|Year : 2022 | Volume
| Issue : 3 | Page : 433-440
Efficacy and tolerability of erenumab for prevention of episodic migraine in India
Debashish Chowdhury1, Jaydip R Chaudhuri2, Pahari Ghosh3, Rahul Kulkarni4, Sumit Singh5, Sneha Thakur6, Anup V Thorat6
1 Department of Neurology, Govind Ballabh Pant Hospital, New Delhi, India
2 Department of Neurology, Yashoda Hospital, Hyderabad, Telangana, India
3 Department of Neurology, Calcutta Medical Research Centre, Kolkata, West Bengal, India
4 Department of Neurology, Deenanath Mangeshkar Hospital and Research Centre, Pune, Maharashtra, India
5 Department of Neurology, Agrim Institute of Neurosciences, Artemis Hospitals, Gurgaon, Haryana, India
6 Medical Affairs, Novartis India Limited, Mumbai, Maharashtra, India
|Date of Submission||24-Feb-2022|
|Date of Acceptance||26-Mar-2022|
|Date of Web Publication||09-Jun-2022|
Director, Professor and Head, Department of Neurology, Govind Ballabh Pant Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: EMPOwER, a 12-week, double-blind (DB), randomized, placebo-controlled study evaluated the efficacy and safety of erenumab in adult patients with episodic migraine (EM) from Asia, the Middle East, and Latin America. This study analyzes the Indian experience for the use of erunumab for prevention of episodic migraine. Objective: The study aimed to evaluate the efficacy and tolerability of erenumab (70 mg and 140 mg) in EM patients from India. Methods: Randomized patients received monthly subcutaneous injections of placebo and erenumab 70 mg or 140 mg for 3 months. The primary endpoint was a change from the baseline in monthly migraine days (MMDs) at month 3. Other endpoints included achievement of ≥50%, ≥75%, and 100% reduction in MMD; a change in monthly acute migraine-specific medication treatment days; a change in patient-reported outcomes; and safety assessment. Results: Of the 539 patients screened, 351 patients were randomized (erenumab, 70 mg: n = 133 and 140 mg: n = 94; placebo: n = 124). The mean (±SD) age, disease duration, and MMD were 35.1 (±8.6) years, 6.77 (±6.01) years, and 7.82 (±2.89) days, respectively. The placebo-adjusted difference in mean MMD for erenumab 70 mg was -0.88 (95% CI, -2.16, 0.39; P = 0.174) days, and that for erenumab 140 mg was -1.01 (-2.42, 0.41; P = 0.164) days versus placebo. Secondary and exploratory endpoints demonstrated consistently better results in both erenumab dosage groups versus placebo. Treatment-emergent adverse events were comparable across groups (erenumab, 70 mg: 22.7% and 140 mg: 24.5%; placebo: 25.2%). Conclusion: Both doses of erenumab showed numerical improvement for efficacy endpoints and were well-tolerated in the Indian population. No new safety signals were reported.
Keywords: Efficacy, erenumab, headache, Indian population, tolerability episodic migraine
|How to cite this article:|
Chowdhury D, Chaudhuri JR, Ghosh P, Kulkarni R, Singh S, Thakur S, Thorat AV. Efficacy and tolerability of erenumab for prevention of episodic migraine in India. Ann Indian Acad Neurol 2022;25:433-40
|How to cite this URL:|
Chowdhury D, Chaudhuri JR, Ghosh P, Kulkarni R, Singh S, Thakur S, Thorat AV. Efficacy and tolerability of erenumab for prevention of episodic migraine in India. Ann Indian Acad Neurol [serial online] 2022 [cited 2022 Aug 14];25:433-40. Available from: https://www.annalsofian.org/text.asp?2022/25/3/433/347014
| Introduction|| |
Migraine is a common disabling neurological disorder, characterized by recurrent episodes of headache. It has a 1-year incidence of 14.7% in the general population and is a leading cause of disability., A population-based study from India however has shown higher (25%) 1-year prevalence of migraine. Despite the need of preventive treatment for migraine patients with ≥4 monthly migraine headache days, a recent American study showed that only around 25% patients actually receive preventive treatment. This is partly because of the fact that conventional preventive medications for migraine are not specific, lack adequate efficacy, and are frequently associated with adverse effects (AEs) and poor adherence. Hence, there is an unmet need to develop novel migraine-specific treatment options.
Erenumab (erenumab-aooe in the United States) is the first Food and Drug Administration (FDA)-approved monoclonal antibody (mAb) for migraine prevention. Previous clinical studies on erenumab from the United States, Japan, and Europe demonstrated superior efficacy compared with placebo.,,,, Because of non-representation of migraine patients from Latin America, the Middle East, and some parts of Asia such as India, in earlier studies, EMPOwER study was conducted on episodic migraine (EM) from 2018 to 2020, and the results were published recently.
This is an analysis of India-specific data from the Global EMPOwER study aimed to strengthen the evidence in the Indian population that was not adequately represented in previous clinical trials of erenumab.
| Methodology|| |
This analysis was performed for Indian EM patients who participated in a randomized, double-blind, phase 3 study [EMPOwER (NCT03333109)], which evaluated the efficacy and safety of erenumab. The study was conducted across 27 research sites in India. The methodology of the EMPOwER study has already been published in the Global publication. Briefly, the details are as follows:
Eligible patients aged 18–65 years with a documented history of migraine for 12 months according to the International Classification of Headache Disorders, third edition (ICHD-3) before screening; ≥4 and <15 days/month of migraine symptoms were included. Patients >50 years old at migraine onset; no treatment response to >2 migraine-preventive therapy; use of botulinum toxin within 4 months; ergotamines or triptans on ≥10 days/month were excluded from the study.
The study protocol and amendments were reviewed and approved by an Independent Ethics Committee or the Institutional Review Board at each participating site, and the study was conducted as per the ICH E6 Guidelines for Good Clinical Practice, originating in the Declaration of Helsinki and applicable regulatory requirements. Additionally, National Ethical Guidelines for Biomedical and Health Research involving Human Participants were followed, as issued by the Indian Council of Medical Research. Written informed consent was obtained from every patient prior to the initiation.
In the double-blind treatment period (DBTP), all eligible patients were randomized (2:3:3) to receive erenumab 140 mg, erenumab 70 mg, or matching placebo once per month.
The primary efficacy endpoint was a change from the baseline in monthly migraine days (MMDs) in the last month (month 3) of the DBTP.
The secondary efficacy endpoints at month 3 were the achievement of ≥50%, ≥75%, and 100% reduction from the baseline in MMD; a change from the baseline in monthly acute migraine-specific medication treatment days; and a change from the baseline in the headache impact test (HIT-6™) total score.
The exploratory efficacy endpoints were the reduction of ≥50%, ≥75%, and 100% from the baseline in MMD in each month; a change from the baseline in monthly acute migraine-specific medication treatment days in each month; and a change from the baseline in migraine-related disability and productivity [measured by the modified Migraine Disability Assessment (MIDAS)] and Headache Impact Test- 6 (HIT-6) in each month of the DBTP.
Safety was evaluated based on AEs, treatment-emergent (TE) AEs, clinical laboratory values, vital signs, and anti-erenumab antibodies.
The primary endpoint variable was evaluated using a linear mixed-effects model for repeated measures; pairwise comparisons (erenumab 70 mg versus placebo and erenumab 140 mg versus placebo) were performed subsequently. The difference of least mean squares (LSMs) versus the placebo group, the associated 95% confidence interval (CI) of the differences, and the nominal two-sided P values were tabulated by visit and treatment. The secondary endpoints were analyzed using a linear mixed-effects model similar to the primary endpoint. The treatment differences and odds ratio (OR) compared to placebo, nominal 95% CI, and nominal P values are reported without adjusting for multiplicity in this sub-group analysis, and safety endpoints were analyzed using the safety analysis set.
| Results|| |
Of the 539 patients screened, 351 were randomized (erenumab 70 mg, n = 133; erenumab 140 mg, n = 94; and placebo, n = 124) in the DBTP [Figure 1].
|Figure 1: Study design and patient disposition (randomized analysis set)|
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Demographics and baseline characteristics
The baseline demographic and disease characteristics were well-balanced between the treatment groups [Table 1]. Of the 351 randomized patients, women: 78.9%; mean (±SD) age: 35.1 (±8.6) years; mean (±SD) age at the onset of a migraine: 28.4 (±9.0) years; duration: 6.77 (±6.01) years; mean (±SD) MMD: 7.82 (±2.89) days; and monthly headache days: 8.86 (±3.37) days were noted. Overall, 39.6% of patients had a history of prior prophylactic migraine treatment failure.
|Table 1: Demographics and baseline characteristics (randomized analysis set)|
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Prior and concomitant therapies
Overall, 317 (90.8%) patients used concomitant acute headache medication during the baseline and DBTP; the corresponding proportion of patients between the erenumab groups and placebo group was balanced. None of the patients had undergone alternative migraine therapies.
The difference in the adjusted means (95% CI; P value) in MMD was -0.88 (-2.16, 0.39; P = 0.174) days for erenumab 70 mg versus placebo and -1.01 (-2.42, 0.41; P = 0.164) days for erenumab 140 mg versus placebo at month 3 [Figure 2].
|Figure 2: Change from the baseline in MMD in the Indian sub-population (full analysis set)|
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At month 3, erenumab 70 mg: 59.4% patients (OR: 1.41 [95% CI: 0.85, 2.34; P = 0.179]) and erenumab 140 mg: 58.9% patients (OR: 1.38 [95% CI: 0.79, 2.42]; P = 0.252) versus placebo: 50.8% patients demonstrated at least a 50% reduction in MMD from the baseline [Table 2]. In the erenumab-treated groups, the change from the baseline in monthly acute migraine-specific medication days at month 3 was numerically less than the placebo group. At month 3, the difference in the adjusted means (95% CI; P value) was 0.05 (-0.01, 0.12; P = 0.116) days for erenumab 70 mg versus placebo and 0.01 (-0.06, 0.09; P = 0.723) days for erenumab 140 mg versus placebo [Table 3]. The reduction from the baseline in the HIT-6™ total scores at month 3 was numerically higher in the erenumab-treated versus placebo group. Higher the reduction, better is the improvement. The difference in the adjusted means (95% CI; P value) was determined as -2.32 (-4.43, -0.20; P = 0.032) days for erenumab 70 mg versus placebo and -2.06 (-4.35, 0.23; P = 0.078) days for erenumab 140 mg versus placebo [Table 3].
|Table 2: Proportion of patients displaying a reduction of at least 50%, 75%, and 100% in MMD (full analysis set)|
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|Table 3: Change from the baseline in monthly acute migraine-specific medication days, HIT-6™ total scores, and migraine-related disability and productivity|
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The proportion of patients with ≥50%, ≥75%, or 100% reduction from the baseline in MMD at each month was higher in erenumab groups versus placebo [Table 2]. The erenumab-treated groups demonstrated a larger decrease in the modified MIDAS scores versus the placebo group [Table 3].
During the DBTP, no serious AEs (SAEs) were observed in the erenumab-treated groups; however, one patient in the placebo group reported two SAEs. The incidence of TEAEs was well-balanced between erenumab and placebo groups and was consistent with previous studies on erenumab with no new safety signals. Pyrexia (5.7%), nasopharyngitis (2.9%), constipation (2.3%), and cough (1.7%) were the most frequently occurring TEAEs among all patients [Table 4]. Nasopharyngitis and cough were reported more frequently in the erenumab 140 mg group (6.4% and 3.2%, respectively) versus erenumab 70 mg (0.8% and 0.8%, respectively) and placebo (2.4% and 1.6%, respectively) groups. In general, the type and pattern of TEAEs observed in the Indian sub-population and the Global EMPoWER study were similar. The majority of AEs reported across treatment groups were observed to be grades 1/2; only one patient in the erenumab 70 mg group reported grade 3 AE, which was unrelated to study treatment. Notable changes in the sitting systolic blood pressure (low or high) were higher in the placebo group (10%) versus erenumab groups (70 mg: 7.8%; 140 mg: 5.4%). However, the elevated sitting systolic and diastolic blood pressures were higher in both erenumab groups (70 mg: 4.7% and 6.3%; 140 mg: 4.3% and 6.5%) versus the placebo group (2.5% each).
During DBTP, overall, 5.5% of the patients developed binding antibodies against erenumab. One patient developed neutralizing antibodies in the erenumab 70 mg-treated group. None of the patients reported immune disorder-related TEAEs. The observed results in Indian EM patients were consistent with those reported by the Global study.
| Discussion|| |
EMPOwER is the first randomized DB study conducted to evaluate the efficacy and safety of erenumab in patients with EM from India. Two different doses (70 mg and 140 mg) of erenumab were administered subcutaneously once monthly, and both these dose groups demonstrated numerically higher mean reduction in MMD change from the baseline to month 3 versus the placebo group. The study however was not powered for demonstration of the statistically significant difference between the test drug and placebo (which was demonstrated by the Global study). The study also demonstrated that both erenumab doses were more efficacious (numerical superiority) in secondary and exploratory endpoints versus placebo.
The findings of this study are consistent with the results of the Global study and two previous studies of erenumab versus placebo in patients with EM.,, The Global study demonstrated a substantial benefit with erenumab 70 mg and 140 mg over placebo in reducing the MMDs per month [–1.1 days (70 mg) and –1.7 days (140 mg)] at month 3. STRIVE, a phase III randomized study, similarly showed a relative decrease in migraine days per month of –1.4 (erenumab 70 mg) and –1.9 (erenumab 140 mg) throughout the final 3 months of the 6-month DBTP. In a randomized phase II study in Japanese patients with EM, a greater reduction in MMD was observed for erenumab versus placebo, with differences of –2.31 and –1.89 days for erenumab 70 and 140 mg, respectively.
The mean age of patients (35.1 years) in the present study was similar to the Global population (37.5 years) but slightly lower than the age of patients included in the STRIVE (40.9 years), the ARISE study (42.1 years), the LIBERTY study (44.4 years), and the Japanese study (44.3 years). The study population comprised predominantly of women, which is consistent with previous studies on erenumab.,,, A majority of the patients (72.1%) at the baseline had migraine with aura consistent with the Global study (70%). However, the ARISE (51.0%) and LIBERTY (35.0%) studies demonstrated a smaller number of patients with aura at the baseline., The baseline aura status in the EMPOwER study was self-reported using an electronic diary, and patients might have confused prodromal symptoms with aura symptoms. Although over 85.8% of patients took acute headache medication, only a very small proportion (4.3%) utilized migraine-specific acute medication in contrast to other studies [Global (36.8%), STRIVE (58.8%), and ARISE (61%)]. Another contrasting finding was a higher placebo response observed in the Global (-3.1 MMD) and Indian population-based EMPOwER study (-3.8 MMD) as compared to the STRIVE (-1.8 MMD) and ARISE studies (-1.8 MMD). The diverse placebo response rate across studies could be because of variations in the study design (inclusion/exclusion criteria, number of treatment arms, trial duration), enrolled patient population (age, gender, prior treatments, medical history), and geographical areas (across multi-national trials).
In our study, both erenumab groups had a greater proportion of patients achieving 50% or greater reduction from the baseline in the mean number of MMD versus the placebo group, which is in line with previously published studies such as ARISE and LIBERTY., Erenumab was also considerably more effective than placebo for reductions in migraine frequency, acute medication usage, increased achievement of ≥75% and 100% reduction in MMD, and functional outcomes (secondary endpoints). These results are consistent with Global EMPOwER and other studies on erenumab.,
The assessment of the effect of migraine therapies on physical functioning, quality of life, and disability outcomes is gaining importance.,,, This study demonstrated greater reduction in the modified MIDAS scores and reduction in HIT-6™ total scores from the baseline in both the erenumab dosage groups versus the placebo group. Previous studies have also shown significant improvement in functional outcomes in migraine patients on erenumab than on placebo.,, These results thus highlight the significance of the treatment response in improving headache disability and reducing headache impact, respectively.
Overall, the incidence of TEAEs was similar across the treatment groups during the DBTP. Findings for hematology and clinical chemistry were comparable across all treatment groups. Neutralizing antibodies developed in four patients; no immune disorder-related TEAEs or deaths were reported throughout the study. Elevated sitting systolic and diastolic blood pressures was reported in both erenumab groups and placebo; however, no such changes were observed in earlier studies., The overall safety profile seen in this study was in line with the Global EMPOwER study. Erenumab was found to be well-tolerated with a favorable tolerability profile in Indian patients with EM.
Propranolol, topiramate, divalproex, and amitriptyline are commonly used conventional migraine preventive drugs around the world, including India.,,, However, the rates of adherence to oral preventive medication are poor in clinical practice., Most of the conventional preventive drugs are non-specific, and exact mechanisms of action in migraine are uncertain. Additionally, they display considerable adverse effects. A monthly injection of erenumab may overcome the necessity of daily oral preventive drugs and help increase treatment adherence. Further, erenumab has a definite migraine-specific mechanism of action and highly favorable tolerability profile which has been demonstrated in this study and in Global randomized clinical trials (RCTs). Therefore, the results of this study provide evidence for an alternative efficacious and well-tolerated treatment option for migraine prevention in Indian episodic migraine patients.
The limitation of the current study is the short 12-week DBTP study assessment, and hence a long-term study in the Indian population is warranted to understand more about sustained efficacy and tolerability of erenumab. Further, the study did not include CM patients. Erenumab has also shown good efficacy in CM patients in a recent Global study. Nevertheless, importantly, EMPOwER is the first study of a migraine-specific drug (a monoclonal antibody to the CGRP receptor) to be conducted in Indian patients with EM, which demonstrated better efficacy and tolerability versus placebo. A low number of dropouts because of AEs in the Indian sub-study further substantiates improved adherence because of a favorable safety profile.
| Conclusion|| |
Based on the findings, once-monthly subcutaneous injection of erenumab was found to be effective in reducing the frequency of migraine episodes along with improvement in headache impact and disability in the Indian EM pateints. The effectiveness of erenumab demonstrated consistently better outcomes in both erenumab dose groups versus placebo. No new safety signals were observed for erenumab in the Indian EM pateints.
Dr. Osvaldo Carlos Bruera, Norma Haydee Deri, Dr. Eduardo Daniel Doctorovich, Dr. Bibiana Saravia, Dr. Carlos Federico Buonanotte, Dr. Maria Teresa Goicochea, Dr. Maria de Lourdes Figuerola, Dr. Thomas Iype, Dr. Rahul Chakor, Prof. Srinivasa Rangasetty, Dr. Manoj Hunnur, Dr. Mukesh Sharma, Dr. Praveen Chander, Dr. Prafulla Shembalkar, Dr. Charulata Sankhla, Dr. Gagandeep Singh, Dr. Ish Anand, Dr. Priyanka Vikas Kashyap, Dr. Boby Varkey Maramattom, Dr. Rahul Baviskar, Dr. Pradeep Kumar Vayyattu Govindankutty, Dr. Suresh Kumar, Dr. M. V. Padma Srivastava, Dr. Jayantee Kalita, Dr. Saroja A O, Dr. Suresh K, Dr. Madhusudhan BK, Dr. Vijaya Pamidimukkala, Dr. Amit Yeole, Dr. Hrishikesh Kumar, Byung Kun Kim, Manho Kim, Dr. KyungMi Oh, Soo Jin Cho, Jeong Wook Park, Jae-Moon Kim, Joung Ho Rha, Seung-han Lee, Heui-soo Moon, Eung Gyu Kim, Miji Lee, Min Kyung Chu, Dr. Taghrid El Hajj, Dr. Achraf Makki, Dr. Souheil Gebeily, Dr. Shawkat Beayni, Dr. Salim Atrouni, Dr. Naji Riachi, Dr. Aline Mourad, Prof. Tai Mei-Ling Sharon, Dr. Mohd Sufian Adenan, Dr. Sapiah Sapuan, Dr. Irene Looi, Dr. Rabani Remli, Carlos Martinez Manzanera, Dr. Luis Roberta Partida Medina, Dr. Jose Oropeza de Alba, Dr. Jose Alfonso Meza Medina, Martha Bolanos, Greg David Dayrit, Dr. Paul Matthew Pasco, Artemio Jr Roxas, Dr. Yasmin Idu Jion, Prof. Lo Yew Long, Shuu-Jiun Wang, Lu-An Chen, Long-Sun Ro, Chun-Pai Yang, Yung Chu Hsu, Kao Chang Lin, Po Jen Wang, Kang Hsu Lin, Surat Tanprawate, Prof. Thanin Asawavichienjinda, Col. Chesda Udommongkol, Dr. Tasanee Tantirittisak, Assoc prof. Somsak Tiamkao, Tai Tran, Le Van Thinh, Subhayan Mondal- Principal Biostatistician, Novartis, Nadia Tenenbaum- Senior Clinical Development Medical Director, Novartis.
Writing assistance for this manuscript was provided by Avinash Bardia, Ph. D and editorial support was provided by Sangita Patil, Ph. D, CMPP (both SIRO Clinpharm Pvt. Ltd., India).
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This study is supported by Novartis Pharma AG, Basel, Switzerland. Erenumab is co-developed by Amgen and Novartis.
Conflicts of interest
Debashish Chowdhury, Jaydip Ray Chaudhuri, Pahari Ghosh, Rahul Kulkarni are the principal investigators for Novartis sponsored trials.
Sumit Singh has attended advisory boards and is a speaker in Novartis sponsored meetings.
Sneha Thakur and Anup Thorat are full time employees of Novartis, India.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]