Migraine Preventive Therapy
What’s in the Pipeline?
by a single clone of cells or cell line and consist of
identical antibody molecules. CGRP antibodies
are currently the most exciting potential preventive
agents being studied. Four CGRPs are now being
studied in Phase III clinical trials. Each of these
appear to be working well in terms of efficacy and
tolerability based on the Phase II data and early
Phase III studies. CGRP is an extremely important
player in the migraine process. It is involved
in vasodilation (widening of blood vessels),
inflammation, and pain transmission.
Serotonin is another neurotransmitter. The
triptans work acutely by stimulating serotonin (5-
HT1 B,D, and F) receptors. By stimulating the D
receptor, the triptans inhibit the release of CGRP. It
is felt that this action reduces not only vasodilation,
but also inflammation and pain transmission. The
effect of this action is short-lived, so the triptans are
used almost exclusively for acute migraine abortive
therapy. It is also believed that onabotulinumtoxinA
may be working, at least in part, in the preventive
therapy of chronic migraine by the prolonged
inhibition of CGRP release for about 12 weeks.
Biologic agents, such as CGRP monoclonal
antibodies, are manufactured in the laboratory
starting with antibodies made in non-human species
(such as mice or rats). Individual components
of these non-human immunoglobulins are then
gradually substituted, making them humanized
(90% human) or even fully humanized (100%
human). This substitution reduces the risks of
immunological reactions against them that could
either inactivate them or cause allergic reactions.
These antibodies also have a long half-life, allowing
them be administered monthly or possibly even
at 3-month intervals. Currently, three of these
potential therapeutic agents are being manufactured
as a subcutaneous (SC) injection that will hopefully
be easily self-administered by patients. The fourth
CGRP is an intravenous (IV) preparation that will
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Volume 6, Issue 3 • 2017
be administered by a nurse.
Another group of potential therapeutic agents
for migraine prevention are referred to as gepants.
The gepants are small molecules (in comparison
to antibodies) that block the CGRP receptor
cells. The first of the gepants to progress through
Phase III testing was telcagepant. Telcagepant
showed efficacy as both an abortive agent for acute
attacks and as a preventive agent. Unfortunately,
telcagepant was associated with liver toxicity and
never became commercially available. Other agents
in this class are currently in clinical trials for both
acute and preventive therapy. These newer gepants
appear to have no evidence of liver toxicity which
hopefully, will be maintained through clinical trials.
A combination drug currently undergoing clinical
trials contains a mixture of dextromethorphan and
quinidine. Its efficacy is attributed to its effect
against glutamate, an excitatory neurotransmitter
that is important in the migraine process. This agent
also could work through modulation of sodium,
potassium, and the calcium channels. At this point,
however, it is too early to tell if this agent will be
of major benefit. Substantial data suggest good
tolerability, as the drug is already commercially
available as a treatment for pseudobulbar affect.
PseudoBulbar Affect (PBA) symptoms are frequent,
uncontrollable outbursts of crying or laughing in
people with certain neurologic conditions, such as
stroke or brain injuries.
One investigational product being evaluated is
a nasal spray of oxytocin. Oxytocin is a hormone
released by the pituitary gland that causes increased
contraction of the uterus during labor and
stimulates the release of milk into the ducts of the
breasts. Oxytocin receptors are often found in the
company of CGRP receptors in the trigeminal
system. Early studies suggest that this drug may
someday be an effective preventive therapy.
Other investigational products are also in early