Analyzing Eptinezumab’s Ability to Extend Interictal Periods and Reduce Migraine Burden

Amaal Starling, MD, FAHS, FAAN

(Credit: Mile for Migraine)

Migraine, a leading cause of global disability, represents a complex neurobiological disorder with a range of symptoms, including headache, sensory sensitivities, nausea, autonomic disturbances, cognitive changes, and fatigue.¹ Attacks can vary in frequency and duration, sometimes lasting hours to more than a week, and a subset of patients may progress to chronic migraine, experiencing headache on 15 or more days per month. The interictal period, the time between migraine attacks, is generally marked by relative neurological stability, though some residual symptoms may persist.² Longer interictal periods are thought to allow the nervous system to recover, potentially enhancing resilience and raising the threshold for future attacks.

At the 2025 American Headache Society (AHS) Annual Meeting, held June 19-22, in Minneapolis, Minnesota, researchers presented new insights from a post hoc analysis of the phase 3b DELIVER study (NCT04418765) evaluating the FDA-approved preventive migraine therapy eptinezumab (Vyepti; Lundbeck) for adults.^3,4 This specific post hoc analysis explored how periods between migraine attacks, the interictal period, may relate to patient-reported quality of life, using data collected over weeks 1 to 12 (n = 853) and weeks 1 to 24 (n = 832) of the trial. Overall, findings from the analysis underscored the value of looking beyond traditional measures, such as monthly migraine days, and considering broader outcomes that may reflect the overall patient experience.

Headache and migraine expert Amaal Starling, MD, FAHS, FAAN, associate professor of neurology at Mayo Clinic College of Medicine, recently spoke with NeurologyLive® to discuss insights from the post hoc analysis of DELIVER. During the conversation, she explored how evaluating periods between migraine attacks can offer a different perspective on patient well-being, the potential role of preventive therapies in shaping these intervals, and the value of incorporating patient-reported outcomes into treatment discussions. Starling also reflected on how shifting the clinical dialogue toward “days of comfort” may help guide care decisions and align with broader treatment goals for individuals living with migraine.

NeurologyLive: Could you provide an overview of the phase 3b DELIVER post hoc analysis of eptinezumab, presented at AHS 2025?

Amaal Starling, MD, FAHS, FAAN: The study examined the interictal period, and what it found is that with eptinezumab, the interictal periods are longer, and they’re associated with improved migraine burden. First of all, what is the interictal period? It’s the time period between attacks and when people have very frequent attacks, these interictal periods are often very, very short. A lot of times, my patients will call this the “roller coaster of migraine”—right as they’re ending one attack, the next one begins. When those interictal periods are so short, patients may even have other migraine symptoms during that interictal period. That’s called the interictal burden, and it’s thought to occur because the brain isn’t really allowed to rest and recover in between attacks.

So, we hypothesized that there would be improved patient outcomes and improved migraine burden if we had longer interictal periods—where the brain is able to rest and recover—and people are able to have a longer period in between migraine attacks and migraine days. The interictal period, as you can imagine, is very important for patients. For some, the interictal burden may be the primary driver for care-seeking behavior. People want fewer attacks. They want fewer migraine days. They want more days without migraine, and they want to feel better in between those migraine days.

This study is a post hoc analysis of the DELIVER study, which was a phase 3b multicenter, randomized, double-blind, placebo-controlled study that looked at the safety and efficacy of eptinezumab in patients with chronic migraine and episodic migraine who had previously been on 2 to 4 preventive treatment options that were found to be ineffective for them. The original study found that eptinezumab was safe and effective in these individuals. But the current study is a post hoc analysis looking at the association between the interictal period—specifically the mean longest interictal period—and improvements in patient-reported quality-of-life measures, both at weeks 1 to 12 and then weeks 1 to 24.

The results indicated that the mean longest interictal period was longer with eptinezumab compared with placebo, and more individuals on eptinezumab compared with placebo had greater than 14 days as their longest interictal period, or greater than 21 days as their longest interictal period. These numbers are significant. Fourteen days is 2 weeks, right? Having that longest period between attacks be 2 weeks—or even 3 weeks—is pretty remarkable for these individuals, who are very treatment-experienced, both with episodic migraine and chronic migraine. In fact, in weeks 1 to 24, I found it striking to see that over 50% of patients had a greater than 14-day interictal period. I thought that was amazing. It’s a data point I share with my patients because it has a great impact on them and really encourages them to take that next step in their migraine care.

Not only do we want these longer interictal periods, but we also want to know that they correlate with improved function—and they did. The longer interictal periods on eptinezumab —greater than 14 days or greater than 21 days—correlated with improvement in the burden of migraine disease, as reported through patient-reported outcomes. Specifically, we looked at the HIT-6 headache impact score, as well as the Patient Global Impression of Change (PGIC), which is my favorite PRO because it basically asks patients: “Are you doing better? Are you doing worse? Are you a lot better?” Patients really found that they were doing better—a lot better—or “very much improved” when they were having those longer interictal periods and were on eptinezumab. Overall, individuals living with migraine who have longer periods of time in between attacks—or these longer interictal periods—are experiencing a reduced burden of migraine and an improvement in their quality of life.

What are the clinical implications of these post hoc findings for patients with migraine?

Number one, it gives us another point to talk about with our patients. When I was initially reviewing this data, I remembered a patient of mine who works in the pain space in psychotherapy. The patient said to me, “You know, it’s interesting that in the headache clinic, you guys always talk about migraine days, but in my practice, I always talk about days with comfort.” So, looking at it in the opposite way.

That’s what I really liked about this study—I’m starting to use this type of language in my practice. Instead of asking patients only about their migraine days and their acute medication days, I’m starting to ask: “What about the days in between attacks? Are you having a larger number of days in between attacks? How are you feeling during those days?”

It’s really opened up another line of communication with my patients, and it also feels like a much more positive conversation. I’m exploring treatment options with my patients where, together, we can identify the longest number of days without symptoms, the longest number of days with reduced migraine symptoms, and improved burden of disease. It has flipped the conversation in a more positive way—looking at how we can extend wellness in our patients.

What do you think needs to be researched further in this area? Were there any limitations when doing this analysis?

Well, this is a post hoc analysis, and post hoc analyses do have limitations, given that the studies are not necessarily powered to look for the findings that were identified. We do need additional studies that are focused directly on looking at the interictal period. In this study, because it was post hoc, we were able to correlate patient-reported outcomes with cohorts of patients who had longer interictal periods. But it would be useful to specifically look at what their burden of symptoms is during those interictal times.

If we’re talking about longer interictal periods resulting in the brain being able to rest and recover, it would be interesting to look at physiologic data that demonstrates that. For example, there is data showing that in individuals with migraine, there are lower sensory thresholds and lower pain thresholds. It would be interesting to see if, by extending interictal periods and allowing the brain to rest and recover, those sensory and pain thresholds improve and approach that of controls—compared with individuals who have shorter interictal periods. Looking at this from a physiologic basis is really the next step of research, as well as directly evaluating the burden of symptoms during the interictal period.

I also want to emphasize the recent IHS statement that encourages us to look at migraine disease as a whole and set the standards for treatment higher. I think this study aligns with that, because IHS talks about migraine freedom and that’s really what we’re talking about here. Can we extend the time between attacks? Can we give individuals more migraine freedom? Can we continue working toward a life where these patients have complete migraine freedom? That’s the goal. Are we there yet with every patient? No, not yet—but it’s definitely a goal. IHS has said that should be one of our goals, and I love that’s where the conversation is going these days, because that’s what our patients deserve—100%.

Transcript edited for clarity. Click here for more coverage of AHS 2025.

REFERENCES
1. Steiner TJ, Stovner LJ, Jensen R, Uluduz D, Katsarava Z; Lifting The Burden: the Global Campaign against Headache. Migraine remains second among the world's causes of disability, and first among young women: findings from GBD2019. J Headache Pain. 2020;21(1):137. Published 2020 Dec 2. doi:10.1186/s10194-020-01208-0
2. Peng KP, May A. Redefining migraine phases - a suggestion based on clinical, physiological, and functional imaging evidence. Cephalalgia. 2020;40(8):866-870. doi:10.1177/0333102419898868
3. Lundbeck Advances Leadership in Migraine With New Data at the American Headache Society 67th Annual Scientific Meeting. News Release. Lundbeck. Published June 19, 2025. Accessed July 10, 2025. https://www.lundbeck.com/us/newsroom/2025/lundbeck-advances-leadership-in-migraine-with-new-data-at-the-am
4. Tepper S, Joshi S, Hirman J, et al. Eptinezumab Treatment was Associated with Longer Interictal Periods and Corresponding Larger Improvements in Quality of Life in Participants With Migraine for Whom 2-4 Prior Preventive Treatments had Failed: A Post Hoc Analysis of the DELIVER. Presented at: 2025 AHS Annual Meeting; June 19-22; Minneapolis, MN. P-341.