3. MIGRAINE
The term migraine derives from the ancient Greek word, hemikranios,
which means “half head,” underscoring the unilateral distribution of head
pain that is present in about 60%–75% of people with migraine.
The migraine attack can consist of up to four phases: the premonitory
phase, aura, headache phase, and postdrome.
The “headache phase” consists of a combination of photosensitivity,
phonosensitivity, olfactory hypersensitivity, cutaneous allodynia, nausea
and vomiting.
4. BACKGROUND
Migraine affects 18% of women and 6% of men in the United States with peak
prevalence occurring between the ages of 25 to 55 years.
Approximately one-third of patients with migraines have 3 or more migraine
headaches per month, and over half report severe impairment or the need
for bed rest.
Migraine is typically characterized by attacks of throbbing, unilateral
headache of moderate or severe pain intensity, associated with nausea,
vomiting, and/or sensitivity to light (photophobia), and sound
(phonophobia). In about 25% of individuals, the migraine headache is
preceded by focal neurological dysfunction (aura).
5. ATOGEPANT
Atogepant is a potent, selective oral CGRP receptor antagonist being
developed for migraine prevention. CGRP is a neuropeptide implicated in the
pathophysiology of migraine.
CGRP levels in the cranial venous outflow are increased during a migraine
attack and exogenously administered CGRP has been shown to trigger
migraine-like headache in people with migraine.
The majority (80 to 90%) of trigeminal Aδ fibers that innervate the dura
contain CGRP, suggesting that these fibers may be involved in neurogenic
inflammation and migraine pain transmission.
6. STUDY RATIONALE
The present study is being performed to prospectively assess the safety,
tolerability and efficacy of atogepant 30 mg and atogepant 60 mg once a day
compared with placebo in the prevention of EM.
This randomized, double-blind, placebo-controlled Phase 3 study is designed to
be a pivotal trial to confirm the efficacy of these doses and dose regimens and
will be used to support registration applications.
7. STUDY OBJECTIVE
PRIMARY OBJECTIVE
To evaluate the safety and tolerability of atogepant 30 mg and 60 mg once a day for the prevention of migraine
in participants with EM.
To prospectively test for superiority of atogepant 30 mg and 60 mg once a day versus placebo for the
prevention of migraine in participants with EM.
SECONDARY ENDPOINTS
Change from baseline in mean monthly headache days across the 12-week treatment period.
Change from baseline in mean monthly acute medication use days across the 12-week treatment
period.
At least a 50% reduction in 3-month average of monthly migraine days.
Change from baseline in MSQ(Migraine Specific Quality of Life Questionnaire v2.1) Role Function-
Restrictive domain score at Week 12
Change from baseline in mean monthly Performance of Daily Activities domain score of the AIM-
D(Activity Impairment in Migraine) across the 12-week treatment period.
Change from baseline in mean monthly Physical Impairment domain score of the AIM-D across the
12-week treatment period.
8. STUDY DESIGN
This was a multicenter, double-blind, parallelgroup, randomized, placebo-controlled
trial conducted from December 14, 2018, to June 19, 2020, in the United States.
A total of 128 sites enrolled at least one participant.
Participants were randomly assigned in a 1:1:1:1 ratio to receive a once-daily dose
of atogepant (10 mg, 30 mg, or 60 mg) or placebo.
Placebo (n = 200)
Atogepant 30 mg once a day (n = 200)
Atogepant 60 mg once a day (n = 200)
Approximately 70% of randomized participants will have taken at least 1 prior migraine
prevention medication with proven efficacy.
FUNDING- Allergan (before acquisition by AbbVie)
9. Participation will begin with a 4-week screening/baseline period. Participants who
complete the 4-week screening/baseline period and meet all entry criteria will be
randomized to the double-blind treatment period of the study at Visit 2 (Randomization
Visit).
The double-blind treatment period will last 12 weeks, with a subsequent follow-up
period of 4 additional weeks. There will be 8 scheduled clinic visits: Visit 1
(Screening/Baseline), Visit 2 (Randomization), Visit 3 (Week 2), Visit 4 (Week 4), Visit
5 (Week 6), Visit 6 (Week 8), Visit 7/ET (Week 12), and Visit 8 (Follow-up).
10.
11. INCLUSION CRITERIA
The following are requirements for entry into the study:
1. Written informed consent and participant privacy information (eg, written authorization
for use and release of health and research study information) obtained from the participant
prior to initiation of any study-specific procedures.
2. Male or female participants ages 18 to 80 years, inclusive, at Visit 1.
3. At least a 1-year history of migraine with or without aura consistent with a diagnosis
according to the ICHD-3.
4. Age of the participant at the time of migraine onset < 50 years.
5. History of 4 to 14 migraine days per month on average in the 3 months prior to Visit 1 in
the investigator’s judgment.
12. 6. 4 to 14 migraine days in the 28-day baseline period per eDiary.
7. Completed at least 20 out of 28 days in the eDiary during baseline period and is able to
read, understand, and complete the study questionnaires and eDiary per investigator’s
judgment.
8. Participants must be using a medically acceptable and effective method of birth control
during the course of the entire study
13. EXCLUSION CRITERIA
The following are criteria for exclusion from participating in the study:
1. Difficulty distinguishing migraine headaches from tension-type or other headaches.
2. Has a history of migraine accompanied by diplopia or decreased level of
consciousness or retinal migraine as defined by ICHD-3, 2018.
3. Has a current diagnosis of chronic migraine, new persistent daily headache,
trigeminal autonomic cephalgia (eg, cluster headache), or painful cranial neuropathy as
defined by ICHD-3.
4. Has ≥ 15 headache days per month on average across the 3 months prior to Visit 1 in
the investigator’s judgment.
5. Has ≥ 15 headache days in the 28-day baseline period per eDiary.
6. History of an inadequate response to > 4 medications (2 of which have different
mechanisms of action) prescribed for the prevention of migraine.
14. 7. Requirement for any medication, diet, or non-pharmacological treatment that is on
the list of prohibited concomitant medications or treatments that cannot be discontinued
or switched to an allowable alternative medication or treatment. This includes
concomitant medications with demonstrated efficacy for the prevention of migraine (eg,
amitriptyline, topiramate, propranolol).
8. Usage of opioids or barbiturates > 2 days/month, triptans or ergots ≥ 10 days/month,
or simple analgesics ≥ 15 days/month in the 3 months prior to Visit 1 per investigator’s
judgment, or during the baseline period (barbiturates are excluded 30 days prior to
screening and through the duration of the study)
9. Female participant is pregnant, planning to become pregnant during the course of the
study, or currently lactating. Women of childbearing potential must have a negative
urine pregnancy test at Visit 1 and Visit 2.
10. An ECG with clinically significant abnormalities at Screening (Visit 1) as
determined by the investigator.
11. QTcF > 450 msec for males and QTcF > 470 msec for females at Visit 1 based on
the final ECG report.
15. 12. Clinically significant cardiovascular or cerebrovascular disease per the
investigator’s opinion including, but not limited to:
13. Hypertension as defined by sitting systolic blood pressure > 160 mm Hg or
sitting diastolic blood pressure > 100 mm Hg at Visits 1 or Visit 2. Vital sign
measurements that exceed these limits may be repeated only once.
14. Clinically significant laboratory values at Visit 1 including but not limited
to:
o ALT or AST > 1 × ULN OR
o Total bilirubin > 1 × ULN
o Serum albumin < 2.8 g/dL.
15. Any clinically significant hematologic, endocrine, pulmonary, renal,
hepatic, gastrointestinal, or neurologic disease:
o Participants on dialysis for renal failure are excluded.
16. 16. History of acute hepatitis within 6 months of Screening (Visit 1); or chronic
hepatitis or a positive result on anti-hepatitis A IgM antibody, hepatitis B surface
antigen, anti–hepatitis C antibody testing, or anti-hepatitis E IgM antibody.
17. In the opinion of the investigator, confounding psychiatric conditions,
dementia, epilepsy or significant neurological disorders other than migraine.
18. Participant has any other concurrent pain condition that, in the opinion of the
investigator, may significantly impact the current headache disorder (eg,
fibromyalgia, facial pain).
19. Significant risk of self-harm based on clinical interview and responses on the
C-SSRS, or of harm to others in the opinion of the investigator; participants must
be excluded if they report suicidal ideation with intent, with or without a plan,
(ie, Type 4 or 5 on the C-SSRS) in the past 6 months or report suicidal behavior in
the 6 months prior to Visit 1 or Visit 2 assessments.
20. History of malignancy in the 5 years prior to Visit 1, except for adequately
treated basal cell or squamous cell skin cancer, or in situ cervical cancer.
21. History of any GI prior procedures or GI conditions (eg, diarrhea syndromes,
inflammatory bowel disease) that may affect the absorption or metabolism of
study intervention; participants with prior gastric bariatric interventions (eg, Lap
Band) which have been reversed are not excluded.
17. 22. At Visit 1, a user of recreational or illicit drugs or has had a history within
the past year of drug or alcohol abuse or dependence. Positive result on the
urine drug screen at Visit 1 unless explained by concomitant medication use
(eg, opioids prescribed for migraine pain).
23. Currently participating or has participated in a study with an
investigational compound or device within 30 days prior to Visit 1 (this
includes studies using marketed compounds or devices).
24. Previous exposure to:
o Atogepant (AGN-241689 or MK8031)
o Injectable monoclonal antibodies blocking the CGRP pathway within the last 6
months
o Ubrogepant and took more than 3 doses of ubrogepant
o Rimegepant and took more than 3 doses of rimegepant
18.
19.
20. PRIMARY EFFICACY END POINTS
The mean number of migraine days per month at baseline ranged from 7.5 to
7.9 in the four trial groups.
The mean change from baseline in the mean number of migraine day per
month across the 12-week treatment period (the primary efficacy end point)
was −3.7 with 10-mg atogepant, −3.9 with 30-mg atogepant, −4.2 with 60-mg
atogepant, and −2.5 with placebo.
The mean difference from placebo was −1.2 days with 10-mg atogepant (95%
confidence interval [CI], −1.8 to −0.6), −1.4 days with 30-mg atogepant (95%
CI, −1.9 to −0.8), and −1.7 days with 60-mg atogepant
21. SECONDARY EFFICACY END POINTS
The mean change from baseline in the mean number of headache days per
month across the 12-week treatment period was −3.9 for 10-mg atogepant,
−4.0 for 30-mg atogepant, −4.2 for 60-mg atogepant, and −2.5 for placebo
(P<0.001 for all comparisons with placebo).
The mean change from baseline in the mean number of days of use of
medication for the treatment of migraine attacks per month across the 12-week
treatment period was −3.7 for 10-mg atogepant, −3.7 for 30-mg atogepant, −3.9
for 60-mg atogepant, and −2.4 for placebo(P<0.001 for all comparisons with
placebo).
A reduction of 50% or more in the 3-month average of migraine days per month
occurred in 55.6% of the participants in the 10-mg atogepant group, 58.7% of
those in the 30-mg atogepant group, 60.8% of those in the 60-mg atogepant
group, and 29.0% of those in the placebo group (P<0.001 for all comparisons
with placebo).
22. Significant differences between all three atogepant doses and placebo were
observed for the secondary end points, with the exception of the score on the
Performance of Daily Activities domain of the AIM-D (difference, −1.2; 95% CI,
−2.6 to 0.2)
and the score on the Physical Impairment domain of the AIM-D (difference,
−1.1; 95% CI, −2.3 to 0.1) for 10-mg atogepant.
23. SAFETY
Adverse events that began or worsened on or after the date of the first dose of
atogepant or placebo until 30 days after the last dose were reported in 486 of
902 participants (53.9%)
The frequency of events was similar between the placebo and atogepant
groups, and no dose relationship was observed.
In the atogepant groups, the most commonly reported adverse events were
constipation (6.9 to 7.7% across doses), nausea (4.4 to 6.1% across doses),
and upper respiratory tract infection (1.4 to 3.9% across doses).
In the placebo group, the most common adverse events were upper respiratory
tract infection (4.5%), urinary tract infection (3.6%), and nasopharyngitis (3.6%).
The incidence of constipation was higher in the atogepant groups (6.9 to 7.7%)
than in the placebo group (0.5%)
24. Serious adverse events were reported in 2 participants who received 10-mg
atogepant (asthma attack and optic neuritis in 1 participant each) and in 2
participants who received placebo (gastric ulcer hemorrhage in 1 participant
and postsurgical laryngospasm with hypoxic brain injury in 1 participant).
The incidence of discontinuation due to adverse events was similar across the
trial groups.
Two participants in the 10-mg atogepant group, two participants in the 30-mg
atogepant group, one participant in the 60-mg atogepant group, and four
participants in the placebo group had elevated ALT or AST levels that were at
least 3 times the upper limit of the normal range. No serious cases of liver
disease were reported, and no case met the criteria for potential Hy’s law
25.
26. DISCUSSION
Oral atogepant at doses of 10 mg, 30 mg, and 60 mg once daily resulted in
significantly greater reductions in the number of migraine days than did placebo
in this 12-week trial.
For the primary end point, atogepant was associated with a reduction of 3.7 to
4.2 days in the mean number of migraine days per month, as compared with a
2.5-day reduction with placebo.
For the secondary end points, significant differences between all three doses of
atogepant and placebo occurred across the 12-week treatment period, with the
exception of the scores on the Performance of Daily Activity domain and the
Physical Impairment domain of the AIM-D for the 10-mg dose.
The percentage of participants with a reduction of at least 50% in the 3-month
average - 55.6% for the 10-mg dose to 60.8% for the 60-mg dose of atogepant,
as compared with 29.0% for placebo
27. Adverse events were reported by 52.2 to 53.7% of the participants across
atogepant doses and by 56.8% of those who received placebo.
Constipation, the most commonly reported adverse event, was observed in 6.9
to 7.7% of the participants across atogepant doses and in 0.5% of those who
received placebo. Previous studies have indicated an association between
CGRP receptor blockade and a decrease in gastrointestinal motility. Although
no serious cases of constipation were reported in this trial, continued monitoring
and evaluation for this adverse event in clinical practice will be appropriate.
Two participants in the 10-mg atogepant group, two participants in the 30-mg
atogepant group, one participant in the 60-mg atogepant group, and four
participants in the placebo group had elevated ALT or AST levels that were at
least 3 times the upper limit of the normal range.
28. DRAWBACKS
Participants with 15 or more headache days per month, so the results cannot
be generalized to the this group.
The trial also excluded participants with clinically significant coexisting
conditions, participants taking triptans or ergots on 10 or more days per month,
and participants who did not have a response to more than four preventive
treatments; trials and real-world studies that include these patients are needed.
The safety of atogepant in pregnant women was not evaluated in this trial.
The 12-week treatment duration is not adequate to assess the long-term safety
and side effects of atogepant
29. SUMMARY
In our trial, atogepant once daily was effective for reducing the number of
migraine days and headache days in the preventive treatment of migraine over
12 weeks.
30. CGRP ANATAGONISTS
There are two types of CGRP inhibitors – monoclonal antibodies and CGRP receptor
antagonists (gepants).
Monoclonal antibodies target either CGRP or the CGRP receptor and are used
for migraine prevention. They are given by injection subcutaneously.
• Eptinezumab - an infusion every 3 months. For IV infusion use.
• Fremanezumab - monthly or quarterly injection.
• Galcanezumab - monthly injection
• Erenumab - an injection every month.
Gepants are small molecule drugs which block the CGRP receptor and are effective
at both relieving migraines and preventing them.
• Rimegepant
• Ubrogepant
