EA042629B1 - COMBINATION THERAPY WITH LASMIDITAN AND CGRP ANTAGONIST FOR USE IN THE TREATMENT OF MIGRAINE - Google Patents

Description

The invention relates to combinations of lasmiditan and a calcitonin gene-related peptide (CGRP) antagonist, for example, to a combination of galcanezumab and lasmiditan, and to methods of using the combinations for the treatment of migraine, in particular migraine not adequately controlled by therapy with lasmiditan or a CGRP antagonist in monotherapy, and more particularly for the treatment of therapy-resistant migraine, which is defined herein as migraine resistant to two or more previous monotherapy and/or dual therapy regimens.

Primary headaches, including migraine, are among the most common diseases and major causes of disability worldwide. Migraine affects more than 14% of adults worldwide. Available treatment options for migraine have poor rates of efficacy, tolerability, and patient compliance. In the 2013 Global Burden of Disease study, migraine was responsible for the loss of more than half of all years of disability attributed to neurological disorders (New strategies for the treatment and prevention of primary headache disorders, N.M. Schuster & A.M. Rapoport , Nature Reviews Neurology (2016) 12, 635-650). Migraine is usually characterized by attacks of severe headache lasting 1-3 days, along with nausea, vomiting, photophobia and phonophobia (migraine without early symptoms), and one third of patients have early neurological symptoms (migraine with early symptoms) (Goadsby, P.J. et al., New England Journal of Medicine, 2002; 346: 257-270).

Lasmiditan, 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide (compound I), is a selective and potent 5-HT-1F receptor agonist that is under development 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).

Calcitonin Gene-Related Peptide (CGRP) is a 37 amino acid peptide found primarily in C and Ad sensory fibers from the dorsal root and trigeminal ganglion, as well as in the central nervous system. CGRP is a pain signaling neuropeptide, and a potent vasodilator, that is released from sensory afferents of the trigeminal nerve and spinal trigeminal nucleus. The role of CGRP in headache and migraine has been established in the art, and a number of clinical studies are currently evaluating the use of anti-CGRP antibodies in the treatment of headache and migraine (see e.g. Dodick et al. Lancet Neurolology; 13(9) : 885-892 (2014)).

This invention relates to combinations of lasmiditan and a calcitonin-related peptide (CGRP) antagonist, such as a combination of lasmiditan and galcanezumab, and methods of using the combinations for the treatment of migraine. More specifically, this invention relates to the use of combinations of lasmiditan and a calcitonin gene-related peptide (CGRP) antagonist for the treatment of migraine that is not sufficiently controlled by lasmiditan or CGRP antagonist therapy alone. More specifically, this invention relates to the use of combinations of lasmiditan and a calcitonin gene-related peptide (CGRP) antagonist for the treatment of therapy-resistant migraine, which is defined herein as migraine resistant to the previous two or more treatment regimens as monotherapy and /or dual therapy.

Treatment of patients with migraine is often unsatisfactory because available relief and preventive therapies are either ineffective or poorly tolerated. Relief of migraine attacks was limited to the use of analgesics, combinations of analgesics with caffeine, ergotamines and triptans. (For a description of such agents, see, for example, New Therapeutic Approaches for the Prevention and Treatment of Migraine, Diener, H.C. et al., (2015) Lancet Neurololgy, 14:1010-22). Lasmiditan represents an innovative approach to the treatment of episodic migraine by selectively targeting 5-HT-1F. While many patients are able to successfully treat migraine attacks with lasmiditan or galcanezumab alone, a proportion of patients are not able to successfully manage migraine attacks with either of these agents alone. These patients may have so many migraine days per month that they still significantly limit their ability to function. In addition, some patients, referred to herein as treatment-resistant migraine patients, will not be able to successfully manage their migraine attacks and will suffer from migraines that are resistant to previous two or more monotherapy and/or dual therapy regimens. As defined herein, treatment-resistant migraine patients will be those who continue to suffer from 3 or more days of migraine per month despite prior two or more monotherapy and/or dual therapy regimens. As used herein, prior two or more monotherapy and/or dual therapy regimens refer to prior unsuccessful attempts at treatment with monotherapy or dual therapy regimens, e.g., triptans, ergotamines, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics and caffeine, or one or two such agents in combination. Treatment-resistant patients have not yet been able to fully recover from recurrent migraine and thus there is a critical unmet need. The inability of these resistant to

- 1 042629 therapy of patients with migraine to achieve adequate relief from a variety of previous treatment regimens demonstrates that their disease is particularly difficult to treat, and the effectiveness in this population is an unexpected and superior result.

The lasmiditan (COL 144, LY 573144, CAS Identification Number 439239-90-4) used in the combinations of this invention can be chemically described as 2,4,6-trifluoro-X-[6-(1methyl-piperidine-4- ylcarbonyl)pyridin-2-yl]benzamide and can be structurally represented as compound (I)

As used herein, Compound I includes its pharmaceutically acceptable salts including, but not limited to: 2,4,6-trifluoro-N[6-(1-methylpiperidin-4ylcarbonyl)pyridin-2-yl]benzamide monohydrochloride salt; and 2,4,6-trifluoro-N-[6-(1-methylpiperidine4-carbonyl)pyridin-2-yl]benzamide hemisuccinate salt. Methods for the preparation of lasmiditan and its salts, as well as some of its formulations and formulation dosages, are known to those skilled in the art and are described in WO 03/084949 and WO 2011/123654.

Galcanezumab (LY 2951742, CAS ID 1578199-75-3) used in the combinations of this invention can be described as a monoclonal antibody targeting calcitonin gene related peptide (CGRP). Galcanezumab monotherapy is being developed for the treatment of 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 the person skilled in the art and are described in WO 2011/156324. Other CGRP antagonists useful in the combinations of this invention and known to those skilled in the art include eptinesumab (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 useful in the combinations of this invention and known to those skilled in the art include small molecule antagonists and monoclonal antibody antagonists targeting CGRP itself or its receptors. Methods for making other CGRP antagonists are known to those skilled in the art.

There is a need for more therapies and different therapies that may be effective in the treatment of migraine, in particular in the treatment of migraine not adequately controlled with lasmitidan or CGRP antagonist therapy alone, and there remains a critical need for the treatment of treatment-resistant migraine, which is defined in this document as migraine resistant to two or more prior monotherapy and/or dual therapy regimens.

This document provides novel uses for combinations of lasmitidan and a calcitonin gene-related peptide (CGRP) antagonist, such as a combination of lasmiditan and galcanezumab, for the treatment of migraine and treatment-resistant migraine. It is believed that the combination of lasmiditan and galcanezumab for the treatment of migraine will be superior to any monotherapy, due to the combined effect on the CGRP pathway in combination with the additional effect of lasmiditan on glutamate signaling. It is believed that the combination of these pharmacological properties will give superior efficacy for the treatment of migraine in patients who suffer from treatment-resistant migraine.

Accordingly, the present invention provides lasmiditan for use in simultaneous, separate or sequential combination with a calcitonin-related peptide (CGRP) antagonist, e.g. treatment of treatment-resistant migraine in a patient. More specifically, a patient suffering from migraine is one who suffers from migraines that are not sufficiently controlled by lasmiditan or CGRP antagonist therapy alone. More specifically, a patient suffering from migraine is one who suffers from treatment-resistant migraine, which is defined herein as migraine resistant to two or more prior monotherapy and/or dual therapy regimens.

Combinations of lasmiditan and a calcitonin gene-related peptide (CGRP) antagonist, such as the combination of lasmiditan and galcanezumab, and methods of using the combinations for the treatment of migraine, in particular migraine not adequately controlled by lasmiditan or antagonist therapy alone

- 2 042629

CGRP, and more specifically for the treatment of treatment-resistant migraine, use several doses and dosing schedules of lasmiditan and galcanezumab, which are described below.

This invention relates to the combined use of pharmaceutical compositions containing an amount of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, wherein for oral administration said composition contains 50-400 mg of lasmiditan per dose or pharmaceutically acceptable salt, and for buccal, sublingual, nasal/intranasal, transdermal, subcutaneous, injection, intravenous or intramuscular administration, said composition contains up to 200 mg of lasmiditan per dose or a pharmaceutically acceptable salt thereof, said composition being administered once, twice or three times a day. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, said composition being for oral administration and the amount of lasmiditan or a pharmaceutically acceptable salt thereof being 50 to 400 mg/dose. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the amount of lasmiditan is 50 mg/dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the amount of lasmiditan is 100 mg/dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the amount of lasmiditan is 200 mg/dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the amount of lasmiditan is 400 mg/dose. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, said composition being 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/dose . This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the amount of lasmiditan or a pharmaceutically acceptable salt thereof administered is between 20 mg and 200 mg/dose. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the amount of lasmiditan or a pharmaceutically acceptable salt thereof administered is between 20 mg and 60 mg/dose. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the amount of lasmiditan or a pharmaceutically acceptable salt thereof administered is between 20 mg and 30 mg/dose. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the administration is intravenous and the amount of lasmiditan or a pharmaceutically acceptable salt thereof administered is up to 200 mg/dose. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the administration of lasmiditan or a pharmaceutically acceptable salt thereof is intravenous over a period of about 20 minutes.

This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the composition contains a semi-succinate salt of lasmiditan. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the composition contains lasmiditan hemisuccinate salt and the amount administered is 50 mg/dose. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the composition contains lasmiditan hemisuccinate salt and the amount administered is 100 mg/dose. The present invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the composition contains lasmiditan hemisuccinate salt and the amount administered is 200 mg/dose.

This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the dose of lasmiditan or its pharmaceutically acceptable salt is administered once a day. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the dose of lasmiditan or its pharmaceutically acceptable salt is administered twice a day. This invention relates to the combined use of a pharmaceutical composition of lasmiditan, wherein the dose of lasmiditan or its pharmaceutically acceptable salt is administered three times a day.

This invention relates to a method of treating migraine in a patient in need thereof, comprising oral administration to the patient of a dose of 50-400 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. The present invention relates to a method for treating migraine in a patient in need thereof, comprising oral administration to the patient of a dose of 50-400 mg of lasmiditan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, said composition being administered once, twice or three times a day .

This invention relates to a method of treating migraine in a patient in need thereof, comprising oral administration to the patient of a dose of 50 mg of lasmiditan or a pharmaceutically acceptable salt thereof and 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 to the patient a dose of 50 mg of lasmiditan, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier, said composition being administered once or twice per day.

This invention relates to a method of treating migraine in a patient in need thereof, comprising oral administration to the patient of a dose of 100 mg of lasmiditan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. The present invention relates to a method for treating migraine in a patient in need thereof, comprising oral administration to the patient of a dose of 100 mg of lasmiditan, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier, said composition being administered once or twice a day.

This invention relates to a method of treating migraine in a patient in need thereof, comprising oral administration to the patient of a dose of 200 mg of lasmiditan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. The present invention relates to a method of treating migraine in a patient in need thereof, comprising oral administration to the patient of a dose of 200 mg of lasmiditan, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier, said composition being administered once or twice a day.

The present invention relates to a method for the treatment of migraine in a patient in need thereof, comprising buccal, sublingual, nasal/intranasal, transdermal, subcutaneous, injection, intravenous or intramuscular administration to the patient of a dose of 50-400 mg of lasmiditan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

The present invention relates to a method for the treatment of migraine in a patient in need thereof, comprising buccal, sublingual, nasal/intranasal, transdermal, subcutaneous, injection, intravenous or intramuscular administration to the patient of a dose of 50-400 mg of lasmiditan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier, while the specified composition is administered once, twice or three times a day.

The present invention relates to a method for combined treatment of migraine in a patient in need thereof, comprising administering a dose of 120 mg of galcanezumab to the patient. The present invention relates to a method for combined treatment of migraine in a patient in need thereof, comprising administering a dose of 240 mg of galcanezumab to the patient. The present invention relates to a method for combined treatment of migraine in a patient in need thereof, comprising administering a dose of 300 mg of galcanezumab to the patient. The present invention relates to a method for combined treatment of migraine in a patient in need thereof, comprising administering a dose of 360 mg of galcanezumab to the patient. Preferably, the dose of galcanezumab is administered at weekly, half-monthly, monthly or quarterly intervals. More preferably, the administration of galcanezumab is monthly. The present invention relates to a method for the combined treatment of migraine in a patient in need thereof, comprising administering to the patient an initial loading dose of 240 mg of galcanezumab, followed by a monthly maintenance dose of 120 mg of galcanezumab. This invention relates to a combined method for the treatment of episodic migraine in a patient, which includes the introduction of a monthly subcutaneous dose of 120 mg of galcanezumab. As used herein, galcanezumab combination treatments are administered according to the regimens described above.

Another aspect of the present invention relates to the use of lasmiditan in combination with galcanezumab as a drug, and in particular a drug adapted for the treatment of migraine in humans.

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

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

In another embodiment, the present invention provides a method of using lasmiditan in simultaneous, separate or sequential combination with a calcitonin gene-related peptide (CGRP) antagonist, in the treatment of a patient with migraine not adequately controlled by treatment with lasmiditan or a CGRP antagonist alone.

In another embodiment, the present invention provides a method of using lasmiditan, in simultaneous, separate or sequential combination with galcanezumab, in the treatment of a patient with migraine not well controlled by treatment with lasmiditan or galcanezumab alone.

In another embodiment, the present invention provides a method of administering lasmiditan in simultaneous, separate or sequential combination with an antagonist.

- 4 042629 calcitonin-gene-related peptide (CGRP), in the treatment of migraine in a patient suffering from treatment-resistant migraine, while migraines of patients were resistant to the previous two or more treatment regimens in the form of monotherapy and / or dual therapy.

In another embodiment, the present invention provides a method of using lasmiditan, in simultaneous, separate or sequential combination with galcanezumab, in the treatment of migraine in a patient suffering from therapy-resistant migraine, wherein the patients' migraines were resistant to the previous two or more treatment regimens in monotherapy and/or dual therapy.

In another embodiment, the present invention provides a method of using lasmiditan in 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 of galcanezumab, followed by a monthly maintenance dose of 120 mg of galcanezumab, and lasmiditan is administered at a dose of 50 mg once or twice a day.

In another embodiment, the present invention provides a method of using lasmiditan in 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 of galcanezumab, followed by a monthly maintenance dose of 120 mg of galcanezumab, and lasmiditan is administered at a dose of 100 mg once or twice a day.

In another embodiment, the present invention provides a method of using lasmiditan in 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 of galcanezumab, followed by a monthly maintenance dose of 120 mg of galcanezumab, and lasmiditan is administered at a dose of 200 mg once or twice a day.

In another embodiment, this invention provides a method of using lasmiditan in simultaneous, separate or sequential combination with galcanezumab, in the treatment of migraine in a patient, wherein galcanezumab is administered as a monthly dose of 120 mg of galcanezumab and lasmiditan is administered at a dose of 50 mg one or two times a day.

In another embodiment, this invention provides a method of using lasmiditan in simultaneous, separate or sequential combination with galcanezumab, in the treatment of migraine in a patient, wherein galcanezumab is administered as a monthly dose of 120 mg of galcanezumab and lasmiditan is administered at a dose of 100 mg one or two times a day.

In another embodiment, this invention provides a method of using lasmiditan in simultaneous, separate or sequential combination with galcanezumab, in the treatment of migraine in a patient, wherein galcanezumab is administered as a monthly dose of 120 mg of galcanezumab and lasmiditan is administered at a dose of 200 mg one or two times a day.

In another embodiment, this invention provides a method of using lasmiditan in simultaneous, separate or sequential combination with galcanezumab, in the treatment of migraine in a patient, wherein galcanezumab is administered as a monthly dose of 120 mg of galcanezumab and lasmiditan is administered at a dose of 50 mg once a day. day.

In another embodiment, this invention provides a method of using lasmiditan in simultaneous, separate or sequential combination with galcanezumab, in the treatment of migraine in a patient, wherein galcanezumab is administered as a monthly dose of 120 mg of galcanezumab and lasmiditan is administered at a dose of 100 mg once a day. day.

In another embodiment, this invention provides a method of using lasmiditan in simultaneous, separate or sequential combination with galcanezumab, in the treatment of migraine in a patient, wherein galcanezumab is administered as a monthly dose of 120 mg of galcanezumab and lasmiditan is administered at a dose of 200 mg once a day. day.

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

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

In another embodiment, the present invention provides a method of using lasmiditan in simultaneous, separate or sequential combination with a calcitonin gene-related peptide (CGRP) antagonist, in the treatment of a patient with a headache selected from the group consisting of episodic headache, chronic headache pain, chronic cluster headache, or episodic cluster headache not adequately controlled by treatment with lasmiditan or a CGRP antagonist alone.

In another embodiment, the present invention provides a method of using lasmiditan, in simultaneous, separate or sequential combination with galcanezumab, in the treatment of a patient with a headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache. headache not adequately controlled with lasmiditan or galcanezumab alone.

In another embodiment, the present invention provides a method of using 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 headaches, and the patient's headaches were resistant to two or more previous treatment regimens in the form of monotherapy and / or dual therapy.

In another embodiment, the present invention provides a method of using 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 suffering from treatment-resistant headaches, wherein the patient's headaches were resistant to two or more prior monotherapy and/or dual therapy regimens.

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

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

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

In another embodiment, the present invention provides a method of using lasmiditan, in simultaneous, separate or sequential combination with galcanezumab, in the treatment of a patient with a headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache. headache, while galcanezumab is administered as a monthly dose of 120 mg, and lasmiditan is administered at a dose of 50 mg once or twice a day.

In another embodiment, the present invention provides a method of using lasmiditan, in simultaneous, separate or sequential combination with galcanezumab, in the treatment of a patient with a headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache. headache, while galcanezumab is administered as a monthly dose of 120 mg, and lasmiditan is administered at a dose of 100 mg once or twice a day.

In another embodiment, the present invention provides a method of using lasmiditan, in simultaneous, separate or sequential combination with galcanezumab, in the treatment of a patient with a headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache. headache, while galcanezumab is administered as a monthly dose of 120 mg, and lasmiditan is administered at a dose of 200 mg once or twice a day.

In another embodiment, the present invention provides a method of using lasmiditan, in simultaneous, separate or sequential combination with galcanezumab, in the treatment of a patient with a headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache. headache, with galcanezumab administered as a monthly dose of 120 mg and lasmiditan administered at a dose of

- 6 042629 mg once a day.

In another embodiment, the present invention provides a method of using lasmiditan, in simultaneous, separate or sequential combination with galcanezumab, in the treatment of a patient with a headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache. headache, while galcanezumab is administered as a monthly dose of 120 mg, and lasmiditan is administered at a dose of 100 mg once a day.

In another embodiment, the present invention provides a method of using lasmiditan, in simultaneous, separate or sequential combination with galcanezumab, in the treatment of a patient with a headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache. headache, while galcanezumab is administered as a monthly dose of 120 mg, and lasmiditan is administered at a dose of 200 mg once a day.

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

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

In another embodiment, the present invention provides a method of treating migraine in a patient comprising administering to a patient in need of such treatment, simultaneously, separately or sequentially, an effective amount of lasmiditan in combination with an effective amount of a calcitonin gene-related peptide (CGRP) antagonist. , while the patient's migraine was insufficiently controlled by treatment with lasmiditan alone or a CGRP antagonist.

In another embodiment, the present invention provides a method of treating migraine in a patient comprising administering to a patient in need of such treatment, simultaneously, separately or sequentially, an effective amount of lasmiditan in combination with an effective amount of a calcitoni gene-related peptide (CGRP) antagonist. , while the patient's migraine was insufficiently controlled by treatment with lasmiditan or galcanezumab alone.

In another embodiment, the present invention provides a method of treating migraine in a patient comprising administering to a patient in need of such treatment, 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 patient is suffering from therapy-resistant migraine, wherein the patients' migraines were resistant to two or more prior monotherapy and/or dual therapy regimens.

In another embodiment, the present invention provides a method for treating migraine in a patient, comprising administering to a patient in need of such treatment, simultaneously, separately or sequentially, an effective amount of lasmiditan in combination with an effective amount of galcanezumab, wherein the patient is suffering from therapy-resistant migraine. , while migraine patients were resistant to the previous two or more treatment regimens in the form of monotherapy and / or dual therapy. As described below, the prior treatments are one of the embodiments identified above.

In another embodiment, the present invention provides a method of any of the embodiments above 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 daily. day.

In another embodiment, the present invention provides a method of any of the embodiments above 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 100 mg once or twice daily. day.

In another embodiment, the present invention provides a method of any of the embodiments above 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 200 mg once or twice daily. day.

In another embodiment, the present invention provides a method of any of the embodiments above wherein galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 50 mg once or twice daily.

In another embodiment, the present invention provides a method of any of the embodiments above wherein galcanezumab is administered as a monthly dose of 120

- 7 042629 mg, and lasmiditan is administered at a dose of 100 mg once or twice a day.

In another embodiment, the present invention provides a method of any of the embodiments above wherein galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 200 mg once or twice daily.

In another embodiment, the present invention provides a method of any of the embodiments above wherein galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 50 mg once daily.

In another embodiment, the present invention provides a method of any of the embodiments above wherein galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 100 mg once daily.

In another embodiment, the present invention provides a method of any of the embodiments above wherein galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 200 mg once daily.

Previous treatments for migraine can leave a significant number of patients without adequate treatment. For example, up to 40% of migraine attacks, approximately 30% of patients do not respond to a particular triptan due to suboptimal efficacy or tolerability issues (see Dodick D.W. Headache. 2005;45:156-162, and Tepper D.E. Headache. 2013(53)577- 578). Because of their vasoconstrictive effects, these drugs may have contraindications, warnings, and precautions for patients with cardiovascular risk factors and diseases (see Alwhaibi M., et al. Pain Res Treat. 2016; 2016:8538101, and Gilmore B., Michael M. Am Fam Physician 2011(83)271-280). In addition, prior therapies are often limited by the occurrence of over-medication headaches at the onset of a migraine, where patients may have a limited number of treatment attempts they can use in a given time period to avoid the onset of an over-medication headache. migraines (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, with previous monotherapy or dual therapy for migraine, a significant proportion of patients may not achieve headache relief and/or pain relief in response to treatment. In addition, some patients, referred to herein as treatment-resistant migraine patients, will not be able to successfully manage their migraine attacks and will suffer from migraines that are resistant to previous two or more monotherapy and/or dual therapy regimens. As defined herein, treatment-resistant migraine patients will be those who continue to suffer from 3 or more days of migraine per month despite prior two or more monotherapy and/or dual therapy regimens. As used herein, prior two or more monotherapy and/or dual therapy regimens refer to prior unsuccessful attempts at treatment with monotherapy or dual therapy regimens, e.g., triptans, ergotamines, non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, blood pressure drugs, anticonvulsants, antidepressants, serotonin antagonists, onabotulinum toxin, and caffeine, either alone or the two such agents in combination. In addition, some patients are unable to successfully manage migraine attacks with either galcanezumab or lasmiditan alone.

These patients with poorly controlled migraine may have a number of migraine days per month that still significantly limits their ability to function. An unsatisfactory treatment attempt is one in which the patient concludes that his symptoms have not been alleviated to the extent that incapacitation has been avoided. Measures of disability for migraine are well known to those skilled in the art, such as the Migraine Disability Score, in which a total score of >11 may represent moderate to severe headache-related disability. In embodiments of the present invention, a Migraine Disability Score of 10 or less, or an equivalent score using criteria known to one of skill in the art, represents disability prevention. Preferably, the combination methods of the present invention provide relief from migraine disability such that patients report an overall Migraine Disability Score of 10 or less. Preferably, in embodiments of the present invention, Migraine Disability Assessment, or equivalent assessment using criteria known to one of skill in the art, will demonstrate no disability.

Preferably, the combination methods of the present invention provide relief from migraine disability such that after administration of lasmiditan, the migraine patient does not have significant clinical disability without the patient reporting complete disability, bed rest, or marked impairment of daily activities. More preferably, the combination methods of the present invention provide relief from migraine disability such that after administration of lasmiditan, the migraine patient does not have moderate disability. More preferably, the combination methods of the present invention provide relief from migraine incapacitation such that after lasmiditan administration, the migraine patient is fully incapacitated. Preferably, patients treated with the combination of the methods provided herein avoid the occurrence of over-medication headaches at the onset of a migraine.

Relief of symptoms, such as relief of a headache, or relief of a patient's most distressing symptom, may, for example, be defined as effective according to the clinical study protocols provided herein. Preferably, the combined methods of the present invention provide headache relief and/or relief of the patient's most distressing symptom. Headache relief, as used herein, is measured by a reduction in pain intensity from moderate or severe from baseline to mild or no pain, or by a reduction in pain from mild from baseline to none 2 hours after ingestion. doses. Absent headache, as used herein, is a reduction in pain intensity from mild, moderate, or severe from baseline to absent at a specified time. The most unpleasant symptom (HNS) was identified by participants at the onset of a migraine attack, prior to dosing, from the associated symptoms of nausea, phonophobia, and photophobia. No most distressing symptom, as used herein, refers to a patient-reported outcome of no migraine-associated HHC 2 hours post-dose, HHC being defined as an associated symptom present and identified as a pre-dose HHC.

As used herein, persistent migraine includes, but is not limited to, persistent chronic migraine and/or persistent episodic migraine. Methods for identifying patients with persistent migraine are known to those skilled in the art. For example, an experienced professional recognizes persistent chronic migraine as shown in the proposed criteria for this pathology provided by the European Headache Federation (EFGB) (see Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition) . The EFGB recommends that persistent chronic migraine be defined as ICHD-3 beta chronic migraine without overdosing in patients who have not responded to treatment with at least three prophylactic drugs at adequate dosages, with each trial period being at least 3 months. The proposed criteria can be briefly described as follows: A) chronic migraine according to beta ICHD-3, without excessive medication; C) prophylactic anti-migraine drugs in adequate dosages used for at least 3 months each; C) contraindications to the use of a prophylactic drug or lack of effect of such a drug with at least three drugs from the following classes: beta-blockers (propranolol up to 240 mg per day, metoprolol up to 200 mg per day, atenolol up to 100 mg per day , bisoprolol up to 10 mg per day), anticonvulsants (valproic acid up to 1.5 g per day, topiramate up to 200 mg per day), tricyclics (amitriptyline up to 150 mg per day) or others (flunarizine up to 10 mg per day, candesartan up to 16 mg per day, onabotulinumtoxin A 155-195 U in accordance with the PREEMPT protocol); and D) adequate treatment of psychiatric or other comorbidities by a multidisciplinary team, if available.

The combination therapies of the present invention are believed to provide improved treatment of migraine, including in patients who are not well controlled with lasmiditan or galcanezumab treatment alone, and/or in patients who suffer from treatment-resistant migraine where the patients' migraines were resistant to previous two or more monotherapy and/or dual therapy regimens and, additionally, they provide a particularly advantageous combination of pharmacological benefits including rapid (particularly within 2 hours, preferably within 1 hour and more preferably within within 30 min after lasmiditan administration), safely and effectively reduce the intensity and/or elimination of headache, while at the same time they provide a clinically acceptable level of side effects such as dizziness, paresthesia and drowsiness. The combination therapies of the present invention may provide these benefits in part because it allows a migraine patient to adequately treat their migraine episodes with a lower dose of lasmiditan, such as 100 or 50 mg, and more preferably do so with a single dose per day, so thereby avoiding the need for a second dose per day. In this regard, the combined treatment methods of the present invention provide patients with migraine with significant reduction and/or more preferably relief from severe migraine symptoms and disability. In another respect, the combination treatment methods of the present invention provide patients with migraine with significant reduction, and more preferably relief from severe migraine symptoms and disability, for an extended period of time, such as 24 hours after lasmiditan administration, or preferably 48 hours after lasmiditan administration.

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As used herein, the term combination therapy or combination includes the administration of a lasmiditan and a CGRP antagonist as part of a particular treatment regimen designed to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, the pharmacokinetic and/or pharmacodynamic synergy resulting from the combination of therapeutic agents. The introduction of these therapeutic agents in combination is usually carried out over a certain period of time (usually minutes, hours, days or weeks, depending on the chosen combination). Combination therapy is intended to encompass the sequential administration of said therapeutic agents, ie where each therapeutic agent is administered at a different time, and also the administration of these therapeutic agents at substantially the same time. Administration can be, for example, by administering to the subject a single dose of an oral formulation containing a fixed ratio of each therapeutic agent, or multiple single doses of an oral formulation of each of the therapeutic agents, or by administering a dose of an oral formulation of lasmiditan and a dose of an injectable formulation of galcanezumab. Sequential or substantially simultaneous administration of each therapeutic agent may be by any suitable route, including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucosal tissues. Therapeutic agents may be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination may be administered by intramuscular or intravenous injection, while the other therapeutic agent of the combination may be administered orally. Alternatively, for example, when applicable, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. The sequence of administration of therapeutic agents is not limitingly critical.

As used herein, the term once daily means that lasmiditan is administered once per 24 hour period or once per calendar day. As used herein, the term once daily means that lasmiditan is administered once per 24 hour period or once per calendar day to prevent or treat a migraine attack. As used herein, the term once daily means that lasmiditan is administered once per 24 hour period or once per calendar day to treat a migraine attack, and such treatment may occur for two or more consecutive days.

As used herein, the term monthly means that galcanezumab is administered once in a 30-day period or once in a calendar month. As used herein, the term monthly means that galcanezumab is administered once per 30 day period or once per calendar month, and the timing of administration during this period may vary. Preferably, as used herein, monthly means that galcanezumab is administered once per 30 day period or once per calendar month, and administered on the same or about the same calendar day each month to provide a regular dosing interval.

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

Where the disorders that can be treated with the combinations of this invention are known from established and accepted classifications, such as migraine, episodic headache, chronic headache, chronic cluster headaches and/or episodic cluster headaches, their classifications may be found in various sources. For example, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV™) (1994, American Psychiatric Association, Washington, D.C.) now provides a diagnostic tool for identifying many of the disorders described in this document. In addition, the International Classification of Diseases, Tenth Edition (ICD-10) provides a classification for many of the disorders described in this document. One skilled in the art will appreciate that there are alternative nomenclatures, nosologies, and classification systems for the disorders described herein, including those described in DSM-IV and ICD-10, and that terminology and classification systems evolve with advances in medical science. In patients with

- 10 042629 Migraine can be additionally diagnosed as migraine with or without early symptoms (1.1 and 1.2) as defined by the International Headache Society (IHS) International Classification of Headache Disorders, 3rd Edition, Beta Version (ICHD-3) (The International Classification of Headache Disorders, 3rd edition (beta version), Cephalalgia 2013; 33: 629-808).

The term pharmaceutical or pharmaceutically acceptable, when used herein as an adjective, means essentially non-toxic and essentially not harmful to the recipient. By pharmaceutical composition is further meant that the carrier, diluent, excipients and salt must be compatible with the active ingredient of the composition (eg a compound of the invention). Those skilled in the art will appreciate that the terms pharmaceutical formulation and pharmaceutical composition are generally used interchangeably and are used as such for the purposes of this application.

In addition, the compounds of this invention, for example salts of these compounds, may exist in either hydrated or non-hydrated (anhydrous) form. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. When the compounds of this invention are amines, they are basic in nature and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. The term acid addition salt refers to a salt of a compound obtained by reacting the compound with a mineral or organic acid. The compounds of this invention form pharmaceutically acceptable acid addition salts with a wide range of organic and inorganic acids, and include the physiologically acceptable salts that are often used in pharmaceutical chemistry. Such salts are also embodiments of this invention. A pharmaceutically acceptable (acid) addition salt is formed from a pharmaceutically acceptable acid, as is well known in the art. Such salts include the 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.

The term "effective amount" means an amount of lasmiditan capable of activating 5-HT-1F receptors or an amount of a CGRP antagonist capable of inhibiting the action of CGRP. In a preferred embodiment, the effective amount means an amount of lasmiditan and an amount of a CGRP antagonist capable of relieving pain in a patient 2 hours after headache treatment with lasmiditan.

The term "treat" or "treatment" as used herein means the treatment of a pre-existing disease state or pathology, such as migraine or headache, in a patient or subject. Treatment may also include inhibition, ie cessation of further development of the disease state or pathology, and alleviation or improvement, ie regression of the disease state or pathology, such as migraine. The term prevent or prevent, as used herein, means to completely or almost completely prevent the occurrence of a disease state or pathology in a patient or subject, especially when the patient or subject is predisposed to or at risk of the disease state or pathology, such as migraine.

Throughout the description, where the compositions are described as having, including or containing specific components, it is assumed that the compositions also consist essentially of or consist of the listed components. Similarly, when methods or processes are described as having, including, or containing specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Additionally, it should be understood that the order of the steps or the order in which certain actions are performed does not matter as long as the invention remains operational. In addition, two or more steps or actions may be performed simultaneously.

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

In a separate formulation, lasmiditan is usually mixed with a vehicle, diluted with a vehicle, or enclosed in such a carrier, which may be in the form of a capsule, sachet, paper or other container. The CGRP antagonist is suitably prepared separately. When the excipient serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a carrier, carrier or medium for the active ingredient. Thus, the formulations may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, 042629 example, 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, starches, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulations may additionally contain lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl propyl hydroxybenzoates; sweeteners and flavors. The compounds of this invention may be formulated to provide rapid, delayed or delayed release of the active ingredient after administration to a patient using procedures known in the art.

An example of clinical research.

The following clinical study designs further illustrate the invention, but should not be construed as limiting the scope of the invention in any way. The following are examples of studies of lasmiditan in combination with galcanezumab in the treatment of migraine. One of skill in the art will appreciate that similar studies may be conducted with patients who have not successfully managed migraine attacks with either lasmiditan or galcanezumab alone. Those skilled in the art will appreciate that such studies may be conducted with patients, referred to herein as treatment-resistant migraine patients, who experience migraine attacks that are resistant to previous two or more treatment regimens as monotherapy and/or dual therapy. therapy. A person skilled in the art may conduct similar studies with 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 treatment-resistant headaches . One of skill in the art can readily identify, using the methods described herein and methods known in the art, patients who have failed to successfully manage migraine attacks with either lasmiditan or galcanezumab, alone, and/or treatment-resistant migraine patients whose migraine attacks are resistant to two or more prior monotherapy and/or dual therapy regimens, and such patients, thus identified, may be subjects of clinical trials such as those described in this document.

Methods for conducting such clinical trials are known to those skilled in the art and are illustrated, for example, by reference to published clinical studies of lasmiditan and galcanezumab presented herein. Methods for evaluating migraine treatment include Patient Reported Outcomes (PRS) such as Quality of Life Scores (QoL), including e.g. HIT-6), Migraine Disability Assessment Scale (MIDAS), Migraine-Limited Quality of Life Questionnaire (MSQoL). In addition, the ePRO diary can be used to record headaches and other migraine symptoms. Based on the diary data, using an automated algorithm, the days can be classified as Migraine Headache Days (BAHDs) (including possible BAHDs). Probable migraine is defined as a headache with or without early symptoms that lasts >30 minutes but lacks one of the ICHD-3 criteria for migraine. Monthly BHVM with episodic migraine medications can be obtained from the ePRO diary and PGI-S, MSQ and MIDAS assessments are performed throughout the study at each monthly visit for PGI-S and MSQ assessments and at 3 and 6 months for MIDAS using a counting device. A study design may be prepared to compare the efficacy of each dosing regimen combination with placebo, or galcanezumab alone, or lasmiditan alone, in terms of the cumulative mean change from baseline in number of days of migraine headaches (MAD) per month during the phase treatment based on ePRO or other relevant clinical data. Other possible indicators of treatment outcome could be the mean proportion of patients with a decrease from baseline in monthly BPH during the double-blind treatment phase, the mean change from baseline in scores migraine-limited quality of life version 2.1 (MSQ v2.1), mean change from baseline in Patient Global Assessment of Disease Severity (PGI-S) (mean over selected months), and/or treatment outcome measure for cumulative Migraine Disability Assessment (MIDAS) scores. These and other assessments of migraine treatment are well known to those skilled in the art.

Relief of migraine with lasmiditan with and without a CGRP antagonist such as galcanezumab by intravenous administration.

To demonstrate the effectiveness of the combination of lasmiditan and galcanezumab, the following

- 12 042629 The study was performed once as described below and once when the patients being evaluated received an initial loading dose of 240 mg galcanezumab followed by a monthly maintenance dose of 120 mg galcanezumab. Treatment groups in the study may include groups with standard doses of 50, 100, or 200 mg lasmiditan for oral administration.

In a multicenter, placebo-controlled, double-blind, cohort, non-preset, adaptive treatment, proof-of-concept, and dose finding study, 130 patients were treated in the hospital during a migraine attack. Patients were assigned to an intravenous dose of lasmiditan or placebo in small groups. The initial dose was 2.5 mg. Subsequent doses were adjusted upward or downward according to the safety and efficacy observed in the previous group. The primary endpoint is headache response, defined as an improvement from moderate or severe headache, from baseline, to mild or no headache 2 hours post-dose. The study is designed to investigate overall dose-response relationships, but is unable to differentiate different doses from placebo, or to detect differences in effects for other migraine symptoms.

Forty-two patients received placebo, and 88 received lasmiditan at doses ranging from 2.5 to 45 mg. Patients were observed in the clinic for 4 hours after treatment and a diary was used to record symptoms and side effects for up to 24 hours. The study was terminated when the dose reached the predetermined efficacy termination criteria. Patients treated in the 10, 20, 30 and 45 mg dose groups of lasmiditan were evaluated for 2 hours for headache response compared to the placebo group. The patient's overall score at 2 h and no need for backup medications were also assessed for statistically significant linear correlations with dose. The effectiveness of lasmiditan in combination with concomitant treatment with galcanezumab in relieving migraine with intravenous administration of lasmiditan at doses of 2.5 to 45 mg was evaluated.

Ways.

The study can be conducted in several centers and in accordance with the Declaration of Helsinki and international standards of Good Clinical Practice. Approval from relevant regulatory authorities and independent ethics committees is required prior to launch. All subjects are limited to those that provide written informed consent.

Study scheme.

The study uses a prospective, randomized, double-blind, placebo-controlled design, with no predetermined group, with adaptive treatment assignment (Olesen J. et al., N Engl J Med 2004: 350: 1104-10; Hall D. B. et al., Contemporary Clinical Trials 2005;26:349-63). Patients are administered the dose level of lasmiditan in small groups, with the first 20 groups consisting of 6 patients (4 receiving lasmiditan and 2 placebo) and the remaining groups consisting of 5 patients (4 lasmiditan and 1 placebo). The first group is assigned a dose level of 2.5 mg. The dose used in subsequent groups depends on the response in relation to headache (moderate or severe headache reduced to mild or absent after 2 hours), the previous group: if there is a response in 2 or fewer out of 4 patients receiving effective treatment, the dose is increased, and if there is a response in 3 or more of the 4 patients receiving effective treatment, the dose is reduced. Dose adjustment rules are chosen to determine doses of lasmiditan with efficacy similar to or better than oral triptan. This dose increase or decrease sequence will be changed if 2 or more effective patients in any group have severe non-serious side effects, in which case the dose will be reduced for the next group regardless of response rate. The occurrence of a serious medication-related adverse event will result in automatic suspension of randomization pending safety review. The minimum allowable dose of lasmiditan is 1 mg and the maximum is 60 mg.

The dose-adjusting up and down process is terminated after selection of an effective dose when the following criteria are met: at least 5 blocks of patients were treated with this dose, and for at least 4 blocks the acceptance rule required a dose reduction. Alternatively, the dose selection process may be terminated without selecting an effective dose if 5 consecutive blocks of patients were treated at the maximum dose with escalation rules requiring the dose to be increased each time.

Screening and selection of patients.

Patients are initially screened for eligibility at an outpatient visit outside of a migraine attack and are encouraged to return to the clinic for study drug treatment for a new, moderate or severe migraine attack within 4 hours of its onset. Upon return to the clinic, study eligibility is confirmed and the patient is randomized. Patients are eligible to participate in the study if they are between 18 and 65 years of age and have a history of at least 1 year of migraine with or without early symptoms, fulfilling IHS diagnostic criteria 1.1 and 1.2.1 (2004), with onset migraine before the age of 50 (Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders (second edition). Cephalalgia

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2004: 24; Suppl 1:1-160). Patients should have 1 to 8 migraine attacks per month and not be using prophylactic migraine medications. Patients are in good general health and have no signs of vascular disease or hypertension. Exclude patients with prior intolerance to triptans. Exclude pregnant or lactating women, as well as women of childbearing potential who are not using a highly reliable form of contraception.

research procedures.

Upon the patient's return to the clinic, the pharmacist or other research staff receive investigator-independent dilution instructions from the online randomization system and prepare the investigational drug for infusion. Both the investigator and the pharmacist have no information about the drug or placebo prescribing, and only the pharmacist knows about the dilution. All patients receive 60 ml intravenous infusion over 20 minutes. Efficacy and safety data before and after administration of study medication are immediately entered into the electronic data collection system, allowing headache response data to be used to guide dosing for subsequent groups.

After baseline evaluation is completed, lasmiditan or placebo is administered intravenously over 20 minutes, and the patient is monitored for safety and efficacy for at least 4 hours. Data are entered simultaneously into an online electronic data collection system. Patients are discharged from the clinic after 4 hours and continue to record migraine symptoms and side effects for up to 24 hours using a diary.

Assessment of symptoms.

A number of different symptoms are assessed. Headache severity is measured on a 4-point scale: 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: 0=capacity, 1=mild disability, 2=moderate disability, 3=severe disability. Data are collected on the Patient's Overall Assessment according to a 7-point scale: 1 = very much better, 2 = much better, 3 = slightly better, 4 = no change, 5 = slightly worse, 6 = much worse, 7 = very much worse.

The primary measure of efficacy is the response to headache ratio, defined as a reduction in headache intensity from moderate or severe headache, relative to baseline, to mild or no headache 2 hours after initiation of study drug infusion (HIS Clinical Trials Subcommittee. Guidelines for Controlled Trials in Migraine: second edition, Cephalalgia 2000: 20: 765-786). Secondary measures of efficacy are: response rate to headache at 10, 20, 40, 60, 90, 180, and 240 minutes after initiation of study drug infusion; frequency of headache relief (reduction from moderate or severe headache, relative to baseline, to no headache) at 10, 20, 40, 60, 90, 120, 180, and 240 minutes after the start of study drug administration; frequency of long-term response, defined as moderate or severe headache, relative to baseline that became mild or absent 2 hours after the start of study medication, and that did not recur (become moderate or severe) within 24 hours after the start of study medication ; the frequency of long-term pain relief, defined as moderate or severe headache, relative to baseline that was absent 2 hours after the start of study medication and that did not recur (become moderate or severe) within 24 hours after the start of study medication; the presence of nausea, vomiting, photophobia and phonophobia, and the category of clinical disability throughout the course of study; the proportion of patients taking backup medication 2-24 hours after starting study medication, and the patient's overall score 2 hours after starting study medication.

statistical methods.

A target sample size of at most 160 patients was chosen, with at least 20 patients receiving an effective dose level and at least 10 patients receiving placebo, to obtain appropriate indicative data from which to select a dose range for further evaluation. The statistical properties of the hypothesis testing criteria to compare one or more dose levels to placebo when doses were allocated using an adaptive treatment prescribing regimen with no predetermined groups were not known. Therefore, formal statistical criteria were not used to declare that a study was positive or negative, and the study did not have the power to be statistically significant. Also, the sample size does not support statistical inferences.

At the end of the study, headache response rates are summarized by dose level. Apply the Mantel-Hansel test to test the dose-response relationship. Fisher's exact test is used to compare the response rates for headache for the selected dose and placebo. In all analyses, the results for each dose level (including placebo) are pooled across all blocks where that dose was used. All patients who received any study drug are included in the population analysis. Patients are analyzed according to the treatment and dose level they are actually receiving.

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Efficiency.

The linear relationship between response rate and dose level is evaluated statistically using the Mantel-Haenszel test to determine the trend. The proportion of patients in each group who achieve a headache response at time points from 10 minutes to 4 hours is counted. Key secondary efficacy parameters are calculated for each group, including Patient Global Score at 2 hours and use of reserve medications for up to 24 hours. Secondary efficacy parameters are: no pain at 2 hours, long-term response to pain, long-term response with no pain, nausea at 2 hours, photophobia at 2 hours, phonophobia at 2 hours, absent/slightly incapacitated at 2 hours, use of reserve drugs, 2-24 h, Patient rating: very much/much better after 2 h.

The anti-migraine efficacy of lasmidan was tested for relief with or without concomitant treatment with galcanezumab. A dose-up and down-dose study design with adaptation is used to minimize patient exposure to the investigational drug or placebo, while still rapidly and reliably testing efficacy and tolerability over a wide dose range. The onset of headache relief may be apparent 20 to 40 minutes after the start of 20 minutes of intravenous infusion.

The physician may evaluate the results of the efficacy study to determine the reported percentage of disability following intravenous administration of lasmiditan, the reported percentage of moderate or severe disability, the Patient's Overall Rating, and the percentage of patients who report very much or much better 2 hours after dosing. The physician may also assess secondary measurable parameters (photophobia, phonophobia, and nausea).

A double-blind, randomized, placebo-controlled, parallel-group dose-range study of oral lasmiditan with and without galcanezumab in the management of migraine.

To demonstrate the efficacy of the combination of lasmiditan and galcanezumab, the following study was performed once as described below and once when the patients being evaluated received an initial loading dose of 240 mg of galcanezumab followed by a monthly maintenance dose of 120 mg of galcanezumab.

Conduct a study to evaluate the effectiveness (response against headache after 2 hours) range of oral doses of lasmiditan. A secondary objective is to investigate the time dependence and effect of a range of lasmiditan dose levels on migraine characteristics, including headache response, pain-free proportion, headache recurrence, nausea, photophobia, phonophobia, vomiting, incapacitation, use of reserve medications, and overall patient score. . The study is investigating the safety and tolerability of a range of doses of lasmiditan in terms of side effects, physical examination, vital signs, laboratory tests, and ECG. The study protocol is set out below.

This is a prospective, randomized, double-blind, placebo-controlled dose range study in subjects with migraine. Patients are asked to treat a single migraine attack at home with an investigational medication. Each study subject's participation consists of a 5-day telephonic visit to confirm eligibility, a treatment period of up to 8 weeks during which the subject is asked to treat one migraine attack with one dose of one of four dose levels of oral lasmiditan or placebo, and a follow-up visit. within 14 days of treatment for an attack.

Following screening, subjects are randomly assigned oral lasmiditan (50, 100, 200, or 400 mg) or matching placebo to be used as the first treatment for a new migraine attack. Subjects are asked not to treat an attack until their suitability has been confirmed by telephone after all screenings have been completed. Once eligibility is confirmed, the subject is asked to treat the next migraine attack within 4 hours of its onset, provided that the severity of the headache at that time is at least moderate and not ameliorated. Subjects record their response to treatment over the next 48 hours using a diary. Subjects are asked not to take backup medications for at least 2 hours after taking study medication. Following treatment for an attack, subjects go to the clinic to schedule a follow-up visit as soon as possible and within 14 days of treatment. Patients are assigned one of four dose levels of lasmiditan or a matching placebo in a 1:1:1:1:1 ratio according to a predetermined randomization list. At least 340 patients are treated for one attack with the study drug.

Criteria for participation/exclusion.

Participation.

Subjects are included in the study only if all of the following criteria are met:

migraine patients with or without early symptoms who meet IHS diagnostic criteria 1.1 and 1.2.1 (2004); a history of migraine for at least 1 year; onset of migraine before the age of 50; history of 1-8 migraine attacks per month; male or female patients aged 18 to 65; female patients of childbearing potential should use a highly effective form of contraception (eg, combined oral contraceptives, IUDs, abstinence, vasectomy partner); is able and does not object to providing written informed consent; is able and does not mind completing a migraine diary to record the details of an attack treated with study medication.

Exception.

Subjects are excluded from the study if any of the following criteria are met: a history of a life-threatening or intolerable side effect to any triptan; use of prescription migraine prevention medications within 30 days prior to screening visit and during study participation (other than galcanezumab, as required by the study design); pregnant or lactating women; women of childbearing potential who do not use highly effective contraception; a history of or evidence of coronary heart disease, ischemic or hemorrhagic stroke, epilepsy, or any other condition in which the patient is at increased risk of seizures; history of hypertension (controlled or uncontrolled); orthostatic hypotension in history; BP in sitting position > 160 mmHg systolic or > 90 mmHg diastolic in 2 repeated measurements at screening; current use of hemodynamically affecting cardiovascular drugs; previous 3 years history or current evidence of abuse of any drug, prescription or illicit, or alcohol; significant renal or hepatic insufficiency; previous participation in this clinical trial; participation in any clinical trial of an experimental drug or device in the previous 30 days; any medical pathology or laboratory analysis that, in the opinion of the investigator, renders the patient unsuitable for study; existing hepatitis B or C, or HIV infection; entities that are employees of the sponsor; relatives or employees reporting directly to the researcher; patients with known hypersensitivity to Compound I, other 5-HT _1F receptor agonists, or to any compound drug product excipient; patients who received drug treatment in a previous lasmiditan study (patients screened but not treated under this protocol are not excluded).

Evaluation criteria include the following.

Efficacy / pharmacodynamics: severe headache (4-point scale: none, mild, moderate, severe); headache recurrence within 48 hours; the presence or absence of nausea; phonophobia, photophobia, vomiting; disability (4-point scale: none, mild, moderate, severe); the need for reserve drugs between 2 and 48 hours (yes or no); overall assessment by the patient (7-point scale); time to headache relief and time to pain relief.

Safety.

Physical examination; side effects (reported spontaneously); vital signs; ECG with 12 leads; clinical laboratory parameters; statistical analysis.

Efficiency.

This multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial is designed to evaluate the efficacy and safety of oral lasmiditan with or without concomitant galcanazumab in the treatment of migraine. The proportion of subjects with headache relief 2 hours post-dose is the primary efficacy parameter. The primary efficacy test tests the null hypothesis that the proportions of subjects with headache relief 2 hours post-dose are similar across the five study arms, in contrast to the alternative hypothesis of a positive linear trend in treatment response rates by applying the Cochran-Armitage test for the trend. The primary analysis is performed on a sample of patients with treatment, which is defined as all subjects who treat an attack with the study medication, using a one-tailed test at a 5% significance level. Patients who have not documented the severity of headache after 2 hours or are using reserve medications up to this point are excluded from the analyzed sample.

Using a logistic regression model that includes data from all five treatment groups, additional efficacy analyzes compare each drug dose group with the placebo group. Additional analyzes are also based on a sample of subjects without violating the protocol.

Sample size is estimated based on a 40% response rate in the placebo group and a 65% response rate in the highest dose group. Assuming that the treatment groups are equally spaced and that the hazard ratios are equal between pairs of adjacent dose groups, the required sample size is estimated using Nam's (1987) approach. Based on a 1:1:1:1:1 randomization, 90% statistical power requires a total sample size of 330 patients (66 per group) based on a one-tailed test with a 5% significance level.

Safety: Side effects can be summarized and incidence can be represented by the treatment group. Laboratory data are pooled into treatment groups based on change from baseline. The safety group may consist of all randomized patients who received at least one dose of study drug or placebo. Side effects can be coded according to the Regulatory Medical Dictionary (version 19.1). Safety parameters can be calculated from treatment-related adverse events (TEAE), serious adverse events (SAEs), mortality, treatment discontinuation due to adverse events, treatment discontinuation rate, vital signs, body weight, and immunogenicity.

Primary analysis may evaluate the efficacy of each dosing regimen combination versus placebo, or galcanezumab alone, or lasmiditan alone, by the cumulative mean change from baseline in migraine headache days (MBD) per month during the treatment phase based on ePRO or other relevant clinical data. Other measures of treatment outcome could be the mean proportion of patients with >50%, >75%, and 100% reduction from baseline in monthly BPH during the double-blind treatment phase. The mean change from baseline in the Area of Limitation of Activities of Daily Activities (R-FR) score, according to the Migraine-Limited Quality of Life Questionnaire version 2.1 (MSQ v2.1), can be calculated as the mean of the selected months of the study. The cumulative mean change, from baseline, in the amount of DHVM during the double-blind treatment phase can be calculated. The mean change from baseline on the Patient's Global Assessment of Severity of Illness (PGI-S) scale (mean value over selected months) can be calculated. A treatment outcome score for a Migraine Disability Assessment (MIDAS) total score can be calculated for a selected point in time, such as the end of the study.

Phase III monotherapy studies have been conducted and published for both lasmiditan and galcanezumab used separately; see, for example, for lasmiditan, 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 report that 2 hours after the first dose, a significantly greater number of patients (p<0.001) did not experience headache (lasmiditan 200 mg: SAMURAI 32.2%, SPARTAN 38.8%; placebo: SAMURAI 15.3%, SPARTAN 21.3%) and Most Discomfort Symptom (HNS) (lasmiditan 200 mg: SAMURAI 40.7%, SPARTAN 48.7%; placebo: SAMURAI 29.5%, SPARTAN 33.5%) versus lasmidan 200 mg with placebo. For both measured parameters, statistical significance was also noted for other dose groups of lasmiditan (100, 50 mg) compared to placebo. The most commonly reported PELV with lasmiditan (>2% or greater than placebo) after the first dose were: dizziness, paresthesia, drowsiness, fatigue, nausea, and lethargy; and most cases were mild to moderate in severity. Based on this analysis, the authors concluded that the main and key measurable parameters were achieved and the safety results were similar in the two phase 3 studies. And see, for example, for galcanezumab, the efficacy and safety of galcanezumab for the prevention of episodic migraine: 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 ) 113, 2018, where the authors concluded that mean monthly migraine headache days were reduced by 4.3 and 4.2 days for galcanezumab 120 and 240 mg, respectively, and by 2.3 days for placebo. Between-group differences (95% CI) compared with placebo were 2.0 (-2.6, -1.5) and 1.9 (-2.4, -1.4), respectively. Both doses were superior to placebo for all key secondary variables measured. Pain at the injection site was the most common side effect occurring with treatment, reported with similar frequency across all treatment groups. Both doses of galcanezumab had significantly more injection site reactions and injection site pruritus, and the 240 mg group had significantly more injection site erythema compared to placebo. Based on this analysis, the authors concluded that galcanezumab 120 or 240 mg once a month was effective, safe, and well tolerated.

It is believed that the combination of lasmiditan and galcanezumab for use in the treatment of migraine will be superior to either monotherapy alone, in particular in some previously treated groups, due to the combined effect on the CGRP pathway in combination with the additional effect of lasmiditan on glutamate signaling. It is believed that the combination of these pharmacological properties will give superior efficacy for the treatment of migraine in patients who suffer from treatment-resistant migraine. Although each agent, namely lasmiditan and galcanezumab individually, has demonstrated efficacy in the treatment of migraine, the present invention, which provides a method for treating migraine in a patient, comprising simultaneously, separately or sequentially administering to a patient in need of such treatment, an effective amount of lasmiditan in combination with an effective amount of galcanezumab may provide additional potential benefits for migraine patients, and in particular for migraine patients who personally do not experience sufficient efficacy in migraine treatment when treated with galcanezumab or lasmiditan alone. Thus, the potential efficacy provided by this combined use of galcanezumab and lasmiditan for the treatment of patients with insufficient disease control with treatment with lasmiditan or galcanezumab alone, and/or the treatment of patients with migraine in whom the disease was resistant to the previous two or

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Claims (30)

more treatment regimens in the form of monotherapy and/or dual therapy, will represent an important additional breakthrough in the treatment of migraine. Preferably, currently proposed combination methods for the treatment of migraine in a patient, including the simultaneous, separate or sequential administration to a patient in need of such treatment, an effective amount of lasmiditan in combination with an effective amount of galcanezumab, can additionally provide efficacy for these patients with undertreated migraine, so that they may be pain-free 2 hours after lasmiditan treatment, or more preferably 1 hour after lasmiditan treatment, and even more preferably also experience relief of their most troublesome symptoms 2 hours after lasmiditan treatment. Preferably, patients treated with the combinations of this invention may also potentially experience lasting pain relief and/or more preferably not experience migraine pain and/or not experience migraine disability, as assessed by methods well known to one of skill in the art, such as as a MIDAS score, or as a known measure of quality of life. Preferably, patients treated with the combinations of this invention will have three or fewer migraine days per month, and more preferably no more than one migraine day per month. Preferably, the combinations of this invention may provide additional potential benefits in the form of efficacy, such as described above, in the treatment of headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache. Preferably, the combination therapy of the present invention will provide improved treatment of migraine as described herein while demonstrating the desired clinical safety and tolerability. CLAIM 1. The use of lasmiditan in simultaneous, separate or sequential combination with a calcitonin gene-related peptide (CGRP) antagonist, for the treatment of migraine in a patient. 2. Use according to claim 1, wherein the calcitonin gene-related peptide (CGRP) antagonist is galcanezumab. 3. The use according to claim 1, where the migraine was insufficiently controlled by treatment with lasmiditan or a CGRP antagonist in monotherapy. 4. Use according to claim 1, wherein the calcitonin gene-related peptide (CGRP) antagonist is galcanezumab and the migraine has not been adequately controlled by treatment with lasmiditan or galcanezumab alone. 5. Use according to claim 1, wherein the patient suffers from therapy-resistant migraine, wherein the patients' migraines were resistant to two or more prior monotherapy and/or dual therapy regimens. 6. Use according to claim 1, wherein the calcitonin gene-related peptide (CGRP) antagonist is galcanezumab and the patient is suffering from therapy-resistant migraine, wherein the patients' migraines were resistant to the previous two or more treatment regimens as monotherapy and/ or dual therapy. 7. Use according to any one of claims 2, 4 or 6 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 daily. 8. Use according to any one of claims 2, 4 or 6 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 100 mg once or twice daily. 9. Use according to any one of claims 2, 4 or 6 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 200 mg once or twice daily. 10. Use according to any one of claims 2, 4 or 6, wherein galcanezumab is administered as 120 mg and lasmiditan is administered at a dose of 50 mg once or twice a day. 11. Use according to any one of claims 2, 4 or 6 wherein galcanezumab is administered as 120 mg and lasmiditan is administered at a dose of 100 mg once or twice a day. 12. Use according to any one of claims 2, 4 or 6, wherein galcanezumab is administered as 120 mg and lasmiditan is administered at a dose of 200 mg once or twice a day. 13. Use according to any one of claims 2, 4 or 6, wherein galcanezumab is administered as 120 mg and lasmiditan is administered at a dose of 50 mg once daily. 14. Use according to any one of claims 2, 4 or 6, wherein galcanezumab is administered as 120 mg and lasmiditan is administered at a dose of 100 mg once daily. 15. Use according to any one of claims 2, 4 or 6, wherein galcanezumab is administered as 120 mg and lasmiditan is administered at a dose of 200 mg once daily. monthly dose monthly dose monthly dose monthly dose monthly dose monthly dose - 18 042629 16. The use of lasmiditan in simultaneous, separate or sequential combination with a calcitonin gene-related peptide (CGRP) antagonist for the treatment of a patient with headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache or episodic cluster headache. headache. 17. Use according to claim 16, wherein the calcitonin gene-related peptide (CGRP) antagonist is galcanezumab. 18. The use of claim 16 wherein the headache selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache was insufficiently controlled by treatment with lasmiditan or a CGRP antagonist alone. 19. The use of claim 16 wherein the calcitonin gene related peptide (CGRP) antagonist is galcanezumab and wherein the headache is selected from the group consisting of episodic headache, chronic headache, chronic cluster headache, or episodic cluster headache , was insufficiently controlled by treatment with lasmiditan or galcanezumab alone. 20. Use according to claim 16, wherein the patient suffers from therapy-resistant headaches, wherein the patient's headaches were resistant to two or more prior monotherapy and/or dual therapy regimens. 21. Use according to claim 16, wherein the calcitonin gene-related peptide (CGRP) antagonist is galcanezumab, wherein the patient is suffering from therapy-resistant headaches, wherein the patient's headaches were resistant to the previous two or more treatment regimens as monotherapy and/or dual therapy. 22. Use according to claim 16 wherein the calcitonin gene-related peptide (CGRP) antagonist is galcanezumab and 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 alone. or twice a day. 23. Use according to claim 16, wherein the calcitonin gene-related peptide (CGRP) antagonist is galcanezumab, 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 100 mg alone. or twice a day. 24. Use according to claim 16, wherein the calcitonin gene-related peptide (CGRP) antagonist is galcanezumab, 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 200 mg once or twice a day. 25. Use according to claim 16 wherein the calcitonin gene related peptide (CGRP) antagonist is galcanezumab, galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 50 mg once or twice a day. 26. Use according to claim 16 wherein the calcitonin gene related peptide (CGRP) antagonist is galcanezumab, galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 100 mg once or twice a day. 27. Use according to claim 16 wherein the calcitonin gene related peptide (CGRP) antagonist is galcanezumab, galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 200 mg once or twice a day. 28. Use according to claim 16 wherein the calcitonin gene related peptide (CGRP) antagonist is galcanezumab, galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 50 mg once daily. 29. Use according to claim 16 wherein the calcitonin gene related peptide (CGRP) antagonist is galcanezumab, galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 100 mg once daily. 30. Use according to claim 16 wherein the calcitonin gene related peptide (CGRP) antagonist is galcanezumab, galcanezumab is administered as a monthly dose of 120 mg and lasmiditan is administered at a dose of 200 mg once daily. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2