Combination therapy of lasmiditan and a CGRP antagonist for use in the treatment of headache

Abstract

To provide a method of treating migraines refractory to two or more conventional monotherapy and / or dual-therapy treatment regimens.SOLUTION: The present invention relates to the combination of lasmiditan and a calcitonin-gene-related-peptide (CGRP) antagonist, such as the combination of lasmiditan and galcanezumab, as well as migraine. More particularly, it relates to a method of using the combination for the treatment of migraines inadequately controlled by lasmiditan or CGRP antagonist therapy alone. It relates to treating therapy-resistant migraine, defined herein as migraine that is refractory to two or more conventional monotherapy and / or dual-therapy treatment regimens.SELECTED DRAWING: None

Description

Detailed Description of the Invention

[0001] The present invention relates to a combination of lasmiditan and a calcitonin gene-related peptide (CGRP) antagonist, such as the combination of galcanezumab and lasmiditan, and to methods of using such combination for the treatment of migraine, particularly migraine that is inadequately controlled by lasmiditan or CGRP antagonist therapy alone, and more particularly to treating therapy-resistant migraine as defined herein as migraine refractory to two or more conventional monotherapy and / or dual therapy treatment regimens.

[0002] Primary headache disorders, including migraine, are the most common disorders and a leading cause of disability worldwide. Migraine affects more than 14% of adults worldwide. Available treatment options for migraine have insufficient rates of efficacy, tolerability, and patient adherence. In the 2013 Global Burden of Disease Study, migraine accounted for more than half of all years lost due to disorders attributable 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). Migraine is typically characterized by episodes of severe headache lasting 1 to 3 days associated with nausea, vomiting, photophobia, and phonophobia (migraine without aura), and in one-third of patients by neurological prodromal symptoms (migraine with aura) (Goadsby P.J. et al., New England Journal of Medicine 2002; 346: 257-270).

[0003] Lasmiditan, namely 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (Compound I), is a selective and very potent 5-HT-1F receptor agonist under development for the treatment of migraine (see, for example, Lasmiditan for the Treatment of Migraine, Capi, M. et al., Expert Opinion Investigational Drugs, (2017), Vol. 26, NO. 2, 227-234).

[0004] Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide found mainly in the dorsal root and trigeminal ganglia, and C and Ad sensory fibers arising from the central nervous system. CGRP is a pain-signaling neuropeptide and a potent vasodilator released from trigeminal sensory afferent nerves and the spinal trigeminal nucleus. The role of CGRP in headache and migraine is well established in the art, and many clinical studies are currently evaluating the use of anti-CGRP antibodies for the treatment of headache and migraine (see, for example, Dodick et al. Lancet Neurolology; 13(9):885-892 (2014)).

[0005] The present invention relates to a combination of lasmiditan and a calcitonin gene-related peptide (CGRP) antagonist, for example, a combination of lasmiditan and galcanezumab, and a method of using the combination for treating migraine. More particularly, the present invention relates to the use of a combination of lasmiditan and a CGRP antagonist for the treatment of migraine that is inadequately controlled by lasmiditan or CGRP antagonist therapy alone. More particularly, the present invention relates to the use of a combination of lasmiditan and a calcitonin gene-related peptide (CGRP) antagonist for the treatment of therapy-resistant migraine as defined herein as migraine refractory to two or more conventional monotherapy and / or dual therapy treatment regimens.

[0006] The management of headache patients is often inadequate because available acute and preventive therapies are either ineffective or poorly tolerated. Acute treatment of migraine attacks has been limited to the use of analgesics, combinations of analgesics and caffeine, ergotamine, and triptans. (For descriptions of such agents, see, for example, New Therapeutic Approaches for the Prevention and Treatment of Migraine, Diener, H.C. et al., (2015) Lancet Neurology, 14:1010 - 22). Rimegepant represents an innovative approach to acute migraine therapy by selectively targeting 5-HT-1F. Many patients will be able to successfully manage migraine attacks with treatment using rimegepant or galcanezumab as monotherapy, but a subset of patients will fail to successfully manage migraine attacks with either of these agents individually. These patients may continue to have a significant number of migraine days per month, which can be disabling. Additionally, some patients, referred to herein as therapy-resistant headache patients, will fail to successfully manage migraine attacks and will suffer from migraines that are resistant to two or more conventional monotherapy and / or dual-therapy treatment regimens. As defined herein, a therapy-resistant headache patient is one who continues to suffer from migraines for more than three days per month despite two or more previous monotherapy and / or dual-therapy treatment regimens. As used herein, two or more conventional monotherapy and / or dual-therapy treatment regimens refer to any of the monotherapy or dual-therapy treatment regimens of triptans, ergotamine, non-steroidal anti-inflammatory drugs (NSAIDs), non-narcotic analgesics, and caffeine, either alone or in combination with two such agents, representing a previous unsatisfactory attempt at treatment. Therapy-resistant patients represent a significant, unmet need because they have not yet achieved substantial freedom from recurrent migraines. The fact that these therapy-resistant headache patients fail to achieve adequate relief from multiple conventional treatment regimens demonstrates that the disease in this patient population is particularly difficult to treat, and efficacy in this population represents surprisingly excellent results.

[0007] The lasmiditan (COL144, LY573144, CAS registration number 439239-90-4) used in the combination of the present invention can be chemically described as 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide and can be structurally represented as Compound I.

Chemical formula

[0008] Galcanezumab (LY2951742, CAS registration number 1578199-75-3), used in the combination of the present invention, can be described as a monoclonal antibody that targets calcitonin gene-related peptide (CGRP). Monotherapy with galcanezumab is under development for migraine and cluster headache (see, for example, New players in the preventive treatment of migraine, Mitsikostas, Dimos D.; Rapoport, Alan M., BMC Medicine (2015), 13, 279 / 1-279 / 7, and Translational pharmacodynamics of calcitonin gene related peptide monoclonal antibody LY2951742 in a capsaicin-induced dermal blood flow model, Vermeersch, S., et al. Journal of Pharmacology and Experimental Therapeutics (2015), 354(3), 350-357). Methods for preparing galcanezumab are known to those skilled in the art and are described in WO2011 / 156324. Other CGRP antagonists that are useful in the combination of the present invention and are known to those skilled in the art include eptinezumab (ALD403), fremanezumab (TEV-48125), erenumab (AMG334), ubrogepant (MK-1602), MK-8031, 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). CGRP antagonists that are useful in the combination of the present invention and are known to those skilled in the art include small molecule antagonists and monoclonal antibody antagonists that target CGRP itself or its receptor.Methods for preparing other CGRP antagonists are known to those skilled in the art.

[0009] There is a need for more different therapies that can be shown to be effective in treating migraine, particularly in treating migraines that are inadequately controlled by lasmiditan or CGRP antagonist therapy alone, and there remains an important unmet need for treating therapy-resistant migraines as defined herein as migraines refractory to two or more conventional monotherapy and / or dual-therapy treatment regimens.

[0010] The present disclosure provides novel methods for the use of a combination of lasmiditan and a calcitonin gene-related peptide (CGRP) antagonist, such as a combination of lasmiditan and galcanezumab, for treating migraine and therapy-resistant migraine. The combination of lasmiditan and galcanezumab for treating migraine is thought to be superior to either monotherapy alone due to the complementary action of lasmiditan to reduce glutamate signaling combined with the combined action in the CGRP pathway. This combination of pharmacological properties is thought to result in superior efficacy in treating the migraines of patients suffering from therapy-resistant migraine.

[0011] Accordingly, the present invention provides for the use of lasmiditan in simultaneous, separate, or sequential combination with a CGRP antagonist, such as galcanezumab, in the treatment of migraine, particularly for the treatment of migraines inadequately controlled by lasmiditan or calcitonin gene-related peptide (CGRP) antagonist therapy alone, and for the treatment of therapy-resistant migraine in a patient. More particularly, the migraine patient being treated is a patient suffering from migraines inadequately controlled by lasmiditan or CGRP antagonist therapy alone. More particularly, the migraine patient being treated is a patient suffering from therapy-resistant migraine as defined herein as migraines refractory to two or more conventional monotherapy and / or dual-therapy treatment regimens.

[0012] A combination of lasmiditan and a calcitonin gene-related peptide (CGRP) antagonist, for example, a combination of lasmiditan and galcanezumab, and methods of using the combination to treat migraine, particularly migraine that is inadequately controlled by lasmiditan or CGRP antagonist therapy alone, and more particularly, to treat therapy-resistant migraine, employ certain dosages and dosing regimens of lasmiditan and galcanezumab as described hereinafter.

[0013] The present invention relates to the combined use of a pharmaceutical composition comprising a certain amount of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. For oral administration, the composition contains 50 to 400 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose. For buccal, sublingual, nasal / intranasal, transdermal, subcutaneous, injection, intravenous or intramuscular administration, the composition contains up to 200 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose, and further the composition is administered once, twice or three times a day. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, the composition is for oral administration, and the amount of lasmiditan or a pharmaceutically acceptable salt thereof is 50 mg to 400 mg per single dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the amount of lasmiditan is 50 mg per single dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the amount of lasmiditan is 100 mg per single dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the amount of lasmiditan is 200 mg per single dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the amount of lasmiditan is 400 mg per single dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, 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 up to 200 mg per single dose. The present invention relates to the combined use of lasmiditan or a pharmaceutically acceptable salt thereof, and the amount of lasmiditan or a pharmaceutically acceptable salt thereof administered is 20 mg to 200 mg per single dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the amount of lasmiditan or a pharmaceutically acceptable salt thereof is 20 to 60 mg per single dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the amount of lasmiditan or a pharmaceutically acceptable salt thereof administered is 20 to 30 mg per single dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, the administration is intravenous, and the amount of lasmiditan or a pharmaceutically acceptable salt thereof administered is up to 200 mg per single dose.The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the administration of lasmiditan or a pharmaceutically acceptable salt thereof is intravenous over about 20 minutes.

[0014] The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the composition contains lasmiditan hemisuccinate. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the composition contains lasmiditan hemisuccinate, and the administered amount is 50 mg per single dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the composition contains lasmiditan hemisuccinate, and the administered amount is 100 mg per single dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the composition contains lasmiditan hemisuccinate, and the administered amount is 200 mg per single dose.

[0015] The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the dose of lasmiditan or a pharmaceutically acceptable salt thereof is administered once a day. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the dose of lasmiditan or a pharmaceutically acceptable salt thereof is administered twice a day. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, and the dose of lasmiditan or a pharmaceutically acceptable salt thereof is administered three times a day.

[0016] The present invention relates to a method for treating migraine in a patient in need thereof, comprising orally administering 50 - 400 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose and a pharmaceutically acceptable diluent or carrier to the patient. The present invention relates to a method for treating migraine in a patient in need thereof, comprising orally administering 50 - 400 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose and a pharmaceutically acceptable diluent or carrier to the patient, and the composition is administered once, twice, or three times a day.

[0017] The present invention relates to a method for treating migraine in a patient in need thereof, comprising orally administering 50 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose, together with a pharmaceutically acceptable diluent or carrier. The present invention relates to a method for treating migraine in a patient in need thereof, comprising orally administering 50 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose, together with a pharmaceutically acceptable diluent or carrier, wherein the composition is administered once or twice daily.

[0018] The present invention relates to a method for treating migraine in a patient in need thereof, comprising orally administering 100 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose, together with a pharmaceutically acceptable diluent or carrier. The present invention relates to a method for treating migraine in a patient in need thereof, comprising orally administering 100 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose, together with a pharmaceutically acceptable diluent or carrier, wherein the composition is administered once or twice daily.

[0019] The present invention relates to a method for treating migraine in a patient in need thereof, comprising orally administering 200 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose, together with a pharmaceutically acceptable diluent or carrier. The present invention relates to a method for treating migraine in a patient in need thereof, comprising orally administering 200 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose, together with a pharmaceutically acceptable diluent or carrier, wherein the composition is administered once or twice daily.

[0020] The present invention relates to a method for treating migraine in a patient in need thereof, comprising buccal, sublingual, nasal / intranasal, transdermal, subcutaneous, injection, intravenous or intramuscular administration of 50 - 400 mg of lasmiditan or a pharmaceutically acceptable salt thereof per single dose, together with a pharmaceutically acceptable diluent or carrier.

[0021] The present invention relates to a method for treating migraine in a patient in need thereof, comprising sumatriptan at a single dose of 50 to 400 mg per single dose or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, for buccal, sublingual, nasal / intranasal, transdermal, subcutaneous, injection, intravenous or intramuscular administration, wherein the composition is administered once, twice, or three times a day.

[0022] The present invention relates to a method for the combined treatment of migraine in a patient in need thereof, comprising administering galcanezumab at a dose of 120 mg. The present invention relates to a method for the combined treatment of migraine in a patient in need thereof, comprising administering galcanezumab at a dose of 240 mg. The present invention relates to a method for the combined treatment of migraine in a patient in need thereof, comprising administering galcanezumab at a dose of 300 mg. The present invention relates to a method for the combined treatment of migraine in a patient in need thereof, comprising administering galcanezumab at a dose of 360 mg. Preferably, the dose of galcanezumab is administered at intervals of weekly, every two weeks, monthly, or quarterly. More preferably, the galcanezumab administration is monthly. The present invention relates to a method for the combined treatment of migraine in a patient in need thereof, comprising administering an initial loading dose of 240 mg of galcanezumab followed by a monthly maintenance dose of 120 mg of galcanezumab. The present invention relates to a combined method for treating episodic migraine in a patient, comprising administering a monthly subcutaneous dose of 120 mg of galcanezumab. As used herein, the combined treatment of administering galcanezumab is according to the dosing schedule provided above.

[0023] Another aspect of the present invention relates to the combination of lasmiditan with galcanezumab as a medicament, particularly a medicament suitable for the treatment of migraine in humans.

[0024] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with a calcitonin gene-related peptide (CGRP) antagonist in the treatment of migraine in a patient.

[0025] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient.

[0026] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with a CGRP antagonist in the treatment of migraine in a patient whose migraine is inadequately controlled by lasmiditan or CGRP antagonist therapy alone.

[0027] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient whose migraine is inadequately controlled by lasmiditan or galcanezumab therapy alone.

[0028] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with a calcitonin gene-related peptide (CGRP) antagonist in the treatment of migraine in a patient suffering from therapy-resistant migraine, wherein the patient's migraine was refractory to two or more conventional monotherapy and / or dual therapy treatment regimens.

[0029] In another embodiment, the present invention provides a method for the simultaneous, separate, or sequential combination use of galcanezumab in the treatment of migraine in a patient suffering from therapy-resistant migraine, wherein the patient's migraine was refractory to two or more conventional monotherapy and / or dual therapy treatment regimens.

[0030] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient, wherein galcanezumab is administered as an initial loading dose of 240 mg, followed by a monthly maintenance dose of 120 mg, and lasmiditan is administered once or twice a day at a dose of 50 mg.

[0031] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient, wherein galcanezumab is administered as an initial loading dose of 240 mg, followed by a monthly maintenance dose of 120 mg, and lasmiditan is administered once or twice a day at a dose of 100 mg.

[0032] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient, wherein galcanezumab is administered as an initial loading dose of 240 mg, followed by a monthly maintenance dose of 120 mg, and lasmiditan is administered once or twice a day at a dose of 200 mg.

[0033] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg, and lasmiditan is administered once or twice a day at a dose of 50 mg.

[0034] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg, and lasmiditan is administered once or twice a day at a dose of 100 mg.

[0035] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once or twice a day at a dose of 200 mg.

[0036] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once a day at a dose of 50 mg.

[0037] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once a day at a dose of 100 mg.

[0038] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of migraine in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once a day at a dose of 200 mg.

[0039] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with a calcitonin gene-related peptide (CGRP) antagonist in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient.

[0040] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient.

[0041] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with a CGRP antagonist in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient whose headache is inadequately controlled by lasmiditan or CGRP antagonist therapy alone.

[0042] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient whose headache is inadequately controlled by lasmiditan or galcanezumab therapy alone.

[0043] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with a calcitonin gene-related peptide (CGRP) antagonist in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient suffering from therapy-resistant headache, wherein the patient's headache was refractory to two or more conventional monotherapy and / or dual therapy treatment regimens.

[0044] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient suffering from therapy-resistant headache, wherein the patient's headache was refractory to two or more conventional monotherapy and / or dual therapy treatment regimens.

[0045] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient, wherein galcanezumab is administered as an initial loading dose of 240 mg, followed by a monthly maintenance dose of 120 mg, and lasmiditan is administered once or twice daily at a dose of 50 mg.

[0046] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient, wherein galcanezumab is administered as an initial loading dose of 240 mg, followed by a monthly maintenance dose of 120 mg, and lasmiditan is administered once or twice daily at a dose of 100 mg.

[0047] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient, wherein galcanezumab is administered as an initial loading dose of 240 mg, followed by a monthly maintenance dose of 120 mg, and lasmiditan is administered once or twice daily at a dose of 200 mg.

[0048] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once or twice daily at a dose of 50 mg.

[0049] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once or twice daily at a dose of 100 mg.

[0050] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once or twice daily at a dose of 200 mg.

[0051] In another embodiment, the present invention provides a method for the use of lasmiditan in a simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once daily at a dose of 50 mg.

[0052] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once daily at a dose of 100 mg.

[0053] In another embodiment, the present invention provides a method for the use of lasmiditan in simultaneous, separate, or sequential combination with galcanezumab in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in a patient, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once daily at a dose of 200 mg.

[0054] In another embodiment, the present invention provides a method for treating migraine in a patient in need thereof, comprising administering simultaneously, separately, or sequentially an effective amount of lasmiditan in combination with an effective amount of a calcitonin gene-related peptide (CGRP) antagonist.

[0055] In another embodiment, the present invention provides a method for treating migraine in a patient in need thereof, comprising administering simultaneously, separately, or sequentially an effective amount of lasmiditan in combination with an effective amount of galcanezumab.

[0056] In another embodiment, the present invention provides a method for treating migraine in a patient in need thereof, comprising administering simultaneously, separately, or sequentially an effective amount of lasmiditan in combination with an effective amount of a calcitonin gene-related peptide (CGRP) antagonist, wherein the migraine in the patient is inadequately controlled by lasmiditan or CGRP antagonist therapy alone.

[0057] In another embodiment, the present invention provides a method of treating migraine in a patient in need thereof, comprising administering an effective amount of lasmiditan in combination with an effective amount of galcanezumab to the patient simultaneously, separately, or sequentially, wherein the migraine in the patient is inadequately controlled by lasmiditan or galcanezumab therapy alone.

[0058] In another embodiment, the present invention provides a method of treating migraine in a patient in need thereof, comprising administering an effective amount of lasmiditan in combination with an effective amount of a calcitonin gene-related peptide (CGRP) antagonist to the patient simultaneously, separately, or sequentially, wherein the patient suffers from therapy-resistant migraine and the patient's migraine is refractory to two or more conventional monotherapy and / or dual-therapy treatment regimens.

[0059] In another embodiment, the present invention provides a method of treating migraine in a patient in need thereof, comprising administering an effective amount of lasmiditan in combination with an effective amount of galcanezumab to the patient simultaneously, separately, or sequentially, wherein the patient suffers from therapy-resistant migraine and the patient's migraine is refractory to two or more conventional monotherapy and / or dual-therapy treatment regimens. As will be described later, the treatment method described above represents "one of the previous embodiments".

[0060] In another embodiment, the present invention provides a method according to any one of the previous embodiments, wherein galcanezumab is administered as an initial loading dose of 240 mg, followed by a monthly maintenance dose of 120 mg, and lasmiditan is administered at a dose of 50 mg once or twice a day.

[0061] In another embodiment, the present invention is any one of the methods of the previous embodiments, wherein galcanezumab is administered at an initial loading dose of 240 mg, followed by a monthly maintenance dose of 120 mg, and rasmiditan is administered once or twice a day at a dose of 100 mg.

[0062] In another embodiment, the present invention is any one of the methods of the previous embodiments, wherein galcanezumab is administered at an initial loading dose of 240 mg, followed by a monthly maintenance dose of 120 mg, and rasmiditan is administered once or twice a day at a dose of 200 mg.

[0063] In another embodiment, the present invention is any one of the methods of the previous embodiments, wherein galcanezumab is administered at a monthly dose of 120 mg, and rasmiditan is administered once or twice a day at a dose of 50 mg.

[0064] In another embodiment, the present invention is any one of the methods of the previous embodiments, wherein galcanezumab is administered at a monthly dose of 120 mg, and rasmiditan is administered once or twice a day at a dose of 100 mg.

[0065] In another embodiment, the present invention is any one of the methods of the previous embodiments, wherein galcanezumab is administered at a monthly dose of 120 mg, and rasmiditan is administered once or twice a day at a dose of 200 mg.

[0066] In another embodiment, the present invention is any one of the methods of the previous embodiments, wherein galcanezumab is administered at a monthly dose of 120 mg, and rasmiditan is administered once a day at a dose of 50 mg.

[0067] In another embodiment, the present invention is any one of the methods of the previous embodiments, wherein galcanezumab is administered at a monthly dose of 120 mg, and rasmiditan is administered once a day at a dose of 100 mg.

[0068] In another embodiment, the present invention provides a method according to any one of the previous embodiments, wherein galsulizumab is administered at a monthly dose of 120 mg and rasmiditan is administered once daily at a dose of 200 mg.

[0069] Conventional treatments for migraine may leave a significant number of patients without adequate treatment. For example, up to 40% of migraine attacks, in about 30% of patients, fail to optimally meet efficacy or tolerability criteria and are unresponsive to specific triptans (see Dodick DW. Headache. 2005;45:156-162 and Tepper DE. Headache. 2013(53)577-578). Due to their vasoconstrictive effects, these medications may have contraindications, warnings, and precautions for patients with cardiovascular risk factors and heart disease (see Alwhaibi M, et al. Pain Res Treat. 2016;2016:8538101 and Gilmore B, Michael M. AM Fam Physician. 2011(83)271-280). Additionally, conventional therapies are often limited by the development of medication overuse headache, where patients may be restricted in the number of treatments they can use within a specific time frame to avoid developing medication overuse headache (see, for example, Diener, H.C. et al., Chronic Headache Due to Overuse of Analgesics and Anti-Migraine Agents. Dtsch Arztebl Int 2018;115:365-70). Thus, a substantial proportion of patients may fail to achieve headache relief and / or pain elimination with conventional monotherapy or combination therapy for migraine. Furthermore, some patients, herein referred to as treatment-resistant migraine patients, may struggle to successfully manage their migraine attacks and suffer from migraines that are unresponsive to two or more conventional monotherapy and / or combination therapy treatment regimens. As defined herein, treatment-resistant migraine patients are those who continue to suffer from migraines for more than three days per month despite two or more conventional monotherapy and / or combination therapy treatment regimens.As used herein, two or more conventional monotherapy and / or dual therapy treatment regimens refer to conventional unsatisfactory treatment attempts by monotherapy or dual therapy treatment regimens, either alone or in combination of two such agents, such as triptans, ergotamine, non-steroidal anti-inflammatory drugs (NSAIDs), non-narcotic analgesics, blood pressure medications, anti-spasmodics, antidepressants, serotonin antagonists, onabotulinum toxin, and caffeine. Further, a population of patients will fail to successfully manage migraine attacks using either galcanezumab or rasmiditan individually.

[0070] These inadequately controlled migraine patients may continue to be significantly impaired, with a high number of migraine days per month. An unsatisfactory treatment attempt is one where the patient concludes, after the full course of therapy, that the symptoms were not alleviated such that the impairment was avoided. Migraine disability scales are well known to those of skill in the art, such as the Migraine Disability Assessment, where a total score of ≧11 may indicate an impairment associated with moderate to severe headache. In embodiments of the present invention, a Migraine Disability Assessment of 10 or less, or an equivalent assessment by means known to those of skill in the art, indicates avoidance of impairment. Preferably, the combination methods of the present invention provide alleviation of migraine disability such that the patient reports a total score of 10 or less on the Migraine Disability Assessment. Preferably, in embodiments of the present invention, a Migraine Disability Assessment or an equivalent assessment by means known to those of skill in the art will demonstrate clinically no impairment. Preferably, the combination methods of the present invention provide alleviation of migraine disability such that there is no significant clinical impairment in migraine patients after administration of rasmiditan, wherein the patient reports no complete impairment, or need for bed rest, or significant interference with daily activities. More preferably, the combination methods of the present invention provide alleviation of migraine disability such that there is no mild interference in migraine patients after administration of rasmiditan. More preferably, the combination methods of the present invention provide alleviation of migraine disability such that migraine patients are not impaired at all after administration of rasmiditan. Preferably, patients treated by the combination methods provided herein avoid the development of medication overuse headache.

[0071] Symptomatic relief such as pain relief from headache, or relief from the patient's most bothersome symptoms, can be defined, for example, as efficacy according to the clinical study protocols provided herein. Preferably, the combination methods of the present invention provide pain relief from headache and / or relief from the patient's most bothersome symptoms. Pain relief from headache as used herein is evaluated by a reduction in pain severity from moderate or severe at baseline to mild or none, or from mild at baseline to none, at 2 hours after administration. Absence of pain from headache as used herein is a reduction in pain severity from mild, moderate, or severe at baseline to none at the indicated time of assessment. The most bothersome symptom (MBS) is identified by the participant at the onset of a migraine attack from among the associated symptoms of nausea, phonophobia, and photophobia, prior to administration. Absence of the most bothersome symptom as used herein refers to the reported result of a patient of no MBS associated with migraine at 2 hours after administration, where MBS is defined as the associated symptoms present and identified as the pre-administration MBS.

[0072] As used herein, refractory headache includes, but is not limited to, refractory chronic headache and / or refractory episodic headache. Means for identifying refractory headache patients are known to those of ordinary skill in the art. For example, refractory chronic headache is recognized by those of ordinary skill in the art as shown in the proposed criteria for this condition 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 EHF recommends that refractory chronic headache should be defined as ICHD-3 beta chronic headache without drug overuse in patients who have failed to respond to treatment with at least three prophylactic medications at appropriate dosages, each using a trial of at least three months. The proposed criteria can be briefly described as follows: A. ICHD-3 beta chronic headache without drug overuse, B. headache prophylactic medications at appropriate dosages each used for at least three months, C. no contraindications or effects for prophylactic medications with at least three medications 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), antispasmodics (valproic acid up to 1.5 g per day, topiramate up to 200 mg per day), tricyclics (amitriptyline up to 150 mg per day), or others (flunarizine up to 10 mg per day, candesartan up to 16 mg per day, onabotulinum toxin 155 - 195 U by PREEMPT), and D. appropriate treatment of psychiatric or other co-morbidities by a multidisciplinary team if available.

[0073] The combination treatment method of the present invention provides improved migraine treatment, including in patients inadequately controlled by lasmiditan or galcanezumab therapy alone, and / or patients suffering from therapy-resistant migraine, where the patient's migraine was refractory to two or more conventional monotherapy and / or dual therapy treatment regimens. It further provides a particularly advantageous combination of pharmacological benefits, including a rapid (specifically within 2 hours, preferably within 1 hour, more preferably within 30 minutes after administration of lasmiditan), safe, and effective reduction and / or elimination of headache pain, and at the same time is considered to provide clinically acceptable levels of adverse effects such as dizziness, paresthesia, and drowsiness. The combination treatment method of the present invention can partially provide these advantages by enabling migraine patients to be appropriately treated for migraine attacks with a lower dose of lasmiditan, such as 100 mg or 50 mg, and more preferably by doing so in a single daily dose to avoid the need for a second administration per day. In this regard, the combination treatment method of the present invention provides a significant reduction in migraine patients and / or more preferably the absence of significant migraine symptoms and disorders. In another aspect, the combination treatment method of the present invention provides a significant reduction in migraine patients and more preferably the absence of significant migraine symptoms and disorders for a sustained period of time, such as 24 hours after administration of lasmiditan, or preferably 48 hours after administration of lasmiditan.

[0074] As used herein, “combination therapy” or “in combination” includes the administration of lasmiditan and a CGRP antagonist as part of a specific treatment administration plan intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effects of the combination include, but are not limited to, pharmacokinetic and / or pharmacodynamic co-actions resulting from the combination of the therapeutic agents. Administration of these therapeutic agents in combination is typically carried out over a defined period of time (usually minutes, hours, days or weeks depending on the selected combination). Combination therapy is intended to include administration of the indicated therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at a different time point, and administration of these therapeutic agents in a substantially simultaneous manner. Administration can be achieved, for example, by administering a single oral dosage form having a fixed ratio of each therapeutic agent or multiple single oral dosage forms for each therapeutic agent, or by administering an oral dosage form of lasmiditan and an injectable dosage form of galcanezumab. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any suitable route including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of a selected combination may be administered by intramuscular or intravenous injection, while other therapeutic agents of the combination may be administered orally. Alternatively, for example where applicable, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The order in which the therapeutic agents are administered is not strictly critical.

[0075] As used herein, "once daily" means that lasmiditan is administered once every 24 hours, or once every calendar day. As used herein, "once daily" means that lasmiditan is administered once every 24 hours, or once every calendar day, for the prevention or treatment of migraine attacks. As used herein, "once daily" means that lasmiditan is administered once every 24 hours, or once every calendar day, for the treatment of migraine attacks, and such treatment may occur for two or more consecutive days.

[0076] As used herein, "monthly" means that galcanezumab is administered once every 30 days, or once every calendar month. As used herein, "monthly" means that galcanezumab is administered once every 30 days, or once every calendar month, and the timing of administration during this period may vary. Preferably, as used herein, "monthly" means that galcanezumab is administered once every 30 days, or once every calendar month, and is administered on the same or approximately the same calendar day of each month to provide a regular dosing interval.

[0077] As described herein, lasmiditan is administered in combination with a CGRP antagonist, such as galcanezumab, to stop migraines. In one embodiment, both lasmiditan and the CGRP antagonist are administered for the relief of acute migraines. In another embodiment, a CGRP antagonist, such as galcanezumab, is administered prophylactically and lasmiditan is administered for the relief of breakthrough acute migraines. The invention also provides a method of treating a condition associated with elevated levels of CGRP, preferably headache and / or migraine, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a combination of lasmiditan of the invention and a CGRP antagonist such as galcanezumab. Some embodiments of the invention provide a method of treating migraine, episodic headache, chronic headache, chronic cluster headache, and / or episodic cluster headache in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a combination of lasmiditan and a CGRP antagonist such as galcanezumab.

[0078] If the disorders that can be treated by the combination of the present invention are known by established and accepted classifications such as migraine, episodic headache, chronic headache, chronic cluster headache, and / or episodic cluster headache, the classification can be recognized from various sources. For example, currently, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV (trademark)) (1994, American Psychiatric Association, Washington, D.C.) provides diagnostic tools for identifying many of the disorders described herein. Also, the 10th edition of the International Classification of Diseases (ICD-10) provides classifications for many of the disorders described herein. Those skilled in the art will recognize 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 the terminology and classification systems evolve with the progress of medical science. Migraine patients can further be diagnosed as having migraine with or without aura (1.1 and 1.2) as defined by the beta version of the International Classification of Headache Disorders, 3rd edition (ICHD-3) of the International Headache Society (The International Classification of Headache Disorders, 3rd edition (beta version), Cephalalgia 2013;33:629-808).

[0079] As used herein as an adjective, the terms "pharmaceutical" or "pharmaceutically acceptable" mean substantially non-toxic and substantially harmless to the recipient. "Pharmaceutical composition" further means that carriers, solvents, excipients and salts must be compatible with the active ingredient of the composition (e.g., the compounds of the present invention). The terms "pharmaceutical formulation" and "pharmaceutical composition" are generally interchangeable, and the fact that the terms are used as such for the purposes of the present application will be understood by those skilled in the art.

[0080] Furthermore, the compounds of the present invention, for example, salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) forms. Non-limiting examples of hydrates include monohydrate, dihydrate, and the like. When the compound of the present invention is an amine, the compound is essentially basic and thus reacts with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. The term "acid addition salt" refers to salts of compounds prepared by the reaction of a compound with a mineral or organic acid. The compounds of the present invention form pharmaceutically acceptable acid addition salts using a wide variety of organic and inorganic acids, including physiologically acceptable salts commonly used in pharmaceutical chemistry. Such salts are also embodiments of the present invention. "Pharmaceutically acceptable (acid) addition salts" are formed from pharmaceutically acceptable acids, as is well known in the art. Such salts include pharmaceutically acceptable salts exemplified 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.

[0081] The term "effective amount" means the amount of lasmiditan capable of activating the 5-HT-1F receptor or the amount of a CGRP antagonist capable of inhibiting the action of CGRP. In a preferred embodiment, "effective amount" means the amount of lasmiditan and the amount of a CGRP antagonist capable of eliminating a patient's pain 2 hours after headache treatment using lasmiditan.

[0082] As used herein, the term "treating" or "treatment" means curing an existing medical condition or state, e.g., curing migraine or headache in a patient or subject. Treating can also include inhibiting, i.e., arresting, further development of a medical condition or state, and alleviating or ameliorating, i.e., causing regression of, a medical condition or state, e.g., migraine. As used herein, the term "preventing" or "prevention" means completely or almost completely arresting the onset of a medical condition or state in a patient or subject, particularly when the patient or subject is predisposed or at risk of developing the medical condition or state, e.g., migraine.

[0083] Throughout this specification, when a composition is described as having, including, or comprising a particular component, it is contemplated that the composition also consists essentially of, or consists of, the recited components. Similarly, when a method or process is described as having, including, or comprising a particular process step, the process is also contemplated to consist essentially of, or consist of, the recited process steps. Further, it should be understood that the order of steps or the order for performing certain actions is not important so long as the invention remains practicable. Moreover, two or more steps or actions can be carried out simultaneously.

[0084] One of ordinary skill in the art of preparing pharmaceutical formulations can readily select the appropriate form and mode of administration according to the specific characteristics of the selected compound, the disorder or condition being treated, the stage of the disorder or condition, and other relevant circumstances (see, e.g., Remington: The Science and Practice of Pharmacy, L.V. Allen, Editor, 22nd Edition, Pharmaceutical Press, 2012). In particular, the components of the combinations of the present invention can, where appropriate, be combined in the same formulation, or alternatively, the components can be formulated separately.

[0085] In a separate formulation, lasmiditan is usually mixed with excipients, diluted by excipients, or encapsulated in a carrier such that it can be in the form of capsules, sachets, in paper or other containers. The CGRP antagonist is separately and appropriately formulated. When the excipient serves as a diluent, the excipient can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the formulation can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing 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, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation can additionally include lubricants such as talc, magnesium stearate, mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents. The compounds of the present invention can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by employing procedures known in the art.

[0086] Examples of clinical studies The following clinical study designs are provided to further illustrate the invention and should in no way be construed as limiting the scope of the invention. Examples of trials of lasmiditan in combination with galcanezumab in the treatment of migraine are provided below. One of ordinary skill in the art will understand that similar trials can be conducted on patients who have not been able to successfully manage migraine attacks using either lasmiditan or galcanezumab alone. One of ordinary skill in the art will understand that similar trials can be conducted on patients with migraine attacks who are refractory to two or more conventional monotherapy and / or dual therapy treatment regimens, referred to herein as therapy-resistant migraine patients. One of ordinary skill in the art will understand that similar trials can be conducted on patients suffering from a headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache, including patients with therapy-resistant headache. One of ordinary skill in the art can readily identify patients who have not been able to successfully manage migraine attacks using either lasmiditan or galcanezumab alone, and / or therapy-resistant migraine patients with migraine attacks that are refractory to two or more conventional monotherapy and / or dual therapy treatment regimens, using the methods described herein as well as methods known in the art, and such identified patients may be subjects for clinical studies, such as those described herein.

[0087] Methods of conducting such clinical studies are known to those of ordinary skill in the art and are exemplified, for example, by the citations of the published lasmiditan and galcanezumab clinical studies provided herein. Methods of evaluating migraine treatment include, for example, determination of patient-reported outcomes (PRO) such as determination of quality of life (QOL), including migraine-specific quality of life, version 2.1 (MSQ v2.1), headache impact test 6 (HIT-6), migraine disability assessment scale (MIDAS), migraine-specific quality of life questionnaire (MSQoL). Further, an ePRO diary can be used to record headache and other migraine symptoms. Based on the diary data, an automated algorithm can be used to classify the number of days as migraine headache days (MHD) (including median MHD). Median migraine is defined as headache with or without aura that lasts for more than 30 minutes but lacks one of the characteristics of migraine in the ICHD-3 beta criteria. The monthly number of MHD due to the use of acute migraine medications can be obtained from the ePRO diary, and the assessments of PGI-S, MSQ, and MIDAS are performed using a slate device at the study site at each monthly visit for PGI-S and MSQ and at 3 and 6 months for MIDAS. Based on ePRO or other relevant clinical data, a study design can be developed to compare the efficacy of each combination dosing regimen compared to placebo, or galcanezumab treatment alone, or lasmiditan treatment, for the overall mean change from baseline in the number of monthly migraine headache days (MHD) during the treatment phase. Other possible outcome measures may be the mean proportion of patients with a reduction from baseline in monthly MHD during the double-blind treatment phase, the mean change from baseline in the role function restriction (R-FR) domain score of migraine-specific quality of life version 2.1 (MSQ v2.1), the mean change from baseline (mean of selected months) in the patient's global impression of severity (PGI-S) rating, and / or the outcome measure for the migraine disability assessment (MIDAS) total score. These and other evaluations of migraine treatment are well known to those of ordinary skill in the art.

[0088] Treatment of Acute Migraine with Rimegepant With and Without CGRP Antagonists Such as Galcanezumab by Intravenous Administration To demonstrate the efficacy of the combination of rimegepant and galcanezumab, the following study is conducted once as described below and once in patients under review, administering a 120 mg monthly maintenance dose of galcanezumab following a 240 mg initial loading dose of galcanezumab. The treatment groups of the study may include unit doses of 50 mg, 100 mg, or 200 mg of rimegepant for oral administration.

[0089] In a multi-site, placebo-controlled, double-blind, group sequential, adaptive treatment allocation, proof-of-concept and dose-finding study, 130 patients are treated at the time of admission during a migraine attack. Patients are assigned to intravenous administration levels of rimegepant or placebo in small cohorts. The starting dose is 2.5 mg. Subsequent doses are adjusted up or down based on the safety and efficacy seen in the preceding cohorts. The primary endpoint is defined as headache response, which is improvement from moderate or severe headache at baseline to mild or no headache 2 hours after administration. This study is designed to explore the overall dose-response relationship but does not attempt to distinguish individual doses from placebo or detect differences in the effects on other migraine symptoms.

[0090] Forty-two patients are administered placebo and 88 are administered rimegepant at doses of 2.5 - 45 mg. Patients are observed at the clinic 4 hours after treatment and use diary cards to record symptoms and adverse events up to 24 hours. The study is terminated when the dose meets the predefined efficacy stopping rules. Patients treated in the 10, 20, 30, and 45 mg rimegepant treatment groups are assessed for headache response at 2 hours compared to the placebo group. The overall impression of the patient at 2 hours and the need for no rescue medication are also assessed for statistically significant linear correlation with the dose. The efficacy of rimegepant in combination with concurrent galcanezumab treatment for the acute treatment of migraine is assessed with intravenous administration of 2.5 - 45 mg of rimegepant.

[0091] Method This trial can be conducted at multiple sites in accordance with the Helsinki Declaration and internationally recognized Good Clinical Practice guidelines. Approval by the relevant regulatory authorities and an independent ethics committee is required before initiation. All subjects will be limited to those who provide written informed consent.

[0092] Trial Design In this trial, a forward - randomized double - blind placebo - controlled design with group - sequential adaptive treatment allocation will be used (Olesen J et al., N Engl J Med 2004:350:1104 - 10, Hall DB et al., Contemporary Clinical Trials 2005;26:349 - 63). Patients will be assigned to the dose levels of lasmiditan in small cohorts. The first 20 cohorts consist of 6 patients (4 receiving lasmiditan and 2 receiving placebo), and subsequent cohorts consist of 5 patients (4 lasmiditan and 1 placebo). The first cohort will be assigned a dose level of 2.5 mg. The doses used in subsequent cohorts will be based on the headache response (reduction of moderate or severe headache to mild or none at 2 hours) in the preceding cohort. If fewer than 2 out of 4 actively treated patients respond, the dose will be increased, and if 3 or more out of 4 actively treated patients respond, the dose will be decreased. The dose - adjustment rule is selected to identify the dose of lasmiditan with potency equal to or greater than that of oral triptans. This order of dose increase or decrease will be modified if 2 or more actively treated patients in any cohort experience non - severe adverse events. If a drug - related serious adverse event occurs, randomization will be automatically interrupted until safety is confirmed. The minimum allowable dose of lasmiditan is 1 mg, and the maximum allowable dose is 60 mg.

[0093] The up-and-down dosing adjustment process selects and ends the effective dose when the following criteria are met. That is, at least five blocks of patients are treated at this dose, and for at least four blocks, if the decision rule requires a decrease in the dose. Alternatively, if five consecutive blocks of patients are treated at the upper limit dose by an increment rule that requires an increase in dose each time, it could end without selecting an effective dose.

[0094] Patient Screening and Selection First, screen patients for eligibility for outpatient visits other than migraine attacks and invite them to revisit the clinic for treatment with the investigational drug for new moderate or severe migraine attacks within 4 hours of onset. At the revisit to the clinic, reconfirm eligibility for this trial and randomize the patients. A patient is eligible for this trial if the patient is 18 - 65 years old, had a migraine onset before the age of 50, meets the IHS diagnostic criteria 1.1 and 1.2.1 (2004), and has a history of migraine with or without aura for at least one year (Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders (second edition). Cephalalgia 2004:24; Suppl 1:1 - 160). The patient must have 1 - 8 migraine attacks per month and must not be using migraine preventive medications. The patient's general health is good and there is no evidence of vascular disease or hypertension. Patients with a previous history of triptan intolerance are excluded. Women who are pregnant or breastfeeding are excluded, as are women of childbearing potential who are not using a highly reliable form of contraception.

[0095] Trial Procedures When the patient revisits the clinic, a pharmacist or other study personnel, independent of the principal investigator of the clinical trial, obtains instructions on the dilution of the investigational drug from an online randomization system and prepares the investigational drug for infusion. Both the principal investigator of the clinical trial and the pharmacist are blinded to whether the drug is active or placebo, and only the pharmacist knows the dilution. All patients receive a 60-ml intravenous infusion over 20 minutes. Data on efficacy and safety before and after administration of the investigational drug are immediately entered into an electronic data capture system so that dose assignment for subsequent cohorts can be done using headache response.

[0096] After completion of the baseline assessment, lasmiditan or placebo is infused intravenously over 20 minutes and the patient is monitored for at least 4 hours for safety and efficacy. Data are entered simultaneously into an online electronic data capture system. The patient is discharged from the clinic after 4 hours and continues to record migraine symptoms and adverse events using a diary card for up to 24 hours.

[0097] Symptom Assessment Multiple different symptoms are assessed. Headache severity is measured on a 4-point scale of 0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain. Related symptoms (nausea, vomiting, photophobia, phonophobia) are recorded as present or absent. Impairment is documented on a 4-point scale of 0 = no impairment, 1 = mild impairment, 2 = moderate impairment, 3 = severe impairment. Data on the patient's overall impression are collected on a 7-point scale of 1 = very good, 2 = fairly good, 3 = somewhat good, 4 = no change, 5 = somewhat bad, 6 = fairly bad, 7 = very bad.

[0098] The primary efficacy measure is headache response, defined as reduction of headache from moderate or severe at baseline to mild or painless 2 hours after initiation of infusion of the investigational drug (HIS Clinical Trials Subcommittee. Guidelines for Controlled Trials in Migraine: second edition, Cephalalgia 2000:20:765 - 786). Secondary efficacy measures are the proportion of headache responses at 10, 20, 40, 60, 90, 180, and 240 minutes after initiation of infusion of the investigational drug, the proportion of headache - free at 10, 20, 40, 60, 90, 120, 180, and 240 minutes after initiation of the investigational drug (reduction from moderate or severe headache at baseline to painless), the proportion of sustained pain - free where moderate or severe headache at baseline becomes mild or painless 2 hours after initiation of the investigational drug and does not recur (become mild, moderate, or severe) within 24 hours after initiation of the investigational drug, nausea, vomiting, photophobia, and phonophobia during the course of the trial, and presence of clinical disability, the proportion of patients using rescue medication between 2 and 24 hours after initiation of the investigational drug, and the overall impression of patients 2 hours after initiation of the investigational drug.

[0099] Statistical methods A target sample size of up to 160 patients, including at least 20 patients treated at an effective - dose level and at least 10 patients treated with placebo, is selected to provide appropriate preliminary data and, based on this data, to select a dose range for further assessment. When using a group - sequential adaptive treatment - allocation design to assign doses, the statistical properties of testing hypotheses to compare one or more dose levels with placebo are not known. Therefore, formal statistical tests are not being used to determine if this trial is "positive" or "negative", and this trial is not seeking statistical significance. Further, no sample size is being sought for statistical consideration.

[0100] At the end of this trial, summarize the headache response rate by dose level. Use the Mantel-Haenszel test to test for the association of dose response. Use Fisher's exact test to compare the headache response rates for the selected dose and placebo. In all analyses, the results for each dose level (including placebo) were pooled across all blocks and were used. Include all patients taking any investigational drug in the analysis population. Analyze patients by the treatment actually received and dose level.

[0101] Efficacy Statistically evaluate the linear relationship between the response rate and dose level using the Mantel-Haenszel test for trend. Tabulate the proportion of patients in each group who achieved headache response at time points from 10 minutes to 4 hours. Tabulate the primary and secondary efficacy parameters for each group, including the overall impression of the patient at 2 hours and the use of rescue medication up to 24 hours. Secondary efficacy parameters are pain-free at 2 hours, persistent pain response at 2 hours, persistent pain-free, nausea, acoustic phobia at 2 hours, photophobia at 2 hours, no impairment / mild impairment at 2 hours, use of rescue medication from 2 to 24 hours, impression at 2 hours: very good / fairly good.

[0102] Examine the efficacy of lasmiditan for acute migraine suppression with or without concomitant galcanezumab treatment. Use a double-blind dose-ranging trial design to rapidly and reliably screen for efficacy and tolerability across a wide dose range while minimizing patient exposure to the investigational drug or placebo. The onset of headache relief may be evident 20 - 40 minutes after the start of a 20-minute intravenous infusion.

[0103] Clinicians can assess the results of the trial's efficacy to determine the proportion of patients reporting a disorder after intravenous administration of lasmiditan, the proportion of reported disorders that are moderate or severe, the overall impression of the patient, and the proportion of patients reporting a "very" or "fairly good" feeling 2 hours after administration. Clinicians can also assess secondary evaluation items (photophobia, acoustic phobia, and nausea).

[0104] Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Dose-Ranging Study of Oral Rasmiditan With and Without Galcanezumab in the Acute Treatment of Migraine To demonstrate the efficacy of the combination of rasmiditan and galcanezumab, the following study is conducted once as described below and once in patients under review who are administered a first loading dose of 240 mg of galcanezumab followed by a monthly maintenance dose of 120 mg of galcanezumab.

[0105] A study is conducted to assess the efficacy (headache response at 2 hours) of the oral dose range of rasmiditan. The secondary objectives are to explore the time course and effects of the dose range of rasmiditan on migraine characteristics, including headache response, proportion of pain-free patients, headache recurrence, nausea, photophobia, phonophobia, vomiting, disability, use of rescue medication, and the patient's overall impression. In this study, the safety and tolerability of various doses of rasmiditan are explored in terms of adverse events, physical examinations, vital signs, laboratory assessments, and electrocardiograms. The study protocol is outlined below.

[0106] This is a prospective, randomized, double-blind, placebo-controlled, dose-ranging study in subjects with migraine. Patients are required to treat migraine attacks with the investigational drug at home. Each subject's participation in the study consists of a screening visit by telephone within 5 days to confirm eligibility, a treatment period of up to 8 weeks during which the subject is required to treat one migraine attack with a single dose of one of four dose levels of oral rasmiditan or placebo, and a follow-up visit within 14 days of treating the attack.

[0107] After screening, subjects are randomly assigned to receive oral lasmiditan (50, 100, 200, or 400 mg) or the corresponding placebo for use as the initial treatment of a new migraine attack. Once all screening assessments are completed, subjects are instructed not to treat an attack until their eligibility is confirmed by phone. Once eligibility is confirmed, subjects are required to treat the next migraine attack within 4 hours of its onset, provided that the headache severity is at least moderate at that time and has not improved. Subjects use a diary card to record their responses over the next 48 hours. Subjects are asked not to use rescue medication for at least 2 hours after taking the investigational drug. Once an attack has been treated, subjects contact the clinic to schedule a follow-up visit as soon as possible, within 14 days of treatment. Patients are assigned to one of the four dose levels of lasmiditan or the corresponding placebo in a 1:1:1:1:1 ratio according to a pre-defined randomization list. At least 340 patients are treated for one attack with the investigational drug.

[0108] Criteria for inclusion / exclusion: Inclusion: Subjects will be included in this trial only if all of the following criteria are met: Migraine patients with or without aura who meet the IHS diagnostic criteria 1.1 and 1.2.1 (2004), a history of migraine for at least one year, onset of migraine before the age of 50, a history of 1 to 8 migraine attacks per month, male or female patients aged 18 to 65, female patients of childbearing potential must be using a highly effective form of contraception (e.g., combination of oral contraceptives, intrauterine device, abstinence, partner's vasectomy), able to provide and willing to provide written informed consent, able to complete and willing to complete a migraine diary card to record details of attacks treated with the investigational drug.

[0109] Exclusions: Exclude the subject from this trial if any of the following criteria are met. That is, a history of life-threatening or intolerable adverse reactions to any triptan; use of prophylactic migraine medications prescribed within 30 days before the screening visit and during the trial (other than galcanezumab by design); women who are pregnant or breastfeeding; fertile women who do not use a highly effective method of contraception; history or evidence of any other condition in patients at high risk of coronary artery disease, ischemic or hemorrhagic stroke, epilepsy or seizure; history of hypertension (controlled or uncontrolled); history of orthostatic hypotension; systolic blood pressure exceeding 160 mmHg or diastolic blood pressure exceeding 90 mmHg in two repeated measurements at the screening visit while seated; current use of cardiovascular medications that stimulate hemodynamics; history or current evidence of any drug, prescription or illegal, or alcohol abuse within the past three years; significant impairment of the kidney or liver; previous participation in this clinical trial; participation in any clinical trial regarding investigational drugs or devices in the past 30 days; any medical condition or clinical test result that, in the judgment of the principal investigator, makes the patient inappropriate for this trial; known infection with hepatitis B or C or HIV; subjects who are employees of the sponsor; relatives of the principal investigator or persons reporting directly to the principal investigator; compound I, other 5-HT 1F patients who have a known allergy to any excipient of a 5-HT

[0110] Criteria included in the assessment: Efficacy / pharmacodynamics: headache severity (4-point scale: none, mild, moderate, severe); headache recurrence within 48 hours; presence or absence of nausea; phonophobia, photophobia, vomiting; disability (4-point scale: none, mild, moderate, severe); need for rescue medication from 2 to 48 hours (yes or no); patient's overall impression (7-point scale); time to headache relief and time to pain disappearance.

[0111] Safety: Physical examination; adverse events (voluntary reporting); vital signs; electrocardiogram using 12 leads; clinical trial parameters; statistical analysis.

[0112] Efficacy: This multicenter, randomized, double-blind, parallel-group, placebo-controlled clinical trial is designed to assess the efficacy and safety of oral lasmiditan with and without concomitant galcanezumab in the acute treatment of migraine. The proportion of subjects with headache relief at 2 hours after dosing is the primary efficacy parameter. In the primary efficacy analysis, the Cochran-Armitage test for trend is used to test the null hypothesis that the proportion of subjects with headache relief at 2 hours after dosing is the same in the five treatment groups against the alternative hypothesis of a positive linear trend in response rates. The primary analysis is performed in a modified intent-to-treat population defined as all subjects treated for attacks with the investigational drug using a one-sided test at the 5% significance level. Patients who failed to document headache severity at 2 hours or use of rescue medication prior to that time are excluded from the analysis set.

[0113] In an additional efficacy analysis, each active dose group is compared to the placebo group using a logistic regression model that includes data from all five treatment groups. The additional analysis is also based on subject sets for each protocol.

[0114] The sample size is estimated assuming a response rate of 40% in the placebo group and 65% in the highest dose group. Using the approach of Nam (1987), the required sample size is estimated assuming that the treatment groups are equally spaced and the response odds ratio is equal between pairs of adjacent dose groups. Based on a 1:1:1:1:1 randomization and a one-sided test at the 5% significance level, a total sample size of 330 patients (66 per group) is required for a 90% multiplier.

[0115] Safety: Adverse events can be summarized, and the event rate can be presented for each treatment group. Summarize the experimental data for each treatment group in terms of changes from the baseline state. The safety population can consist of all randomized patients who received at least a single dose of the investigational drug or placebo. Adverse events can be coded using the Medical Dictionary for Regulatory Activities (version 19.1). Safety parameters can be calculated as treatment-emergent adverse events (TEAE), serious adverse events (SAE), death, discontinuation due to adverse events, discontinuation rate, vital signs, body weight, and immunogenicity.

[0116] In the primary analysis, based on ePRO or other relevant clinical data, the efficacy of each combination dosing regimen can be evaluated by comparing the overall mean change from baseline in the number of monthly migraine headache days (MHD) during treatment with placebo, or galcanezumab alone, or lasmiditan alone. Other outcome measures may be the mean proportion of patients with a reduction from baseline of 50% or more, 75% or more, and 100% in monthly MHD during double-blind treatment. The mean change from baseline in the role function restriction (R-FR) domain score of the Migraine-Specific Quality of Life Questionnaire, version 2.1 (MSQ v2.1) can be calculated as the mean for the selected months of this trial. The overall mean change from baseline in the number of MHD during the double-blind treatment period can be calculated. The mean change from baseline can be calculated in the patient's global impression of severity (PGI-S) rating (mean for the selected months). An outcome measure for the total score of the Migraine Disability Assessment (MIDAS) can be calculated at selected time points such as the end of this trial.

[0117] Phase 3 studies of both lasmiditan and galcanezumab as monotherapies have been conducted and published. For example, for lasmiditan, see Phase 3 Studies (SAMURAI, SPARTAN) of Lasmiditan Compared to Placebo for Acute Treatment of Migraine (S50.008), Linda A. Wietecha, Bernice Kuca, Josephine Asafu-Adjei, Sheena K. Aurora, Neurology April 2018, 90(15 Supplement) S50.008, where the authors found that at 2 hours after the first dose, pain from headache was eliminated in a significantly higher proportion of patients (p<0.001) using 200 mg of lasmiditan compared to placebo (lasmiditan 200 mg: SAMURAI 32.2%, SPARTAN 38.8%, placebo: SAMURAI 15.3%, SPARTAN 21.3%), and the most bothersome symptoms (MBS) were eliminated (lasmiditan 200 mg: SAMURAI 40.7%, SPARTAN 48.7%, placebo: SAMURAI 29.5%, SPARTAN 33.5%). Significance was also observed for other lasmiditan dosing groups (100 mg, 50 mg) compared to placebo for both endpoints. The TEAEs most frequently reported after the first dose using lasmiditan (more than 2% and more than placebo) were dizziness, paresthesia, drowsiness, fatigue, nausea, and somnolence, and most events were mild to moderate in severity. From this analysis, the authors concluded that the primary and key secondary endpoints were met and the safety results were consistent across the two Phase 3 studies.Also, for example, regarding galcanezumab, reference is made to Efficacy and safety of galcanezumab for the prevention of episodic migraine Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial, Vladimir Skljarevski, Manjit Matharu, Brian A Millen, Michael H Ossipov, Byung-Kun Kim and Jyun Yan Yang, Cephalalgia 0(0)1-13, 2018. Here, the authors concluded that the mean number of days with episodic migraine per month decreased by 4.3 and 4.2 days with galcanezumab 120 and 240 mg, respectively, and by 2.3 days with placebo. The group differences (95% confidence intervals) compared to placebo were 1.9 (-2.4, -1.4) and 2.0 (-2.6, -1.5), respectively. Both doses were superior to placebo for all key secondary outcome measures. Injection site pain was the most common adverse event occurring with treatment and was reported at similar rates in all treatment groups. All galcanezumab doses had significantly more injection site reactions and injection site pruritus, and the 240 mg group had significantly more injection site erythema compared to placebo. From this analysis, the authors concluded that monthly administration of galcanezumab 120 or 240 mg was effective, safe, and well tolerated.

[0118] The combination of rimegepant and galcanezumab for use in the treatment of migraine is thought to be superior to either monotherapy alone, particularly in certain populations that have previously failed treatment, due to the combined effect on the CGRP pathway in combination with the complementary effect of rimegepant to reduce glutamate signaling. This combination of pharmacological properties is thought to result in superior efficacy for the treatment of migraine in patients suffering from therapy-resistant migraine. Each agent, namely rimegepant and galcanezumab alone, has demonstrated efficacy in the treatment of migraine, but the present invention provides a method of treating migraine in a patient comprising administering to the patient in need of treatment for migraine an effective amount of rimegepant in combination with, separately from, or sequentially to an effective amount of galcanezumab, which can provide additional potential benefits to migraine patients, more particularly to migraine patients who have not individually experienced adequate migraine treatment efficacy when treated with either galcanezumab or rimegepant alone. Thus, the potential efficacy provided by the combination of galcanezumab and rimegepant of the present invention to treat patients inadequately controlled by rimegepant or galcanezumab monotherapy alone and / or to treat migraine patients whose disease has been refractory to two or more conventional monotherapy and / or dual therapy treatment regimens represents an important further advance in migraine therapy. Preferably, the provided combination method of treating migraine in a patient in need of treatment for migraine, which comprises administering to the patient an effective amount of rimegepant in combination with, separately from, or sequentially to an effective amount of galcanezumab, can further provide efficacy to these inadequately treated migraine patients, whereby the patient can be pain free 2 hours after treatment with rimegepant, more preferably 1 hour after treatment with rimegepant, and even more preferably will also experience relief from the patient's most bothersome symptoms 2 hours after treatment with rimegepant.Preferably, a patient treated by the combination of the present invention may potentially experience relief of persistent pain, and / or more preferably freedom from pain due to migraine, and / or disappearance of migraine disorder, as evaluated by methods well known to those skilled in the art, such as MIDAS, or by well-known quality of life measures. Preferably, a patient treated with the combination of the present invention will experience migraine on three or fewer days per month, more preferably one or fewer days per month. Preferably, the combination of the present invention can provide further potential advantages in the form of effectiveness in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache, as previously described. Preferably, the combination therapy of the present invention will provide the improved migraine treatment described herein while demonstrating desirable clinical safety and tolerability.

Claims

**Claim 1** A pharmaceutical composition for oral treatment of migraine in a patient, comprising a combination of lasmiditan and rimegepant, and comprising a fixed-dose combination tablet comprising a unit dose of lasmiditan selected from 50 mg, 100 mg, or 200 mg. **Claim 2** A pharmaceutical composition for oral treatment of migraine in a patient, comprising a combination of lasmiditan and ubrogepant, and comprising a fixed-dose combination tablet comprising a unit dose of lasmiditan selected from 50 mg, 100 mg, or 200 mg. **Claim 3** A pharmaceutical composition for oral treatment of migraine in a patient, comprising a combination of lasmiditan and olcegepant, and comprising a fixed-dose combination tablet comprising a unit dose of lasmiditan selected from 50 mg, 100 mg, or 200 mg. **Claim 4** A pharmaceutical composition for oral treatment of migraine in a patient, comprising a combination of lasmiditan and MK-8031, and comprising a fixed-dose combination tablet comprising a unit dose of lasmiditan selected from 50 mg, 100 mg, or 200 mg.

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