A novel tool for exploring calcitonin gene-related peptide mechanisms in primary headaches

Novel CGRP-targeted small molecule antagonists and monoclonal antibodies are making giant strides in clinical trials, but to date there has been little insight into the basic mechanisms of CGRP.  Dr Philip R Holland, Lecturer in Neuroscience at King’s College, London discusses a new stable CGRP analogue that offers the possibility of exploring underlyIng and central effects of CGRP.

The triptans were originally developed over 25 years ago,1 yet significant questions remain regarding their mechanisms and sites of action.2 Fast-forward to 2017 and we find ourselves facing a familiar situation. While there has been significant progress on the clinical efficacy of both calcitonin gene-related peptide (CGRP)-targeted small molecule antagonists3,4 and monoclonal antibodies,5-7 there remains a major unmet need to advance our understanding of the basic mechanisms of CGRP, its acute and chronic blockade, and potential side effects therein.8

We have known for some time that CGRP can trigger migraine attacks in both migraine with and without aura patients9,10 within a similar timescale to the established trigger glyceryl trinitrate (GTN), highlighting its important role in migraine-related pain cascades. However, the nature of the mechanisms that lead to activation of the pain-processing trigeminovascular system remains elusive.

Despite significant preclinical advances highlighting a role for peripheral and central CGRP in both photophobia11,12 and altered trigeminal nociception,13 studies have been limited by the relatively transient pharmacodynamics of CGRP. Native CGRP has a half-life of less than 30 minutes14 and for experimental agonists such as CGRP(1-37) this is less than 15 minutes. As such, it is difficult to obtain stable elevated CGRP and receptor activation in vivo to mimic the potential increased CGRP in patients and preclinical data has been inconsistent.

Although CGRP administration in rats has similar migraine-triggering properties to GTN, it does not appear to upregulate c-Fos in the trigeminal nucleus caudalis despite effects in other nuclei.15,16 While such discrepancies may be mechanistic and point to specific loci of action, it is impossible to rule out technical limitations due to the short bioavailability of CGRP in vivo.

Importantly, a novel stable analogue of CGRP has recently been described17 that has enabled hitherto elusive cardiovascular effects of CGRP to be detected.18 This α-CGRP analogue has similar pharmacokinetics to native CGRP with a significantly increased half-life of greater than ten hours in rodents, while plasma levels were detectable out to at least 24 hours following a single subcutaneous dose.

The primary outcome of the current study was cardiovascular protection, but the authors did explore light aversion following acute or chronic (five week) administration. While there were no detectable differences between CGRP analogue-treated and sham mice (positive control with GTN) there are a number of reasons that could explain this. For example, recent studies by Russo and colleagues11 identified a heterogeneous response in C57BL/6J mice and further utilized significantly higher light intensities of up to 27,000 lux (direct midday sunlight > 100,000 lux) to explore CGRP-dependent photophobic behaviors in mice. Consequently, despite this apparent lack of a photophobic-like response to this novel α-CGRP, for the first time to the best of my knowledge there is now a stable CGRP receptor agonist that has the potential to unmask significant cross-disciplinary mechanistic insight.

Currently, we stand at an important juncture in terms of migraine therapy with novel CGRP-targeted small molecule antagonists and monoclonal antibodies making giant strides in clinical trials. Yet we should not lose sight of the underlying mechanisms. The development of a stable α-CGRP analogue presents us with an opportunity to explore the underlying peripheral and central effects of CGRP in primary headaches and subsequently inform the likely impact of its chronic reduction.

Dr Philip R Holland (Kings College London)

  1. Humphrey PP, Feniuk W, Perren MJ, Beresford IJ, Skingle M, Whalley ET. Serotonin and migraine. Ann N Y Acad Sci. 1990;600(1990):587-98; discussion 98-600.
  2. Akerman S, Romero-Reyes M, Holland PR. Current and novel insights into the neurophysiology of migraine and its implications for therapeutics. Pharmacol Ther. 2017;172(2017):151-70.
  3. Marcus R, Goadsby PJ, Dodick D, Stock D, Manos G, Fischer TZ. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34(2014):114-25.
  4. Voss T, Lipton RB, Dodick DW, Dupre N, Ge JY, Bachman R, et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia. 2016;36(2016):887-98.
  5. Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol. 2015;14(2015):1081-90.
  6. Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 2014;13(2014):1100-7.
  7. Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, et al. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(2016):382-90.
  8. MaassenVanDenBrink A, Meijer J, Villalon CM, Ferrari MD. Wiping Out CGRP: Potential Cardiovascular Risks. Trends Pharmacol Sci. 2016;37(2016):779-88.
  9. Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010;30(2010):1179-86.
  10. Lassen LH, Haderslev PA, Jacobsen VB, Iversen HK, Sperling B, Olesen J. CGRP may play a causative role in migraine. Cephalalgia. 2002;22(2002):54-61.
  11. Mason BN, Kaiser EA, Kuburas A, Loomis MM, Latham JA, Garcia-Martinez LF, Russo AF. Induction of Migraine-Like Photophobic Behavior in Mice by Both Peripheral and Central CGRP Mechanisms. J Neurosci. 2017;37(2017):204-16.
  12. Recober A, Kaiser EA, Kuburas A, Russo AF. Induction of multiple photophobic behaviors in a transgenic mouse sensitized to CGRP. Neuropharmacology. 2010;58(2010):156-65.
  13. Pozo-Rosich P, Storer RJ, Charbit AR, Goadsby PJ. Periaqueductal gray calcitonin gene-related peptide modulates trigeminovascular neurons. Cephalalgia. 2015;35(2015):1298-307.
  14. Braslis KG, Shulkes A, Fletcher DR, Hardy KJ. Pharmacokinetics and organ-specific metabolism of calcitonin gene-related peptide in sheep. J Endocrinol. 1988;118(1988):25-31.
  15. Bhatt DK, Ramachandran R, Christensen SL, Gupta S, Jansen-Olesen I, Olesen J. CGRP infusion in unanesthetized rats increases expression of c-Fos in the nucleus tractus solitarius and caudal ventrolateral medulla, but not in the trigeminal nucleus caudalis. Cephalalgia. 2015;35(2015):220-33.
  16. Ramachandran R, Bhatt DK, Ploug KB, Olesen J, Jansen-Olesen I, Hay-Schmidt A, Gupta S. A naturalistic glyceryl trinitrate infusion migraine model in the rat. Cephalalgia. 2012;32(2012):73-84.
  17. Nilsson C, Hansen TK, Rosenquist C, Hartmann B, Kodra JT, Lau JF, et al. Long acting analogue of the calcitonin gene-related peptide induces positive metabolic effects and secretion of the glucagon-like peptide-1. Eur J Pharmacol. 2016;773(2016):24-31.
  18. Aubdool AA, Thakore P, Argunhan F, Smillie SJ, Schnelle M, Srivastava S, et al. A Novel alpha-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy and Heart Failure. Circulation. 2017(2017).