Lecture on migraine: from the prodromal phase to future paradigm shifts

At the AAN 2023 meeting, Prof. Peter Goadsby (King's College London, UK) was honoured with the Robert Wartenberg Lectureship. In his lecture, Prof. Goadsby reflected on the road to identifying successful therapeutic targets and developing therapeutics for migraine. He stressed the importance of prodromal symptoms, often mistaken for triggers. He also predicted 2 paradigm shifts.

“Prof. Goadsby is the type of clinician-scientist who nearly single-handedly by this pursuit changed the treatment paradigm in the field of migraine by advancing insights into the pathophysiology of a complex disease that was already believed to have been understood” [1]. These introductory words came from Prof. Natalia Rost (Massachusetts General Hospital, MA, USA). In his following lecture, Prof. Goadsby described the current armamentarium of migraine medications, including triptans, monoclonal antibodies, gepants, ditans, and neuromodulation techniques, and the underlying biology. He stressed the importance of including participants in migraine clinical trials who have previously failed on other agents, not only because they lower placebo rates, but also because these are the patients you often encounter in clinical practice.

One of the central ideas Prof. Goadsby discussed was that of migraine as a network disorder with many targets. “Migraine is typically thought of as a linear process. I think that is a too-limited view of what is a complex, networked neurological disorder. Think of the phases of migraine not linearly but as integrated; think of the symptomatology as a totality.” He advised the audience to go through all symptomatology with patients. “Put it in people's minds. It only takes about 5 minutes extra.”

According to Prof. Goadsby, prodromal (premonitory) migraine symptoms are easily confused with triggers. For example, about 5% of patients experience photophobia in the prodromal phase, so they will often consider light a trigger. Or they experience food cravings in the prodromal phase and assume food to be a trigger when it is, in fact, a prodromal symptom. “A patient can feel empowered just by hearing this explanation.”

A possible paradigm shift Prof. Goadsby predicted, centred around pituitary adenylate cyclase-activating polypeptide (PACAP). This is a secretin/glucagon superfamily peptide with a saturable transport system into the brain. Research by Prof. Goadsby and others from the past 30 years revealed that PACAP is elevated in migraine without aura and can be normalised with sumatriptan [1]. These data already suggested that PACAP (or its receptors) could be a promising target for migraine therapeutics.

Only a few days before the lecture by Prof. Goadsby, positive phase 2 proof-of-concept results of the HOPE trial (NCT05133323) on Lu AG09222 in migraine prevention were announced [2]. Lu AG09222 is a monoclonal antibody that binds and inhibits signalling mediated by the pituitary adenylate cyclase-activating polypeptide (PACAP). The double-blind, placebo-controlled HOPE trial assessed the efficacy, safety, and tolerability of a single intravenous infusion of Lu AG09222 in 237 migraine patients. It resulted in significantly fewer monthly migraine days in weeks 1–4 compared with placebo (P=0.01). The full trial results are not yet available.

Another paradigm shift could be using gepants in the prodromal stage of migraine. This was precluded by results of the UBR PRODROME study (NCT04492020) presented at the AAN 2023 meeting [3]. This placebo-controlled cross-over study evaluated the efficacy, safety, and tolerability of ubrogepant 100 mg when administered during the prodrome of a migraine attack. Participants treated 2 events that qualified as prodromal, meaning they were confident a headache would follow these events between 1 and 6 hours later. In 477 participants, 45.5% of treated prodromal events in the ubrogepant group were followed by the absence of moderate/severe headache within 24 hours, compared with 28.6% of events in the placebo group (P<0.0001). The number of symptoms and time to absence after treatment were also shorter than with a placebo. Prof. Goadsby: “Why is this important? Because 75% of people have some form of disability during the prodromal phase of migraine. That is what we neurologists are about, namely treating people with disabling problems.”

1. Goadsby P. Migraine: then, now, and tomorrow - progress through biology. PL3.004, AAN 2023 Annual Meeting, 22–27 April, Boston, USA.
2. H. Lundbeck A/S. Lundbeck announces positive phase 2 Proof of Concept results with Lu AG09222 in migraine prevention. Corporate press release, 19 April 2023.
3. Dodick DW, et al. Ubrogepant for the acute treatment of migraine when administered during the prodrome (premonitory phase): Results from a phase 3, randomized, double-blind, placebo-controlled, crossover study. S47.001, AAN 2023 Annual Meeting, 22–27 April, Boston, USA.

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Posted on 26 June 2023