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Efficacy of Rimegepant Plus Calcitonin Gene-Related Peptide Monoclonal Antibody for Migraine

December 14, 2021

Carina Leggio, PA-SIII

Advisor: Emmanuelle Schindler, MD, PhD

ID
7290

Transcript

  • 00:00So hi everyone, I'm Karina.
  • 00:02This is my thesis presentation
  • 00:04entitled efficacy of her magic pant
  • 00:07plus calcitonin gene related peptide
  • 00:10monoclonal antibody for migraine and
  • 00:12my advisor was Doctor Schindler.
  • 00:15So just to give some background,
  • 00:17migraine is estimated to affect
  • 00:19about 15% of the global population,
  • 00:21and it's characterized by painful,
  • 00:24unilateral headache attacks often
  • 00:26associated with nausea, vomiting,
  • 00:28photophobia, and phonophobia.
  • 00:29And it's managed with a board
  • 00:32of therapy during a pain attack,
  • 00:35prophylactic therapy to prevent attacks,
  • 00:37and often a combination of both.
  • 00:40There is calcitonin gene related peptide
  • 00:43CGRP and its receptor and they have a
  • 00:46role in the provocation of migraines.
  • 00:48So CGRP is a neuropeptide.
  • 00:50It binds to the CGRP receptor and it
  • 00:53causes potent vasodilation specifically
  • 00:55within the trigeminal gangland and
  • 00:58its proposed that elevated levels
  • 01:00of CGRP may lead to sensitization
  • 01:03of those neuronal circuits so that
  • 01:05the usual sensory inputs like light,
  • 01:08sounds, tastes and odors.
  • 01:10Are then experienced as bothersome.
  • 01:13And so this peptide and its receptor
  • 01:15have been targeted in the development of
  • 01:18both preventive and abortive therapies.
  • 01:22So one of these medications
  • 01:24is called magic pants.
  • 01:25It's brand name is Nartec
  • 01:27oral dissolving tablet,
  • 01:28and it's actually produced here in
  • 01:30New Haven and its uses for the acute
  • 01:34treatment of migraine as an abortive.
  • 01:36And it's part of the small molecule
  • 01:39CGRP receptor antagonist class,
  • 01:40it has a couple of proposed mechanisms,
  • 01:43one of which is that it competes with
  • 01:45the initial CGRP binding event and
  • 01:47blocks the activation of the receptor,
  • 01:49or it potentially displaces the bound CGRP.
  • 01:53And deactivates the receptor and
  • 01:55this medication was just approved
  • 01:58by the FDA in February of 2020.
  • 02:03Then there are the monoclonal antibodies
  • 02:05and these are used as a preventive
  • 02:07migraine therapy and they include class
  • 02:09members such as air knob, galcanezumab,
  • 02:11feminism, ABBA Neptunism app,
  • 02:14and their mechanisms for gallicanism,
  • 02:17gallicanism, AB, feminism,
  • 02:18admin eptinezumab is that they neutralize
  • 02:21some portion of the circulating CGRP ligands
  • 02:24which prevent the peptide from signaling.
  • 02:26Erenumab is a little different in that
  • 02:28it blocks the CGRP receptor instead
  • 02:31of the peptide and these are given.
  • 02:34As once monthly injections or via Ivy,
  • 02:37and they're actually giving
  • 02:39quarterly for feminism,
  • 02:40AB, and eptinezumab.
  • 02:44So this led to my development of a
  • 02:47problem which is given that Japan's
  • 02:49and Mads both act on the CGRP system.
  • 02:52It begs the questions.
  • 02:53Would patients using both experience of
  • 02:55greater benefit and is this combination safe?
  • 02:58So published reports of the use of both
  • 03:00oral where magicant for acute treatment
  • 03:02and a map for prevention, or limited.
  • 03:04There is a small case series that
  • 03:06demonstrated possible efficacy in
  • 03:08treating refractory migraine with Roma,
  • 03:11Japan and Erin AB and then following
  • 03:13this there was an open label.
  • 03:15Substudy of 13 migraine patients
  • 03:17simultaneously using their magic
  • 03:19pants with a map which showed
  • 03:21no serious adverse events.
  • 03:22However, efficacy was not reported.
  • 03:27So therefore further study in the form
  • 03:29of a randomized controlled trial to
  • 03:30investigate the safety and efficacy
  • 03:32of our measure pant in the setting of
  • 03:34common map therapy is necessary and,
  • 03:36if shown to be effective as well as safe,
  • 03:39this therapeutic approach may provide the
  • 03:41best opportunity to expand evidence based
  • 03:43migraine management plan to improve the
  • 03:45quality of life in migraine patients.
  • 03:50So I developed the hypothesis that when using
  • 03:53her magic pan as an abortive intervention,
  • 03:55adult subjects on antique GRP or anti
  • 03:58receptor map preventive will have a
  • 04:00different incidence proportion of freedom
  • 04:02from pain at two hours compared to those
  • 04:05who have never used a map preventive
  • 04:07and one definition that I want to draw
  • 04:09attention to is the freedom from pain.
  • 04:11So for the purpose of this study it's
  • 04:14defined as on a zero to three pain numerical
  • 04:16rating scale where zero is no pain,
  • 04:18one mild to moderate and three severe.
  • 04:21It's the reduction from moderate two
  • 04:23or three severe at the time of Drug
  • 04:26Administration to no pain for 0.
  • 04:32So for my methods, UM,
  • 04:34we're looking at a population of adults,
  • 04:36so ages 18 to 65 years old,
  • 04:38with at least one year history of migraine.
  • 04:41And this is further divided into our study,
  • 04:43or monoclonal antibody population who
  • 04:46were treated with a map for at least
  • 04:49three months prior to the screening
  • 04:51and then our control population,
  • 04:52or those who have never used an
  • 04:55antique P or anti CGRP receptor map.
  • 04:58Our target sample size would
  • 05:00be 450 subjects and.
  • 05:01The study design would be a biphasic trial.
  • 05:05So the primary phase would be randomized,
  • 05:08double blind,
  • 05:09placebo controlled single attack
  • 05:10study and the secondary phase would
  • 05:13be a two month open label Multi
  • 05:15Attack study and I further delineate
  • 05:17delineated this in the table below.
  • 05:19So you can see the two groups,
  • 05:21there's the control group and
  • 05:22the monoclonal antibody group.
  • 05:24They both undergo a running
  • 05:25period of four weeks.
  • 05:27The primary phase which is the blinded
  • 05:29phase is when the subjects will be asked.
  • 05:32To treat one migraine attack of moderate
  • 05:35to severe intensity and they'll be
  • 05:38allocated and blinded to being given
  • 05:41either were magic pant or placebo
  • 05:43to treat that one migraine attack.
  • 05:46Then,
  • 05:46during the secondary phase,
  • 05:47which is the open label phase,
  • 05:49it'll go on for eight weeks and
  • 05:51patients and all of the groups will
  • 05:53all treat her multiple migraine
  • 05:54attacks with her magic pan.
  • 06:00So we're going to collect data
  • 06:02through an electronic patient.
  • 06:03Reported outcomes diary.
  • 06:04So at the time of a migraine attack,
  • 06:07the subjects will begin to document
  • 06:09in their ipro diary by rating their
  • 06:11pain on a scale of zero to three,
  • 06:13and documenting other
  • 06:14symptoms such as photophobia,
  • 06:16phonophobia, or nausha,
  • 06:17and if their pain is rated at two or three,
  • 06:20they'll be asked to self administer
  • 06:22the allocated intervention.
  • 06:23So during phase one it could
  • 06:25be re measure pant or placebo,
  • 06:27and during the second phase it will be.
  • 06:30Where magic pants.
  • 06:31And then they'll reevaluate their pain
  • 06:33and symptoms at several time points.
  • 06:35Most importantly,
  • 06:362 hours after the intervention,
  • 06:38and they'll also complete a migraine
  • 06:41specific quality of Life Questionnaire,
  • 06:43which will be done during the
  • 06:45running period and at the
  • 06:47end of weeks four and eight,
  • 06:49and the SQ is this is a valid
  • 06:51and reliable measure to assess
  • 06:53the effect of migraine on daily
  • 06:55functioning among migraine patients.
  • 06:58Our primary outcome would be freedom
  • 06:59from pain at two hours and will also
  • 07:02look at several secondary outcomes,
  • 07:04including but not limited to,
  • 07:06pain relief at two hours,
  • 07:08freedom from most bothersome
  • 07:09symptom at 2 hours,
  • 07:11and quality of life scores.
  • 07:15So some strengths of this study.
  • 07:18First is that the protocol was written
  • 07:20in accordance with the guidelines of
  • 07:22the International Headache Society for
  • 07:24controlled trials of acute treatment
  • 07:26of migraine attacks and adults.
  • 07:27So some of the elements,
  • 07:28such as the measurement of
  • 07:30freedom from pain at two hours,
  • 07:31is derived from these guidelines.
  • 07:33The guidelines also limits subjects
  • 07:35from having to treat multiple
  • 07:37migraine attacks with placebos.
  • 07:39Therefore,
  • 07:39most migraine studies comparing an
  • 07:42abortive to placebo consists of
  • 07:44subjects only treating one migraine.
  • 07:46Attack with the intervention and
  • 07:48the conclusions are drawn from that.
  • 07:51So I decided to come up with this
  • 07:54unique biphasic design in which I'm
  • 07:56maintaining a phase with blinding
  • 07:58and randomization to investigate
  • 08:00a single migraine attack similar
  • 08:02to the traditional studies.
  • 08:04However,
  • 08:04with the addition of the secondary phase,
  • 08:07it allows for analysis of consistency
  • 08:09of response to our measure pant and its
  • 08:13treatment of multiple migraine attacks,
  • 08:15and this is all while still meeting
  • 08:17the ethical guidelines such that
  • 08:18no subject is treating more than
  • 08:20one migraine attack. With placebo.
  • 08:23And lastly,
  • 08:24I believe a strength is the inclusion
  • 08:27of the MSQ because it really provides
  • 08:30a more comprehensive measurement of
  • 08:32the medications impact on patients
  • 08:34overall migraine management.
  • 08:37Some limitations of mine is that there is
  • 08:42variability in the types of preventives
  • 08:44the control subjects are taking,
  • 08:46so the control subjects are allowed to
  • 08:48be on preventive that aren't mapped.
  • 08:50These can include tapir,
  • 08:52may Botox injections or beta blockers,
  • 08:54and this does present a
  • 08:57potential confounding variable.
  • 08:58However, in order to maintain the
  • 09:00external validity of the study,
  • 09:01it's necessary to include subjects on
  • 09:03preventive for their migraines and
  • 09:05better emulate this study population.
  • 09:07Large uhm and another limitation is
  • 09:11that there's no active comparator,
  • 09:12so in this study were magic Pant
  • 09:14is being compared to placebo,
  • 09:16and it might be argued that the
  • 09:18inclusion of an active comparator
  • 09:19or standard of care treatment would
  • 09:21strengthen the clinical implications
  • 09:23of the study results.
  • 09:24However,
  • 09:25it's really beyond the scope of this trial,
  • 09:27which is primarily focused on comparing
  • 09:29the effects and safety of the drug in
  • 09:32those taking versus not taking a CGRP map.
  • 09:35And depending on the results from this study,
  • 09:37the inclusion of an active comparator.
  • 09:39In similar future studies
  • 09:40would be might be warranted.
  • 09:45And for clinical significance.
  • 09:46So this study really addresses
  • 09:48both preventive and abortive
  • 09:49treatment of migraine,
  • 09:51which are the two pillars of
  • 09:53migraine management long term.
  • 09:55And although the main objective
  • 09:56is to determine the efficacy over
  • 09:58magic and in the acute setting,
  • 10:00incorporation of the migraine medication
  • 10:02in combination with the maps in the
  • 10:05long term is what really expands
  • 10:06the impacts of this study because
  • 10:08there's no known cure for migraine,
  • 10:10it's only managed.
  • 10:13And then in terms of quality of life
  • 10:16and disability for migraine patients,
  • 10:17spending less time in pain,
  • 10:19having fewer disability work days
  • 10:21and therefore less time spent in a
  • 10:23health care setting really speaks
  • 10:25to the impacts that this could have.
  • 10:28If this is a more effective
  • 10:30way of managing migraines.
  • 10:32And also it has impacts directly on
  • 10:34the health care system and that it's
  • 10:36cost saving to both the patient and
  • 10:38to the health system when there are
  • 10:40fewer visits to the ER and fewer
  • 10:43hospitalizations related to migraine care.
  • 10:45Treating migraine attacks at home
  • 10:46and being seen as an outpatient
  • 10:49is not only more economical,
  • 10:51but also less distressing for the patient.
  • 10:54So I'd like to acknowledge my thesis advisor,
  • 10:58Dr. Schindler.
  • 10:58She was really great.
  • 11:00She helped tremendously in her
  • 11:02guidance throughout the development
  • 11:03of my protocol and she also helped
  • 11:05give me a lot of great advice about
  • 11:08scientific writing throughout the
  • 11:09project for to Rosanna and Megan.
  • 11:12Thank you for facilitating the thesis
  • 11:14process in a really organized and at
  • 11:16least like a little less overwhelming,
  • 11:18way that was really much appreciated.
  • 11:20And for my mom, dad and my sister Adriana,
  • 11:24who.
  • 11:24Supporting me through PA school and
  • 11:27this project. I appreciate them.
  • 11:30Any references?