Study evaluates fremanezumab therapy benefit among migraine patients

Episodic or chronic migraine subjects responding to fremanezumab over a twelve-week period showed clinically significant response rates, declined the frequency of migraine days, improved headache-linked disability and health-related quality of life (HRQoL), and showed fewer days with acute headache medication usage.

In the pathophysiology of migraine, the calcitonin gene-related peptide (CGRP) plays an essential role. To prevent migraine, the monoclonal antibodies targeting the CGRP ligand or its receptor are safe and effective. However, its promising benefits have not been completely explored. Therapy benefit, as determined by the therapeutic response rate, is measured as a decline in the headache outcome (like the decline of the number of migraine days or of moderate to severe headache days) from baseline.

Therapy effects vary on the basis of responder status. This may not appropriately capture their advantages in the responders. Though the optimal responder rates for therapeutics preventing migraine have not been established, a response rate of ≥ 50% decline from baseline is frequently utilized as a vital threshold for individuals suffering from episodic migraine.

The other response rates (like ≥ 75% and 100%) may also be utilized to quantify even better therapeutic advantages. Due to the severity of the disease and symptoms for patients having a chronic migraine, a decreased response rate threshold of ≥ 30% may be significant. Fremanezumab (fully-humanized monoclonal antibody) selectively targets CGRP. It has been granted approval in the European Union, United States, and many other countries as preventive therapy of migraine in adults.

In the previous placebo-controlled randomized clinical trials, fremanezumab displayed efficacy as a preventive therapy for both episodic as well as chronic migraine, with promising safety and tolerability profile. Furthermore, the findings from the HALO CM and HALO EM randomized trials illustrated vital improvements in monthly average migraine days in subjects given fremanezumab quarterly or monthly in comparison with the subjects given a placebo.

Therapy effects are worse in subjects who do not respond to therapy in comparison with subjects responding to therapy. The medical care providers and individuals suffering from migraine may have a substantial interest in the extent of improvement in responders, compared to those who do not respond, as responders would continue the treatment and gather the preventive advantages.

Rationale behind research

Currently, there is a paucity of clinical trial results offering data on improvements attained among responders. Thus, this study was performed to examine fremanezumab treatment benefits in patients suffering from migraine.

Objective

A post hoc responder analysis was carried to investigate the therapy advantages of fremanezumab in migraine patients who responded to therapy during the twelve-week phase III randomized HALO EM and HALO CM trials.

Study outcomes

The outcomes were a decline in (i) monthly migraine days, (ii) headache days of at least moderate severity, (iii) acute headache medication usage, (iv) headache-linked disability, and (v) alterations in the overall HRQoL. 

Outcomes

Baseline: There were no vital differences reported at baseline.

Study outcomes

• Overall, 857 subjects from the HALO trials were recognized as responders (Episodic migraine: 429 [73.8%]; Chronic migraine: 428 [56.7%])
• Decline in the monthly average number of migraine days was higher among episodic migraine (quarterly: 5.4 days; monthly: 5.5 days) and chronic migraine (quarterly: 8.7 days; monthly: 9.1 days) responders when compared to the overall population
• Percentage of subjects attaining ≥ 50% decline in the average monthly number of migraine days was  higher in responders (episodic migraine: quarterly, 59.8%; monthly, 63.7%; chronic migraine: quarterly, 52.8%; monthly, 59.0%) in comparison with the overall population
• In comparison with the overall populations, a higher decline in the average number of days of acute headache medication usage, a higher decline in headache-linked disability scores, and better improvements in HRQoL were noted among episodic and chronic responders

Fremanezumab is linked with remarkable improvements in migraine frequency, headache-linked disability, and HRQoL in a considerable percentage of subjects having episodic and chronic migraine who respond to therapy. A substantial percentage of subjects responded to fremanezumab therapy when utilizing study-specific thresholds of a decline of ≥2 monthly migraine days for subjects with episodic migraine (quarterly: 73.5%; monthly: 74.1%) and ≥ 4 monthly average migraine days for subjects with chronic migraine (quarterly: 58.0%; monthly: 55.4%).

A decline of ≥ 4 monthly average migraine days aligns with a response rate of ≥ 30%, that is clinically vital for subjects having chronic migraine. Although the decline of ≥ 2 monthly average migraine days  (≥ 25%) for episodic migraine subjects is reduced in comparison with the generally accepted threshold for a clinically vital response (≥ 50%), this threshold was meant to capture the wider range of episodic migraine subjects incorporated in this analysis, some of whom could have less than four monthly average migraine days.

Utilizing an elevated threshold to define responders would have additionally raised magnitude of the effect in the study outcomes. However, this reduced threshold permits for a distinction between effects in subjects with little to no response compared to subjects with a significant improvement. The large variance between efficacy results in subgroups divided at this 25% threshold indicates that this is a reasonable cut point to distinguish nonresponders and responders. It was found that subjects responding to fremanezumab display higher improvements in all the outcomes compared to the overall trial populations.

A substantial decrease in the monthly average migraine days  was witnessed in episodic migraine responders (59%–60% decline) and chronic migraine responders (54%–57%) in comparison with the total study populations (37%–42% and 30%–32%, respectively). The response rates (≥ 50% and ≥ 75% decline in the monthly average migraine days) were also greater in responders compared to the overall populations. The episodic and chronic migraine responders had higher decline in monthly average number of days of acute headache medication usage.

Improvements in headache-related disability scores (Migraine Disability Assessment [MIDAS] and 6-item Headache Impact Test [HIT-6]) and HRQoL (14-item MigraineSpecific Quality of Life [MSQoL]) were also higher in episodic and chronic migraine responders compared to the overall population. The over usage of acute headache medicines must be considered in treating and long-term management of migraineurs. In chronic migraine subjects, acute medication overusage is related to an elevated risk of developing medication over usage headache, that is also related to a poorer prognosis, further comorbidities, higher disability, and lowered HRQoL in individuals suffering from chronic migraine.

As per the criteria of International Classification of Headache Disorders, the medication overuse headache develops as a consequence of regular overusage of acute or symptomatic headache medication for more than three months on ≥ 10 days/month for opioids, ergot derivatives, triptans, or combination analgesics or on ≥ 15 days/month for acetaminophen, nonopioid analgesics, or nonsteroidal anti-inflammatory drugs.

In this study, the average number of days per month in which the acute headache medicine was utilized in episodic migraine responders was 7.9 days at baseline and 3.7 days following12 weeks of fremanezumab therapy (52.9%–53.7% decline). In chronic migraine responders, it was 13.0 to 13.3 days at baseline and 6.6 days following 12 weeks of fremanezumab treatment (49.3%– 50.4% decline). This indicates that individuals having episodic or chronic migraine who respond to fremanezumab use less acute headache medicine. This can lead to resolution of the medication overuse headache or lower the chances of developing medication overuse headache.

The positive patient-centered outcomes like headache associated disability and HRQoL illustrate vital improvements in subjects receiving fremanezumab. Compared to the episodic and chronic nonresponders, the responders witnessed a higher decline in headache-linked disability.

Improvements in HIT-6 scores noted in chronic migraine responders (a decline of 8.3 and 9.7 points with fremanezumab quarterly and monthly dosing, respectively) considerably exceeded the minimal clinically important difference (MCID) for HIT-6 score in subjects having a chronic daily headache (2.3 points). In comparison with the nonresponders, the responder groups on monthly and quarterly dosing attained a higher decline that exceeded MCID in HIT-6 scores.

This outcome emphasizes the significant advantages attained between responder and non-responder chronic migraine subjects, as defined in this analysis. For chronic migraine responders, the subjects treated with quarterly fremanezumab witnessed a shift in HIT-6 scores  to grade 3 (substantial impact; HIT-6 score of 56–59) from grade 4 (severe impact; HIT-6 score of 60–78). On the other hand, subjects treated with monthly fremanezumab witnessed a shift from grade 4 to grade 2 (moderate impact; HIT-6 score of 50–55) following 12 weeks of treatment.

The episodic migraine responders witnessed vital improvements in MIDAS scores (72% decline), with shifts from baseline scores that depicted severe disability (MIDAS score ≥ 21) to end-of-therapy scores indicating only mild disability (MIDAS score ~ 10) following fremanezumab therapy. As per the consensus statement of American Headache Society, the proof of therapeutic advantages with anti-CGRP monoclonal antibodies incorporates considerable improvement in a validated migraine-specific participant-reported outcome measure, like a 30% decline in the MIDAS score for subjects with baseline scores above 20 or a decline of at least five points on HIT-6, both of which were attained by fremanezumab responders in the current assessment.

The chronic and episodic migraine responders also noted better improvements in all the three domains of the MSQoL in comparison with the nonresponders. This indicates that individuals responding to fremanezumab therapy have decreased disability and elevated HRQoL. These findings may aid physicians to manage patient expectations when utilizing fremanezumab for the preventive therapy of migraine.

Fremanezumab-responsive subjects witness a higher decline in headache days of at least moderate severity and migraine days, improvements in overall HRQoL and disability, and decline in acute headache medication usage. Persistence (patient's ability to continue on therapy over an extended time period), was found to be poor with older migraine preventive medicines. The efficacy paucity, delayed onset of efficacy, and extended titration periods lead to poor persistence for various migraine medicines.

On the other hand, fremanezumab responders were found to have an early and robust decline in frequency of migraine, which may motivate subjects to continue with therapy. The adherence can also be improved by selecting monthly or quarterly dosing in comparison with dosing once or multiple times a day, which is known to produce poorer adherence in patients with migraine.