Abstract
Erenumab, a fully human monoclonal antibody targeting the calcitonin gene‐related peptide receptor, is efficacious and safe for prevention of attacks of migraine in adults. This phase I, randomized, open‐label, multiple‐dose study evaluated the safety, tolerability, and pharmacokinetics (PK) of erenumab in children and adolescents with migraine. The initial treatment phase lasted 12 weeks, followed by an optional 40‐week extension phase for adolescents. Primary end points were PK of erenumab, incidence of treatment‐emergent adverse events (TEAEs), and changes in clinical and laboratory assessments. Participants received erenumab 35 mg (n = 4), 70 mg (n = 17), or 140 mg (n = 32) q4w. The mean age was 14.1 years. Of the 53 participants, 48 (90.6%) completed the initial treatment phase and 36 (67.9%) received erenumab during the extension phase. Mean exposures to erenumab based on the maximum observed concentration and the area under the drug concentration–time curve during the dosing interval increased approximately dose‐proportionally. A total of 42 participants (79.2%) reported TEAEs (307.2 per 100 participant‐years); and four (7.5%) reported serious TEAEs not considered treatment‐related. The most common TEAEs were upper respiratory tract infection, headache, and vomiting. No clinically significant changes were reported in vital signs, electrocardiograms, and laboratory and neurological assessments. Overall, the observed PK profile of erenumab in children and adolescents with migraine is consistent with that in adults when body weight differences are taken into consideration. The safety profile of erenumab in children and adolescents is consistent with that in adults.
Study Highlights.
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
Erenumab, a fully human monoclonal antibody targeting the calcitonin gene‐related peptide receptor, is efficacious and safe for the prevention of migraine in adults.
WHAT QUESTION DID THIS STUDY ADDRESS?
What is the pharmacokinetic (PK) and safety profile of erenumab in children and adolescents with migraine?
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
This phase I study demonstrated that the PK profile of erenumab in 53 children and adolescents with migraine is similar to that in adults when adjusted for differences in body weight. Erenumab appears safe and well‐tolerated in adolescents and children with migraine.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
This study provides the first clinical pharmacology data for erenumab in children and adolescents, which is critical in informing dosing strategies in ongoing phase III studies evaluating the efficacy and safety of erenumab in these populations.
INTRODUCTION
Migraine is a debilitating neurological disease affecting more than 10% of the global population and is among the leading causes of years lived with disability worldwide. 1 , 2 , 3 In children and adolescents, the prevalence of migraine ranges from 2% to greater than 20% and increases with age. 4 , 5 , 6 , 7
Migraine significantly impacts the social functioning and school performance in children and adolescents in the United States despite acute treatment. 8 , 9 A cross‐sectional analysis of over 34,000 children (ages 6–17 years) from the U.S. National Survey of Children's Health data set found that 1514 (3.7%) had headache as reported by parents. 9 After adjusting for covariates, children with headache had increased school absenteeism and school‐reported problems compared with children without headache.
Treatment options for migraine prevention in children and adolescents are limited. Topiramate is the only US Food and Drug Administration–approved preventive medication for adolescents (≥12 years of age) with migraine. The randomized, double‐blind, placebo‐controlled CHAMP study in over 300 participants 8–17 years old did not identify significant differences in headache frequency reduction or headache‐related disability with amitriptyline, topiramate, or placebo over a 24‐week period. 10 There remains an unmet medical need for new preventive treatments for migraine in children and adolescents.
Erenumab (erenumab‐aooe in the United States) is a fully human monoclonal antibody against the calcitonin gene‐related peptide (CGRP) receptor approved for prevention of attacks of migraine in adults. Erenumab antagonizes CGRP receptor function. The long‐term efficacy and safety of erenumab in migraine prevention has been demonstrated in several global clinical studies in adults. 11 , 12 , 13 , 14 , 15 Erenumab has a well‐established safety and efficacy profile that is superior to established oral standard‐of‐care treatment options in adults with migraine. 16 , 17
The pharmacokinetics (PK) of erenumab in adults was evaluated in phase I, randomized, double‐blind, placebo‐controlled, single‐dose and multiple‐dose studies in patients with migraine and healthy participants. 18 , 19 Erenumab was evaluated at subcutaneous (s.c.) doses of 70 and 140 mg once every 4 weeks (q4w). Erenumab exhibits nonlinear kinetics as a result of binding to the CGRP receptor. 20 Based on data from a single‐dose study, the mean maximum observed concentration (C max; SD) was 6.1 (2.1) μg/mL and 15.8 (4.8) μg/mL for the 70 and 140 mg doses, respectively. 20 The area under the drug concentration–time curve during the dosing interval (AUClast; SD) was 159 (58) day × μg/mL and 505 (139) day × μg/mL, respectively. The effective half‐life of erenumab is ~28 days. Following a single s.c. dose of 70 mg or 140 mg to healthy adults, median peak serum concentrations were attained in ~6 days and estimated absolute bioavailability was 82%. Following a single intravenous (i.v.) dose, the mean (SD) volume of distribution during the terminal phase was estimated to be 3.86 (0.77) L. At low concentrations, erenumab elimination is predominantly through saturable binding to the CGRP receptor, whereas at higher concentrations elimination is largely through a nonspecific, non‐saturable proteolytic pathway. 20
The objective of this study was to evaluate the safety, tolerability, and PK profile of multiple doses of erenumab in children and adolescents with migraine. The dose selection was based on prior experience in adults, where body weight was found to be the only significant covariate influencing PK of erenumab. 18 , 19 In that population PK dataset with a body weight range of 49–104 kg, for every 10 kg increase in body weight, linear clearance and central volume of distribution increased by 11% and 14%, respectively. 19 Adolescents (12 to <18 years of age) tend to overlap with adults in terms of body weight, whereas the body weight of children (6 to <12 years of age) is roughly 50% that of adolescents. Thus, it was hypothesized that the PK profile of 35 and 70 mg q4w dosing in patients weighing less than 40 kg would be similar to that of 70 and 140 mg q4w dosing, respectively, in children, adolescents, and adults weighing greater than or equal to 40 kg.
METHODS
Study design
This was a phase I, multicenter, randomized, open‐label, multiple‐dose study to evaluate the safety, tolerability, and PK of erenumab in children (6 to <12 years of age) and adolescents (12 to <18 years of age) with migraine (Figure S1). This study was conducted at nine centers in the United States. Participants had to weigh at least 18 kg at the time of consent and were grouped according to baseline body weight (<40 kg [cohort 1] and ≥40 kg [cohort 2]). Participants in cohort 1 were randomized in a 1:2 ratio to receive either 35 or 70 mg erenumab q4w; participants in cohort 2 were randomized in a 1:4 ratio to receive either 70 or 140 mg erenumab q4w. The study consisted of a 12‐week initial treatment phase for all participants followed by an optional 40‐week extension phase for adolescents (12 to <18 years). Erenumab was administered three times in the initial treatment phase—on days 1, 29, and 57. The study ran from May 4, 2018, to November 23, 2021.
The study protocol and all amendments, the informed consent form, and any accompanying materials provided to participants and their guardians were reviewed and approved by an institutional review board at each study center. The study was conducted in accordance with International Conference on Harmonization Good Clinical Practice guidelines, the Declaration of Helsinki, and local regulations. All participants provided written informed consent prior to inclusion. The study protocol was registered with ClinicalTrials.gov (NCT03499119).
Participants
Participants were male and female children and adolescents 6 to less than 18 years of age with a body weight greater than or equal to 18 kg and a history of migraine (with or without aura) according to International Classification of Headache Disorders‐III for greater than or equal to 12 months and greater than or equal to 4 monthly migraine days for at least 3 months before screening. Enrollment was staggered by age category, with adolescents (i.e., participants 12 to <18 years of age) starting enrollment first.
Participants were excluded if they had used more than two migraine‐preventive medications within the past 1 month or used opioid or butalbital‐containing analgesics on greater than or equal to 4 days per month for any indication within 2 months before screening. Concomitant use of agents for the prevention of migraine (up to 2 treatments on a stable dose) and for the acute treatment of migraine were permitted during the study. Additional exclusions included history of migraine with brainstem aura or hemiplegic migraine headache; history of hypertension; history of chronic or frequent clinically significant painful condition other than migraine; history of chronic anemia; or uncontrolled asthma or uncontrolled diabetes.
Objectives and end points
The primary objective was to evaluate the safety, tolerability, and PK profile of multiple s.c. doses of erenumab in children and adolescents with migraine. Primary end points were treatment‐emergent adverse events (TEAEs); changes in vital signs; 12‐lead electrocardiograms (ECGs); clinical laboratory assessments; neurological assessments; and serum PK parameters of erenumab, including time to maximum concentration (T max), C max, trough concentration (C trough), and AUC from 0 to 28 days (AUCtau; where tau is the approximate duration of the dosing interval).
Exploratory end points included change from baseline in Modified Pediatric Migraine Disability Assessment (PedMIDAS) 21 total score, occurrence of anti‐erenumab antibodies, and effect of erenumab on suicide ideation, as evaluated by Columbia Suicide Severity Rating Scale (C‐SSRS).
PK sample collection and bioanalysis method
Serum samples were obtained from all participants at predose and at scheduled timepoints throughout the study (days 1 [prior to dose of erenumab], 4 [later removed by protocol amendment], 8, 15, 29 [prior to dose of erenumab], 57 [prior to dose of erenumab], 64, 71, 85, and 169 [safety follow‐up visit]) for determination of erenumab concentrations using a validated assay. 19
Anti‐erenumab antibody sample collection and bioanalysis method
Serum samples for anti‐erenumab antibody assessment were collected at baseline (before the first drug administration) and at regular intervals throughout the study. Serum samples were first tested in a validated electrochemiluminescence‐based bridging immunoassay to detect antibodies capable of binding to erenumab (anti‐erenumab binding antibodies) and positive samples were subsequently tested in a cell‐based bioassay to determine the neutralizing activity against erenumab (anti‐erenumab neutralizing antibodies). 22
Statistical analysis
Sample size determination
A total of 52–60 participants were planned for the study, including 12–22 in cohort 1 (<40 kg) and 35–38 in cohort 2 (≥40 kg). It was anticipated that most participants in cohort 1 would be 6 to <12 years of age and participants in cohort 2 would be 12 to <18 years of age. The sample size, based on clinical and practical considerations, was consistent with sample sizes used in phase I studies. Assuming PK parameters are similar among children, adolescents, and adults, the proposed sample size provided greater than 80% power to estimate 95% confidence intervals within 60%–140% of the true parameters for both weight cohorts combined and across the two age categories. 23
Overall analysis
The safety analysis set included randomized participants who received greater than or equal to one dose of investigational product (IP). No formal hypothesis testing was performed. Descriptive statistics were provided for selected demographic, safety, and PK data for the safety analysis set. Descriptive statistics on continuous measurements included means, medians, SDs, first quartiles, third quartiles, minimums, and maximums, whereas categorical data were summarized using frequency counts and percentages.
PK analyses
Noncompartmental analysis (NCA) was performed for erenumab PK parameter estimation using Phoenix WinNonlin version 8.3.2 software (Certara). The following PK parameters were estimated: (a) C max after s.c. administration, (b) T max, (c) AUCtau, where tau is equal to about 28 days after dosing, estimated using the linear trapezoidal method for dose one and dose three and utilized AUClast, as long as the actual sampling time for the nominal day 29 and day 85 samples were within 25 to 31 days after the prior dose (e.g., approximately within 11% of nominal time), (d) accumulation ratio (AR) calculated as AUCtau,dose3/AUCtau,dose1, (e) C trough, estimated by the predose concentration at days 29, 57, and 85.
Data were excluded from the erenumab concentration summary statistics if subjects missed the previous dose or if actual time deviated from by more than 30% from the nominal sample collection time. Data were excluded from the NCA if subjects missed the previous dose, if the intensive PK profile was missing more than two samples, or if PK values at either the beginning or the end of the intensive PK profile were missing. For calculation of AUCtau, the nominal day 29 and day 85 samples were required to fall within 25–31 days postdose to be included. Entire subject profiles were excluded from the NCA if the predose PK sample concentration on day 1 was greater than 5% of their C max value.
Anti‐erenumab antibody (binding and neutralizing) formation were assessed at predose and at various timepoints throughout the study, including end of study. Anti‐erenumab antibody data were reviewed for each participant. The incidence and percentage of participants who developed anti‐erenumab antibodies (binding and, if positive, neutralizing) at any time were tabulated.
Safety analyses
Safety data included summaries by body weight and erenumab dosage group. The participant incidence and exposure‐adjusted participant incidence of all TEAEs, serious TEAEs, device‐related TEAEs, TEAEs leading to discontinuation of the IP, and fatal adverse events (AEs) were summarized. The Medical Dictionary for Regulatory Activities version 24.0 was used to code each AE to a system organ class and preferred term. The severity of each AE was graded using the Common Terminology Criteria for Adverse Events version 4.03. Additional safety analyses, including vital signs, clinical laboratory tests, neurological assessments, ECGs, and C‐SSRS results were summarized by group. The C‐SSRS is a clinician rating of suicidal behavior and ideation, and it was administered to study subjects at each study visit.
Modified PedMIDAS
The change from baseline in migraine‐related disability and productivity was summarized at each timepoint based on scoring of the modified PedMIDAS using a 1‐month recall period. This modified PedMIDAS score is the sum of scores from six questions indicating the number of productive days lost due to headache over the past month in school as well as the home setting, with a higher score indicating a worse outcome. The only modification was the recall interval change from the standard, validated 3‐month interval to a shorter 1‐month interval. The use of PedMIDAS is only for general observation of disability and impact and not powered for response patterns to be evaluated. It was intended to be self‐administered by the participant and their parent.
RESULTS
Participant disposition and demographics
A total of 53 participants were randomized and administered erenumab during the initial treatment phase (Table 1, Figure S2). Participants weighing less than 40 kg at baseline were enrolled in cohort 1 (n = 13) and received either 35 mg (n = 4) or 70 mg (n = 9). Participants weighing greater than or equal to 40 kg at baseline were enrolled in cohort 2 (n = 40) and received either 70 mg (n = 8) or 140 mg (n = 32). Of the 53 participants, 48 (90.6%) completed treatment with the IP during the initial treatment phase; five (9.4%) discontinued treatment with the IP because of either AEs (n = 2 [3.8%]) or decision by the sponsor (n = 3 [5.7%]; two participants were discontinued due to clinical site closure and one due to coronavirus disease 2019‐related lockdown). A total of 36 (67.9%) participants received erenumab during the extension phase, with 29 (80.6%) completing treatment; seven (19.4%) discontinued treatment with the IP because of participant request (n = 5 [13.9%]), loss to follow‐up (n = 1 [2.8%]), or protocol deviation (n = 1 [2.8%]).
TABLE 1.
Baseline demographics.
| Cohort 1 (<40 kg) | Cohort 2 (≥40 kg) | Overall (N = 53) | |||
|---|---|---|---|---|---|
| Erenumab 35 mg q4w s.c. (n = 4) | Erenumab 70 mg q4w s.c. (n = 9) | Erenumab 70 mg q4w s.c. (n = 8) | Erenumab 140 mg q4w s.c. (n = 32) | ||
| Age, mean (SD), years | 10.8 (1.7) | 10.4 (1.0) | 14.6 (1.3) | 15.4 (1.5) | 14.1 (2.5) |
| Children (6 to <12 years), n (%) | 3 (75.0) | 7 (77.8) | 0 (0.0) | 0 (0.0) | 10 (18.9) |
| Adolescents (12 to <18 years), n (%) | 1 (25.0) | 2 (22.2) | 8 (100.0) | 32 (100.0) | 43 (81.1) |
| Sex, n (%) | |||||
| Male | 3 (75.0) | 6 (66.7) | 4 (50.0) | 9 (28.1) | 22 (41.5) |
| Female | 1 (25.0) | 3 (33.3) | 4 (50.0) | 23 (71.9) | 31 (58.5) |
| Race, n (%) | |||||
| White | 4 (100.0) | 6 (66.7) | 7 (87.5) | 26 (81.3) | 43 (81.1) |
| Black/African American | 0 (0.0) | 2 (22.2) | 1 (12.5) | 4 (12.5) | 7 (13.2) |
| Weight, mean (SD), kg a | 34.1 (4.7) | 35.5 (3.3) | 62.9 (10.8) | 70.1 (15.4) | 60.4 (19.5) |
| BMI, mean (SD), kg/m2 | 16.5 (1.4) | 17.7 (1.1) | 23.5 (4.6) | 24.9 (5.1) | 22.8 (5.4) |
Abbreviations: BMI, body mass index; q4w, once every 4 weeks; s.c., subcutaneous; SD, standard deviation.
One subject weighing 40.7 kg was incorrectly randomized to cohort 1. They received the 70 mg erenumab dose.
Of the 53 participants, 22 (41.5%) were male subjects, 31 (58.5%) were female subjects, and 43 (81.1%) were White (Table 1). The mean (SD) age was 14.1 (2.5) years (range, 9–17). Ten participants (18.9%) were children 6 to less than 12 years old and 43 participants (81.1%) were adolescents 12 to less than 18 years old. In cohort 1, one participant in the 35 mg group and two participants in the 70 mg group were adolescents and all other participants were children. In cohort 2, all participants were adolescents. The mean (SD) weight in cohort 1 was 34.1 (4.7) kg for the 35 mg group and 35.5 (3.3) kg for the 70 mg group, and the mean (SD) weight in cohort 2 was 62.9 (10.8) kg for the 70 mg group and 70.1 (15.4) kg for the 140 mg group.
Pharmacokinetics
Erenumab was administered as multiple s.c. doses of 35, 70, or 140 mg q4w in children and adolescents with migraine. Mean (SD) serum concentration–time profile is presented in Figure 1, and descriptive statistics of NCA parameter estimates are summarized in Tables 2 and 3. In cohort 1, median T max after the first and third doses was 7.0–7.2 days with erenumab 35 mg and 7.0–10.0 days with erenumab 70 mg. In cohort 2, T max after the first and third doses was 9.0 days with erenumab 70 mg and 7.0–7.2 days with erenumab 140 mg. Mean exposures to erenumab based on C max and AUCtau following the third dose increased in an approximate dose‐proportional manner for the increase in dose from 35 to 70 mg in cohort 1 and the increase in dose from 70 to 140 mg in cohort 2. After the first dose, mean exposures to erenumab 35 and 70 mg in cohort 1 were similar to those of erenumab 70 and 140 mg, respectively, in cohort 2. After the third dose, mean exposures to erenumab 70 and 140 mg in cohort 2 were numerically higher than those of erenumab 35 and 70 mg, respectively, in cohort 1.
FIGURE 1.
Mean (SD) serum concentration–time profile of erenumab based on cohort assignment and erenumab dose in linear‐linear (a) and linear‐log (b) scales. SD, standard deviation.
TABLE 2.
PK parameter estimates following administration of erenumab in cohort 1 (<40 kg).
| First dose | Third dose | ||||||
|---|---|---|---|---|---|---|---|
| T max (days) | C max (μg/mL) | AUCtau (day*μg/mL) | T max (days) | C max (μg/mL) | AUCtau (day*μg/mL) | AR AUCtau | |
| 35 mg q4w s.c. | |||||||
| n | 3 | 3 | 2 | 3 | 3 | 3 | 2 |
| Mean | 7.92 | NR | 11.3 | 229 | NR | ||
| SD | 0.947 | NR | 3.14 | 47.7 | NR | ||
| Minimum | 2.9 | 6.83 | 165 | 7.0 | 7.68 | 176 | 1.46 |
| Median | 7.0 | 8.47 | 175 | 7.2 | 12.9 | 243 | 1.47 |
| Maximum | 7.2 | 8.47 | 185 | 8.0 | 13.3 | 269 | 1.47 |
| CV% | 12 | NR | 28 | 21 | NR | ||
| Geometric mean | 7.88 | NR | 11.0 | 226 | NR | ||
| CV% geometric mean | 12 | NR | 32 | 22 | NR | ||
| 70 mg q4w s.c. | |||||||
| n | 9 | 9 | 6 | 9 | 9 | 6 | 4 |
| Mean | 13.3 | 251 | 18.9 | 482 | 1.68 | ||
| SD | 4.85 | 108 | 7.29 | 115 | 0.192 | ||
| Minimum | 2.9 | 3.08 | 65.8 | 7.0 | 3.18 | 336 | 1.45 |
| Median | 7.0 | 14.0 | 282 | 10 | 20.3 | 465 | 1.70 |
| Maximum | 14 | 20.0 | 357 | 21 | 30.0 | 667 | 1.87 |
| CV% | 37 | 43 | 39 | 24 | 11 | ||
| Geometric mean | 12.0 | 221 | 16.7 | 471 | 1.67 | ||
| CV% geometric mean | 60 | 70 | 73 | 24 | 12 | ||
Note: The PK analysis set contained all randomized subjects who received at least one dose of erenumab and had at least one PK concentration result.
Abbreviations: AR, accumulation ratio calculated as (AUCtau,Dose3)/(AUCtau,Dose1); AUCtau, area under the concentration–time curve (AUC) for the dosing interval (0–28 days after dosing), estimated using the linear trapezoidal method; C max, maximum observed drug concentration; CV, coefficient of variation; NR, not reported; PK, pharmacokinetic; q4w, every 4 weeks; s.c., subcutaneous; SD, standard deviation; T max, time to reach C max.
TABLE 3.
PK parameter estimates following administration of erenumab in cohort 2.
| First dose | Third dose | ||||||
|---|---|---|---|---|---|---|---|
| T max (days) | C max (μg/mL) | AUCtau (day*μg/mL) | T max (days) | C max (μg/mL) | AUCtau (day*μg/mL) | AR AUCtau | |
| 70 mg q4w s.c. | |||||||
| n | 8 | 8 | 6 | 7 | 7 | 5 | 5 |
| Mean | 7.16 | 147 | 14.1 | 304 | 1.93 | ||
| SD | 1.76 | 31.3 | 5.54 | 111 | 0.433 | ||
| Minimum | 2.9 | 4.84 | 112 | 6.0 | 7.89 | 180 | 1.33 |
| Median | 9.0 | 7.16 | 151 | 9.0 | 14.1 | 329 | 2.16 |
| Maximum | 15 | 10.1 | 192 | 26 | 22.3 | 437 | 2.28 |
| CV% | 25 | 21 | 39 | 37 | 22 | ||
| Geometric mean | 6.97 | 144 | 13.2 | 286 | 1.89 | ||
| CV% geometric mean | 25 | 22 | 41 | 41 | 25 | ||
| 140 mg q4w s.c. | |||||||
| n | 30 | 30 | 19 | 27 | 27 | 21 | 16 |
| Mean | 13.4 | 300 | 23.7 | 539 | 1.71 | ||
| SD | 4.53 | 102 | 8.83 | 217 | 0.309 | ||
| Minimum | 2.9 | 7.92 | 175 | 4.0 | 11.8 | 259 | 1.06 |
| Median | 7.0 | 12.2 | 277 | 7.2 | 22.3 | 475 | 1.73 |
| Maximum | 16 | 25.8 | 551 | 15 | 48.5 | 1000 | 2.10 |
| CV% | 34 | 34 | 37 | 40 | 18 | ||
| Geometric mean | 12.8 | 285 | 22.2 | 500 | 1.68 | ||
| CV% geometric mean | 31 | 33 | 37 | 41 | 20 | ||
Note: The PK analysis set contained all randomized subjects who received at least one dose of erenumab and had at least one PK concentration result.
Abbreviations: AR, accumulation ratio calculated as (AUCtau,Dose3)/(AUCtau,Dose1); AUCtau, area under the concentration–time curve (AUC) for the dosing interval (0–28 days after dosing), estimated using the linear trapezoidal method; C max, maximum observed drug concentration; CV, coefficient of variation; PK, pharmacokinetic; q4w, every 4 weeks; s.c., subcutaneous; SD, standard deviation; T max, time to reach C max.
Mean (SD) C trough values ranged from 3.92 (0.626) to 7.77 (2.79) μg/mL across all cohorts following the first dose. Following the third dose, mean (SD) C trough values ranged from 5.43 (0.861) to 14.9 (5.87) μg/mL across all cohorts. Mean AR ranged from 1.71 to 1.93 from the first dose to the third dose across all cohorts.
One of 52 patients (1.9%) developed anti‐erenumab binding antibodies. The patient was from the 70 mg group of cohort 1, who had had a single binding antibody positive sample result at the safety follow‐up visit during the initial treatment phase (after 12‐week treatment), which was the last on‐study antibody assessment for the patient. This individual did not have any AEs reported and had PK concentrations similar to those of others in the same dose group. No participant developed anti‐erenumab neutralizing antibodies at any time during the study.
Safety and tolerability
The safety analysis set included all 53 participants who received erenumab. During the initial treatment phase, 10 children and 43 adolescents received the IP, up to three doses. During the optional extension phase, 35 adolescents (12 to <18 years) received the IP, up to 10 doses (13 doses total). The mean (SD) erenumab exposure was 248.9 (137.8) days. The total exposure to treatment was 36.1 participant‐years. During the entire study, 42 participants (79.2%) reported TEAEs (Table 4). The exposure‐adjusted participant incidence of TEAEs per 100 participant‐years was 307.2. Most of the AEs were of grade 2 or lower severity. The most common AEs were upper respiratory tract infection, headache, and vomiting, each occurring in 10 participants (18.9%).
TABLE 4.
Summary of exposure‐adjusted incidence of TEAEs.
| Cohort 1 (<40 kg) | Cohort 2 (≥40 kg) | Overall (N = 53) | |||
|---|---|---|---|---|---|
| Erenumab 35 mg q4w s.c. (n = 4) | Erenumab 70 mg q4w s.c. (n = 9) | Erenumab 70 mg q4w s.c. (n = 8) | Erenumab 140 mg q4w s.c. (n = 32) | ||
| TEAEs, n (%)/e [r] | 2 (50.0)/1.5 [132.8] | 6 (66.7)/2.0 [301.9] | 6 (75.0)/2.3 [258.4] | 28 (87.5)/7.9 [356.5] | 42 (79.2)/13.7 [307.2] |
| Serious AEs | 0 (0.0)/2.2 [0.0] | 1 (11.1)/5.4 [18.4] | 1 (12.5)/7.5 [13.3] | 2 (6.3)/29.7 [6.7] | 4 (7.5)/44.9 [8.9] |
| Leading to IP discontinuation | 0 (0.0)/2.2 [0.0] | 0 (0.0)/5.8 [0.0] | 0 (0.0)/7.6 [0.0] | 2 (6.3)/31.1 [6.4] | 2 (3.8)/46.6 [4.3] |
| Most common TEAEs (>7% overall population), n (%)/e [r] | |||||
| Upper respiratory tract infection | 0 (0.0)/2.2 [0.0] | 0 (0.0)/5.8 [0.0] | 2 (25.0)/6.3 [31.5] | 8 (25.0)/26.4 [30.3] | 10 (18.9)/40.8 [24.5] |
| Headache | 0 (0.0)/2.2 [0.0] | 1 (11.1)/5.3 [18.9] | 2 (25.0)/7.2 [27.6] | 7 (21.9)/26.9 [26.0] | 10 (18.9)/41.6 [24.0] |
| Vomiting | 0 (0.0)/2.2 [0.0] | 1 (11.1)/5.3 [18.7] | 3 (37.5)/6.8 [44.2] | 6 (18.8)/27.4 [21.9] | 10 (18.9)/41.7 [24.0] |
| Abdominal pain upper | 1 (25.0)/1.9 [52.2] | 0 (0.0)/5.8 [0.0] | 0 (0.0)/7.6 [0.0] | 5 (15.6)/27.2 [18.4] | 6 (11.3)/42.5 [14.1] |
| Abdominal pain | 0 (0.0)/2.2 [0.0] | 0 (0.0)/5.8 [0.0] | 0 (0.0)/7.6 [0.0] | 5 (15.6)/28.3 [17.7] | 5 (9.4)/43.9 [11.4] |
| Nausea | 0 (0.0)/2.2 [0.0] | 1 (11.1)/5.3 [18.7] | 0 (0.0)/7.6 [0.0] | 4 (12.5)/29.6 [13.5] | 5 (9.4)/44.8 [11.2] |
| Gastroenteritis viral | 0 (0.0)/2.2 [0.0] | 0 (0.0)/5.8 [0.0] | 0 (0.0)/7.6 [0.0] | 4 (12.5)/27.9 [14.3] | 4 (7.5)/43.5 [9.2] |
| Nasal congestion | 0 (0.0)/2.2 [0.0] | 0 (0.0)/5.8 [0.0] | 1 (12.5)/6.4 [15.7] | 3 (9.4)/29.3 [10.2] | 4 (7.5)/43.7 [9.1] |
| Nasopharyngitis | 0 (0.0)/2.2 [0.0] | 0 (0.0)/5.8 [0.0] | 1 (12.5)/7.3 [13.8] | 3 (9.4)/29.0 [10.4] | 4 (7.5)/44.2 [9.0] |
| Dizziness | 0 (0.0)/2.2 [0.0] | 0 (0.0)/5.8 [0.0] | 0 (0.0)/7.6 [0.0] | 4 (12.5)/29.3 [13.6] | 4 (7.5)/44.9 [8.9] |
| Epistaxis | 0 (0.0)/2.2 [0.0] | 2 (22.2)/4.4 [45.6] | 1 (12.5)/6.9 [14.4] | 1 (3.1)/31.2 [3.2] | 4 (7.5)/44.8 [8.9] |
| Cough | 0 (0.0)/2.2 [0.0] | 1 (11.1)/5.5 [18.2] | 1 (12.5)/7.6 [13.2] | 2 (6.3)/30.6 [6.5] | 4 (7.5)/45.8 [8.7] |
Abbreviations: AEs, adverse events; e, sum across all subjects, the total time at risk in years. Time at risk is defined as time from first IP dose date through to onset of first event or EOS date; IP, investigational product; q4w, once every 4 weeks; r, exposure‐adjusted subject incidence per 100 subject years (n/e * 100); s.c., subcutaneous; TEAE, treatment‐emergent adverse event.
Two participants (3.8%) had AEs of headache leading to discontinuation of erenumab during the initial treatment phase. Both participants were adolescents in the 140 mg group of cohort 2. One participant had a grade 1 headache possibly related to the IP and the other had a grade 2 headache judged not related to the IP.
Serious TEAEs were reported for four participants (7.5%). One adolescent in the 140 mg group of cohort 2 reported grade 2 gastritis during the open‐label extension phase; one adolescent in the 140 mg group of cohort 2 reported grade 3 appendicitis during the initial treatment phase; one adolescent in the 70 mg group of cohort 2 reported a grade 4 suicide attempt during the initial treatment phase; and one adolescent in the 70 mg group of cohort 1 reported grade 4 suicidal ideation during the open‐label extension phase. No action was taken with the IP for any of the serious AEs, and none was considered related to treatment. The adolescent who attempted suicide did so due to intractable headache and pressures with schoolwork. Medical history included adjustment disorder with mixed anxiety and depressive mood. The participant with grade 4 suicidal ideation reported a recent family argument and had a medical history that included attention deficit hyperactivity disorder, depression, oppositional defiance disorder, and disruptive behavior disorder.
There were no deaths during the study.
No clinically significant findings were observed for vital signs, ECGs, clinical laboratory tests, and neurological assessments.
Modified PedMIDAS
Efficacy was not evaluated in this study. An exploratory objective of the study was to evaluate the effect of erenumab on migraine‐related disability and productivity as measured by the modified (monthly) PedMIDAS patient‐reported outcome. Reductions in PedMIDAS total score were observed in each cohort and dose group, which were maintained during the extension phase, indicating improvements in outcome (Table S1).
DISCUSSION
PK and safety results from a phase I, multicenter, randomized, open‐label, multiple‐dose study of erenumab in children and adolescents with migraine are presented. Overall, erenumab was well‐tolerated and had a manageable safety profile in 53 participants between 9 and 17 years old at doses ranging from 35 to 140 mg q4w. The PK profile of erenumab in children and adolescents with migraine appears to be qualitatively similar to that in adults with migraine when body weight is considered. 18 , 19 Based on cross‐study comparison with previously published PK in healthy adults, mean erenumab exposures in children and adolescents based on AUC and C max appear to be within twofold of adult exposures when body weight is accounted for (e.g., exposures in children <40 kg receiving 35 mg q4w or 70 mg q4w exposures appear to be similar to adult exposures at 70 mg q4w or 140 mg q4w, respectively; exposures in children and adolescents greater than or equal to 40 kg receiving 70 mg q4w or 140 mg q4w appear to be similar to adult exposures at the same doses). 18 , 19 Observed accumulation ratios were consistent with those observed in adults. 18 Statistical testing for differences in PK across cohorts was not prespecified or conducted in this study. Mean erenumab serum exposures in this study appear to increase with increasing dose, and appear to vary based on body weight across cohorts. These findings potentially support differentiating low and high doses for children and adolescents based on body weight in future studies.
AE profiles for participants enrolled in cohort 1 (subjects weighing <40 kg) and cohort 2 (subjects weighing ≥40 kg) were generally consistent across cohorts and dosing groups considering the relatively small sample sizes and differences in exposure between cohorts. The safety profile of erenumab in children (age 6 to <12 years) and adolescents (age 12 to <18 years) appears to be consistent with the known safety profile of erenumab in adults; no new or unexpected safety signals were identified.
The finding that one of 52 participants with immunogenicity data available (1.9%) had anti‐erenumab binding antibodies was consistent with prior studies in adults. A post hoc analysis assessing immunogenicity of erenumab across six clinical trials in participants with episodic and chronic migraine found that the incidence of development of anti‐erenumab binding antibodies was low (2.7–5.0%), and a small proportion of the participants (0%–0.2%) developed neutralizing antibodies during the double‐blind treatment period of these studies. 22 The analysis found that immunogenicity had no meaningful clinical impact on efficacy or safety of erenumab in participants with migraine.
Efficacy was not evaluated in this study. However, an exploratory analysis using a modified PedMIDAS suggested that erenumab reduced migraine‐related disability. The PedMIDAS questionnaire is a reliable and valid assessment of the disability of childhood and adolescent headaches. PedMIDAS is an assessment of the impact and disability of migraine over a 3‐month period, so this monthly assessment suggests that a longer assessment may show additional benefit consistent with PedMIDAS validation. The 1‐month recall has not been validated for PedMIDAS, thus assessment of efficacy in this small PK study is limited. In addition, imbalances existed in baseline PedMIDAS mean scores between groups. However, the direction of change in PedMIDAS suggests positive benefit on disability. A larger study with the validated 3‐month recall for PedMIDAS should be expected to support this observation.
Currently, no migraine‐specific preventive medications are approved for children and adolescents with migraine. Nonspecific migraine‐preventive medications approved in children and adolescents include propranolol in Finland for children greater than 7 years of age and topiramate in the United States for adolescents. A systematic review and network meta‐analysis of randomized clinical trials of preventive pharmacologic treatments in children and adolescents found that propranolol and topiramate were significantly more effective than placebo in the short term (<5 months); however, no significant long‐term effects for migraine prophylaxis relative to placebo were found for any intervention. 24 In addition, both of these drugs can negatively impact school and social life. The CHAMP study in children and adolescents did not identify significant differences in headache frequency reduction or headache‐related disability with amitriptyline, topiramate, or placebo over a 24‐week period. 10 There remains a significant unmet medical need for migraine prevention in children and adolescents.
A limitation of this study is the small sample size. The study only included 10 participants who were children (6 to <12 years) and 13 participants who weighed less than 40 kg, limiting the generalizability of these findings. However, the sample size generally aligns with those of other phase I studies in children and adolescents. 25 , 26 , 27 Additionally, the calculation of AUCtau was based on a limited number of PK samples during the dosing interval (4 or 5), and some subjects had different numbers of PK samples after dose 1 (4 or 5 samples) versus dose 3 (4 samples) which were used to calculate AUC, and, therefore, the corresponding AR between dose 1 and dose 3. Given the long half‐life of erenumab, we anticipate that these limitations to the sampling scheme and the PK parameter calculations had a minor impact. Another limitation of the study is that AUCtau could not be calculated for all enrolled participants due to PK parameter exclusions, resulting in a limited number of AUC and AR values. One subject weighing 40.7 kg was incorrectly randomized to cohort 1 and received the 70 mg erenumab dose. The study was also geographically limited to the United States and included a preponderance of White participants (81.1%), potentially limiting the generalizability of these findings. The study did not include a placebo comparator group, so the observations reported here need to be confirmed in an adequately powered, randomized, placebo‐controlled study. The descriptive nature of data reporting limits the potential for comparisons.
Based on the results of the current study, erenumab is being further investigated in the phase III, randomized, placebo‐controlled OASIS studies in children and adolescents with chronic (NCT03832998) or episodic (NCT03836040) migraine. Safety and PK insights from the current study informed the dosing strategy for these phase III studies.
AUTHOR CONTRIBUTIONS
A.D.H., G.P.dS.L., N.P., M.M., R.K., and J.W.M. wrote the manuscript. A.D.H. and G.P.dS.L. designed the research. A.D.H. and J.W.M. performed the research. A.D.H., G.P.dS.L., N.P., M.M., R.K., and J.W.M. analyzed the data.
FUNDING INFORMATION
Amgen provided financial support for the study and participated in the study design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript.
CONFLICT OF INTEREST STATEMENT
A.D.H. has served as an advisor and/or received funding for his institution or himself from Alder/Lundbeck, Allergan/AbbVie, Amgen, Biohaven/Pfizer, Curelator, Lilly, Teva, Theranica, Upsher‐Smith, and NIH. G.P.dS.L., N.P., M.M., and R.K. are/were employees of Amgen at the time the study was conducted. G.P.dS.L., N.P., and M.M. disclose Amgen stock ownership. J.W.M. has received research funding from AbbVie, Amgen, Biohaven/Pfizer, Eli Lilly, Lundbeck, Teva, and Theranica and speaker/consultant fees from AbbVie, Otsuka, Eli Lilly, and Neurelis.
Supporting information
Table S1
ACKNOWLEDGMENTS
Additional biostatistical support was provided by Deyuan Jiang and immunogenicity analysis for anti‐drug antibodies by Yanchen Zhou. Medical writing support was provided by Eugene Gillespie, PhD, Qais Al‐Hadid, PhD, and Sara Chiou, PhD (all employees of Amgen Inc.). Graphical support was provided by Robert Dawson (Cactus Communications on behalf of Amgen Inc.).
Hershey AD, Paiva da Silva Lima G, Pannacciulli N, Mackowski M, Koukakis R, McVige JW. Pharmacokinetics and safety of erenumab in pediatric patients with migraine: A phase I, randomized, open‐label, multiple‐dose study. Clin Transl Sci. 2024;17:e13755. doi: 10.1111/cts.13755
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Associated Data
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Supplementary Materials
Table S1