Abstract
Introduction
This study aimed to assess the efficacy and safety of once daily oral zavegepant as a preventive treatment for chronic migraine.
Methods
This multicenter, randomized, double-blind, placebo-controlled phase 2/3 study consisted of a 12-week double-blind treatment (DBT) phase and a 52-week open-label extension (OLE). Adults with ≥ 1-year history of chronic migraine (with or without aura), ≥ 15 headache days/month, ≥ 8 migraine days/month, and ≥ 1 headache-free day/month during the 3 months prior to screening were randomly assigned 2:2:1:1 to zavegepant 100 mg, 200 mg, placebo for zavegepant 100 mg, or placebo for zavegepant 200 mg. Following a 28-day observation phase (OP), participants took the study treatment every calendar day. The primary endpoint was mean change from the OP in number of migraine days/month in the DBT phase. This study was stopped prematurely due to recruitment challenges.
Results
Of 1753 screened participants, 522 were treated and 411 completed the DBT phase. Participants were predominantly female (n = 391, 79.5%) and mean (SD) age of chronic migraine onset was 26.5 (11.7) years. The mean (97.5% CI) changes from the OP in number of migraine days/month in the DBT phase were – 7.0 (– 8.10, – 5.92), – 6.3 (– 7.45, – 5.10), and – 5.6 (– 6.80, – 4.37) for zavegepant 100 mg, 200 mg, and placebo groups, respectively. The corresponding least squares (LS) mean change differences (zavegepant–placebo pooled; 97.5% CI) were – 1.4 (– 2.72, – 0.12) and – 0.7 (– 2.07, 0.69) for zavegepant 100 mg and zavegepant 200 mg groups, respectively. During DBT, 21 (12.1%) and 14 (8.0%) participants had at least one adverse event considered zavegepant-related in the zavegepant 100 mg and 200 mg groups, respectively, with corresponding rates of nine (5.8%) and nine (6.3%) participants during the OLE.
Conclusions
Oral zavegepant had a favorable safety and tolerability profile for up to 200 mg daily. Additional research is needed to determine the effectiveness of oral zavegepant as a preventive migraine treatment.
Trial Registration
ClinicalTrials.gov number: NCT04804033.
Keywords: Chronic migraine, Migraine, Oral, Preventive, Zavegepant
Plain Language Summary
Migraine is a long-term condition that causes repeated headaches called migraine attacks. Migraine preventive treatments are taken regularly to help prevent future migraine attacks. The aim of this study was to test zavegepant soft capsules for the preventive treatment of migraine. In this study, adults with migraine were assigned to one of four study treatments for 12 weeks: zavegepant 100 mg, zavegepant 200 mg, placebo for zavegepant 100 mg, or placebo for zavegepant 200 mg. People took the study treatment every calendar day. Researchers looked at changes in the number of days when a person has migraine symptoms (called migraine days). Researchers also looked at the side effects people had. This study was stopped early as it was challenging to find enough people to take part. A total of 411 people completed all 12 weeks of treatment. People taking zavegepant 100 mg had an average of seven fewer migraine days each month. People taking zavegepant 200 mg had an average of six fewer migraine days per month. People taking any dose of placebo had an average of almost six fewer migraine days per month. During the 12 weeks, 21 out of 173 people taking zavegepant 100 mg, and 14 out of 175 people taking zavegepant 200 mg, had a side effect that may have been caused by the treatment. Researchers concluded that further study is needed to tell if zavegepant soft capsules are effective as a preventive treatment for migraine.
Key Summary Points
| Why carry out this study? |
| Most traditional oral preventive migraine treatments were not developed to treat migraine and are associated with suboptimal safety, tolerability, and adherence. |
| This phase 2/3 study evaluated the efficacy and safety of oral zavegepant as a preventive treatment for chronic migraine over a 12-week double-blind treatment (DBT) phase and a 52-week open-label extension (OLE). |
| What was learned from the study? |
| This study was terminated early owing to recruitment challenges, which precludes definitive statements about dose response and achieving study objectives. |
| Overall, the data reflect a favorable safety profile for oral zavegepant at doses up to 200 mg daily. |
| Additional research is needed to determine the effectiveness of oral zavegepant as a preventive migraine treatment. |
Introduction
Chronic migraine is characterized by headache on ≥ 15 days per month with at least eight of those days linked to migraine [1]. Patients with chronic migraine experience frequent migraine attacks that drastically reduce their quality of life, increase migraine-related disability, and interfere with their ability to perform daily activities [2, 3], resulting in substantial societal costs [4].
Calcitonin gene-related peptide (CGRP) receptor antagonists have been established as therapeutic options for the acute and preventive treatment of migraine [5–7], including chronic migraine [6]. Zavegepant is a small-molecule CGRP receptor antagonist indicated for the acute treatment of migraine with or without aura in adults and is administered as a nasal spray [8]. The efficacy of single doses of zavegepant nasal spray for the acute treatment of migraine was demonstrated in double-blind, placebo-controlled clinical trials [9, 10]. A long-term, phase 2/3, open-label safety study demonstrated zavegepant 10 mg nasal spray was safe and well tolerated for the acute treatment of migraine when administered up to eight times a month for up to 52 weeks [11].
An oral soft gelatin formulation of zavegepant was developed as a preventive treatment for chronic migraine. The oral soft gelatin formulation of zavegepant was selected based on safety and PK data from two phase 1 studies, BHV3500-103 study and BHV3500-107. The BHV3500-103 study evaluated a single dose of zavegepant 50 mg in three different oral formulations in healthy participants to evaluate safety, tolerability, and to characterize pharmacokinetics (PK). The BHV3500-107 study evaluated multiple ascending doses of oral zavegepant from 50 to 300 mg for 14 days. In each study, oral zavegepant was well tolerated and the majority of adverse events were mild in intensity. The PK of zavegepant oral soft gelatin capsules was also evaluated in the drug-drug interaction study BHV3500-111. Following oral dosing of the soft gelatin capsule, zavegepant reached peak plasma concentration within 2 h, followed by a multiphasic decline, with an effective half-life of 4–5 h [12].
The primary objective of this phase 2/3 study was to compare the efficacy of oral zavegepant 100 mg and 200 mg to placebo as a preventive treatment for chronic migraine over a 12-week double-blind treatment (DBT) phase. Oral zavegepant safety were further evaluated in a 52-week open-label extension (OLE) phase.
Methods
Study Design
This was a multicenter, randomized, double-blind, placebo-controlled phase 2/3 study to assess the efficacy and safety of zavegepant for migraine prevention over a 12-week DBT phase and a 52-week OLE phase. Study design is summarized in Fig. 1. The DBT phase consisted of a 28-day (+ 3 days) observation phase (OP), a baseline/randomization visit (day 1 of treatment), and a 12-week treatment phase. Participants were assessed for baseline laboratory profiles at the pre-randomization laboratory visit, which was required to occur within 96 h (4 days + 2 days) of the baseline visit. At the baseline visit, eligibility for continued participation was assessed before randomization.
Fig. 1.
Study schematic of DBT and OLE phases. DBT double-blind treatment, EOT end of treatment, OLE open-label extension, PBO placebo, ZAV zavegepant
Participants were randomly assigned (2:2:1:1) to zavegepant 100 mg, 200 mg, placebo for zavegepant 100 mg, or placebo for zavegepant 200 mg and instructed to take four (zavegepant 100 mg or matching placebo) or eight (zavegepant 200 mg or matching placebo) 25 mg soft gelatin capsules of the blinded study drug every calendar day. The selection of oral zavegepant doses was partly based on safety and PK results from the studies BHV3500-103 and BHV3500-107 relative to those as defined for the intranasal administration of zavegepant [13]. Randomization was stratified by stable prophylactic migraine medication use (yes or no). Participants were instructed to take the capsules fasting, at least 1 h before breakfast/first meal of the day (and at least 4 h after the previous meal). If participants had a migraine attack during the DBT phase, they were permitted to treat the migraine with their standard-of-care acute treatment medication and instructed to continue taking the study drug. During the DBT phase, study visits occurred at baseline and weeks 2, 4, 8, and 12.
Upon completion of the DBT phase, eligible participants could continue the same dosing regimen (zavegepant 100 mg or 200 mg daily, taken as four or eight 25 mg soft gelatin capsules, respectively) in the OLE phase for up to 52 weeks. During the OLE phase, study visits occurred at weeks 14 and 16, and every 4 weeks thereafter until week 64. If participants had a migraine during the OLE phase, they were permitted to treat the migraine with their standard-of-care medication and instructed to continue to taking the study drug. Participants who were not eligible to enter the OLE phase were to continue to the follow-up phase. All randomly assigned participants were to complete the follow-up visits at weeks 2 and 8, regardless of completing either treatment phase.
This study was conducted in accordance with Good Clinical Practice guidelines, the Declaration of Helsinki and all applicable local regulations. The protocol was approved by an Institutional Review Board/Independent Ethics Committee (Advarra, MD, USA) prior to initiation. All participants provided written informed consent prior to participating in the study. With the exception of 1 site that used a local IRB, the remaining sites utilized Advarra, the central IRB. The site that utilized the local IRB did not randomize any subjects into the trial.
Participants
Eligible participants were adults with ≥ 1-year history of chronic migraine (with or without aura) consistent with a diagnosis according to the International Classification of Headache Disorders (3rd Edition), migraine onset prior to 50 years of age, onset of chronic migraine prior to 65 years of age, and untreated migraine attacks lasting 4–72 h. Participants were required to have had ≥ 15 headache days per month, ≥ 8 migraine days per month, and ≥ 1 headache-free day per month during the last 3 months prior to the screening visit. During the OP, participants were required to have had ≥ 8 migraine days, ≥ 15 headache days, and ≥ 1 non-headache day. Participants could remain on one prophylactic migraine medication during the DBT phase (excluding CGRP antagonists) if the dose had been stable for at least 3 months prior to the screening visit and was not expected to change during the study. Participants with contraindications for use of triptans could be included provided they meet all other criteria.
A migraine day was defined as a day with a headache lasting at least 30 min and either (i) nausea and/or vomiting, or photophobia and phonophobia, or (ii) two or more of the following headache features: unilateral pain, pulsating pain, moderate or severe pain intensity, or pain aggravated by/causing avoidance of physical activity. Days on which acute migraine-specific medication (i.e., triptan or ergotamine [though not permitted]) was taken were also classified as migraine days, regardless of pain intensity or symptoms. A headache day was defined as either (i) a migraine day (as above), (ii) a day with a non-migraine headache lasting at least 30 min, or (iii) a day on which medication was taken to treat a headache or aura.
Key exclusion criteria were participants with a history of basilar migraine or hemiplegic migraine; history of HIV disease; evidence of uncontrolled, unstable, or recently diagnosed cardiovascular disease, including ischemic heart disease, coronary artery vasospasm, and cerebral ischemia during the 6 months prior to the screening visit; history of myocardial infarction, acute coronary syndrome, percutaneous coronary intervention, cardiac surgery, stroke, or transient ischemic attack during the 6 months prior to the screening visit; uncontrolled hypertension or uncontrolled diabetes; chronic pain syndromes; history or diagnosis of Gilbert’s syndrome or any other active hepatic or biliary disorder; body mass index > 33.0 kg/m2; exposure to non-biological investigational agents (other than zavegepant) within 30 days prior to the screening visit; exposure to biological investigational agents such as monoclonal antibodies within 6 months prior to the screening visit; and past participation in a clinical trial within 30 days prior to the screening visit.
Outcomes and Assessments
The primary endpoint was the mean change from the OP in number of migraine days per month over the entire DBT phase (weeks 1–12). Secondary endpoints included the following: proportion of participants with ≥ 50% reduction from the OP in number of moderate to severe migraine days (i.e., migraine days of moderate or severe pain intensity) per month over the entire DBT phase (weeks 1–12); mean change from the OP in number of migraine days per month in the first 4 weeks (weeks 1–4) and last 4 weeks (weeks 9–12) of the DBT phase; mean number of acute migraine-specific medication days per month over the entire DBT phase (weeks 1–12); mean changes from baseline to week 12 of the DBT phase in migraine-specific quality of life (MSQoL) restrictive role function domain score and Migraine Disability Assessment (MIDAS) total score; incidence of adverse events (AEs) by intensity, serious AEs (SAEs), AEs leading to study drug discontinuation, and grade 3 to 4 laboratory test abnormalities during the DBT and OLE phases; incidence of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevations > 3 × upper limit of normal (ULN) concurrent with total bilirubin > 2 × ULN during the DBT and OLE phases; and incidence of hepatic-related AEs by intensity, and hepatic-related AEs leading to study drug discontinuation during the DBT and OLE phases.
Upon completion of the screening visit, participants were provided with an electronic diary (eDiary) to document migraine occurrence, migraine pain features and associated symptoms, and use of acute migraine medication. Participants recorded all concomitant medications, including standard-of-care migraine medications (both prophylactic and acute), taken in the concomitant medication paper diary. At select study visits, participants completed the MSQoL Questionnaire version 2.1 and MIDAS to assess migraine-related disability.
Statistical Analysis
This study planned to screen approximately 2900 individuals with the aim of randomizing approximately 1440 participants. Per protocol and well before the trial was discontinued early, it was estimated that a sample size of approximately 480 randomly assigned participants per zavegepant treatment group and 240 per placebo treatment group, as such approximately 440 participants per zavegepant treatment group and 220 per placebo treatment group were planned to be in the migraine analysis set. Assuming zavegepant provides a 1-day advantage over placebo, pooled on the mean change in migraine days per month over the entire DBT phase, and a common standard deviation of 4.2 days, the study would have had ≥ 90% power for the primary endpoint with an alpha level of 0.025.
The DBT efficacy analysis set was defined as enrolled participants who were randomly assigned only once and took ≥ 1 dose of double-blind study drug. The migraine analysis set was defined as participants in the DBT efficacy analysis set with ≥ 14 days (not necessarily consecutive) of eDiary efficacy data in both the OP and ≥ 1 month in the DBT phase.
The primary endpoint was assessed for the migraine analysis set using a linear mixed effects model with repeated measures and included the following variables: change from the OP in number of migraine days per month as the dependent variable; participant as a random effect; number of migraine days per month in the OP as a covariate; and fixed effects for treatment group, randomization stratum (i.e., stable prophylactic migraine medication use through randomization), month, and month-by-treatment group interaction. Migraine days per month were based on 4-week intervals and were prorated to account for missing migraine reports.
The proportion of participants with ≥ 50% reduction from the OP in number of moderate or severe migraine days per month over the entire DBT phase was analyzed using Mantel–Haenszel risk estimation stratified by randomization stratum for the migraine analysis set. The mean changes from the OP in number of migraine days per month in the first 4 weeks (weeks 1–4) and last 4 weeks (weeks 9–12) of the DBT phase were assessed for the migraine analysis set from the same model as the primary endpoint. The mean number of acute migraine-specific medication days per month was analyzed using a similar model as the primary endpoint, except the number of acute migraine-specific medication days per month was the dependent variable and there was no covariate. The mean changes from baseline in MSQoL restrictive role function domain score and MIDAS total score at week 12 were analyzed for the DBT efficacy analysis set using linear regression models.
Safety endpoints were assessed descriptively in all participants who took ≥ 1 dose of the study drug during each phase (DBT safety analysis set, OL zavegepant safety analysis set).
Results
Participants
This study was stopped prematurely due to recruitment challenges and as a strategic decision based upon an adjusted clinical development plan and was not based upon any safety concern. Participant disposition from screening to completion of DBT is summarized in Fig. 2. Following the DBT phase, 401 participants in the DBT safety analysis set continued to the next phase (OLE, n = 300 [57.5%]; follow-up, n = 101 [19.3%]). In total, 107 (35.9%) participants in the OL zavegepant safety analysis set completed the OLE phase.
Fig. 2.
Participant disposition from screening to completion of DBT. AE adverse event, DBT double-blind treatment
Participant baseline demographics, clinical characteristics, and migraine history are presented for the migraine analysis set in Table 1. Participant characteristics were generally comparable across treatment groups. Overall, participants had a mean (SD) age of 42.4 (13.1) years, were predominantly female (n = 391, 79.5%), had a mean (SD) age of chronic migraine onset of 26.5 (11.7) years (approximately 5 years after migraine onset), had a mean (SD) number of migraine days per month in the OP of 15.7 (4.6), and had a mean (SD) number of moderate or severe migraine days per month in the OP of 13.4 (4.8) (Table 1).
Table 1.
Baseline demographics, clinical characteristics, and migraine history (migraine analysis set)
| ZAV 100 mg, N = 164 | ZAV 200 mg, N = 163 | PBO 100 mg, N = 82 | PBO 200 mg, N = 83 | PBO pooled, N = 165 | Overall, N = 492 | |
|---|---|---|---|---|---|---|
| Age, mean (SD), y | 42.2 (12.9) | 43.3 (13.4) | 41.4 (13.3) | 42.0 (13.0) | 41.7 (13.1) | 42.4 (13.1) |
| Sex, n (%) | ||||||
| Female | 123 (75.0) | 134 (82.2) | 69 (84.1) | 65 (78.3) | 134 (81.2) | 391 (79.5) |
| Male | 41 (25.0) | 29 (17.8) | 13 (15.9) | 18 (21.7) | 31 (18.8) | 101 (20.5) |
| Race, n (%) | ||||||
| White | 123 (75.0) | 122 (74.8) | 64 (78.0) | 58 (69.9) | 122 (73.9) | 367 (74.6) |
| Black | 34 (20.7) | 34 (20.9) | 14 (17.1) | 17 (20.5) | 31 (18.8) | 99 (20.1) |
| Other | 7 (4.3) | 7 (4.3) | 4 (4.9) | 7 (8.4) | 11 (6.7) | 25 (5.1) |
| Not reported | 0 | 0 | 0 | 1 (1.2) | 1 (0.6) | 1 (0.2) |
| Weight, mean (SD), kg | 75.8 (13.4) | 75.0 (13.6) | 74.1 (16.6) | 75.3 (14.0) | 74.7 (15.3) | 75.2 (14.1) |
| BMI, mean (SD), kg/m2 | 27.1 (4.0) | 26.9 (4.0) | 26.4 (4.5) | 27.0 (4.1) | 26.7 (4.3) | 26.9 (4.1) |
| Stable prophylactic migraine medication use through randomization, n (%)a | ||||||
| Yes | 21 (12.8) | 14 (8.6) | 6 (7.3) | 6 (7.2) | 12 (7.3) | 47 (9.6) |
| No | 143 (87.2) | 149 (91.4) | 76 (92.7) | 77 (92.8) | 153 (92.7) | 445 (90.4) |
| Migraine days per month during the OP, mean (SD), n | 14.9 (4.2) | 16.1 (4.8) | 16.2 (4.1) | 15.8 (5.1) | 16.0 (4.6) | 15.7 (4.6) |
| Moderate or severe migraine days per month during the OP, mean (SD), n | 12.8 (4.7) | 14.1 (5.1) | 13.2 (4.3) | 13.6 (4.9) | 13.4 (4.6) | 13.4 (4.8) |
| Headache days per month during the OP, mean (SD), n | 19.7 (5.9) | 19.9 (7.2) | 18.6 (3.4) | 19.5 (6.6) | 19.0 (5.2) | 19.6 (6.2) |
| Age at migraine onset, mean (SD), yb | 20.6 (10.7) | 22.0 (11.6) | 20.1 (9.7) | 22.3 (10.9) | 21.2 (10.4) | 21.3 (10.9) |
| Age at chronic migraine onset, mean (SD), yb | 26.8 (11.9) | 26.8 (12.2) | 25.8 (11.8) | 26.2 (10.4) | 26.0 (11.1) | 26.5 (11.7) |
| Migraine days per month, mean (SD), nb,c | 13.7 (5.9) | 14.7 (7.3) | 13.9 (4.9) | 14.5 (7.4) | 14.2 (6.2) | 14.2 (6.5) |
| Average duration of untreated migraine attacks, mean (SD), hb | 27.3 (20.5) | 28.9 (22.1) | 30.1 (21.7) | 24.9 (19.4) | 27.5 (20.7) | 27.9 (21.1) |
| Primary migraine type, n (%)b | ||||||
| Without aura | 99 (60.4) | 110 (67.5) | 48 (58.5) | 56 (67.5) | 104 (63.0) | 313 (63.6) |
| With aura | 65 (39.6) | 53 (32.5) | 34 (41.5) | 27 (32.5) | 61 (37.0) | 179 (36.4) |
BMI body mass index, OP observation phase, PBO placebo, SD standard deviation, ZAV zavegepant
aBased on self-reported nonstudy medication use. bBased on self-reported migraine history. cMigraine attacks of any pain intensity in the 3 months prior to screening
Efficacy
The mean (97.5% CI) changes from the OP in number of migraine days per month over the entire DBT phase were – 7.0 (– 8.10, – 5.92), – 6.3 (– 7.45, – 5.10), and – 5.6 (– 6.80, – 4.37) for zavegepant 100 mg, 200 mg, and placebo pooled groups, respectively (Fig. 3). The least squares (LS) mean change differences (zavegepant–placebo pooled; 97.5% CI) were – 1.4 (– 2.72, – 0.12) and – 0.7 (– 2.07, 0.69) for zavegepant 100 mg and zavegepant 200 mg groups, respectively. The mean (97.5% CI) changes from the OP in number of migraine days after each month by individual treatment groups is shown in Fig. 4. Notably, between week 4 and week 12, the response in the placebo 200 mg group markedly increased relative to the other treatment groups.
Fig. 3.
Mean change from the OP in number of migraine days per month over the entire DBT phase (migraine analysis set). CI confidence interval, DBT double-blind treatment, OP observation phase, PBO placebo; ZAV zavegepant
Fig. 4.
Mean change from the OP in number of migraine days after each month (4 weeks) by individual treatment (migraine analysis set). CI confidence interval, DBT double-blind treatment, OP observation phase, PBO placebo, ZAV zavegepant
The proportion of participants with a ≥ 50% reduction from the OP in number of moderate or severe migraine days per month over the entire DBT phase is shown in Fig. 5. The stratified percentage differences (zavegepant–placebo pooled; 97.5% CI) were 16.6 (4.4, 28.8) and 6.6 (– 5.6, 18.9) for zavegepant 100 mg and zavegepant 200 mg groups, respectively.
Fig. 5.
Proportion of participants with a ≥ 50% reduction from the OP in number of moderate or severe migraine days per month over the entire DBT phase (migraine analysis set). CI confidence interval, DBT double-blind treatment, OP observation phase, PBO placebo, ZAV zavegepant
The mean (97.5% CI) changes from the OP in number of migraine days per month in the first 4 weeks of the DBT phase were – 5.7 (– 6.89, – 4.51), – 5.1 (– 6.26, – 3.87), and – 3.9 (– 5.10, – 2.72) for zavegepant 100 mg, zavegepant 200 mg, and placebo pooled groups, respectively. The mean (97.5% CI) changes from the OP in number of migraine days per month in the last 4 weeks of the DBT phase were – 7.8 (– 9.11, – 6.59), – 7.2 (– 8.56, – 5.83), and – 6.8 (– 8.22, – 5.38) for zavegepant 100 mg, zavegepant 200 mg, and placebo pooled groups, respectively.
Exposure–Response
A higher median plasma zavegepant concentration was observed at 1 h post dose, at weeks 4 and 8, for zavegepant 200 mg compared with zavegepant 100 mg (Fig. 6A). No clear trend was observed at week 8 between plasma zavegepant concentration and change from the OP in number of migraine days per month (Fig. 6B).
Fig. 6.
Box–whisker plot of A observed zavegepant concentrations at 1 h post dose at week 4 and week 8 and B observed change in monthly migraine days from baseline vs. zavegepant concentration at 1 h post dose following 8 weeks of treatment. CFB change from baseline
Quality of Life and Disability
Mean (97.5% CI) changes from baseline at week 12 in MSQoL restrictive role function domain score and total MIDAS score are shown in Fig. 7. The LS mean change differences (zavegepant–placebo pooled; 97.5% CI) for MSQoL restrictive role function scores were 4.5 (– 0.97, 9.92) and 0.0 (– 5.76, 5.81) for zavegepant 100 mg and zavegepant 200 mg groups, respectively (Fig. 7A).
Fig. 7.
Mean (97.5% CI) change from baseline at week 12 in A MSQoL restrictive role function domain score and B total MIDAS score (DBT efficacy analysis set). CI confidence interval, DBT double-blind treatment, MIDAS Migraine Disability Assessment, MSQoL migraine-specific quality of life, PBO placebo, ZAV zavegepant
For MIDAS total score, the LS mean change differences (zavegepant–placebo pooled; 97.5% CI) were – 9.4 (– 18.57, – 0.17) and –9.2 (– 18.92, 0.51) for zavegepant 100 mg and zavegepant 200 mg groups, respectively (Fig. 7B).
Safety
A summary of AEs for the DBT and OLE phases is presented in Table 2. During DBT, 21 (12.1%) and 14 (8.0%) participants had at least one AE considered zavegepant-related in the zavegepant 100 mg and 200 mg groups, respectively. During the OLE, nine (5.8%) and nine (6.3%) participants had at least one AE considered zavegepant-related in the zavegepant 100 mg and 200 mg groups, respectively. During DBT 1 (0.6%) participant in each zavegepant group experienced an SAE (hypertensive heart disease, zavegepant 100 mg; iron deficiency anemia, zavegepant 200 mg). During the OLE, 1 (0.6%, nephrolithiasis) and 3 (2.1%; n = 2, cholecystitis; n = 1, intestinal obstruction; n = 1, lung disorder) participants experienced at least one SAE in the zavegepant 100 mg and 200 mg groups, respectively. There were no instances of medication-overuse headache AEs. There were no hepatic-related AEs during DBT that led to study drug discontinuation, and 1 (0.7%) participant who received zavegepant 200 mg had a hepatic-related AE during the OLE that led to zavegepant discontinuation.
Table 2.
Summary of AEs for DBT and OLE (DBT safety analysis set, OL zavegepant safety analysis set)
| DBT safety analysis set | OL zavegepant safety analysis set | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| ZAV 100 mg, N = 173 | ZAV 200 mg, N = 175 | ZAV pooled, N = 348 | PBO 100 mg, N = 86 | PBO 200 mg, N = 88 | PBO pooled, N = 174 | ZAV 100 mg, N = 155 | ZAV 200 mg, N = 143 | ZAV pooled, N = 298 | |
| Any AE | 63 (36.4) | 51 (29.1) | 114 (32.8) | 31 (36.0) | 30 (34.1) | 61 (35.1) | 66 (42.6) | 67 (46.9) | 133 (44.6) |
| Moderate or severe AE | 20 (11.6) | 25 (14.3) | 45 (12.9) | 13 (15.1) | 9 (10.2) | 22 (12.6) | 29 (18.7) | 37 (25.9) | 66 (22.1) |
| Related to study drug AE | 21 (12.1) | 14 (8.0) | 35 (10.1) | 11 (12.8) | 17 (19.3) | 28 (16.1) | 9 (5.8) | 9 (6.3) | 18 (6.0) |
| AE leading to study drug discontinuation | 2 (1.2) | 5 (2.9) | 7 (2.0) | 3 (3.5) | 4 (4.5) | 7 (4.0) | 2 (1.3) | 4 (2.8) | 6 (2.0) |
| SAE | 1 (0.6) | 1 (0.6) | 2 (0.6) | 0 | 1 (1.1) | 1 (0.6) | 1 (0.6) | 3 (2.1) | 4 (1.3) |
| Medication-overuse headache AE | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Hepatic-related AE | 1 (0.6) | 0 | 1 (0.3) | 2 (2.3) | 0 | 2 (1.1) | 2 (1.3) | 4 (2.8) | 6 (2.0) |
| Hepatic-related AE leading to study drug discontinuation | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.7) | 1 (0.3) |
| Potential drug abuse AE | 6 (3.5) | 4 (2.3) | 10 (2.9) | 1 (1.2) | 1 (1.1) | 2 (1.1) | 4 (2.6) | 5 (3.5) | 9 (3.0) |
| Cardiovascular AE | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.7) | 1 (0.3) |
| Suicidality AE | 0 | 0 | 0 | 0 | 1 (1.1) | 1 (0.6) | 0 | 0 | 0 |
AE adverse event, DBT double-blind treatment, OLE open-label extension, PBO placebo, SAE serious adverse event ZAV zavegepant
AEs by preferred term of any intensity occurring in ≥ 2% of participants in any treatment group during the DBT or OLE phases are presented in Table 3 and a summary of laboratory abnormalities of CTCAE/DAIDS ≥ grade 3 is presented in Table 4. In the DBT safety analysis set there were no participants with ALT or AST elevations > 3 × ULN. There were no participants with AST or ALT elevations > 3 × ULN concurrent with total bilirubin > 2 × ULN during the DBT. In the OL safety analysis set, two (1.4%) participants had ALT elevations > 3 × ULN, four (2.9%) participants had AST elevations > 3 × ULN, of whom 1 (0.7%) participant had AST elevations > 5 × ULN, and 1 (0.7%) participant had AST > 10 × ULN (all occurring in the zavegepant 200 mg group). There were no participants with AST or ALT elevations > 3 × ULN concurrent with total bilirubin > 2 × ULN during the OLE.
Table 3.
Summary of AEs by preferred term of any intensity occurring in ≥ 2% of participants in any treatment group during DBT or OLE (DBT safety analysis set, OL zavegepant safety analysis set)
| Number (%) of participants with AE | DBT safety analysis set | OL zavegepant safety analysis set | |||||||
|---|---|---|---|---|---|---|---|---|---|
| ZAV 100 mg, N = 173 | ZAV 200 mg, N = 175 | ZAV pooled, N = 348 | PBO 100 mg, N = 86 | PBO 200 mg, N = 88 | PBO pooled, N = 174 | ZAV 100 mg, N = 155 | ZAV 200 mg, N = 143 | ZAV pooled, N = 298 | |
| Nausea | 12 (6.9) | 5 (2.9) | 17 (4.9) | 8 (9.3) | 5 (5.7) | 13 (7.5) | 3 (1.9) | 6 (4.2) | 9 (3.0) |
| COVID-19 | 8 (4.6) | 8 (4.6) | 16 (4.6) | 1 (1.2) | 2 (2.3) | 3 (1.7) | 12 (7.7) | 12 (8.4) | 24 (8.1) |
| Upper respiratory tract infection | 4 (2.3) | 4 (2.3) | 8 (2.3) | 1 (1.2) | 0 | 1 (0.6) | 5 (3.2) | 2 (1.4) | 7 (2.3) |
| Constipation | 3 (1.7) | 4 (2.3) | 7 (2.0) | 0 | 0 | 0 | 2 (1.3) | 1 (0.7) | 3 (1.0) |
| Nasopharyngitis | 5 (2.9) | 1 (0.6) | 6 (1.7) | 1 (1.2) | 1 (1.1) | 2 (1.1) | 7 (4.5) | 4 (2.8) | 11 (3.7) |
| Abdominal pain upper | 3 (1.7) | 2 (1.1) | 5 (1.4) | 2 (2.3) | 2 (2.3) | 4 (2.3) | 1 (0.6) | 2 (1.4) | 3 (1.0) |
| Sinusitis | 3 (1.7) | 1 (0.6) | 4 (1.1) | 2 (2.3) | 4 (4.5) | 6 (3.4) | 4 (2.6) | 4 (2.8) | 8 (2.7) |
| Back pain | 1 (0.6) | 3 (1.7) | 4 (1.1) | 0 | 2 (2.3) | 2 (1.1) | 2 (1.3) | 3 (2.1) | 5 (1.7) |
| Cough | 4 (2.3) | 0 | 4 (1.1) | 2 (2.3) | 0 | 2 (1.1) | 3 (1.9) | 3 (2.1) | 6 (2.0) |
| Dyspepsia | 2 (1.2) | 2 (1.1) | 4 (1.1) | 1 (1.2) | 3 (3.4) | 4 (2.3) | 1 (0.6) | 0 | 1 (0.3) |
| Urinary tract infection | 2 (1.2) | 1 (0.6) | 3 (0.9) | 6 (7.0) | 1 (1.1) | 7 (4.0) | 6 (3.9) | 2 (1.4) | 8 (2.7) |
| Diarrhea | 1 (0.6) | 2 (1.1) | 3 (0.9) | 1 (1.2) | 5 (5.7) | 6 (3.4) | 2 (1.3) | 3 (2.1) | 5 (1.7) |
| Nasal congestion | 2 (1.2) | 1 (0.6) | 3 (0.9) | 2 (2.3) | 1 (1.1) | 3 (1.7) | 0 | 0 | 0 |
| Blood creatine phosphokinase increased | 1 (0.6) | 2 (1.1) | 3 (0.9) | 1 (1.2) | 0 | 1 (0.6) | 5 (3.2) | 3 (2.1) | 8 (2.7) |
| Oropharyngeal pain | 2 (1.2) | 0 | 2 (0.6) | 2 (2.3) | 1 (1.1) | 3 (1.7) | 1 (0.6) | 0 | 1 (0.3) |
| Gastroenteritis | 0 | 2 (1.1) | 2 (0.6) | 0 | 0 | 0 | 0 | 3 (2.1) | 3 (1.0) |
| Vomiting | 2 (1.2) | 0 | 2 (0.6) | 1 (1.2) | 2 (2.3) | 3 (1.7) | 1 (0.6) | 4 (2.8) | 5 (1.7) |
| Dizziness | 1 (0.6) | 0 | 1 (0.3) | 2 (2.3) | 1 (1.1) | 3 (1.7) | 0 | 2 (1.4) | 2 (0.7) |
| Flatulence | 0 | 0 | 0 | 0 | 2 (2.3) | 2 (1.1) | 0 | 0 | 0 |
| Ear infection | 0 | 0 | 0 | 1 (1.2) | 0 | 1 (0.6) | 1 (0.6) | 4 (2.8) | 5 (1.7) |
| Pyrexia | 0 | 0 | 0 | 0 | 0 | 0 | 2 (1.3) | 3 (2.1) | 5 (1.7) |
| ALT increased | 0 | 0 | 0 | 1 (1.2) | 0 | 1 (0.6) | 1 (0.6) | 3 (2.1) | 4 (1.3) |
| AST increased | 0 | 0 | 0 | 2 (2.3) | 0 | 2 (1.1) | 0 | 3 (2.1) | 3 (1.0) |
AEs are displayed in descending order of ZAV pooled during DBT
AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, DBT double-blind treatment, OLE open-label extension, PBO placebo, ZAV zavegepant
Table 4.
Summary of laboratory test worst abnormalities of CTCAE/DAIDS ≥ grade 3 in any group (DBT safety analysis set, OL zavegepant safety analysis set)
| Number (%) of participants with abnormality/ Number of participants with data (n) | DBT safety analysis set | OL zavegepant safety analysis set | ||||||
|---|---|---|---|---|---|---|---|---|
| ZAV 100 mg, N = 173 | ZAV 200 mg, N = 175 | ZAV Pooled, N = 348 | PBO 100 mg, N = 86 | PBO 200 mg, N = 88 | PBO Pooled, N = 174 | ZAV 100 mg, N = 155 | ZAV 200 mg, N = 143 | |
| Hemoglobin, low, n | 166 | 160 | 326 | 81 | 83 | 164 | 149 | 136 |
| Grade 3 | 0 | 1 (0.6) | 1 (0.3) | 0 | 0 | 0 | 0 | 1 (0.7) |
| Neutrophils, low, n | 166 | 160 | 326 | 81 | 83 | 164 | 149 | 136 |
| Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.7) | 1 (0.7) |
| AST increased, n | 170 | 168 | 338 | 85 | 85 | 170 | 152 | 139 |
| Grade 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.7) |
| Creatine kinase increased, n | 170 | 168 | 338 | 85 | 85 | 170 | 152 | 139 |
| Grade 3 | 4 (2.4) | 4 (2.4) | 8 (2.4) | 1 (1.2) | 0 | 1 (0.6) | 4 (2.6) | 2 (1.4) |
| Grade 4 | 1 (0.6) | 3 (1.8) | 4 (1.2) | 0 | 0 | 0 | 6 (3.9) | 5 (3.6) |
| Glucose fasting, low, n | 106 | 95 | 201 | 50 | 51 | 101 | 87 | 78 |
| Grade 4 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (1.1) | 0 |
| LDL cholesterol, high, n | 150 | 147 | 297 | 69 | 73 | 142 | 109 | 107 |
| Grade 3 | 7 (4.7) | 6 (4.1) | 13 (4.4) | 2 (2.9) | 5 (6.8) | 7 (4.9) | 7 (6.4) | 8 (7.5) |
| LDL cholesterol, fasting, high, n | 72 | 63 | 135 | 30 | 38 | 68 | 48 | 53 |
| Grade 3 | 4 (5.6) | 1 (1.6) | 5 (3.7) | 1 (3.3) | 3 (7.9) | 4 (5.9) | 4 (8.3) | 4 (7.5) |
| LDL cholesterol, not fasting, high n | 45 | 49 | 94 | 22 | 21 | 43 | 32 | 25 |
| Grade 3 | 0 | 3 (6.1) | 3 (3.2) | 0 | 1 (4.8) | 1 (2.3) | 1 (3.1) | 1 (4.0) |
| Potassium, high, n | 167 | 161 | 328 | 81 | 83 | 164 | 149 | 134 |
| Grade 3 | 0 | 0 | 0 | 2 (2.5) | 0 | 2 (1.2) | 0 | 2 (1.5) |
| Grade 4 | 0 | 0 | 0 | 1 (1.2) | 0 | 1 (0.6) | 0 | 0 |
| Triglycerides, high, n | 150 | 147 | 297 | 69 | 73 | 142 | 109 | 107 |
| Grade 3 | 1 (0.7) | 0 | 1 (0.3) | 0 | 0 | 0 | 1 (0.9) | 0 |
| Grade 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.9) |
| Triglycerides, fasting, high, n | 72 | 63 | 135 | 30 | 38 | 68 | 48 | 53 |
| Grade 4 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (1.9) |
| Triglycerides, not fasting, high, n | 45 | 49 | 94 | 22 | 21 | 43 | 32 | 25 |
| Grade 3 | 1 (2.2) | 0 | 1 (1.1) | 0 | 0 | 0 | 1 (3.1) | 0 |
| Urine glucose, high, n | 148 | 142 | 290 | 69 | 71 | 140 | 108 | 101 |
| Grade 3 | 1 (0.7) | 0 | 1 (0.3) | 0 | 0 | 0 | 1 (0.9) | 0 |
CTCAE Version 5.0 (DAIDS Version 2.1 for glucose, LDL cholesterol, and urinalysis)
AST aspartate aminotransferase, CTCAE common terminology criteria for adverse events, DAIDS Division of AIDS, DBT double-blind treatment, LDL low-density lipoprotein, OLE open-label extension, ZAV zavegepant
Discussion
This multicenter, randomized, double-blind, placebo-controlled phase 2/3 study evaluated the efficacy and safety of daily oral zavegepant 100 mg and 200 mg to placebo as a preventive treatment for chronic migraine over a 12-week DBT phase and a 52-week OLE phase. For the primary endpoint, zavegepant 100 mg appeared to provide a potentially greater benefit for the preventive treatment of migraine than zavegepant 200 mg, with LS mean change differences (zavegepant – placebo pooled) of – 1.4 (– 2.72, – 0.12) and – 0.7 (– 2.07, 0.69), respectively. A similar trend was observed with other outcome measures including the proportion of participants with ≥ 50% reduction in moderate or severe monthly migraine days and MSQoL measures. However, exploratory exposure–response analyses showed that, compared with zavegepant concentrations at 1 h post dose across placebo, 100 mg, and 200 mg groups, there was no clear trend of greater benefit at higher zavegepant concentrations for the mean change in migraine days per month from the OP over the entire DBT phase. As such, the apparent numerical superiority of zavegepant 100 mg compared with placebo, but not zavegepant 200 mg, could be a chance finding owing to a variable response and limited sample size in this terminated study. Nevertheless, this result was somewhat surprising. There is variation in the dose response of other CGRP receptor antagonists. In the preventive treatment of migraine, doses of 120 mg had similar efficacy to 240 mg for monoclonal antibody galcanezumab [14]. Whereas, for the orally administered atogepant, higher doses were more effective in lowering migraine days but were accompanied by an increased incidence of adverse events [15]. As such, we may expect some numerical ascending separation with oral zavegepant. Furthermore, participants in each dose cohort in this study received different quantities of 25 mg capsules per dose (four soft gelatine capsules to match zavegepant 100 mg and eight to match zavegepant 200 mg), which may have contributed to the large placebo response observed in this study and, ultimately, affecting the placebo-subtracted response rate. This may have particular bearing for the efficacy assessment of the zavegepant 200 mg group as between week 4 and week 12, the response in the placebo 200-mg group markedly increased relative to the other treatment groups. Still, in light of the stated limitations, findings related to the dose–response data should be treated as exploratory and hypothesis-generating only.
Data from this study suggested a favorable safety profile for oral zavegepant administered at doses up to 200 mg for the preventive treatment of chronic migraine for up to 64 weeks. No new safety signals were identified from those reported for zavegepant administered as a nasal spray in the acute treatment of migraine [9–11]. In general, the incidence of AEs and laboratory abnormalities was similar for the zavegepant 100 and 200 mg groups, with the exception of zavegepant-related AEs during DBT, which were more frequent in the zavegepant 100 mg group (12.1%) than the zavegepant 200 mg group (8.0%). Reassuringly, there were low rates of SAEs (< 3% in both DBT and the OLE). Liver safety was also similar to that reported for zavegepant nasal spray; there were no hepatic-related AEs that led to zavegepant discontinuation during DBT, and only 1 (0.7%) participant experienced a hepatic-related AE during the OLE that led to zavegepant discontinuation. There were few instances of elevated liver enzymes, and no participants had AST or ALT elevations > 3 × ULN concurrent with total bilirubin > 2 × ULN during DBT and the OLE. Furthermore, there were no notable differences between instances of ALT or AST elevations between zavegepant 100 mg and placebo.
This study had important limitations that should be considered when interpreting the findings. Most importantly, this study was terminated early, which precludes definitive statements about dose–response and achieving study objectives. We also observed a large placebo response in efficacy, quality of life, and migraine-related disability measures. Placebo responses in preventive migraine trials are known to have increased between 1990 and 2021 [16]. A high placebo response can be problematic because it both reduces the placebo-subtracted response rate and increases the number of participants needed to discern the true clinical effect of an intervention [17, 18]. The mechanisms underlying the placebo effect/response are multifaceted and affected by numerous psychological, physiological, and contextual factors. As different capsule quantities per dose were used in this study to match zavegepant treatment groups, it is possible both the placebo-subtracted response rate and the apparent greater clinical benefit with the lower dose of zavegepant were affected leading to the apparent non-monotonic nature of the observed dose response. Nevertheless, on the basis of the data collected, the results suggest an oral formulation of zavegepant may be a viable option for migraine prevention if further development were to occur.
Conclusions
Oral zavegepant, at daily doses of 100 mg or 200 mg for up to 1 year, had a favorable safety and tolerability profile in this study of the preventive treatment of chronic migraine. Additional research is needed to determine the effectiveness of oral zavegepant as a preventive migraine treatment.
Acknowledgements
The authors would like to thank the participants of this study.
Medical Writing/Editorial Assistance
Medical writing support was provided by Leon Adams, PhD, CMPP, of Engage Scientific Solutions and was funded by Pfizer.
Author Contributions
All authors; Robert J. Fountaine, Sergey Dubrovin, Linda Mosher, Jing Liu, Mohamed H. Shahin and Terence Fullerton contributed to data analysis, visualization, data interpretation, supervision, funding, drafting of the manuscript, manuscript review and revision, and approval of the completed manuscript.
Funding
This study was sponsored by Pfizer, who also funded the journals Rapid Service and Open Access.
Data Availability
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.
Declarations
Conflict of Interest
Robert J. Fountaine, Sergey Dubrovin, Linda Mosher, Jing Liu, Mohamed H. Shahin and Terence Fullerton are employed by and own stock/stock options in Pfizer Inc.
Ethical Approval
This study was conducted in accordance with Good Clinical Practice guidelines, the Declaration of Helsinki and all applicable local regulations. The protocol was approved by an Institutional Review Board/Independent Ethics Committee prior to initiation. All participants provided written informed consent prior to participating in the study. With the exception of 1 site that used a local IRB, the remaining sites utilized Advarra, the central IRB. The site that utilized the local IRB did not randomize any subjects into the trial.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.