4) Pregnancy 5 (1.3) 0 (0.0) Lack of efficacy 12 (3.1) 0 (0.0) Other 5 (1.3) 2 (0.8) OLTP: open-label treatment phase. *Following an amendment, patients were required to increase erenumab dose to 140 mg. yAdverse events leading to discontinuation are detailed in Table 3. zFatality, previously reported, due to arteriosclerosis, occurring in patient with prior history of hypertension and left anterior hemiblock (ECG), who on autopsy showed evidence of severe coronary artery disease and presence of cardiac stimulants (liver tissue) – considered not related to the investigational product by the investigator (12). were driven by patient request (Table 2); however, were each reported in two patients (Table 4). The further detail on reasons for patient request were not types and nature of AEs and the patient incidence captured, such that additional information cannot be rates and severity (usually non-serious and Grade 2) provided for these patients. were comparable with previous observations and did not reveal any new safety concerns. Safety Serious adverse events. Exposure-adjusted serious AE Adverse events. The exposure-adjusted AE patient inci- (SAE) patient incidence rates were 4.2 per 100 dence rate was 132.0 per 100 patient-years (142.0 prior patient-years; the exposure-adjusted patient incidence to and 128.1 following dosage increase). The most fre- rates in the OLTP were similar to the placebo rates quent AEs ( 4.0 per 100 patient-years) were reported from the DBTP (Table 3). SAEs were in general iso- as viral upper respiratory tract infection, upper respira- lated events without a clear treatment-related pattern. tory tract infection, sinusitis, influenza, and back pain The most frequent SAEs (occurring in two patients (Table 3). Based on pooled results from four completed each) were adjustment disorder, syncope, uterine leio- placebo-controlled trials (3–5,7), none of these events myoma, and breast cancer. One death, which occurred have been found to be increased in erenumab-treated during the first year of the OLTP at 70 mg, was con- patients relative to placebo, and in fact these events founded by comorbidities, as previously reported (12). were similar to the common events occurring in the double-blind placebo-controlled portion of this and Cardiovascular and cerebrovascular safety. There were only other studies. Furthermore, the exposure-adjusted two patients reporting a cardiovascular event in the patient incidence rates of AE during the OLTP were OLTP, and no patient reported a cerebrovascular lower than the placebo incidence rates from the event (Table 5). An event of myocardial ischemia was DBTP. Sixteen patients discontinued erenumab treat- reported during the first year of the OLTP (12) based ment due to AEs; one patient experienced an AE during on results of an exercise treadmill test confounded by the DBTP that led to treatment discontinuation during sumatriptan administration 4 hours prior to the event. the OLTP (Table 4). None of the AEs leading to treat- Since then, one additional event was reported, which ment discontinuation occurred in more than was increased blood creatine phosphokinase MB that one patient except for rash and depression, which was noted during an evaluation for myocarditis based Ashina et al. 1459 Table 3. Exposure-adjusted patient incidence rates of adverse events. Double-blind treatment phase Open-label treatment phase Erenumab Erenumab Erenumab Erenumab Placebo 70 mg 70 mg 140 mg 70/140 mg (n¼ 153) (n¼ 106) (n¼ 383) (n¼ 250) (n¼ 383) n (r) n (r) n (r) n (r) n (r) All AEs 82 (350.1) 57 (326.2) 323 (142.0) 179 (128.1) 335 (132.0) Grade 2 37 (117.1) 23 (98.0) 245 (66.9) 133 (70.2) 273 (63.6) Grade 3 2 (5.3) 3 (11.5) 55 (8.8) 18 (6.3) 67 (7.7) Serious AEs 0 (0.0) 1 (3.8) 29 (4.4) 14 (4.9) 39 (4.2) AEs leading to discontinuation of IP 2 (5.3) 3 (11.5) 15 (2.2) 1 (0.3) 16 (1.6) Fatal* 0 (0.0) 0 (0.0) 1 (0.1) 0 (0.0) 1 (0.1) Most frequent AEs (>4.0/100 patient-years) Viral upper respiratory tract infection 12 (33.9) 6 (22.3) 85 (14.8) 40 (15.1) 100 (12.9) Upper respiratory tract infection 3 (8.0) 3 (11.4) 52 (8.3) 29 (10.6) 62 (7.2) Sinusitis 2 (5.3) 2 (7.5) 30 (4.6) 15 (5.3) 42 (4.6) Influenza 5 (13.5) 1 (3.8) 36 (5.5) 7 (2.4) 38 (4.2) Back pain 4 (10.8) 1 (3.8) 30 (4.6) 10 (3.5) 38 (4.2) Serious AEs occurring in >1 patient Adjustment disorder 1 (0.1) 1 (0.3) 2 (0.2) Syncope 2 (0.3) 0 (0.0) 2 (0.2) Uterine leiomyoma 1 (0.1) 1 (0.3) 2 (0.2) Breast cancer 2 (0.3) 0 (0.0) 2 (0.2) AEs: adverse events; IP: investigational product; n: number of patients reporting at least one occurrence of event; r: exposure-adjusted patient incidence rate per 100 patient-years (n/e*100). *Fatality, previously reported, due to arteriosclerosis, occurring in patient with prior history of hypertension and left anterior hemiblock (ECG), who on autopsy showed evidence of severe coronary artery disease and presence of cardiac stimulants (liver tissue) – considered not related to the investigational product by the investigator. Note: Each column includes adverse events that occurred while receiving the open-label erenumab at that dose level. Table 4. Exposure-adjusted patient incidence rates of adverse events leading to discontinuation of erenumab during the OLTP. Erenumab 70 mg Erenumab 140 mg Erenumab 70/140 mg (n¼ 383) (n¼ 250) (n¼ 383) n (r) n (r) n (r) AEs leading to discontinuation 15 (2.2) 1 (0.3) 16 (1.6) of investigational product Rash 2 (0.3) 0 (0.0) 2 (0.2) Depression 2 (0.3) 0 (0.0) 2 (0.2) Pancreatic cyst 1 (0.1) 0 (0.0) 1 (0.1) Febrile convulsion 1 (0.1) 0 (0.0) 1 (0.1) Breast cancer 1 (0.1) 0 (0.0) 1 (0.1) Dyspnoea exertional 1 (0.1) 0 (0.0) 1 (0.1) Oedema peripheral 1 (0.1) 0 (0.0) 1 (0.1) Biliary cirrhosis primary 1 (0.1) 0 (0.0) 1 (0.1) Headache 1 (0.1) 0 (0.0) 1 (0.1) Invasive lobular breast carcinoma 1 (0.1) 0 (0.0) 1 (0.1) Syncope 1 (0.1) 0 (0.0) 1 (0.1) Myocardial ischaemia 1 (0.1) 0 (0.0) 1 (0.1) Influenza-like illness 1 (0.1) 0 (0.0) 1 (0.1) Suicide attempt 0 (0.0) 1 (0.3) 1 (0.1) Lung adenocarcinoma stage III 1 (0.1) 0 (0.0) 1 (0.1) n: number of patients reporting at least one occurrence of event; r: exposure-adjusted patient incidence rate per 100 patient-years (n/e*100). 1460 Cephalalgia 39(11) Table 5. Exposure-adjusted patient rates of cardio- and cerebrovascular disorder events during the OLTP. Erenumab 70 mg Erenumab 140 mg Erenumab 70/140 mg (n¼ 383) (n¼ 250) (n¼ 383) n (r) n (r) n (r) Cardiovascular adverse events 2 (0.3) 0 (0.0) 2 (0.2) Ischemic heart disease 2 (0.3) 0 (0.0) 2 (0.2) Cardiac disorders 1 (0.1) 0 (0.0) 1 (0.1) Myocardial ischemia 1 (0.1) 0 (0.0) 1 (0.1) Investigations 1 (0.1) 0 (0.0) 1 (0.1) Blood creatine 1 (0.1) 0 (0.0) 1 (0.1) phosphokinase MB increased Cerebrovascular adverse events 0 (0.0) 0 (0.0) 0 (0.0) n: number of patients reporting at least one occurrence of event; r: exposure-adjusted rate per 100 patient-years. Note: Table based on the following search criteria: Ischemic central nervous system vascular conditions SMQ (narrow), ischemic heart disease SMQ (narrow) and peripheral arterial disease (PAD) AMQ (narrow). Coded using MedDRA version 20.0. Table 6. Incidence of cardiovascular and cerebrovascular events in persons with migraine. # Patients with event Person-years (PY) of Rate (95% CI) (n¼ 741,007 persons) follow-up per 100 PY Cardiovascular events 8,250 1,981,899 0.42 (0.41, 0.43) Cerebrovascular events 11,591 1,978,926 0.59 (0.58, 0.60) Data are incidence rates from MarketScan database of adult patients with migraine identified from January 2010 through December 2011 followed through 30 September, 2015. on symptoms of feeling listless and tired, and intermit- related hepatotoxicity (Table 8). There were eight tent inability to take a full breath after having severe patients with ALT or AST increases greater than three laryngitis for two weeks. This event was adjudicated by times the upper limit of normal (only one with ALT an independent clinical endpoint committee as not greater than five times the upper limit of normal) over being an event of myocardial infarction or hospitaliza- this long-term observation period, corresponding to tion for unstable angina. Given the lack of a placebo 1.8% and 0.8% of patients receiving 70 mg and 140 mg arm, a large claims database of migraine patients was (Table 8). Among the eight patients with ALT or analyzed to establish background rates for cardiovas- AST> 3ULN, one had ALT and AST decreased to cular and cerebrovascular events. The background >1ULN to 3 ULN and the other seven decreased patient incidence rate of cardiovascular events was to< 1 ULN by the latest assessment. The patients with 0.42 per 100 person-years and 0.59 per 100 person- total bilirubin> 2 ULN had total bilirubin reduced years for cerebrovascular events, which are both to> 1 ULN to 1.5 ULN by the latest assessment. higher than the exposure-adjusted cardiovascular and cerebrovascular patient incidence rates in this long- Anti-drug antibodies. No patients in any group had pre- term interim analysis (0.2 per 100 patient-years, and existing antibodies prior to the first erenumab dose. 0.0 per 100 patient-years, respectively) (Table 6). Among 400 subjects with postbaseline results after There were no meaningful changes in systolic/diastolic receiving 70 mg or 140 mg during DBTP or OLTP, 38 blood pressure or heart rate up to 3.3 years of follow- (9.5%) developed non-neutralizing binding antibodies, up (Table 7 and Figure 2). 29 of whom had a transient response (negative result at last time point tested), and three (0.8%) developed neu- Liver function. There were no cases of suspected Hy’s law tralizing antibodies, two of whom had a transient (alanine aminotransferase (ALT) or aspartate amino- response. Since the interim analysis after 52 weeks of transferase (AST)> 3 upper limit of normal (ULN) the OLTP, only two patients have newly developed a and total bilirubin> 2 ULN and alkaline phosphatase positive non-neutralizing binding antibody, both of (ALP)< 2 ULN) predictive of potential for drug- which were transient. Ashina et al. 1461 Table 7. Blood pressure and heart rate at Year 3 during the discontinuation due to constipation. During the pla- OLTP. cebo-controlled studies, constipation events were mild and tended to dissipate over time, so it is unsurprising Erenumab that it is not observed over longer treatment. 70/140 mg Retention rates in long-term clinical trials provide an (n¼ 240) indication of the long-term efficacy and tolerability of Systolic blood pressure, mmHg therapies, and hence are of particular importance in OLTP baseline 118.4 (12.3) chronic conditions. Of 383 patients who entered into Year 3 120.7 (13.1) the OLTP, patient retention rates at year 3 were rela- tively high (62%), highlighting the favorable long-term Patients with increase from OLTP baseline of20 mmHg, n (%) tolerability profile of erenumab and patient satisfaction with treatment, in contrast to those observed in long- <120 mmHg at Year 3 2 (0.8) term studies with other migraine preventatives (18). In 120–129 mmHg at Year 3 7 (2.9) the 8-month open-label extension of the pivotal topir- 130–139 mmHg at Year 3 6 (2.5) amate trials, 29% of participants withdrew and of those 140 mmHg at Year 3 10 (4.2) withdrawing 42% withdrew due to an adverse event Diastolic blood pressure, mmHg (18). The observed discontinuation rate due to reported OLTP baseline 74.9 (9.5) lack of efficacy or adverse events with erenumab in this Year 3 77.7 (9.3) analysis was low (<5%). This is in contrast to the high Patients with increase from discontinuation rates for commonly used migraine OLTP baseline of10 mmHg, n (%) prophylactics (18–20). <80 mmHg at Year 3 11 (4.6) In short-term phase 1 and phase 2 clinical trials of 80–99 mmHg at Year 3 23 (9.6) erenumab (including the double-blind treatment period 100 mmHg at Year 3 18 (7.5) of the study reported here), there was a low incidence of Heart rate, beats/min binding and neutralizing anti-erenumab antibodies. OLTP baseline 70.1 (9.6) The incidence of anti-erenumab antibodies remained low throughout the OLTP, and only two patients devel- Year 3 71.7 (10.2) oped positive non-neutralizing binding antibodies since Note: Data represent mean (SD) unless otherwise indicated. the 52-week interim analysis of the OLTP, indicating n: number of patients with observed results at Year 3. that late development of anti-erenumab antibodies occurs infrequently. The development of anti-erenumab antibodies has not been associated with any clinical Discussion finding or safety events. This three-year interim safety update of a five-year Long-term safety assessments are often complicated long-term open label study confirms the favorable tol- by lack of placebo comparison, which makes it difficult erability and safety profile of erenumab seen in short- to distinguish spontaneously occurring AEs or labora- term and one-year OLE trials (3,4,6,7,12). This tory abnormalities from those due to treatment. In the publication represents the longest-term data for a absence of a placebo comparison, context can be added CGRP pathway-targeted therapy to date and allows to events observed during open-label treatment by for an assessment of the risk-benefit profile of erenu- comparing with background rates observed in real- mab treatment over 3 years of treatment. The safety world settings. Given that CGRP can mediate vaso- profile of erenumab remained in line with that observed dilation, at least in theory inhibition of CGRP’s effects during the DBTP, with no increase in the rate of AEs might pose a vascular risk, though this has not been over time or following the dose increase, and no evi- observed in short-term placebo-controlled erenumab dence of cardiovascular or cerebrovascular risk. studies (3–7). Previously published epidemiological stu- Safety and tolerability profiles during the OLTP dies have shown an increased risk of cardiovascular (total exposure 961 patient-years) were similar to and cerebrovascular events in patients with migraine those observed for erenumab 70 mg in the double- compared to those without migraine, particularly blind parent study (total exposure 23.9 patient-years) among patients who experience migraine with aura and overall were similar to placebo (34.1 patient-years) (15–17). Overall, migraine is significantly associated in the parent study. Although constipation was identi- with myocardial infarction (Odds Ratio (OR)¼ 2.2, fied as a common AE in the pooled analysis of the 95% CI¼ 1.7–2.8) and stroke (OR¼ 1.5, 95% double-blind studies (11), patient incidence rates for CI¼ 1.2–2.1) (21). In the Nurses’ Health Study II, constipation were low in this OLTP (1.8 per 100 adjusted for CV risk factors, the hazard ratios (95% patient-years) and there were no cases of treatment CIs) for women with migraine were 1.50 (1.33–1.69) for 1462 Cephalalgia 39(11) Systolic blood pressure Diastolic blood pressure 150 100 120 75 Year 1 Year 2 Year 3 Year 1 Year 2 Year 3 90 50 BL1234567891011121316192225 28313437 BL12345678910111213 1619 222528 31 34 37 Months Months Heart rate Year 1 Year 2 Year 3 BL12345678910111213 1619 22252831 3437 Months Figure 2. Blood pressure and heart rate over time during the OLTP. BL: Open-label treatment phase baseline; study month: four weeks. Table 8. Incidence of liver function test abnormalities during the OLTP. Erenumab 70 mg Erenumab 140 mg (n¼ 383) (n¼ 250) n (%) n (%) ALT or AST> 3 ULN* 7 (1.8) 2 (0.8) Total bilirubin> 2 ULN 0 (0.0) 1 (0.4) ALT or AST> 3 ULN and total 0 (0.0) 0 (0.0) bilirubin> 2 ULN and ALP< 2 ULN ULN: Upper limit of normal; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase. *Only one case was> 5 ULN for ALT in erenumab 140 mg group. major CV events, 1.39 (1.18–1.64) for MI, 1.62 (1.37– incidence rates. The cardiovascular background rates 1.92) for stroke, and 1.37 (1.02–1.83) for CV mortality (0.42/100 person-years) were higher than those when compared to study participants without migraine observed in the OLTP of this study (0.2/100 patient- (22). In women, migraine with aura was the second years), consistent with the preclinical (23) and clinical strongest single contributor to major cardiovascular observations (24,25) to date that erenumab does not disease risk with an incidence rate of 7.9 per 1000 increase the risk of adverse cardiovascular/cerebrovas- women per year (17). Therefore, in order to context- cular events. ualize cardiovascular/cerebrovascular patient incidence The frequency of elevated ALT or AST> 3 ULN rates in our study, a cohort of patients with migraine during the OLTP with 3 years of exposure was low from the MarketScan claims database of 741,007 per- given the long duration of follow-up. For each of sons over a similar follow-up period as this interim these cases, elevation was< 5 ULN. For context, analysis was analyzed to establish background patient the frequency of ALT or AST elevation> 3 ULN Systolic blood pressure (mmHg) Mean (SD) Heart rate (beats/minute) Mean (SD) Diastolic blood pressure (mmHg) Mean (SD) Ashina et al. 1463 over 12 weeks in the pooled placebo groups of four In this three-plus years, long-term study of an anti- completed studies (3,4,6,7) was 0.5%. Given the much body targeting the CGRP receptor, erenumab was longer period of observation in the OLTP, the low level found to be safe and well-tolerated with a spectrum (> 3 but< 5 ) of AST or ALT elevation in few and rate of AEs consistent with shorter-term placebo- patients supports that long-term treatment with erenu- controlled studies. The favorable tolerability and safety mab does not increase liver function tests. More profile, and the low discontinuation rates, suggest that importantly there were no cases of Hy’s law, which adherence is favorable with erenumab and may result in predicts the potential for severe liver toxicity. positive long-term outcomes. Clinical implications . Erenumab (in the US, erenumab-aooe) is a fully human anti-CGRP receptor monoclonal antibody approved in the US and EU for migraine prevention. . In this three-year, long-term study, erenumab was found to be safe and well-tolerated with a spectrum and rate of adverse events consistent with shorter-term placebo-controlled studies. . The favorable tolerability and safety profile, and the low discontinuation rates, suggest that adherence is favorable with erenumab and may result in positive long-term outcomes. Electrocore LLC, Eli Lilly, eNeura, Neurolief, Novartis, Acknowledgements Ipsen, Impel, Satsuma, Supernus, Sun Pharma (India), This study was fully funded by Amgen Inc. Erenumab is co- Theranica, Teva, Vedanta, WL Gore, Nocira, PSL Group developed in partnership with Amgen Inc. and Novartis. Jon Services, University of British Columbia, Zosano, ZP Opco, Nilsen (Amgen Inc.) provided medical writing support for Foresite Capital, Oppenheimer. CME fees or royalty payments: this manuscript. Healthlogix, Medicom Worldwide, Medlogix Communications, Mednet, Miller Medical, PeerView, WebMD Health/ Declaration of conflicting interests Medscape, Chameleon, Academy for Continued Healthcare The authors declared the following potential conflicts of inter- Learning, Universal meeting management, Haymarket, est with respect to the research, authorship, and/or publica- Global Scientific Communications, Global Life Sciences, tion of this article: MA reports research grants from Global Access Meetings, UpToDate (Elsevier), Oxford Lundbeck Foundation, Research Foundation of the Capital University Press, Cambridge University Press, Wolters Region of Copenhagen, and Novo Nordisk Foundation; con- Kluwer Health; Stock options: Aural analytics, Healint, sulting from Allergan, Amgen Inc., Alder, Eli Lilly, Novartis Theranica, Second Opinon/Mobile Health, Epien, GBS/ and Teva. Nocira, Matterhorn/Ontologics, King-Devick Technologies. PJG reports grants and personal fees from Amgen and Eli- Consulting without fee: Aural Analytics, Healint, Second Lilly and Company, and personal fees from Alder Opinion/Mobile Health, Epien; Board of Directors: Epien, Biopharmaceuticals, Allergan, Autonomic Technologies Matterhorn/Ontologics, King-Devick Technologies. Patent: Inc., Dr Reddy’s Laboratories, Electrocore LLC, eNeura, 17189376.1-1466:vTitle: Botulinum Toxin Dosage Regimen Novartis, Scion, Teva Pharmaceuticals, and Trigemina Inc., for Chronic Migraine Prophylaxis without fee. Professional and personal fees from MedicoLegal work, NEJM Journal society fees or reimbursement for travel: American Academy Watch, Up-to-Date, Oxford University Press, and Wolters of Neurology, American Brain Foundation, American Kluwer; and a patent Magnetic stimulation for headache Headache Society, American Migraine Foundation, assigned to eNeura without fee. International Headache Society, Canadian Headache Society. UR reports consulting fees, speaking/teaching fees, and/or Other: Use agreement through employer: Myndshft. research grants – Allergan, Amgen, Autonomic JK reports employee and stock/stock options: Novartis Technologies, Eli Lilly and Co, Medscape, Novartis, Pharma AG. CoLucid, StreaMedUp, Teva. GR, FZ, SC, and DM report: Employees and stock/stock SS reports consultant/ad board fees: Alder Biopharmaceuticals; options, Amgen Inc. Allergan, Inc.; Amgen; Avanir Pharmaceuticals, Inc.; Curelator, Inc.; Dr. Reddy’s Laboratories; eNeura Inc.; electroCore Medical, LLC; Lilly USA, LLC; Medscape, Funding LLC.; NINDS; Supernus Pharmaceuticals, Inc.; Teva The authors disclosed receipt of the following financial sup- Pharmaceuticals; Theranica; and Trigemina, Inc. port for the research, authorship, and/or publication of this DWD reports the following conflicts: Personal fees: Amgen, article: This study was sponsored by Amgen Inc. 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