Journal of Clinical Medicine & Health Care

Prevalence of Migraine in Saudi Arabia and the Proposed Introduction of Eptinezumab: A Pooled and Meta-Analysis from Clinical Trials.

Ibrahim S AlKhattabi¹, Khulood K AlRaddadi^2* and Aisha K AlRaddadi³

¹School of Medicine, Dentistry and Nursing, University of Glasgow, Glasgow, United Kingdom
²National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia
³Department of Family Medicine, Ministry of Health, Riyadh, Saudi Arabia

*Corresponding author
Khulood K. AlRaddadi, Neurosurgery department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.

ABSTRACT
Introduction: Chronic migraines (CM) affect a significant portion of the Saudi population, yet patients lack access to Eptinezumab, a drug with proven preventive efficacy and a strong safety record. This analysis aims to evaluate Eptinezumab’s effectiveness in managing CM and advocate for its availability to Saudi patients.

Methods: We performed a meta-analysis of data from two clinical trials registered on ClinicalTrials.gov (Identifiers: NCT02275117 and NCT02974153), involving patients treated with 100mg or 300mg doses of Eptinezumab or a placebo, delivered through IV infusion.

Results: The analysis included data from over 1400 individuals, revealing that Eptinezumab significantly reduces MMDs, with the 300mg dosage being more effective than the 100mg. The 300mg dose reduced MMDs by an average of -8.2 days, while the 100mg dose achieved a reduction of -7.7 days.

Discussion: Our findings confirm the substantial benefits of Eptinezumab in reducing the burden of CM, with both dosages showing effectiveness. The 300mg dose, in particular, provides a greater reduction in MMDs. These results, paired with the drug’s excellent safety profile, suggest that Eptinezumab would be a valuable addition to the treatment options available to Saudi patients.

Conclusion: The administration of Eptinezumab at the studied dosages demonstrates prolonged preventive effects on CM with minor side effects. This supports the potential for introducing Eptinezumab in Saudi Arabia, proposing it as a promising CM treatment to improve patient outcomes.

Keywords: Eptinezumab, Headache, Migraine, Meta-Analysis, Saudi Arabia 

Introduction
Migraine is marked by recurrent, often unilateral pulsating headaches, typically with nausea and sensitivity to light and sound. The trigeminovascular system plays a key role in migraine pain, involving trigeminal ganglia neurons, cerebral arteries, and meningeal arteries [1]. 

Migraines are classified into several types including migraine with aura, without aura, chronic migraine (CM), and episodic migraine (EM). CM is defined by having 15 or more headache days per month over 3months, with at least 8 days exhibiting migraine features like unilateral pulsating pain with moderate-to-severe intensity, often accompanied by nausea, vomiting, light and sound sensitivity, and possibly aura. CM can greatly affect daily functioning and is often associated with psychiatric disorders and medication overuse headaches [2]. Migraine headaches cost the US approximately $17 billion annually, mainly from outpatient care and loss of workplace productivity [3].

Migraine prevalence varies globally. In US, migraines led to about 4 million ER visits in 2016 [4]. Europe had a 1-year prevalence of 14%, peaking between ages 20 and 50 [5].

The incidence of migraine in Saudi Arabia is high, reaching up to 20%, but comprehensive research on its prevalence across the general population is lacking [6-11]. There’s also a gap in data regarding the effectiveness and safety of migraine treatments among Saudi patients and their small sample sizes limit their conclusiveness, pointing to a need for more extensive research. 

Eptinezumab is not yet approved for migraine management in Saudi Arabia, but its efficacy and safety are increasingly supported by evidence. It has been approved in USA and is currently under review by the Canadian FDA for migraine prevention [12]. No previous meta-analyses have conducted on Eptinezumab’s efficacy. The goal of this study is to compile and analyze meta-analytic data on the effectiveness of Eptinezumab in treating migraines, drawing from existing clinical trials. The findings may motivate the Saudi FDA to initiate a clinical trial for Eptinezumab among Saudi patients and contemplate its approval in the country. The study also provides a brief overview of current and novel therapies for migraine.

Methodology
Study Design/data analysis
This review was a mixed-methods study, incorporating both quantitative and qualitative approaches. The quantitative component evaluated the prevalence of migraine in Saudi Arabia, while the qualitative part assessed the efficacy of Eptinezumab in treating migraines through patient and healthcare provider testimonials. Research databases such as PubMed, EMBASE, and the Cochrane Library were searched using specific keywords. Descriptive statistics were used to calculate the prevalence rates. Data analyses were conducted using IBM® SPSS26® software. Only publicly available data from prior studies were used, which did not require separate ethical approval.

Search Strategy
The search strategy for the meta-analysis aimed at identifying all clinical trials evaluating the efficacy and safety of Eptinezumab in CM patients. A comprehensive search was conducted on the ClinicalTrials.gov database using the specific identifiers for the relevant clinical studies. (Table 1)

Inclusion Criteria were IV Eptinezumab at 100mg or 300mg, or placebo comparisons trials in CM patients that reports Efficacy (e.g., monthly migraine days (MMDs) reduction) with all safety and adverse events data.

Exclusion Criteria were non-CM-focused trials or studies not assessing Eptinezumab or using non-IV administration and studies that Lack of explicit efficacy/safety outcomes.

The database was queried for detailed information on trial design, patient demographics, intervention specifics, outcomes, and adverse events related to the use of Eptinezumab.

Statistical Analysis
The statistical analysis for the pooled data from the clinical trials was conducted using a meta-analytic approach. The primary efficacy endpoint was the change from baseline in the mean number of MMDs. Secondary endpoints included the proportion of patients experiencing a 50% or greater reduction in MMDs, and changes in acute medication use.

For the efficacy analysis, weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated for continuous outcomes, while risk ratios (RRs) with 95% CIs were calculated for dichotomous outcomes. The safety analysis evaluated the incidence of adverse events, comparing Eptinezumab with placebo, and reported as risk differences with 95% CIs.

All statistical analyses were performed using Cochrane Review Manager (RevMan 5.4) software, and a p-value of less than 0.05 was considered statistically significant.

Results 
Two clinical trials (NCT02275117 and NCT02974153) involving 1436 individuals with CM were analyzed. In the study, 949 participants were administered Eptinezumab and 487 received a placebo. Of the Eptinezumab group, 478 received 100mg and 471 received 300mg. A high adherence to the treatment protocol was noted, with 98.88% (1420 patients) completing the protocol and only 1.11% (16 patients) withdrawing within the first 12 weeks, due to various reasons including withdrawal of consent, loss to follow-up, failure to meet study criteria, or multiple protocol violations.

The demographic and baseline characteristics indicated an average age of 38.7 years with a majority being female (86.78%) and White (91%). (Table 2) Participants had a long-standing history of migraine, averaging 18.2 years, and reported an average of 20.88 headache days, including 16.36 MMDs, during the 28-day screening period. More than half of the participants (56.82%) were not in a state of medication overuse, while 43.17% were classified as having medication overuse headache.

The meta-analysis revealed that both 100mg and 300mg doses of Eptinezumab significantly reduced MMDs compared to placebo. For the 100mg dose, the mean reduction was -2.10 days with a 95% confidence interval of (-2.88, -1.39) and P < 0.00001. For the 300mg dose, the reduction was even greater, with a mean difference of -2.60 days and a 95% confidence interval of (-3.32, -1.88) and P < 0.00001. These results, underscore the efficacy of Eptinezumab in reducing the frequency of MMDs. (Figure 1).

Discussion
Part 1 - brief review
1. Overview of current therapies for migraine. 
Nearly all migraine sufferers (98%) use acute treatments, with half relying on OTC drugs like aspirin and NSAIDs, and others using prescription medications. Abortive treatments are common for immediate relief, whereas severe cases may need prescription drugs including opioids, which are linked to negative health outcomes when used regularly [13-15].
 
Preventive migraine therapy, targeting a reduction in attack frequency and severity, is underutilized, with only about 5% of patients undergoing such treatment [16]. Effective prevention can cut attack frequency by 50% and involves pharmacological agents like beta-blockers, anticonvulsants, and antidepressants, alongside lifestyle adjustments such as stress management and sleep improvement [2,17]. Table 3 summarizes the most used groups.

2. The novel therapeutic options for migraine.
Calcitonin gene-related peptide (CGRP) Antagonist
CGRP antagonists like Olcegepant and Telcagepant are potential acute migraine treatments without the vasoconstrictive effects of triptans, making them safer for patients with cardiovascular concerns [18]. Telcagepant can be taken orally and is well-tolerated, but concerns over liver enzyme elevations may limit its long-term use [19].

Calcitonin gene-related peptide (CGRP) antagonists - monoclonal antibody (mAb)
Eptinezumab is a humanized IgG1 monoclonal antibody targeting CGRP, produced using Pichia pastoris yeast, and binds to both α and β forms of human CGRP with high affinity (KD 20 pM) [20]. It blocks the CGRP pathway, providing a recognized method for both acute and preventive migraine treatment [21]. Clinical trials have shown that IV Eptinezumab at doses of 100mg and 300mg is effective for migraine prevention in adults with CM, demonstrating a significant reduction in migraine occurrence from day 1 and an acceptable safety profile. Over half of the patients experienced a substantial decrease in migraine frequency from the baseline, and more than one-third achieved a 75% reduction in MMDs within the first month. These benefits, including patient-reported outcomes, were noted as early as the first month [21,22]. Beyond CM, Eptinezumab is also effective in managing EM, as demonstrated by several clinical studies [23-26]. Regarding safety, Eptinezumab has been associated with a low incidence of treatment-emergent adverse events (TEAEs), such as nasopharyngitis, upper respiratory tract infections, and nausea. Hypersensitivity reactions post-drug administration are typically mild to moderate and can be effectively managed using antihistamines or corticosteroids for one day [27]. Overall, these factors contribute to the high safety profile of Eptinezumab.

Botulinum Toxin
A meta-analysis highlighted its effectiveness in reducing CM frequency after 2 months and improving life quality after 3 months, with a slightly higher risk of adverse events in patients receiving the toxin (risk ratio of 1.32, p = 0.002) [28]. In Saudi Arabia, its use for CM prophylaxis has proven efficient and safe [17].

Part 2 - meta-analysis
The pooled data from two clinical trials showed that a single IV Eptinezumab every 12 weeks was effective in managing adults CM. The analysis involves over 1400 patients indicated that Eptinezumab at both 100mg and 300mg doses has effectively reduced MMDs, with the 300mg dose achieving a greater reduction, averaging -8.2 days, compared to -7.7 days for the 100mg dose, making it more preferred by patients.

Further meta-analysis comparing the two doses establishing that Eptinezumab 300mg was significantly more effective than the 100mg dose, reducing MMDs by an average of -2.60 days (95% CI {-3.32, -1.88}; P <0.00001) versus -2.10 days for the 100mg dose (95% CI {-2.81, -1.39}; P <0.00001). The placebo response observed in the clinical trials could be attributed to factors such as the method of delivery, frequency of site visits, patient expectations, or other contextual elements. Despite the placebo effect, Eptinezumab demonstrated statistically significant and clinically meaningful differences in reducing migraine frequency over the 12-week treatment period.

In Saudi Arabia, the prevalence of migraines is reportedly high, as indicated by published evidence (Figure 2). Current medications for migraine management in the Saudi population appear to be less effective than Eptinezumab. Presently, Onabotulinumtoxin A is emerging as the most promising novel treatment for migraines in Saudi Arabia, although studies on its effectiveness are limited. Introducing Eptinezumab to the Saudi market could potentially alleviate both the health impact of migraines on patients and the economic burden on the government. The involvement of major medical centers in Saudi Arabia in conducting clinical studies on Eptinezumab for migraine management could be a crucial step toward gaining approval for the drug’s use in the country. This move may improve the therapeutic landscape for migraine sufferers in Saudi Arabia.

Strengths and Limitations
In this manuscript, we analyze the efficacy of Eptinezumab in preventing migraines, based on a meta-analysis of clinical trials conducted in different population. Despite potential variability and publication bias, our results indicate that Eptinezumab could significantly reduce migraine frequency and severity. We explore its implications for migraine management and call for further research to confirm these findings.

Conclusion 
This analysis evaluated Eptinezumab’s efficacy in CM prevention in adults via two clinical trials. IV Eptinezumab, every 12 weeks, significantly reduced MMDs by -7.7 days with 100mg and -8.2 days with 300mg. Patients also experienced improved daily life and condition perception. With minor side effects, Eptinezumab was safe. Considering high migraine rates in Saudi Arabia and limited treatment options, the authors recommend that the Saudi FDA explore eptinezumab’s potential through local clinical studies.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors’ Contribution
-Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: all authors.
-Drafting the work or reviewing it critically for important intellectual content: all authors.
-Final approval of the version to be published: all authors.
-Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: all authors.

Acknowledgement: Part of this article was submitted in full completion of the requirements for the MSc Clinical Pharmacology degree of Ibrahim S. Alkhattabi at University of Glasgow’s. We want to offer a great appreciation to Dr William Miller for his mentoring and encouragement during this project.

Conflicts of Interest: All authors declare they have no commercial associations that might pose a conflict of interest in relation to the manuscript. 

Sources of Funding: No specific funding was received for this work. 

Consent to publication and to participate: Not applicable.

Ethics approval: Not applicable.

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