The present study concluded that the number of headache-free days’ increases with regular functional performance in the patients with an episodic and chronic migraine treated with fremanezumab.

An episodic and chronic migraine affects approx 12% and 1% of the general population respectively.  A chronic migraine can be defined as headaches occurring on at least 15 d/mo, with at least eight days of a migraine per month. Migraine is ranked as seventh highest among medical causes of disability worldwide.  In a recent study examining 2,959 patients with EM, 14.8% reported avoidance and lifestyle compromise, 10.6% reported interictal anxiety, and 26% reported interictal symptoms. Migraine should be best defined as a chronic neurologic disorder with persistent interparoxysmal physiologic compromise rather than the conventional view which illustrates migraine as an episodic or paroxysmal headache disorder with attacks divided into discrete phases in between patients which are symptom-free. It can be demonstrated as persistent symptoms punctuated by continuous headache attacks and other attack-related symptoms such as overlapping phases of prodrome (commonly referred to as premonitory), aura, headache, and postdrome. Postdrome and prodrome symptoms are common and affect around 80% of the migraine population. Phase related and interictal non-headache symptom in addition to signs of frequent comorbid conditions is essential in fully describing the burden of disease.

Fremanezumab, formerly known as TEV-48125, is a humanised immunoglobulin G2a monoclonal antibody that selectively binds to calcitonin gene-related peptide (CGRP) and preventing its binding to receptors. Phase 2 and phase 3 trials assessing the safety and efficacy have been completed for chronic and episodic migraines. In the trials, a daily headache calendar was formed and completed. On headache free days they were asked to answer questions focused on functional performance for the day. The study was organised to evaluate the effect of fremanezumab on functional performance on headache-free days.

Objective:

The purpose of this post hoc analysis was to determine the effect of fremanezumab on the functional status on headache-free days in phase 2 an episodic migraine (EM) and chronic migraine (CM) studies. 

Study outcomes:

• Patient demographic characteristics were evaluated at baseline
• Other outcomes include evaluation of efficacy and safety of fremanezumab and the change in the mean number of days for each possible response of functional status from baseline to the entire treatment period (weeks 1–12)

Time Points: 3 months

Outcomes

Baseline: There were no significant differences observed at baseline

Study outcomes:

• An increased number of headache-free days were experienced in those receiving fremanezumab with normal function in school/ household chore/ work performance and concentration/mental fatigue measures compared to their baseline over the entire treatment period in episodic and chronic migraineurs. (Fig 2.)

• There was no severe safety signals or clinically relevant changes in vital signs, ECG parameters, or laboratory findings associated with the use of fremanezumab, thereby well tolerated and safe

In both HFEM and CM trials, patients with fremanezumab indicated an increase in the number of headache-free days with regular functional performance in domains of work, school, household chores, as well as energy and ability to concentrate when compared to placebo. An increase in the headache-free days with the regular performance was observed in HFEM trial with 225- and 675-mg doses of fremanezumab and in CM trial with a 900-mg dose of fremanezumab. With an increase in headache-free days, patients experienced a reduction in interictal anxiety, avoidance behaviour and lifestyle compromise with normal functioning. It is an important observation because all other preventive migraine therapies lead to a variety of side effects (e.g., cognitive difficulties) contributing to the burden of interictal symptom and reduction in medication adherence & persistence.

Acute medications for management of migraine are often administered at the onset of a headache, but it can also be taken as the form of anticipatory treatment on headache-free days in a subset of patients especially if prodromal symptoms are experienced, in an attempt to preempt the headache phase. Additionally, patients may also use acute treatment in the absence of a headache as an anxiety response of fear of having a headache (cephalalgiaphobia). An increase in headache-free days also reduces the intake of acute treatments resulting in the decrease in any associated side effects that may contribute to impaired functional performance on headache-free days. Overall, administration of fremanezumab reduces the use of acute medications by 5 and 6.5 days/month compared to the reduction of 3 and four days/month for those taking placebo during the HFEM and CM studies.

Another possibility is that there might be an effect on the prodrome, postdrome-, or interictal-phase symptoms along with the headache phase of the attack on headache-free days. The prodrome phase of migraine is thought to be centrally mediated at the level of the hypothalamus. It is believed that fremanezumab might have a direct effect on central networks because other CGRP-monoclonal antibodies are not supposed to cross blood-brain barrier due to their high molecular weight. Fremanzumab may also reduce the CGRP-mediated transmission in the trigeminovascular system, and this reduction in peripheral afferent activity can modulate the central networks that generated the migraine attack. Modulation of CGRP also affects comorbid conditions such as depression, anxiety, irritable bowel syndrome, and other chronic pain disorders that were not assessed. Evaluation of the effect of CGRP-modulating therapies on functional performance during headache-free days and on non-headache symptoms helps to provide insight into potential pathophysiologic mechanisms of migraine. It can also aid in illustrating the role of CGRP monoclonal antibodies such as fremanezumab in the blockade on migraine-related comorbidities and pathophysiology of migraine. Further prospective research is warranted for the effect of CGRP monoclonal antibodies on headache-free days.