On 29 June, at the 10th Congress of the European Academy of Neurology (EAN), the early treatment of migraine to optimise care in a variety of different contexts was covered in two presentations during an AbbVie-sponsored satellite symposium, followed by a panel discussion.

A migraine attack consists of up to five distinct phases: prodrome / premonitory, aura, headache, postdrome, and interictal phase. Acute treatment is typically administered during the headache phase following the onset of headache pain, but there is significant evidence that initiating treatment at the earliest onset of headache pain results in better outcomes for patients compared with waiting until pain becomes moderate-to-severe in intensity.

Despite the evidence that early initiation of acute treatment results in better outcomes, many patients do not take their medication in a timely manner. First, many patients are unaware that early administration can improve outcomes. This was also highlighted by key opinion leaders (KOLs) recently interviewed by GlobalData, who noted that when a patient is not responding well to an acute therapy, such as a triptan, their first solution is to often educate the patient that taking the drug early in their migraine episode will maximise treatment effectiveness. A further key challenge highlighted during the symposium is that due to the variability of migraine episodes, many patients do not like to take medication early, but rather will hold out until the pain is sufficiently severe that they are then required to take acute medication. As such, significant patient education will be required to drive a shift in the administration habits of patients. Panellists also noted that while triptans are first-line acute therapies, the favourable side effect profiles of the gepants present an opportunity for earlier treatment, as patients may be more willing to take these drugs earlier in their migraine episode.

Recent research has shown that even earlier administration of acute treatment during the prodrome stage affects treatment outcomes. In a Phase III, cross-over trial (PRODROME: NCT04492020) in patients experiencing two to eight migraine attacks per month, 45.5% of patients who took AbbVie’s Ubrelvy (ubrogepant) (n=418) experienced an absence of moderate-to-severe headache within 24 hours post-dose compared with 28.6% of patients on placebo (n=423). Although these results demonstrated the efficacy of administering Ubrelvy at this early stage, it requires patients to be able to reliably predict their prodromal symptoms, which is not realistic for all migraine patients. However, one panelist believed that it would be possible for patients to learn how to identify their prodromal stage. This would likely require significant patient education and would

also need to be highly individualized. Ultimately, the panelists agreed that it was unlikely for there to be a paradigm shift towards treating at the prodrome stage given both the significant challenges that already exist around patients being unwilling to take acute medication early and concerns of patients over-diagnosing their prodromal stage, leading to medication overuse headaches (MOHs). MOHs are a risk factor with triptans. As such, this strategy would be limited to the newer, significantly more expensive gepants, which have not been associated with MOH.

In addition to the early timing of acute treatment, the importance of using early-onset of preventive medication was also discussed during the symposium. Clinical evidence is available for the four anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs), as well as atogepant, rimegepant, and onabotulinumtoxin A, showing efficacy in just one week. In comparison, old oral preventive drugs such as beta-blockers, tricyclic antidepressants, and antiepileptic medications take longer to show an effect. For preventive treatment, patients ranked the onset of effect as an important treatment goal. The earlier that patients can see that a preventive medication is effective, the more likely they are to persist with that treatment. Lack of compliance has been a significant challenge with the old oral preventive therapies, particularly as many of the drugs also have poor side-effect profiles. In contrast, the anti-CGRP mAbs and gepants have demonstrated greater efficacy for migraine prevention and have fewer side-effects concerns, making them more attractive options for patients. However, despite the potential benefits of early prevention with these therapies, the panel acknowledged that their higher price points mean that there are reimbursement restrictions in many European countries that would prevent them from being used early in a prevention landscape.

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Additionally, migraine is not a static disease, with some patients experiencing progression from episodic to chronic migraine, known as migraine chronification. One risk factor for progression is a high number of monthly headache days, or high frequency episodic migraine. Therefore, the efficacy of the anti-CGRP mAbs and gepants at reducing headache days could also mean that they may be expected to reduce chronification. Another risk factor for migraine chronification is comorbid depression, and it had also been demonstrated that early and effective preventive treatment can positively influence psychiatric comorbidities, including depression. For example, in a Phase IV trial (UNITE: NCT04041284), treatment with Ajovy (fremanezumab) was associated with a reduction in Hamilton Depression Rating Scale scores. This further highlights the benefits of early preventive therapy for migraine. However, the panel agreed that the data behind using preventive treatments at an early stage to prevent progression to chronic migraine is less established and requires further study and data to support its practice.

Overall, despite the benefits of early migraine intervention, both in the timing for acute treatment and in the early onset of preventive effects, significant challenges remain for this to become more widely implemented.