EA046122B1 - LONG-TERM ADMINISTRATION OF LASMIDITAN AT NIGHT FOR THE PREVENTION OF MIGRAINE - Google Patents

Description

This invention relates to the long-term administration of lasmiditan at night for the prevention of migraine, in particular for the prevention of treatment-resistant migraine, which is defined herein as migraine refractory to two or more previous treatment regimens, or for the prevention of migraine as monotherapy and/or dual therapy. therapy. The methods of this invention provide new means for modifying the disease state of patients with recurrent migraine and thereby reduce the patient's susceptibility to recurrent migraine attacks. Thus, the disease modifying methods of the present invention by chronic administration of lasmiditan provide safe, tolerable, effective and convenient oral agents for preventing migraine and restoring patients to a generally migraine-free state of function.

Migraine is a serious, chronic, and disabling neurological disorder characterized by attacks of moderate to severe headache associated with other distressing symptoms. Migraine attacks usually last from 4 to 72 hours if left untreated or ineffectively treated. People with migraines may experience warning symptoms even before the headache begins, and attacks may be aggravated by even minor physical activity. In addition, people with migraine are more likely to experience comorbid depression, anxiety, panic disorder, sleep disturbances, chronic pain syndromes, and suicide attempts throughout their lives, as well as an increased risk of ischemic stroke and other cardiovascular diseases. The prevalence of migraine in the United States and Western Europe ranges from 11 to 12%, and is more common among women (16 to 18%) than among men (6 to 7%). The disease is particularly common among people aged 25 to 55 years, and its burden is severe for both patients and society. Migraine sufferers report that pain is the most severe and disabling symptom during an attack, while other annoying symptoms include photophobia, phonophobia, nausea and vomiting. Among those with frequent migraine attacks, 78% reported that they were not fully functional at work, with a 15-day decrease in productivity at work or school over a 3-month period. Research shows that approximately 90% of people with migraines have decreased ability to perform activities, and approximately 33% require bed rest during migraine attacks. Migraine is reported to be the second leading cause of lost time due to disability, severely impacting occupational, educational, home, family and social responsibilities.

Available treatment options for migraine have poor rates of efficacy, tolerability, and patient compliance. In the 2013 Global Burden of Disease study, migraine accounted for more than half of all disability time attributed to neurological disorders (New strategies for the treatment and prevention of primary headache disorders, N.M. Schuster & A.M. Rapoport, Nature Reviews Neurology (2016), 12, 635-650). While patients with relatively infrequent migraine attacks (such as those occurring once or twice a month) typically manage their individual attacks by taking rescue medications only as needed, patients with more frequent migraine attacks are often given preventive medications. There are currently four approved oral medications available in the United States for migraine prophylaxis: propranolol, timolol, divalproex sodium, and topiramate. Despite the availability of some oral prophylactic treatment options, many patients experience poor response or tolerability issues, and an analysis of individuals taking oral medications for migraine prophylaxis showed poor adherence to treatment, with only 26-29% still taking the drug after 6 months and from 17 up to 20% were still taking the drug after 12 months. Consequently, there remains a significant need for alternative orally administered effective and well-tolerated agents that can reduce the frequency of migraine and improve patient functioning.

Lasmiditan is a selective and potent 5-HT _1F receptor agonist that is under development for acute, on-demand treatment of migraine (see, e.g., Rubio-Beltran et al., Pharmacol Ther. 2018; 186:88-97, and Lasmiditan for the Treatment of Migraine, Capi, M. et al., Expert Opinion Investigational Drugs, (2017), Vol. 26, No. 2, 227-234). Lasmiditan (COL 144, LY 573144, CAS ID 439239-90-4), can be chemically described as 2,4,6-trifluoro[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide and can be structurally represented as:

Previous clinical studies of lasmiditan used acute, as-needed treatment regimens for the relief of migraine pain and symptoms and the treatment of migraine. See, for example, Phase 3 Studies (SAMURAI, SPARTAN) of Lasmiditan Compared to Placebo for Acute Treatment of Migraine (S50.008), Linda A. Wietecha, Bernice Kuca, Josephine Asaiu-Adjei, Sheena K. Aurora, Neurology April 2018 ,

- 1 046122 (15 Supplement) S50.008; in which the authors reported that 2 hours after the first dose, significantly more patients (p<0.001) were free of headache (lasmiditan 200 mg: SAMURAI 32.2%, SPARTAN 38.8%; placebo: SAMURAI 15.3%, SPARTAN 21.3%) and symptom of most concern (MBS) (lasmiditan 200 mg: SAMURAI 40.7%, SPARTAN 48.7%; placebo: SAMURAI 29.5%, SPARTAN 33.5%) at a dose of lasmiditan 200 mg compared to placebo. For both endpoints, statistical significance was also noted for the other dose groups of lasmiditan (100 mg, 50 mg) compared with placebo. The most common TEAEs reported with lasmiditan (>2% or greater than placebo) after the first dose were: dizziness, paresthesia, somnolence, fatigue, nausea, and lethargy; and most cases were mild to moderate in severity. From this analysis, the authors concluded that the primary and key secondary endpoints were met, and safety results were comparable between the two phase 3 studies. In summary, on-demand, acute use of lasmiditan provides effective treatment for a significant proportion of patients with migraine, however Some patients may continue to have attacks, and improved methods of treating and/or preventing the occurrence of these attacks represent an important therapeutic goal.

Treatment of patients with migraine is often unsatisfactory because available relief and preventive therapies are either ineffective or poorly tolerated. Relief of migraine attacks was limited to the use of analgesics, combinations of analgesics with caffeine, ergotamines and triptans. Despite the availability of certain migraine preventive medications, many patients do not respond to or cannot tolerate these treatments. (For a description of such agents, see, for example, New Therapeutic Approaches for the Prevention and Treatment of Migraine, Diener, N.S. et al., (2015), Lancet Neurology, 14:1010-22.) In countries such as the United States, Germany, France and Japan, approximately 43% of patients experienced failure of prophylactic drugs or a change in treatment. Among patients with episodic or chronic migraine who are receiving oral prophylactic treatment, side effects and lack of effectiveness are the most common reasons for discontinuing their treatment. Previous treatments for migraine may leave a significant number of patients without adequate treatment. For example, in up to 40% of migraine attacks, ~30% of patients do not respond to a particular triptan due to suboptimal efficacy or tolerability issues (see Dodick D.W. Headache. 2005;45:156-162 and Tepper D.E. Headache. 2013; (53) :577-578). Because of their vasoconstrictive effects, these drugs may have contraindications, warnings, and precautions for patients with cardiovascular risk factors and diseases (see Alwhaibi M, et al. Pain Res Treat. 2016;2016:8538101 and Gilmore V, Michael M Am Fam Physician 2011;(83):271-280). Thus, with prior migraine prophylaxis or treatment as monotherapy or dual therapy, a significant proportion of patients may not achieve headache relief and/or pain relief in response to treatment or prophylaxis. In addition, some patients, referred to herein as treatment-resistant migraine patients, will not be able to successfully manage their migraine attacks and will suffer from migraines that are refractory to two or more prior prophylaxis or treatment regimens of monotherapy and/or dual therapy . Such patients with poorly controlled migraine may have a number of migraine days per month that remains significantly limiting.

There is a need for more and different therapies that may be effective in preventing migraine and/or reducing patients' susceptibility to migraine and, in particular, in preventing treatment-resistant migraine. Treatment-resistant migraine is defined herein as migraine refractory to two or more prior prophylaxis and/or treatment regimens as monotherapy and/or dual therapy. Thus, there is a need for new prevention options for patients who suffer from migraine attacks and have not previously benefited from migraine prevention medications.

This invention provides long-term administration of lasmiditan at night and methods for the prevention of migraine. Long-term overnight dosing of lasmiditan represents an innovative approach to migraine prevention by selectively targeting 5-HT1F with long-term overnight dosing that coincides with the patient's sleeping hours. In addition, the present invention provides for the use of long-term administration of lasmiditan at night to reduce the susceptibility of patients to migraine. In addition, the present invention provides long-term overnight administration of lasmiditan and methods for the prevention of treatment-resistant migraine, which is defined herein as migraine refractory to two or more prior treatment or prophylactic regimens as monotherapy and/or dual therapy.

Preclinical studies, such as those described in Example 1, indicate that the use of lasmiditan can produce unexpectedly durable improvements in the dysfunctional state of the trigeminal nerve system. Likewise, phase III clinical trials, such as those described in Example 2, provide striking and unexpected evidence that the reduction in the susceptibility of migraine patients to migraine attacks may increase over time over time.

- 2 046122 periods of using lasmiditan as needed. These studies led to the concept that long-term, nightly administration of lasmiditan would provide an improved means of reducing the susceptibility of migraine patients to migraine and/or preventing migraine in patients in a clinically useful manner. The present invention provides long-term overnight administration of lasmiditan so that a patient with migraine will have 8 hours, and more preferably 12 hours, between the time of administration and the subsequent time window in which the patient is willing to drive or engage in similar activities. This regimen is advantageous in that treatment with lasmiditan may be associated with mild to moderate dizziness, paraesthesia, drowsiness, fatigue, nausea, and lethargy, and as a result, patients may be required to refrain from driving for a period of time after administration. In addition, the present invention provides long-term administration of lasmiditan at night, so that a patient with migraine can additionally use either lower or higher doses of lasmiditan, so that effective prevention is achieved for a particular patient. In particular, the present invention provides long-term administration of lasmiditan at night, preferably using a total dosage per administration of 25 to 200 mg per night.

Accordingly, the present invention provides long-term nightly administration of lasmiditan to reduce the susceptibility of patients to migraine and/or prevent migraine and, in particular, to prevent treatment-resistant migraine. Methods of chronically administering lasmiditan at night to reduce patients' susceptibility to migraine and/or prevent migraine and, in particular, prevent treatment-resistant migraine, use specific doses and dosing regimens for administering lasmiditan, which are described below.

The present invention provides long-term nightly administration of lasmiditan to reduce patient susceptibility to migraine and/or prevention of migraine, and in particular, prevention of treatment-resistant migraine, comprising administration of a total nightly dose of 25-200 mg of lasmiditan or a pharmaceutically acceptable salt thereof, such as hemisuccinate salt, and a pharmaceutically acceptable diluent or carrier.

The present invention provides long-term nightly administration of lasmiditan for reducing the susceptibility of patients to migraine and/or preventing migraine and, in particular, for preventing treatment-resistant migraine, comprising administering a total nightly dose of 25 mg of lasmiditan or a pharmaceutically acceptable salt thereof, such as a hemisuccinate salt, and a pharmaceutically acceptable diluent or carrier.

The present invention provides long-term nightly administration of lasmiditan for reducing the susceptibility of patients to migraine and/or preventing migraine and, in particular, for preventing treatment-resistant migraine, comprising administering a total nightly dose of 50 mg of lasmiditan or a pharmaceutically acceptable salt thereof, such as a hemisuccinate salt, and a pharmaceutically acceptable diluent or carrier.

The present invention provides long-term nightly administration of lasmiditan for reducing the susceptibility of patients to migraine and/or preventing migraine and, in particular, for the prevention of treatment-resistant migraine, comprising administration of a total nightly dose of 75 mg of lasmiditan or a pharmaceutically acceptable salt thereof, such as a hemisuccinate salt, and a pharmaceutically acceptable diluent or carrier.

The present invention provides long-term nightly administration of lasmiditan to reduce the susceptibility of patients to migraine and/or prevention of migraine, and in particular, prevention of treatment-resistant migraine, comprising administration of a total nightly dose of 100 mg of lasmiditan or a pharmaceutically acceptable salt thereof, such as a hemisuccinate salt, and a pharmaceutically acceptable diluent or carrier.

The present invention provides long-term nightly administration of lasmiditan for reducing the susceptibility of patients to migraine and/or preventing migraine and, in particular, for preventing treatment-resistant migraine, comprising administering a total nightly dose of 150 mg of lasmiditan or a pharmaceutically acceptable salt thereof, such as a hemisuccinate salt, and a pharmaceutically acceptable diluent or carrier.

The present invention provides long-term nightly administration of lasmiditan for reducing the susceptibility of patients to migraine and/or preventing migraine and, in particular, preventing treatment-resistant migraine, comprising administering a total nightly dose of 200 mg of lasmiditan or a pharmaceutically acceptable salt thereof, such as a hemisuccinate salt, and a pharmaceutically acceptable diluent or carrier.

This invention provides the compound 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or a pharmaceutically acceptable salt thereof long-term administration at night.

This invention provides the compound 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or a pharmaceutically acceptable salt thereof long term

- 3,046,122 nights for at least five consecutive nights.

The present invention provides the compound 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or a pharmaceutically acceptable salt thereof chronically administered at night for at least 30 consecutive nights.

The present invention provides the compound 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or a pharmaceutically acceptable salt thereof long-term administration at night once every two nights for at least ten consecutive nights.

The present invention provides the compound 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or a pharmaceutically acceptable salt thereof continuously administered at night, once every two nights for at least 30 consecutive nights.

The present invention provides the compound 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or a pharmaceutically acceptable salt thereof long-term administration at night, and the patients' migraine is refractory to two or more previous treatment and/or prophylaxis regimens in the form of monotherapy and/or dual therapy.

Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 25 to 200 mg. Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg. Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 50 mg. Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose of 75 mg. Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 100 mg. Use according to any of the above embodiments, wherein 2.4.6-tri(|)tor-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose of 150 mg. Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 200 mg.

The present invention provides the compound 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or a pharmaceutically acceptable salt thereof administered orally at night at a dose of 25-200 mg per dose. The present invention provides the compound 2,4,6-trifluoro-H[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or a pharmaceutically acceptable salt thereof salt is administered orally at night at a dose of 25-200 mg per dose for at least five consecutive nights. The present invention provides the compound 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or its pharmaceutically an acceptable salt is administered orally at night at a dose of 25-200 mg per dose for at least 30 consecutive nights. The present invention provides the compound 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or its pharmaceutically an acceptable salt is administered orally at night at a dose of 25-200 mg per dose once every two nights for at least ten consecutive nights. The present invention provides the compound 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for use in the prevention of migraine, wherein the compound or its pharmaceutically an acceptable salt is administered orally at night at a dose of 25-200 mg per dose every other night for at least 30 consecutive nights. Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg. Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 50 mg. Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose of 75 mg. Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin- 4 046122

2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 100 mg. Use according to any of the above embodiments, wherein 2.4.6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 150 mg. Use according to any of the above embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 200 mg.

The present invention provides long-term overnight administration of lasmiditan, comprising administration of a pharmaceutical composition of lasmiditan, wherein the composition is for oral administration and the amount of lasmiditan or a pharmaceutically acceptable salt thereof is from about 25 to about 200 mg per dose. This invention provides long-term overnight administration of a pharmaceutical composition of lasmiditan, wherein the composition is for buccal, sublingual, nasal/intranasal, transdermal, subcutaneous, injection, intravenous or intramuscular administration, and the amount of lasmiditan or a pharmaceutically acceptable salt thereof administered is from about 25 to about 200 mg per dose. The present invention provides long-term overnight administration of lasmiditan, comprising administration of a pharmaceutical composition of lasmiditan, wherein the composition is for oral administration and the amount of lasmiditan or a pharmaceutically acceptable salt thereof is from about 25 to about 100 mg per dose. The present invention provides long-term overnight administration of lasmiditan, comprising administration of a pharmaceutical composition of lasmiditan, wherein the composition is for oral administration and the amount of lasmiditan or a pharmaceutically acceptable salt thereof is from about 100 to about 200 mg per dose.

The present invention provides long-term overnight administration of lasmiditan, comprising administration of a pharmaceutical composition of lasmiditan, the amount of lasmiditan being 25 mg per dose. The present invention provides long-term overnight administration of lasmiditan, comprising administration of a pharmaceutical composition of lasmiditan, the amount of lasmiditan being 50 mg per dose. The present invention provides long-term overnight administration of lasmiditan, comprising administration of a pharmaceutical composition of lasmiditan, the amount of lasmiditan being 75 mg per dose. The present invention provides long-term overnight administration of lasmiditan, comprising administration of a pharmaceutical composition of lasmiditan, the amount of lasmiditan being 100 mg per dose. The present invention provides long-term overnight administration of lasmiditan, comprising administration of a pharmaceutical composition of lasmiditan, the amount of lasmiditan being 150 mg per dose. The present invention provides long-term overnight administration of lasmiditan, comprising administration of a pharmaceutical composition of lasmiditan, the amount of lasmiditan being 200 mg per dose.

The present invention provides for long-term overnight administration of a pharmaceutical composition of lasmiditan, the composition containing a hemisuccinate salt of lasmiditan. The present invention provides long-term overnight administration of a pharmaceutical composition of lasmiditan, wherein the composition contains the hemisuccinate salt of lasmiditan and the administered amount is 25 mg per dose. The present invention provides long-term overnight administration of a pharmaceutical composition of lasmiditan, wherein the composition contains the hemisuccinate salt of lasmiditan and the administered amount is 50 mg per dose. The present invention provides long-term overnight administration of a pharmaceutical composition of lasmiditan, wherein the composition contains the hemisuccinate salt of lasmiditan and the administered amount is 75 mg per dose. The present invention provides long-term overnight administration of a pharmaceutical composition of lasmiditan, wherein the composition contains the hemisuccinate salt of lasmiditan and the administered amount is 100 mg per dose. The present invention provides long-term overnight administration of a pharmaceutical composition of lasmiditan, wherein the composition contains the hemisuccinate salt of lasmiditan and the administered amount is 150 mg per dose. The present invention provides long-term overnight administration of a pharmaceutical composition of lasmiditan, the composition containing the hemisuccinate salt of lasmiditan, and the administered amount is 200 mg per dose.

In one embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient. In another embodiment, the invention provides a method of chronic administration of lasmiditan at night for the prevention of migraine in a patient, wherein lasmiditan is administered at a dose of 25 to 200 mg. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night for the prevention of migraine in a patient, wherein lasmiditan is administered at a dose of 25 mg. In another embodiment, the invention provides a method of chronic administration of lasmiditan at night for the prevention of migraine in a patient, wherein lasmiditan is administered at a dose of 50 mg. In another embodiment, the invention provides a method of chronic administration of lasmiditan at night for the prevention of migraine in a patient, wherein lasmiditan is administered at a dose of 75 mg. In another embodiment, the invention provides a method of chronic administration of lasmiditan at night for the prevention of migraine in a patient, wherein lasmiditan is administered at a dose of 100 mg. In another embodiment, the invention provides a method of long-term use of lasmiditan at night for the prevention of migraine in a patient, wherein lasmiditan is administered at a dose of 150

- 5 046122 mg. In another embodiment, the invention provides a method of chronic administration of lasmiditan at night for the prevention of migraine in a patient, wherein lasmiditan is administered at a dose of 200 mg.

In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient, for example, for at least five consecutive nights. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least five consecutive nights, wherein lasmiditan is administered at a dose of 25 to 200 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least five consecutive nights, wherein lasmiditan is administered at a dose of 25 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least five consecutive nights, wherein lasmiditan is administered at a dose of 50 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least five consecutive nights, wherein lasmiditan is administered at a dose of 75 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least five consecutive nights, wherein lasmiditan is administered at a dose of 100 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least five consecutive nights, wherein lasmiditan is administered at a dose of 150 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least five consecutive nights, wherein lasmiditan is administered at a dose of 200 mg.

In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient, for example for at least 30 consecutive nights. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least 30 consecutive nights, wherein lasmiditan is administered at a dose of 25 to 200 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least 30 consecutive nights, wherein lasmiditan is administered at a dose of 25 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least 30 consecutive nights, wherein lasmiditan is administered at a dose of 50 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least 30 consecutive nights, wherein lasmiditan is administered at a dose of 75 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least 30 consecutive nights, wherein lasmiditan is administered at a dose of 100 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least 30 consecutive nights, wherein lasmiditan is administered at a dose of 150 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night to prevent migraine in a patient for at least 30 consecutive nights, wherein lasmiditan is administered at a dose of 200 mg.

In another embodiment, the invention provides a method of chronically administering lasmiditan at night once every other night to prevent migraine in a patient for at least ten nights. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for migraine prophylaxis in a patient for at least ten nights, wherein lasmiditan is administered at a dose of 25 to 200 mg. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for migraine prophylaxis in a patient for at least ten nights, wherein lasmiditan is administered at a dose of 25 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night once every other night to prevent migraine in a patient for at least ten nights, wherein lasmiditan is administered at a dose of 50 mg. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for the prevention of migraine in a patient for at least ten nights, wherein lasmiditan is administered at a dose of 75 mg. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for the prevention of migraine in a patient for at least ten nights, wherein lasmiditan is administered at a dose of 100 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night once every other night to prevent migraine in a patient for at least ten nights, wherein lasmiditan is administered at a dose of 150 mg. In another embodiment, the invention provides a method of chronically administering lasmiditan at night once every other night to prevent migraine in a patient for at least ten nights, wherein lasmiditan is administered at a dose of 200 mg.

In another embodiment, the invention provides a method of chronically administering lasmiditan at night once every other night to prevent migraine in a patient for at least

- 6,046,122 nights. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for migraine prophylaxis in a patient for at least 30 nights, wherein lasmiditan is administered at a dose of 25 to 200 mg. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for the prevention of migraine in a patient for at least 30 nights, wherein lasmiditan is administered at a dose of 25 mg. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for the prevention of migraine in a patient for at least 30 nights, wherein lasmiditan is administered at a dose of 50 mg. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for the prevention of migraine in a patient for at least 30 nights, wherein lasmiditan is administered at a dose of 75 mg. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for the prevention of migraine in a patient for at least 30 nights, wherein lasmiditan is administered at a dose of 100 mg. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for the prevention of migraine in a patient for at least 30 nights, wherein lasmiditan is administered at a dose of 150 mg. In another embodiment, the invention provides a method of long-term administration of lasmiditan at night once every other night for the prevention of migraine in a patient for at least 30 nights, wherein lasmiditan is administered at a dose of 200 mg.

In another embodiment, the invention provides a method of long-term use of lasmiditan at night for the prevention of migraine in a patient, wherein the patients' migraine was refractory to two or more prior treatment and/or prophylactic regimens in the form of monotherapy and/or dual therapy. In another embodiment, the invention provides a method of long-term use of lasmiditan at night for the prevention of migraine in a patient, wherein the patients' migraine was refractory to previous two or more regimens of treatment and/or prophylaxis in the form of monotherapy and/or dual therapy, wherein lasmiditan is administered at a dose from 25 to 200 mg. In another embodiment, the invention provides a method of long-term use of lasmiditan at night for the prevention of migraine in a patient, wherein the patients' migraine was refractory to previous two or more regimens of treatment and/or prophylaxis in the form of monotherapy and/or dual therapy, wherein lasmiditan is administered at a dose 25 mg. In another embodiment, the invention provides a method of long-term use of lasmiditan at night for the prevention of migraine in a patient, wherein the patients' migraine was refractory to the previous two or more regimens of treatment and/or prophylaxis in the form of monotherapy and/or dual therapy, wherein lasmiditan is administered at a dose 50 mg. In another embodiment, the invention provides a method of long-term use of lasmiditan at night for the prevention of migraine in a patient, wherein the patients' migraine was refractory to previous two or more regimens of treatment and/or prophylaxis in the form of monotherapy and/or dual therapy, wherein lasmiditan is administered at a dose 75 mg. In another embodiment, the invention provides a method of long-term use of lasmiditan at night for the prevention of migraine in a patient, wherein the patients' migraine was refractory to previous two or more regimens of treatment and/or prophylaxis in the form of monotherapy and/or dual therapy, wherein lasmiditan is administered at a dose 100 mg. In another embodiment, the invention provides a method of long-term use of lasmiditan at night for the prevention of migraine in a patient, wherein the patients' migraine was refractory to previous two or more regimens of treatment and/or prophylaxis in the form of monotherapy and/or dual therapy, wherein lasmiditan is administered at a dose 150 mg. In another embodiment, the invention provides a method of long-term use of lasmiditan at night for the prevention of migraine in a patient, wherein the patients' migraine was refractory to previous two or more regimens of treatment and/or prophylaxis in the form of monotherapy and/or dual therapy, wherein lasmiditan is administered at a dose 200 mg.

The present invention provides a method for preventing migraine in a patient in need, comprising administering to the patient an overnight oral dose of 25-200 mg of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2- yl]benzamide or a pharmaceutically acceptable salt thereof. The present invention provides a method for preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 25 mg of 2.4.6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof.

The present invention provides a method for preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 50 mg of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl] benzamide or a pharmaceutically acceptable salt thereof. The present invention provides a method for preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 75 mg of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl] benzamide or a pharmaceutically acceptable salt thereof.

The present invention provides a method for preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 100 mg of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl] benzamide or a pharmaceutically acceptable salt thereof.

- 7 046122

The present invention provides a method for preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 150 mg of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl] benzamide or a pharmaceutically acceptable salt thereof.

The present invention provides a method for preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 200 mg of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl] benzamide or a pharmaceutically acceptable salt thereof.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 25-200 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

The present invention provides a method for preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 25 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 50 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 75 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

The present invention provides a method for preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 100 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

The present invention provides a method for preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 150 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 200 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

The present invention provides a method of chronic administration of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof at night for the prevention of migraine in a patient.

This invention provides a method of chronic administration of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof at night for the prevention of migraine in a patient for at least at least five nights in a row.

This invention provides a method of chronic administration of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof at night for the prevention of migraine in a patient for at least at least 30 nights in a row.

This invention provides a method of long-term administration of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof once every two nights for the prevention of migraine in a patient in for at least ten nights.

This invention provides a method of long-term administration of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof once every two nights for the prevention of migraine in a patient in for at least 30 nights.

This invention provides a method of long-term administration of 2,4,6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof at night for the prevention of migraine in a patient whose migraine patients was refractory to the previous two or more treatment and/or prophylaxis regimens in the form of monotherapy and/or dual-component therapy.

The present invention provides a method in accordance with any of the previous embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg to 200 mg.

The present invention provides a method in accordance with any of the previous embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose of 25 mg.

The present invention provides a method in accordance with any of the previous embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose of 50 mg.

The present invention provides a method in accordance with any of the previous embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose of 75 mg.

The present invention provides a method according to any of the preceding embodiments, wherein 2,4,6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose of 100 mg.

- 8 046122

The present invention provides a method in accordance with any of the previous embodiments, wherein 2.4.6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl|benzamide or a pharmaceutically acceptable salt thereof is administered at a dose 150 mg.

The present invention provides a method in accordance with any of the previous embodiments, wherein 2.4.6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered at a dose 200 mg.

The present invention provides a method of chronic administration of 2.4.6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof at night for the prevention of cluster headache in a patient.

This invention provides a method of chronic administration of 2.4.6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl|benzamide or a pharmaceutically acceptable salt thereof at night for the prevention of cluster headache in a patient for at least at least five nights in a row.

This invention provides a method of chronic administration of 2.4.6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl|benzamide or a pharmaceutically acceptable salt thereof at night for the prevention of cluster headache in a patient for at least at least 30 nights in a row.

This invention provides a method of chronic administration of 2,4,6-trifluoro-N-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl|benzamide or a pharmaceutically acceptable salt thereof once every two nights for the prevention of cluster headache in patient for at least ten nights.

This invention provides a method of chronic administration of 2,4,6-trifluoro-N-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl|benzamide or a pharmaceutically acceptable salt thereof once every two nights for the prevention of cluster headache in patient for at least 30 nights.

The present invention provides a method of chronic administration of 2,4,6-trifluoro-N-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl|benzamide or a pharmaceutically acceptable salt thereof at night for the prevention of cluster headache in a patient. Moreover, the patients’ migraine was refractory to the previous two or more treatment and/or prevention regimens in the form of monotherapy and/or dual-component therapy.

This invention provides a method according to any one of claims 1 to 6. wherein 2.4.6-trifluoro-H-[6-(1methylpiperidin-4-ylcarbonyl)pyridin-2-yl|benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 25 to 200 mg.

The present invention provides a method in accordance with any of the previous embodiments. wherein 2.4.6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 25 mg.

The present invention provides a method in accordance with any of the previous embodiments. wherein 2.4.6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 50 mg.

The present invention provides a method in accordance with any of the previous embodiments. wherein 2.4.6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 75 mg.

The present invention provides a method in accordance with any of the previous embodiments. wherein 2.4.6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 100 mg.

The present invention provides a method in accordance with any of the previous embodiments. wherein 2.4.6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 150 mg.

The present invention provides a method in accordance with any of the previous embodiments. wherein 2.4.6-trifluoro-H-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered in a dose of 200 mg.

This invention provides a method for preventing migraine in a patient. who needs it. comprising administering to the patient an overnight oral dose of 25-200 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least five consecutive nights.

This invention provides a method for preventing migraine in a patient. who needs it. comprising administering to a patient an overnight oral dose of 25 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least five consecutive nights.

This invention provides a method for preventing migraine in a patient. who needs it. comprising administering to the patient an overnight oral dose of 50 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for a period of

- 9 046122 for at least five nights in a row.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient an overnight oral dose of 75 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least five consecutive nights.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient a nightly oral dose of 100 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least five consecutive nights.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient a nightly oral dose of 150 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least five consecutive nights.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient a nightly oral dose of 200 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least five consecutive nights.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient a nightly oral dose of 25-200 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least 30 consecutive nights.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient a nightly oral dose of 25 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least 30 consecutive nights.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient a nightly oral dose of 50 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least 30 consecutive nights.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient a nightly oral dose of 75 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least 30 consecutive nights.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient a nightly oral dose of 100 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least 30 consecutive nights.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient a nightly oral dose of 150 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least 30 consecutive nights.

The present invention provides a method of preventing migraine in a patient in need thereof, comprising administering to the patient a nightly oral dose of 200 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier for at least 30 consecutive nights.

While many patients can successfully treat their migraine attacks with lasmiditan as needed, a subset of patients are unable to successfully manage their migraine attacks with this treatment. Likewise, migraine can be prevented in many patients with a CGRP antagonist or other prophylactic monotherapy. However, for a significant group, none of these approaches will provide sufficient prevention or cure for migraine, and these patients may have a number of migraine days per month that is still significantly disabling. In addition, some patients, referred to herein as patients with treatment-resistant migraine, will not be able to successfully prevent or manage their migraine attacks and will suffer from migraine that is refractory to two or more prior monotherapy treatment and/or prophylaxis regimens and /or two-component therapy.

As defined herein, treatment-resistant migraine patients are those who continue to suffer from migraine on 3 or more days per month despite prior two or more treatment and/or prophylactic regimens in the form of monotherapy and/or dual therapy . As used herein, previous two or more treatment and/or prophylactic regimens as monotherapy and/or dual therapy means previous unsatisfactory attempts at treatment with treatment or prophylaxis regimens as monotherapy or dual therapy, treatment regimens may include triptans, ergotamines,

- 10 046122 non-steroidal anti-inflammatory drugs (NSAIDs), non-narcotic analgesics, blood pressure drugs, anticonvulsants, antidepressants, serotonin antagonists, onabotulinum toxin and caffeine, either alone or two such agents in combination. Medicines used to prevent migraine attacks may typically include beta blockers (eg, propranolol, atenolol, metoprolol, nadolol, and timolol), calcium channel blockers (eg, verapamil, diltiazem, nimodipine), tricyclic antidepressants (eg, amitriptyline, nortriptyline). , imipramine), selective serotonin reuptake inhibitors (eg, fluoxetine, paroxetine and sertraline), anticonvulsants (eg, divalproex sodium, gabapentin and topiramate), serotonin antagonists (eg, methysergide and methylergonovine) and other drugs that include magnesium salts ( such as magnesium oxide, slow-release magnesium chloride, and magnesium diglycinate), vitamins (such as riboflavin), and herbs (such as Mig-99 and petasites). Alternatively, a class of drugs commonly used to prevent migraine attacks may be antibodies or small molecule antagonists to CGRP. Such CGRP antagonists known to one skilled in the art include, for example, eptinesumab (ALD403), fremanezumab (TEV-48125), erenumab (AMG334), ubrogepant (MK-1602), MK-8031 (atogepant), olcegepant or rimegepant ( BHV-3000; BMS-927711) (see, for example, New strategies for the treatment and prevention of primary headache disorders, N.M. Schuster & A.M. Rapoport, Nature Reviews Neurology (2016), 12, 635-650).

As defined herein, patients with treatment-resistant migraine will include patients with refractory migraine. As used herein, refractory migraine includes, but is not limited to: refractory chronic migraine and/or refractory episodic migraine. Methods for identifying patients with refractory migraine are known to one skilled in the art. For example, one skilled in the art will recognize refractory chronic migraine as illustrated by the proposed criteria for this disorder provided by the European Headache Federation (EHF) (see Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders , ^3rd edition). The EFGB recommends that refractory chronic migraine be defined as ICHD-3 beta chronic migraine without drug overuse in patients who have not responded to treatment with at least three prophylactic drugs at adequate dosages, with each trial period of at least 3 month. The proposed criteria can be briefly described as follows:

A) chronic migraine according to beta ICHD-3 without excessive medication use;

B) prophylactic medications for migraine in adequate dosages, used for at least 3 months each;

C) contraindications to or lack of effect from a prophylactic drug in the case of at least three drugs from the following classes: beta-blockers (propranolol up to 240 mg per day, metoprolol up to 200 mg per day, atenolol up to 100 mg per day , bisoprolol up to 10 mg per day), anticonvulsants (valproic acid up to 1.5 g per day, topiramate up to 200 mg per day), tricyclic antidepressants (amitriptyline up to 150 mg per day) or others (flunarizine up to 10 mg per day, candesartan up to 16 mg per day, onabotulinumtoxinA 155-195 units in accordance with the PREEMPT protocol); And

D) adequate treatment of mental health or other comorbidities by a multidisciplinary team, if available.

An unsatisfactory treatment attempt is one in which, after a full course of treatment, the patient concludes that his symptoms have not been relieved enough to avoid disability. Preferably, the methods of the present invention provide prevention of disability due to migraine such that, following a regimen of chronic lasmiditan at night, the patient with migraine does not have significant clinical disability, and the patient does not report migraine attacks and associated total disability, need for bed rest, or noticeable impairment daily activities. More preferably, the methods of the present invention prevent disability due to migraine, such that after a long-term nightly dosing regimen of lasmiditan, the migraine patient is not mildly impaired. More preferably, the methods of the present invention prevent disability due to migraine, such that following a long-term nightly dosing regimen of lasmiditan, the migraine patient is completely free of disability. A disability score for migraine is well known to one skilled in the art, for example a migraine disability score in which a total score of >11 may represent a moderate to severe headache-related disability. In embodiments of the present invention, a migraine disability score of 10 or less, or an equivalent score using criteria known to one skilled in the art, represents prevention of disability. Preferably, the methods of the present invention prevent disability due to migraine such that patients report that the overall disability assessment score

- 11 046122 ability due to migraine is 10 or less. Preferably, in embodiments of the present invention, a migraine disability assessment or equivalent assessment using criteria known to one skilled in the art will demonstrate clinical absence of disability.

Treatment-resistant patients have not yet achieved complete relief from recurrent migraine, and thus there is a critical unmet need. The failure of these treatment-resistant migraine patients to achieve adequate relief with multiple prior treatment regimens demonstrates that their disease is particularly difficult to treat, and efficacy in this population represents an unexpected and exceptional finding. This invention is the result of striking and unexpected preclinical and clinical observations that provide evidence that lasmiditan has persistent and relatively long-term effects that appear to persist after the compound is no longer present at levels for acute pharmacological action. Thus, these observations led to the concept of long-term nightly dosing of lasmiditan to reduce migraine susceptibility. These methods provide new means to potentially modify the disease state of patients with recurrent migraine and thereby reduce the patient's susceptibility to recurrent migraine. These methods may be particularly useful in modifying the disease state of patients with recurrent migraine who have been refractory to two or more prior treatment and/or prophylaxis regimens as monotherapy and/or dual therapy, representing an important unmet medical need. More specifically, there is an unmet need for alternative regimens to provide safe, tolerable, effective and convenient oral agents for the prevention of migraine and to restore patients to a generally migraine-free state.

This paper presents new methods of long-term, nightly administration of lasmiditan for the prevention of migraine and treatment-resistant migraine. It is believed that long-term nightly administration of lasmiditan will be superior to on-demand treatment and will provide a new means of modifying the disease state of patients with recurrent migraine and thereby reducing patients' susceptibility to recurrent migraine. The pharmacological results of these dosing regimens are believed to demonstrate superior efficacy for the prevention of migraine in patients suffering from migraine and the prevention of treatment-resistant migraine, which is defined here as migraine refractory to two or more prior migraine prophylaxis regimens as monotherapy and/or dual therapy. therapy.

The methods of this invention are believed to provide improved migraine prevention, including in patients who suffer from treatment-resistant migraine, where the patients' migraine was refractory to two or more prior monotherapy and/or dual therapy regimens, and, additionally, they provide a particularly advantageous combination of pharmacological benefits, including safe, tolerable and effective prevention of migraine attacks, while at the same time they provide a clinically acceptable level of side effects such as dizziness, paresthesia and somnolence. The prophylactic methods of this invention may provide these benefits in part by allowing a patient with migraine to adequately prevent migraine attacks with a lower dose of lasmiditan, such as 25 or 50 mg administered at night, and, alternatively, if a particular patient requires a higher dose, such patients 100, 150 or 200 mg can be administered to achieve effective prophylaxis. In this regard, the prophylactic methods of this invention provide migraine patients with significant reduction and/or more preferably relief from severe migraine symptoms and disability.

As used herein, the term long-term overnight administration includes the administration of lasmiditan in a specific treatment regimen designed to provide the benefit of long-term and regular administration of lasmiditan at specified doses. In particular, long-term overnight administration includes administration every night for at least five consecutive nights or as long as necessary to prevent migraine attacks in patients. Additionally, long-term overnight administration includes administration once every two nights for a total period of at least ten consecutive nights or for as long as necessary to prevent migraine attacks in patients. If the patient occasionally misses a night, then he can simply resume dosing on the next night indicated for administration, and such a case will continue to represent long-term dosing overnight. Bedtime may include any specific time of day when the patient intends to sleep or rest for a period of time that the patient typically perceives as sleep time. Bedtime can include any specific time of day prior to the sleep cycle, with the sleep cycle defined as the sleep portion of the 24-hour sleep/wake cycle, also known as the circadian rhythm. Preferably, overnight administration will occur 12 hours before the next window in which the patient wishes to drive. Preferably, overnight administration will occur 8 hours before the next window in which the patient wishes to drive. When used in this document, the term overnight means that

- 12 046122 lasmiditan is administered once every 24 hours or once every calendar day, preferably for at least 5 consecutive days or as long as necessary for migraine prevention. As used herein, a particular dose or dose range at night or every night means that the dose or range represents the maximum cumulative dose per night or over a 24-hour period of a calendar day. As used herein, the term overnight continuous means that lasmiditan is administered every night or every other night on an ongoing, continuous basis, preferably for a period of at least 10 days or as long as necessary for migraine prophylaxis. As used herein, the term long-term means that lasmiditan is administered on an ongoing, continuous basis when dosages are administered to a patient and/or when dosages are prescribed to a patient as part of a treatment regimen.

As used herein, lasmiditan includes its pharmaceutically acceptable salts, including, but not limited to, 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin2-yl]benzamide monohydrochloride salt and 2 ,4,6-trifluoro-N-[6-(1-methylpiperidin-4-carbonyl)pyridin-2-yl]benzamide hemisuccinate salt. Methods for producing lasmiditan and its salts, as well as some of its compositions and finished dosage forms are known to a person skilled in the art and are described in WO 2003/084949 and WO 2011/123654.

Embodiments of the present invention provide combinations of lasmiditan with contraceptives for the prevention of menstrual migraine. Contraceptives are well known to one skilled in the art, such as combined oral contraceptives, also called birth control pills, which include a combination of estrogen (eg, ethinyl estradiol) and progestin.

In some embodiments, the patient is a person who has been diagnosed with a condition or disorder in need of prophylaxis with a pharmaceutical composition described herein. In some embodiments, the patient is a person who is at risk for a condition or disorder for which administration of a pharmaceutical composition described herein is indicated. In cases where disorders that can be treated using the methods of this invention are known by established and accepted classifications, for example, migraine, episodic headache, chronic headache, chronic cluster headaches and/or episodic cluster headaches, their classifications may be found in different sources. For example, the current fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV™) (1994, American Psychiatric Association, Washington, DC) provides a diagnostic tool for identifying many of the disorders described herein. In addition, many of the disorders described in this document are classified in the International Classification of Diseases, Tenth Revision (ICD-10). One skilled in the art will appreciate that there are alternative nomenclatures, nosologies, and classification systems for the disorders described herein, including those described in DSM-IV and ICD-10, and that terminology and classification systems evolve as medical science advances. Patients with migraine may be additionally diagnosed with migraine with or without warning symptoms (1.1 and 1.2), as defined by the International Headache Society (IHS) International Classification of Headache Disorders, 3rd edition, beta version (ICHD-3) ( The International Classification of Headache Disorders, ^3rd edition (beta version), Cephalalgia 2013;33:629-808). In some embodiments, the human patient has been diagnosed with episodic migraine before taking lasmiditan long-term, preferably at night, for migraine prophylaxis. In some embodiments, the human patient was diagnosed with chronic migraine prior to receiving lasmiditan. In some embodiments, a human patient experiences premonitory symptoms of migraine headaches. In some embodiments, the human patient does not experience premonitory symptoms of migraine headaches.

As used herein, the term migraine includes, but is not limited to, migraine attacks. As used herein, the term migraine attack refers to the following description. Symptoms may overlap during different phases of a migraine attack, and not all patients experience the same clinical manifestations. During the prodromal phase, most patients experience symptoms that may precede the headache phase by up to 72 hours. These include changes in mood and activity, irritability, fatigue, food cravings, repeated yawning, neck stiffness, and phonophobia. These symptoms may persist into the premonitory phase, headache, and even into the postdromal phase. Some patients experience a phase of warning symptoms, in which about a third of patients experience temporary neurological impairment during attacks. ICHD-3 defines warning symptoms as 1 or more transient, fully reversible neurological disorders, at least 1 of which must be unilateral, occurring over 5 minutes or more, and each lasting 5 to 60 minutes. While visual symptoms are warning signs that may demonstrate

- 13 046122 positive (atrial fibrillation), negative (scotoma) or both, occur in more than 90% of cases and represent the most common disorder, sensory, motor, speech, brain stem and retinal symptoms may also be observed - harbingers.

A transient wave of neuronal cortical depolarization is considered to be a pathophysiological brain mechanism underlying the clinical phenomenon of premonitory symptoms in migraine. In the headache phase, headache attacks, which can last from 4 to 72 hours, are accompanied by nausea, photophobia and phonophobia, or both. The headache can be one-sided, throbbing, of moderate or severe intensity and worsens with physical activity; two of these characteristics are sufficient to meet diagnostic criteria. In the postdromal phase, the characteristic symptoms reflect those observed during the predromal phase. Typical postdromal symptoms include fatigue, difficulty concentrating, and a stiff neck. It remains unclear whether these symptoms arise in the predromal phase and persist throughout the headache phase and the postdromal phase, whether they can also occur during the headache phase or even appear after the end of the headache phase.

The term migraine headache, as used herein, refers to a headache, with or without warning symptoms, lasting >30 minutes, with two of the following required characteristics (A and B):

A) at least two of the following characteristics of headache: 1) unilateral localization, 2) pulsating nature, 3) moderate to severe pain intensity, and 4) exacerbation due to normal physical activity or an urge to abandon it; And

B) during headache, at least one of the following: a) nausea and/or vomiting and/or b) photophobia and phonophobia.

The term probable migraine headache, as used herein, refers to a headache lasting more than 30 minutes, with or without warning symptoms, but without one of the International Headache Society ICHD3 definitions of migraine.

A migraine headache day, as used herein, refers to a calendar day on which a migraine headache or probable migraine headache occurs. ICHD migraine headache day, as used herein, refers to the calendar day on which a migraine headache occurs. A migraine headache attack refers to the beginning of any day in which a migraine headache or probable migraine headache is reported, and ends when a migraine-free day occurs. Non-migraine headache refers to all headaches lasting more than 30 minutes that do not meet the definition of migraine or probable migraine. A non-migraine headache day refers to the calendar day on which a non-migraine headache occurs. A headache day refers to a calendar day on which any type of headache occurs (including migraine, probable migraine, and non-migraine headache).

Episodic migraine, as used herein, refers to 4–14 days with migraine headache and <15 days with headache over a 30-day period in the prospective baseline period. Chronic migraine, as used herein, refers to at least 15 headache days over a 30-day period in the prospective baseline period, of which at least 8 were migraine. A migraine headache day refers to a calendar day on which a migraine headache or probable migraine headache occurs.

The term pharmaceutical or pharmaceutically acceptable when used herein as an adjective means essentially non-toxic and not substantially harmful to the recipient. By pharmaceutical composition it is further meant that the carrier, diluent, excipients and salt are compatible with the active ingredient of the composition (eg, a compound of the invention). Those skilled in the art will appreciate that the terms pharmaceutical formulation and pharmaceutical composition are generally used interchangeably and are used as such for the purposes of this application. In addition, the compounds of this invention, for example, salts of these compounds, can exist in either hydrated or non-hydrated (anhydrous) form. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. When the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts.

The term acid addition salt refers to a salt of a compound obtained by reacting the compound with a mineral or organic acid. The compounds of this invention form pharmaceutically acceptable acid addition salts with a wide range of organic and inorganic acids and include physiologically acceptable salts that are often used in pharmaceutical chemistry. Such salts are also embodiments of the present invention. A pharmaceutically acceptable (acid) addition salt is formed from a pharmaceutically acceptable

- 14 046122 acid, as is well known in the art.

Such salts include pharmaceutically acceptable salts, examples of which are given in Berge, S. M., Bighley, L. D., and Monkhouse, D. C., J. Pharm. Sci., 66:1, (1977), which are well known to those skilled in the art.

The term "effective amount" or "therapeutically effective amount" means an amount or dose of lasmiditan in a pharmaceutical composition, such as a total amount administered in an application, that, when administered single or multiple doses to a patient, provides the desired pharmacological effect in the patient, such as an amount capable of activating 5-HT1F receptors. In a preferred embodiment of the invention, an effective amount means an amount of lasmiditan that, when administered chronically at night, is capable of relieving a patient of a migraine attack for one or more days after administration.

Dose refers to a predetermined amount of lasmiditan calculated to produce the desired therapeutic effect in a patient.

When used herein, mg refers to milligram. When used herein, doses described in mg refer to the active pharmaceutical ingredient lasmiditan free base equivalent by weight, for example, a 100 mg dose refers to 100 mg active pharmaceutical ingredient lasmiditan free base equivalent. As used herein, a given dose may be interpreted to describe doses approximately the stated amount, those doses that are 10 percent higher or lower than the stated dose are also expected to provide beneficial regimens similar to the stated dose.

As used herein, the term prophylaxis (or prevent or prevent) refers to preventing, avoiding, avoiding, anticipating, reducing the incidence of, stopping or controlling the symptoms of a disease, disorder and/or condition. Prophylaxis refers to the administration of an agent to a subject who is not yet exhibiting symptoms of the disease, disorder and/or pathological condition at the time of administration. In contrast, the term treat or treatment as used herein means the alleviation or modulation of a pre-existing disease or pathological condition, such as an existing migraine attack in a patient or subject. In embodiments of the invention that relate to a method of prophylaxis as described herein, such embodiments also constitute additional embodiments for use in such prophylaxis or, alternatively, in the manufacture of a medicament for use in such prophylaxis.

As used herein, the term reduction of migraine susceptibility refers to a change in the disease state of a migraine patient in which etiopathological factors and/or dysfunction of an organ, such as the trigeminal system, that predispose the patient to susceptibility to migraine are now altered such that for migraine, the patient moved closer to homeostasis, and the propensity and/or risk that that patient would subsequently develop migraine was significantly clinically reduced. Reduced susceptibility to migraine may be observed in a patient with migraine who experiences fewer migraine headache days and/or fewer migraine attacks after treatment with chronic lasmiditan, even if blood and/or tissue levels of lasmiditan are quite low or nil, such that previously administered doses no longer interact with 5-HT _1F receptors within the known pharmacologically significant dose response range. Consequently, the previous long-term administration of lasmiditan at night is no longer applicable but has resulted in a change in the patient's disease. This change in disease results in a subsequent reduction in migraine susceptibility. This reduction in migraine susceptibility moves the patient closer to a state of clinical absence of migraine attacks and thus results in a significant reduction in disability caused by migraine and facilitates the resumption of normal daily activities.

When used herein, the terms month, month and their derivatives refer to a period of time that is 28 to 31 consecutive days unless otherwise noted. As used herein, the term about means a satisfactory closeness to the specified numerical value, such as plus or minus 10% of the specified numerical value.

Non-limiting examples of propranolol include propranolol hydrochloride, ANAPRILIN®, AVLOCARDYL®, INDERAL®, OBZIDAN®, REXIGEN®, BETADREN®, DEXPROPRANOL® and DOCITON®.

Non-limiting examples of metoprolol include metoprolol fumarate, metoprolol succinate, metoprolol tartrate, LOPRESSOR®, BETALOC®, TORPOL®, SELOKEN®, SPESIKOR®, SPESICOR® and TOPROL XL®.

Non-limiting examples of topiramate include calcium topiramate, potassium topiramate, sodium topiramate and TORAMACH®.

Non-limiting examples of valproate include sodium valproate, divalproex sodium, di

- 15 046122 valproex, valproic acid, DEPACON®, DEPAKENE® and DEPAKOTE®.

Non-limiting examples of amitriptyline include amitriptyline hydrochloride, amitriptyline pamoate, ELAVTL® and LEVATE®.

Non-limiting examples of flunarizine include flunarizine dihydrochloride, flunarizine hydrochloride, SIBELIUM®, FLUFENAL®, FLUVERT®, ZINASEN®, ISSIUM®, VERTEX®, NOVOFLUNARIZINE® and APO-FLUNARIZINE®.

Non-limiting examples of candesartan include candesartan cilexetil, BIOPRESS®, ATACAND®, AMIAS® and RATACAND®.

Non-limiting examples of botulinum toxin A include onabotulinumtoxinA, BOTOX®, DYSPORT® and XEOMIN®.

Non-limiting examples of botulinum toxin B include rimabotulinum toxin B and MYOBLOC®.

Throughout the specification, where compositions are described as having, including, or containing specific components, it is intended that the compositions also consist essentially of or consist of the listed components. Likewise, when methods or processes are described as having, including, or containing specific process steps, the processes also consist essentially of or consist of the listed processing steps. In addition, it should be understood that the order of the steps or the order in which certain actions are performed is not important so long as the invention can be practiced. In addition, two or more stages or activities may be carried out simultaneously.

One skilled in the art of formulation can readily select the appropriate form and route of administration depending on the particular characteristics of the compound selected, the disorder or condition being treated, the stage of the disorder or condition, and other relevant circumstances (see, for example, Remington: The Science and Practice of Pharmacy, L. V. Allen, Editor, ^22nd Edition, Pharmaceutical Press, 2012). In particular, the components of these combinations may be combined in the same formulation, where appropriate, or, alternatively, they may be formulated in separate formulations.

When formulated, lasmiditan is typically mixed with an excipient, diluted with an excipient, or enclosed in a carrier, which may be in the form of a capsule, sachet, paper bag, or other container. If the excipient serves as a diluent, it may be a solid, semi-solid or liquid material that acts as an excipient, carrier or vehicle for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, starch capsules, infusions, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments containing, for example, up to up to 10% by weight of the active compound, soft and hard gelatin capsules, gels, suppositories, sterile injectable solutions and sterile packaged powders. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The compositions may further contain: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavors. The compounds of this invention can be formulated to provide rapid, delayed or delayed release of the active ingredient after administration to a patient using procedures known in the art.

Brief description of graphic materials

Fig. 1. Inhibition of extravasation of plasma proteins caused by stimulation of the trigeminal nerve into the dura mater of rats after preliminary administration of the hemisuccinate salt of 2,4,6trifluorotrifluoro-H-[6-(1-methylpiperidin-4-carbonyl)pyridin-2-yl]benzamide or carrier (H2O).

Lasmiditan or vehicle is administered via gastric tube 1 hour before electrical stimulation of the trigeminal ganglion. Dosages of lasmiditan are given as free base equivalents. Data are expressed as extravasation ratio (stimulated/unstimulated). Data are presented as mean ± SEM. *p < 0.05 compared with vehicle (ANOVA followed by Dunnett's post hoc test, mean ± SEM, n = 4).

Fig. 2. Inhibition of extravasation of plasma proteins caused by stimulation of the trigeminal nerve into the dura mater of rats after preliminary administration of the hemisuccinate salt of 2,4,6trifluorotrifluoro-H-[6-(1-methylpiperidin-4-carbonyl)pyridin-2-yl]benzamide ( 10 mg/kg, po) or vehicle (H2O).

Lasmiditan or vehicle is administered by gastric tube 1, 24, or 48 hours before electrical stimulation of the trigeminal ganglion. The dosage of lasmiditan is stated as the free base equivalent. Data are expressed as extravasation ratio (stimulated/unstimulated). Data are presented as mean ± SEM. *p<0.05 compared with vehicle (ANOVA followed by apo

- 16 046122 Dunnett's posterior test, mean ± SEM, n= 4).

Fig. 3. Improvement in disability over 12 months with lasmiditan for the acute treatment of migraine: interim analysis of changes in the Migraine Disability Assessment Scale (MIDAS) in the GLADIATOR trial.

Examples

Example 1. Preclinical studies of neurogenic inflammation of the dural membrane and activation of the trigeminal nerve system.

Migraine is a painful condition thought to be associated with neurogenic inflammation of the dural membrane and activation of the trigeminal system. The 5-HT1F receptor is ubiquitously expressed in the central nervous system and peripheral nerves, including the trigeminal ganglia, dorsal root ganglia, and trigeminal caudate nucleus. Plasma protein extravasation (PPE), one of the components of neurogenic inflammation, can be induced in the rat dura mater by electrical stimulation of the trigeminal ganglion. Given the role of the trigeminal nerve in migraine physiology, this study is useful in characterizing the ability of lasmiditan hemisuccinate to block plasma protein extravasation into the rat dura mater following electrical stimulation of the trigeminal ganglion.

To examine the ability of lasmiditan to modify dysfunction in target tissue, the duration of effect after a single oral dose of lasmiditan hemisuccinate was also determined. Electrical stimulation of the trigeminal ganglion in rats and guinea pigs can be used to induce neurogenic inflammation in the meninges (dura mater). Briefly, unilateral electrical stimulation of the left or right trigeminal ganglion using stereotactically implanted electrodes is used to induce ipsilateral neurogenic inflammation and enhance plasma protein extravasation. The selective 5-HT1 agonist lasmiditan (lasmiditan hemisuccinate) inhibits plasma protein extravasation into the dura mater in Sprague-Dawley rats following oral (PO) administration. Lasmiditan hemisuccinate significantly blocks PPE in the dura mater 24 hours after oral administration of a single 10 mg/kg dose. However, the compound was not effective 48 hours after dosing. Plasma and brain lasmiditan concentrations are measured for all dose levels and time points at the end of each experiment.

The efficacy observed 24 hours post-dose is not attributable to lasmiditan exposure at any site and is therefore striking and unexpected to represent a long-lasting pharmacological effect that is believed to reflect a possible change in migraine susceptibility. Thus, the present invention, which provides administration and dosage regimens for the use of lasmiditan to modify migraine susceptibility, is supported by this unexpected in vivo observation in a model of neurogenic dural membrane inflammation and trigeminal system activation.

Efficiency mark.

Compounds 1 hour after oral administration of Lasmiditan hemisuccinate are dissolved in sterile water. All doses of lasmiditan are given as equivalent doses of free base based on weight of salt. Male Sprague-Dawley rats from Envigo (250-350 g, n=4/group) were fasted overnight prior to dosing. Animals are administered orally via gavage (dose volume 2 ml/kg) test compound or vehicle 1 hour before stimulation time and returned to cages with access to water only. Approximately 50 min after dosing, rats are anesthetized with Nembutal (65 mg/kg, i.p.) and implanted with stainless steel stimulating electrodes (Rhodes Medical Systems) to a depth of 9.2 mm from the dura. The femoral vein is exposed and fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) (20 mg/kg, i.v.) is injected into the femoral vein 2 min before stimulation. FITC-BSA acts as a marker of protein extravasation. The left trigeminal ganglion is stimulated for 5 min at 1.0 mA (5 Hz, 5 ms pulse duration) using a Model S48 Grass stimulation device with a PSIU6 photoelectric isolator unit (Grass-Telefactor). Five minutes after stimulation, blood samples were collected by cardiac puncture and the rats were sacrificed by exsanguination with 40 ml saline. Collect 1 mL of blood and place in a 1.5 mL EDTA-coated tube (Fisher, cat. no. 540734) on ice. Plasma is separated by centrifugation at 10,000 rpm (941 g) for 30 minutes at 4°C. The top of the skull is removed to collect the brain and dural membranes. Brain and plasma samples are frozen at 80°C until thawed for compound quantification. Samples of the membrane are removed from both hemispheres, washed with water and leveled on glass slides. The slides were dried for 15 min on a slide warmer, then the tissues were covered with a 70% glycerol/water solution. A fluorescence microscope (Zeiss) equipped with a diffraction monochromator and spectrophotometer was used to quantify the FITC-BSA dye in each dural sample. Extravasation caused by electrical stimulation of the trigeminal ganglion is an ipsilateral effect (ie, occurs only on the side of the dura on which the trigeminal ganglion is stimulated). This allows the use of another (unstimulated)

- 17 046122 half of the dura mater as a control. The ratio of extravasation into the dura mater from the stimulated side to the non-stimulated side is calculated, and the extravasation ratio is recorded for each animal. The mean extravasation ratio and standard error of the mean (SEM) were calculated for each treatment group. Controls give a ratio of approximately 1.8. In contrast, a compound that effectively prevents dural extravasation from the stimulated side will produce a ratio of approximately 1. Data obtained are analyzed using one-way ANOVA followed by Dunnett's post hoc analysis to determine statistical significance (p<0.05). Levels of the compound in plasma and brain samples from each animal are analyzed by methods known to one skilled in the art.

Evaluation of compound efficacy 24 or 48 hours after oral administration.

Male Envigo Sprague-Dawley rats (250-350 g, n=4/group) were fasted overnight prior to dosing and during the po dosing study. Animals are administered orally via gavage the test compound or vehicle and returned to cages with access to water only; food is given 1 hour later. 24 or 48 hours after dosing, animals are anesthetized with Nembutal (65 mg/kg, i.p.) and placed in a stereotaxic frame (David Kopf Instruments). The remainder of the protocol is identical to the method immediately above for assessing the efficacy of the Compound 1 hour after oral administration.

Results.

Lasmiditan hemisuccinate dose-dependently inhibits plasma protein extravasation into the dura mater when assessed 1 hour after oral administration in rats. Doses of 1 and 10 mg/kg, but not 0.1 mg/kg, were statistically different compared to vehicle-treated animals (Fig. 1). To assess the pharmacological duration of action, inhibition of plasma protein extravasation into the dura mater was assessed at 1, 24 and 48 hours after a single oral dose (10 mg/kg) of lasmiditan. Strikingly, this dose of lasmiditan was equally effective at 1 and 24 hours post-dose, but not at 48 hours (Figure 2). Levels of unbound lasmiditan in plasma and brain, measured 1 hour after administration, increased with dose, as shown in Table. 1. However, plasma and brain concentrations of unbound drug measured 24 hours after a 10 mg/kg dose were not different from the effects associated with the ineffective dose of 0.1 mg/kg after 1 hour. Thus, the efficacy of lasmiditan observed after 24 hours after dosing is not associated with a long-term exposure profile of the compound.

Table 1

Plasma and brain levels of unbound lasmiditan in rats from studies of plasma protein extravasation into the dura mater

Dose (mg/kg, po) Time after dose administration (hours) Concentration of unbound drug in plasma (nM, mean ± SD; η = 4) Brain concentration of unbound drug (nM, mean ± SD; η = 4) 0.1 1 6.0 + 1.9 2.0 + 0.1 1 1 67 ± 19.8 16.6 + 3.6 10 1 767 ± 254 242 + 95 10 24 6.2 ±2.5 2.1 ±0.9 10 48 BQL BQL

FU^^i = 0.459, RCbrain = 0.117, BQL - below the level of quantitative determination.

Example of clinical studies.

Lasmiditan has been shown to be effective for the on-demand treatment of acute migraine attacks with or without warning symptoms in adults. In phase 3 studies, lasmiditan demonstrated statistically significant superiority over placebo in the primary endpoint of freedom from pain and the key secondary endpoint of freedom from MBS at 2 hours after dosing of study drug. Lasmiditan was generally well tolerated, with the most common TEAEs including dizziness, paresthesia, somnolence, fatigue, and nausea. Typically, these TEAEs were mild to moderate in severity and of short duration. All doses of lasmiditan were associated with impaired driving in a computerized driving simulator study of healthy volunteers. Patients should limit driving, operating heavy machinery, or other similar activities after taking the study drug, as described in the informed consent form (ICF). Clinical data from an acute treatment program suggest that single or multiple doses intermittently

- 18 046122 ski-administered lasmiditan may have a preventive effect against migraine. The idea of this invention is that long-term administration of lasmiditan once at night can reduce the frequency of migraine attacks.

The following clinical study designs further illustrate the invention, but should not be construed as limiting the scope of the invention in any way. Below are examples of studies of lasmiditan for migraine prevention. One skilled in the art will appreciate that similar studies could be conducted in patients who have not successfully controlled their migraine attacks with either lasmiditan or galcanezumab alone. One skilled in the art will appreciate that similar studies can be conducted in patients, referred to herein as treatment-resistant migraine patients, who experience migraine attacks that are refractory to prior two or more treatment and/or prophylactic monotherapy regimens and /or two-component therapy. One skilled in the art can conduct similar studies with patients suffering from headache selected from the group consisting of: episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache, including patients with treatment-resistant headaches . One skilled in the art can readily identify, using the methods described herein and methods known in the art, patients who have not successfully controlled their migraine attacks with either lasmiditan or galcanezumab alone, and/or patients with treatment-resistant migraine whose migraine attacks are refractory to two or more previous treatment and/or prophylactic regimens in the form of monotherapy and/or dual therapy, and such patients identified in this way can be subjects of clinical trials, such as those described in this document.

Methods for conducting such clinical trials are known to one skilled in the art and are illustrated, for example, by reference to published clinical studies of lasmiditan presented herein. Methods for assessing migraine treatment include Patient Reported Outcomes (PROs) such as quality of life (QoL) measures including, for example: Migraine Quality of Life version 2.1 (MSQ v2.1), Headache Impact Assessment-6 (HIT) -6), Migraine Disability Assessment Scale (MIDAS), Migraine Quality of Life Questionnaire (MSQoL). Additionally, the ePRO diary can be used to record headache attacks and other migraine symptoms. Based on the diary data, using an automated algorithm, days can be classified as Migraine Headache Days (MHD) (including probable MHD). Probable migraine is defined as a headache with or without warning symptoms and lasting >30 minutes, but without one of the signs of migraine according to the ICHD-3 beta criterion. Monthly MHD counts using episodic migraine medications can be obtained through the ePRO diary, and PGI-S, MSQ, and MIDAS assessments are completed at the study site at each monthly PGI-S and MSQ assessment visit, and at the 3rd and 6th months for MIDAS using a calculator. A study design may be prepared to compare the effectiveness of each overnight dosing regimen with placebo on the cumulative mean change from baseline in the number of migraine headache days (MHD) per month during the treatment phase, based on ePRO or other relevant clinical data. Other possible outcome measures may include the mean proportion of patients with a decrease from baseline in monthly MHD during the double-blind treatment phase, the mean change from baseline in the R-FR score on the Patient Quality of Life Questionnaire migraine score v2.1 (MSQ v2.1), the mean change from baseline in the Patient Global Impression of Severity (PGI-S) (average of selected months), and/or the treatment outcome measure for the Migraine Disability Assessment total score ( MIDAS). These and other evaluations of migraine treatment are well known to one skilled in the art.

Example 2. Improvement in disability over 12 months with lasmiditan for the acute treatment of migraine: interim analysis of changes in the Migraine Disability Assessment Scale (MIDAS) in the GLADIATOR trial.

The placebo-controlled phase 3 studies SAMURAI (NCT02439320) and SPARTAN (NCT02605174) evaluated lasmiditan doses of 50 mg [SPARTAN only], 100 mg, and 200 mg. Compared with placebo, all doses of lasmiditan showed significantly higher rates of freedom from pain and freedom from most bothersome symptoms two hours after dosing (Kuca et al., J. Head and Face Pain, 2017;57:1311-2, Wietecha et al., Cephalgia, 2017;37(suppl):367-8). GLADIATOR (NCT02565186) is a prospective, randomized, open-label, phase 3 study to evaluate the long-term intermittent use of lasmiditan (100 or 200 mg) for the acute treatment of migraine. An interim analysis of the effect of lasmiditan on migraine disability assessed by the MIDAS scale in the GLADIATOR trial is described below and provided surprising and unexpected evidence of durable benefits in patients with migraine

- 19 046122 new.

Ways.

Patients who completed SAMURAI or SPARTAN were offered participation in GLADIATOR, with randomization to 100 or 200 mg lasmiditan, an uncontrolled, open-label study. Patients were randomized to receive either 100 or 200 mg of lasmiditan regardless of their treatment assignment in the main studies, and were not required to use lasmiditan for all migraine attacks. This interim analysis includes patients with MIDAS score data at GLADIATOR initiation and post-baseline assessments. The presented analysis is based on the MIDAS questionnaire, which was used at baseline and after 3, 6, 9 and 12 months. Additional analyzes were also conducted in the subgroup of patients who completed 12 months. Changes were modeled using a mixed model repeated measures analysis. MIDAS measures time lost due to migraine in days over 3 months. This includes restrictions on activities at work, household or family activities, social activities and leisure activities. MIDAS has demonstrated reliability and accuracy; scores correlate with clinical judgment of the need for medical care (see Stewart et al., Neurology, 1999;53:988-94, and Stewart et al., Neurology, 2001;56:S20-8).

Overview of the GLADIATOR Study Design.

Key inclusion criteria were patients who met SAMURAI or SPARTAN criteria and had at least moderate disability due to migraine (MIDAS scores >11). Patients were randomized 1:1 to acute treatment of migraine with either lasmiditan 100 mg for up to 12 months or lasmiditan 200 mg for up to 12 months. Patients used lasmiditan as the first treatment for each new migraine attack (<4 hours after migraine onset). A second dose was allowed between 2 and 24 hours for elimination (elimination: not achieving headache-free status after 2 hours, completed 2-hour assessments, and took a second dose of study drug between 2 and 24 hours after the first dose) or in case of relapse (relapse : A headache-free state was achieved after 2 hours, but then a recurrence of mild, moderate, or severe migraine was observed and a second dose of study drug was taken within 24 hours of the first dose of migraine. Safety and effectiveness assessments were conducted, including MIDAS questionnaires at baseline and 3, 6, 9 and 12 months.

MIDAS questionnaire.

(See, for example, Stewart et al., Neurology, 1999;53:988-94, Stewart et al., Neurology, 2001;56:S20-8). The sum of questions 1-5 below represents the total MIDAS score.

1. How many days in the last 3 months have you missed work or school because of headaches?

2. How many days during the last 3 months was your productivity at work or school reduced by half or more due to headaches? (Do not include the days you indicated in question 1 that you missed work or school.)

3. During the last 3 months, how many days did you not do housework (such as housework, home repairs and maintenance, shopping, caring for children and relatives) because of headaches?

4. On how many days in the last 3 months was your productivity at home reduced by half or more due to headaches? (Do not include the days you indicated in question 3 when you did not do housework.)

5. During the last 3 months, how many days did you miss family, social, or recreational activities because of headaches?

Additional questions include the following:

A. How many days in the last 3 months have you had a headache? (If the headache lasted more than 1 day, count each day).

Q. On a scale of 0 to 10, how painful were these headaches on average? (where 0 = no pain at all and 10 = pain as bad as possible).

results

A summary of baseline characteristics is presented in Table. 2. Data are presented for a total of 2037 patients who were treated for an average of 5.6 months. The average age is 43.2 years, and 85% of the sample is female.

- 20 046122

table 2

Lasmiditan 100 Lasmiditan

Treatment group mg 200 mg (N = 974) (N = 1063)

Age, average, years (SD) 42.8 (12.3) 43.6 (12.4) Women, η (%) 828 (85.0) 904 (85.0) Body mass index, kg/ ^m2 31.1 (8.2) 31.0(8.1) White, η (%) 774 (76.4) 837 (78.7) History of migraine, average, years (SD) 18.8(12.8) 18.8 (12.9) Migraine attacks/month, mean p(SD)| 5.2(1.8) 5.2(1.8) Migraine with warning symptoms, η (%) 356 (36.6) 366 (34.5) Use of drugs for migraine prevention, η (%) 214(22.0) 234 (22.0) Overall MIDAS score, mean (IQR) 29.4(15.36) 28.9 (15.35) Headache in past 3 months, average number of days (IQR) 15.5(8, 20) 15.5 (8, 20) Headache severity, mean (IQR) on a scale from 0 (no pain) to 10 (as strong as possible) 7.4 (7, 8) 7.3 (6.8)

f For the past 3 months, MIDAS is an assessment of disability due to migraine.

SD - standard deviation.

IQR represents the interquartile range.

MIDAS score grading definitions are shown in the table below.

MIDAS assessment Definition of gradation 0-5 Little or no disability 6-10 Mild disability 11-20 Moderate disability 21+ Severe disability

GLADIATOR: Overall MIDAS Score

Table 3

Group Average overall score according to MIDAS [IQR] Subjects Initial indicator 29.4 [15, 36] η = 972 Lasmiditan 100 mg 3 months 21.2 [10, 26]* η = 818 Lasmiditan 100 mg 6 months 19.1 [8, 24.5]* η = 672 Lasmiditan 100 mg 9 months 17.3 [7.21]* η = 541 Lasmiditan 100 mg 12 months 15.3 [5, 20]* η = 429

*P<0.001 compared to baseline; mixed model for repeated measures.

There were no significant differences between lasmiditan doses.

- 21 046122

GLADIATOR: Overall MIDAS Score

Table 4

Group Average overall score according to MIDAS [IQR] Subjects Initial indicator 28.9 [15.35] η = 1063 Lasmiditan 200 mg 3 months 21.1 [9, 25]* η = 884 Lasmiditan 200 mg 6 months 18.1 [7, 22]* η = 719 Lasmiditan 200 mg 9 months 16.1 [5, 19]* η = 581 Lasmiditan 200 mg 12 months 13.4 [4, 16]* η = 418

*P<0.001 compared to baseline; mixed model for repeated measures.

There were no significant differences between doses of lasmiditan.

Table 5

GLADIATOR: MIDAS Total Scores for Patients with 12-Month Data (Analysis of Subjects Who Completed Treatment)

Group Average overall score according to MIDAS [IQR] Subjects Initial indicator 27.7 [15, 34] η = 429 Lasmiditan 100 mg 3 months 20.5 [10, 24.5]* η = 428 Lasmiditan 100 mg 6 months 18.2 [8, 24]* η = 428 Lasmiditan 100 mg 9 months 16.7 [7.21]* η = 429 Lasmiditan 100 mg 12 months 15.3 [5, 20]* η = 429

*P<0.001 compared to baseline; mixed model for repeated measures.

There were no significant differences between lasmiditan doses.

Table 6

GLADIATOR: MIDAS Total Scores for Patients with 12-Month Data (Analysis of Subjects Who Completed Treatment)

Group Average overall score according to MIDAS [IQR] Subjects Initial indicator 26.2 [14, 31] n = 418 Lasmiditan 200 mg 3 months 18.6 [9, 22]* n = 418 Lasmiditan 200 mg 6 months 16.3 [6, 20]* n = 416 Lasmiditan 200 mg 9 months 15.3 [5.17]* n = 418 Lasmiditan 200 mg 12 months 13.4 [4, 16]* n = 418

*P<0.001 compared to baseline; mixed model for repeated measures.

There were no significant differences between lasmiditan doses.

- 22 046122

Table 7

GLADIATOR: Days with headache according to MIDAS in the last 3 months

Group Average number of headache days in past 3 months [IQR] Subjects Initial indicator 15.5 [8, 20] η = 974 Lasmiditan 100 mg 3 months 11.8 [4.5, 15]* η = 820 Lasmiditan 100 mg 6 months 10.6 [4, 14]* η = 673 Lasmiditan 100 mg 9 months 9.5 [3, 13]* η = 541 Lasmiditan 100 mg 12 months 8.8 [3, 10]* η = 429

*P<0.001 compared to baseline; mixed model for repeated measures.

No significant differences were observed between doses of lasmiditan

*P<0.001 compared to baseline; mixed model for repeated measures.

There were no significant differences between lasmiditan doses.

Table 9

GLADIATOR: number of headache days according to MIDAS in the last 3 months for patients with 12 months of data (analysis of subjects who completed treatment)

Group Average number of headache days in past 3 months [IQR] Subjects Initial indicator 14.3 [8, 18] η = 429 Lasmiditan 100 mg 3 months 10.6 [5, 15]* η = 428 Lasmiditan 100 mg 6 months 10.2 [4, 13]* η = 428 Lasmiditan 100 mg 9 months 9.2 [3, 12]* η = 429 Lasmiditan 100 mg 12 months 8.8 [3, 10]* η = 429

*P<0.001 compared to baseline; mixed model for repeated measures.

There were no significant differences between lasmiditan doses.

- 23 046122

Table 10

GLADIATOR: number of headache days according to MIDAS in the last 3 months for patients with 12 months of data (analysis of subjects who completed treatment)

Group Average number of headache days in past 3 months [IQR] Subjects Initial indicator 14.5 [7, 18] n = 418 Lasmiditan 200 mg 10.6 [4, 15]* n = 418 3 months Lasmiditan 200 mg 6 months 10.0 [4, 12.5]* η = 416 Lasmiditan 200 mg 9 months 8.5 [3, 12]* n = 418 Lasmiditan 200 mg 12 months 8.2 [2, 10]* n = 418

*P<0.001 compared to baseline; mixed model for repeated measures.

There were no significant differences between lasmiditan doses.

Table 11 GLADIATOR: Headache according to MIDAS in the last 3 months

Group Average headache severity over the past 3 months [IQR]f Subjects Initial indicator 7.4 [7, 8] η = 974 Lasmiditan 100 mg 3 months 7.0 [6, 8]* η = 820 Lasmiditan 100 mg 6 months 6.7 [6, 8]* η = 673 Lasmiditan 100 mg 9 months 6.7 [6, 8]* η = 541 Lasmiditan 100 mg 12 months 6.4 [5, 8]* η = 429

*P<0.001 compared to baseline; mixed model for repeated measures.

f Rated on a scale of 0-10, where 0 = no pain at all and 10 = pain as bad as possible.

There were no significant differences between lasmiditan doses.

Table 12 GLADIATOR: Headache according to MIDAS in the last 3 months

Group Average headache severity over the last 3 Subjects months [IQR]f Initial indicator 7.3 [6, 8] η = 1063 Lasmiditan 200 mg 3 months 6.9 [6, 8]* η = 884 Lasmiditan 200 mg 6 months 6.7 [6, 8]* η = 718 Lasmiditan 200 mg 9 months 6.5 [6, 8]* η = 580 Lasmiditan 200 mg 12 months 6.2 [5, 8]* η = 415

*P<0.001 compared to baseline; mixed model for repeated measurements - 24 046122.

t Rated on a scale of 0-10, where 0 = no pain at all and 10 = pain as bad as possible.

There were no significant differences between lasmiditan doses.

Table 13 GLADIATOR: Headache according to MIDAS in the last 3 months for patients with 12 months of data (analysis of subjects who completed treatment)

Group Average headache severity over the past 3 months [IQR]f Subjects Initial indicator 7.4 [7, 8] η = 429 Lasmiditan 100 mg 3 months 7.1 [6, 8] C η = 428 Lasmiditan 100 mg 6 months 6.9 [6, 8]* η = 428 Lasmiditan 100 mg 9 months 6.8 [6, 8]* η = 429 Lasmiditan 100 mg 12 months 6.4 [5, 8]* η = 429

*P<0.001, P=0.003 compared with baseline; mixed model for repeated measures.

t Rated on a scale of 0-10, where 0 = no pain at all and 10 = pain as bad as possible.

There were no significant differences between lasmiditan doses.

Table 14 GLADIATOR: Headache according to MIDAS in the last 3 months for patients with 12 months of data (analysis of subjects who completed treatment)

Group Average headache severity over the past 3 months [IQR]f Subjects Initial indicator 7.4 [7.8] n = 415 Lasmiditan 200 mg 3 months 7.0 [6, 8]* n = 415 Lasmiditan 200 mg 6 months 6.8 [6, 8]* n = 413 Lasmiditan 200 mg 9 months 6.5 [6, 8]* n = 415 Lasmiditan 200 mg 6.2 [5, 8]* n = 415 12 months

*P<0.001 compared to baseline; mixed model for repeated measures.

t Rated on a scale of 0-10, where 0 = no pain at all and 10 = pain as bad as possible.

There were no significant differences between lasmiditan doses.

Patients randomized to receive 100 mg lasmiditan or 200 mg lasmiditan had, on average, severe migraine disability at baseline (mean MIDAS score 21+). Patients demonstrated significant clinically significant improvement in MIDAS score over 12 months of treatment (summarized in Fig. 3). Migraine disability, headache days, and headache in the past 3 months improved over time with both doses. There were no significant differences between lasmiditan doses for any of the outcomes. Changes from baseline in the analysis of subjects who completed the study were similar to those for the overall population at each time point. This result suggests that the overall conclusion is not affected by missing data/selective attrition.

Treatment with lasmiditan resulted in a reduction in migraine disability scores on the MIDAS scale, number of headache days, and migraine severity over time, and these long-term effects were similar between the 100 and 200 mg lasmiditan groups. The observed reduction in disability over several months, for example up to 12 months, is striking and unexpectedly leads to the concept that long-term administration of lasmiditan, preferably at night, represents a means of achieving durable, disease-modifying, reduction in migraine susceptibility in some migraine patients. Thus, the inventive teachings disclosed herein are supported by the unexpected observations obtained from the study of lasmiditan in the Gladiator study.

Example 3. Long-term use of lasmiditan at night for the prevention of migraine.

This study will test the primary hypothesis that long-term nightly dosing of lasmiditan is superior to placebo for prevention in patients with treatment-resistant migraine. A similar study could be conducted in patients with migraine without the additional criteria that previous prevention efforts had failed. The primary endpoint of this study is the overall mean change in the number of migraine headache days per month from baseline during the 3-month double-blind treatment phase in the general population (episodic and chronic migraine).

All key secondary objectives will be tested in both the general population (episodic and chronic migraine) and the episodic migraine subpopulation unless otherwise specified. The specific methodology (including test order and population) to test the following key secondary endpoints will be specified in the statistical analysis plan.

The secondary objective of the study is to compare long-term lasmiditan and placebo at night for migraine prevention in the episodic migraine subpopulation, with the secondary objective reflecting the overall mean change from baseline in the number of migraine headache days per month during the 3-month double-blind phase. treatment of patients with episodic migraine. The secondary objective of the study is to compare long-term lasmiditan and placebo at night for a 50% response rate, with the secondary objective reflecting the percentage of patients with a >50% reduction from baseline in the number of migraine headache days per month over 3 months. double-blind treatment phase. The secondary objective of the study is to compare long-term use of lasmiditan and placebo at night on changes in performance, with the secondary objective reflecting the mean change from baseline in the limitation of daily activities group score on the Migraine Quality of Life Questionnaire, version 2.1 (MSQ v2.1). ) in the 3rd month. The secondary objective of the study is to compare long-term lasmiditan and placebo at night for a 75% response rate, with the secondary objective reflecting the percentage of patients with a >75% reduction from baseline in the number of migraine headache days per month over 3 -one-month double-blind treatment phase. The secondary objective of the study is to compare long-term lasmiditan and placebo at night for a 100% response rate, with the secondary objective reflecting the percentage of patients with a 100% reduction from baseline in the number of migraine headache days per month over a 3-year period. month-long double-blind treatment phase.

This study may be a multicenter, randomized, double-blind, parallel, placebo-controlled study of long-term nightly dosing of lasmiditan in patients who meet the International Classification of Headache Disorders (ICHD) criteria for a diagnosis of migraine with or without warning symptoms or chronic migraine and who have not previously received an effect from 2-4 standard methods of migraine prevention. The study consists of four periods, including a prospective baseline period to determine patient eligibility.

The study includes six treatment groups: long-term nightly lasmiditan (25, 50, 75, 100, 150, and 200 mg/night) and placebo. After a 1-month prospective baseline period, eligible patients will be randomized 1:1 to receive placebo or long-term nightly lasmiditan for up to 3 months of double-blind treatment. Lasmiditan is taken orally at night, in one dose, in the form of one or more tablets until the specified study dose is reached. Patients who complete the double-blind treatment phase may proceed to the 3-month open-label treatment phase. Thereafter, all patients in the open-label treatment phase will receive lasmiditan at night at the dose indicated for each group.

The study will screen approximately 764 potential study participants to randomize approximately 420 patients with migraine, of which approximately 250 patients have episodic migraine, or these numbers will be adjusted for the size of study groups if necessary. Unless otherwise specified, statistical analyzes will be performed on the initial study population (ITT), which includes all patients who were randomized and received at least one dose of the study product. Patients in the ITT population will be analyzed according to the treatment group to which they were randomized. When assessing change from baseline, pa

- 26 046122 The patient will only be included in the analysis if he/she has a baseline and follow-up measurement. The primary analysis will evaluate the effectiveness of long-term nightly dosing of lasmiditan compared with placebo in the overall mean change from baseline in the number of monthly migraine headache days and probable migraine headache days during the 3-month double-blind treatment phase. The primary analysis will be performed using a mixed model repeated measures method based on restricted maximum likelihood.

Patients can be included in the study only if they meet all of the following screening criteria: 1) age between 18 and 75 years (inclusive) at the time of screening; 2) have a diagnosed migraine as defined by the International Headache Society ICHD-3 guidelines (1.1, 1.2 or 1.3) (ICHD-3 2018), with a history of migraine headaches for at least 1 year before the 1st visit and the onset of migraine before the age of 50 years; 3) have a history prior to one visit of at least 4 days with migraine headache and at least 1 day without headache per month on average over the past 3 months; 4) have, prior to one visit, documentation (medical or pharmacy record or physician confirmation) of a previous adverse outcome with 2-4 categories of migraine preventive medications in the past 10 years from the following list due to inadequate effectiveness (i.e., maximum tolerated dose for at least 2 months) and/or safety/tolerability considerations, the list including (a) propranolol or metoprolol, (b) topiramate, (c) valproate or divalproex, (d) amitriptyline, (e) flunarizine, ( f) candesartan, (g) botulinum toxin A or B, and (h) a locally approved drug for migraine prophylaxis (patients meeting criteria (f) and (h) only should not exceed 20% of the total study population); 5) from visit 2 to visit 3 (prospective baseline period), have a frequency of 4 or more days with migraine headache and at least 1 day without headache in a 30-day period (to avoid reporting bias, patients are not told number of days with migraine or headache on which the study classification is based); and 6) from Visit 2 to Visit 3 (prospective baseline period), there should be sufficient compliance with daily headache entries in ePRO, as evidenced by completion of at least 80% of daily diary entries.

Long-term nightly administration of lasmiditan for use in migraine prophylaxis is believed to be superior to prior prophylactic therapies, particularly in some previously untreated groups, due to its sustained effect on the trigeminal system. These pharmacological properties are believed to provide superior efficacy for migraine prevention in patients who suffer from treatment-resistant migraine. Thus, the potential efficacy provided by the use of the lasmiditan of this invention for the prevention of migraine in patients whose disease is refractory to two or more prior treatment regimens or prophylaxis as monotherapy and/or dual therapy represents an important additional advance in the prevention of migraine. Preferably, patients treated in accordance with the administration regimens of the present invention may potentially not experience migraine pain and/or migraine disability, as assessed by methods well known to one of ordinary skill in the art, such as the MIDAS assessment, or by known indicators of quality of life. Preferably, patients treated in accordance with the administration regimens of this invention will have three or fewer migraine days per month, and more preferably no more than one migraine day per month. Preferably, the administration regimens of this invention will provide improved migraine prevention as described herein while demonstrating the desired clinical safety and tolerability.

Example 4: The LAIL Study is a randomized, double-blind, controlled, phase 2 trial of once-nightly lasmiditan for the prophylactic treatment of episodic migraine in adults.

In the LAIL study, lasmiditan will be administered once daily, at least 8 hours before driving, and administration is recommended before bedtime. When used in this document, the indications reflect the nightly dosing regimen. Patients should not drive or engage in other activities requiring alertness for at least 8 hours after taking each dose of study drug, even if they feel well enough to do so. To minimize these effects, patients are advised to take doses of the study drug at bedtime. If possible, based on the 8-hour limit, dosage is recommended to be taken before bedtime. This regimen is an example of overnight administration as used herein, which may include any specific time of day when the patient intends to sleep or rest for a period of time that the patient typically perceives as sleep time, and is administered at night will preferably occur 8 hours before the next window in which the patient wishes to drive. This regimen also provides an example of overnight administration as used

- 27 046122 herein, this means that lasmiditan is administered once every 24 hours or once every calendar day, preferably for at least 5 consecutive days, or preferably for a period of at least 10 days, or as long as necessary for migraine prevention. This regimen is also an example of long-term administration, as used herein, meaning that lasmiditan is administered on an ongoing, continuous basis as the patient takes doses and/or as the patient is prescribed to take doses as part of a treatment regimen.

Goals ^{a Endpoints} Primary • Test the hypothesis that at least 1 dose of lasmiditan (50 mg/day or 100 mg/day) is superior to placebo in preventing migraine headache in patients with episodic migraine • Overall mean change from baseline in number of migraine headache days per month during the 3-month double-blind treatment phase Key secondary objectives If lasmiditan (50 or 100 mg/day) is statistically significantly superior to placebo in the primary objective, the following key secondary objectives will be tested, adjusted for multiplicity: The specific methodology (including test order, correlation, and type I error distribution and propagation) for tests of the following key secondary endpoints will be specified in the statistical analysis plan (SAP): Compare lasmiditan with placebo for: • 50% response rate • Percentage of patients with >50% reduction from baseline in number of migraine headache days per month • legal capacity • Average change w.r.t. the initial level of the group indicator

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activity restrictions in MSQ v2.1 in month 3 • number of days per month using emergency (abortive) treatment for migraine • Overall mean change from baseline in number of days per month using medications for acute headache treatment • dream • Overall mean change from baseline in patient-reported sleep quality (PROMIS-SF vl.O, sleep disturbance 4a) Other secondary goals Endpoints Compare lasmiditan with placebo for: • 30% response rate • Percentage of patients with a decrease by >3 0% of baseline number of migraine headache days per month • 75% response rate • Percentage of patients with a decrease by >7 5% of baseline number of migraine headache days per month • 100% response rate • Percentage of patients with a 100% reduction from baseline in the number of migraine headache days per month • onset of a stable response in 50% of cases • The initial month in which the percentage of patients who experience at least a 50% reduction in the number of migraine headache days per month that is maintained in all subsequent months up to month 3 occurs statistically. • days with moderate to severe headache • Overall mean change in number of days with moderate or severe headache

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pain per month relative to baseline level • start of effect • An initial month in which the mean change from baseline in the number of migraine headache days per month is statistically divided and maintained in all subsequent months until month 3 • headache days per month • Overall mean change in headache days per month from baseline • days with migraine headache according to ICHD-3 • Overall mean change in ICHD-3 migraine headache days per month from baseline • hours of migraine headaches per month • Overall mean change in number of hours with migraine headaches per month from baseline • hours with headache in month • Overall mean change in number of headache hours per month from baseline • disability and health-related quality of life • Changes from the baseline to the 3rd month in the following indicators: o MIDAS Total Score and Individual Items o MSQ v2.1 Total Score and Activities of Daily Living Limitation and Emotional Function scores • general impression of the patient about severity and change • Average change from baseline in PGI-S score at 3

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migraine conditions month • Average PGI-C score in month 3 • symptoms of allodynia • Average change from baseline in ASC-12 score at month 3 • migraine attacks • Overall mean change in number of migraine attacks per month from baseline • onset of migraine attacks after dosing • Overall average time difference onset of migraine attacks Estimate: • pharmacokinetics lasmiditana • Mean plasma concentrations of lasmiditan • changes in efficacy, safety and functional outcomes During study period IV (follow-up): • Mean changes in all continuous efficacy, safety and functional outcome measures also assessed during the double-blind treatment period Tertiary goals Endpoints Compare lasmiditan with placebo for: • symptoms associated with migraine • Overall mean change from baseline in number of migraine headache days per month with: o nausea and/or vomiting o photophobia and phonophobia o warning symptoms o prodromal symptoms • Overall mean change in number of symptom-free and headache-free days from baseline per month • symptoms of depression and anxiety • Average changes from baseline to month 3 for the following indicators: about PHQ-9 about GAD-7 • changes in health-related quality of life • Changes from the baseline to the 3rd month in the following indicators: about HCRU o Employment status

Abbreviations:

ASC-12 = 12-item Allodynia Symptom Checklist;

GAD = 7-item Generalized Anxiety Disorder Scale;

HCRU = Health Resource Utilization Questionnaire;

ICHD = International Classification of Headache Disorders;

MIDAS = Migraine Disability Assessment;

MSQ v2.1 = Migraine Quality of Life Questionnaire version 2.1;

PGI-S = Patient Global Impression of Severity;

PHQ-9 = Patient Health Questionnaire-9;

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PROMIS-SF = Patient-Reported Outcome Measurement Information System Short Form [v1.0, Sleep Disorder 4a];

SAP = statistical analysis plan.

^a All targets refer to Study Period III (3-month double-blind treatment period) unless specified in this table during Study Period IV.

^b Definitions of baseline and endpoint will vary depending on the assessment.

For primary and key secondary objectives, baselines and endpoints are defined in Section 9. For other assessments, baselines and endpoints will be defined in SAP.

Migraine and headache endpoint definitions:

End point Definition/criteria Migraine headache Headache, with or without warning symptoms, lasting >30 minutes with two of the following required characteristics (A and B): A. At least 2 of the following headache characteristics: • One-sided arrangement • Pulsating nature • Moderate to severe pain intensity • Worsening due to or urge to limit daily physical activity AND B. During a headache, at least one of the following: • Nausea and/or vomiting • Photophobia and phonophobia (Definition adapted from IHSICHD-3 standard definition) Possible migraine headache Headache lasting >30 minutes, with or without warning symptoms, but without one of the characteristics of migraine in the ICHD-3 IHS definition. To be precise, she answers • either at least two criteria A and none of criteria B, or • one criterion A and at least one criterion B. Migraine Headache Day (Primary Goal) Calendar day on which a migraine headache or probable migraine headache occurs

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pain. A day with a migraine headache according to ICHD Calendar day on which a migraine headache occurs. Migraine headache attack Begins any day when a migraine headache or probable migraine headache is reported and ends when a migraine-free day occurs. Non-migraine headache All headaches lasting >30 minutes that do not meet the definition of migraine or probable migraine. A day with a non-migraine headache Calendar day on which a non-migraine headache occurs. A day with a headache The calendar day on which any type of headache occurs (including migraine, probable migraine, and non-migraine headache).

Abbreviations:

ICHD = International Classification of Headache Disorders;

IHS = International Headache Society.

Overall plan.

The LAIL study is a multicenter, double-blind, randomized, placebo-controlled, phase 2 trial of lasmiditan in adult patients with episodic migraine. The study will consist of four consecutive periods (see diagram below and schedule of activities):

Study period I (screening): 3-30 days.

Study period II (prospective baseline): 30-40 days after study period I.

Study period III (double-blind): approximately 90 days.

Study period IV (follow-up): up to 32 days.

During Study Period III, patients will be randomly assigned in a 2:1:1 ratio to 1 of 3 oral once-daily (QD) groups:

Placebo

Lasmiditan:

mg,

100 mg (see Section 6.1 for dose selection approach for this treatment group).

Scheme

Period Period Study period Study III Study I Study II Double-blind treatment (once daily)

Screening Initial

Study period IV Follow-up

Placebo

3-30 days

Lasmiditan 50 mg

Lasmiditan 100 mg

Electronic patient diary (daily) ^{3 Months} C: -1 O (1 week) 1 2 3 (1 week) 4 ^P ° ^Se ' 1 2 3 4 5 6 7 801 ^b 802 tion:

Randomization ^a In addition to the daily eDiary patient diary, patients will complete a paper diary.

^b An 801 visit is a telephone call to assess any withdrawal symptoms and side effects associated with the study treatment.

Schedule of Events (SoA).

During the treatment period, unscheduled visits may be conducted at the discretion of the investigator. The eligibility period for the prospective baseline assessment will last 30 to 40 days. In researchers and patients

- 33 046122 there may be up to five additional days to register for visit 3 (over 40 days); however, eligibility will be based on a 30-40 day period. An early termination (ET) visit applies to early terminations occurring before the 7th visit. An 801 visit will be a telephone call; this will occur 7 days after visiting 7 or ET. Visit 801 will be used to assess any withdrawal symptoms and AEs (adverse events) associated with the study treatment, as well as any other planned assessments according to the Schedule of Events. Other evaluations (including laboratory tests and additional follow-up visits) may be prompted by observed AEs, if necessary in the opinion of the investigator.

Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective Outcomes SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 h 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Assessments and procedures Informed consent X Demographics X Characteristics of migraine according to IHS criteria X History of migraine X Full medical examination X X X Height X Weight X X X X Disease history X

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective outgoing SP III Treatment period (3 months) ET SPIV Follow up Notes Visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Substance use X Psychoactive substance: alcohol, coffee and nicotine, tobacco 12-lead ECG X X X X Performed before blood sampling.

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective Outcomes SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Vital Signs X X X X X X X X Includes blood pressure and pulse in a sitting position, measured in three repetitions. Before administering the dose and before drawing blood. Inclusion and exclusion criteria X Confirmation of eligibility X X

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective outgoing SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Analysis of AEs X X X X X X X X X Familiarization with concomitant medications X X X X X X X X X X Implementation of an electronic diary, including assessment of the patient's ability to use the electronic diary X Providing an electronic patient diary and a paper patient diary, as well as providing training on how to use the electronic diary X

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective outgoing SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Patient education video X If possible and if permitted by local regulations and ethics boards, patients will watch a video education designed to address patient expectations regarding participation in a placebo-controlled study and the differences between medical and IMT treatments. And research.

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective outgoing SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post more Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 N.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Dispensing of the study drug X X X X Entry in the patient's electronic diary See details. Patients will fill out electronic diaries daily, starting with the 2nd visit. Detailed information about the patient's electronic diary.

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective Outcomes SP III Treatment period (3 months) ET SPIV Follow up Prime mania Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Entry in the patient's paper log See details. If necessary, you and patients will use a paper log to record the appointment of related drugs for headaches and headaches. Detailed information about the patient's paper log.

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective outgoing SP III Treatment period (3 months) ET SPIV Follow up Prime mania Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Analysis of the electronic diary and paper journal of patients X X X X X X X Randomization X Assessing patient compliance with study drug instructions X X X X X Collection unused/empty packages of investigational medicinal product X X X X X Clinical laboratory testing and sampling schedule General blood analysis X X X X X

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective outgoing SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Clinical chemistry X X X X X No food intake is required. Analysis of urine X X X FSH X Women only, if necessary, to confirm the condition of menopause

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective Outcome SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Serology test Pregnancy should only be performed on women of childbearing age. Serological pregnancy test X X X After a positive urine test, a serology pregnancy test should be performed for confirmation. Collect serum for a pregnancy test at the 7th visit or at the ET if the patient does not enter Study IV.

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective Outcomes SP III Treatment period (3 months) ET SPIV Follow up Notes Visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Urine pregnancy test X X X X A urine pregnancy test should only be performed on women of childbearing age. Performed locally. After a positive urine test, a serological pregnancy test should be performed to confirm.

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective Outcomes SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Urine drug screening X Sample for pharmacogenetics X Before dosing Research samples of biomarkers X X X Visit 3: before entering doses Pharmacokinetics X X X Visit 6: Additional sample for PK will be collected using microsampling method.

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective Outcomes SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Indicators, questionnaires and results Baseline CSSRS/screening visit X C-SSRS regarding last visit X X X X X X X X X Supplementary form on self-harm X X X X X X X X X Administrator's account works only with spontaneous messages.

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Procedure SPI Pose menu e 1 Screen ING SPII Visit 2 Prospective Outcome SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Self-harm follow-up form X X X X X X X X X Required if additional form is initiated and self-edit according to instructions. MIBS-4 X X X X X X MSQv2.1 X X X X X X PGI-S X X X X X PGI-C X X GAD-7 X X X X PHQ-9 X X X X PROMIS-SF vl.O, sleep disorder 4a X X X X X X

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective Outcome SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 ASC-12 X X X Accident/injury assessment Initial visit X Assessment of traffic accidents/injuries since last visit X X X X X X

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Procedure SPI Visit 1 Screen ING SPII Visit 2 Prospective Outcomes SP III Treatment period (3 months) ET SPIV Follow up Notes Not visited 3 Post 4 Post 5 Post 6 Episode 7 Message 801 Post 802 Month of research -1 0 n.d. 1 2 3 4 Target interval (days) since previous visit 30-45 7 23 thirty thirty 7 23 Interval tolerance (days) ±2 ±2 ±2 ±2 ±2 ±2 Allowable interval (days) between visits 3-30 30-40 Assessment of chronic pain not associated with migraine X X X X X X Questionnaire IC administered by physician to assess other chronic pain conditions Assessments after the 3rd NICU visit are intended only for those who have chronic pain identified at the 3rd NICU visit.

Abbreviations:

AE = adverse event;

ASC-12 = 12-item Allodynia Symptom Checklist;

C-SSRS = Columbia University Suicidal Severity Scale;

ET = early termination;

FSH = follicle stimulating hormone;

GAD-7 = 7-item Generalized Anxiety Disorder Scale;

IHS = International Headache Society;

MIBS-4 = 4-item Migraine Interictal Severity Scale;

MSQ v2.1 = Migraine Quality of Life Questionnaire, version 2.1;

PGI-C = Patient Global Impression of Change;

PGI-S = Patient Global Impression of Severity;

PHQ-9 = Patient Health Questionnaire-9;

PK = pharmacokinetics;

PROMIS-SF = Patient-Reported Outcome Measurement Information System Short Form [v1.0, Sleep Disorder 4a];

SP = study period.

The duration of the randomized treatment phase (3 months) is considered sufficient to evaluate the safety and efficacy of the drug for migraine prevention and meets regulatory requirements for compounds with similar indications and patient populations. Among patients randomized to placebo in migraine prevention trials, response to placebo at 3 months ranged from 14 to 31% (Speciali et al., 2010), highlighting the importance of comparing the study active drug with placebo. Considering

- 49 046122 The half-life of lasmiditan is short, the drug concentration should be negligible 2 days after stopping use. Patients will be assessed for withdrawal effects within the first 7 days after stopping treatment. A 1-month follow-up period was included to further evaluate patient safety and migraine incidence.

This phase 2 study will examine two doses of lasmiditan: 50 and 100 mg. Systemic exposure to lasmiditan 50 and 100 mg is predicted to reach or exceed the exposure observed in rats treated with an oral dose of 1 mg/kg lasmiditan, which resulted in positive and statistically significant effects in various pharmacological rat models thought to be related to migraine. Doses of 100 mg lasmiditan are expected to maintain mean unbound brain concentrations above the in vitro 5-HT1F receptor inhibition constant for a greater duration than for 50 mg lasmiditan, which may provide greater efficacy for 100 mg lasmiditan compared with 50 mg lasmiditan. While the efficacy of lasmiditan for 2-hour pain relief in completed phase 3 single-episode studies of lasmiditan appeared to be dose-dependent, migraine recurrence rates were also low in the dose range of 50 to 200 mg for 2 to 24 hours after dosing. In a long-term, open-label study of intermittent treatment of migraine attacks with lasmiditan over a 12-month treatment period, there was a reduction in migraine-related disability, number of headache days, headache severity, and number of migraine attacks treated with lasmiditan. These results were similar for the 100 and 200 mg doses.

TEAEs reported for lasmiditan from completed single-episode phase 3 studies were primarily neurologic in nature, mostly mild to moderate in severity, and the likelihood of TEAEs generally increased with increasing dosage of lasmiditan. Based on studies of lasmiditan for the acute treatment of migraine, lasmiditan 100 mg and 200 mg demonstrated similar efficacy on endpoints that may be associated with prophylactic treatment of migraine, but the 200 mg dose was numerically superior to TEAE. This phase 2 study will examine 50 and 100 mg of lasmiditan once daily for the prophylactic treatment of migraine.

Dosage regimen.

Lasmiditan should be administered once daily/night at least 8 hours before driving, and the dose is recommended to be taken at bedtime. This treatment regimen is believed to maximize tolerability and provide an opportunity to observe the effectiveness of lasmiditan in preventing migraine. In healthy volunteers, acute treatment with lasmiditan was shown to worsen simulated driving performance in a dose-dependent manner, which was reversed by 8 hours post-dose. Because this is an important potential safety issue, patients participating in the LAIL study will be instructed not to drive for at least 8 hours after dosing. To allow at least 8 hours before driving, this study recommended dosing at bedtime. While TEAEs reported with lasmiditan are generally mild to moderate and short in duration, the bedtime dosing recommendation is intended to mitigate potential tolerability issues observed with intermittent, acute treatment with lasmiditan, which are considered less acceptable with long-term preventive treatment at night. These include TEAEs (eg, drowsiness, lethargy, or fatigue) that may be considered bothersome during waking hours. Another consideration supporting the recommendation of dosing before bedtime is that migraine attacks peak in the early morning hours. An analysis of 3592 migraine attacks in 1696 adults found that migraine attacks often begin between 4 and 9 a.m. (Fox and Davis 1998), with nearly half of attacks occurring during this 5-hour window. Although the prolonged pharmacodynamic effects of lasmiditan are considered an advantage of the present dosing regimens, dosing at bedtime will provide higher drug concentrations during the morning hours, the time of greatest occurrence of migraine attacks.

A patient is considered to have completed the study if he/she has completed all phases of the study, including the last visit or last scheduled procedure listed in the Schedule of Activities. The end of the study is defined as the date of the last visit or last scheduled procedure listed in the Schedule of Activities for the last patient.

Study population.

All patients must meet the following selection criteria. Patients' eligibility for inclusion in the study will be based on the results of the screening history, physical examination, neurological examination, clinical laboratory tests, electrocardiogram (ECG), and history of migraine at the time of screening and the prospective baseline period, as described in the Inclusion and Exclusion Criteria sections. The nature of any associated pathological conditions present during the physical examination and any pre-existing pathological conditions should be documented. Individuals who do not meet the criteria for participation in this study (individuals not

- 50 046122 screened) for certain reasons, as stated, may be considered for re-screening again.

Patients can only be included in the study if all of the following criteria are met:

1. Patients must be between 18 and 75 years of age inclusive at the time of signing the informed consent.

2. Have a diagnosed migraine with or without warning symptoms, as defined by guidelines from the International Headache Society (IHS) International Classification of Headache Disorders (1.1, 1.2.1) (ICHD-3 2018), with at least a history of migraine 1 year before visit 1 and onset of migraine before age 50 years.

3. Prior to 1 visit, have a history of 4 to 14 days of migraine headaches and at least two migraine attacks per month on average over the past 3 months.

4. From Visit 2 to Visit 3 (prospective baseline period), migraine frequency ranged from 4 to 14 days and at least 2 migraine attacks (see Definitions) in the electronic diary entries. To avoid reporting bias, patients were not told the number of migraine headache days on which the study classification was based.

5. From visit 2 to visit 3 (prospective baseline period), patients should be sufficiently proficient in entering daily headache information into ePRO, as evidenced by completion of at least 80% of daily diary entries.

6. Patients must be able to sign informed consent as described, which includes compliance with the requirements and restrictions listed on the informed consent form (IF) and in this protocol.

7. The patient must be dutiful and willing to follow the study procedures.

8. Women of childbearing potential must have a negative pregnancy test and agree to use a highly effective method of contraception.

Subjects are excluded from the study if any of the following criteria are met:

9. Previous users of lasmiditan, including those who previously completed or dropped out of this study.

10. In the opinion of the investigator, have a known hypersensitivity to lasmiditan or any excipient of lasmiditan oral tablets, or any sensitivity to ditan, or a known hypersensitivity to multiple drugs.

11. Have a history of using CGRP monoclonal antibodies for migraine prophylaxis for 4 months after 1 visit.

12. Have a history of failure of more than 4 classes of migraine prophylactic medications.

13. Used no more than 9 triptan doses per month in the 3 months prior to visit 1 and <9 triptan doses during the prospective baseline period.

14. According to the investigator, are currently taking medications or other therapies to prevent migraine headaches. Botulinum toxin A and B injected into the head or neck area for therapeutic use must be discontinued at least 3 months before the 2nd visit. Use of medications, nerve blocks, or devices (eg, transcranial magnetic stimulation) in the head or neck area or for migraine prophylaxis should be discontinued at least 30 days before the two visits.

15. Have a history of persistent daily headache, cluster headache or migraine of various subtypes, including migraine with precursor symptoms in the brainstem (basilar type migraine) (1.2.2), hemiplegic (sporadic or familial) migraine (1.2.3 ) or retinal migraine (1.2.4), as defined in IHS ICHD-3.

16. Have a history of headache (eg, cluster headache, medication overuse headache) other than migraine or tension-type headache, as defined by IHS ICHD-3, within 3 months before randomization.

17. Prior to 1 visit, have a history of >15 headache days (migraine, probable migraine, or any other headache) per month on average over the past 3 months or are suspected of having chronic migraine as defined by the IHS ICHD-3 definition.

18. Have a history of head or neck injury within 6 months prior to 1 visit.

19. Have a history of head trauma associated with a significant change in the quality or frequency of headaches.

20. Have a positive urine screen for drug abuse on 1 visit.

21. Have a history of recurrent dizziness and/or vertigo, including benign paroxysmal positional vertigo, Meniere's disease, vestibular migraine and other symptoms

- 51 046122 tibular disorders.

22. In the opinion of the investigator, have significant impairment of renal or hepatic function, or if they meet the criteria for liver surveillance.

23. Women who are breastfeeding.

24. Have an acute, serious or unstable medical condition that, in the opinion of the investigator, indicates a medical problem that would preclude participation in the study (eg, symptomatic bradycardia).

25. Are unwilling or unable to comply with the rules for using a data collection device.

Unscreened individuals are defined as patients who agreed to participate in a clinical trial but were not subsequently randomly assigned to the study treatment. Individuals ineligible for this study (individuals not screened) may be rescreened only once if: patients are taking a concomitant medication that requires a stable dose for a specified period of time before the 2nd visit and additional time is required to meet the duration requirement. The interval between screening and rescreening should be at least 45 days, or longer if required by the inclusion/exclusion criteria or concomitant medication list.

Investigational treatment means any investigational treatment and/or placebo intended to be administered to a study participant (patient) in accordance with the study protocol. This study involves double-blind treatment with lasmiditan 50 and 100 mg or placebo administered orally once daily for the prevention of migraine headaches. Lasmiditan will be administered once daily at least 8 hours before driving, recommended at bedtime. To ensure anonymity throughout the study, patients in all treatment groups will receive two tablets per day (one of each size) controlled by two placebos to ensure anonymity of the study treatment once daily.

Research group Injectable tablets (once daily) With active ingredient Placebo Lasmiditan, 50 mg Lasmiditan, 100 mg ^a Placebo corresponding to lasmiditan 50 mg Placebo corresponding to lasmiditan 100 mg Lasmiditan, 50 mg X X Lasmiditan, 100 mg X X Placebo X X

^a The starting dose of lasmiditan will vary: during the first week of treatment, patients in this group will receive 50 mg of lasmiditan once daily, followed by 100 mg once daily.

The study drug will be administered at approximately the same time each day, with recommended administration at bedtime. Patients will record the date and time of administration of the selected dose in their electronic diary. Dose changes are not permitted in this study.

This is a double-blind study (ie, the patient and investigator will not be aware of the treatment being studied). The following stratification factors will be used: geographic region or country, migraine frequency at baseline (<8 vs. >8 migraine headache days per month).

Enrollment of patients with infrequent migraine headaches (ie, <8 migraine headache days per month) will be stopped if the number of such patients exceeds 176. If the investigator, site assessment staff, or patient are unmasked, the patient should be excluded from the study.

Patient compliance with study treatment will be assessed at each visit. Methods to assess adherence will include direct questioning and counting of returned pills.

At each visit, information on adherence to the study product will be collected based on the percentage of tablets taken of the total number prescribed.

Indications for use, dates of administration, and dosage of any medication or vaccine (including all over-the-counter and prescription medications for migraine and other conditions, vitamins and/or herbal supplements) that the patient is receiving at the time of study entry or receives during time of study, should be recorded along with the reason for use, dates of administration, including start and end dates, dosage information, including dose and frequency, by

- 52 046122 introductions.

If necessary, patients will use their journal to record the use of concomitant migraine medications. Study personnel must record all concomitant medications throughout the patient's participation in the study.

All doses of lasmiditan were associated with impaired driving in a computerized driving simulator study of healthy volunteers. Patients should limit driving, operating heavy machinery, or other similar activities after taking the study drug as described in the FIS. To minimize these effects, patients are advised to take doses of lasmiditan at bedtime. They must also wait at least 8 hours before driving, operating heavy machinery, or performing other similar activities.

Patients who discontinue the study or take the investigational product during the double-blind treatment phase (Study Period III) immediately proceed to Study Period IV. Patients who discontinue study product prematurely for any reason must complete adverse event management and other follow-up procedures in the protocol. Temporary termination of the study is not permitted.

The electronic diary will be used to collect information for the initial performance assessment. In addition to information collected through the electronic diary and patient log, on-site assessments will be conducted in accordance with the Schedule of Activities.

Secondary efficacy measures include the Migraine Quality of Life Questionnaire, version 2.1. The MSQ v2.1 is a self-report health instrument that has been designed to target the physical and emotional functioning that is particularly important for people suffering from migraine. The instrument consists of 14 items that fall into three groups (Jhingran et al., 1998b): limitation of daily activities, prevention of daily activities, and emotional function. The restrictive group specifically measures disability in relation to the impact on the performance of normal activities, the preventive group focuses on complete functional impairment, and the emotional group assesses feelings associated with monthly disability during migraine headache days. Responses are provided using a 6-point Likert scale ranging from none of the time to all of the time. Raw scores for each group are calculated as the sum of item responses, with the total giving a total raw score, which is then converted to a 0–100 scale, with higher scores indicating better health status and a positive change in scores reflecting functional improvement (Jhingran et al., 1998a; Martin et al., 2000). The instrument was developed with a 4-week reassessment period and is considered reliable, valid, and sensitive to change in functional impairment due to migraine (Jhingran et al., 1998b; Bagley et al., 2012).

Another secondary effectiveness measure will be the Patient-Reported Outcome Measurement Information System (Sleep Disorders Short Form 4a) (PROMIS®). PROMIS® is part of an initiative of the National Institutes of Health. The stated goal is to provide clinicians and researchers with access to effective, accurate, valid, and responsive measures of the health and well-being of adults and children (HealthMeasures, 2013). The PROMIS Initiative used modern measurement theory and an evidence-based approach to instrument development using quantitative, qualitative, and mixed methods. This approach produced patient self-report banks with excellent psychometric properties. The PROMIS-SD Patient Self-Report Item Bank (HealthMeasures WWW) was developed through an iterative process of literature search, item collection and screening, expert content review, qualitative patient research, and pilot testing. The resulting 27 items assess self-reports of perceived sleep quality, sleep depth, and sleep-related recovery. This includes perceived difficulty and concern in falling asleep or staying asleep, as well as perceptions of sleep adequacy and satisfaction. PROMIS-SD has demonstrated excellent measurement properties, including internal consistency and convergent validity. The validity of the item bank has been demonstrated by moderate to high correlations with existing scales and the ability to discriminate between people with and without sleep disorders (Buysse et al., 2010). PROMIS-SD has been tested and has demonstrated evidence of validity (e.g., expected associations, separation into known groups) in a wide range of populations ( Busse et al., 2013 , Cook et al., 2012 , Fenton et al., 2011 , Stachler et al. . 2014). Subsequent studies using item analysis and clinical judgment reduced the 27-item scale to 8 items. The authors reported that the 8-item version had greater measurement accuracy than the Pittsburgh Sleep Quality Index (PSQI) (Yu et al., 2012). Further reduction in the number of items resulted in a 4-item version (PROMIS-SF SD 4a). The resulting 4 items measure sleep quality, sleep onset, sleep problems, and calmness. A study conducted by Jensen et al. (2016), demonstrated that ver

- 53 046122 This 4-point item has adequate reliability and accuracy. Each question has 5 answer options, ranging in value from 1 to 5. To assign a grade, the overall initial score is determined by summing the values of the answers to each question. Once the overall raw score has been calculated, use the appropriate score conversion table in the PROMIS Sleep Disorders Assessment Manual to convert the overall raw score to a T-score for each participant. The T-score rescales the original score into a standardized score with a mean of 50 and a standard deviation (SD) of 10. A higher score indicates more sleep disturbance.

Another secondary efficacy assessment may include the Migraine Disability Assessment (MIDAS). MIDAS is a patient assessment scale that was developed to quantify headache-related disability over a 3-month period. This instrument consists of five items reflecting the number of days missed or with reduced productivity at work or at home, as well as at social events. Each question is answered as the number of days in the last 3 months of assessment, ranging from 0 to 90, with the total score being the sum of the five numerical responses. A higher score indicates greater disability (Stewart et al., 1999, 2001). This instrument is considered reliable and valid, and its results are consistent with clinical judgments of medical need (Stewart et al., 1999, 2001). For clinical interpretability, 4 categorical grades were developed based on the overall assessment: grade I (0 to 5) - little or no disability, grade II (6 to 10) - mild disability, grade III (11 to 20) - moderate incapacity and IV degree (21+) - severe incapacity. The severe disability category was subsequently divided into grade IV-A (severe [21 to 40]) and grade IV-B (very severe [41 to 270]), since the majority of patients with chronic migraine are in the grade IV group (Blumenfeld et al., 2011). Two additional questions (A and B) collect information on headache frequency and headache intensity. They are not assessed in the MIDAS questionnaire, but are included to provide clinically relevant information that can assist in treatment decisions and adjustments.

Another secondary assessment of effectiveness may include the Patient's Global Impression of Severity. The Patient Global Impression of Severity Scale (PGI-S) (Guy, 1976) is a patient rating instrument that measures the current severity of illness. The PGI-S includes a range of possible responses from 1 (okay, not bad at all) to 7 (very bad). The patient's overall impression of change may represent another secondary assessment of effectiveness. The Patient Global Impression of Change (PGI-C) scale (Guy, 1976) is a patient rating instrument that measures change in a patient's symptoms. This is a 7-point scale in which a score of 1 means the patient is much better, a score of 4 means the patient has no change, and a score of 7 means the patient is much worse. Another secondary efficacy assessment may include the 12-item Allodynia Symptom Checklist. The ASC-12 (Lipton et al., 2008) is a validated, quantitative, patient-administered 12-item instrument to measure the presence and severity of cutaneous allodynia associated with headache attacks. The instrument was designed to provide differentiated rather than dichotomous responses (present/absent). The ASC-12 asks how often a patient experiences increased pain or skin discomfort during the most severe type of headache while performing each of 12 items, such as combing hair, wearing glasses, and exposure to heat or cold. Each of the 12 items has the following response options: does not apply to me (0 points), never (0 points), rarely (0 points), less than half the time (1 point), and half the time or more (2 points). The total score ranges from 0 to 24 and gives the following degrees of allodynia (Lipton et al., 2008): none (0 to 2 points), mild (3 to 5 points), moderate (6 to 8 points) and severe ( 9 points or more).

Other performance assessments include information collected through an electronic diary and a patient log. Patients' responses to the acute migraine drug will be recorded locally. Other tertiary assessments are described below.

The Patient Health Questionnaire-9 (PHQ-9) is a 9-item patient-administered instrument that was developed to screen for MDD and measure the severity of depressive symptoms (Kroenke et al., 2001). The following 9 items refer to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria for MDD and continue to apply to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V): anhedonia, depressed mood , trouble sleeping, feeling tired, changes in appetite, feelings of guilt, self-blame or low self-esteem, trouble concentrating, feeling slowed down or restless, and thoughts about dying or hurting yourself. Each item is rated on a 4-point scale (0 = never, 1 = a few days, 2 = more than half the time, 3 = almost every day) based on symptoms over the past 2 weeks. The total score ranges from 0 to 27, with levels of depression severity defined as follows: 0-4 minimal, 5-9 mild, 10-14 moderate, 15-19 moderately severe, and 20-27 severe. The instrument is considered reliable and valid for use in research and clinical settings (Kroenke et al., 2001), including in patients with migraine (Seo and Park, 2015a).

- 54 046122

The Generalized Anxiety Disorder 7-Item (GAD-7) is a 7-item questionnaire that was developed to identify GAD and measure the severity of anxiety symptoms (Spitzer et al., 2006). The instrument was developed based on the GAD symptom criteria in DSM-IV (still applicable in DSM-V), as well as a review of existing anxiety scales, with items addressing the following: feeling nervous, uncontrollable worry, excessive worry, difficulty relaxing, agitation, irritability and fearfulness.

The patient determines how much these symptoms have bothered him over the past 2 weeks. Each of the 7 items is rated on a 4-point scale (0 = not at all, 1 = several days, 2 = more than half the days, 3 = almost every day) with a total score ranging from 0 to 21. Anxiety severity levels are defined as follows: 0- 4 = minimal, 5-9 = mild, 10-14 = moderate, and 15-21 = severe. The instrument is considered reliable and valid for use in research and clinical settings (Spitzer et al., 2006), including in patients with migraine (Seo and Park, 2015b).

Planned time points for all safety assessments are specified in the Schedule of Activity (SoA). A complete physical examination will include, at a minimum, an assessment of the cardiovascular, respiratory, gastrointestinal and nervous systems. Height and weight will also be measured and recorded. Researchers should pay particular attention to clinical features associated with previous serious illnesses. Adverse events (AEs) are recorded based on examinations. Vital signs include body temperature, blood pressure and pulse. Blood pressure and pulse will be measured in triplicate in a sitting position before blood collection and study drug administration. Height and weight will be assessed as indicated in the Schedule of Events. Any clinically significant vital sign measurements that lead to the diagnosis should be reported as AEs.

Each patient will have one 12-lead digital electrocardiogram (ECG) performed at the visits indicated in the Schedule of Activities. ECGs should be recorded in accordance with the study-specific recommendations included in the ECG manual. The screening ECG will be interpreted on site. The remaining ECGs will be interpreted centrally. Patients should lie supine for approximately 5 to 10 minutes before ECG recording and remain supine but awake during ECG recording. Any clinically significant ECG findings that lead to a diagnosis should be reported as an AE.

With the exception of laboratory test results, which may make the study non-anonymous, laboratory test results will be provided to the investigator. Appendix 2 provides a list of clinical laboratory tests that must be performed, and the SoA specifies the timing and frequency. The investigator should review the laboratory report, document the report, and record any clinically significant changes that occur during the study in the AE section of the CRF. Clinically significant laboratory abnormalities are those that are not related to the underlying medical condition unless the investigator considers them to be more serious than expected for the participant's condition. All laboratory tests with values considered clinically significant abnormalities during study participation should be repeated until the values return to normal or baseline values or are no longer considered clinically significant by the investigator or medical observer. If such values do not return to normal/baseline levels within a period of time deemed reasonable by the investigator, the etiology should be determined and the organizer notified. All laboratory assessments required by the protocol, as defined in Appendix 2, must be performed in accordance with the laboratory manual and SoA. Any clinically significant laboratory test results that lead to a diagnosis should be reported as an AE. If the study patient has elevated ALT >3X ULN, ALP >2X ULN, or elevated TBL >2X ULN, liver testing including ALT, AST, ALP, TBL, conjugated bilirubin, gamma-glutamyl transferase, and creatine kinase, to confirm abnormalities and determine the corresponding increase or decrease. If the disorder persists or worsens, the investigator should initiate clinical and laboratory monitoring in consultation with the study's medical supervisor. Monitoring of ALT, AST, TBL, and ALP should be continued until levels normalize or return to approximately baseline levels.

Because lasmiditan is a central nervous system drug, assessment of suicidal ideation and behavior will be monitored during the study using the Columbia Suicidal Severity Rating Scale (C-SSRS). The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicidal ideation and behavior during a questionnaire assessment period (Posner et al., 2011). The scale includes suggested questions to solicit information needed to determine whether suicidal thoughts or actions have occurred. The C-SSRS is administered by an appropriately trained healthcare professional with at least 1 year of patient care/clinical experience according to the activity schedule.

- 55 046122

To further evaluate the effect of lasmiditan on driving, patients will be asked to answer questions related to road traffic accidents and traffic violations according to the Intervention Schedule.

Venous blood samples will be collected at the visits and time points specified in the Schedule of Activities to determine plasma concentrations of lasmiditan and its metabolites.

When collecting a blood sample, the time (in 24-hour format) and date of last dose (usually from the previous evening) should be recorded before blood collection. You should also record the exact time and date of blood collection. A validated assay will be used to determine plasma concentrations of lasmiditan and its metabolite(s). Information about drug concentrations that may unblind the study will not be shared with study sites or personnel handling anonymized data until the study is unblinded.

Study staff will inquire about health care resource utilization and employment status (HCRU) when documenting patient responses. The HCRU consists of three questions regarding the number of emergency department visits, number of days in the hospital, and any other health care provider visits that have occurred since the patient's last study visit other than visits related to the patient's participation in the clinical trial. Patients will also be asked about the number of medical incidents associated with migraine. The initial visit will include the same questions, but within the framework of the last 6 months. Employment status will also be asked, given correlations and potential confounding with health status measures such as MIDAS.

The primary hypothesis is to determine that at least one dose of lasmiditan (50 mg/day or 100 mg/day) is superior to placebo in preventing migraine headache in patients with episodic migraine. Approximately 541 patients will be screened to find 292 patients randomized 2:1:1 to placebo (n=146), lasmiditan 50 mg (n=73) or lasmiditan 100 mg (n=73). Assuming a study discontinuation rate of 20% and an effect size of 0.55, this sample size is expected to provide approximately 90% confidence that the most effective dose of lasmiditan will be separated from placebo at a one-sided significance level of 0.05 or 0. 1 or preferably at a two-sided significance level of 0.05 for all intent-to-treat (ITT) patients in this study.

The three analysis groups were defined as follows: ITT group, safety group, and follow-up group. The ITT and safety groups included all patients who were randomized and received at least one dose of the study product. The follow-up group included all patients who entered the observation phase (study period IV). Unless otherwise specified, all efficacy analyzes will be performed according to the ITT principle in the ITT group; those. patients will be analyzed according to the treatment they were assigned at randomization, regardless of whether they actually received another treatment. Safety analysis will be performed in the safety group based on the treatment received by the patient. Analyzes for the follow-up phase (study period IV) will be based on the follow-up group only. Unless otherwise specified, analyzes will be performed for the ITT group in the efficacy analysis and for the safety group in the safety analysis. When change from baseline is assessed, the patient will be included in the analysis only if he/she has a baseline and follow-up measurement. Continuous performance variables with repeated measures will be analyzed using a mixed repeated measures model (MMRM). The MMRM will include fixed categorical effects of treatment, a baseline category for the frequency of migraine headache days (<8 vs. >8 migraine headache days per month), pooling by country, month, and an interaction by month of treatment, and continuous fixed covariates for baseline and interaction of baseline by month. For the primary endpoint model, the baseline frequency of migraine headache days category will be excluded from the covariates because the continuous number of migraine headache days per month is already in the model. For the analysis of the Study III period, visit 3 is defined as baseline, and all scheduled visits between visit 5 and visit 7 are defined as follow-up. For continuous efficacy variables without repeated measures, an analysis of covariance (ANCOVA) model with last observation carried forward (LOCF) will be used that contains main effects of treatment, baseline migraine headache days frequency category and pooling by country, and a continuous fixed baseline covariate . Type III sum of squares for weighted means (LSMeans) will be used for statistical comparisons. For the Study III period analysis, Visit 3 is defined as the baseline, and the last non-missing observation between Visit 3 and Visit 7 will be the post-baseline observation. Binary performance variables with repeated measures will be analyzed using a generalized linear mixed model (GLIMMIX) as a pseudo-likelihood mixed effects repeated measures analysis. The GLIMMIX model will include fixed categorical effects of treatment, month, and the interaction between treatment by month, as well as contiguous effects.

- 56 046122 discontinuous fixed baseline covariate. For binary efficacy variables without repeated measures, comparisons between treatment groups will be performed using logistic regression with the same model terms as the ANCOVA model. Pooling across countries can be removed to ensure model convergence. For continuous safety variables with repeated measures, MMRM methods will be used, as well as an ANCOVA model with LOCF substitution if deemed appropriate. When an ANCOVA model is used to assess safety, the model will contain a main effect of treatment as well as a continuous fixed covariate for baseline. Type III sum of squares for LSMeans will be used for statistical comparisons. For categorical safety variables (such as AEs and other categorical changes of interest) as well as for categorical baseline characteristics, comparisons between treatment groups will be made using Fisher's exact test. Treatment effects will be assessed based on a 2-sided significance level of 0.05 for all efficacy and safety analyses, unless otherwise stated. Type I error due to multiple comparisons for primary and key secondary objectives will be controlled according to the multiple comparisons procedure defined in SAP. For analyzes of other data (other secondary targets or tertiary targets), there will be no adjustment for multiplicity. Countries will be combined as necessary for statistical analysis purposes. Additional exploratory data analysis will be conducted as needed.

The number and percentage of ITT patients who completed the study or terminated the study early will be tabulated for all treatment groups for Study Period III. Reasons for discontinuation will be compared between treatment arms for study period III with the ITT arm. In addition, subcategories of treatment discontinuation based on patient decision will be summarized. For Study Period IV, the number and percentage of ITT patients who enter Study Period IV will be tabulated for all treatment groups, and among these patients, the number and percentage of patients who complete Study Period IV will be noted. Only descriptive statistics will be presented for the treatment groups in period IV of the study. The investigator's patient allocation will be summarized for Study Period III for all ITT patients. The investigator's patient allocation will also be listed for all study periods.

The following patient characteristics at baseline will be summarized by treatment group for all ITT patients. Demographic data (age, sex, ethnicity, height, weight, body mass index), migraine and/or headache scores from the ePRO diary for the 30-day baseline period, alcohol, tobacco, caffeine and nicotine consumption, medical history and pre-existing pathological conditions, medical history and pre-existing pathological conditions will be summarized by the preferred term within the system organ class (SOC).

The proportion of patients receiving concomitant medications collected from the eCRF and acute medications collected from the headache medication log will be aggregated for all ITT patients for study period III and study period IV separately.

A patient will be considered generally compliant with the study product during Study Period III if all non-missing, visit-based compliance data for Visits 5-7 indicate compliance. The percentage of patients who are compliant with the study product at each individual visit and overall will be compared between treatment groups using Fisher's exact test.

Compliance with the electronic patient-reported outcome diary will be calculated for each 1-month period (including baseline, 1st, 2nd, 3rd and 4th months) and for the entire study period III (1st to 4th month). 3rd month). Compliance with the diary in each period is calculated as:

The actual number of days in the diary for a certain period

Expected number of days in the diary for a certain period of xYO

The primary efficacy endpoint is the overall mean change from baseline in the number of migraine headache days per month during the 3-month double-blind treatment phase (study period III), and the primary analysis will evaluate the effectiveness of lasmiditan compared with placebo in the overall group ITT. The primary analysis will be conducted using the restricted maximum likelihood MMRM method. Analyzes will include categorical fixed effects of treatment pooled by country, month, and treatment by month interaction, as well as continuous fixed covariates of baseline number of migraine headache days and baseline number of migraine headache days by month interaction.

An unstructured covariance structure will be used to model errors across patients. The Kenward-Roger approximation (Kenward and Roger, 1997) will be used to estimate the degrees of freedom of the denominator. If the model does not converge with positive definite

- 57 046122 Hessian and G matrices according to the default fitting algorithm used by PROC MIXED, the Fisher scoring algorithm will be implemented by specifying the SCORING option in SAS®. If the model still does not converge, it will be fitted using covariance matrices of the next order, specified by a decreasing number of covariance parameters, until convergence is achieved: heterogeneous Toeplitz, heterogeneous first-order autoregressive, Toeplitz, first-order autoregressive. When an unstructured covariance matrix is not used, sandwich estimators will be used to estimate the standard errors of the fixed effects parameters (Diggle and Kenward, 1994). Sandwich valuation is implemented by specifying the EMPIRICAL option in SAS®. When the sandwich estimator is used, the Kenward-Roger approximation for the denominator degrees of freedom cannot be used. Instead, the denominator degrees of freedom will be binned across and within patients using the DDFM=BETWITHIN option in SAS®. PROC MIXED SAS® will be used to perform the analysis.

Secondary outcomes will be analyzed using the ITT arm for the double-blind treatment phase (study period III). Analysis models for continuous secondary measures will be the same as for primary analyzes (section 9.4.3.1), and the GLIMMIX model will be used to analyze the percentage of patients with a >50% reduction in migraine headache days from baseline per month.

In order to control for overall Type I error, the primary and a subset of secondary targets will be selected. Selected secondary analyzes will be tested using a multiple comparison procedure that maintains the overall Type I error at a two-sided alpha level of 0.05. If any of the null hypotheses are rejected for the primary endpoints, the selected secondary endpoints will be tested according to the multiple comparison procedure.

Deviations from the baseline for secondary and tertiary indicators will be analyzed. Definitions of these baselines will be included in SAP. In addition, categorical analysis will be performed to measure frequency. No multiplicity adjustments will be made for analyzes of other secondary or tertiary endpoints.

Safety and tolerability of treatment will be assessed by summarizing the following data: TEAE, SAE, AEs leading to discontinuation, vital signs and weight, ECG, laboratory measurements, C-SSRS, motor vehicle accidents/traffic violations, AEs associated with discontinuation . Unless otherwise specified, the categorical safety review will include both scheduled and unscheduled visits. Comparisons between treatment groups for all categorical safety end points will be made using Fisher's exact test for study period III and safety group. For analyzes in period IV of the study, only descriptive statistics will be presented. Analysis of continuous safety data will be conducted for study period III and study period III/IV using the safety group. Only values collected during scheduled visits will be used in these analyses.

Treatment-emergent adverse events are defined as reported adverse events that first occurred or increased during the follow-up phase compared with the initial phase. For each TEAE, the reported severity level of the event (mild, moderate, or severe) will be determined by the judgment of the patient or physician. The Medical Dictionary of Regulatory Terminology (MedDRA) lowest level term (LLT) will be used in calculating treatment-emergent events. For each LLT, the maximum severity at the starting moment will be used as the starting severity. If the maximum severity during the follow-up period is greater than the maximum severity at the initial time, the event is considered to be caused by treatment during a certain period after the initial time. Safety analyzes for each study period will use all visits up to the last scheduled visit in the previous study period as the baseline. For each patient and TEAE, the maximum severity for the displayed MedDRA level (preferred term, high-level term, or SOC) represents the maximum post-baseline severity observed when all associated LLTs are mapped to that MedDRA level. For sex-related events, the denominator and percentage calculation will include only patients of a particular sex.

Concentrations of lasmiditan and its metabolite(s) will be illustrated graphically and summarized descriptively, which may include a visual comparison of lasmiditan concentrations by collection method. A population-based approach can be used to characterize the PK of lasmiditan in patients with migraine, assess the magnitude of PK variability associated with bedtime dosing, and identify potential factors that may influence PK. If necessary, data from other clinical studies on lasmiditan may be combined with data from this study to support analyses. If warranted and based on available data, exposure-response relationships of lasmiditan concentrations with efficacy endpoints and/or safety endpoints, as well as potential factors that may influence these endpoints, may also be examined. Additional tests may be performed if necessary.

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The tests described below will be performed by a central laboratory. Protocol requirements for inclusion or exclusion of patients are detailed in the protocol. Additional tests may be performed at any time during the study if necessary by the investigator or required by local regulations.

Clinical laboratory tests

General blood testa Hemoglobin Hematocrit Red Blood Cell Count (RBC) Average cell volume Average hemoglobin content in an erythrocyte Average hemoglobin concentration in erythrocytes White blood cells (WBC) Leukocyte formula Neutrophils, segmented Lymphocytes Monocytes Eosinophils Basophils Platelets Cell morphology Clinical chemistry Sodium Chloride Potassium bicarbonate Total bilirubin Conjugated bilirubin Total protein Alkaline phosphatase (ALP) Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Gamma-glutamyltransferase (GGT) Blood urea nitrogen (BUN) Creatinine Creatinine kinase (CK) Uric acid Calcium Glucose Urinalysis for the detection of prohibited drugs (UDS) ^ab General urine analysis ^{a, c} Specific gravity pH Protein Glucose Ketones Bilirubin Urobilinogen Blood Nitrite Leukocyte esterase urine Microscopic examination of sediment Albumin Cholesterol (total) Triglycerides Hormones (female) Pregnancy (serum ³¹ ' ¹¹ and urine ^e ) Follicle stimulating hormone (FSH) ^aLG Pharmacogenomics sample ⁸ Pharmacokinetic (PK) samples ^a ' ⁸ (lasmiditan concentration)

Saved samples ¹

Biomarker Research Samples

Serum

Abbreviations:

ALT = alanine aminotransferase;

ALP = alkaline phosphatase;

AST = aspartate aminotransferase;

BUN = blood urea nitrogen;

CK = creatine kinase;

FSH = follicle stimulating hormone;

GGT = gamma-glutamyltransferase;

PK = pharmacokinetics;

RBC = red blood cell;

WBC = white blood cell.

^a Performed by designated laboratory.

^b Performed only during screening.

^c Results will be confirmed by the central laboratory/other laboratory during initial testing.

^d A serological pregnancy test should only be performed in women of childbearing age.

^e Urine pregnancy testing should only be performed on women of childbearing age. Performed on site and before dosing.

^f Women only, if necessary to confirm menopausal status (details in inclusion criteria).

^g Results will not be made available to field researchers.

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Abbreviations.

Term Definition 5-HT 5-hydroxytryptamine ACE angiotensin converting enzyme AE Adverse Event: Any adverse medical event in a patient or clinical trial subject who has been administered a pharmaceutical product that does not necessarily have a causal relationship with that treatment. Thus, an adverse event can be any adverse and unexpected sign (including a laboratory abnormality), symptom, or disease that is temporally associated with the use of a medicinal (investigational) product, regardless of whether it is related to the medicinal (investigational) product. product or not.

alkaline phosphate alkaline phosphatase ALT alanine aminotransferase ARB angiotensin receptor blocker ASC-12 12-Item Allodynia Symptoms Checklist ACT aspartate aminotransferase blind A single-blind study is a study in which study in which the researcher and/or his staff know about the prescribed treatment, but the patient does not know, or vice versa, or when the customer knows about the prescribed treatment, but the researcher and/or his staff and the patient do not. A double-blind study is a study in which neither the patient nor any of the study personnel or clients involved in the treatment or clinical evaluation of the patients are aware of the treatment received. CGRP calcitonin gene-encoded peptide CIOMS Council of International Scientific and Medical Organizations complaint A complaint is any written, electronic or oral communication alleging a defect related to the identity, quality, purity, durability, reliability, safety or effectiveness or performance of a drug or drug delivery system. compliance Comply with all research-related, Good Clinical Practice (GCP) and applicable regulatory requirements. COA/eCOA clinical outcome assessment/electronic clinical outcome assessment CONSORT Unified standards for reporting test results

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CRP clinical trial physician: the person responsible for the medical conduct of the trial. CRP duties may be performed by a physician, clinical research specialist, global security physician, or other health care professional. CRS clinical research specialist C-CASA Columbia Classification Algorithm for Suicide Assessment C-SSRS Columbia University Suicidal Severity Scale DMC data monitoring committee DNA Deoxyribonucleic acid ECG electrocardiogram EDC electronic research data recording system eCRF electronic individual registration card e-diary electronic diary (for example, an ePRO device called eDiary) inclusion in The act of prescribing a patient for treatment. Patients who study included in the study represent those assigned to treatment. join Patients entering the study are those who sign the informed consent form directly or through their legal representatives. ERB Ethics Council

ET early termination

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EU European Union FSH follicle-stimulating hormone GAD-7 7-Item Generalized Anxiety Disorder Scale GTR generalized anxiety disorder GCP good clinical practice GLIMMIX generalized linear mixed model SHRAA Health Insurance Continuity and Accountability Act I.B. Explorer Brochure FIS informed consent form ICH International Council for Harmonization ICHD International classification of headaches I.H.S. International Headache Society MKR interquartile range

Informed The process by which a patient voluntarily agrees to participate in a particular study after he has been informed of all aspects of the study that are relevant to the patient's decision to participate. Informed consent is documented using a written, signed and dated informed consent form.

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intermediate Interim analysis is the analysis of data analysis clinical trials divided into treatment groups, which are carried out before the creation/locking of the final database. researched Dosage form of the active ingredient or placebo, product tested or used as a reference in clinical trials, including products already on the market when they are used or formulated (formulated or packaged) in a manner other than the approved form, or marketed products used for unapproved indications, or marketed products, used to obtain additional information about the approved form. IRBIEC Medical Institution Expert Council/Independent Ethics Committee ITT Intent to treat: a principle that states that the effect of a treatment policy can best be assessed by assessing based on the patient's intention to treat (i.e., planned treatment regimen) rather than actual treatment. This results in patients assigned to a treatment group being monitored, assessed and analyzed as a member of that group, regardless of their compliance with the planned course of treatment. IWRS interactive web response system LLT Lowest level term LOCF Carrying the last observation forward LSMeans weighted averages MAOI monoamine oxidase inhibitor

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M.B.S. symptom of greatest concern BDR major depressive disorder MedDRA Medical dictionary of terminology for regulatory activities

MLBS-4 4-item interictal migraine severity scale MSQv2.1 Quality of Life Questionnaire for Migraine Patients, version 2.1 mITT changed intention to treat MMRM repeated measures mixed model NIMH National Institute of Psychiatry NRI norepinephrine reuptake inhibitor NSAIDs non-steroidal anti-inflammatory drug PGI-C The patient's general impression of the change in condition PGI-S Patient's overall impression of severity PHQ-9 Patient Health Questionnaire-9 FC/FD pharmacokinetics/pharmacodynamics ePRO patient-reported results electronically PROMIS-SF Patient-Reported Outcome Measurement Information System Short Form [Sleep Disorder 4a, vl.O] QD once a day QTcF corrected QT interval (Frederick's formula) PHK ribonucleic acid

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SAE serious adverse event

SAP statistical analysis plan

SAC Statistical Analysis Center Screening The act of determining whether a person meets the minimum requirements to become part of a pool of potential candidates to participate in a clinical trial.

SNRI serotonin-norepinephrine reuptake inhibitor

SP study period

SSRI selective serotonin reuptake inhibitor

SUSAR suspected unexpected serious adverse reactions

TBL total bilirubin

TCA tricyclic antidepressant

TENS transcutaneous electrical nerve stimulation

TEAE Adverse event resulting from treatment:

an adverse medical event that occurs during a specified period of treatment, was not present before treatment, or worsens compared to the condition before treatment and does not necessarily have a causal relationship with the specified treatment.

ULN upper limit of normal

US United States of America

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Claims (5)

Raporport A. How to Choose a Preventive Medication for Migraine. American Headache Society Information for Health Care Professionals. 2018. Available at https: //americanheadachesociety. org/wp-content/uploads/2018/05/Alan_Rapoport__Migraine_Prevention_Medications.pdf. Accessed July 12, 2019. Sacco S, Kurth T. Migraine and the risk for stroke and cardiovascular disease. Curr Cardiol Rep. 2014;16(9):524. Seo JG, Park SP. Validation of the Patient Health Questionnaire-9 (PHQ-9) and PHQ-2 in patients with migraine. J Headache Pain. 2015a;16:65. Seo JG, Park SP. Validation of the Generalized Anxiety Disorder-7 (GAD-7) and GAD-2 in patients with migraine. J Headache Pain. 2015b; 16:97. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology; American Headache Society. Evidencebased guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337-1345. Silberstein SD. Preventive migraine treatment. Continuum (Minneap Minn). 2015;21(4 Headache):973-989. Special! JG, Peres M, Bigal ME. Migraine treatment and placebo effect. Expert Rev Neurother. 2010;10(3):413-419. Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 2006;166(10):1092-1097. Stachler RJ, Schultz LR, Nerenz D, Yaremchuk KL. PROMIS evaluation for head and neck cancer patients: a comprehensive quality-of-life outcomes assessment tool. Laryngoscope. 2014;124(6):1368-1376. Woldeamanuel YW, Cowan RP. Migraine affects 1 in 10 people worldwide featuring recent rise: A systematic review and meta-analysis of community-based studies involving 6 million participants. J Neurol Sci. 2017;372:307-315. Yu L, Buysse DJ, Germain A, Moul DE, Stover A, Dodds NE, Johnston KL, Pilkonis PA. Development of short forms from the PROMIS™ sleep disturbance and Sleep-Related Impairment item banks. Behav Sleep Med. 201 l;10(l):6-24. CLAIM 1. The use of 2,4,6-trifluoro-I-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for the prevention of migraine in a patient, wherein 2,4,6- trifluoro-I[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered orally at night at a dose of 25 to 200 mg per dose for at least five consecutive nights. 2. Use according to claim 1, wherein 2,4,6-trifluoro-I-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2yl]benzamide or a pharmaceutically acceptable salt thereof is administered orally at night in a dose of 25 to 200 mg per dose for at least 30 consecutive nights. 3. The use of 2,4,6-trifluoro-I-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof for the prevention of migraine in a patient, wherein 2,4,6- trifluoro-I[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide or a pharmaceutically acceptable salt thereof is administered orally at night once every two nights at a dose of 25 to 200 mg per dose for at least ten nights in a row. 4. Use according to claim 3, wherein 2,4,6-trifluoro-I-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2yl]benzamide or a pharmaceutically acceptable salt thereof is administered orally at night once every two nights at a dose of 25 to 200 mg per dose for at least 30 consecutive nights. 5. Use according to any one of claims 1-4, wherein the patients’ migraines were refractory to the previous ones -