PACAP Pathway and Its Role in Migraine

Sun, PhD,Jennifer;

PACAP Pathway and Its Role in Migraine

February 20, 2021

Jennifer S. Sun, PhD

Publication

Article

NeurologyLiveFebruary 2021

Volume 4

Issue 1

The PACAP pathway has shown promise as a potential novel therapeutic target in the treatment of migraine.

Migraine is a heritable,^1-3 complex brain disorder that produces an assortment of neurological and systemic effects.⁴ Diagnosis is based on criteria related to the number and duration of attacks, as well as headache characteristics and the presence of accompanying symptoms.^5,6 These symptoms are often debilitating and can be triggered by hormonal fluctuations or stress.^3,6 Further, patients with migraine are more likely to experience medication overuse headache and comorbidities such as insomnia, depression, anxiety, gastric ulcers, and gastrointestinal bleeding.^1,6

Jennifer S. Sun, PhD

Despite the prevalence and significant burden of migraine,^6,7 the majority of patients living with the disorder are overlooked⁶ or treated unsatisfactorily.⁵ This is due in part to the challenge of identifying effective treatment to address the complex pathophysiology of migraine.^4,5 Lack of efficacy and the development of adverse effects (AEs) often result consequently in patients’ dissatisfication with medications, particularly before the recent advent of more targeted preventive migraine treatments.⁵ The continued development of such agents promises to change this landscape.

Investigational migraine therapeutics focus on receptors of the trigeminovascular system, the activation and sensitization of which yields migraine headaches.^2,3 Eptinezumab (Vyepti, Lundbeck Seattle BioPharmaceuticals), a humanized monoclonal antibody (mAb) inhibitor of the calcitonin gene-related peptide (CGRP), received FDA approval in February 2020 as the first intravenous migraine prophylactic in adults.6 Clinical trials,^8-11 along with an open-label safety study¹² and pharmacokinetic data,¹³ show that quarterly infusions of eptinezumab achieve 100% bioavailability¹³ after administration and significantly decrease the number of migraines experienced per month. Modulation of other signaling systems and factors which are involved upstream or alongside the trigeminovascular system (the endocannabinoid system⁶) are also being considered for therapy development. These factors can potentially be used in combination therapy with CGRP active agents.⁶ Of particular recent interest is the pituitary adenylate cyclase–activating peptide (PACAP) signaling pathway.

PACAP is a pleiotropic signaling neuropeptide⁴ belonging to the glucagon-growth hormone–releasing factor-secretin superfamily.⁵ It exists in 2 biologically active forms, PACAP-27 and PACAP-38.^7,14 PACAP-38, the predominant form, shows a remarkable degree of evolutionary conservation.¹⁵ PACAP is known to regulate learning, memory, and behavior7,16 through its modulation of neuronal growth, development, and repair.^4,16 It shares important close anatomical similarities with CGRP in central nervous system regions associated with migraine pathophysiology,¹⁷ suggesting that PACAP may play a role similar to that of CGRP in its contribution to migraine.¹ Preclinical data, however, indicate that PACAP and CGRP have differentiated pharmacology with respect to migraine-associated symptoms.¹

Human studies confirm PACAP as a key player in migraine pathophysiology. Intravenous administration of PACAP-38 caused headache in all healthy subjects and migraine-like attacks in 58% of patients with a history of migraine without aura (NCT00380263).^18,19 However, administration of a functionally related neuropeptide, vasoactive intestinal peptide (VIP), did not induce migraine-like attacks in patients with migraine.¹⁵ PACAP-38 is released from both the parasympathetic and sensory system.²⁰ Consequent PACAP-38-induced migraine in the sensory system is attributed to modulation of nociceptors outside the blood-brain barrier.⁷ PACAP-38-mediated vasodilation through the sensory nerves that innervate the cranial vasculature may contribute to pain during migraine attacks.^6,7 Moreover, a clinical trial demonstrated that plasma PACAP-38 levels were increased after PACAP-38 infusion in patients who subsequently experienced migraine attacks (NCT01471990),^2,21,22 suggesting de novo synthesis or release of PACAP-38 during migraine.²¹ PACAP may therefore be useful as a biomarker of primary headaches.^17,20

PACAP’s actions are mediated through 3 G protein-coupled receptors: VIP type 1 receptor, VIP type 2 receptor, and PACAP type 1 (PAC1) receptor.¹⁵ Studies indicate that the PAC1 receptor is the most important mediator of PACAP signaling, perhaps due to its 1000-fold higher affinity for PACAP than for VIP.^7,15 Both PACAP and the PAC1 receptor have thus been suggested as novel targets for migraine treatment, which might provide new therapeutic options for patients who do not respond to CGRP-blocking drugs (FIGURE).¹⁵ Unfortunately, no statistically significant differences in mean monthly migraine days were found in a phase 2a, randomized, double-blind, placebo-controlled study of the safety and efficacy of 12 weeks of treatment with AMG 301 (Amgen; NCT03238781),²³ a PAC1 receptor–targeting mAb. However, anti- PACAP antibodies still have the potential to be effective in the treatment of migraine.⁴

FIGURE. How Antibodies Developed for Prophylactic Antimigraine Treatment Target PACAP or Its Receptors, Disrupting Signaling

ALD1910 (Alder BioPharmaceuticals)²⁴ is a potent, selective, high-affinity, neutralizing mAb that targets both PACAP-271 and PACAP-381,5 to block PACAP signaling, offering a new mechanism-specific approach for migraine therapy. ALD1910 recognizes a nonlinear epitope within PACAP-38 and effectively blocks its binding to its cell-surface receptors in a dose-dependent manner.¹ A first-in-human, randomized, double-blind, placebo-controlled study (NCT04197349)²⁴ in a healthy population began in September 2019 to assess the safety, tolerability, and pharmacokinetic profile of ALD1910 at 7 ascending doses. This study was completed in August 2020, with results forthcoming.

Considering the prevalence and heterogeneity of migraine,^1,5,6 the development of therapeutic agents with mechanistically diverse targets will lead to more treatment options. A number of migraine regulators have been identified as promising targets. Targeting multiple levels in the same pathway might lead to more effective prevention of migraine.⁶ However, selective antibodies have the greatest therapeutic potential; such agents should reduce potential AEs while maintaining efficacy for most patients with migraine.¹⁵ mAbs that block activation of the trigeminovascular system should potently prevent the onset of migraine attacks.^2,3,6 The ideal agent would exhibit limited drug-drug interactions, an important consideration in a patient population susceptible to polypharmacy.⁴