Prevention and treatment of migraine

Abstract

The present disclosure provides medicaments and methods for the prophylactic treatment of migraine, in particular the prophylactic or prophylactic treatment of chronic migraine.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to the following U.S. Provisional Applications: U.S. Provisional Application No. 63 / 269,105, filed on March 9, 2022; U.S. Provisional Application No. 63 / 347,265, filed on May 31, 2022; U.S. Provisional Application No. 63 / 404,352, filed on September 7, 2022; and U.S. Provisional Application No. 63 / 480,365, filed on January 18, 2023. The contents of each of these applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to medicaments and methods for treating migraine, particularly for preventing or prophylactically treating chronic migraine. Background Art

[0004] Migraine is a highly prevalent, severe and disabling neurological disease with a significant unmet need for effective treatments. (Holland, PR and Goadsby, PJ, Neurotherapeutics, 2018). Migraine affects more than one billion people worldwide and was reported as the second leading cause of disability in the 2016 Global Burden of Disease Study. See GBD 2019 Disease and Injury Collaborators. Global Burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systemic analysis for the Global Burden of Disease Study 2019, Lancet, 2020, Vol. 396: pp. 1204-1222.

[0005] Chronic migraine represents a particularly debilitating type of migraine. Chronic migraine can be severely disabling and difficult to control. Compared with patients with episodic migraine, patients with chronic migraine experience more frequent headaches, comorbid pain and affective disturbances, and fewer pain-free intervals. Diener et al., "Chronic migraine--classification, characteristics and treatment.", Nat Rev Neurol., February 14, 2012, Vol. 8, No. 3: pp. 162-171; see also Agosti, "Migraine Burden of Disease: From the Patient's Experience to a Socio-Economic View", Headache: The Journal of Head and Face Pain, Vol. 58: pp. 17-32 (2018).

[0006] Current preventive treatments for chronic migraine include botulinum toxin type A, topiramate, or monoclonal antibodies targeting calcitonin gene-related peptide (CGRP). There remains a need for methods and dosing regimens for oral CGRP therapy for the preventive treatment of chronic migraine. Summary of the invention

[0007] In an embodiment, the present disclosure provides a method for preventing and treating chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to a patient in need thereof. In an embodiment, atrogepam is administered in an amount of 30 mg twice daily. In an embodiment, atrogepam is administered in an amount of 60 mg once daily.

[0008] In embodiments, the disclosure provides methods for statistically significant treatment of migraine in a patient in need thereof, wherein the migraine is a chronic migraine. In embodiments, the method comprises administering atrogepam or a pharmaceutically acceptable salt thereof to each patient in an amount of 30 mg twice daily or 60 mg once daily, wherein said treatment achieves a statistically significant least squares mean difference in the number of migraine days per month from baseline to week 12 of said treatment in said patient compared to placebo. In embodiments, treatment with atrogepam also achieves a statistically significant improvement in one or more of:

[0009] (a) change from baseline in mean number of headache days per month;

[0010] (b) change from baseline in mean monthly acute medication use days;

[0011] (c) the proportion of patients who achieved a reduction of at least 50% in the mean number of migraine days per month over 3 months;

[0012] (d) change from baseline in the MSQ v2.1 role function limitation domain score;

[0013] (e) change from baseline in mean monthly daily activities performance domain score on the Migraine Activity Impairment Diary (AIM-D);

[0014] (f) change from baseline in the mean monthly physical impairment domain score on the AIM-D; or

[0015] (g) Change from baseline in HIT-6 (Headache Impact Test) total score.

[0016] In an embodiment, the present disclosure provides a method for the prophylactic treatment of chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to a patient in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves a statistically significant reduction from baseline in the average number of migraine days per month. In an embodiment, treatment with atrogepam also achieves a statistically significant improvement in one or more of the following:

[0017] (h) change from baseline in mean number of headache days per month;

[0018] (i) change from baseline in mean monthly acute medication use days;

[0019] (j) the proportion of patients who achieved a reduction of at least 50% in the mean number of migraine days per month over 3 months;

[0020] (k) change from baseline in the MSQ v2.1 role function limitation domain score;

[0021] (l) change from baseline in mean monthly daily activities performance domain score on the Migraine Activity Impairment Diary (AIM-D);

[0022] (m) change from baseline in the mean monthly physical impairment domain score on the AIM-D; or

[0023] (n) Change from baseline in HIT-6 (Headache Impact Test) total score. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 A schematic diagram of the phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted to evaluate the efficacy, safety, and tolerability of atrogepam in the prevention of chronic migraine is provided.

[0025] Figure 2AThe least square mean change (+ / - SE) from baseline in monthly migraine days (MMRM) during the double-blind treatment period in the modified intent-to-treat (mITT) population is shown. Both atrogepam doses (30 mg twice daily and 60 mg once daily) demonstrated statistical and clinical improvement in the change from baseline in monthly migraine days (primary efficacy endpoint). Figure 2B The distribution of mean MMD changes from baseline over the 12-week treatment period by treatment group is shown, in 2-day increments. Across a range of mean changes from baseline in MMD, a treatment benefit of 60 mg atrogepam compared with placebo was observed.

[0026] Figure 3 The least square mean change (+ / - SE) from baseline in the number of headache days per month (MMRM) during the double-blind treatment period for the mITT population is shown. This analysis demonstrated that treatment with 60 mg once daily and 30 mg twice daily atrogepam resulted in a statistically and clinically significant improvement in the number of headache days per month.

[0027] Figure 4 The least square mean change (+ / - SE) from baseline in acute medication use days (MMRM) during the double-blind treatment period for the mITT population is shown. This analysis demonstrated that treatment with 60 mg once daily and 30 mg twice daily atrogepam resulted in a statistically and clinically significant improvement in acute medication use days per month.

[0028] Figure 5 The cumulative distribution function of the percent reduction from baseline in the mean number of migraine days per month over 3 months for the mITT population is shown. This analysis demonstrated that treatment with 60 mg once daily and 30 mg twice daily atrogepam resulted in a statistically and clinically significant improvement in the mean number of migraine days per month over 3 months.

[0029] Figure 6 Mean changes from baseline in monthly migraine days and weekly migraine days (inset) during Weeks 1-4 are shown for 30 mg BID atrogepam and 60 mg QD atrogepam versus placebo. In adults with CM, atrogepam demonstrated an early and sustained reduction in migraine days. Results showed a statistically significant effect of treatment during each week of the first 4-week interval, as well as as early as the first full day after study drug initiation.

[0030] Figure 7 shows the proportion of patients with MMD reduction of ≥30%, ≥50%, ≥75%, or 100% at weeks 1-4, 5-8, and 9-12 for patients treated with 30 mg BID atrogepam, 60 mg QD atrogepam, and placebo. Both atrogepam dosing regimens increased the proportion of participants with CM who achieved a mean MMD reduction of ≥30%, ≥50%, ≥75%, or ≥100% within 12 weeks. A higher proportion of participants with CM treated with atrogepam reported overall improvements in PGI-C and treatment satisfaction.

[0031] Figure 8 Changes from baseline in AIM-D daily activities performance are shown for Weeks 1-4, Weeks 5-8, and Weeks 9-12, and over 12 weeks. Treatment with 60 mg once daily and 30 mg twice daily atrogepam demonstrated statistically significant improvements from baseline in AIM-D PDA (least squares mean difference [LSMD]: 30 mg BID, -4.85 [95% CI: -6.75, -2.95]; 60 mg QD, -3.38 [-5.27, -1.49]; P < .001) and PI (LSMD: 30 mg BID, -4.19 [95% CI: -5.95, -2.43]; 60 mg QD, -2.71 [-4.47, -0.96]; P < .01) domain scores relative to placebo throughout the 12-week treatment period.

[0032] Fig. 9 Changes from baseline in WAPI total work productivity loss are shown for Weeks 1-4, Weeks 5-8, and Weeks 9-12. Both doses of atrogepam (30 mg BID and 60 mg QD) demonstrated nominally significant improvements in attendance, total work productivity loss, and activity impairment at all time points for both doses versus placebo, as well as nominally significant improvements in absenteeism at Weeks 4 and 12 (p<.05).

[0033] Fig.10 Changes from baseline in the MSQ Role Functioning Limitation domains are shown at Weeks 4, 8, and 12. Increases (improvements) from baseline in the three MSQ domain scores were significantly greater in both atrogepam treatment groups (30 mg BID and 60 mg QD) compared to placebo.

[0034] Fig.11The mean MMD change from baseline for participants with and without acute medication overuse headache is shown throughout the 12-week treatment period. Among those with acute medication overuse at baseline, the least squares mean (LSM) of the mean MMD change from baseline for participants treated with atrogepam (30 mg BID and 60 mg QD) was -8.3 and -7.5, compared to -5.6 in the placebo group. Regardless of acute medication overuse at baseline, atrogepam was shown to be effective and was associated with a greater reduction in acute medication use days in people with chronic migraine.

[0035] Fig.12 Data are shown for patients treated with 30 mg BID atrogepam, 60 mg QD atrogepam, and placebo who experienced a reduction from baseline in mean weekly migraine days during the first month of administration.

[0036] Fig.13 Shown are the proportions (%) of patients treated with 30 mg BID atrogepam, 60 mg QD atrogepam, and placebo who experienced a one-day migraine during the first week of treatment.

[0037] Fig.14 A revised schematic diagram of the phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted to evaluate the efficacy, safety, and tolerability of atrogepam in the prevention of chronic migraine is provided.

[0038] Fig.15 Changes from baseline in WAPI attendance are shown for Weeks 1-4, Weeks 5-8, and Weeks 9-12. Both doses of atrogepam (30 mg BID and 60 mg QD) demonstrated nominally significant improvements in attendance, total work productivity loss, and activity impairment at all time points for both doses versus placebo, as well as nominally significant improvements in absenteeism at Weeks 4 and 12 (p<.05).

[0039] Fig.16 Changes from baseline in AIM-D physical impairment are shown for Weeks 1-4, Weeks 5-8, and Weeks 9-12, and over 12 weeks. Treatment with 60 mg once daily and 30 mg twice daily atrogepam showed statistically significant improvements (i.e., decreases) in AIM-D PI from baseline throughout the 12-week treatment period (least squares mean difference [LSMD]).

[0040] Fig.17Changes from baseline in WPAI absence are shown for Weeks 1-4, Weeks 5-8, and Weeks 9-12. Both doses of atrogepam (30 mg BID and 60 mg QD) demonstrated nominally significant improvements in attendance, total work productivity loss, and activity impairment at all time points for both doses versus placebo, as well as nominally significant improvements in absence at Weeks 4 and 12 (p<.05).

[0041] Fig.18 Changes from baseline in WPAI disability are shown for Weeks 1-4, Weeks 5-8, and Weeks 9-12. Both doses of atrogepam (30 mg BID and 60 mg QD) demonstrated nominally significant improvements in attendance, total work productivity loss, and disability at all time points for both doses versus placebo, as well as nominally significant improvements in absence at Weeks 4 and 12 (p<.05).

[0042] Fig.19 Figures are provided describing the disposition of participants in each period of a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of atrogepam in the prevention of chronic migraine.

[0043] Fig. 20 Changes from baseline in the MSQ emotional functioning domain at Weeks 4, 8, and 12 are shown.

[0044] Fig.21 Changes from baseline in the MSQ Role Functioning Impairment domain at Weeks 4, 8, and 12 are shown.

[0045] Fig. 22 Shown are changes from baseline in Headache Impact Test (HIT-6) scores for both doses of atrogepam (30 mg BID and 60 mg QD) relative to placebo at Weeks 4, 8, and 12. Both doses showed statistically significant improvements relative to placebo at Week 12 (P<0.001), and nominally significant improvements relative to placebo at Weeks 4 and 8 (nominal P<0.001).

[0046] Fig.23 Participants were shown to have sustained responses at months 2-3, with an initial response of ≥30% or ≥50% reduction in mean MMD.

[0047] Fig.24 The percentage of initial non-responders who experienced a ≥30% or ≥50% reduction in mean MMD in subsequent months is shown.

[0048] FIG. 25 shows the change from baseline in AIM-D (A) daily activities performance and (B) physical impairment at Weeks 1, 2, 3, and 4.

[0049] FIG. 26 shows the change from baseline in EQ-5D-5L (A) descriptive system index and (B) visual analog scale scores at Weeks 1-2 and 4. DETAILED DESCRIPTION

[0050] Migraine is a debilitating condition that affects 14% of the population and can be classified as either episodic migraine (EM) or chronic migraine (CM). Chronic migraine is a debilitating neurological condition in which the patient experiences headaches on 15 or more days per month for more than three months, with the patient having features of migraine on at least eight days per month. Episodic migraine is characterized by headaches occurring less than 15 days per month. Lipton et al., "Episodic and chronic migraine headache: breaking down barriers to optimal treatment and prevention," Headache, March 2015; Vol. 55, No. 2 (Suppl.): pp. 103-122; quiz 123-6; Headache Classification Committee., Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, H, Lainez MJ, Lance JW, Lipton RB, Nappi G, Sakai F, Schoenen J, Silberstein SD, Steiner TJ Cephalalgia., June 2006; Vol. 26, No. 6: pp. 742-746.

[0051] Beyond the 15-day threshold, chronic migraine differs from episodic migraine in terms of both disease burden and treatment needs for patients. See Ishii et al., “Chronic versus episodic migraine: The 15-day threshold does not adequately reflect substantial differences in disability across the full spectrum of headache frequency.” Headache, July 2021; Vol. 61, No. 7: pp. 992-1003. Chronic migraine is particularly debilitating and difficult to control. Clinical and population-based studies have shown that chronic migraine results in greater migraine-related disability and headache-related quality of life impairment compared with episodic migraine. Chronic migraine is associated with higher rates of comorbidities, higher indirect and indirect costs, and different counseling and treatment patterns compared with episodic migraine. Buse et al., “Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers,” Journal of Neurology, Neurosurgery & Psychiatry, 2010, 81: 428-432; Mungoven et al., “Chronic Migraine Pathophysiology and Treatment: A Review of Current Perspectives.”, Front. Pain Res., August 25, 2021.

[0052] In an embodiment, the present disclosure provides a method for preventive or prophylactic treatment of chronic migraine. In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine (such as the prophylactic treatment of chronic migraine), which includes oral administration of an effective amount of an oral CGRP receptor antagonist. In an embodiment, the CGRP receptor antagonist is atrogepam. The chemical name of atrogepam is (S)-N-((3S, 5S, 6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl) piperidin-3-yl)-2'-oxo-1', 2', 5,7-tetrahydrospiro [cyclopentene [b] pyridine -6,3'-pyrrolo [2,3-b] pyridine] -3-carboxamide, and it has the following structural formula:

[0053]

[0054] The molecular formula is C 29 H 23 F6N5O3, and a molecular weight of 603.5. Atrogepam is a small molecule calcitonin-related peptide (CGRP) receptor antagonist that blocks the binding of CGRP to the receptor and antagonizes CGRP receptor function. Atrogepam can be administered orally, reaching maximum plasma concentration after 2 hours, with a half-life of approximately 11 hours.

[0055] In an embodiment, a patient in need of treatment for chronic migraine meets the definition of chronic migraine as listed in the International Classification of Headache Disorders, 3rd edition (ICHD-3).

[0056] Preventive or prophylactic treatments may reduce the frequency and / or intensity of migraine attacks. In embodiments, the preventive or prophylactic treatment methods of the present disclosure may reduce the frequency and / or intensity of migraine attacks. In embodiments, the preventive or prophylactic treatment methods of the present disclosure may reduce the frequency and / or intensity of symptoms associated with migraine attacks, including headaches. In embodiments, administration of atrogepam may provide fewer migraine symptoms or symptoms of reduced intensity. In embodiments, non-headache symptoms of migraine may be reduced or eliminated. In embodiments, the preventive methods of the present disclosure may avoid symptoms associated with migraine attacks, including headaches. In embodiments, the preventive methods of the present disclosure include the entire range of symptoms experienced by a patient during a migraine attack, and include more than just prevention of headaches associated with a migraine attack.

[0057] In embodiments, patients in need of treatment for chronic migraine headaches may suffer from one or more symptoms of migraine headaches, including, for example, sinusitis, nausea, nasopharyngitis, photophobia, changes in appetite, cognitive and concentration difficulties, cold hands and feet, diarrhea or other bowel changes, excitement or irritability, fatigue, frequent urination, memory changes, weakness, yawning, stretching, seeing bright or flashing lights, loss of vision, seeing dark spots, tingling sensations, speech disorders, aphasia, tinnitus, gastric retention, pulsating or throbbing pain on one or both sides of the head, extreme sensitivity to light, sound or smell, pain worsening during physical activity, and vomiting, abdominal pain or heartburn, loss of appetite, dizziness, cataracts, and fainting. In embodiments, administration of a prophylactically effective amount of atrogepam results in improvement, reduction in frequency, or reduction in intensity of symptoms.

[0058] In an embodiment, the present disclosure provides a method for the prophylactic or preventive treatment of chronic migraine, the method comprising administering a therapeutically effective amount of atrogepam or a pharmaceutically acceptable salt thereof to a patient in need thereof. In an embodiment, atrogepam is orally administered at a once daily (QD) dose of 60 mg or a twice daily (BID) dose of 30 mg. In an embodiment, atrogepam is orally administered at a once daily (QD) dose of 60 mg. In an embodiment, atrogepam is orally administered at a twice daily (BID) dose of 30 mg.

[0059] In an embodiment, atrogepam is orally administered at a once daily dose of 60 mg for at least about 1 week, or at least about 2 weeks, or at least about 3 weeks, or at least about 4 weeks, or at least about 8 weeks, or at least about 12 weeks, or at least about 16 weeks, or at least about 20 weeks, or at least about 24 weeks, or at least about 28 weeks, or at least about 32 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 44 weeks, or at least about 48 weeks, or at least about 52 weeks. In an embodiment, atrogepam is administered for at least about one month, or at least about two months, or at least about three months.

[0060] In an embodiment, atrogepam is orally administered at a dose of 30 mg twice daily (i.e., BID) for at least about 1 week, or at least about 2 weeks, or at least about 3 weeks, or at least about 4 weeks, or at least about 8 weeks, or at least about 12 weeks, or at least about 16 weeks, or at least about 20 weeks, or at least about 24 weeks, or at least about 28 weeks, or at least about 32 weeks, or at least about 36 weeks, or at least about 40 weeks, or at least about 44 weeks, or at least about 48 weeks, or at least about 52 weeks. In an embodiment, atrogepam is administered for at least about one month, or at least about two months, or at least about three months.

[0061] In embodiments, treatment with 30 mg BID or 60 mg QD of atrogepam for the prophylactic treatment of chronic migraine achieves a statistically significant change from baseline in the mean number of migraine days per month. In embodiments, treatment with atrogepam achieves a statistically significant change from baseline in the mean number of headache days per month. In embodiments, treatment with atrogepam achieves a reduction in the mean number of migraine days per month over 3 months of at least 50% in a statistically significant proportion of subjects. In embodiments, treatment with atrogepam achieves a statistically significant change from baseline in the MSQ v2.1 Role Functioning Limitation domain score. In embodiments, treatment with atrogepam achieves a statistically significant change from baseline in the mean monthly Performance of Daily Activities domain score of the AIM-D. In embodiments, treatment with atrogepam achieves a statistically significant change from baseline in the mean monthly Physical Disability domain score of the AIM-D. In embodiments, treatment with atrogepam achieves a statistically significant change from baseline in the HIT-6 total score.

[0062] In the embodiment, during the 12-week treatment period, treatment with atrogepam 30 mg BID or 60 mg QD for the preventive treatment of chronic migraine achieved a statistically significant reduction from baseline in the mean monthly migraine days over the entire 12-week treatment period, a statistically significant change from baseline in the mean monthly acute medication use days over the entire 12-week treatment period, a statistically significant proportion of patients achieving at least a 50% reduction in the mean monthly migraine days over 3 months, a statistically significant change from baseline in the MSQv2.1 Role Functioning Limitation domain score at 12 weeks, a statistically significant change from baseline in the mean monthly Performance of Daily Activities domain score of the AIM-D over the entire 12-week treatment period, and a statistically significant change from baseline in the mean monthly Physical Impairment domain score of the AIM-D over the entire 12-week treatment period.

[0063] In embodiments, treatment with atrogepam at 30 mg BID or 60 mg QD for the preventive treatment of chronic migraine during the 12-week treatment period achieved a statistically significant reduction from baseline in the mean monthly migraine days over the entire 12-week treatment period, a statistically significant change from baseline in the mean monthly acute medication use days over the entire 12-week treatment period, a statistically significant proportion of patients achieving at least a 50% reduction in the mean monthly migraine days over 3 months, a statistically significant change from baseline in the HIT-6 total score at Week 12, and a statistically significant change from baseline in the MSQv2.1 Role Functioning Limitation domain score at Week 12.

[0064] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, such as the prophylactic treatment of chronic migraine, comprising administering atrogepam to one or more patients in need thereof in an amount of 60 mg once daily or 30 mg twice daily, wherein treatment with atrogepam achieves a reduction in mean monthly migraine days (MMD) from baseline. In embodiments, treatment with atrogepam achieves a reduction in mean monthly migraine days from baseline of at least about 6 days, or at least about 6.2 days, or at least about 6.4 days, or at least about 6.8 days, or at least about 7 days, or at least about 7.2 days, or at least about 7.4 days.

[0065] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to each of the patients in an amount of 60 mg once daily or 30 mg twice daily, and the treatment achieves a statistically significant least squares mean difference in monthly migraine days (MMD) from baseline of the treatment in the patient compared to placebo. In embodiments, treatment with atrogepam achieves a least squares mean difference in mean monthly migraine days from baseline to week 12 of at least about -1, or at least about -1.2, or at least about -1.4, or at least about -1.6, or at least about -1.8, or at least about -2, or at least about -2.2, or at least about -2.4 compared to placebo. In embodiments, treatment with atrogepam achieves a statistically significant improvement in migraine days from baseline within the first week of treatment, or within the first two weeks of treatment, or within the first three weeks of treatment, or within the first four weeks of treatment. In embodiments, treatment with atrogepam achieves an improvement from baseline as early as the first full day after initiating treatment with atrogepam.

[0066] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily, resulting in a reduction in the average number of migraine days per month. In embodiments, treatment with 30 mg twice daily atrogepam achieves a reduction in the average number of migraine days per month from baseline of at least about 6 days, or at least about 6.2 days, or at least about 6.4 days, or at least about 6.8 days, or at least about 7 days, or at least about 7.2 days, or at least about 7.4 days. In embodiments, the present disclosure provides a method for the prophylactic treatment of chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily, wherein treatment with atrogepam results in a reduction in the average number of migraine days per month from baseline of about 7.3 days over the entire 12-week treatment period. In embodiments, the present disclosure provides a method for the prophylactic treatment of chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily, wherein treatment with atrogepam achieves a reduction from baseline in the average number of migraine days per month of about 7.4 days over the entire 12-week treatment period. In embodiments, treatment with atrogepam achieves a statistically significant improvement from baseline in the number of migraine days within the first week of treatment, or within the first two weeks of treatment, or within the first three weeks of treatment, or within the first four weeks of treatment. In embodiments, treatment with atrogepam achieves an improvement from baseline as early as the first full day after initiation of treatment with atrogepam.

[0067] In embodiments, the present disclosure provides a method for prophylactic treatment of migraine in a patient in need thereof, wherein the migraine is chronic migraine, comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 30 mg twice daily, and wherein the treatment achieves a statistically significant least squares mean difference in the mean monthly migraine days from baseline of the treatment in the patient compared to placebo. In embodiments, treatment with atrogepam achieves a least squares mean difference in the mean monthly migraine days from baseline of the treatment to week 12 of at least about -1, or at least about -1.2, or at least about -1.4, or at least about -1.6, or at least about -1.8, or at least about -2, or at least about -2.2, or at least about -2.4 compared to placebo. In embodiments, treatment with atrogepam achieves a least squares mean difference in the mean monthly migraine days from baseline of the treatment to week 12 of at least about -2.2 compared to placebo. In embodiments, treatment with atrogepam achieves a least squares mean difference in mean monthly migraine days from baseline to week 12 of said treatment of at least about -2.4 compared to placebo throughout the 12-week treatment period. In embodiments, treatment with atrogepam achieves a statistically significant improvement from baseline in migraine days within the first week of treatment, or within the first two weeks of treatment, or within the first three weeks of treatment, or within the first four weeks of treatment. In embodiments, treatment with atrogepam achieves an improvement from baseline as early as the first full day after initiation of treatment with atrogepam.

[0068] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 60 mg QD, resulting in a reduction in the average number of migraine days per month. In an embodiment, treatment with 60 mg QD atrogepam achieves a reduction in the average number of migraine days per month from baseline of at least 6 days, or at least about 6.2 days, or at least about 6.4 days, or at least about 6.8 days. In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 60 mg once daily, wherein treatment with atrogepam achieves a reduction in the average number of migraine days per month from baseline of about 6.7 days throughout the 12-week treatment period. In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 60 mg QD, wherein treatment with atrogepam achieves a reduction from baseline in the average number of migraine days per month of about 6.8 days over the entire 12-week treatment period. In embodiments, treatment with atrogepam achieves a statistically significant improvement from baseline in the number of migraine days within the first week of treatment, or within the first two weeks of treatment, or within the first three weeks of treatment, or within the first four weeks of treatment. In embodiments, treatment with atrogepam achieves an improvement from baseline as early as the first full day after initiation of treatment with atrogepam.

[0069] In embodiments, the present disclosure provides a method for prophylactic treatment of migraine in a patient in need thereof, wherein the migraine is chronic migraine, comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 60 mg once daily, and wherein the treatment achieves a statistically significant least squares mean difference in the mean number of monthly migraine days from baseline of the treatment to week 12 in the patient compared to placebo. In embodiments, treatment with atrogepam achieves a least squares mean difference in the mean number of monthly migraine days from baseline of the treatment to week 12 of at least about -1, or at least about -1.2, or at least about -1.4, or at least about -1.6, or at least about -1.8 compared to placebo. In embodiments, treatment with atrogepam achieves a least squares mean difference in the mean number of monthly migraine days from baseline of the treatment to week 12 of about -1.8 compared to placebo. In embodiments, treatment with atrogepam achieves a statistically significant improvement from baseline in migraine days within the first week of treatment, or within the first two weeks of treatment, or within the first three weeks of treatment, or within the first four weeks of treatment. In embodiments, treatment with atrogepam achieves an improvement from baseline as early as the first full day after initiation of treatment with atrogepam.

[0070] In embodiments, the present disclosure provides a method for the prevention and treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need in an amount of 30 mg BID, wherein treatment with atrogepam results in a reduction of ≥30% in the average number of migraine days per month (MMD). In embodiments, a statistically significant greater number of patients treated with 30 mg BID atrogepam achieved a reduction of ≥30% in the average number of migraine days per month compared to placebo throughout the 12-week treatment period. In embodiments, at least about 50% of patients treated with atrogepam, or at least about 55% of patients treated with atrogepam, or at least about 60% of patients treated with atrogepam, or at least about 61% of patients treated with atrogepam, or at least about 62% of patients treated with atrogepam achieved a reduction of ≥30% in MMD throughout the 12-week treatment period.

[0071] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 30 mg BID, wherein treatment with atrogepam results in a reduction of ≥50% in the average number of migraine days per month. In embodiments, a statistically significant greater number of patients treated with 30 mg BID atrogepam achieved a reduction of ≥50% in the average number of migraine days per month compared to placebo throughout the 12-week treatment period. In embodiments, at least about 30% of patients treated with atrogepam, or at least about 35%, or at least about 37%, or at least about 40%, or at least about 41%, or at least about 42% of patients treated with atrogepam achieved a reduction of ≥50% in MMD throughout the 12-week treatment period.

[0072] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 30 mg BID, wherein treatment with atrogepam results in a reduction of ≥75% in the average number of migraine days per month. In embodiments, a statistically significant greater number of patients achieves a reduction of ≥75% in the average number of migraine days per month compared to placebo throughout the 12-week treatment period. In embodiments, at least about 10%, or at least about 15%, or at least about 16%, or at least about 17%, or at least about 18%, or at least about 19%, or at least about 20%, or at least about 21% of patients treated with atrogepam achieve a reduction of at least ≥75% in MMD throughout the 12-week treatment period.

[0073] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 60 mg QD, wherein treatment with atrogepam results in a reduction of ≥30% in the average number of migraine days per month. In an embodiment, a statistically significantly greater number of patients treated with atrogepam achieve a reduction of ≥30% in the average number of migraine days per month compared to placebo. In an embodiment, at least about 50%, or at least about 55%, or at least about 56%, or at least about 57%, or at least about 58%, or at least about 59% of patients treated with atrogepam achieve a reduction of ≥30% in the average number of migraine days per month throughout the 12-week treatment period.

[0074] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 60 mg QD, wherein treatment with atrogepam achieves a reduction of ≥50% in the average number of migraine days per month. In an embodiment, a statistically significant greater number of patients treated with atrogepam achieve a reduction of ≥50% in the average number of migraine days per month compared to placebo. In an embodiment, at least about 30%, or at least about 35%, or at least about 36%, or at least about 37%, or at least about 38%, or at least about 39%, or at least about 40%, or at least about 41% of patients treated with atrogepam achieve a reduction of ≥50% in the average number of migraine days per month throughout the 12-week treatment period.

[0075] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 60 mg QD, wherein treatment with atrogepam achieves a ≥75% reduction in the average number of migraine days per month. In an embodiment, a statistically significantly greater number of patients treated with atrogepam achieve a ≥75% reduction in the average number of migraine days per month compared to placebo. In an embodiment, at least about 10%, or at least about 15%, or at least about 16%, or at least about 17%, or at least about 18% of patients treated with atrogepam achieve a ≥75% reduction in the average number of migraine days per month throughout the 12-week treatment period.

[0076] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, such as the prophylactic treatment of chronic migraine, comprising administering atrogepam in an amount of 60 mg once daily (QD) or 30 mg twice daily (BID) to one or more patients in need thereof, wherein treatment with atrogepam achieves a reduction from baseline in the average number of headache days per month. In embodiments, treatment with 30 mg BID or 60 mg QD atrogepam achieves a reduction in the average number of headache days per month of at least about 6 days, or at least about 6.5 days, or at least about 6.7 days, or at least about 6.9 days, or at least about 7 days, or at least about 7.2 days, or at least about 7.3 days, or at least about 7.4 days.

[0077] In embodiments, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to each of said patients in an amount of 60 mg once daily or 30 mg twice daily, and wherein said treatment achieves a statistically significant least squares mean difference in the number of headache days per month from baseline of said treatment to week 12 in said patient as compared to placebo. In embodiments, treatment with atrogepam achieves a least squares mean difference in the mean number of headache days per month from baseline of said treatment to week 12 as compared to placebo of at least about -1, or at least about -1.2, or at least about -1.4, or at least about -1.5, or at least about -1.6, or at least about -1.7, or at least about -1.8, or at least about -1.9, or at least about -2, or at least about -2.1, or at least about -2.2, or at least about -2.3.

[0078] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily, and wherein treatment with atrogepam achieves a reduction from baseline in the average number of headache days per month. In embodiments, treatment with 30 mg twice daily atrogepam achieves a reduction in the average number of headache days per month of at least about 6 days, or at least about 6.5 days, or at least about 6.7 days, or at least about 6.9 days, or at least about 7 days, or at least about 7.2 days, or at least about 7.3 days, or at least about 7.4 days. In embodiments, treatment with 30 mg BID atrogepam achieves a reduction from baseline in the average number of headache days per month of at least about 7.3 days throughout the 12-week treatment period. In embodiments, treatment with 30 mg BID atrogepam achieves a reduction from baseline in the average number of headache days per month of at least about 7.4 days throughout the 12-week treatment period.

[0079] In embodiments, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering to the patient atrogepam or a pharmaceutically acceptable salt thereof in an amount of 30 mg twice daily, and wherein the treatment achieves a statistically significant least squares mean difference in the number of headache days per month from baseline of the treatment to week 12 in the patient as compared to placebo. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in the mean number of headache days per month from baseline to week 12 as compared to placebo of at least about -1, or at least about -1.2, or at least about -1.4, or at least about -1.5, or at least about -1.6, or at least about -1.7, or at least about -1.8, or at least about -1.9, or at least about -2, or at least about -2.1, or at least about -2.2, or at least about -2.3. In embodiments, treatment with 30 mg twice daily atrogepam achieves a least squares mean difference in mean monthly headache days from baseline to week 12 of about -2.1 compared to placebo. In embodiments, treatment with 30 mg twice daily atrogepam achieves a least squares mean difference in mean monthly headache days from baseline to week 12 of about -2.3 compared to placebo.

[0080] In embodiments, the disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 60 mg once daily, wherein treatment with atrogepam achieves a reduction from baseline in the average number of headache days per month. In embodiments, treatment with 60 mg of atrogepam once daily results in a reduction in the average number of headache days per month of at least about 6 days, or at least about 6.5 days, or at least about 6.7 days, or at least about 6.9 days, or at least about 7 days. In embodiments, treatment with 60 mg of atrogepam achieves a reduction from baseline in the average number of headache days per month of at least about 6.9 days throughout the 12-week treatment period. In embodiments, treatment with 60 mg of atrogepam achieves a reduction from baseline in the average number of headache days per month of at least about 7 days throughout the 12-week treatment period.

[0081] In embodiments, the disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 60 mg once daily, and wherein the treatment achieves a statistically significant least squares mean difference in the number of headache days per month from baseline to week 12 of the treatment compared to placebo. In embodiments, treatment with 60 mg once daily atrogepam achieves a least squares mean difference in the mean number of headache days per month from baseline to week 12 of at least about -1, or at least about -1.2, or at least about -1.4, or at least about -1.5, or at least about -1.6, or at least about -1.7, or at least about -1.8 compared to placebo. In embodiments, treatment with 60 mg once daily atrogepam achieves a least squares mean difference in the mean number of headache days per month from baseline to week 12 of about -1.7 compared to placebo. In embodiments, treatment with 60 mg once daily atrogepam achieved a least squares mean difference in mean monthly headache days from baseline to week 12 of about -1.8 compared to placebo.

[0082] In an embodiment, treatment with 30 mg BID atrogepam or 60 mg QD atrogepam achieves a reduction in acute medication use days from baseline. In an embodiment, the present disclosure provides a method for the preventive treatment of chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves a change in the average monthly acute medication use days from baseline. In an embodiment, acute medication use days refers to the number of days a patient takes medication to treat acute migraine. Drugs used for the acute treatment of migraine include, for example, triptans, ergots, opioids, analgesics (including acetaminophen), NSAIDs (including aspirin), and antiemetics. In embodiments, treatment with 30 mg BID or 60 mg QD atrogepam achieves a reduction from baseline in mean monthly acute drug use days of at least about 5 days, or at least about 5.5 days, or at least about 6 days, or at least about 6.1 days, or at least about 6.2 days, or at least about 6.3 days, or at least about 6.4 days, or at least about 6.5 days, or at least about 6.6 days, or at least about 6.7 days.

[0083] In embodiments, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to each of said patients in an amount of 60 mg once daily or 30 mg twice daily, and wherein said treatment achieves a statistically significant least squares mean difference in the number of acute medication use days per month from baseline of said treatment to week 12 in said patient as compared to placebo. In embodiments, treatment with 30 mg BID atrogepam or 60 mg QD atrogepam achieves a least squares mean difference in the mean number of acute medication use days per month from baseline to week 12 as compared to placebo of at least about -1, or at least about -1.5, or at least -2, or at least -2.1, or at least -2.2, or at least -2.3, or at least -2.4, or at least -2.5, or at least -2.6.

[0084] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily, wherein treatment with atrogepam achieves a reduction in the average number of days of acute medication use per month from baseline. In embodiments, treatment with 30 mg twice daily atrogepam achieves a reduction in the average number of days of acute medication use per month from baseline of at least about 5 days, or at least about 5.5 days, or at least about 6 days, or at least about 6.1 days, or at least about 6.2 days, or at least about 6.3 days, or at least about 6.4 days, or at least about 6.5 days, or at least about 6.6 days, or at least about 6.7 days. In embodiments, treatment with 30 mg BID atrogepam achieves a reduction in the average number of days of acute medication use per month from baseline of at least about 6.6 days. In embodiments, treatment with 30 mg BID atrogepam achieves a reduction in the average number of days of acute medication use per month from baseline of at least about 6.7 days.

[0085] In embodiments, the present disclosure provides a method for prophylactic treatment of migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 30 mg twice daily, and wherein the treatment achieves a statistically significant least squares mean difference in the number of acute medication use days per month from baseline of the treatment to week 12 in the patient compared to placebo. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in the mean number of acute medication use days per month from baseline to week 12 compared to placebo of at least about -1, or at least about -1.5, or at least about -2, or at least about -2.1, or at least about -2.2, or at least about -2.3, or at least about -2.4, or at least about -2.5, or at least about -2.6. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in mean monthly acute medication use days from baseline to Week 12 of at least about -2.5 compared to placebo. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in mean monthly acute medication use days from baseline to Week 12 of at least about -2.6 compared to placebo.

[0086] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 60 mg once daily, wherein treatment with atrogepam achieves a reduction from baseline in the average number of days of acute medication use per month. In embodiments, treatment with 60 mg of atrogepam once daily results in a reduction in the average number of days of acute medication use of at least about 5 days, or at least about 5.5 days, or at least about 6 days, or at least about 6.1 days, or at least about 6.2 days. In embodiments, treatment with 60 mg of atrogepam once daily achieves a reduction from baseline in the average number of days of acute medication use of at least about 6.2 days throughout the 12-week treatment period.

[0087] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine in a patient in need thereof, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 60 mg once daily, and wherein the treatment achieves a statistically significant least squares mean difference in the number of days of acute medication use per month from baseline to week 12 of the treatment in the patient compared to placebo. In an embodiment, treatment with 60 mg QD atrogepam achieves a least squares mean difference in the mean number of days of acute medication use per month from baseline to week 12 of at least about -1, or at least about -1.5, or at least about -2, or at least about -2.1 compared to placebo. In an embodiment, treatment with 60 mg once daily atrogepam achieves a least squares mean difference in the mean number of days of acute medication use per month from baseline to week 12 of at least about -2.1 compared to placebo.

[0088] In embodiments, treatment with 30 mg BID atrogepam or 60 mg QD atrogepam achieves a reduction from baseline in the average number of migraine days per month over 3 months. In embodiments, the disclosure provides a method for the preventive treatment of migraine, wherein the migraine is chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves a reduction from baseline in the average number of migraine days per month over 3 months. In embodiments, there is a statistically significant change from baseline in the proportion of patients who achieve a ≥50% reduction in the average number of migraine days per month over 3 months with treatment with 30 mg twice daily or 60 mg once daily atrogepam.

[0089] In embodiments of the present disclosure, treatment with atrogepam results in an improvement (i.e., an increase) in the MSQ v2.1 Role Functioning Limitation domain score from baseline. In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves an increase in the MSQ v2.1 Role Functioning Limitation domain score from baseline. In embodiments, treatment with 30 mg twice daily or 60 mg once daily atrogepam achieves a statistically significant improvement in the MSQ v2.1 Role Functioning Limitation domain score from baseline.

[0090] The MSQv2.1 is a 14-item questionnaire designed to measure impairment in health-related quality of life caused by migraine in the past 4 weeks. It is divided into three domains: the role function limitation domain assesses how migraine limits people's daily social and work-related activities; the role function interference domain assesses how migraine interferes with these activities; and the emotional function domain assesses emotions related to migraine. Participants respond to the items using a 6-point scale ranging from "none of the time" to "all of the time." The original dimension scores are calculated as the sum of the item responses and are rescaled to a 0 to 100 scale, with higher scores indicating better quality of life.

[0091] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves an increase from baseline in the MSQv2.1 Role Functioning Limitation domain score of at least about 20 points, or at least about 21 points, or at least about 22 points, or at least about 23 points, or at least about 24 points, or at least about 25 points.

[0092] In embodiments, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to each of said patients in an amount of 60 mg once daily or 30 mg twice daily, and wherein said treatment achieves a statistically significant least squares mean difference in MSQ v2.1 Role Functioning Limitation domain score from baseline of said treatment to week 12 in said patient as compared to placebo. In embodiments, treatment with 30 mg BID atrogepam or 60 mg QD atrogepam achieves a least squares mean difference in MSQ v2.1 Role Functioning Limitation domain score as compared to placebo of at least about 4, at least about 4.5, or at least about 5, or at least about 5.5, or at least about 5.7, or at least about 6, or at least about 6.5, or at least about 7, or at least about 7.4, or at least about 7.5, or at least about 7.6, or at least about 7.7, or at least about 7.8, or at least about 7.9.

[0093] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily, wherein treatment with atrogepam achieves an increase from baseline in the MSQ v2.1 Role Functioning Limitation domain score. In embodiments, treatment with 30 mg twice daily atrogepam achieves an increase from baseline in the MSQ v2.1 Role Functioning Limitation domain score of at least about 20 points, or at least about 21 points, or at least about 22 points, or at least about 23 points, or at least about 24 points, or at least about 25 points. In embodiments, treatment with 30 mg twice daily atrogepam achieves an increase from baseline in the MSQ v2.1 Role Functioning Limitation domain score of at least about 24.7 at week 12 over a 12-week treatment period. In embodiments, treatment with 30 mg twice daily atrogepam achieves an increase from baseline in the MSQ v2.1 Role Functioning Limitation domain score of at least about 25 at week 12 over a 12-week treatment period.

[0094] In embodiments, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 30 mg twice daily, and wherein the treatment achieves a statistically significant least squares mean difference in MSQ v2.1 Role Functioning Limitation domain score from baseline of the treatment to week 12 in the patient compared to placebo. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in MSQ v2.1 Role Functioning Limitation domain score from baseline to week 12 compared to placebo of at least about 4, at least about 4.5, or at least about 5, or at least about 5.5, or at least about 5.7, or at least about 6, or at least about 6.5, or at least about 7, or at least about 7.4, or at least about 7.5, or at least about 7.6, or at least about 7.7, or at least about 7.8, or at least about 7.9. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in MSQ v2.1 Role Functioning Limitation domain score from baseline to Week 12 of at least about 7.4. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in MSQ v2.1 Role Functioning Limitation domain score from baseline to Week 12 of at least about 7.9.

[0095] In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 60 mg once daily, wherein treatment with atrogepam achieves an increase from baseline in the MSQ v2.1 Role Functioning Limitation domain score. In embodiments, treatment with 60 mg once daily atrogepam achieves an increase from baseline in the MSQ v2.1 Role Functioning Limitation domain score of at least about 20, or at least about 21, or at least about 22, or at least about 23. In embodiments, treatment with 60 mg QD atrogepam achieves an increase from baseline in the MSQ v2.1 Role Functioning Limitation domain score of at least about 22 at week 12 over a 12-week treatment period.

[0096] In embodiments, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 60 mg once daily, and wherein the treatment achieves a statistically significant least squares mean difference in MSQ v2.1 Role Functioning Limitation domain score from baseline to week 12 of the treatment in the patient compared to placebo. In embodiments, treatment with 60 mg QD atrogepam achieves a least squares mean difference in MSQ v2.1 Role Functioning Limitation domain score from baseline to week 12 of at least about 4, or at least about 4.5, or at least about 5, or at least about 5.5, or at least about 6 compared to placebo. In embodiments, treatment with 60 mg QD atrogepam achieves a least squares mean difference in MSQ v2.1 Role Functioning Limitation domain score from baseline to week 12 of at least about 6.1 compared to placebo.

[0097] In an embodiment of the present disclosure, treatment with atrogepam results in an improvement (reduction) in the average monthly daily activities performance domain score of the AIM-D scale from baseline. In an embodiment, the present disclosure provides a method for the preventive treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves an improvement in the average monthly daily activities performance domain score of the AIM-D scale from baseline. In an embodiment, treatment with atrogepam results in an improvement in the average monthly physical impairment domain score of the AIM-D scale from baseline. In an embodiment, the present disclosure provides a method for the preventive treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves an improvement in the average monthly physical impairment domain score of the AIM-D scale from baseline.

[0098] AIM-D (Migraine Activity Disorder Diary) is a daily diary measure of 11 functions that assess the impact of migraine. It consists of two domains that assess the performance of daily activities (PDA: 7 items) and physical impairment (PI: 4 items). Participants were asked to use a 6-point rating scale to rate the difficulties in the performance of daily activities (i.e., difficulties in doing housework, running errands, leisure activities at home, outdoor leisure social activities, strenuous physical activities, concentration and clear thinking) and physical impairment (i.e., walking, moving the body, bending forward, moving the head) experienced in the past 24 hours: "not difficult at all", "a little difficult", "a little difficult", "very difficult", "extremely difficult" and "I can't do it at all". Three items include the response of "I don't have ..." (i.e., "I don't have planned errands"). AIM-D was developed as an electronic daily diary, using the same set of questions in headache and non-headache versions. The original domain scores were rescaled to a 0 to 100 scale, with higher scores indicating greater migraine impact.

[0099] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves a reduction from baseline in the mean monthly performance in daily activities score on the AIM-D of at least about 11 points, or at least about 11.5 points, or at least about 12 points, or at least about 12.5 points, or at least about 13 points, or at least about 13.5 points, or at least about 14 points, or at least about 14.1 points, or at least about 14.2 points.

[0100] In an embodiment, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to each of said patients in an amount of 60 mg once daily or 30 mg twice daily, and wherein said treatment achieves a statistically significant least squares mean difference in mean monthly daily activities performance scores of the AIM-D from baseline to week 12 of said treatment in said patients compared to placebo. In embodiments, treatment with 30 mg BID atrogepam or 60 mg QD atrogepam achieves a least squares mean difference in mean monthly daily activities performance scores on the AIM-D from baseline to week 12 compared to placebo of at least about -1, or at least about -2, or at least about -2.5, or at least about -3, or at least about -3.3, or at least about -3.5, or at least about -3.8, or at least about -4, or at least about -4.5, or at least about -4.6, or at least about -4.7, or at least about -4.8.

[0101] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 30 mg twice daily, wherein treatment with atrogepam achieves a decrease in the average monthly daily activities performance score of AIM-D from baseline. In an embodiment, treatment with 30 mg twice daily atrogepam achieves a decrease in the average monthly daily activities performance score of AIM-D from baseline by at least about 11 points, or at least about 11.5 points, or at least about 12 points, or at least about 12.5 points, or at least about 13 points, or at least about 13.5 points, or at least about 14 points, or at least about 14.1 points, or at least about 14.2 points. In an embodiment, treatment with 30 mg BID of atrogepam achieves a decrease in the average monthly daily activities performance score of AIM-D from baseline by at least about 14.2 points.

[0102] In embodiments, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 30 mg twice daily, and wherein the treatment achieves a statistically significant least squares mean difference in mean monthly performance of daily activities scores of the AIM-D from baseline of the treatment to week 12 in the patient compared to placebo. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in mean monthly performance of daily activities scores of the AIM-D from baseline of the treatment to week 12 compared to placebo of at least about -1, or at least about -2, or at least about -2.5, or at least about -3, or at least about -3.3, or at least about -3.5, or at least about -3.8, or at least about -4, or at least about -4.5, or at least about -4.6, or at least about -4.7, or at least about -4.8. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in mean monthly performance of daily activities scores on the AIM-D from baseline to week 12 of said treatment of about -4.8 compared to placebo.

[0103] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 60 mg once daily, wherein treatment with atrogepam achieves a decrease in the average monthly daily activities performance score of AIM-D from baseline. In an embodiment, treatment with 60 mg once daily atrogepam achieves a decrease in the average monthly daily activities performance score of AIM-D from baseline by at least about 11 points, or at least about 11.5 points, or at least about 12 points, or at least about 12.5 points, or at least about 12.8 points. In an embodiment, treatment with 60 mg QD atrogepam achieves a decrease in the average monthly daily activities performance score of AIM-D from baseline by at least about 12.8 points throughout the 12-week treatment period.

[0104] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine in a patient in need thereof, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 60 mg once daily, and wherein the treatment achieves a statistically significant least squares mean difference in the mean monthly daily activities performance score of the AIM-D from baseline of the treatment to week 12 in the patient compared to placebo. In an embodiment, treatment with 60 mg QD atrogepam achieves a least squares mean difference in the mean monthly daily activities performance score of the AIM-D from baseline of the treatment to week 12 compared to placebo of at least about -1, or at least about -2, or at least about -2.5, or at least about -3, or at least about -3.3. In an embodiment, treatment with 60 mg QD atrogepam achieves a least squares mean difference in the mean monthly daily activities performance score of the AIM-D from baseline of the treatment to week 12 compared to placebo of about -3.3.

[0105] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves a reduction from baseline in the mean monthly physical impairment domain score of the AIM-D of at least about 9 points, or at least about 9.5 points, or at least about 10 points, or at least about 10.5 points, or at least about 11 points, or at least about 11.5 points, or at least about 12 points.

[0106] In an embodiment, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to each of said patients in an amount of 60 mg once daily or 30 mg twice daily, and wherein said treatment achieves a statistically significant least squares mean difference in mean monthly physical impairment domain scores of the AIM-D from baseline to week 12 of said treatment in said patients compared to placebo. In embodiments, treatment with 30 mg BID atrogepam or 60 mg QD atrogepam achieves a least squares mean difference in mean monthly physical impairment domain scores on the AIM-D from baseline to Week 12 compared to placebo of at least about -1, or at least about -1.5, or at least about -1.7, or at least about -2, or at least about -2.2, or at least about -2.5, or at least about -2.7, or at least about -3, or at least about -3.2, or at least about -3.5, or at least about -3.7, or at least about -4, or at least about -4.1, or at least about -4.2.

[0107] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 30 mg twice daily, wherein treatment with atrogepam achieves a reduction from baseline in the mean monthly physical impairment domain score of the AIM-D. In an embodiment, treatment with 30 mg twice daily atrogepam achieves a reduction from baseline in the mean monthly physical impairment domain score of the AIM-D of at least about 9 points, or at least about 10 points, or at least about 10.5 points, or at least about 11 points, or at least about 11.5 points, or at least about 12 points. In an embodiment, treatment with 30 mg twice daily atrogepam achieves a reduction from baseline in the mean monthly physical impairment domain score of the AIM-D of at least about 12.1 points.

[0108] In an embodiment, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering to the patient atrogepam or a pharmaceutically acceptable salt thereof in an amount of 30 mg twice daily, and wherein the treatment achieves a statistically significant least squares mean difference in mean monthly physical impairment domain scores of the AIM-D from baseline to week 12 of the treatment in the patient compared to placebo. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in mean monthly physical impairment domain scores of the AIM-D from baseline to week 12 of at least about -1, or at least about -1.5, or at least about -1.7, or at least about -2, or at least about -2.2, or at least about -2.5, or at least about -2.7, or at least about -3, or at least about -3.2, or at least about -3.5, or at least about -3.7, or at least about -4, or at least about -4.1, or at least about -4.2 compared to placebo. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in mean monthly physical impairment domain scores of the AIM-D from baseline to week 12 of about -4.2 compared to placebo.

[0109] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 60 mg once daily, wherein treatment with atrogepam achieves a reduction from baseline in the mean monthly physical impairment domain score of the AIM-D. In an embodiment, treatment with 60 mg once daily atrogepam achieves a reduction from baseline in the mean monthly physical impairment domain score of the AIM-D of at least about 9 points, or at least about 9.5 points, or at least about 10 points, or at least about 10.5 points. In an embodiment, treatment with 60 mg QD atrogepam achieves a reduction from baseline to week 12 in the mean monthly physical impairment domain score of the AIM-D of at least about 10.6 points.

[0110] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine in a patient in need thereof, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 60 mg once daily, and wherein the treatment achieves a statistically significant least squares mean difference in the mean monthly physical impairment domain score of the AIM-D from baseline to week 12 of the treatment in the patient compared to placebo. In an embodiment, treatment with 60 mg QD atrogepam achieves a least squares mean difference in the mean monthly physical impairment domain score of the AIM-D from baseline to week 12 compared to placebo of at least about -1, or at least about -1.5, or at least about -1.7, or at least about -2, or at least about -2.2, or at least about -2.5, or at least about -2.7. In an embodiment, treatment with 60 mg QD atrogepam achieves a least squares mean difference in the mean monthly physical impairment domain score of the AIM-D from baseline to week 12 of about -2.7.

[0111] In embodiments of the present disclosure, treatment with atrogepam results in an improvement (i.e., a decrease) in the HIT-6 total score from baseline. In embodiments, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam to one or more patients in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves an improvement (i.e., a decrease) in the HIT-6 total score from baseline. In embodiments, treatment with atrogepam achieves a statistically significant decrease in the HIT-6 total score from baseline.

[0112] The HIT-6 (Headache Impact Test) is a 6-question assessment that measures the impact of headache on a participant's ability to function at work, school, home, and in social situations. It assesses the impact of headache on normal daily life and the participant's ability to function. Responses are based on frequency using a 5-point scale ranging from "never" to "always." The total HIT-6 score, which ranges from 36 to 78, is the sum of the responses, with each response assigned a score ranging from 6 (never) to 13 (always), with higher scores indicating a greater impact from the headache. See Yang et al., "Validation of the Headache Impact Test (HIT-6 TM )across episodic and chronic migraine”, Cephalalgia, February 2011, Vol. 31, No. 3: pp. 357-367.

[0113] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein treatment with atrogepam achieves a reduction from baseline in HIT-6 total score of at least about 6 points, or at least about 6.5 points, or at least about 7 points, or at least about 7.5 points, or at least about 7.8 points, or at least about 8 points, or at least about 8.2 points, or at least about 8.4 points.

[0114] In embodiments, the present disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to each of said patients in an amount of 60 mg once daily or 30 mg twice daily, and wherein said treatment achieves a statistically significant least squares mean difference in HIT-6 total score from baseline of said treatment to week 12 in said patient compared to placebo. In embodiments, treatment with 30 mg BID atrogepam or 60 mg QD atrogepam achieves a least squares mean difference in HIT-6 total score of at least about -1, or at least about -1.5, or at least about -2, or at least about -2.5, or at least about -2.6, or at least about -2.8, or at least about -3, or at least about -3.1, or at least about -3.2, or at least about -3.3 compared to placebo.

[0115] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 30 mg twice daily, wherein treatment with atrogepam achieves a decrease in HIT-6 total score from baseline. In an embodiment, treatment with 30 mg twice daily atrogepam achieves a decrease in HIT-6 total score from baseline of at least about 6 points, or at least about 6.5 points, or at least about 7 points, or at least about 7.5 points, or at least about 7.8 points, or at least about 8 points, or at least about 8.2 points, or at least about 8.4 points. In an embodiment, treatment with 30 mg atrogepam achieves a decrease in HIT-6 total score from baseline to week 12 of the treatment of at least about 8.4 points.

[0116] In embodiments, the disclosure provides a method for prophylactically treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 30 mg twice daily, and wherein the treatment achieves a statistically significant least squares mean difference in HIT-6 total score from baseline of the treatment to week 12 in the patient compared to placebo. In embodiments, treatment with 30 mg BID atrogepam achieves a least squares mean difference in HIT-6 total score compared to placebo of at least about -1, or at least about -1.5, or at least about -2, or at least about -2.5, or at least about -2.6, or at least about -2.8, or at least about -3, or at least about -3.1, or at least about -3.2, or at least about -3.3. In embodiments, at Week 12, treatment with 30 mg BID atrogepam achieved a least squares mean difference in HIT-6 total score of about -3.3 compared to placebo.

[0117] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to one or more patients in need thereof in an amount of 60 mg once daily, wherein treatment with atrogepam achieves a decrease in HIT-6 total score from baseline. In an embodiment, treatment with 60 mg of atrogepam once daily achieves a decrease in HIT-6 total score from baseline of at least about 6 points, or at least about 6.5 points, or at least about 7 points, or at least about 7.5 points, or at least about 7.8 points. In an embodiment, treatment with 60 mg of atrogepam once daily achieves a decrease in HIT-6 total score from baseline to week 12 of the treatment of about 7.8 points.

[0118] In an embodiment, the present disclosure provides a method for the prophylactic treatment of migraine in a patient in need thereof, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to the patient in an amount of 60 mg once daily, and wherein the treatment achieves a statistically significant least squares mean difference in HIT-6 total score from baseline of the treatment to week 12 in the patient compared to placebo. In an embodiment, treatment with 60 mg QD atrogepam achieves a least squares mean difference in HIT-6 total score from baseline of the treatment to week 12 of at least about -1, or at least about -1.5, or at least about -2, or at least about -2.5, or at least about -2.6 compared to placebo. In an embodiment, treatment with 60 mg QD atrogepam achieves a least squares mean difference in HIT-6 total score from baseline of the treatment to week 12 of about -2.6 compared to placebo.

[0119] Example

[0120] Example 1

[0121] A phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate the efficacy, safety, and tolerability of atrogepam for the prevention of chronic migraine. A total of 778 participants from 133 sites in North America, Europe, and East Asia were randomized in a 1:1:1 ratio to one of three treatment groups (placebo, 30 mg BID atrogepam, and 60 mg QD atrogepam).

[0122] The study consisted of a 4-week screening and baseline period, a 12-week double-blind treatment period, and an additional 4-week follow-up period. The total study duration was 20 weeks. The study design is summarized in Figure 1 and Fig.14 Participant disposition information and other relevant participant screening information is also available at Fig.19 Found in.

[0123] The primary efficacy endpoint was the change from baseline in the mean number of migraine days per month over the entire 12-week treatment period.

[0124] Secondary endpoints included change from baseline in mean monthly headache days throughout the 12-week treatment period; change from baseline in mean monthly acute medication use days throughout the 12-week treatment period; at least a 50% reduction in mean monthly migraine days throughout the 12-week treatment period; change from baseline in the MSQv2.1 Role Functioning Limitation domain score at Week 12; change from baseline in mean AIM-D Monthly Functioning and Activity Disability scores throughout the 12-week treatment period; and change from baseline in the HIT-6 total score at Week 12.

[0125] Inclusion criteria included a history of at least 1 year of chronic migraine consistent with a diagnosis according to the International Classification of Headache Disorders, 3rd Revision (ICHD-3), and participants were <50 years of age at the time of migraine attacks. Inclusion criteria also included the frequency of headache / migraine days as confirmed by a history of an average of ≥15 headache days per month in the 3 months before Visit 1, ≥15 headache days per electronic diary (eDiary) during the 4-week screening / baseline period, and ≥8 days identified as migraine days per eDiary during the 4-week screening / baseline period, according to the investigator. Participants were also required to use a medically acceptable and effective method of contraception throughout the study.

[0126] Exclusion criteria included a history of migraine with diplopia or decreased level of consciousness or retinal migraine; a current diagnosis of new-onset daily persistent headaches, trigeminal autonomic cephalalgia (e.g., cluster headache), or painful cranial neuropathy; a history of inadequate response to >4 medications prescribed for migraine prevention (2 of which had different mechanisms of action); and women who were pregnant, planned to become pregnant during the study, or were breastfeeding.

[0127] The trial included 778 randomized participants (259 assigned to placebo, 257 assigned to 30 mg BID atrogepam, and 262 assigned to 60 mg QD atrogepam) with a history of chronic migraine for at least one year. The safety population included 773 participants, and the modified intention-to-treat population included 755 participants. The subject populations are summarized in Table 1.

[0128] Table 1: Subject population

[0129] group Placebo Atrogepam 30 mg BID Atrogepan 60mg QD overall Filtered 1489 Intention to treat 259 257 262 778 Security 255 257 261 773 Modified intention to treat 246 253 256 755 Treatment interruption assumption estimate 249 254 257 760

[0130] All screened participants including those who signed the informed consent form.

[0131] The intention-to-treat population included all randomized participants. Random assignment to treatment group.

[0132] The modified intention-to-treat (mITT) population included all randomized participants who received at least 1 dose of the study intervention, had evaluable baseline eDiary data, and had at least 1 evaluable post-baseline 4-week (weeks 1-4, 5-8, and 9-12) eDiary data during the double-blind treatment period. Randomly assigned treatment group.

[0133] The analysis population for the interrupted treatment hypothesis estimate (OTHE) included all randomized participants who received at least one dose of study treatment, had evaluable baseline eDiary data, and had evaluable eDiary data for at least one of the four post-baseline cycles (weeks 1-4, 5-8, 9-12) during the double-blind treatment and follow-up periods, regardless of study or non-study treatment.

[0134] Randomization was stratified by region (North America 29.3%, Europe 35.3%, East Asia 35.3%), previous use of proven migraine preventive medications (current use 10.7%, past use 70.1%, never use 19.3%), number of failed medications (0 or 1 or more failures with the same mechanism of action 42.8%, 2 or more failures with different mechanisms of action 37.9%), and overuse of acute headache medications (yes 65.3%, no 34.7%).

[0135] Baseline demographics for the safety population are provided in Table 2. Demographics were generally balanced between treatment groups.

[0136] Table 2: Baseline Demographics (Safety Group)

[0137]

[0138]

[0139] The migraine medical history and migraine treatment history of the safety population are provided in Table 3 and Table 3a, respectively.

[0140] Table 3: Migraine history - safety group

[0141]

[0142] Table 3a—Migraine Treatment History—Safety Population

[0143] Acute migraine treatment, n (%) yes 250(98.0) 252(98.1) 258(98.9) 760(98.3) Triptans 189(74.1) 185(72.0) 184(70.5) 558(72.2) Ergots or ergot combinations 1(0.4) 6(2.3) 10(3.8) 17(2.2) NSAID 189(74.1) 170(66.1) 181(69.3) 540(69.9) Opioids or opioid combinations 9(3.5) 11(4.3) 8(3.1) 28(3.6) Antiemetics 36(14.1) 38(14.8) 42(16.1) 116(15.0) Barbiturates 0 1(0.4) 1(0.4) 2(0.3) other 84(32.9) 79(30.7) 87(33.3) 250(32.3) no 5(2.0) 5(1.9) 3(1.1) 13(1.7)

[0144] A subset of patients (11%) were allowed to use a concomitant migraine preventive medication (e.g., amitriptyline, propranolol, topiramate). Patients were allowed to use acute headache treatments as needed (i.e., triptans, ergotamine derivatives, NSAIDs, acetaminophen, and opioids). Patients with acute medication overuse and medication overuse headache were also enrolled. Concomitant medications that act on the CGRP pathway for acute or preventive migraine treatment were not allowed. The study excluded patients who had a myocardial infarction, stroke, or transient ischemic attack within six months before screening.

[0145] The primary and secondary efficacy endpoint analyses for the mITT population are shown in Table 4. Both the 60 mg once daily (QD) and 30 mg twice daily (BID) doses achieved the primary endpoint of a statistically and clinically significant reduction in mean monthly migraine days from baseline compared to placebo throughout the 12-week treatment period. The study also demonstrated that treatment with 60 mg QD atrogepam and 30 mg BID atrogepam resulted in statistically and clinically significant improvements in all secondary endpoints after adjustment for multiple comparisons.

[0146] Table 4: Summary of Multiply Adjusted Primary and Secondary Efficacy Analyses—mITT Population

[0147]

[0148]

[0149]

[0150] Of the 1489 participants screened, 755 were included in the modified intention-to-treat population (30 mg BID atrogepam, n=253; 60 mg QD atrogepam, n=256; placebo, n=246). The baseline mean (SE) numbers of MMD were 18.6 (5.1) for 30 mg BID atrogepam, 19.2 (5.3) for 60 mg QD atrogepam, and 18.9 (4.8) for placebo. The mean MMD change from baseline over 12 weeks was -7.5 (SE 0.4) days for 30 mg BID atrogepam, -6.9 (SE 0.4) days for 60 mg QD atrogepam, and -5.1 (SE 0.4) days for placebo. The least squares mean differences from placebo were -2.4 days for 30 mg BID atrogepam (95% CI -3.5 to -1.3; adjusted p<0.0001) and -1.8 days for 60 mg QD atrogepam (95% CI -2.9 to -0.8; adjusted p=0.0009). The most common (≥5%) adverse events in the atrogepam group were constipation (30 mg BID: 28 [10.9%]; 60 mg QD: 26 [10%]; placebo: 8 [3.1%]) and nausea (30 mg BID: 20 [7.8%]; 60 mg QD: 25 [9.6%]; placebo: 9 [3.5%]). Throughout the 12 weeks, patients in the 60 mg QD atrogepam and 30 mg BID atrogepam treatment groups of the study experienced a reduction of 6.88 and 7.46 migraine days per month, respectively, compared to a reduction of 5.05 migraine days per month in the placebo group, based on the mITT population (60 mg QD vs. placebo, p=0.0009; 30 mg BID vs. placebo, p<.0001, adjusted for multiple comparisons). 30 mg BID atrogepam and 60 mg QD atrogepam demonstrated clinically relevant reductions in MMD over 12 weeks. Both doses of atrogepam were well tolerated, and the results were consistent with the known safety profile of atrogepam.

[0151] Figure 2A Shown are the least squares mean changes (+ / - SE) from baseline in monthly migraine days (MMRM) during the double-blind treatment period for the mITT population. Figure 3 Shown are the least squares mean changes (+ / - SE) from baseline in monthly headache days (MMRM) during the double-blind treatment period for the mITT population. Figure 4 Shown are the least squares mean changes (+ / - SE) from baseline in acute medication use days (MMRM) during the double-blind treatment period for the mITT population. Figure 5 The cumulative distribution function of the percentage reduction from baseline in the mean number of migraine days per month in the mITT population over the 3 months is shown. Figure 5As shown in the results of the current study, the primary efficacy endpoint and key secondary endpoints demonstrated statistically significant improvements between each atrogepan dose group and the placebo group.

[0152] Results of the analysis included the change from baseline in mean MMD during the 4-week interval, the change in weekly migraine days during weeks 1-4, and the proportion of participants with daily migraine during the first 7 days of treatment. In adults with CM, atrogepam demonstrated an early and sustained reduction in migraine days. Results showed a statistically significant effect of treatment during each week of the first 4-week treatment interval and as early as the first full day after the start of study drug. Figure 6 The mean change from baseline of the monthly migraine days for weeks 1-4, 5-8, and 9-12, and the mean change from baseline of the weekly migraine days during weeks 1-4 (inset). The baseline MMD range of the treatment group was 18.6 to 19.2. During the 1-4 weeks of treatment, the mean change from baseline of MMD was -6.6 for 30 mg BID atrogepam, -6.2 for 60 mg QD atrogepam, and -3.7 for placebo (P<0.001). During the subsequent 4-week interval, this significantly greater MMD reduction was maintained in the atrogepam treatment group compared with placebo (P<0.001). The baseline weekly migraine days of the treatment group ranged from 4.6 to 4.8. During each week of the first month of treatment, the average reduction of weekly migraine days in the two atrogepam treatment groups was greater than that of placebo (P≤0.009). During the 28-day baseline period, participants in each treatment group reported a daily incidence of migraine days ranging from 66.3% to 68.4%. Participants treated with atrogepam were significantly less likely to have a migraine on the first full day after treatment initiation than those receiving placebo (P ≤ 0.03).

[0153] Participants treated with atrogepam (30 mg BID and 60 mg QD) were significantly more likely than placebo-treated participants to experience a ≥30% (62.1% and 59.0% vs. 43.1%; P<0.001), ≥50% (42.7% and 41.0% vs. 26.0%; P<0.001), or ≥75% (21.3% and 18.8% vs. 5.7%; P<0.001) reduction in mean MMD over 12 weeks, respectively. A significantly greater proportion of participants experienced a ≥30% or ≥50% reduction in mean MMD for both atrogepam doses vs. placebo during Weeks 1-4 and 5-8, and for 30 mg BID atrogepam vs. placebo during Weeks 9-12. Fig. 7 shows the proportion of patients with MMD reduction of ≥30%, ≥50%, ≥75% or 100% in 1-4 weeks, 5-8 weeks and 9-12 weeks for patients treated with 30mg BID atrogepam, 60mg QD atrogepam and placebo. In each 4-week interval evaluated, for two doses of atrogepam, the proportion of participants experiencing ≥75% or 100% response was higher. At week 12, a significantly higher proportion of participants treated with atrogepam compared to placebo met the response criteria based on PGI-C (64.0% and 52.8% vs. 35.3%; P<0.001) and satisfaction with the study drug (64.6% and 59.2% vs. 40.1%; P<0.001). In all 4-week intervals of the two dosing regimens, the proportion of participants treated with atrogepam who experienced ≥75% or 100% reduction was greater than the proportion of participants corresponding to the placebo group. The proportion of participants treated with atrogepam who experienced ≥75% or 100% MMD reduction increased at each 4-week interval. Table 4a provides PGI-C and treatment satisfaction for the mITT participant population. A significantly higher proportion of participants treated with atrogepam met the PGI-C-based response criteria and were satisfied with the study drug compared with placebo.

[0154] Table 4a: PGI-C and treatment satisfaction (mITT population)

[0155]

[0156] BID, twice daily; mITT, modified intention-to-treat; OR, odds ratio; PGI-C, patient global impression of change.

[0157] QD, once daily.

[0158] a Defined as a response of “much better” or “very good”

[0159] b Defined as a “satisfied” or “very satisfied” response

[0160] All analyses were performed at the nominal significance level without adjustment for multiplicity.

[0161] During the 1-4 week treatment period, greater reductions in mean MMD were observed in both atrogepan-treated groups compared with placebo. Fig.12 Data are shown for patients treated with 30 mg BID atrogepam, 60 mg QD atrogepam, and placebo who experienced a reduction from baseline in mean weekly migraine days during the first month of administration. During each week of the first month of treatment, greater reductions in weekly migraine days were observed in participants treated with atrogepam compared to placebo. Fig.13 The proportion (%) of patients treated with 30 mg BID atrogepam, 60 mg QD atrogepam, and placebo who experienced a one-day migraine during the first week of treatment is shown. Efficacy was observed in both atrogepam treatment groups as early as the first day after the start of treatment. Treatment-emergent adverse events were reported by 63.2% of participants in the 60 mg QD atrogepam group, 56.4% of participants in the 30 mg BID atrogepam group, and 49.4% of participants in the placebo group. The most common (≥5%) adverse events in the atrogepam group were constipation (30 mg BID: 28 [11%]; 60 mg QD: 26 [10%]; placebo: 8 [3%]) and nausea (30 mg BID: 20 [8%]; 60 mg QD: 25 [10%]; placebo: 9 [4%]).

[0162] Atrogepam demonstrated statistically significant improvements in PRO measures of the impact of migraine on daily functioning and work productivity. Figure 8 and Table 5 show the change from baseline in AIM-D daily activities performance at Weeks 1-4, Weeks 5-8, and Weeks 9-12, and for the entire 12 weeks. Fig. 9The changes from baseline in WPAI total work productivity loss at Weeks 1-4, Weeks 5-8, and Weeks 9-12 are shown in Table 6. Both doses of atrogepam demonstrated statistically significant improvements from baseline in AIM-D PDA (least squares mean difference [LSMD]: 30 mg BID, -4.85 [95% CI: -6.75, -2.95]; 60 mg QD, -3.38 [-5.27, -1.49]; P < .001) and PI (LSMD: 30 mg BID, -4.19 [95% CI: -5.95, -2.43]; 60 mg QD, -2.71 [-4.47, -0.96]; P < .01) domain scores relative to placebo throughout the 12-week treatment period. Both atrogepam doses demonstrated nominally significant improvements in AIM-D PDA and PI domain scores at Weeks 1-4, Weeks 5-8, and Weeks 9-12 (for 30 mg BID only) versus placebo. Both atrogepam doses showed significant improvements in attendance ( Fig.15 ), overall work productivity loss ( Fig. 9 ) and mobility impairment ( Fig.18 ), and absences at weeks 4 and 12 for both doses versus placebo ( Fig.17 Nominally significant improvements were observed in the 24-hour follow-up. Both doses (30 mg BID atrogepam and 60 mg QD atrogepam) improved attendance ( Fig.15 ), overall work productivity loss ( Fig. 9 ) and mobility impairment ( Fig.18 ), and absences at weeks 4 and 12 for both doses versus placebo ( Fig.17 ) were observed in the control group (P < .05). A graphical approach with a weighted Bonferroni test procedure was used to control the overall type I error rate at a two-sided α = 0.05 level for the key secondary end-point comparisons between each atrogepan dose and placebo. For exploratory end points, nominal P values ​​are provided without adjustment for multiplicity.

[0163] Atogepam demonstrated statistically significant improvements in the PRO measure of migraine impact on functional ability, as well as a reduction in the overall impact of headache. Fig.10Changes from baseline in the MSQ Role Functioning Limitation domain at Weeks 4, 8, and 12 are shown. At Week 12, increases (improvements) from baseline in all 3 MSQ domain scores were significantly greater in both atrogepam treatment groups (30 mg BID and 60 mg QD) compared with placebo (RFR: least squares mean difference [LSMD]: 30 mg BID, 7.96 [95% CI: 4.30, 11.63]; 60 mg QD, 6.15 [2.51, 9.79]; P < .001; role functioning: LSMD: 30 mg BID, 8.10 [95% CI: 4.80, 11.39]; 60 mg QD, 6.86 [3.58, 10.13]; nominal P < .001; emotional functioning: LSMD: 30 mg BID, 6.36 [95% CI: 2.48, 10.24]; 60 mg QD QD, 6.81 [2.95, 10.66]; nominal P < .01).

[0164] Both doses of atrogepan demonstrated statistically significant improvements from baseline in mean monthly AIM-D PDA and PI domain scores compared to placebo throughout the 12-week treatment period. AIM-D PDA least squares mean difference (LSMD): 30 mg BID, 4.85 (95% CI: -6.75, -2.95); 60 mg QD, -3.38 (-5.27, -1.49); P < 0.001. AIM-D PI LSMD: 30 mg BID, -4.19 (95% CI: -5.95, -2.43); 60 mg QD, -2.71 (-4.47, -0.96); P < 0.01. Both atrogepan doses showed statistically significant improvements from baseline in mean monthly AIM-D PDA and PI domain scores compared to placebo at Weeks 1-4, Weeks 5-8, and Weeks 9-12 (for 30 mg BID only) compared to placebo in AIM-D PDA ( Figure 8 ) and PI( Fig.16 ) domain scores showed nominally significant improvements.

[0165] Both atrogepam doses were significantly higher in the attendance group ( Fig.15 ), overall work productivity loss ( Fig. 9 ) and mobility impairment ( Fig.18 ), and absences at weeks 4 and 12 for both doses versus placebo ( Fig.17 ) was observed in the control group (nominal P < 0.05).

[0166] Similar results were observed for all MSQ v2.1 domain scores at weeks 4 and 8 (e.g., Fig.10). Both atrogepam doses demonstrated significant improvements in HIT-6 scores compared with placebo at all time points assessed. Across all time points and doses, atrogepam-treated participants had a significantly greater proportion of HIT-6 responders (score reduction of ≥5 points) compared with placebo-treated participants (nominal P < .001). At week 12, both atrogepam-treated groups demonstrated statistically significant improvements from baseline in the MSQv2.1 Role Functioning Limitation domain score.

[0167] Table 5: Changes from baseline in AIM-D daily activities performance at weeks 1-4, 5-8, 9-12, and for the entire 12 weeks Changes

[0168]

[0169] Table 6: Change from Baseline in WPAI Total Work Productivity Loss at Weeks 1-4, 5-8, and 9-12

[0170]

[0171] Compared with placebo ( Fig.21 , least square mean difference [LSMD]: 30 mg BID, 7.96 [95% CI: 4.30, 11.63]; 60 mg QD, 6.15 [2.51, 9.79]; P < 0.001). Nominally significant improvements were observed at weeks 4 and 8 ( Fig.10 ).

[0172] At Week 12, both atrogepan-treated groups showed nominally significant improvements from baseline in MSQ v2.1 domain scores for role impairment (LSMD: 30 mg BID, 8.10 [95% CI: 4.80, 11.39]; 60 mg QD, 6.86 [3.58, 10.13]; nominal P < 0.001) and emotional function (LSMD: 30 mg BID, 6.36 [95% CI: 2.48, 10.24]; 60 mg QD, 6.81 [2.95, 10.66]; nominal P < 0.01) compared with placebo. Similar results were observed at Weeks 4 and 8 ( Fig.21 ).

[0173] like Fig. 22As shown, at Week 12, both atrogepam doses demonstrated statistically significant improvements in HIT-6 scores versus placebo (P<0.001). At Weeks 4 and 8, all atrogepam doses demonstrated nominally significant improvements in HIT-6 scores versus placebo (nominal P<0.001). For both atrogepam doses, the minimally important difference between the groups (≥2.3 points) was achieved at the earliest time point assessed (Week 4) and throughout the double-blind period. The proportion of participants who met HIT-6 responder criteria (≥5-point reduction in score) was nominally significantly greater in atrogepam-treated versus placebo-treated participants at all time points and doses (nominal P<0.001).

[0174] Regarding acute medication overuse, 500 (66.2%) of the 778 participants randomized to treatment and 755 in the modified intention-to-treat population had acute medication overuse at baseline: placebo: n = 169 (68.7%); 30 mg BID atrogepam: n = 161 (63.6%); 60 mg QD atrogepam: n = 170 (66.4%), where acute medication overuse was defined as use of triptans ≥ 10 days / month, use of ergots ≥ 10 days / month, use of simple analgesics ≥ 15 days / month, or use of any combination of triptans, ergots, or simple analgesics ≥ 10 days / month. Participants who used opioids and / or barbiturates > 4 days / month were excluded. Outcomes assessed included change from baseline in mean MMD and mean number of days of acute medication use per month, and a ≥50% reduction in mean MMD over 12 weeks. Among those patients with acute medication overuse at baseline, the least squares mean (LSM) change from baseline in mean MMD was -8.3 and -7.5 in participants treated with atrogepam (30 mg BID and 60 mg QD) compared with -5.6 in the placebo group. Fig.11The change from baseline in MMD for participants with and without acute medication overuse headache throughout the 12-week treatment period is shown. The LSM change from baseline in mean monthly acute medication use days was -8.4 and -8.1 in acute medication overuse patients treated with atrogepam and -5.5 in the placebo group (LSM difference [95% CI]: -2.8 [-4.1, -1.6] and -2.6 [-3.9, -1.3], respectively). In addition, a nominally significantly greater proportion (P<0.001) of acute medication overuse participants treated with 30 mg BID atrogepam (44.7%) and 60 mg QD atrogepam (41.8%) achieved a ≥50% reduction in mean MMD throughout the 12-week treatment period compared with placebo (24.9%). Regardless of acute medication overuse at baseline, atrogepan was shown to be effective and was associated with a greater reduction in acute medication use days among persons with CM.

[0175] Table 7 presents the results of the analysis of the primary and secondary endpoints in the analysis population for the discontinuation of treatment hypothesis estimation after multiple adjustments. Participants in the discontinuation of treatment hypothesis estimation population who initiated new migraine preventive treatment during the double-blind or safety follow-up period had their data excluded from the analysis during the follow-up period that began after the new migraine preventive treatment, whereas those participants who discontinued study treatment for all reasons except initiation of new migraine preventive treatment had their data collected after the discontinuation of study treatment, and the data of those who discontinued treatment were included in the analysis. The results for the primary efficacy endpoint and all key secondary endpoints showed that there were statistically significant treatment differences between each atrogepant dose group.

[0176] Table 7: Summary of primary and secondary efficacy analyses with multiple adjustments—analysis of estimates for treatment interruption assumptions Analysis Group

[0177]

[0178]

[0179] Throughout the 12 weeks, patients in the 60 mg QD and 30 mg BID atrogepam treatment groups of the study experienced a reduction of 6.75 and 7.33 migraine days per month, respectively, compared to a reduction of 5.09 migraine days per month in the placebo group, based on the OTHE population (60 mg QD vs. placebo, p=0.0024; 30 mg BID vs. placebo, p=.0001, adjusted for multiple comparisons).

[0180] In the safety population, 760 subjects were included in the treatment interruption hypothesis estimation population and 269 were included in the European subpopulation (placebo n=88, 30 mg BID atrogepam n=91, 60 mg QD atrogepam n=90). The least squares (LS) mean changes in MMD were -8.44 in the 30 mg BID atrogepam subgroup and -8.00 in the 60 mg QD atrogepam subgroup, compared with -5.42 in the placebo group. The LS mean difference [95% CI] vs placebo was large in both groups (30 mg BID atrogepam: -3.02 [-4.82, -1.22]; 60 mg QD atrogepam: -2.59 [-4.39, -0.79]). A higher proportion of participants had a ≥50% reduction in mean MMD over 3 months with 30 mg BID atrogepam (48.4%; OR [95% CI]: 1.87 [1.01, 3.44]; nominal P = 0.0457) and 60 mg QD atrogepam (46.7%; OR [95% CI]: 1.84 [1.00, 3.41]; nominal P = 0.0511) compared with placebo (33.0%).

[0181] Of note, the majority of participants who experienced an initial response during month 1 continued to experience a ≥30% or ≥50% response throughout the 12-week treatment period. Although a significant proportion of participants treated with atrogepan in the trial experienced a treatment response within the first month, a significant proportion of those who did not experience a treatment response experienced a ≥30% or ≥50% reduction in MMD in the second or third month. Sustained responses were calculated by assessing the proportion of participants who had an initial response at month 1 and continued to experience at least that degree of response at months 2 and 3. Initial response thresholds of ≥30%, ≥50%, and ≥75% reduction in mean MMD from baseline were assessed. Subsequent responses were calculated by assessing the proportion of participants treated with atrogepam who experienced a mean MMD reduction of <30% or <50% from baseline at month 1, followed by a mean MMD reduction of ≥30% or ≥50% from baseline at month 2 and at month 2 or month 3, and assessing the proportion of participants treated with atrogepam who experienced a mean MMD reduction of <30% or <50% at month 1 and month 2, followed by a mean MMD reduction of ≥30% or ≥50% at month 3. For these analyses, one month was defined as every 4-week treatment interval (i.e., weeks 1-4, 5-8, and 9-12). For this analysis, a total of 755 participants (mean age: 42.1 years; 87.5% female) were evaluable for efficacy and were included in the mITT population (30 mg twice daily atrogepam, n=253; 60 mg once daily atrogepam, n=256). Among participants who experienced a ≥30% or ≥50% response at Month 1, the majority experienced a sustained response of ≥30% (atogepam 30 mg bid: 81.8% [108 / 132]; 60 mg once daily: 81.6% [102 / 125]) or ≥50% (atogepam 30 mg bid: 71.6% [68 / 95]; 60 mg once daily: 74.2% [69 / 93]) throughout the trial. Fig.23 ). Among participants who experienced a ≥75% response at Month 1, 46.9% (23 / 49) in the 30 mg twice daily group and 52.5% (21 / 40) in the 60 mg once daily group experienced a sustained response throughout the trial. Among participants who had a <30% reduction in mean MMD from baseline at Month 1, 27.4%-36.4% experienced a ≥30% reduction in mean MMD at Month 2 (atogepam 30 mg twice daily, 36 / 99; 60 mg once daily, 31 / 113) and 41.7%-52.1% experienced a ≥30% reduction in mean MMD at Month 2 or Month 3 (atogepam 30 mg twice daily, 50 / 96; 60 mg once daily, 45 / 108; Fig.24Among participants with a <50% reduction in mean MMD from baseline at month 1, 19.2%-23.5% experienced a ≥50% reduction in mean MMD at month 2 (atogepam 30 mg bid, 32 / 136; 60 mg once daily, 28 / 146) and 27.3%-39.4% experienced a ≥50% reduction in mean MMD at months 2 or 3 (atogepam 30 mg bid, 52 / 132; 60 mg once daily, 38 / 139; Fig.24 Many participants who did not experience a ≥30% reduction in mean MMD at month 1 or month 2 experienced a ≥30% response at the end of the trial (atogepam 30 mg bid, 23.3% [14 / 60]; 60 mg once daily, 17.1% [13 / 76]). Many participants who did not experience a ≥50% reduction in mean MMD at month 1 or month 2 experienced a ≥50% response at the end of the trial (atogepam 30 mg bid, 20.0% [20 / 100]; 60 mg once daily, 8.2% [9 / 110]).

[0182] The study demonstrated that treatment with 60 mg QD atrogepam and 30 mg BID atrogepam resulted in statistically and clinically significant improvements in all primary and secondary endpoints in both efficacy analysis populations.

[0183] The overall safety of this study was consistent with the safety results observed in previous studies of atrogepam in the episodic migraine population. Each dose of atrogepam was generally well tolerated. For the safety population, the mean treatment durations were 80.1 days, 79.7 days, and 80.3 days for the 30 mg BID atrogepam, 60 mg QD atrogepam, and placebo groups, respectively. Serious adverse events occurred in 2.7% of patients treated with 60 mg QD atrogepam and 1.6% of patients treated with 30 mg BID atrogepam, compared to 1.2% of patients treated with placebo. The most common adverse events reported with a frequency ≥5% and greater than placebo in at least one atrogepam treatment group were constipation (10.0% for 60 mg QD atrogepam, 10.9% for 30 mg BID atrogepam, and 3.1% for placebo) and nausea (9.6% for 60 mg QD atrogepam, 7.8% for 30 mg BID atrogepam, and 3.5% for placebo).

[0184] Adverse events in the safety population are summarized in Table 8.

[0185] Table 8: Overall Summary of Adverse Events – Safety Population

[0186]

[0187] Treatment-emergent adverse events that occurred in ≥2% of participants in at least one treatment group are summarized in Table 9. Constipation, nausea, dizziness, decreased appetite, fatigue, urinary tract infection, abdominal pain, and back pain occurred more frequently in both dose groups than in the placebo group. Upper abdominal pain occurred more frequently in the 30 mg BID atrogepam group than in the placebo group. Pyrexia occurred more frequently in the 60 mg QD atrogepam group than in the placebo group.

[0188] Table 9: ≥2% Treatment-Emergent Adverse Events—Safety Population

[0189]

[0190] Treatment-emergent serious adverse events in the safety population are summarized in Table 10. No serious adverse events were considered by the investigator to be related to study treatment.

[0191] Table 10: Treatment-emergent serious adverse events – safety population

[0192]

[0193]

[0194] Table 11 shows the number and percentage of participants with clinically significant post-baseline liver-related laboratory parameter values. Post-baseline elevations in ALT or AST (≥3*ULN) occurred in 5 participants, 1 / 254 (0.4%) in the placebo group, 2 / 255 (0.8%) in the 30 mg BID atrogepam group, and 2 / 257 (0.8%) in the 60 mg QD atrogepam group. All cases in the atrogepam dose group were judged to be unlikely to be related to study drug. No participant met potential Hy's postulate criteria. No liver safety issues related to atrogepam were identified.

[0195] Table 11: Number of Participants with Clinically Significant Post-Baseline Liver-Related Laboratory Parameter Values—Safety Population

[0196]

[0197]

[0198] The 30 mg BID atrogepam group and the 60 mg QD atrogepam group showed statistically significant improvements over the placebo group in the primary efficacy endpoint and all key secondary efficacy endpoints. Both doses were well tolerated, and the safety results were consistent with the safety profile of atrogepam.

[0199] Example 2

[0200] Analysis of diary-based patient-reported outcome data from the trial disclosed herein showed that atrogepam provided rapid improvements in daily function, physical impairment, and quality of life (QOL) relative to placebo. Effective preventive treatment of chronic migraine (CM) should reduce migraine symptoms and attack frequency and improve function and QOL soon after initiation of treatment. Analysis of data obtained from the trial was used to evaluate the impact of the early onset of action of atrogepam on function and QOL in patients with CM.

[0201] Patient-reported outcome (PRO) measures included the performance of daily activities (PDA) domain and physical impairment (PI) domain from the AIM-D, and the European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) descriptive system and visual analogue scale (VAS) administered via a daily diary. Scores for each domain were converted to a 0 to 100 scale, with higher scores indicating greater burden of migraine. Changes in PDA and PI scores and the proportion of participants who achieved clinically meaningful within-patient changes in the PDA domain (≥12.5 points) and PI domain (≥10 points) were compared between participants treated with atrogepam and those treated with placebo. The EQ-5D-5L measures 5 dimensions of QOL, including mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Indicator scores range from 0 to 1, with scores closer to 1 indicating better health status. The EQ VAS used a vertical scale ranging from 0 ("the worst health you can imagine") to 100 ("the best health you can imagine"). Changes from baseline in the AIM-DPDA and PI scores were calculated for each week for Weeks 1, 2, 3, and 4. Changes from baseline in the EQ-5D-5L descriptive system were assessed at Weeks 1-2 and Week 4 (Week 3 data were not collected) using log data at these time points in the trial.

[0202] In people with CM, atrogepam significantly improved daily function and reduced physical impairment as early as week 1, and improved QOL within the first 2 weeks. These results suggest that atrogepam is able to rapidly improve function and QOL in people with CM. As disclosed herein, a total of 755 participants comprised the modified intention-to-treat population (placebo, n=246; 30 mg BID atrogepam, n=253; 60 mg QD atrogepam, n=256). Mean (SD) baseline values ​​were similar between the AIM-D PDA group (60 mg QD atrogepam: 30.5 [18.0]; placebo 28.9 [16.7]) and the AIM-DPI group (60 mg QD atrogepam 27.0 [17.9]; placebo 25.1 [15.7]). Compared with placebo, 60 mg QD atrogepam showed greater improvement from baseline in AIM-D PDA as early as Week 1 (least square mean difference [LSMD]: -5.83; nominal P < 0.0001) and greater reduction in PI (LSMD: -4.12; nominal P = 0.0004) scores (Figure 25). In contrast to these results, greater improvements in AIM-D PDA and greater reductions in PI domain scores were observed for atrogepam 60 mg compared with placebo at Weeks 2, 3, and 4. At Week 1, the proportion of participants achieving a clinically relevant reduction in AIM-D PDA ≥ 12.5 was 29.4% for placebo and 42.9% for 60 mg QD atrogepam (nominal P = 0.008), and the proportion of participants achieving a clinically relevant reduction in AIM-D PI ≥ 10 was 30.4% for placebo and 43.7% for 60 mg QD atrogepam (nominal P = 0.003). Similar AIM-D PDA and PI results were shown in the 30 mg BID atrogepam group. The mean (SD) baseline values ​​of the EQ-5D-5L descriptive system (60 mg QD atrogepam 0.76 [0.13]; placebo 0.77 [0.11]) and VAS scores (60 mg QD atrogepam 65.0 [16.4]; placebo 64.4 [15.4]) were similar between groups. Greater improvements in mean EQ-5D-5L descriptive system (LSMD: 0.04; nominal P = 0.0003) and VAS (LSMD: 4.47; nominal P = 0.0018) scores were observed with atrogepam 60 mg versus placebo within the first 2 weeks, and consistent results were observed at Week 4 ( FIG. 26 ). Similar EQ-5D-5L results were observed in the 30 mg BID atrogepam group.

[0203] In participants with chronic migraine (CM) and moderate to severe depressive symptoms as measured by the 9-item Patient Health Questionnaire (PHQ-9), atrogepam demonstrated greater treatment benefits than placebo in terms of reduction in migraine days, responder rates, and patient-reported outcomes including the Migraine Specific Quality of Life Questionnaire v2.1 (MSQ v2.1) and Patient Global Impression of Change (PGIC). Depression is a common comorbidity in patients with migraine and a risk factor for conversion of EM to CM. Depressive symptoms predict increased headache-related disability and poorer health-related quality of life (HRQoL) in patients with migraine. Therefore, trial data analyses were used to evaluate the effect of atrogepam in participants with baseline symptoms of CM and moderate to severe depression. Specifically, trial data analyses evaluated the effect of atrogepam on change in monthly migraine days, ≥50% and ≥75% responder rates, change in MSQ v2.1 domain scores, and PGIC in participants with CM and moderate to severe depressive symptoms. PHQ-9 is a validated screening and diagnostic tool designed to improve the recognition rate of depression and facilitate diagnosis and treatment. A cut-off score of ≥10 points was used to identify participants with moderate or severe depressive symptoms to determine eligibility and as a continuous outcome to measure changes in depression. As disclosed above, MSQ v2.1 is a 14-item measure of health-related quality of life that assesses the impact attributed to migraine in the past 4 weeks and includes three domains: role function limitation (RFR), role function impairment (RFP), and emotional function (EF). PGIC is a single item used to measure the subject's impression of the overall change in migraine since the first dose of the study intervention. This article provides the results of a study of atrogepam 60mg QD dose. Similar results were observed for the 30BID dose (excluded for simplicity). For the endpoint changes in the number of migraine days per month and each MSQv2.1 domain score from baseline, a mixed model (MMRM) based on restricted maximum likelihood for repeated measures was used to analyze the comparison between treatment groups. Logistic regression models were used to analyze the PGIC response rate at week 12 and the response rate ≥50% or 75% during the 12-week double-blind treatment period. ANCOVA models were used to analyze the change from baseline in PHQ-9 scores at week 12.

[0204] Atrogepam 60 mg QD demonstrated treatment benefits over placebo in terms of reduction in monthly migraine days, proportion of participants achieving ≥50% or ≥75% responder rate, MSQ v2.1 domain scores, and PGIC in the subgroups of participants with CM and moderate to severe depressive symptoms.

[0205] Of the 778 participants enrolled, 755 (n=253 in the 30 mg BID atrogepam group, n=256 in the 60 mg QD atrogepam group, and n=246 in the placebo group) were included in the modified intention-to-treat population. Of these, 109 (42.6%) in the 60 mg QD atrogepam group and 89 (36.2%) in the placebo group were participants with CM and moderate to severe depressive symptoms at baseline. Among participants with CM and moderate to severe depression, 60 mg QD atrogepam showed a greater reduction in migraine days compared with placebo throughout the 12-week treatment period, least squares mean difference (LSMD): -3.04 (95% CI: -4.78, -1.29; p=0·0007) (Table 12). A greater proportion of participants on 60 mg QD atrogepam achieved a ≥50% (odds ratio (OR) = 3.7 [95% CI: 1.86, 7.37; p = 0.0002]) and ≥75% (OR = 13.64 [95% CI: 1.75, 106.2; p = 0.01]) reduction in monthly migraine days compared to placebo (Table 12).

[0206] Table 12: Monthly migraine days and responder rates during the entire 12-week treatment period (mITT population)

[0207]

[0208] MMRM = mixed effects model for repeated measures of change from baseline.

[0209] SD = standard deviation, SE = standard error of least squares,

[0210] CI = confidence interval,

[0211] LSMD = least squares mean difference.

[0212] The population-level summary for this endpoint was the logistic regression odds ratio for each atrogepan group relative to placebo, with baseline monthly migraine days as a covariate and regional stratification, acute medication overuse, number of migraine preventive medications and failures, and treatment group as fixed factors.

[0213] Greater improvements in MSQ v2.1 domain scores were observed at Week 4, and this effect was maintained throughout Week 12 (RFR, LSMD (95% CI): 8.77 (2.23, 15.32) [p = 0.009]; RFP, LSMD (95% CI): 8.89 (2.80, 14.99) [p = 0.004]; EF, LSMD (95% CI): 9.24 (2.05, 16.43) [p = 0.01]) Table 13. A greater proportion of participants in the 60 mg QD atrogepam group reported better or very good PGIC at Week 12 compared to placebo (OR = 2.52 [95% CI: 1.35, 4.70; p = 0.004]). A greater reduction in PHQ-9 scores was observed with 60 mg QD atrogepam versus placebo at Week 12 (LSMD (95% CI): -1.38 (-2.89, 0.12) [p=0.07]) (Table 2).

[0214] Table 13: MSQv2.1 Domain Scores at Week 12 (mITT Population)

[0215]

[0216]

[0217] LS, least squares; LSMD, least squares mean difference; MMRM, mixed-effects model of repeated measures change from baseline; SE, least squares standard error.

[0218] RFR, role function limitation domain;

[0219] RFP, role functioning impairment field;

[0220] EF, emotional functioning domain

[0221] ANCOVA Change from Baseline.

[0222] PHQ-9, 9-item Patient Health Questionnaire

[0223] Similarly, in participants with chronic migraine (CM) and moderate to severe depressive symptoms, atrogepam demonstrated statistically significant treatment benefits compared with placebo in terms of fewer headache days, fewer moderate / severe headache days, fewer days of acute medication use, and patient-reported outcomes including the Headache Impact Test-6 (HIT-6) and AIM-D. The analyses further confirmed the efficacy of atrogepam in participants with baseline symptoms of CM and moderate to severe depression.

[0224] The trial data analysis evaluated the effects of atrogepam on the reduction of headache days, moderate / severe headache days, reduction of days of acute medication use, headache and migraine assessed by HIT-6 and AIM-D, and moderate to severe depressive symptoms measured by PHQ-9. A cut-off score of ≥10 was used to identify participants with moderate or severe depressive symptoms to determine eligibility and as a continuous outcome measuring changes in depressive symptoms. Results of the study with atrogepam 60 mg QD dose are presented here. Results were similar for the 30 BID dose (excluded for simplicity). For endpoints other than PHQ-9, comparisons between treatment groups were analyzed using a mixed model (MMRM) based on restricted maximum likelihood for repeated measures. ANCOVA models were used to analyze PHQ-9-related endpoints.

[0225] In people with CM and moderate or severe depressive symptoms, 60 mg QD atrogepam showed multiple nominal significant treatment benefits superior to placebo in terms of patient-reported outcomes of reduced headache days, reduced moderate / severe headache days, reduced acute medication use days, and HIT-6 and AIM-D scores. As disclosed herein, of the 778 participants enrolled, 755 (n=253 in the 30 mg BID atrogepam group, n=256 in the 60 mg QD atrogepam group, and n=246 in the placebo group) were included in the modified intention-to-treat population (mITT population). Among them, 109 (42.6%) in the 60 mg QD atrogepam group and 89 (36.2%) in the placebo group had a PHQ-9 score of ≥10 and were included in the analysis. Compared with placebo, 60 mg QD atrogepam demonstrated greater reductions in headache days, acute medication use days, and moderate / severe headache days throughout the 12-week treatment period (headache days, least squares mean difference (LSMD): -2.86 [95% CI: -4.51, -1.21; p = 0.0007]; moderate / severe headache days, LSMD: -2.68 [95% CI: -4.30, -1.06; p = 0.001]); acute medication use days, LSMD: -3.53 [95% CI: -5.15, -1.91; p < 0.0001] (Table 14).

[0226] Table 14: Monthly headache days, acute medication use, and moderate / severe headache days during the entire 12-week treatment period Number (mITT group)

[0227]

[0228]

[0229] MMRM = mixed effects model for repeated measures of change from baseline. SD = standard deviation, SE = standard error of least squares, CI = confidence interval, LSMD = least squares mean difference.

[0230] A greater reduction in HIT-6 scores was observed with atrogepan compared with placebo at week 4, and this effect was maintained until week 12, LSMD: -3.18 (95% CI: -5.54, -0.82; p = 0.008) (Table 15). A greater improvement in AIM-D PDA and a greater reduction in PI domain scores were also observed throughout the 12-week treatment period (PDA, LSMD (95% CI): -5.91 (-9.44, -2.38) [p = 0.001]; PI, LSMD (95% CI): -4.63 (-7.99, -1.28) [p = 0.007]) (Table 2). A greater reduction in PHQ-9 scores was observed with 60 mg QD atrogepam versus placebo at Week 12 (LSMD (95% CI): -1.38 (-2.89, 0.12) [p=0.07]) (Table 15).

[0231] Table 15: HIT-6 and PHQ-9 scores at week 12, and AIM-D PDA and PI domain scores (mITT population)

[0232]

[0233]

[0234] HIT-6, 6-item Headache Impact Test; AIM-D, Activity Impairment in the Migraine Diary; PDA, Performance of Daily Activities; PI, physical impairment; LS, least squares; LSMD, least squares mean difference; MMRM, mixed-effects model for repeated measures change from baseline; SE, standard error of least squares. ANCOVA for change from baseline. PHQ-9, 9-item Patient Health Questionnaire.

Claims

1. A method for the preventive treatment of migraine, wherein the migraine is a chronic migraine, the method comprising administering atrogepam or a pharmaceutically acceptable salt thereof to a patient in need of treatment of migraine in an amount of 60 mg once daily or 30 mg twice daily.

2. The method of claim 1, wherein treatment with atrogepam achieves a reduction in mean monthly migraine days of at least about 6.7 days from baseline.

3. The method of claim 1, wherein treatment with atrogepam achieves a reduction from baseline in mean monthly migraine days of at least about 1.8 days.

4. The method of claim 1, wherein treatment with atrogepam achieves a reduction from baseline in mean monthly migraine days of at least about 7.3 days.

5. The method of claim 1, wherein treatment with atrogepam achieves a reduction from baseline in mean monthly migraine days of at least about 7.4 days.

6. The method of claim 1, wherein administration of atrogepam achieves a statistically significant change in the mean number of migraine days per month from baseline to week 12 of said treatment.

7. The method of any one of the preceding claims, wherein administration of atrogepam achieves a statistically significant change in the mean number of headache days per month from baseline to week 12 of the treatment.

8. The method of any of the preceding claims, wherein administration of atrogepan achieves a statistically significant change in the mean number of days of acute medication use per month from baseline to week 12 of the treatment.

9. The method of any of the preceding claims, wherein administration of atrogepam achieves a statistically significant change in the proportion of patients with a ≥50% reduction in the mean number of migraine days per month over the 3 months from baseline to week 12.

10. The method of any one of the preceding claims, wherein administration of atrogepam achieves a statistically significant change in the MSQv2.1 Role Functioning Limitation domain score from baseline to week 12 in the patient.

11. The method of any of the preceding claims, wherein administration of atrogepam achieves a statistically significant change in mean monthly Activities of Daily Living performance domain score of the AIM-D from baseline to week 12 in the patient.

12. The method of any of the preceding claims, wherein administration of atrogepam achieves a statistically significant change in the mean monthly physical impairment domain score of the AIM-D from baseline to week 12 in the patient.

13. The method of any of the preceding claims, wherein administration of atrogepam achieves a statistically significant change in HIT-6 total score from baseline to week 12 in the patient.

14. A method of treating migraine in a patient in need thereof, wherein the migraine is chronic migraine, said method comprising administering to each patient atrogepam or a pharmaceutically acceptable salt thereof in an amount of 30 mg twice daily or 60 mg once daily, wherein said treatment achieves a statistically significant least squares mean difference in the number of migraine days per month from baseline to week 12 of said treatment in said patient as compared to placebo.

15. The method of claim 14, wherein the least squares mean difference in monthly migraine days compared to placebo is at least about -1.

6.

16. The method of claim 14, wherein the least squares mean difference in monthly migraine days compared to placebo is at least about -1.

8.

17. The method of claim 14, wherein the least squares mean difference in monthly migraine days compared to placebo is at least about -2.

2.

18. The method of claim 14, wherein the least squares mean difference in migraine days per month compared to placebo is at least about -2.4.

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