D A N I S H H E A D A C H E

C E N T E R

The PACAP Receptor: A Novel Target for

Migraine Treatment

Faculty of Health and Medical Sciences

DEPARTMENT OF NEUROLOGY & DANISH HEADACHE CENTER

Glostrup Hospital, the Capital Region of Denmark

Messoud Ashina, MD, PhD, DMSc

Professor of Neurology

Rigshospitalet Glostrup

DANISH HEADACHE CENTER

Disclosures

Personal fees from Alder BioPharmaceuticals, Allergan, Amgen,

Autonomic Technologies Inc. (ATI), and Eli Lilly Autonomic Technologies Inc. (ATI), and Eli Lilly

Principal investigator for Amgen trials 20120178, 20120295,

20130255, and 20120297, and GM-11 gammaCore®-R trial

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PACAP belongs to the secretin/glucagon/Vasoactive

intestinal polypeptide (VIP) familyintestinal polypeptide (VIP) family

Arimura et al. Jpn J Physiol. 1998

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CNS and PNSNeurotransmission, neuromodulation, regulation of cicardian clock, behavioral actions, learning and memory procession

Immune systemRegulation of immune reponses

Vascular systemVasodilation

Endocrine systemRegulation of pituitary, adrenal

and pacreatic secretion

Respiratory systemBronchodilation

Urogenital systemRegulation of micturation

pathways

Gastrointestinal systemRegulator of lipid/carbohydrate mebolism, liver cell proliferation

PACAP38 VIP

Diané et al., J Metabolic Synd 2014Vaudry et al. Pharmacol Rev. 2009

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Pain-sensitive structures

Wolff 1963 Olesen et al, Lancet Neurology 2009

Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38)

Vasoactive intestinal peptide (VIP) Uddman et al. J Cereb Blood Flow Metab. 1993; Jansen-Olesen et al. J Auton Nerv Syst. 1994; Baun et al. Eur J Pharmacol. 2011

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What triggers migraines?

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Human model of migraine

PACAP & VIPModified from Olesen et al. Cephalalgia 2009

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10

0

1

2

3

4

5

6

7

8

9

10

0 40 80 120 4 6 8 12

Hea

dach

e in

ten

sity

(V

RS

) VIP

Migraine-like attacks (n=0/12)

Rahmann et al. Cephalalgia 2008

0

1

2

3

4

5

6

7

8

9

10

0 40 80 4 8 12

Hea

da

che

inte

nsi

ty (

VR

S)

PACAP38

Migraine-like attacks (7/12)

Schytz et al. Brain 2009

min hoursVIP

min hoursPACAP

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Recruited (n=34)

Drop outs (n=10)

STUDY FLOW CHARTSTUDY DESIGN

Baseline

Infusion

MEASUREMENTS

Clinical dataHeadache interviewsMigraine symptomsOther symptoms

Physiological dataHeart rate

Blood pressureRespiratory freq.

Double blind randomized crossover study

Included (n=24)

Completed (n=22)

Drop outs (n=2)

In-hospital phase(0-5 h)

Post-hospital phase(6-24 h)

InfusionPACAP38 / VIP

Respiratory freq.End-tidal CO2 pressure

Biochemical dataPlasma PACAP38 conc.

Plasma VIP conc.Plasma tryptase conc.

Neuroimaging dataMR-angiographyFunctional MRIAnatomical MRIMR-venography

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16

18

20

22

Headache

Migraine

91%

73%

82%

Headache/migraine after PACAP38 and VIP

2

4

6

8

10

12

14

PACAP VIP

Migraine

18%

Amin et al, Brain 2014Intravenous PACAP38 (10 pmol/kg/min) infusion over 20 min

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MRI angiographyMRI angiographyMRI angiographyMRI angiographyBaseline

PACAP-38

Amin et al., Brain 2014

2 hours after

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An axial view of a 3D reconstruction of the time-of-flight MR-angiography scan

Before (A) and after (B) subcutaneous injection of 6 mg

sumatriptan, showing marked extracranial vasoconstriction

A B

Amin et al., Brain 2014

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RestingRestingRestingResting----statestatestatestate functionalfunctionalfunctionalfunctional connectivityconnectivityconnectivityconnectivity MRIMRIMRIMRI

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RestingRestingRestingResting----state functional connectivity MRIstate functional connectivity MRIstate functional connectivity MRIstate functional connectivity MRI

PACAP-38

Amin et al., Neurology 2016

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PACAP38PACAP38PACAP38PACAP38----induced induced induced induced migrainemigrainemigrainemigraine attacksattacksattacksattacksSalience Network

Sensorimotor Network

Default Mode NetworkINCREASED CONNECTIVITYR+L inferior frontal gyrus INCREASED CONNECTIVITYR premotor cortex INCREASED CONNECTIVITYL primary auditory cortexL somatosensory cortex IIL somatosensory cortex IIL premotor cortexL visual cortex V4DECREASED CONNECTIVITYNone DECREASED CONNECTIVITYL visual cortex V1, V2, V3 DECREASED CONNECTIVITYR frontal lobeR cerebellumCognitive functions

EmotionsSpeech/languageWorking memory

Motor function in faceCognitive affected

Photophobia

Phono/photophobiaPain perception

Cognitive functionsPain modulation

Amin et al., Neurology 2016

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PACAP38 induced more migraine than VIP

Conclusions

PACAP38-induces marked dilation of extracerebral arteries blocked by sumatriptan

The pre-ictal phase is associated with change of functional connectivity of core brain networks

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No migraine

25 %

PACAP38 induced migraine

Genetics? Biochemical markers?

CGRP

75 %

Migraine

Schytz et al. Brain 2009; Amin et al. Brain 2014

TNF alfa

Premonitory symptoms?

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Migraine after PACAP38 infusion

Guo et al., Cephalalgia 2016

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No attacks (n=9)

VIPPACAP38

Attack (n=23)

P=0.363 P=0.819

CGRP TNFaP=0.792 P=0.448

Guo et al., Cephalalgia 2016

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11 out of 23 patients (48%) with induced attack had PS after PACAP

Results – PACAP38

Guo et al., Cephalalgia 2016

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Familial predisposition has no effect on migraine response

Conclusions

Changes in plasma CGRP or TNF alfa have no effect on migraine response

PACAP38 induces premonitory symptoms in 48% of patients

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PACAP & VIP receptors

Drug target?

PACAP38 has 1000 times higher affinity for the PAC1-R than VIP

Dickinson & Fleetwood-Walker. TIPS 1999

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