Phase III trial evaluates the long-term safety and tolerability of eptinezumab to treat chronic migraine

Clinical Research 5 min 492

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Created On: 11/08/2021

Phase III trial evaluates the long-term safety and tolerability of eptinezumab to treat chronic migraine

Migraine, a chronic neurological disorder, is a leading cause of long-term disability and poses an enormous burden on the healthcare system.

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Key take away

In patients with chronic migraine, intravenous administration of 300 mg eptinezumab led to an early and sustained decline in migraine-associated burden, with limited long-term immunogenicity, improved quality of life and favourable safety over two years.

Background

Migraine, a chronic neurological disorder, is a leading cause of long-term disability and poses an enormous burden on the healthcare system. It is estimated that about 40% of individuals suffering from migraine are candidates for preventive migraine therapy, and many patients receiving preventive treatment discontinue it due to lack of efficacy and associated adverse effects. In addition, due to the long-lasting nature of migraine, people may use preventive therapy for years while ignoring the requirement for understanding the tolerability and safety of effective long-term migraine preventive therapy.

Eptinezumab, a humanized monoclonal antibody, has received approval recently in the United States for the preventive therapy of migraine in adults. It inactivates calcitonin gene-related peptide (CGRP), which plays a significant role in initiating migraine. In double-blind, placebo-controlled studies carried out in subjects suffering from chronic and episodic migraine, this anti-CGRP agent displayed good tolerability across all doses. No apparent dose-associated trend was witnessed in the severity, nature, or frequency of treatment-emergent adverse events (TEAEs).

Rationale behind research

Previous evidence has been lacking in investigating the long-term efficacy and safety of eptinezumab among individuals with chronic migraine. Therefore, this open-label phase III (PREVAIL) trial was carried out.

Objective

This analysis was performed to examine immunogenicity, long-term safety, and effect on participant-reported outcomes of repeat doses of eptinezumab in adults suffering from chronic migraine.

Method

Study outcomes

The major outcome was the assessment of safety, immunogenicity, and patient-reported outcomes (PROs) such as the patient global impression of change (PGIC), migraine disability assessment (MIDAS) questionnaire, 6-item headache impact test (HIT-6) and patient-identified most bothersome symptom (MBS) associated with migraine.

Result

Outcomes

Baseline: There were no vital differences reported at baseline.

Study outcomes

During the two years, the most commonly noted treatment-emergent adverse events were sinusitis (7.8%), migraine (5.5%), nasopharyngitis (14.1%), bronchitis (5.5%), upper respiratory tract infection (7.8%), and influenza (6.3%)
The rate of discontinuation due to side effects was 6.3% that included three subjects having infusion-associated hypersensitivity
At week 24, the occurrence of anti-eptinezumab antibodies peaked and reduced despite continued dosing to non-detectable levels at week 104
At the initial assessment (week 4), improvements in participant-reported outcomes were witnessed that sustained through week 104 (Figure 2)

Conclusion

In individuals having chronic migraine, 300 mg of eptinezumab given once every 12 weeks for up to eight doses displayed favourable long-term tolerability and safety when used as a preventive therapy. During the initial year of trial, 79 (61.7%) subjects witnessed ≥1 TEAE while 91 (71.1%) subjects witnessed ≥1 TEAE across the entire two years, thus indicating a lack of cumulative effect on safety endpoints. Most of the TEAEs were moderate or mild in severity. The occurrence of severe TEAEs and study drug-linked adverse events was low.

Interruption of eptinezumab administration and discontinuation due to noxious events was not frequent. The results demonstrated consistency with the previous placebo-controlled, double-blind clinical trials. In few patients (18%), anti-drug antibodies were developed. At week 24, the occurrence of anti-drug antibodies was maximal (17.5%). Despite continued dosing, it was found to decline to 5.3% and 0% by the end of week 48 (the primary study phase) and week 104 (end of the analysis), respectively.

These outcomes were consistent with anti-drug antibody development in the two-phase III PROMISE studies, in which the prevalence of anti-drug antibody with the 300-mg dose was found to increase at 17–17.5% at week 24. Only 7% (9/128) of treated patients developed neutralizing antibodies. Thus, there was no proof of an impact from the development of anti-drug antibodies, including neutralizing antibodies on eptinezumab's safety profile.

Following the initial dose of eptinezumab, remarkable improvements were noted in the patient-reported outcome measures and were maintained or improved following each subsequent dosage. For example, in week 12, substantial change over twice the American Headache Society threshold in the mean decline in MIDAS total score was reported, which was sustained till week 104. Comparable changes were noted in the self-identified MBS and PGIC, with about 60% of participants reported very much or much improvement in both measures at week four, and about 80% of participants reported improvement (very much or much) at week 48.

Substantial improvements in PROs yield promising clinical benefits, considering the raised level of life-activity hindrance and disability associated with migraine. Approximately 85% of chronic migraine people had baseline MIDAS scores that indicated severe disability in the International Burden of Migraine Study-II (IBMS-II). In the Chronic Migraine and Epidemiology Outcomes (CaMEO) assessment, the baseline mean MIDAS score were estimated to be 60.5 in chronic migraine subjects. For any migraine intervention, enhancing life impact is a desirable outcome.

In the present study, a high persistence with therapy was noted. About 92% of subjects completed the first year of the study, and 79% of subjects completed both years. It suggested substantial improvement over established oral prophylactic treatments, for which persisted overall rates ranged from 25 to 76%. Average time to discontinuation of oral prophylactic treatments was estimated to be 1-3 months as per the findings of retrospective claims. Side effects (34–53%) and perceived lack of efficacy (39–48%) were the most common reasons for discontinuing prophylactic therapy. Only 6.3% of participants (n=8) discontinued treatment early due to TEAE.

This trial's extended duration allowed to explore the tolerability and safety of repeated administration of eptinezumab to alleviate chronic migraine. In addition, the 300-mg dose was utilized to offer the data for the maximum dose level determined in the vital clinical trials. The International Headache Society acknowledges all the PRO outcome measures except patient-identified MBS incorporated in this study as valid instruments to assess participant satisfaction and headache-associated healthcare outcomes. This is the most extended open-label safety clinical trial of eptinezumab in people having a chronic migraine to date. But, the PRO outcomes in this study illustrated consistency with those from PROMISE-2 pivotal trial and offer insight into eptinezumab's long-term safety and tolerability to manage chronic migraine.

Limitations

The lack of a placebo control restricts interpretation regarding internal validation and clinical relevance since there may be robust placebo responses in the migraine prevention trials.