Abstract
Background
In phase 2 and 3 studies, fremanezumab, a monoclonal CGRP antibody, was an effective preventive treatment for high-frequency episodic migraine (HFEM) and chronic migraine (CM).
Objective
Post-hoc analyses evaluated population-wise 50%, 75% and 100% responder rates, and the extent to which individual responders sustained a 50%, 75% and 100% reduction in migraine days, moderate-to-severe (M/S) headache days and days of acute medication use during all three treatment months of the fremanezumab phase 2 studies.
Design/methods
HFEM patients received either placebo or three once-monthly injections of 225 mg or 675 mg. CM patients received either placebo or three once-monthly injections of 900 mg, or an initial loading dose of 675 mg and subsequent injections of 225 mg. Patients reported headache-related data daily using an electronic diary.
Results
In the HFEM study, the percent of patients on fremanezumab doses 225 mg and 675 mg were greater compared to the percent of placebo patients with sustained 50% reduction in migraine days (39% and 35% vs. 10% for placebo, both p < 0.0001), M/S headache days (36% and 38% vs. 16% placebo, p = 0.0017 and p = 0.0007 respectively), and acute medication use days (36% and 27% vs. 8% placebo, p < 0.0001 and p = 0.0003). Likewise, although there were fewer patients with sustained 75% reduction, there were increases in the percent of patients on fremanezumab 225 mg and 675 mg in the HFEM study relative to placebo patients in migraine days (19% and 11% vs. 3% placebo, p = 0.0002 and p = 0.0176), M/S headache days (19% and 15% vs. 2% placebo, p = 0.0001 and p = 0.0011) and days of acute medication use (16% and 8% vs. 2% placebo, p = 0.0005 and p = 0.0377). In the CM study, there were increases in the percent of patients on fremanezumab 675/225 mg and 900 mg with 50% sustained reduction in M/S headache days (32% and 40% vs. 15% placebo, p = 0.0058 and p = 0.0002) and days of acute medication use (26% and 22% vs. 11% placebo, p = 0.0098 and p = 0.0492). There were also increases in the percent of patients on fremanezumab 675/225 mg and 900 mg compared to patients on placebo with 75% sustained reduction in M/S headache days (10% and 13% vs. 3%, p = 0.0665 and p = 0.0203). Few patients had 100% sustained reductions in these parameters in either study.
Conclusions
Post-hoc results must be interpreted with caution; nonetheless, a statistically significant percentage of patients who initially responded to fremanezumab within 1 month sustained this response over the subsequent 2 months. Sustained reduction in individual patients may provide a novel patient-centric, clinically meaningful endpoint for future trials assessing the effectiveness of preventive migraine treatments.
Trials are registered as http://clinical trials.gov as NCT02025556 and NCT02021773.
Keywords
Introduction
Fremanezumab (formerly known as TEV-48125 or LBR-101), a fully humanized monoclonal antibody against calcitonin gene-related peptide (CGRP), has been shown to be effective for high-frequency episodic migraine (HFEM) and chronic migraine (CM) prevention (1–3).
Responder rates, considered to be an important clinical endpoint, are often reported on a population basis for a specified period of time. The extent to which individual responders sustain a response over time is a more patient-centric endpoint but has not been previously reported.
It is not uncommon for patients with migraine to report a loss of drug efficacy (i.e. tachyphylaxis) over time (4). In their systematic review, Rizzoli and Loder (2011) reported that tachyphylaxis can be due to a number of reasons, from issues related to pharmacokinetics, pharmacodynamics, behavioral mechanisms such as learned tolerance, and cross tolerance from one drug to another that shares a similar mechanism of action, and can affect up to 8% of patients on a migraine prophylactic medication (5). Consequently, this novel endpoint of sustained benefit takes that concern into account and is therefore clinically meaningful. Demonstrating sustained response with continued use of a prophylactic treatment can have several implications: It may lead to better patient compliance, more headache-free days, a reduction in acute medication use, improved quality of life, and even a reduction in missed work days. With these post-hoc analyses, we evaluated the percentage of patients with HFEM and CM who demonstrated at least a 50%, 75%, or 100% reduction in migraine days, moderate-to-severe headache days, and acute medication use at month 1 and continued to show this response during treatment months 2 and 3.
Methods
Study design
Fremanezumab was evaluated in two randomized, double-blinded, placebo-controlled 12-week phase 2 b studies in patients with high-frequency episodic migraine (HFEM) and chronic migraine (CM) (1,2). The two studies were performed in 62 sites (headache centers, neurology clinics and primary care facilities) in the US from January 2014 to January 2015. Both studies were conducted in accordance with the GCP and the US FDA guidelines for safety monitoring and were registered at clinicaltrials.gov as NCT02025556 and NCT02021773. All patients provided written informed consent before enrolling in the study, and all protocols were approved by institutional review committees for each site.
To be eligible for the HFEM study, patients had to suffer from high frequency EM defined as having headaches for 8 or more days per month for at least three months, confirmed during the 28-day run-in period. They had 8–14 days of headache fulfilling one of the following criteria (migraine day, probable migraine, or relieved by ergot or triptan derivatives) per month and were allowed to use one standard migraine preventive drug at stable doses for at least two months before study onset and acute migraine medications up to 14 days per month (maximum of 4 days of opioids or barbiturates). Eligible patients in the CM trial had CM defined as per the International Classification of Headache Disorders (ICHD III beta) and confirmed during the 28-day run-in period (6). Patients had to have 15 or more headache days per month for at least 3 months prior to study entry and have at least 15 headache days during the 28-day run-in period. Eight of the headache days during the run-in period had to fulfill one of the following criteria (migraine day, probable migraine, or relieved by ergot or triptan derivatives) per month. They were allowed to have used two different migraine preventive drugs at stable doses for at least three months prior to study entry. Patients could use up to one concomitant migraine preventive medication during the HFEM and CM studies and were allowed to treat their acute migraine as usual. Patients were excluded if they used onabotulinumtoxinA for migraine or for any medical or cosmetic reasons during the 6 months prior to study entry.
The HFEM and CM studies were 16-week, multicenter, randomized, double-blinded, placebo-controlled, parallel-group studies consisting of a 28-day screening period, and a three-month blinded treatment period. During the 28-day screening period, eligible patients were trained to provide daily headache and migraine symptom data using the electronic headache diary. To be randomized into the blinded treatment period, they had to demonstrate compliance with the diary by entering data a minimum of 22/28 days (∼80% compliance).
If patients met eligibility requirements in the 28-day run-in period, they were stratified based on gender and preventive medication use, and then randomization (1:1:1) was done into either the placebo arm or one of the two fremanezumab dose arms via an electronic interactive web response system (IWRS) by study coordinators using the eClinical Operating System portal. Randomization occurred using a randomization scheme developed centrally by a staff member at the contract research organization (CRO) (NCGS Inc., Charleston, South Carolina, USA) who had no further role in the study.
To protect the treatment blind, study sites had two blinded study coordinators at each clinic visit; one performed the clinical assessment and the other performed the treatment administration. The clinical assessment included reviewing with patients how to complete the electronic diary and performing safety assessments. For treatment administration, patients were masked to treatment allocation; they all received four injections at each 28-day treatment visit and the injections were identical in packaging and appearance regardless of treatment group. Participants allocated to fremanezumab received one of two dosing strategies: Participants in the HFEM study were randomized to receive monthly injections of 225 mg or 675 mg for 3 months; those in the CM study were randomized to receive either monthly injections of 900 mg, or an initial loading dose of 675 mg at month 1 and subsequent injections of 225 mg at months 2 and 3.
During the study, patients were asked to log into the web-based interactive system every day and record diary data for the previous 24-hour period. As a part of diary entry, patients were asked questions focused on the occurrence of headaches, migraines, associated symptoms and the use of acute medications during the previous day. The IWRS system allowed patients to back enter one day of information and was locked thereafter.
Outcomes and analyses
The occurrence of migraine days was the primary endpoint in the HFEM study and a secondary endpoint in the CM study. For both studies, a migraine day was defined as a day in which migraine with aura, migraine without aura, or probable migraine occurred. In accordance with the ICHD-3 (6), the minimum duration of a migraine day was 4 hours unless a triptan or drug containing an ergot was used, in which case we specified no minimum duration. The number of days with moderate-to-severe headaches was an exploratory endpoint in the HFEM and a secondary endpoint in the CM study. The number of days with headache of moderate to severe severity (M/S) was defined as a day with at least 4 consecutive hours of moderate to severe headaches.
The use of acute medications was an exploratory endpoint in both HFEM and CM studies. As part of the daily headache diary entry, patients provided information on the use of acute medication consumption by responding to questions regarding the previous day and selecting from a list of the most frequently used medications to treat migraine attacks. Patients had an opportunity to enter the name of a used medication if it was not included in the list and patients could enter information on acute medication use at any hour in the e-diary.
Analyses for the primary, secondary, and exploratory endpoint analyses for the HFEM and CM studies have been described previously (1,2). In these analyses, changes in the endpoints from the baseline period to months 1, 2, and 3 of the treatment period were analyzed using the mixed-effects model repeated measurement (MMRM) analysis method. Post-hoc analyses described herein examined the proportion of patients in each treatment group who experienced 50%, 75% and 100% reduction from baseline in the number of migraine days, M/S headache days and days of acute medication use during study months 1, 2, and 3. Furthermore, we examined the proportion of patients in each treatment group who reported sustained 50%, 75% and 100% reductions in these parameters during each month of fremanezumab treatment.
All outcome variables were analyzed by the Intent-to-Treat (ITT) principle, which included all randomized participants who received at least one dose of study drug and provided at least one measurement. All statistical tests were 2-sided at alpha level of 0.05 and all p-values presented are nominal without multiplicity adjustment. The analyses were conducted with SAS (Version 9.2).
Role of the funding source
The post-hoc analyses were designed by all authors, some of whom are employees of the funding source, Teva Pharmaceutical Industries. The funder was responsible for data collection, data analysis, and interpretation. All authors were involved in writing the manuscript. They had access to all data in the study and there were no agreements with the sponsor that would preclude the authors’ ability to analyze and interpret data and publish manuscripts independently when and where they choose.
Results
Patient disposition
Baseline demographic and disease characteristics of patients in the HFEM and CM studies.
Mean (SD) values are provided unless otherwise noted.
Safety
The tolerability and safety findings for the HFEM and CM studies of this report have been fully described earlier (1,2). For both studies, the most common adverse effects (AEs) were injection site reactions (pain, erythema and/or pruritus). There were no relevant changes in vital signs or blood pressure between groups and no treatment emergent anti-drug antibody response occurred.
50%, 75% and 100% response rates per month
We conducted post-hoc analyses to determine the groupwise percentage of patients experiencing 50%, 75% and 100% reduction in the number of migraine days, number of M/S headache days, and days of acute medication use during each month of the study. For each treatment month, there were statistically greater numbers of HFEM patients on fremanezumab with 50% reduction and 75% reduction in migraine days compared to patients on placebo (see Supplementary Table 1). For the CM study, there were greater numbers of CM patients on fremanezumab with 50% reduction in migraine days during most of the treatment months, but there was only a statistical difference in the first month for those treated with fremanezumab compared to placebo with a 75% reduction in migraine days. The number of patients with 100% reduction in migraine days was small for all groups.
For M/S headache days, the fremanezumab treated groups in the HFEM and CM studies had a statistically greater number of patients with 50% and 75% reduction in this parameter compared to placebo groups. The fremanezumab groups in both studies showed 50% or higher percentages of patients with 50% reduction during the treatment months 1–3, a third showed 75% reduction, and 9–17% had 100% reduction. In comparison, the percentage of placebo patients with 50% reduction in M/S headache days ranged from 24–40%, 75% reduction 7–21%, and 100% reduction 2–10%.
The pattern continued for the 50% and 75% reduction in the days of use of acute medications. There were statistically greater numbers of HFEM patients on fremanezumab with 50% reductions and 75% reductions in days with acute medication use compared to patients on placebo. The percent of HFEM patients with 100% reduction in days of acute medication use was small for all treatment groups. In the CM study, there were statistically greater number of CM patients on fremanezumab with 50% reductions compared to placebo patients in acute medication use. There were few patients with 75% and 100% reduction in days with acute medication use in the CM study.
50%, 75% and 100% sustained response rates
Percent of patients with sustained 50%, 75% and 100% reductions in migraine days, M/S headache days and days of acute medication use during all three months of the fremanezumab HFEM and CM phase 2 studies.
95% CI: 95% confidence interval, odds ratio and 95% CI were based on Cochran Mantel-Haenzel Test, patients with missing data were considered non-responders; p values were based on chi-square tests; p values < 0.05 were considered statistically significant, p values between p > 0.05 and p ≤ 0.10 were considered a nonsignificant statistical trend, and p values of p > 0.10 nonsignificant.
Percent of patients with sustained reduction in migraine days, M/S headache days and days with acute medication use in the HFEM study.
For the CM study, the differences between treatment groups in the percentage of patients with sustained 50% reductions were not as large, with roughly 18% of placebo patients and 24% and 33% of fremanezumab 675/225 mg and 900 mg patients having sustained 50% reduction in migraine days (Figure 2). There were statistically greater percentages of patients treated with fremanezumab 675/225 mg and 900 mg compared to placebo for sustained 50% reductions in M/S headache days and days with acute medication use (Table 2). While increased in the fremanezumab groups relative to the placebo group, few patients in any group in the CM study experienced sustained 75% or 100% reductions in migraine days, M/S headache days, or days with acute medication use.
Percent of patients in the CM study with sustained reductions in migraine days, M/S headache days and days with acute medication use.
Discussion
Tachyphylaxis of preventive treatments for migraine is a frequent problem reported by patients and encountered by clinicians. The extent to which efficacy is sustained over time is frequently raised by patients. Unfortunately, previous prevention trials provide little guidance as sustained responses in individual patients has hitherto not been addressed in clinical trials, either as a pre-specified endpoint or on post-hoc analysis. This post-hoc analysis supported our hypothesis that fremanezumab may be associated with sustained efficacy in a substantial percentage of those who show an initial response in terms of migraine days, M/S headache days, and acute medication use. This impact was not as apparent in the CM subjects, and that could be due to the added complexity of chronic migraine and other factors that can play a role in the maintenance of daily headache. Prospectively replicating these data with a larger group would be helpful in clarifying the benefit of this treatment in patients with both HFEM and CM. Likewise, we did not see a clear dose-response relationship, as both the high and low doses of fremanezumab in either study seemed to show sustained efficacy in a similar fashion. We anticipate that this positive outcome will spur future controlled trials that will not only support the sustained benefit that we noted over 3 months in our small post-hoc analysis, but also demonstrate the full extent of sustained benefit of these biologics.
As this was a post hoc analysis, there were several limitations to note. The sample sizes in the subgroups of the analysis were quite small. Patients were also not asked to list their acute medications, which made it impossible to determine if the frequency of use of certain acute medications were affected more than others. As often happens in CNS trials, a proportion of patients on placebo, in particular those in the CM study, showed reductions in migraine days, M/S headache, and days of acute medication use. This placebo response may be due to the nature of caretaking that occurs in a clinical trial, the parenteral administration of the treatment, the active to placebo randomization ratio, and the anticipation and heightened expectation of being on a therapeutic medication that is based on an important disease mechanism (7). Future studies should consider study design methods to lessen occurrence of placebo response (8). Furthermore, while we presume that reductions in migraine days, M/S headache days, and use of acute medications translates into improvements in quality of life measures, participants were not queried regarding these parameters specifically.
Future studies should evaluate these endpoints prospectively, including sustained benefit in migraine days, M/S headache days, and acute medication use. Given the importance of acute analgesic use and the significant role medication overuse plays in the chronification of migraine, this specific endpoint should be studied more closely, to better clarify the role of fremanezumab in the management of medication overuse as it relates to migraine. Study participants should also be asked to complete quality of life measures to fully understand the impact of the improvements brought on by fremanezumab. Additionally, we should attempt to determine sustained responses over a longer period of time (e.g. 6–12 months) in all subgroups of responders (50%, 75%, and 100%), as this can help identify which patients to especially recommend this treatment.
While tolerance to preventive migraine medications has been studied extensively (5), the potential mechanisms by which a novel medication continues to exert a sustained response is not as well studied. Some preventive migraine treatments with reported tachyphylaxis may exert their effects on migraine through the endogenous descending pain modulation network, including the opioidergic system, and the tolerance that occurs for patients taking opioids for pain relief may be occurring for headache relief as well (5). A recent paper by Melo-Carrillo proposes that fremanezumab as an anti-CGRP antibody is believed to be acting peripherally on the Aδ meningeal nociceptors and central high threshold (HT) trigeminovascular neurons, preventing the cerebral release of CGRP involved in migraine headaches (9). Further studies are needed to understand how this selective mechanism plays a role in fremanezumab’s sustained beneficial effects on migraine.
Article highlights
Patients often report that they feel that a drug has lost efficacy over time in treating migraine. Post-hoc analyses were conducted in the HFEM and CM phase 2 studies of fremanezumab to assess the response rates of individual patients with 50%, 75% and 100% reductions in migraine parameters in the first month of fremanezumab treatment who sustained this response over study months 2 and 3. The results of these analyses showed that the percentage of patients with 75% and 100% sustained reductions were small, especially for the placebo patients. Overall there were greater percentages of patients taking fremanezumab who had 50% and 75% sustained reductions in migraine days, moderate-to-severe headache days and acute medication use. Sustained reductions for 3 months or longer in migraine frequency and medication consumption in individual patients may provide a novel patient-centric, clinically meaningful endpoint for future trials assessing the effectiveness of preventive migraine treatments.
Supplemental Material
Supplementary Table -Supplemental material for Sustained reductions in migraine days, moderate-to-severe headache days and days with acute medication use for HFEM and CM patients taking fremanezumab: Post-hoc analyses from phase 2 trials
Supplemental material, Supplementary Table for Sustained reductions in migraine days, moderate-to-severe headache days and days with acute medication use for HFEM and CM patients taking fremanezumab: Post-hoc analyses from phase 2 trials by Rashmi B Halker Singh, Ernesto Aycardi, Marcelo E Bigal, Pippa S Loupe, Mirna McDonald and David W Dodick in Cephalalgia
Footnotes
Acknowledgements
The authors greatly appreciate the work of the investigators who led and conducted the HFEM and CM studies on fremanezumab and the patients who participated in these studies. All authors were involved in the design of the analyses. MM conducted the statistical analyses, and RHS and PSL prepared the first manuscript draft. All authors revised manuscript content and approved the final version.
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RHS reports consulting (advisory board) for Amgen. EA, MEB, and MM were employees of Teva Pharmaceuticals, who was sponsoring the clinical development of fremanezumab at the time the HFEM and CM studies were conducted. MEB is now Senior Vice President and Chief Medical Officer Purdue Pharma. PSL is an employee of Teva Pharmaceuticals Ltd. David W Dodick has provided consultation, within the past 5 years, to Acorda, Allergan, Amgen, Alder, Promius, eNeura, Eli Lilly & Company, Insys therapeutics, Autonomic Technologies, Teva, Xenon, Tonix, Trigemina, Boston Scientific, Nocira, Zosano, Biocentric, Biohaven, Magellan, Theranica, Charleston Laboratories, Supernus, Gore and Electrocore. Royalties: Oxford University Press and Cambridge University Press (Book Royalty). He receives editorial/honoraria from UpToDate, MedNet LLC, Peer View Institute for Medical Education, Medicom, Chameleon Communications, Medscape, WebMD, Academy for Continued Healthcare Learning, Haymarket Medical Education, Global Scientific Communications, HealthLogix, Miller Medical, Academy for Continued Healthcare Learning, MeetingLogiX, Wiley Blackwell, and Medicom. Stock/options: Nocira, Epien, Healint, Theranica, and Mobile Health. He has a consulting use agreement with NAS and Myndshft. He has a board position at King-Devick Technologies, Inc. and Epien Inc.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The post-hoc analyses described in this report were conducted as part of the phase 2 HFEM and CM clinical development studies sponsored by Teva Pharmaceuticals Ltd, Israel.
References
Supplementary Material
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