For the past decade, the calcitonin gene-related peptide (CGRP) pathway has been a major focus of migraine drug development. The resulting monoclonal antibodies and gepants have transformed clinical practice, establishing CGRP as one of the most successful therapeutic targets in migraine.

While the field’s near laser focus on the neuropeptide has meant relief for many people with migraine, struggles remain for those who don’t respond to CGRP-targeted therapies.

Now, researchers are expanding their efforts in pursuit of a broader set of biological targets, from pituitary adenylate cyclase-activating polypeptide (PACAP) and amylin to ion channels involved in neuronal excitability.

“CGRP advanced the field, but it did not solve migraine,” said Shaheen Lakhan, MD, PhD, neurologist, and researcher based in Miami. “Many patients have an incomplete response, lose benefit over time, or do not respond at all. That tells us migraine is not governed by a single molecular pathway.”

The question is no longer simply whether migraine can be treated beyond CGRP, experts say, but which of these emerging approaches is most likely to shape clinical practice.

The Case for PACAP

After CGRP, one of the most clinically advanced targets in migraine research is PACAP.

“What’s exciting about PACAP monoclonal antibodies is that they operate on a parallel pathway to CGRP mechanisms,” said Amaal J. Starling, MD, fellow of the American Academy of Neurology (AAN) and associate professor of neurology, Mayo Clinic, Scottsdale, Arizona. “Thus, we hope that PACAP monoclonal antibodies can benefit patients who did not respond to CGRP antagonism.”

The peptide’s involvement may also begin earlier in a migraine attack, including during the prodromal phase, Starling noted, raising the possibility that therapies targeting the pathway could affect not only the pain phase but also non-headache symptoms of migraine.

This potential independence from CGRP is central to the interest in PACAP as a therapeutic target. PACAP is a neuropeptide that helps regulate signaling in the brain, blood vessels, and autonomic nervous system. Although it overlaps with CGRP in migraine biology, it acts through different receptors and signaling pathways, which may allow it to trigger migraine even when CGRP is blocked.

“PACAP is not simply CGRP 2.0,” Lakhan said. “It may represent another important node in the migraine network and could potentially benefit patients whose disease is not predominantly CGRP-driven.”

Evidence that the pathways may be at least partly distinct comes from a human provocation study in which PACAP triggered migraine attacks despite pretreatment with a CGRP-blocking antibody.

Clinical studies have provided further support for targeting this pathway. In the phase 2 HOPE trial, a single infusion of the experimental anti-PACAP monoclonal antibody bocunebart reduced monthly migraine days over 4 weeks in patients who had previously failed preventive treatments.

In the phase 2b PROCEED trial, one intravenous bocunebart regimen produced a statistically significant reduction in monthly migraine days among patients with prior preventive treatment failures.

Two other intravenous bocunebart regimens evaluated in the trial produced numerical, but not statistically significant, improvements. The results have not yet been published in a peer-reviewed journal.

Lakhan said the bocunebart results are “encouraging, especially because the study included patients with difficult-to-treat migraine. However, the effect was still modest, and this remains an early-stage signal rather than a therapeutic breakthrough.” He views PACAP as “complementary to CGRP, not a replacement for it.”

Starling said a key question is whether bocunebart will be effective for patients who do not respond to — or only partially benefit from — CGRP-targeted therapies.

Other PACAP pathway drugs have also entered clinical testing, but bocunebart is the most advanced. AMG 301, which targets the PAC1 receptor, failed to improve migraine prevention in phase 2 study.

The anti-PACAP antibody LY3451838 also entered phase 2 testing in treatment-resistant migraine but did not progress, whereas ALD1910, another anti-PACAP antibody, advanced through early-phase testing without moving into later-stage development.

One possible reason bocunebart may differ is that it neutralizes the PACAP peptide itself rather than blocking a single receptor, potentially interrupting signaling across several PACAP-responsive receptors.

Potential Next-Gen Targets

Several investigational approaches aim to modulate ion channels involved in neuronal excitability, vascular signaling, and activation of the trigeminovascular system.

In separate randomized crossover provocation studies, the ATP-sensitive potassium channel opener levcromakalim triggered migraine attacks, as did the investigational large-conductance calcium-activated potassium channel opener MaxiPost. The findings provide human evidence implicating both channels in migraine pathophysiology and suggest that selectively blocking them could have therapeutic potential.

Therapies targeting transient receptor potential (TRP) channels are further along in clinical development. Among them is BHV-2100, a TRPM3 antagonist designed to reduce nociceptor activity. Phase 1 data showed favorable tolerability and pharmacokinetics, and a phase 2 acute migraine trial involving 647 participants has been completed, although results have not yet been publicly reported.

In a phase 2b study, the investigational oral TRPM8 antagonist elismetrep produced dose-related improvements across acute migraine outcomes and was generally well tolerated. However, the highest dose narrowly missed statistical significance on the primary endpoint of pain freedom at 2 hours in the electronic-diary analysis. Further studies are planned.

Starling also pointed to interest in repurposing suzetrigine, a sodium-channel blocker approved for moderate-to-severe acute pain, for migraine. In a recent single-center retrospective study, approximately two thirds of patients treated with the drug experienced improvement in headache symptoms.

Amylin has emerged as another potential therapeutic target. In a human provocation study, the amylin analogue pramlintide triggered migraine-like attacks, providing evidence that the pathway may play a role in migraine pathophysiology. Lakhan said the amylin research is important because it broadens the biological map of migraine.

“It supports the idea that multiple peptide systems may converge on the same clinical syndrome through different mechanisms.” For now, however, amylin is “scientifically provocative but therapeutically immature,” he said.

Nitric oxide is also a well-established experimental migraine trigger, but translating this biological insight into an effective treatment pathway has been challenging. In a 12-week preventive trial, the selective inducible nitric oxide synthase inhibitor GW274150 failed to outperform placebo. More broadly inhibiting nitric oxide signaling may not be a viable alternative because of its important role in cardiovascular function.

Beyond Trial and Error

The expanding range of therapeutic targets could eventually move migraine care beyond a one-size-fits-all approach, Starling said. Given the genetic and clinical heterogeneity of the disease, different patients may respond to different biological targets, while some may ultimately benefit from sequential or combination approaches.

Like Starling, Lakhan believes future treatment will be individualized. “Migraine biology is a network, not a hierarchy,” he said.

Different patients may have different dominant pathways, he added, and some may ultimately require sequential or combination treatments that act across multiple mechanisms. That individualized approach could eventually extend beyond pharmacotherapy to incorporate devices, digital tools, and behavioral interventions, he added.

Lakhan said the goal is not simply to have more treatments available but to reduce trial and error, intervene earlier. and achieve more sustained disease control.

Starling also sees a broader shift in how treatment success is defined, with a growing emphasis on disabling features that go beyond monthly migraine days and headache pain to include symptoms such brain fog, nausea, and sensory sensitivities.

“Migraine is abnormal processing of so many different sensations. Pain is only one of them,” Starling said. “Targeting pathways involved earlier in the attack could eventually help address some of these other non-headache/pain symptoms of migraine that current therapies do not adequately treat.”

Lakhan reported having no relevant disclosures. Starling reported receiving consulting fees from AbbVie, Allergan, Amgen, Amneal, Aspeya, Axsome Therapeutics, Biopharm Communications, Global Learning Collaborative, Eli Lilly, eNeura, Everyday Health, Impel, IntegrityCE, Lundbeck, MedIQ, Medscape, Miller Medical, Neurolief, Novartis, Pfizer, Salvia, Satsuma, TCG Soleil, Teva, Theranica, UpToDate, WebMD, and Woodberry Associates.