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Eptinezumab is safe and effective in preventing chronic and episodic migraine
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Eptinezumab efficacy and safety are independent of gender, age, and BMI
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Eptinezumab was effective regardless of migraine disease characteristics
ABSTRACT
Purpose
In the PROMISE-1 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-1) and PROMISE-2 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2) clinical trials, eptinezumab 100 mg and 300 mg met the primary efficacy end point, significantly reducing mean monthly migraine days across weeks 1 to 12. Clinical efficacy was also shown across key secondary end points. However, to determine if clinical efficacy varies across subgroups, it is necessary to determine efficacy in patients with different sociodemographic features and headache characteristics. These post hoc analyses of patients in PROMISE-1 and PROMISE-2 evaluated the impact of intrinsic factors on the efficacy and safety of eptinezumab in subgroups defined according to baseline demographic and migraine disease characteristics.
Methods
PROMISE-1 and PROMISE-2 were Phase III, parallel-group, double-blind, randomized, placebo-controlled trials of repeat quarterly intravenous infusions of eptinezumab or placebo in adults with episodic (PROMISE-1) or chronic (PROMISE-2) migraine.
Findings
Demographic and baseline characteristics were similar across treatment groups in both the PROMISE-1 and the PROMISE-2 studies. Analyses did not show a clear pattern of baseline demographic characteristics driving treatment effects except for the obesity subgroups. For the ≥50% migraine responder rate in the obese class I (body mass index 30.0–35.0 kg/m2) subgroup, although separation from placebo was not as large (<10% separation compared with ≥10% separation across most baseline demographic factors), both doses showed improved ≥50% migraine responder rate compared with placebo, with slightly better results in patients receiving eptinezumab 300 mg.
Implications
Eptinezumab treatment showed consistent clinically relevant reductions from baseline in mean monthly migraine days compared with placebo based on ≥50% migraine responder rate across clinically important intrinsic subgroups of adults with episodic or chronic migraine. ClinicalTrials.gov identifiers: NCT02559895 (PROMISE-1) and NCT02974153 (PROMISE-2).
Migraine is more prevalent in women (20.7% vs 9.7% in men) and during young adulthood through midlife. Associated comorbidities include but are not limited to psychiatric, cardiac, neurologic, and medical conditions.
Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the Migraine in America Symptoms and Treatment (MAST) study.
Increased migraine headache intensity and increased number of monthly headache days are associated with increased rates of inflammation-related comorbidities, psychiatric disorders, and sleep disorders. Some factors, such as correct dosing in obese patients, drug interactions, acute medication overuse, cardiac history, and conditions such as pregnancy, may also contribute to the complexity of treating individuals with migraine.
Furthermore, various subgroups of patients may be predisposed to increased migraine frequency or severity. Studies have shown that having a body mass index (BMI) that is too high (obesity) or too low (underweight) is related to increased risk of migraine and migraine frequency.
Migraines related to the menstrual cycle have been reported as difficult to treat and are often more severe or debilitating than nonmenstrual migraines.
Evaluating clinical efficacy in subgroups of patients is important for determining whether a treatment effect might not be homogeneous across the entire population, as genetic, environmental, demographic, disease, behavioral, and comorbidity factors could potentially affect treatment.
The availability of calcitonin gene–related peptide (CGRP) monoclonal antibodies has provided the first class of medications specifically developed for migraine prevention, with data showing the class is generally safe, well tolerated, and effective in reducing monthly migraine days (MMDs).
Eptinezumab (ALD403) is a humanized immunoglobulin G1 monoclonal antibody that binds to both the α and β forms of the CGRP ligand with high affinity, exhibiting linear pharmacokinetic variables with Cmax achieved at the end of intravenous administration and a half-life of 27 days.
Rational design of a monoclonal antibody (mAB) inhibiting calcitonin gene-related peptide (CGRP), ALD403, intended for the prevention of migraine (p2.155).
In pivotal Phase III studies (PROMISE-1 [Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-1] and PROMISE-2 [Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2]), eptinezumab 100 mg and 300 mg met the primary efficacy end point, significantly reducing mean MMDs over weeks 1 to 12.
These post hoc subgroup analyses of patients in the Phase III PROMISE-1 and PROMISE-2 studies were undertaken to assess the clinical efficacy and safety profile of eptinezumab for the preventive treatment of migraine when categorized according to patient demographic characteristics, baseline clinical characteristics, and migraine history.
Participants and Methods
Study Design
Two nearly identically designed, multicenter, double-blind, randomized, placebo-controlled Phase III studies enrolled adult participants (aged 18–75 years) with episodic migraine (EM; PROMISE-1; NCT02559895) or chronic migraine (CM; PROMISE-2; NCT02974153) for the prevention of migraine with eptinezumab, based on International Classification of Headache Disorders, 3rd edition, criteria.
Briefly, in both studies, patients were randomized in equal ratio to receive eptinezumab or placebo administered intravenously over 30 minutes to 1 hour every 12 weeks. Patients in PROMISE-1 received up to 4 doses of eptinezumab, and patients in PROMISE-2 received up to 2 doses. The primary end point in both studies was the change in frequency of migraine days across weeks 1 to 12. A key secondary efficacy end point in both trials was the ≥50% migraine responder rate (MRR) across weeks 1 to 12. The ≥50% MRR is also one of the current thresholds for defining successful preventive treatment for migraine according to the American and International Headache Societies.
Per protocol, a ≥50% migraine responder was defined as a patient who achieved ≥50% reduction from baseline in MMDs. These reductions were evaluated by comparing the baseline frequency of MMDs versus the migraine frequency in 4-week intervals. Results from these 4-week intervals (weeks 1–4, weeks 5–8, and weeks 9–12) were combined to produce 12-week responder end points; a percent change from baseline was determined, which was used to determine the responder status. All efficacy assessments were documented by use of an electronic diary. Safety and tolerability data were collected at all visits.
Pooling the ≥50% MRR data from PROMISE-1 and PROMISE-2 was deemed appropriate given that the protocols and study methodology for both trials was similar, with the key differentiator being the frequency of migraine in the patient population studied (EM and CM, respectively). Both studies were conducted concurrently in the United States and the country of Georgia (with PROMISE-2 including additional study sites throughout Europe), with the same drug product, with nearly identical operational protocols.
Both studies were performed in accordance with the International Conference on Harmonisation E6 Consolidated Guidance for Good Clinical Practice, the United States Code of Federal Regulations 21 (parts 50 and 56), and the ethical principles of the Declaration of Helsinki. Institutional review board approval was obtained from all study centers, with all patients providing written informed consent. Both studies were prospectively enrolled on Clinicaltrials.gov before the first participant was enrolled. All statistical analyses were performed by a contracted research organization and were directed or designed by Pacific Northwest Statistical Consulting under contractual agreement with H. Lundbeck A/S.
Patient Population
Full inclusion and exclusion criteria have been published previously.
Briefly, eligibility for study enrollment included male and female subjects aged 18 to 75 years (PROMISE-1) or aged 18 to 65 years (PROMISE-2) who were diagnosed with migraine at or before 50 years of age. Patients must have had a documented history of EM (PROMISE-1) or CM (PROMISE-2) for ≥12 months before screening, based on the International Classification of Headache Disorders, 3rd edition, criteria.
For the 3 months before screening, patients must have reported ≤14 headache days per month, including ≥4 migraine days in PROMISE-1 or 15 to 26 headache days per month, including ≥8 migraine days, in PROMISE-2. For the purpose of the present analysis, patient subgroups were defined according to various demographic and clinical characteristics that were obtained before treatment (Table I). For migraine disease characteristics, age at migraine diagnosis, migraine onset relative to menarche (female subjects), duration of disease, aura, baseline headache days, baseline migraine days, and menstrual trigger were the common evaluations across both studies and utilized for this analysis.
Table IBaseline demographic characteristics of the pooled PROMISE-1 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-1) and PROMISE-2 (Prevention of Migraine via Intravenous ALD403 Safety and Efficacy-2) trial populations.
Only captured in PROMISE-2; percentage is out of the total population for both treatment arms and placebo (PROMISE-1 and PROMISE-2).
139 (24.1%)
147 (25.7%)
145 (24.7%)
Baseline headache days, mean (SD)
16.4 (5.90)
16.4 (5.93)
16.6 (5.94)
Baseline migraine days, mean (SD)
13.3 (5.41)
13.2 (5.50)
13.3 (5.49)
aOther includes Black or African American, Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple races, and other; SD: standard deviation.
† Only captured in PROMISE-2.
‡ Only captured in PROMISE-2; percentage is out of the total population for both treatment arms and placebo (PROMISE-1 and PROMISE-2).
Subgroups used in this post hoc subgroup analysis were defined based on sex, age at screening (18–29 years, 30–39 years, 40–49 years, or ≥50 years), and BMI (underweight/normal [≤24.9 kg/m2], overweight [25.0–29.9 kg/m2], obese class I [30.0–35.0 kg/m2], or obese class II [>35.0 kg/m2]). Any subanalysis of race was not possible due to the small numbers in individual patient populations other than White. Subgroup populations of age at migraine diagnosis and duration of migraine diagnosis were reported for the pooled population and stratified into quartiles for subsequent analyses based on the data across all treatment groups from the PROMISE-1 and PROMISE-2 studies. All efficacy analyses were based on the full analysis population, which consisted of all patients who were randomized to receive study drug, with patients analyzed within the group to which they were randomized. Safety analyses were based on patients who received ≥1 dose of study drug (safety population), with patients analyzed based on the treatment they received.
Statistical Analysis
To ensure consistency and appropriate comparison across the PROMISE-1 (EM) and PROMISE-2 (CM) trials, the comparative efficacy analysis was based on the ≥50% MRR over weeks 1 to 12, a key secondary end point in both studies. Responder rate (ie, percent change from baseline), as opposed to a mean change from baseline, was used because it allowed for pooling of the two Phase III studies. The efficacy of eptinezumab, reduction in MMDs, was generally proportional to baseline migraine days; thus, the efficacy from the 2 studies was similar when using the percent change scale.
Descriptive statistics were used to summarize the ≥50% MRR according to treatment group and subgroup. For age at migraine diagnosis and duration of migraine, subgroups were created by dividing patients into quartiles based on the values for the respective subgrouping variable. Confidence intervals for the subgroup responder rates and for the difference between treatment groups were produced by using the normal approximation.
Integrating the data from the 2 studies followed the Guidelines of the International Conference on Harmonisation Common Technical Document for the Registration of Pharmaceuticals for Human Use. Efficacy analyses were based on the pooled full analysis population, which included patients randomized to treatment whose first experience with eptinezumab was in either PROMISE-1 or PROMISE-2. In this analysis, subgroups with a population <10% across treatment arms were excluded to maintain the integrity of the statistical analysis.
Results
Demographic Characteristics
A total of 1960 participants were enrolled and treated across the Phase III PROMISE studies and were included in the safety population analysis (Figure 1). The PROMISE-1 study also included a 30-mg treatment arm (n = 219), which is not included in this analysis. A total of 1737 patients (99.8%) were included in the efficacy analysis. Of the 199 participants (11.4%) who discontinued treatment early (eptinezumab 100 mg, 10.7%; eptinezumab 300 mg, 10.3%; placebo, 13.3%), the most common reasons were withdrawal of consent by patient (eptinezumab 100 mg, n = 27; eptinezumab 300 mg, n = 28; placebo, n = 46), adverse events (eptinezumab 100 mg, n = 8; eptinezumab 300 mg, n = 13; placebo, n = 9), and loss to follow-up (eptinezumab 100 mg, n = 15; eptinezumab 100 mg, n = 13; placebo, n = 18). There was no apparent relationship between eptinezumab dose and study drug discontinuation or study discontinuation.
Demographic and baseline characteristics for the individual PROMISE-1 and PROMISE-2 studies have been previously reported and showed similar findings among the treatment and placebo groups.
The baseline demographic and clinical characteristics pooled across the 2 trials are listed in Table I. In the pooled population, the majority of eptinezumab-treated patients and patients receiving placebo were female, and mean ages were similar across both eptinezumab dose groups and the placebo group. Few of the patients were aged between 65 and 74 years, and the majority of patients were White. Mean BMI was comparable in eptinezumab-treated patients and patients receiving placebo. These characteristics are similar to those of people with migraine in the general population as estimated according to survey-based methods.
Overall, the results from the two Phase III studies are generally consistent, with similar ≥50% MRRs (PROMISE-1: eptinezumab 100 mg, 49.8%; eptinezumab 300 mg, 56.3%; placebo, 37.4%; PROMISE-2: eptinezumab 100 mg, 57.6%; eptinezumab 300 mg, 61.4%; placebo, 39.3%) observed across weeks 1 to 12 of treatment.
The pooled efficacy results of the PROMISE-1 and PROMISE-2 trials, based on ≥50% MRRs, are presented in Tables II and III. The ≥50% MRRs grouped according to baseline migraine and demographic characteristics are displayed in Figures 2 and 3, respectively. Within these subgroup analyses, 64 comparisons of the ≥50% MRR between eptinezumab and placebo were performed. For each of these comparisons, the ≥50% MRR was numerically higher for each eptinezumab treatment arm compared with placebo. Across most demographic factors, ≥50% MRR was always ≥10% higher for eptinezumab compared with placebo. In the case of obesity, obese classes I and II (n = 322 and 217, respectively) saw separation from placebo at >10% for eptinezumab 300 mg and less separation from eptinezumab 100 mg (5.0% and 2.6% in class I and class II) (Table II, Figure 3).
Table IIMigraine responder rate (≥50%) over weeks 1 to 12 in subgroups defined according to baseline demographic characteristics (full analysis population).
Table IIIMigraine responder rate (≥50%) over weeks 1 to 12 in subgroups defined according to baseline disease characteristics (full analysis population).
Figure 2≥50% migraine responder rate higher in patients treated with eptinezumab vs placebo across all subcategories of migraine history and disease characteristics.
Figure 2≥50% migraine responder rate higher in patients treated with eptinezumab vs placebo across all subcategories of migraine history and disease characteristics.
There was a consistent and robust effect observed in favor of both doses of eptinezumab across all subcategories of migraine history and disease characteristics at baseline (Table III, Figure 2). In the analysis of difference versus placebo in ≥50% MRR, the only cases in which the benefit over placebo was not ≥10% higher was in 2 patient subgroups treated with 100-mg eptinezumab: patients with an age at migraine diagnosis of 20 to <30 years (9.7% separation from placebo), and patients who had received a migraine diagnosis <9 years ago (7.9% separation from placebo).
Pooled Safety
Eptinezumab had a consistently low prevalence of treatment-emergent adverse events, with a smaller percentage of patients experiencing serious and grade 3 treatment-emergent adverse events on eptinezumab than patients receiving placebo. Adverse events identified as related to study treatment included nasopharyngitis, which was infrequent but more common with eptinezumab compared with placebo. Overall, the most common treatment-emergent adverse events were nasopharyngitis (6.2%, 8.2%, and 5.8% for eptinezumab 100 mg, eptinezumab 300 mg, and placebo, respectively) and upper respiratory tract infection (6.4%, 7.3%, and 6.1%) (Table IV).
Table IVSummary of treatment-emergent adverse events (TEAEs) according to treatment group (pooled safety population). Values are given as no. (%).
AE
Eptinezumab 300 mg (N = 574)
Eptinezumab 100 mg (N = 579)
Placebo (N = 588)
Patients with any TEAE
311 (54.2)
296 (51.1)
303 (51.5)
Patients with any study drug–related TEAE
85 (14.8)
68 (11.7)
48 (8.2)
Patients with any serious TEAE
7 (1.2)
7 (1.2)
9 (1.5)
Patients with any grade 3 or higher TEAE
15 (2.6)
10 (1.7)
18 (3.1)
Patients with any TEAE of special interest
57 (9.9)
46 (7.9)
29 (4.9)
Patients with any TEAE leading to study drug discontinuation
13 (2.3)
9 (1.6)
8 (1.4)
Patients with any TEAE leading to interruption of study drug infusion
9 (1.6)
9 (1.6)
6 (1.0)
Patients with any TEAE resulting in death
0
0
0
TEAEs occurring in >2% of patients in any eptinezumab treatment group and with greater incidence than in the placebo group
Gastrointestinal disorders
64 (11.1)
41 (7.1)
51 (8.7)
Nausea
17 (3.0)
11 (1.9)
15 (2.6)
General disorders and administration site conditions
38 (6.6)
37 (6.4)
31 (5.3)
Fatigue
14 (2.4)
16 (2.8)
8 (1.4)
Infections and infestations
165 (28.7)
152 (26.3)
159 (27.0)
Nasopharyngitis
47 (8.2)
36 (6.2)
34 (5.8)
Upper respiratory tract infection
42 (7.3)
37 (6.4)
36 (6.1)
Influenza
18 (3.1)
5 (0.9)
14 (2.4)
Urinary tract infection
16 (2.8)
11 (1.9)
9 (1.5)
Musculoskeletal and connective tissue disorders
41 (7.1)
45 (7.8)
47 (8.0)
Arthralgia
14 (2.4)
10 (1.7)
9 (1.5)
Back pain
9 (1.6)
14 (2.4)
13 (2.2)
Nervous system disorders
48 (8.4)
44 (7.6)
63 (10.7)
Dizziness
13 (2.3)
15 (2.6)
12 (2.0)
Respiratory, thoracic, and mediastinal disorders
41 (7.1)
35 (6.0)
25 (4.3)
Cough
12 (2.1)
10 (1.7)
7 (1.2)
Adverse events were coded by using Medical Dictionary for Regulatory Activities version 20.1. Patients were counted only once per system organ class and per preferred term. Summary results are presented in alphabetical order of system organ class. TEAEs are sorted in decreasing order of preferred term frequency in the “Eptinezumab 300 mg” column.
In general, this pooled analysis showed that most patient characteristics captured across the PROMISE-1 and PROMISE-2 clinical trials did not affect the efficacy, safety, or tolerability of eptinezumab in the prevention of migraine. Although both the 100- and 300-mg doses did not exceed a 10% separation from placebo on the ≥50% MRR for the obesity class II patients and the 100-mg dose did not exceed a 10% separation for a few subpopulations of patients (obesity classes I and II, patients with a migraine diagnosis between 20 and 30 years of age, and patients with a diagnosis of migraine for <9 years), the percentage of patients with ≥50% MRR was still higher for eptinezumab-treated patients than that achieved with placebo. A potential confounder of this study is that these subgroup populations were smaller in number, perhaps influencing the study results. Further exploration is required to determine how these factors may confound the overall clinical efficacy profile of eptinezumab. In addition, these data do not allow prediction of which type of patients respond better to higher doses of eptinezumab.
The ≥50% MRR was affected for both doses of eptinezumab in the subpopulation of patients reported as obese class II (BMI >35 kg/m2); however, separate analyses of PROMISE-1 and PROMISE-2 did not reveal any pattern between weight and efficacy of eptinezumab.
and that pharmacokinetic properties can be affected by obesity for a number of drug classes (eg, antibacterials, anticoagulants, antidiabetics, anticancer agents, neuromuscular blockers).
Although previous population pharmacokinetic analysis of eptinezumab has shown that body weight can affect eptinezumab clearance, the effect is small enough that dose adjustments based on weight are unnecessary, and this difference was not expected to have a large impact on eptinezumab efficacy.
In addition, a Phase I study of healthy subjects randomized to receive eptinezumab 100 mg or placebo with a BMI between ≥25.0 and <40.0 kg/m2 in the 2 months before screening found that eptinezumab was safe and well tolerated.
Understanding the dynamics of pharmacokinetic and pharmacodynamic effects in obese patients is an ongoing effort that will result in models that can be used to predict the effects of obesity on drug pharmacokinetic variables and efficacy.
In both studies and across this pooled analysis, eptinezumab was generally safe and well tolerated, with no new or subgroup-specific treatment-emergent adverse events identified in this analysis compared with the primary trials.
A limitation of this analysis is its post hoc design. Although data were pooled for this analysis from 2 different Phase III studies to increase sample size, the studies used for the present analysis were essentially identical in design other than the 2 migraine groups included (EM and CM up to 26 days per month), covered a similar geographic scope, used the same treatment regimens, and had similar patient characteristics. However, there may be differences across subgroups for different migraine diagnoses (EM or CM) that were masked by pooling these studies. Indeed, it seems that PROMISE-2 (CM) resulted in greater positive results in several end points compared with PROMISE-1 (EM), possibly as a result of room for greater improvement (CM patients generally experience higher MMDs at baseline compared with EM patients). In addition, the small sample size of some of the subgroups limited the statistical power for detecting significant differences between eptinezumab and placebo across all subpopulations. Certain subgroups in PROMISE-1 and PROMISE-2, specifically race and ethnicity, were not fully representative of a real-world population, and thus no clinical conclusions should be drawn from this integrated analysis. Additional subgroups (including socioeconomic factors such as education, employment, household income, and health coverage), as well as migraine history (including familial migraine, previous preventive medication, acute medication, disease duration, presence/absence of allodynia, and home/workplace burden) and associated comorbidities (including mood, respiratory, and cardiovascular disorders), were not consistently captured across the PROMISE clinical trial programs (or were explicitly excluded from participation), thus preventing further analyses.
Conclusions
The demonstrated efficacy and safety profile of eptinezumab in the 2 previous Phase III clinical trials PROMISE-1 and PROMISE-2 was independent of the intrinsic baseline characteristics of participants in the studies, including sex, age, and BMI. In addition, eptinezumab 100 mg and eptinezumab 300 mg were effective regardless of migraine disease characteristics.
Acknowledgments
This work was sponsored and funded by H. Lundbeck A/S. All statistical analyses were performed by a contracted research organization and were directed or designed by Pacific Northwest Statistical Consulting under a contractual agreement with H. Lundbeck A/S. The authors thank Sarah Russell, PhD, and Philip Sjostedt, BPharm, of The Medicine Group, LLC, for providing medical writing support, which was funded by H. Lundbeck A/S in accordance with Good Publication Practice guidelines.
All authors and H. Lundbeck A/S prepared, reviewed, and approved the manuscript and made the decision to submit the manuscript for publication.
Disclosures
The authors have indicated that they have no other conflicts of interest regarding the content of this article.
The sponsor participated in the design and conduct of the study; data collection, management, analysis, and interpretation; and preparation, review, and approval of the manuscript.
References
Burch R
Rizzoli P
Loder E.
The prevalence and impact of migraine and severe headache in the United States: figures and trends from government health studies.
Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the Migraine in America Symptoms and Treatment (MAST) study.
Rational design of a monoclonal antibody (mAB) inhibiting calcitonin gene-related peptide (CGRP), ALD403, intended for the prevention of migraine (p2.155).
Female subjects only.
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