Nature - USA (2020-10-15)

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TARGETING MIGRAINE
DISEASE BIOLOGIES
The pathophysiology of migraine
is complex and incompletely
understood. CGRP is central
to current models of migraine
pathophysiology and acts in
part by promoting meningeal
vasodilation, and in part
by promoting neurogenic
inflammation and altered
nociception, ultimately leading
to the sensation of pain and
headache^15. Although the
trigeminal nerve and its CGRP-
releasing ganglion fibers are
believed to be an important
contributor to the development
and maintenance of migraine
attacks, other factors could also
be potential entry points for
alleviating migraine either alone
or in combination with blocking
of CGRP signaling. One of these
factors is the neuropeptide
PACAP^16 (Fig. 2).
Systemic administration of
PACAP can trigger migraine-
like attacks in susceptible
individuals, and elevated
concentrations of PACAP
have been reported in patients
with migraine during attacks.
PACAP receptors are expressed
in the CNS and in peripheral
structures associated with
headache biology, including
vagal efferent, middle
meningeal arteries, trigeminal
ganglia, dorsal root ganglia,
trigeminal nucleus caudalis
and sphenopalatine ganglia.

Collectively, this suggests that

PACAP signalling mechanisms

are involved in mediating distinct

cranial autonomic symptoms,

associated with headache and

migraine pathophysiology.

Furthermore, and much like

CGRP, PACAP is implicated

in vasodilation through the

sensory nerves that innervate

the cranial vasculature. PACAP

is also implicated in dural

inflammation, peripheral

sensitisation, and central pain

sensitisation and transmission^17.

Dural mast cell degranulation

has been proposed as a putative

mechanism for headache pain

and migraine^18. Mast cells

release PACAP, which has also

been demonstrated to be a

significant mediator of mast cell

degranulation. PACAP-mediated

inflammatory processes within

deeper brain structures may

also be involved in mediating

these dural changes, which again

may lead to trigeminovascular

activation that could further

drive disease pathogenesis^19.

Therefore, PACAP signaling

blockade is a promising

therapeutic option for migraine

prevention. Lundbeck’s anti-

PACAP monoclonal antibody

has, because it binds to the

ligand, the potential to broadly

prevent PACAP signalling

through all its confirmed

receptors and is in early-

phase clinical development

(NCT04197349).

Finally, modulation

of the endocannabinoid

system (Fig. 2), which is an area

of interest to Lundbeck in several

diseases, might hold promise

for the development of future

therapies. The endocannabinoid

system has been shown to

be involved in processing

of nociceptive signals in the

trigeminovascular system^20.

Targeting multiple levels in the

same pathway by stimulating the

endocannabinoid system in both

the primary nociceptive afferents

and at the central level in the

presence of CGRP or PACAP

blockade might lead to more

effective prevention of headache

and migraine.

OUR COMMITMENT TO

PEOPLE LIVING WITH

MIGRAINE

For more than 70 years,

Lundbeck has been at the

forefront of neuroscience

research, advancing our

understanding of the biology of

the central nervous system and

bringing innovative therapies

to millions of people living with

brain disease worldwide. We

are committed to understanding

what is most important to

people living with migraine and

determined to help them achieve

the outcomes that matter

most to them. Focused on

transforming migraine treatment

and prevention, we are resolute

in our pursuit of therapies that

support a future where migraine

no longer controls people’s lives.

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