Efficacy of Rimegepant Plus Calcitonin Gene-Related Peptide Monoclonal Antibody for Migraine
December 14, 2021Carina Leggio, PA-SIII
Advisor: Emmanuelle Schindler, MD, PhD
Information
- ID
- 7290
- To Cite
- DCA Citation Guide
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?