Combination therapy of lasmiditan and CGRP antagonist for use in treatment of migraine

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 methods of using the 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, defined herein as migraine that is refractory to two or more conventional monotherapy and / or dual therapy treatment regimens.

[0002] Primary headache disorders, including migraine, are the most common disease and a leading cause of disability worldwide. Migraine affects more than 14% of adults worldwide. Available treatment options for migraine suffer from inadequate efficacy, tolerability, and patient adherence rates. In the 2013 Global Burden of Disease Study, migraine accounted for more than half of all years lost due to disability attributable to neurological disorders (New strategies for the treatment and prevention of primary headache disorders, NMSchuster & AMRapoport, Nature Reviews Neurology (2016) 12, 635-650). Migraine is typically characterized by 1-3 days of severe headache attacks associated with nausea, vomiting, photophobia, and phonophobia (migraine without aura), as well as neurological aura symptoms in one third of patients (migraine with aura) (Goadsby PJ et al., New England Journal of Medicine 2002;346:257-270).

[0003] Lasmiditan, i.e., 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide (Compound I), is a selective and highly potent 5-HT-1F receptor agonist being developed for the treatment of migraine (see, e.g., 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 dorsal root and trigeminal ganglion, and in C and Ad sensory fibers originating from the central nervous system.CGRP is a pain signaling neuropeptide and a potent vasodilator released from trigeminal sensory afferents and spinal trigeminal nucleus.The role of CGRP in headache and migraine has been 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, such as a combination of lasmiditan and galcanezumab, and a method of using the combination to treat migraine. More specifically, the present invention relates to the use of a combination of lasmiditan and a calcitonin gene-related peptide (CGRP) antagonist for the treatment of migraine that is inadequately controlled by lasmiditan or a calcitonin gene-related peptide (CGRP) antagonist therapy alone. More specifically, 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, defined herein as migraine that is refractory to two or more conventional monotherapy and / or dual therapy treatment regimens.

[0006] Management of migraine patients is often inadequate because available acute and preventive therapies are ineffective or poorly tolerated. Acute treatment of migraine attacks has been limited to the use of analgesics, analgesics in combination with caffeine, ergotamines, and triptans. (For a description of such agents, see, e.g., New Therapeutic Approaches for the Prevention and Treatment of Migraine, Diener, HC et al., (2015) Lancet Neurololgy, 14:1010-22). Lasmiditan represents an innovative approach to acute migraine therapy by selectively targeting 5-HT-1F. Although many patients will be able to successfully manage their migraine attacks with treatment using lasmiditan or galcanezumab as monotherapy, a population of patients will fail to successfully manage their migraine attacks with either of these drugs individually. These patients may continue to experience significant disability due to the number of migraine days per month. Furthermore, some patients, referred to herein as therapy-resistant migraine patients, will fail to manage migraine attacks and suffer from migraines that are resistant to two or more conventional monotherapy and / or dual therapy treatment regimens. As defined herein, a therapy-resistant migraine patient is a patient who continues to suffer from migraines on three or more 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 unsatisfactory conventional treatment trials using either monotherapy or dual therapy regimens, such as triptans, ergotamines, nonsteroidal anti-inflammatory drugs (NSAIDs), non-narcotic analgesics, and caffeine, alone or in combination with two such drugs. Therapy-resistant patients represent a significant unmet need, as they have not yet achieved substantial freedom from recurrent migraines. The failure of these therapy-resistant migraine patients to achieve adequate relief from multiple conventional treatment regimens demonstrates that their disease is particularly difficult to treat, and efficacy in this population represents a surprisingly good result.

[0007] Lasmiditan (COL144, LY573144, CAS Registry 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. [ka] As used herein, compound I includes its pharmaceutically acceptable salts, including but not limited to 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-ylcarbonyl)-pyridin-2-yl]-benzamide monohydrochloride and 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide hemisuccinate. Methods for preparing lasmiditan and salts and certain formulations and dosage forms thereof are known to those skilled in the art and are described in WO03 / 084949 and WO2011 / 123654.

[0008] Galcanezumab (LY2951742, CAS Registry 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). Galcanezumab monotherapy 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 useful in the combinations of the present invention and known to those skilled in the art include eptinsumab (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, NMSchuster & AMRapoport, Nature Reviews Neurology (2016) 12, 635-650). CGRP antagonists useful in the combination of the present invention and known to those of skill 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 of skill in the art.

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

[0010] Provided herein is a novel method for the use of the combination of lasmiditan and calcitonin gene-related peptide (CGRP) antagonist, such as the combination of lasmiditan and galcanezumab, for the treatment of migraine and therapy-resistant migraine.It is believed that the combination of lasmiditan and galcanezumab for the treatment of migraine will be superior to either monotherapy alone, due to the combined action on CGRP pathway combined with the complementary action of lasmiditan to reduce glutamate signaling.It is believed that the combination of these pharmacological properties will result in superior efficacy in the treatment of migraine in patients suffering from therapy-resistant migraine.

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

[0012] Combinations of lasmiditan and calcitonin gene-related peptide (CGRP) antagonists, such as combinations 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 doses and administration schedules of lasmiditan and galcanezumab, which are described below.

[0013] The present invention relates to a pharmaceutical composition combination comprising an amount of lasmiditan or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable diluent or carrier, wherein for oral administration, the composition comprises 50-400 mg of lasmiditan or a pharma- ceutically acceptable salt thereof per single dose, and for buccal, sublingual, nasal / intranasal, transdermal, subcutaneous, injectable, intravenous or intramuscular administration, the composition comprises up to 200 mg of lasmiditan or a pharma- ceutically acceptable salt thereof per single dose, and further wherein the composition is administered once, twice or three times daily. The present invention relates to a pharmaceutical composition combination of lasmiditan, wherein the composition is for oral administration, and wherein the amount of lasmiditan or a pharma- ceutically acceptable salt thereof is 50 mg-400 mg per single dose. The present invention relates to a pharmaceutical composition combination of lasmiditan, wherein the amount of lasmiditan is 50 mg per single dose. The present invention relates to a pharmaceutical composition combination of lasmiditan, wherein the amount of lasmiditan is 100 mg per single dose. The present invention relates to a pharmaceutical composition combination of lasmiditan, the amount of lasmiditan is 200mg per single dose. The present invention relates to a pharmaceutical composition combination of lasmiditan, the amount of lasmiditan is 400mg per single dose. The present invention relates to a pharmaceutical composition combination of lasmiditan, the composition for buccal, sublingual, nasal / intranasal, transdermal, subcutaneous, injectable, intravenous or intramuscular administration, the amount of lasmiditan or its pharma- ceutically acceptable salt administered is up to 200mg per single dose. The present invention relates to a pharmaceutical composition combination of lasmiditan or its pharma- ceutically acceptable salt administered is 20mg-200mg per single dose. The present invention relates to a pharmaceutical composition combination of lasmiditan, the amount of lasmiditan or its pharma- ceutically acceptable salt administered is 20mg-60mg per single dose. The present invention relates to a combination of a pharmaceutical composition with lasmiditan, wherein the amount of lasmiditan or a pharma- ceutical acceptable salt thereof administered is 20-30 mg per single dose.The present invention relates to a combination of a pharmaceutical composition with lasmiditan, wherein the administration is intravenous and the amount of lasmiditan or a pharma-ceutical acceptable salt thereof administered is up to 200 mg per single dose.The present invention relates to the combination of a pharmaceutical composition of lasmiditan, wherein the administration of lasmiditan or a pharma- ceutically acceptable salt thereof is intravenous over a period of about 20 minutes.

[0014] The present invention relates to a combination of pharmaceutical compositions of lasmiditan, the composition comprising a hemisuccinate salt of lasmiditan. The present invention relates to a combination of pharmaceutical compositions of lasmiditan, the composition comprising a hemisuccinate salt of lasmiditan, the amount administered is 50 mg per single dose. The present invention relates to a combination of pharmaceutical compositions of lasmiditan, the composition comprising a hemisuccinate salt of lasmiditan, the amount administered is 100 mg per single dose. The present invention relates to a combination of pharmaceutical compositions of lasmiditan, the composition comprising a hemisuccinate salt of lasmiditan, the amount administered is 200 mg per single dose.

[0015] The present invention relates to a pharmaceutical composition combination of lasmiditan, wherein the dose of lasmiditan or a pharma- ceutically acceptable salt thereof is administered once a day.The present invention relates to a pharmaceutical composition combination of lasmiditan, wherein the dose of lasmiditan or a pharma- ceutically acceptable salt thereof is administered twice a day.The present invention relates to a pharmaceutical composition combination of lasmiditan, wherein the dose of lasmiditan or a pharma- ceutically acceptable salt thereof is administered three times a day.

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

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

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

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

[0020] The present invention relates to a method for the treatment of migraine in a patient in need of such treatment comprising buccal, sublingual, nasal / intranasal, transdermal, subcutaneous, injectable, intravenous or intramuscular administration of 50-400 mg per single dose of lasmiditan or a pharma- ceutically acceptable salt thereof and a pharma-ceutically acceptable diluent or carrier to said patient.

[0021] The present invention relates to a method for the treatment of migraine in a patient in need of such treatment comprising buccal, sublingual, nasal / intranasal, transdermal, subcutaneous, injectable, intravenous or intramuscular administration of 50-400 mg of lasmiditan or a pharma- ceutically acceptable salt thereof per single dose in combination with a pharma- ceutically acceptable diluent or carrier to said patient, wherein the composition is administered once, twice or three times daily.

[0022] The present invention relates to a method for the combined treatment of migraine headaches in a patient in need of such treatment, comprising administering to said patient a dose of 120 mg of galcanezumab.The present invention relates to a method for the combined treatment of migraine headaches in a patient in need of such treatment, comprising administering to said patient a dose of 240 mg of galcanezumab.The present invention relates to a method for the combined treatment of migraine headaches in a patient in need of such treatment, comprising administering to said patient a dose of 300 mg of galcanezumab.The present invention relates to a method for the combined treatment of migraine headaches in a patient in need of such treatment, comprising administering to said patient a dose of 360 mg of galcanezumab.Preferably, the dose of galcanezumab is administered at weekly, semi-monthly, monthly or quarterly intervals.More preferably, galcanezumab administration is monthly. The present invention relates to a method for combination treatment of migraine in a patient in need thereof, comprising administering to said patient 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 combination method for treating episodic migraine in a patient, comprising administering a monthly subcutaneous dose of 120 mg of galcanezumab.As used herein, the combination treatment of administering galcanezumab is according to the dosing schedule provided above.

[0023] Another aspect of the invention relates to the combination of lasmiditan with carcanezumab as a medicament, particularly as a medicament suitable for the treatment of migraine headaches 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 headaches 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 calcitonin gene-related peptide (CGRP) antagonist in the treatment of migraine in patients 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 patients 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, where the patient's migraine has been refractory to two or more conventional monotherapy and / or dual therapy treatment regimens.

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

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

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

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

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

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

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

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

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

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

[0039] 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 a 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 a 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 calcitonin gene-related peptide (CGRP) antagonist in the treatment of headaches selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in patients inadequately controlled by lasmiditan or a calcitonin gene-related peptide (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 headaches selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache in patients 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 a 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 has been 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 headaches 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 has been refractory to two or more conventional monotherapy and / or dual therapy treatment regimens.

[0045] In another embodiment, the invention provides a method for the use of lasmiditan in simultaneous, separate or sequential combination with galcanezumab in the treatment of a 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 loading dose of 240 mg, followed by monthly maintenance doses of 120 mg, and lasmiditan is administered at a dose of 50 mg once or twice daily.

[0046] In another embodiment, the invention provides a method for the use of lasmiditan in simultaneous, separate or sequential combination with galcanezumab in the treatment of a 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 loading dose of 240 mg, followed by monthly maintenance doses of 120 mg, and lasmiditan is administered at a dose of 100 mg once or twice daily.

[0047] In another embodiment, the invention provides a method for the use of lasmiditan in simultaneous, separate or sequential combination with galcanezumab in the treatment of a 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 loading dose of 240 mg, followed by monthly maintenance doses of 120 mg, and lasmiditan is administered at a dose of 200 mg once or twice daily.

[0048] In another embodiment, the invention provides a method for the use of lasmiditan in simultaneous, separate or sequential combination with galcanezumab in the treatment of a 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 at a dose of 50 mg once or twice daily.

[0049] In another embodiment, the invention provides a method for the use of lasmiditan in simultaneous, separate or sequential combination with galcanezumab in the treatment of a 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 at a dose of 100 mg once or twice daily.

[0050] In another embodiment, the invention provides a method for the use of lasmiditan in simultaneous, separate or sequential combination with galcanezumab in the treatment of a 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 at a dose of 200 mg once or twice daily.

[0051] In another embodiment, the invention provides a method for the use of lasmiditan in simultaneous, separate or sequential combination with galcanezumab in the treatment of a 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 in a monthly dose of 120 mg and lasmiditan is administered once daily in a dose of 50 mg.

[0052] In another embodiment, the invention provides a method for the use of lasmiditan in simultaneous, separate or sequential combination with galcanezumab in the treatment of a 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 in a monthly dose of 120 mg and lasmiditan is administered once daily in a dose of 100 mg.

[0053] In another embodiment, the invention provides a method for the use of lasmiditan in simultaneous, separate or sequential combination with galcanezumab in the treatment of a 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 in a monthly dose of 120 mg and lasmiditan is administered once daily in a dose of 200 mg.

[0054] In another embodiment, the present invention provides a method of treating migraine in a patient in need of such treatment, comprising simultaneously, separately or sequentially administering to the patient 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 of treating migraine in a patient in need thereof comprising simultaneously, separately or sequentially administering to the patient an effective amount of lasmiditan in combination with an effective amount of galcanezumab.

[0056] In another embodiment, the present invention provides a method of treating migraine in a patient comprising simultaneously, separately or sequentially administering to a patient in need thereof 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 comprising simultaneously, separately or sequentially administering to a patient in need thereof an effective amount of lasmiditan in combination with an effective amount of galcanezumab, 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 comprising simultaneously, separately or sequentially administering to a patient in need thereof an effective amount of lasmiditan in combination with an effective amount of a calcitonin gene-related peptide (CGRP) antagonist, wherein the patient suffers from therapy-resistant migraine, and the patient's migraine has been 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 comprising simultaneously, separately or sequentially administering to a patient in need thereof an effective amount of lasmiditan in combination with an effective amount of galcanezumab, wherein the patient suffers from therapy-resistant migraine and the patient's migraine has been refractory to two or more conventional monotherapy and / or dual therapy treatment regimens. As explained below, the above-mentioned method of treatment represents "one of the preceding embodiments."

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

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

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

[0063] In another embodiment, the invention provides a method of any one of the previous embodiments, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered at a dose of 50 mg once or twice daily.

[0064] In another embodiment, the invention provides a method of any one of the previous embodiments, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered at a dose of 100 mg once or twice daily.

[0065] In another embodiment, the invention provides a method of any one of the previous embodiments, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered at a dose of 200 mg once or twice daily.

[0066] In another embodiment, the invention provides a method of any one of the previous embodiments, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once daily at a dose of 50 mg.

[0067] In another embodiment, the invention provides a method of any one of the previous embodiments, wherein galcanezumab is administered at a monthly dose of 120 mg and lasmiditan is administered once daily at a dose of 100 mg.

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

[0069] Conventional treatment of migraine may leave a significant number of patients undertreated. For example, up to 40% of migraine attacks, about 30% of patients, fail to respond to certain triptans due to suboptimal efficacy or tolerability issues (see Dodick DW.Headache.2005;45:156-162, and Tepper DE.Headache.2013(53)577-578). Due to their vasoconstrictive effects, these drugs may have contraindications, warnings, and cautions for patients with cardiovascular risk factors and heart disease (see Alwhaibi M,et al.Pain Res Treat.2016;2016:8538101, Gilmore B,Michael M.AM Fam Physician.2011(83)271-280). Furthermore, conventional therapies are often limited by the onset of migraine overuse headaches, where patients may be limited in the number of treatments they can use in a particular time frame to avoid the onset of migraine overuse headaches (see, for example, Diener, HC et al., Chronic Headache Due to Overuse of Analgesics and Anti-Migraine Agents. Dtsch Arztebl Int 2018;115:365-70). Thus, for conventional monotherapy or dual therapy migraine treatments, a significant proportion of patients may fail to achieve headache relief and / or pain relief in response to treatment. Furthermore, some patients, referred to herein as therapy-resistant migraine patients, will fail to successfully manage migraine attacks and suffer from migraines that are refractory to two or more conventional monotherapy and / or dual therapy treatment regimens. As defined herein, a therapy-resistant migraine patient is one who continues to suffer from migraine headaches on 3 or more days per month despite two or more conventional monotherapy and / or dual therapy treatment regimens.As used herein, two or more conventional monotherapy and / or dual therapy treatment regimens refers to conventional unsatisfactory treatment attempts with monotherapy or dual therapy regimens, either alone or in combination with two such agents, such as triptans, ergotamines, nonsteroidal anti-inflammatory drugs (NSAIDs), non-narcotic analgesics, blood pressure medications, anticonvulsants, antidepressants, serotonin antagonists, onabotulinum toxin, and caffeine. Additionally, a population of patients will fail to successfully manage their migraine attacks with either galcanezumab or lasmiditan individually.

[0070] These inadequately controlled migraine patients may continue to be significantly disabled, with a high number of migraine days per month. An unsatisfactory treatment trial is one in which the patient concludes that symptoms have not been alleviated to such an extent that disability is avoided after a full course of therapy. Migraine disability measures are well known to those skilled in the art, such as the Migraine Disability Assessment, where a total score of ≥11 may represent disability associated with moderate to severe headache. In an embodiment of the invention, a Migraine Disability Assessment of 10 or less, or an equivalent assessment by means known to those skilled in the art, represents avoidance of disability. Preferably, the combination method of the invention provides relief of migraine disability such that the patient reports a total score of 10 or less on the Migraine Disability Assessment. Preferably, in an embodiment of the invention, a Migraine Disability Assessment or an equivalent assessment by means known to those skilled in the art will demonstrate clinical absence of disability. Preferably, the combination method of the invention provides relief of migraine disability such that the migraine patient has no significant clinical disability after administration of lasmiditan, in which the patient does not report complete disability, or the need for bed rest, or significant interference with daily activities. More preferably, the combination method of the present invention provides relief from migraine disorder after administration of lasmiditan such that the migraine patient is not disturbed to a minor extent. More preferably, the combination method of the present invention provides relief from migraine disorder after administration of lasmiditan such that the migraine patient is not disturbed at all. Preferably, patients treated with the combination method provided herein avoid the onset of migraine overuse headache.

[0071] Symptomatic relief, such as headache pain relief, or relief from the most bothersome symptoms of the patient, can be defined as efficacy, for example, according to the clinical study protocol provided herein.Preferably, the combination method of the present invention provides headache pain relief and / or relief from the most bothersome symptoms of the patient.Headache pain relief, as used herein, is assessed by a reduction in pain severity from moderate or severe at baseline to mild or none, or a reduction in pain severity from mild to none at baseline, 2 hours after administration.No headache pain, as used herein, is a reduction in pain severity from mild, moderate, or severe at baseline to none at the indicated evaluation.The most bothersome symptoms (MBS) are identified by the participant at the onset of the migraine attack from the associated symptoms of nausea, phonophobia, and photophobia before administration.No most bothersome symptoms, as used herein, refers to the patient-reported result of no MBS associated with migraine 2 hours after administration, where MBS is defined as the associated symptoms present and is identified as the MBS before administration.

[0072] As used herein, refractory migraine includes, but is not limited to, refractory chronic migraine and / or refractory episodic migraine. Means of identifying refractory migraine patients are known to those skilled in the art. For example, refractory chronic migraine is recognized by those skilled 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 migraine should be defined as ICHD-3 beta chronic migraine without drug overuse in patients who fail to respond to treatment with at least three preventive drugs at appropriate dosages, each with at least three months of trial. The proposed criteria can be briefly described as follows: A. ICHD-3 beta chronic migraine without medication overuse, B. migraine prophylaxis at appropriate doses used for at least 3 months each, C. no contraindication or effect for prophylaxis with at least 3 medications from the following classes: beta-blockers (propranolol up to 240 mg daily, metoprolol up to 200 mg daily, atenolol up to 100 mg daily, bisoprolol up to 10 mg daily), anticonvulsants (valproic acid up to 1.5 g daily, topiramate up to 200 mg daily), tricyclics (amitriptyline up to 150 mg daily), or other (flunarizine up to 10 mg daily, candesartan up to 16 mg daily, onabotulinumtoxin 155-195 U with PREEMPT), and D. appropriate treatment of psychiatric or other comorbid conditions by a multidisciplinary team, if available.

[0073] The combination treatment method of the present invention is believed to provide improved migraine treatment, including in patients who are inadequately controlled by lasmiditan or galcanezumab therapy alone, and / or suffer from therapy-resistant migraine, where the migraine of the patient is refractory to two or more conventional monotherapy and / or dual therapy treatment regimens, and further provide a particularly advantageous combination of pharmacological benefits, including 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 provide a clinically acceptable level of adverse effects, such as dizziness, paresthesia, and somnolence.The combination treatment method of the present invention can provide these advantages in part by allowing migraine patients to adequately treat migraine attacks with lower doses of lasmiditan, for example 100 mg or 50 mg, more preferably by doing so in a single dose per day, thereby avoiding the need for a second dose per day. In this respect, the combination treatment method of the present invention provides migraine patients with a significant reduction and / or more preferably the absence of significant migraine symptoms and impairments. In another respect, the combination treatment method of the present invention provides migraine patients with a significant reduction and more preferably the absence of significant migraine symptoms and impairments for a sustained period of time, for example 24 hours after administration of lasmiditan, or preferably 48 hours after administration of lasmiditan.

[0074] As used herein, "combination therapy" or "in combination" includes administration of lasmiditan and a CGRP antagonist as part of a specific treatment regimen intended to provide beneficial effects 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-action resulting from the combination of therapeutic agents. The 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 combination selected). Combination therapy is intended to encompass administration of the indicated therapeutic agents in a sequential manner, i.e., each therapeutic agent is administered at different times, as well as administration of these therapeutic agents in a substantially simultaneous manner. Administration can be accomplished, for example, by administering to the subject 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. The 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, the first therapeutic agent of the selected combination can be administered by intramuscular or intravenous injection, while the other therapeutic agents of the combination can be administered orally. Alternatively, for example, all therapeutic agents can be administered orally or all therapeutic agents can be administered by intravenous injection, where applicable. The order in which the therapeutic agents are administered is not strictly important.

[0075] As used herein, "once a day" means that lasmiditan is administered once per 24 hours or once per calendar day. As used herein, "once a day" means that lasmiditan is administered once per 24 hours or once per calendar day for the prevention or treatment of migraine attacks. As used herein, "once a day" means that lasmiditan is administered once per 24 hours or once per calendar day for the treatment of migraine attacks, and such treatment may occur on 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 about the same calendar day of each month to provide a regular administration interval.

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

[0078] If the disorder that can be treated by the combination of the present invention is known by an established and accepted classification, such as migraine, episodic headache, chronic headache, chronic cluster headache, and / or episodic cluster headache, the classification can be found in various sources.For example, currently, the 4th edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV™) (1994, American Psychiatric Association, Washington, DC) 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 terms and classification systems evolve with the progress of medical science. Migraine patients can further be diagnosed with migraine with or without aura (1.1 and 1.2) as defined by the International Headache Society (IHS) International Classification of Headache disorders, 3rd ed., (ICHD-3) beta (The International Classification of Headache Disorders, 3rd ed. (Beta), Cephalalgia 2013;33:629-808).

[0079] The term "pharmaceutical product" or "pharmaceutical acceptable" as used herein as an adjective means substantially non-toxic and substantially harmless to the recipient. A "pharmaceutical composition" further means that the carrier, solvent, excipient and salt must be compatible with the active ingredient of the composition (e.g., the compound of the present invention). It will be understood by those skilled in the art that the terms "pharmaceutical formulation" and "pharmaceutical composition" are generally interchangeable, and the terms are used as such for the purposes of this application.

[0080] Furthermore, the compounds of the present invention, for example, the salts of the compounds, can exist in hydrated or non-hydrated (anhydrous) form. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. When the compounds of the present invention are amines, they are basic in nature and therefore react with any of a large number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. The term "acid addition salt" refers to the salt of the compound prepared by reacting the compound with a mineral or organic acid. The compounds of the present invention form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids, including physiologically acceptable salts that are often 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 the pharmaceutically acceptable salts exemplified in Berge, SM, Bighley, LD, and Monkhouse, DC, J.Pharm.Sci., 66:1, (1977), which are well known to those skilled in the art.

[0081] The term "effective amount" refers to the amount of lasmiditan that can activate the 5-HT-1F receptor, or the amount of a CGRP antagonist that can inhibit the action of CGRP. In a preferred embodiment, "effective amount" refers to the amount of lasmiditan and the amount of a CGRP antagonist that can eliminate pain in a patient 2 hours after headache treatment with lasmiditan.

[0082] The term "treating" or "treatment" as used herein means curing an already existing condition or condition, e.g., migraine or headache, in a patient or subject. Treating can also include inhibiting, i.e., arresting, the further development of a condition or condition, and alleviating or remitigating, i.e., causing the regression of a condition or condition, e.g., migraine. The term "preventing" or "prevention" as used herein means completely or nearly completely arresting the development of a condition or condition in a patient or subject, especially when the patient or subject is susceptible to or at risk of developing a condition or condition, e.g., migraine.

[0083] Throughout this specification, when a composition is described as having, including, or comprising a particular component, it is assumed 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 also consists essentially of or consists of the recited process steps. Furthermore, 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 operable. Moreover, two or more steps or actions can be performed simultaneously.

[0084] Those skilled in the art of preparing formulations can easily select the appropriate form and mode of administration according to the specific characteristics of the selected compound, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances (see, for example, Remington: The Science and Practice of Pharmacy, LV Allen, Editor, 22nd Edition, Pharmaceutical Press, 2012).In particular, the components of the combination of the present invention can be combined in the same preparation as appropriate, or alternatively, the components can be formulated separately.

[0085] In separate preparations, lasmiditan is usually mixed with excipients, diluted by excipients, or enclosed in a carrier, such as in the form of capsules, sachets, paper or other containers. The CGRP antagonist is appropriately formulated separately. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier or medium for active ingredient. Thus, the preparation can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing up to 10% by weight of 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, gum acacia, 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, sweeteners, and correctives.The compound of the present invention can be formulated to provide rapid, sustained, or delayed release of active ingredient after administration to a patient by adopting procedures known in the art.

[0086] Examples of clinical studies The following clinical study design further describes the present invention, but should not be construed as limiting the scope of the present invention in any way. An example of the study of lasmiditan in combination with galcanezumab in the treatment of migraine is provided below. Those skilled in the art will understand that similar studies can be performed on patients who have not been able to successfully manage their migraine attacks with either lasmiditan or galcanezumab individually. Those skilled in the art will understand that similar studies can be performed on patients who have migraine attacks that are refractory to two or more conventional monotherapy and / or dual therapy treatment regimens, referred to herein as therapy-resistant migraine patients. Those skilled in the art can perform similar studies on patients who suffer from headaches selected from the group consisting of episodic headaches, chronic headaches, chronic cluster headaches, or episodic cluster headaches, including patients with therapy-resistant headaches. One of skill in the art can readily use the methods described herein as well as methods known in the art to identify patients who have not been able to successfully manage their migraine attacks with either lasmiditan or galcanezumab individually, and / or therapy-resistant migraine patients whose migraine attacks are refractory to two or more conventional monotherapy and / or dual therapy treatment regimens, and such patients so identified may be subjects for clinical studies, such as those described herein.

[0087] Methods for carrying out such clinical studies are known to those skilled in the art, and are exemplified, for example, by the references provided herein for published clinical studies of lasmiditan and galcanezumab. Methods for evaluating migraine treatment include patient-reported outcome measures (PROs), such as quality of life (QOL) measures, including, for example, Migraine-Specific Quality of Life, Version 2.1 (MSQ v2.1), Headache Impact Examination 6 (HIT-6), Migraine Disability Assessment Scale (MIDAS), and Migraine-Specific Quality of Life Questionnaire (MSQoL). In addition, ePRO diaries can be used to record headaches and other migraine symptoms. Based on the diary data, an automated algorithm can be used to classify days as migraine days (MHDs), including medium MHDs. Medium migraine is defined as a headache with or without aura, lasting 30 minutes or more, but lacking one of the migraine hallmarks in the ICHD-3 beta criteria. The monthly number of MHDs due to acute migraine medication use can be obtained from the ePRO diary, and PGI-S, MSQ, and MIDAS assessments are performed using a Slate device at the study site at monthly visits 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 effectiveness 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 days (MHDs) during the treatment phase. Other possible outcome measures may be the mean proportion of patients with a reduction from baseline in monthly MHDs during the double-blind treatment phase, the mean change from baseline in the Migraine-Specific Quality of Life v2.1 (MSQ v2.1) Role Functioning Limitation (R-FR) domain score, the mean change from baseline in the Patient Global Impression of Severity (PGI-S) rating (average of selected months), and / or the Migraine Disability Assessment (MIDAS) total score. Evaluation of these and other migraine treatments is well known to those of skill in the art.

[0088] Acute treatment of migraine with lasmiditan, with and without intravenous CGRP antagonists such as galcanezumab To demonstrate the efficacy of the combination of lasmiditan and galcanezumab, the following study will be conducted once as described below and once in which patients under evaluation will receive a loading dose of 240 mg of galcanezumab followed by a monthly maintenance dose of 120 mg of galcanezumab. Treatment arms of the study may include unit doses of 50 mg, 100 mg, or 200 mg of lasmiditan for oral administration.

[0089] In this multicenter, placebo-controlled, double-blind, group-sequential, adaptive treatment allocation, proof-of-concept and dose-finding study, 130 patients will be treated at the time of hospitalization during a migraine attack. Patients will be assigned to intravenous dose levels of lasmiditan or placebo in small cohorts. The starting dose will be 2.5 mg. Subsequent doses will be adjusted up or down depending on safety and efficacy seen in prior cohorts. The primary endpoint will be headache response, defined as improvement from moderate or severe headache at baseline to mild or absent headache at 2 hours post-dose. The study is designed to explore overall dose-response associations but is not designed to distinguish individual doses from placebo or to detect differences in effect on other migraine symptoms.

[0090] 42 patients will receive placebo and 88 will receive lasmiditan at doses between 2.5 and 45 mg. Patients will be observed in the clinic for 4 hours after treatment and will record symptoms and adverse events up to 24 hours using diary cards. The study will be terminated when the dose meets the predefined efficacy stopping rule. Patients treated in the 10, 20, 30, and 45 mg lasmiditan dose groups will be assessed for 2-hour headache response compared to the placebo group. Patient global impression at 2 hours and absence of need for rescue medication will also be assessed for a statistically significant linear correlation with dose. The efficacy of lasmiditan in combination with concurrent galcanezumab treatment for the acute treatment of migraine headaches will be assessed at intravenous doses of 2.5 to 45 mg lasmiditan.

[0091] method The study will be multi-center and conducted in accordance with the Declaration of Helsinki and internationally recognized Good Clinical Practice. Approval by relevant regulatory authorities and independent ethics committees is required prior to initiation. All subjects will be limited to those who provide written informed consent.

[0092] Study design The study uses a prospective, randomized, double-blind, placebo-controlled design with group-sequential adaptive treatment allocation (Olesen J et al., N Engl J Med 2004:350:1104-10; Hall DB et al., Contemporary Clinical Trials 2005;26:349-63). Patients are assigned to lasmiditan dose levels in small cohorts, with the first 20 cohorts consisting of 6 patients (4 receiving lasmiditan and 2 placebo) and subsequent cohorts consisting of 5 patients (4 lasmiditan and 1 placebo). The first cohort is assigned a dose level of 2.5 mg. The dose used in subsequent cohorts will depend on the headache response of the preceding cohort (reduction of moderate or severe headache to mild or absent at 2 hours). If 2 or less of 4 actively treated patients respond, the dose will be increased, and if 3 or more of 4 actively treated patients respond, the dose will be decreased. Dose adjustment rules will be selected to identify a dose of lasmiditan with efficacy equal to or greater than that of oral triptans. This sequence of dose increase or decrease will be modified if 2 or more actively treated patients in any cohort experience a non-serious adverse event. The occurrence of a drug-related serious adverse event will automatically interrupt randomization until safety confirmation has been performed. The minimum tolerated dose of lasmiditan is 1 mg, and the maximum tolerated dose is 60 mg.

[0093] The upward or downward titration process was terminated with the selection of an effective dose when the following criteria were met: at least five blocks of patients were treated at this dose and for at least four blocks the decision rule required a dose reduction, or it could be terminated without the selection of an effective dose if five consecutive blocks of patients were treated at the upper limit dose with the titration rule requiring a dose increase each time.

[0094] Patient Screening and Selection First, patients are screened for eligibility for outpatient visits outside of migraine attacks and invited to return to the clinic for treatment with the investigational drug for a new moderate or severe migraine attack within 4 hours of onset. At the return visit to the clinic, eligibility for the study is reconfirmed and the patient is randomized. Patients are eligible for the study if they are 18-65 years of age, have migraine onset before age 50, meet IHS diagnostic criteria 1.1 and 1.2.1 (2004), and have a history of migraine with or without aura for at least 1 year (Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders (second edition). Cephalosalgia 2004:24; Suppl 1:1-160). Patients must have 1-8 migraine attacks per month and must not be using migraine prophylactic medications. Patients must be in good general health with no evidence of vascular disease or hypertension. Patients with previous triptan intolerance will be excluded. Pregnant or lactating women will be excluded, as will women of fertility who are not using a highly reliable form of contraception.

[0095] Test procedure When the patient returns to the clinic, a pharmacist or other investigator, independent of the investigator, retrieves the investigational drug dilution description from the online randomization system and prepares the investigational drug for infusion. Both investigators and pharmacists are blinded to active or placebo, and only the pharmacist knows the dilution. All patients receive a 60 ml intravenous infusion over 20 minutes. Efficacy and safety data before and after investigational drug administration are immediately entered into an electronic data capture system so that headache responses can be used to drive dose allocation for subsequent cohorts.

[0096] After completing baseline assessments, lasmiditan or placebo is infused intravenously over 20 minutes and patients are monitored for safety and efficacy for at least 4 hours. Data are simultaneously entered into an online electronic data capture system. Patients are discharged from the clinic after 4 hours and continue to record migraine symptoms and adverse events using diary cards for up to 24 hours.

[0097] Symptom assessment A number of different symptoms are assessed. Headache severity is measured on a 4-point scale with 0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain. Associated symptoms (nausea, vomiting, photophobia, phonophobia) are recorded as present or absent. Disability is documented on a 4-point scale with 0=no disability, 1=mild disability, 2=moderate disability, 3=severe disability. Data on the patient's global impression is collected on a 7-point scale with 1=very good, 2=fairly good, 3=slightly good, 4=unchanged, 5=fairly bad, 6=fairly bad, 7=very bad.

[0098] The primary efficacy measure was headache response, defined as a reduction in headache from moderate or severe at baseline to mild or painless 2 hours after the start of the study drug infusion (HIS Clinical Trials Subcommittee. Guidelines for Controlled Trials in Migraine: second edition, Cephalalgia 2000:20:765-786). Secondary efficacy measures were the proportion of headache responses at 10, 20, 40, 60, 90, 180, and 240 minutes after the start of the study drug infusion; the proportion of headache-free (reduction from moderate or severe headache at baseline to pain-free) at 10, 20, 40, 60, 90, 120, 180, and 240 minutes after the start of study drug; the proportion of persistent pain-free patients whose moderate or severe headache at baseline had become mild or pain-free 2 hours after the start of study drug and did not recur (did not become mild, moderate, or severe) within 24 hours of starting study drug; the presence of nausea, vomiting, photophobia, and phonophobia during the course of the study, and clinical disability; the proportion of patients using rescue medication 2 to 24 hours after the start of study drug; and patient global impression 2 hours after the start of study drug.

[0099] statistical methods A target sample size of at most 160 patients is selected, including at least 20 patients treated at effective dose levels and at least 10 patients treated with placebo, to provide adequate preliminary data, on which a dose range is selected for further evaluation.When using group sequential adaptive treatment allocation design to allocate doses, there are no known statistical properties for testing hypotheses and comparing one or more dose levels with placebo.Therefore, no formal statistical test is used to declare the study "positive" or "negative", and the study does not require statistical significance.Furthermore, no sample size is required for statistical consideration.

[0100] At the end of the study, headache response rates will be summarized by dose level. The Mantel-Haenszel test will be used to test for dose-response association. Fisher's exact test will be used to compare headache response rates for selected doses and placebo. In all analyses, results for each dose level (including placebo) will be combined across all blocks and therefore used. All patients taking any investigational drug will be included in the analysis population. Patients will be analyzed by treatment and dose level actually received.

[0101] Effectiveness The linear relationship between response rate and dose level is statistically evaluated with the Mantel-Haenszel test for trend. The proportion of patients in each group who achieved a headache response from 10 minutes to 4 hours is tabulated. Key secondary efficacy parameters are tabulated for each group including patient global impression at 2 hours and use of rescue medication up to 24 hours. Secondary efficacy parameters are: no pain at 2 hours, persistent pain response at 2 hours, no persistent pain, nausea, phonophobia at 2 hours, photophobia at 2 hours, no disability / mild disability at 2 hours, use of rescue medication from 2 to 24 hours, impression at 2 hours: very good / fairly good.

[0102] Examine the acute migraine suppression efficacy of lasmiditan with or without concurrent galcanezumab treatment. An up-down dose-adaptation study design will be used to rapidly and reliably screen for efficacy and tolerability across a wide dose range while minimizing patient exposure to investigational drug or placebo. Onset of headache relief may be evident 20-40 minutes after initiation of a 20-minute intravenous infusion.

[0103] Clinicians can assess efficacy outcomes from the study to determine the proportion reporting impairment after intravenous administration of lasmiditan, the proportion reporting moderate or severe impairment, patient global impression, and the proportion of patients reporting feeling "very" or "fairly well" 2 hours after administration. Clinicians can also assess secondary endpoints (photophobia, phonophobia, and nausea).

[0104] A double-blind, randomized, placebo-controlled, parallel-group, dose-ranging study of oral lasmiditan with and without galcanezumab in the acute treatment of migraine To demonstrate the efficacy of the combination of lasmiditan and galcanezumab, the following study will be conducted once as described below and once in which patients under evaluation will receive a loading dose of 240 mg of galcanezumab followed by monthly maintenance doses of 120 mg of galcanezumab.

[0105] The study will be conducted to assess the efficacy (headache response at 2 hours) of a range of oral doses of lasmiditan. Secondary objectives will explore the time course and effect of a range of dose levels of lasmiditan on migraine characteristics including headache response, proportion of pain-free patients, headache recurrence, nausea, photophobia, phonophobia, vomiting, disability, use of rescue medication, and patient global impression. The study will explore the safety and tolerability of different doses of lasmiditan in terms of adverse events, physical examination, 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 suffering from migraine. Patients will be asked to treat a migraine attack with the investigational drug at home. Each subject's participation in the study will consist of a telephone screening visit within 5 days to confirm eligibility, a treatment period of up to 8 weeks during which subjects will be asked to treat one migraine attack with a single dose of one of four dose levels of oral lasmiditan 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 a matching placebo for use as initial treatment of a new migraine attack. Once all screening assessments are completed, subjects are instructed not to treat attacks until eligibility is confirmed by phone. Once eligibility is confirmed, subjects are asked to treat their next migraine attack within 4 hours of its onset, provided that headache severity is at least moderate at that time and has not improved. Subjects will record their response over the next 48 hours using diary cards. Subjects will be asked not to use rescue medication until at least 2 hours after taking the study drug. Once an attack has been treated, subjects will contact the clinic to schedule a follow-up visit as soon as possible, but within 14 days of treatment. Patients will be assigned to one of four dose levels of lasmiditan or a matching placebo in a 1:1:1:1:1:1 ratio by a predefined randomization list. At least 340 patients will treat one attack with the study drug.

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

[0109] Exclusions: Subjects will be excluded from the study if any of the following criteria are met: history of life-threatening or intolerable adverse reactions to any triptan; use of prescribed migraine prophylactic medication (other than galcanezunab by design) within 30 days prior to the screening visit and during study participation; pregnant or breastfeeding women; fertile women not using highly effective contraception; history or evidence of coronary artery disease, ischemic or hemorrhagic stroke, epilepsy, or any other condition that places the patient at high risk for seizures; history of hypertension (controlled or uncontrolled); history of orthostatic hypotension; systolic blood pressure >160 mmHg in the sitting position on two repeated measurements at screening or diastolic blood pressure >90 mmHg;current use of hemodynamically active cardiovascular medications;history or current evidence of any drug, prescription or illicit, or alcohol abuse within the past 3 years;significant renal or hepatic impairment;prior participation in this clinical trial;participation in any clinical trial of an experimental drug or device within the past 30 days;any medical condition or laboratory test result that, in the opinion of the investigator, makes the patient unsuitable for this study;known hepatitis B or C or HIV infection;subjects who are employees of the sponsor;relatives of the investigator or personnel reporting directly to the investigator;Compound I, other 5-HT 1F Patients suffering from known hypersensitivity to the receptor agonist or to any of the excipients in the compound formulation; patients who have been treated with the study drug in a prior lasmiditan study (patients who were screened but not treated under the protocol are not excluded).

[0110] The criteria for assessment include: Efficacy / Pharmacodynamics: Severity of headache (4-point scale: none, mild, moderate, severe); recurrence of headache within 48 hours; presence or absence of nausea; phonophobia, photophobia, vomiting; disability (4-point scale: none, mild, moderate, severe); need for rescue medication for 2 to 48 hours (yes or no); Patient's global impression (7-point scale); time to headache relief and time to pain freedom.

[0111] Safety: Physical examination; adverse events (self-reported); vital signs; 12-lead electrocardiogram; clinical laboratory parameters; and 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 concurrent galcanazumab in the acute treatment of migraine. The proportion of subjects with headache relief at 2 hours post-dose is the primary efficacy parameter. The primary efficacy analysis will use a Cochran-Armitage test for trend to test the null hypothesis that the proportion of subjects with headache relief at 2 hours post-dose is the same in the five study arms, and the alternative hypothesis of a positive linear trend in response rates. The primary analysis will be performed in the modified intention-to-treat population, defined as all subjects who treat an attack with the investigational drug, using a one-sided test at the 5% level of significance. Patients who fail to document headache severity at 2 hours or the use of rescue medication prior to that time point will be excluded from the analysis set.

[0113] Additional efficacy analyses will compare each effective dose group to the placebo group using a logistic regression model that includes data from all five treatment groups. Additional analyses will also be based on the per-protocol subject set.

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

[0115] Safety: Adverse events can be summarized and event rates can be presented by treatment group. Experimental data are summarized by treatment group in terms of change from baseline status. The safety population can consist of all randomized patients who received at least a single dose of investigational drug or placebo. Adverse events can be coded in the Medical Dictionary for Regulatory Activities (Version 19.1). Safety parameters can be calculated as treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), deaths, discontinuations due to adverse events, discontinuation rates, vital signs, body weights, immunogenicity.

[0116] The primary analysis may assess the efficacy of each combination dosing regimen compared to placebo, or galcanezumab alone, or lasmiditan alone, on the overall mean change from baseline in the number of monthly migraine days (MHD) during the treatment phase based on ePROs or other relevant clinical data. 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 Migraine Specific Quality of Life Questionnaire Version 2.1 (MSQ v2.1) Role Functioning Limitation (R-FR) domain score may be calculated as an average for selected months of the study. The overall mean change from baseline in the number of MHDs during the double-blind treatment period may be calculated. The mean change from baseline in the Patient Global Impression of Severity (PGI-S) rating (average for selected months) may be calculated. The outcome measure for the Migraine Disability Assessment (MIDAS) total score may be calculated at selected time points, such as the end of the study.

[0117] Phase III monotherapy studies of both lasmiditan and garcenazemab used separately 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 See Supplement (S50.008), where the authors reported that 2 hours after the first dose, a significantly higher proportion of patients (p<0.001) were free of headache pain (Lasmiditan 200 mg: SAMURAI 32.2%, SPARTAN 38.8%, Placebo: SAMURAI 15.3%, SPARTAN 21.3%) and free of most bothersome symptoms (MBS) (Lasmiditan 200 mg: SAMURAI 40.7%, SPARTAN 48.7%, Placebo: SAMURAI 29.5%, SPARTAN 33.5%) using Lasmiditan 200 mg compared to placebo. For both endpoints, significance was also observed for the other Lasmiditan dose groups (100 mg, 50 mg) compared to placebo. The most frequently reported TEAEs with lasmiditan (≥2% and higher than placebo) after the first dose were dizziness, paresthesia, somnolence, fatigue, nausea, and lethargy, with most events being mild to moderate in severity.From this analysis, the authors concluded that the primary and key secondary endpoints were met and that safety results were consistent across the two phase 3 studies.See, for example, 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, where the authors concluded that the mean number of monthly migraine days was reduced by 4.3 and 4.2 days with galcanezumab 120 and 240 mg, and by 2.3 days with placebo. The group differences (95% confidence intervals) from 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 endpoints. Injection site pain was the most common treatment-emergent adverse event and was reported at similar rates in all treatment groups. Both galcanezumab doses were associated with significantly more injection site reactions and injection site pruritus, and the 240 mg group was associated with significantly more injection site erythema compared with placebo. From this analysis, the authors concluded that galcanezumab 120 or 240 mg administered once monthly was effective, safe, and well tolerated.

[0118] It is believed that the combination of lasmiditan and galcanezumab used for the treatment of migraine will be superior to either monotherapy alone, especially in certain populations where treatment has previously failed, due to the combined effect on CGRP pathway in combination with the complementary effect of lasmiditan reducing glutamate signaling.It is believed that the combination of these pharmacological properties will result in superior efficacy for migraine treatment in patients suffering from therapy-resistant migraine.Although each drug, i.e., lasmiditan and galcanezumab alone, has demonstrated efficacy in the treatment of migraine, the present invention provides a method for treating migraine in a patient in need of treatment, comprising administering an effective amount of lasmiditan in combination with an effective amount of galcanezumab simultaneously, separately, or sequentially, can provide additional potential benefits to migraine patients, more particularly to migraine patients who do not individually experience adequate migraine treatment efficacy when treated with either galcanezumab or lasmiditan alone. Thus, the potential efficacy offered by the inventive combination of galcanezumab and lasmiditan for treating patients inadequately controlled by lasmiditan or galcanezumab therapy alone and / or for treating migraine patients whose disease has been refractory to two or more conventional monotherapy and / or dual therapy treatment regimens would represent an important further advance in migraine therapy.Preferably, the presently provided combination method of treating migraine in a patient in need of treatment, comprising simultaneously, separately or sequentially administering to said patient an effective amount of lasmiditan in combination with an effective amount of galcanezumab, can further provide efficacy to these inadequately treated migraine patients, whereby said patients can be pain-free 2 hours after treatment with lasmiditan, more preferably 1 hour after treatment with lasmiditan, and even more preferably, will also experience relief from their most bothersome symptoms 2 hours after treatment with lasmiditan.Preferably, patients treated with the combination of the present invention can potentially experience sustained pain relief and / or more preferably migraine pain relief and / or migraine disability relief as assessed by methods known to those skilled in the art, such as the MIDAS, or by known quality of life measures.Preferably, patients treated with the combination of the present invention will experience 3 migraines or less per month, more preferably 1 migraine or less per month.Preferably, the combination of the present invention can provide additional potential benefits in the form of efficacy, as described immediately above, in the treatment of headaches selected from the group consisting of episodic headaches, chronic headaches, chronic cluster headaches, or episodic cluster headaches.Preferably, the combination therapy of the present invention will provide improved migraine treatment as described herein, while demonstrating desirable clinical safety and tolerability.

Claims

1. A pharmaceutical composition comprising a combination of lasmiditan and rimegepant for use in the oral treatment of migraine in a patient, the pharmaceutical composition comprising a fixed dose combination tablet containing a unit dose of lasmiditan selected from 50 mg, 100 mg, or 200 mg.

2. A pharmaceutical composition comprising a combination of lasmiditan and ubrogepant for use in the oral treatment of migraine in a patient, the pharmaceutical composition comprising a fixed dose combination tablet containing a unit dose of lasmiditan selected from 50 mg, 100 mg, or 200 mg.

3. A pharmaceutical composition comprising a combination of lasmiditan and olcegepant for use in the oral treatment of migraine in a patient, the pharmaceutical composition comprising a fixed dose combination tablet containing a unit dose of lasmiditan selected from 50 mg, 100 mg, or 200 mg.

4. A pharmaceutical composition comprising a combination of lasmiditan and MK-8031 for use in the oral treatment of migraine in a patient, the pharmaceutical composition comprising a fixed dose combination tablet containing a unit dose of lasmiditan selected from 50 mg, 100 mg, or 200 mg.