Is PACAP the next big thing in migraine therapy?

In this issue of the journal, Johnson et al. (1) from Eli Lilly present an interesting study on their new anti-pituitary adenylate cyclase activating peptide (PACAP) antibody. Their study includes a collection of preclinical studies, as well as clinical phase I in healthy subjects and phase II data on therapy-resistant migraine patients. Their PACAP-neutralizing monoclonal antibody LY3451838 showed a high degree of specificity to block PACAP-induced activation of human vasoactive intestinal peptide (VIP)/PACAP receptors (PAC1, VPAC1 and VPAC2) but no blockage was seen upon VIP-induced activation. The phase 1 data showed mild side effects, with a long half-life T_1/2 that ranged between 213 to 340 hours depending on the dose used. The phase 2 data obtained with LY3451838 (1500 mg intravenously), versus placebo, revealed a reduction in mean monthly migraine headache days (MMHDs) to LY3451838 for chronic migraine (CM) (−4.7 days) and episodic migraine (EM) (−1.7) versus placebo (CM, −3.0 days; EM, −1.2 days). The pattern was similar at one month and three months, however the responses were not significantly different between treatment with LY3451838 and placebo.

PACAP belongs to a group of peptides named the VIP/glucagon/growth hormone releasing factor/secretin superfamily and was first isolated from the pituitary by Arimura (2). PACAP and VIP have been implicated in many physiological and endocrine functions, including general circulation, neuroendocrinology, circadian rhythms, metabolic stress and inflammation (3). In addition, PACAP was found in numerous human brain regions some of which have since been related to central nervous system disorders and migraine (4,5), and is related to the trigeminovascular and autonomic systems (6). PACAP has therefore been implicated to have a role in primary headache conditions (7). A plethora of subsequent studies have since examined various aspects of the two forms of PACAP, PACAP38 and PACAP27, in the hope this could serve as a new anti-migraine target and its inhibition serve as novel therapy for subjects with weak or no response to calcitonin gene-related peptide (CGRP) system acting monoclonal antibodies or gepants (8).

The PAC1 receptor was initially selected as a key site to unlock this mystery. Detailed analysis of PAC1 receptors in trigeminal and sphenopalatine ganglia, the spinal trigeminal nucleus and the dura mater supported this hypothesis (9). This work suggested a role for the PAC1 receptor in the trigeminal-autonomic system that is implicated in primary headaches. The results prompted AMGEN to perform a phase 2 randomized, double-blind, placebo-controlled trial of AMG301, a PAC1 receptor selective monoclonal antibody for migraine prevention (10). Unfortunately, there was no benefit of this drug over placebo, and the development was discontinued.

Meanwhile, basic research kept on and discovery of several splice variants of the PAC1 receptor, as well as a possible involvement of a human MRGPRX2 receptor on mast cells, offered the possibility to look for another broader way to block the PACAP system: using a monoclonal antibody towards PACAP (11,12). The Lundbeck company was first to reveal results of their antibody Lu AG09222 in studies in vivo on healthy volunteers to find out specificity towards intravenous PACAP administration (13). The report demonstrated that Lu AG09222 inhibited PACAP38-induced cephalic vasodilation and increases in heart rate and reduced concomitant headache. Therefore, it was decided to forward this monoclonal antibody to a phase 2 trial in migraine prevention (14). Thus, a phase 2 randomized, placebo-controlled trial was conducted in adults with migraine for whom two to four previous preventive treatments had failed to provide benefits. Subjects received 750 mg of Lu AG09222 (n = 97), 100 mg of Lu AG09222 (n = 46) or placebo (n = 94). The primary endpoint was MMHDs, during weeks 1 to 4 in subjects with 16.7 monthly migrane days overall. Treatment with 750 mg Lu AG09222 reduced this by −6.2 days in the 750 mg dose of Lu AG09222 group and by −4.2 days in the placebo group. This translated into a significant reduction in MMHDs by −2.0. Strangely, the data for 100 mg were not presented.

The results obtained by Johnson et al. (1) showed a difference between LY3451838 (1500 mg) treated and placebo for CM at one and three months of −1.5 and −2.3 MMHDs, and for EM of −0.5 and −0.7 MMHDs (however, there was no significant difference compared to placebo) (1). The two PACAP antibodies were studied in phase 2 reports in very high dosages, putatively to obtain a positive signal. Only the study on Lu AG09222 monoclonal antibody reported a significant response. The successful blocking of CGRP and CGRP receptors in migraine prophylaxis has been confirmed to be stable over the years with respect to the molecules used. The interest in developing other targets in migraine therapy is currently a hot research project. However, antagonizing PACAP is a complex target since the peptide is a hormone that can pass the blood–brain barrier, interact with many different mechanisms and receptors in the central and peripheral nervous systems, involved in vasodilatation, intestinal motility, cell proliferation, reproduction and inflammation (15).

Is a PACAP monoclonal antibody the next big thing in migraine prophylaxis? The available data do not provide solid support to this question. A way forward might be (i) larger trials; (ii) analysis of specific subgroups; (iii) combination treatments; (iv) finding optimal dosing; or (v) effects in cluster headache where the parasympathetic ganglia contain large amounts of PACAP that is activated in cluster attacks.