Treatment of amyotrophic lateral sclerosis with Dazzcolant

Abstract

The applicant discloses a method and composition for treating patients suffering from amyotrophic lateral sclerosis (ALS), comprising the administration of a heteroarylketone condensed azadecalin compound. In embodiments, the heteroarylketone condensed azadecalin compound is dazcholilant:(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone, which has the following chemical structure. Appropriate dosages include daily administration of 150 mg and 300 mg of dazcholant. Appropriate dosages also include daily administration of dazcholant with food, water, or food and water. Daily administration of dazcholant for seven days or more is effective in increasing exposure to dazcholant by approximately twofold. Administration of such heteroarylketone condensed azadecalin compounds may include oral administration, enteral administration, or other methods. Pharmaceutical compositions containing dazcholant are useful in the treatment of patients with ALS. Suitable pharmaceutical compositions containing dazcholant include, for example, pharmaceutical compositions for oral administration and pharmaceutical compositions for enteral administration. [Formula 1] JPEG2026509959000013.jpg4766

Description

[Technical Field]

[0001] Amyotrophic lateral sclerosis (ALS) is a devastating, ultimately fatal neurodegenerative disease with few treatment options. Survival time after onset is only about 3-5 years, and most patients die from respiratory failure. Characteristics of ALS include the loss of motor neurons in the spinal cord, brainstem, and cerebral cortex, leading to muscle weakness and ultimately paralysis. Initial symptoms vary; some patients experience weakness in the upper limbs first, while others experience weakness in the lower limbs first. About one-third of ALS patients present with bulbar palsy (bulbar onset), experiencing difficulty speaking (dysarthria) or difficulty swallowing (dysphagia) in the early stages of disease progression. [Background technology]

[0002] Many theories have been proposed to identify the underlying causes of ALS. These include nerve damage due to excess glutamate ("excitotoxicity"), nerve damage due to excess oxygen free radicals (e.g., diseases related to superoxide dismutase (SOD)), protein misfolding, inflammation, abnormal axonal transport, mitochondrial dysfunction, and endoplasmic reticulum dysfunction (see, e.g., Xu et al., Translational Neurodegeneration 2021; 10:29). Hormonal abnormalities may also be a contributing factor: high levels of estrogen and progesterone may slow disease progression (Pape et al., Rev Neurol (Paris). 2020 May; 176(5): 301-315). Cortisol level dysregulation has been reported in ALS patients (Patacchioli et al., J Endocrinol Invest. 2003;26:RC23-RC25; Spataro et al., J Neurol Sci. 2015;358(1-2):282-286).

[0003] Treatment for ALS may include the administration of riluzole (an inhibitor of glutamate neurotransmission) or edaravone (an antioxidant) in the hope of slowing the progression of the disease. Other medications used to treat patients with ALS include Tiglutik® (a riluzole thickener), Exservan® (a riluzole oral film), RELYVRIO® (AMX-0035), a combination of two drugs, sodium phenylbutyrate and taurursodiol, and Nuedexta® (dextromethorphan hydrobromide and quinidine sulfate) for the treatment of dysregulation (PBA). Qalsody® (tofersen) is FDA approved for the treatment of ALS patients associated with mutations in the superoxide dismutase 1 (SOD1) gene. However, because the disease progresses even with approved drug treatments, palliative care is included in the treatment of all patients.

[0004] Therefore, in order to improve patient care and slow the progression of the disease, improved methods and improved compositions are needed for use in the treatment of patients suffering from ALS. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] This specification discloses a novel method for treating amyotrophic lateral sclerosis (ALS). This method involves administering an effective amount of a heteroarylketone condensed azadecalin compound to a target. Preferably, the heteroarylketone condensed azadecalin compound is a compound that modulates glucocorticoid receptors (GRs). Compounds that modulate GRs are referred to as GR modulators (GRMs). GRM compounds that have little to no modulating effect on other steroid hormone receptors (such as progesterone receptors, aldosterone receptors, or androgen receptors) are referred to as selective GRMs (SGRMs). In embodiments, the method for treating ALS disclosed herein comprises administering to the subject an effective amount of the SGRM heteroarylketone condensation azadecalin compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone (also referred to as "Dazcolirant" or "CORT133176", having the following structure). [ka] Dazzcorrant is disclosed in Example 1 of U.S. Patent No. 8,859,774 (the entirety of which is incorporated herein by reference). [Means for solving the problem]

[0006] In some embodiments, the GRM (e.g., SGRM) is administered orally. In some embodiments, the GRM or SGRM may be administered by injection, infusion, transdermal administration, or by other means or route of administration. In some embodiments, the GRM (e.g., Dazkollant) may be administered with food and water, or with both food and water. In other embodiments, the GRM (e.g., Dazkollant) may be administered without food.

[0007] In the embodiment, the effective dose of the GRM (e.g., SGRM such as Dazkollant) is 50 to 500 milligrams (mg / day). For example, in the embodiment, the daily dose of the GRM (e.g., SGRM such as Dazkollant) is 50, 75, 100, 125, 150, 200, 225, 250, 300, 350, 375, 400, 450, 500, 525, or 600 mg / day. Normally, the GRM (e.g., SGRM such as Dazkollant) is administered once a day, but in the embodiment, it may be administered twice a day, three times a day, every other day, every three days, every four days, or at other intervals as needed or convenient. The GRM (e.g., SGRM such as Dazkollant) may be administered to the patient for the required period. For example, the administration of the aforementioned GRM (e.g., SGRM such as Dazcorlinant) may be continued for several weeks, several months, or several years, as needed.

[0008] This method provides an improved method for treating ALS. [Brief explanation of the drawing]

[0009] [Figure 1A] Figure 1A shows the plasma concentrations of 300 mg of dazcholant in healthy human volunteers with and without food in a PK study in which dazcholant was administered. When dazcholant was administered to subjects who were eating, a greater exposure to dazcholant was observed compared to the exposure observed in subjects who were fasting. [Figure 1B] Figure 1B shows the pharmacokinetic parameters of dazcholant administration to healthy human volunteers. When dazcholant was administered to subjects during feeding, a higher exposure to dazcholant was observed compared to the exposure observed in subjects during fasting. [Figure 2A] Figure 2A shows the steady-state PK profile of dascolyrant after administration once daily (QD) for 14 days in a brain permeability study. [Figure 2B]Figure 2B shows the pharmacokinetic parameters of dazcholant administration to healthy human volunteers who received dazcholant daily for 14 consecutive days at the indicated dose. A dose-proportional increase in dazcholant exposure was observed. [Figure 3] Figure 3 shows the timeline of the Phase 2 trial of Dazcolinant for the treatment of ALS disclosed herein. [Modes for carrying out the invention]

[0010] (Introduction) The methods disclosed herein can be used to treat patients suffering from ALS by administering an effective amount of heteroarylketone condensed azadekarin glucocorticoid receptor modulator (GRM), preferably a heteroarylketone condensed azadekarin selective glucocorticoid receptor modulator (SGRM) effective in treating ALS. In preferred embodiments, the SGRM is dazucorlinant (also known as CORT113176):(R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone, which has the following structure. [ka]

[0011] In an embodiment, the method disclosed herein can be used to treat a patient suffering from ALS by administering an effective amount of a heteroaryl ketone condensed azadecalin GRM or SGRM together with another ALS therapeutic agent effective for treating ALS. In an embodiment, other ALS treatments can include, for example, administration of riluzole or edaravon or other agents. In a preferred embodiment, a patient suffering from ALS is administered dazcolilant together with riluzole or edaravon or other agents (e.g., Tiglutik®, Exservan™, RELYVRIO™, or Nuedexta® or other agents used in the treatment of ALS).

[0012] In embodiments of the methods disclosed herein, an effective amount of heteroarylketone condensed azadecalin GRM or SGRM (e.g., Dazcholant) is administered to a patient suffering from ALS to treat the patient. In this embodiment, the effective dose of a GRM or SGRM such as Dazcolinant for treating ALS may be, for example, 10 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 175 mg / day, 200 mg / day, 225 mg / day, 250 mg / day, 300 mg / day, 350 mg / day, 375 mg / day, 400 mg / day, 450 mg / day, 500 mg / day, 525 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, 1000 mg / day, or any other dose effective for treating ALS. In embodiments, the heteroarylketone condensed azadecalin GRM or SGRM (e.g., Dazkollant) may be administered orally, without food, with food, with water, or with both food and water. In embodiments, the heteroarylketone condensed azadecalin GRM or SGRM (e.g., Dazkollant) may be administered once daily (QD), twice daily, three times daily, or any other number of times. Administration of the heteroarylketone condensed azadecalin GRM or SGRM (e.g., Dazkollant) may be continued for several weeks, months, or years as needed. For example, administration of Dazkollant may be continued for 2 weeks or more, 5 weeks or more, 10 weeks or more, 36 weeks or more, 52 weeks or more, 104 weeks or more, 156 weeks or more, or 208 weeks or more or longer.

[0013] An effective amount of dazucorilant or other GRM or SGRM may be in the form of a capsule, pill, tablet, liquid, emulsion, or other composition suitable for oral administration and can be administered, for example, orally to the patient via the mouth. In experiments, when dazucorilant is orally administered to healthy volunteers, it has been observed that dazucorilant distributes into the cerebrospinal fluid, indicating that dazucorilant passes through the human blood-brain barrier. When dazucorilant is administered for several consecutive days, the plasma level of dazucorilant increases compared to when the same dose of dazucorilant is administered for only one day, and the plasma level of dazucorilant reaches a steady state in about 7 days.

[0014] In an embodiment, the administration of a GRM or SGRM such as dazucorilant may be assisted or carried out by a straw, feeding tube, oral syringe, or other instrument or device that aids the patient in ingesting an oral therapeutic agent. Thus, in an embodiment, the administration of a GRM or SGRM such as dazucorilant may be carried out via a feeding tube or other enteral administration means (e.g., nasogastric tube, orogastric tube, duodenal tube, or gastric tube) instead of or in addition to the administration of a capsule, pill, or solution to the patient.

[0015] (Definition) As used herein, "about" refers to ±5% of the specified value, unless otherwise specified.

[0016] As used herein, the term "patient" refers to a human who is receiving, scheduled to receive, or has received medical treatment for a disease or condition such as ALS.

[0017] The terms "amyotrophic lateral sclerosis" and "ALS" used in this book refer to neurodegenerative diseases, as their names suggest. This disease is characterized by the progressive degeneration of motor neurons in both the brain and spinal cord, leading to progressive muscle weakness, constant physical disability, and death. Death usually occurs within 3 to 5 years of symptom onset. Only a small number of ALS patients survive for more than 10 years, 50% die within 30 months of symptom onset, and only 20% survive for 5 to 10 years (Riva et al. 2016 J. Neurol. 263:1241-1254). Respiratory failure is the most common cause of death in ALS patients (Riva et al. 2016 J. Neurol. 263:1241-1254; Turner et al. 2013 Lancet Neurol. 12:310-322).

[0018] As used herein, the ENCALS risk profile refers to a score that represents seven patient characteristics of ALS patients as a single score (a weighted average of the patient characteristics) and is used to estimate the overall prognosis of patients (see, for example, (Westeneng) et al., Lancet Neurol. 2018;17(5):423-433; van Eijk et al., Neurology. 2019;92(5):e451-e460; van Eijk et al., Neurology. 2021;97(11):528-536). ("ENCALS" is an abbreviation for European Network for the Cure of ALS.) The ENCALS risk profile is a calculator for inclusion and exclusion criteria based on a multivariate risk profile developed by combining patient prognostic characteristics. The ENCALS risk profile aims to provide the ability to assess the eligibility of patients in a larger patient population and to maximize the generalizability of trial results. This helps characterize and identify patients who may be suitable for inclusion in the trial.

[0019] The El Escorial Definite classification defines ALS as the clinical presence of upper and lower motor neuron signs in three or more regions on the screening day. The El Escorial Definite classification uses the El Escorial criteria to provide a diagnosis of ALS based on signs of motor neuron degeneration detected by clinical or specialist tests. In the ENCALS risk profile, a patient is considered to have "Definite ALS" only if they have three or more affected regions, regardless of the presence or absence of known pathogenic mutations.

[0020] The ALSFRS-R is a questionnaire for qualified healthcare providers used to estimate the degree of a patient's functional impairment.

[0021] As used herein, the terms “effective dose” or “therapeutic dose” refer to the amount of a pharmacological agent effective in treating, eliminating, or alleviating at least one symptom of the disease being treated. In some cases, “therapeutic effective dose” or “effective dose” may refer to the amount of a functional agent or pharmaceutical composition useful in exhibiting a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art.

[0022] As used herein, the terms “administer,” “give administration,” “administered,” or “administer” refer to providing a compound or composition (e.g., one described herein) to a subject or patient. For example, a compound or composition may be administered orally to a patient (i.e., the subject takes the compound or composition orally as a tablet, capsule, liquid, or in any other form suitable for oral administration). Oral administration may be performed buccally (the compound or composition is absorbed in the oral cavity, e.g., sublingually). Administration may be performed enterally (e.g., by administration through a tube such as a nasogastric tube, oral gastric tube, duodenal tube, or gastric tube). Administration may also be performed by injection, i.e., by delivering the compound or composition via a needle, microneedle, pressure injector, or other means of skin puncture or forcibly passing the compound or composition through the subject's skin. The injection may be administered intravenously (i.e., into a vein), intraarterially (i.e., into an artery), intraperitoneally (i.e., into the peritoneum), intramuscularly (i.e., into the muscle), or via other routes of administration. Other routes of administration include rectal, vaginal, percutaneous, pulmonary (e.g., by inhalation), subcutaneously (e.g., by absorption into the skin from an implant containing the compound or composition), or other routes.

[0023] As used herein, the term "AUC" refers to the area under the curve (of the change in plasma concentration over time after drug administration). AUC provides a measure of the plasma level of an administered drug that cannot be attributed to a single measurement.

[0024] The term "AUC" is used in this specification. 0-24 " refers to the AUC from 0 to 24 hours after administration (0 hours is the time when the target drug was administered).

[0025] The term "AUC" is used in this specification. inf " refers to the AUC extrapolated from 0 hours to infinity (0 hours is the time when the target drug was administered).

[0026] The term "AUC" is used in this specification. last" refers to the AUC from 0 hours to the time of the last measurable concentration of the administered drug (e.g., Dazcolinant).

[0027] The term "C" as used in this specification max This refers to the maximum plasma concentration of the administered drug (e.g., Dazcolinant) after administration.

[0028] As used herein, the term “combination therapy” refers to the administration of at least two drugs to a subject in order to treat a disease. The at least two drugs may be administered simultaneously for the entire duration of treatment or for part thereof, or sequentially in any order. The at least two drugs may be administered according to the same or different dosing schedules. In some cases, one drug may be administered according to a scheduled dosing schedule, and the other drug may be administered intermittently. In some cases, both drugs may be administered intermittently. In some embodiments, one drug, such as dazkollant, is administered daily, and the other drug, such as riluzole, edaravone, or other drugs, may be administered daily, or every two, three, or four days, or according to a different schedule. In some embodiments, one drug, such as dazkollant, is administered daily, or every two, three, or four days, or according to a different schedule. In such embodiments, the other drug, such as riluzole, edaravone, or other drugs, may be administered daily, or every two, three, or four days, or according to a different schedule.

[0029] As used herein, the term “glucocorticoid receptor” (“GR”) refers to type II GR, a family of intracellular receptors that specifically bind to glucocorticoids such as cortisol and / or cortisol analogs such as dexamethasone (see, for example, Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292). (The term “glucocorticoid” may be abbreviated as “GC.”) Type II glucocorticoid receptors are also called cortisol receptors. This term includes isoforms of GR, recombinant GR, and mutant GR.

[0030] The term "glucocorticoid receptor modulator" (GRM) refers to any compound that modulates the binding of glucocorticoids to GR, or modulates the biological response related to the binding of GR to an agonist. For example, GRMs acting as agonists, such as dexamethasone, enhance the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human hepatocellular carcinoma cell line, ECACC, UK). GRMs acting as antagonists, such as mifepristone, reduce the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0031] As used herein, the term “selective glucocorticoid receptor modulator” (SGRM) refers to a selective GRM, i.e., a composition or compound that selectively modulates the binding of glucocorticoids to GR, or any biological response related to the binding of GR to an agonist. Being “selective” means that the drug preferentially binds to GR over other nuclear receptors such as the progesterone receptor (PR), mineralocorticoid receptor (MR), androgen receptor (AR). A selective glucocorticoid receptor modulator may bind to MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or has an affinity (K) 10 times higher than its affinity for MR, AR, and PR. d It is preferable to bind to GR at 1 / 10 of the value. Dazucorilant is SGRM.

[0032] Examples of heteroarylketone condensed azadecalin GRM and SGRM compounds are described in U.S. Patents No. 8,859,774, No. 9,273,047, No. 9,707,223, and No. 9,956,216, all of which are incorporated herein by reference in their entirety. In embodiments, the heteroarylketone condensed azadecalin GRM is an SGRM dazcholant (Example 1 of U.S. Patent No. 8,859,774).

[0033] As used herein, the term “compound” is used to describe a molecular portion of a unique, identifiable chemical structure. A molecular portion (“compound”) may exist in a free species form, unassociated with other molecules. A compound may also exist as part of a larger aggregate, associated with other molecules, but still retaining its chemical identity. A solvate, in which a molecular portion of a defined chemical structure (“compound”) is associated with molecules of a solvent, is an example of such an associated form. A hydrate is a solvate in which the associated solvent is water. The description of “compound” refers to the molecular portion (of the described structure) itself, regardless of whether it exists in a free or associated form.

[0034] As used herein, the term “composition” is intended to encompass products containing specified amounts of specified components, such as the compounds, their tautomers, their derivatives, their analogues, their stereoisomers, their polymorphs, their deuterated species, their pharmaceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, their pharmaceutically acceptable solvates, and pharmaceutically acceptable compositions, as well as any products directly or indirectly resulting from combinations of specified components in specified amounts. Such terms relating to pharmaceutical compositions are intended to encompass products containing an active component and an inactive component constituting a carrier, as well as any products directly or indirectly resulting from combinations, complex formation, or aggregation of any two or more components, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any compositions produced by mixing the compounds of the present invention with a pharmaceutically acceptable carrier.

[0035] As used herein, the term “pharmaceutically acceptable carrier” includes all solvents, dispersions, coatings, antimicrobial and antifungal agents, isotonic absorption retarders, and similar substances that are suitable for pharmaceutically acceptable administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in compositions is considered unless conventional media or agents are incompatible with the active compound. Auxiliary active compounds may also be incorporated into compositions.

[0036] "Pharmacopoeia-acceptable excipients" and "pharmacopoeia-acceptable carriers" refer to substances that can be included in the compositions of the present invention without causing serious adverse toxic effects to the patient, thereby assisting the administration and absorption of the active agent to the target. As used herein, these terms include all solvents, dispersions, coatings, antimicrobial and antifungal agents, antioxidants, isotonic absorption retarders, and similar substances that are suitable for pharmacopoeia. Non-limiting examples of pharmacopoeia-acceptable excipients include water, sodium chloride (NaCl), physiological saline, Ringer's lactate solution, sucrose, glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavorings and colorings, and similar substances. Those skilled in the art will understand that other pharmaceutical excipients may also be useful in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in compositions should be considered unless conventional media or agents are incompatible with the active compound. Auxiliary active compounds may also be incorporated into the compositions. Those skilled in the art will understand that other pharmaceutical excipients are also useful in the present invention.

[0037] "Salt" means an acid acid or base salt of a compound used in the methods disclosed herein. Specific examples of pharmaceutically acceptable salts include salts of mineral acid salts (hydrochloric acid, hydrobromic acid, phosphoric acid, and similar), salts of organic acid salts (acetic acid, propionic acid, glutamic acid, citrate, and similar), and quaternary ammonium salts (methyl iodide, ethyl iodide, and similar). Pharmaceutically acceptable salts are understood to be non-toxic. Additional information regarding appropriate pharmaceutically acceptable salts is provided in "Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985," which is incorporated herein by reference.

[0038] (Pharmaceutical composition and administration) In embodiments, the present invention provides a pharmaceutical composition for treating ALS, comprising a pharmaceutically acceptable excipient and a GRM such as Dazkollant. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient and a SGRM. In preferred embodiments, the pharmaceutical composition comprises Dazkollant and one or more pharmaceutically acceptable excipients.

[0039] Appropriate formulations can be prepared and administered in various oral, parenteral, and topical dosage forms. GRM can be administered orally. For example, GRM can be administered as tablets, capsules, or liquid formulations as described herein. Oral formulations include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, gels, syrups, slurries, and suspensions suitable for ingestion by the patient.

[0040] For example, Dazcolinant is formulated in various ways, such as in Lipid Fractionation Cassification System (LFCS) Type III and LFCS Type IV formulations. These formulations were evaluated in hard shell capsules (Type III and Type IV) and in soft gelatin (softgel) capsules (LFCS Type IV).

[0041] When preparing pharmaceutical compositions from GRM and SGRM, the pharmaceutically acceptable carrier may be solid or liquid. Examples of solid dosage forms include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that function as diluents, fragrances, binders, preservatives, tablet disintegrants, or encapsulating materials. Detailed information on formulation and administration techniques is found in scientific literature and patent documents, for example, in the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA ("Remington's").

[0042] In the case of a powder, the carrier is a finely divided solid, a mixture of a finely divided active ingredient, GRM or SGRM, for example, Dazcorlinant. In the case of a tablet, the active ingredient is mixed in an appropriate proportion with a carrier having the required binding properties and compressed into a desired shape and size.

[0043] Powders and tablets preferably contain 5% or 10% to 70% of the active compound (e.g., Dazcorillant). Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting-point waxes, cocoa butter, and the like. The term "formulation" is intended to provide a capsule in which the active compound is formulated with an encapsulating material as a carrier, and the active ingredient is surrounded by the carrier, with or without other carriers, and therefore associated with the carrier. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0044] Suitable solid excipients include, but are not limited to, carbohydrate or protein fillers, such as sugars like lactose, sucrose, mannitol, or sorbitol; starches from corn, wheat, rice, potato, or other plants; celluloses such as methylcellulose, hydroxypropyl methylcellulose, or sodium carboxymethylcellulose; gums such as gum arabic and gum tragacanth; and proteins such as gelatin and collagen. Disintegrants or solubilizers such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or salts thereof such as sodium alginate may be added as needed.

[0045] The core of the sugar-coated tablet is coated with a suitable coating, such as a concentrated sugar solution, which may also include gum arabic, talc, polyvinylpyrrolidone, carbol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the coating of the tablet or sugar-coated tablet for product identification or to indicate the amount (dosage) of the active ingredient. The pharmaceutical formulations of the present invention can also be used orally, for example, using gelatin push-fit capsules, or soft-seal capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules may contain a GR modulator mixed with a filler or binder such as lactose or starch, a lubricant such as talc or magnesium stearate, and a stabilizer as needed. In soft capsules, the GR modulator compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol, with or without a stabilizer.

[0046] Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. Liquid formulations may contain salts, such as sodium chloride, or sugars, such as sucrose. For parenteral injection, liquid formulations can be prepared by dissolving them in an aqueous polyethylene glycol solution.

[0047] The pharmaceutical compositions disclosed herein may be provided as salts and can be formed from many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and others. The salts tend to be readily soluble in aqueous solvents or other protic solvents, which are the corresponding free base forms. In other cases, the formulation may be a lyophilized powder containing 1 mM to 50 mM histidine, 0.1% to 2% sucrose, and 2% to 7% mannitol (in a pH range of 4.5 to 5.5), which is mixed with a buffer before use.

[0048] GRM and SGRM can be administered orally and enterally. Alternatively, GRM and SGRM can be administered by injection, i.e., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal injection. In embodiments, the compositions of the present invention are useful for parenteral administration, such as intravenous (IV) administration or administration into body cavities or organ lumens. The formulation for administration usually comprises a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Suitable vehicles and solvents that can be used include water and Ringer's solution (isotonic sodium chloride). Furthermore, sterile fixative oil can be used as a solvent or suspension medium, as conventionally. In the case of intravenous (IV) administration, the formulation may be a sterile injection formulation such as a sterile aqueous suspension or oily suspension for sterile injection. This suspension can be formulated according to known techniques using a suitable dispersant or wetting agent and suspension agent. The sterile injection formulation may also use a sterile injection solution or suspension in a non-toxic, parenterally acceptable diluent or solvent such as 1,3-butanediol solution.

[0049] Furthermore, there are solid formulations intended to be converted into liquid formulations for oral administration immediately before use. Such liquid forms include solutions, suspensions, and emulsions. These formulations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and similar substances.

[0050] Oil suspensions can be prepared by suspending SGRM in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin, or in a mixture thereof. The oil suspension may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Adding sweeteners such as glycerol, sorbitol, or sucrose can provide an oral formulation with a pleasant mouthfeel. These formulations can be preserved by adding antioxidants such as ascorbic acid. For an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be the above-mentioned vegetable oil or mineral oil, or a mixture thereof. Suitable emulsifiers include natural gums such as acacia gum and tragacanth gum, natural phospholipids such as soy lecithin, fatty acids such as sorbitan monooleate, esters or partial esters derived from hexitol anhydride, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may contain sweeteners and flavorings, as in the formulations of syrups and elixirs. Such formulations may also contain lubricants, preservatives, or colorants.

[0051] The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is divided into unit doses containing an appropriate amount of the active ingredient, such as a GRM or SGRM, including, for example, Dazcorlinant. The unit dosage form may be a packaged formulation. The package contains individual amounts of the formulation, such as divided tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or a package of an appropriate number of any of these.

[0052] The amount of the active ingredient in a unit dose formulation can be changed or adjusted within the range of 1 mg to 1000 mg, more typically 10 mg to 600 mg, and most typically 50 mg to 500 mg. Appropriate dosages include approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, or 600 mg, depending on the individual use and the potency of the active ingredient. The composition may optionally contain other suitable therapeutic agents.

[0053] In some embodiments, the GRM is administered in one dose. In other embodiments, the GRM is administered in more than one dose, for example, two, three, four, five, six, seven, or more doses. In some cases, the doses are equal. In other cases, the doses are different. The doses may be increased or decreased during the administration period. The doses may vary depending on the patient's characteristics, etc.

[0054] The formulation can be administered as a single or multiple doses, depending on the patient's needs and tolerance in terms of dosage and frequency. In one embodiment, an effective amount of GRM, such as dazzyrinth, is administered as a single dose. In another embodiment, the GRM is administered in more than one dose, for example, two, three, or more doses, over a period of 2 to 12 hours, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hours, or other periods. The formulation provides a sufficient amount of active agent to effectively treat ALS. Therefore, in one embodiment, the pharmaceutical formulation for orally administering a GRM such as dazzyrinth is a dose of approximately 1 mg to approximately 20 mg per kilogram of body weight per day (mg / kg / day), approximately 1.5 to 15 mg / kg / day, or approximately 2 to 10 mg / kg / day.

[0055] In the methods disclosed herein, any appropriate GRM dose may be used. The dose of GRM administered, for example, Dazkollant, may be about 10 mg / day or more, about 20 mg / day or more, about 25 mg / day or more, about 30 mg / day or more, about 50 mg / day or more, about 75 mg / day or more, about 100 mg / day or more, about 125 mg / day or more, about 150 mg / day or more, about 175 mg / day or more, about 200 mg / day or more, about 225 mg / day or more, about 250 mg / day or more, about 300 mg / day or more, about 350 mg / day or more, about 375 mg / day or more, about 400 mg / day or more, about 450 mg / day or more, about 500 mg / day or more, about 525 mg / day or more, about 600 mg / day or more, or more. In embodiments, the GRM is administered orally. In some embodiments, the GRM is administered in at least one dose. That is, the GRM can be administered in one, two, three, four, five, six, seven, eight, nine, ten, or more doses. In embodiments, the GRM is administered orally in one, two, three, four, five, six, seven, eight, nine, ten, or more doses.

[0056] The duration of treatment with a GRM or SGRM for ALS may vary depending on the severity of the patient's symptoms and the patient's response to the GRM or SGRM. In embodiments, treatment may be continued for as long as necessary. In embodiments, treatment may be continued as long as the patient is able to take oral medication. In some embodiments, dazkollant may be administered for a period of up to approximately two years or more. In embodiments, administration of a heteroarylketone condensed azadecalin GRM or SGRM such as dazkollant may be continued for one week, two weeks, three weeks, four weeks, five weeks, ten weeks, fifteen weeks, twenty weeks, twenty-four weeks, thirty weeks, thirty-six weeks, for forty-eight weeks, fifteen weeks, twenty-four weeks, twenty-four weeks, thirty-five weeks, twenty-eight weeks or longer, as necessary to treat the patient. In embodiments, administration of a GRM such as dazkollant may be continued as long as the patient requires such administration or as long as the patient remains in a condition to receive such GRM administration.

[0057] In some embodiments, administration of GRM or SGRM may not be continuous, but may be interrupted over one or more periods, followed by resumption over one or more periods. Appropriate periods for interruption are 1–10 weeks, 2–8 weeks, 3–6 weeks, and 4–5 weeks.

[0058] SGRMs may be used in combination with other active agents known to be effective in modulating glucocorticoid receptors, or in combination with adjuvants that may not be effective on their own but may contribute to the efficacy of the active agent. For example, dazkollant may be administered to patients with ALS together with riluzole or edaravone, or with both riluzole and edaravone. Dazkollant may be administered to ALS patients together with Tiglutik®, Exservan®, RELYVRIO®, Nuedexta®, sodium phenylbutyrate, tauursodiol, dextromethorphan, quinidine sulfate, or other agents used to treat ALS or related conditions. Such administration may be carried out orally, enterally, or by other means or a combination of means.

[0059] In some embodiments, co-administration involves administering one active agent, GRM, or SGRM within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of the second active agent. Examples of such second active agents include riluzole or edaravone. Co-administration involves administering the two active agents simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., by preparing a single pharmaceutical composition containing both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active agents and / or adjuvants may be bound or conjugated to each other.

[0060] A pharmaceutical composition containing the GR modulator of the present invention can be formulated on an acceptable carrier, placed in a suitable container, and labeled for the treatment of an indication. In the case of administration of GRM or SGRM, such a label may include, for example, instructions regarding dosage, frequency of administration, and method of administration. [Examples]

[0061] The following examples are for illustrative purposes only and are not limiting. Those skilled in the art will readily recognize various non-essential parameters that can be changed or modified to obtain essentially similar results.

[0062] (Example 1. In vitro test of Dazzcolinant) Dazcolinant binds competitively and reversibly to GR with high affinity (0.28 nM). Functional GR antagonism is demonstrated when dazcolinant binds to human liver cancer cell lines (K i , 14nM) and rat liver cancer cell line (K i This has been demonstrated in vitro by its ability to inhibit the effect of dexamethasone (a potent and selective GR agonist) on tyrosine aminotransferase (TAT) activity at a concentration of 4.2 nM. Dazkollant inhibited the dexamethasone-induced increase in TAT activity in primary cultured monkey and human hepatocytes. Dazkollant is more selective for GR than other nuclear hormone receptors, as well as a variety of other receptors, enzymes, and ion channels. For example, Dazkollant is more selective for GR than progesterone receptor (PR), androgen receptor, and estrogen receptor, showing no significant binding to these receptors at a concentration of 10 μM (0%, 1.5%, and 37.5%, respectively). Its selectivity for GR over mineralocorticoid receptor (MR) was demonstrated using an MR reporter gene assay, where Dazkollant showed 23% inhibition at a concentration of 5 μM.

[0063] The in vivo distribution of Dazzcolant was determined by quantitative whole-body autoradiography (QWBA) in rats. 14After single oral administration of C-dazucorilant to male and female rats, the radiation was steadily absorbed, and the maximum concentration in the tissue usually occurred about 12 hours after administration. That the tissue:blood ratio in the brain and spinal cord exceeded 0.1 within the first 24 hours after administration indicated that the drug-related substances had passed through the blood-brain barrier.

[0064] In vivo efficacy in reducing symptoms associated with ALS has been demonstrated in Wobbler mice, a well-known model of ALS. When dazucorilant was administered for 21 days, many aspects of the disease in these mice were improved, such as reduction of forelimb atrophy, overcoming the performance decline in the Rotarod test, and suppression of neurodegeneration and inflammation.

[0065] (Example 2. Pharmacokinetics and Pharmacodynamics of Dazucorilant in Healthy Volunteers) One hundred and ten healthy male and female volunteers (aged 18 - 60 years, BMI 18 - 30 kg / m 2 , body weight ≤ 102 kg, "First In Human (FIH)" trial) were enrolled in a randomized, double-blind, placebo-controlled trial (NCT04249323, EudraCT 2019 - 004258 - 27) to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of dazucorilant. In Part 1, single escalating doses of dazucorilant (50 - 1000 mg) were administered to healthy volunteers with or without food (n = 63). In Part 2, dazucorilant was administered to healthy volunteers multiple times (100 - 300 mg once daily [QD] for 14 days, n = 36). In Part 3, dazucorilant was administered to healthy volunteers to establish proof of pharmacological effect (n = 11). Additionally, for the brain permeability of dazucorilant, 16 healthy male volunteers (aged 18 - 65 years, BMI 18 - 30 kg / m 2A phase 1 randomized, partially double-blind, placebo-controlled trial (NCT04994743, EudraCT 2021-002456-36) was conducted in subjects weighing ≤100 kg to evaluate the pharmacokinetic activity (PK) of multiple oral doses of dazcholilant (150 mg or 300 mg once daily (QD) for 14 days) in plasma and cerebrospinal fluid (CSF).

[0066] Results: A single dose of dazcholant up to 1000 mg was considered safe and well-tolerated in fasted subjects, and up to 900 mg in fed subjects. Multiple doses of up to 300 mg once daily were considered safe, and multiple doses of up to 200 mg once daily were also safe and generally well-tolerated. No serious or significant adverse events were reported during administration. The most common adverse events were gastrointestinal, nervous system, musculoskeletal, and connective tissue disorders. A positive food effect (1.3 to 1.7 times increase compared to food exposure) was observed (see Figures 1A and 1B). Compared to dazcholant 150 mg, dazcholant exposure after oral administration of dazcholant 300 mg showed an increase in dazcholant exposure that was more than dose-proportional. Plasma accumulation approximately doubled with multiple doses, and steady-state exposure was achieved in approximately 7 days (see Figures 2A and 2B). The distribution of Dazcorlinant into the cerebrospinal fluid was observed, confirming its cerebral permeability.

[0067] (Dose-proportional or greater exposure increase and positive food effects in first-in-human trials) After gradually increasing the dose threefold (150 mg to 450 mg under fasting conditions), AUC (0-inf) and C max The exposure levels of Dazcorillant, as measured, increased 4.0 times and 3.4 times, respectively (Table 1). Furthermore, when the dose was doubled (450 mg to 900 mg once during ingestion), the exposure levels increased 2.8 times and 2.2 times, respectively (Table 1). [Table 1]

[0068] After consuming a high-fat breakfast, a significantly positive food effect was observed compared to fasting, with exposure increasing by more than twofold (Table 2). [Table 2]

[0069] Achieving twofold accumulation in plasma and steady-state exposure after approximately 7 days in brain permeability tests. In the brain permeability study, after administration once daily for one week, AUC (0-24) and C max The accumulation ratio (days 1-7) showed that exposure to 150 mg or 300 mg of Dazcorilant in a fasted state increased 1.7 to 1.9 times. After 2 weeks of once-daily administration (days 1-14), exposure increased 1.6 to 2.0 times (AUC). 0-24 and C max (Based on the accumulation ratio). The accumulation ratio from day 7 to day 14 was in the range of 0.9 to 1.1, indicating that exposure to Dazcorlinant reached a steady state within one week of once-daily administration. Steady-state exposure (C max AUC 0-24 The effect was approximately four times higher when administered at 300 mg compared to 150 mg of Dazcorillant. (See Figure 2A.)

[0070] Dazcolirant has the expected pharmacological effects. As expected, a single dose of prednisone decreased eosinophils, lymphocytes, and osteocalcin, while increasing neutrophils. Dazcholant improved the effect of prednisone on these parameters. This was due to the combined use of prednisone and Dazcholant compared to prednisone alone, resulting in a reduction in AUEC (Auditory Elevation Cycle) of eosinophils, lymphocytes, and osteocalcin from baseline. (0-24) This was demonstrated by a statistically significant difference in the changes (Table 3). Similar to other SGRMs (Pivonello et al., Front Endocrinol (Lausanne). 2021; 12:662865), no significant effect of Dazcorrinant on morning or evening cortisol or ACTH levels was observed in Part 2 of the FIH trial. [Table 3]

[0071] In the brain permeability test, dazcholant was detected in the cerebrospinal fluid of all participants after administering 150 mg and 300 mg of dazcholant once daily for one week under feeding conditions. This result indicates that dazcholant can permeate the human brain.

[0072] Identified safe and well-tolerated doses of Dazkolirant A single dose of dazcorrinant up to 1000 mg was considered safe and well-tolerated in fasted patients, and up to 900 mg in fed patients. Multiple doses of up to 300 mg once daily were considered safe, and multiple doses of up to 200 mg once daily were also safe and generally well-tolerated.

[0073] Conclusion: The presented studies established the pharmacokinetics, safety, tolerability, and pharmacological effects of dazcholant in healthy volunteers. Across all presented studies, 111 healthy volunteers received dazcholant. Adverse events were mild to moderate, reflecting the intolerance at higher doses, and no serious safety concerns were identified.

[0074] (Example 3. Phase 2 multicenter randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of dascolyrant in patients with amyotrophic lateral sclerosis) A Phase 2 trial (DAZALS, NCT05407324, EudraCT 2021-005611-31) is underway to evaluate whether Dazzolilant benefits ALS patients by delaying functional loss.

[0075] Study Diagram: Figure 3 shows a schematic diagram of the timeline followed by subjects who received dazocolant 150 mg / day, dazocolant 300 mg / day, or placebo in this study.

[0076] Eligibility Criteria: Patients must be 18 years of age or older and have ALS (sporadic or familial). Patients with an ENCALS risk profile score of -6 to -3 are eligible to enroll in this study. Such patients may be receiving treatment with riluzole and / or edaravone, but such prior treatment is not required. If riluzole and / or edaravone administration is ongoing, the patient's dosage must be stable (i.e., the dosage of riluzole or edaravone must not change during the study period). Patients who meet any of the following conditions will be excluded from enrollment: a history of clinically significant neurological disorders other than ALS, inability to swallow capsules, renal or hepatic impairment, decreased platelet count, use of non-invasive ventilation (e.g., CPAP) at any time of day at screening, use of mechanical ventilation via tracheostomy at screening, use of any form of oxygen supplementation at screening, use of glucocorticoids, need for regular systemic glucocorticoid use, or a history of clinically significant impairment or unstable medical condition other than ALS.

[0077] Identifying eligible ALS patients for the trial: Eligible ALS patients are those whose disease is not very advanced and is progressing slowly, as assessed using the ENCALS risk profile calculator. Therefore, the eligibility criteria are designed to exclude patients in advanced stages of the disease or those with slow disease progression. The rate of ALS progression is determined by several interdependent patient characteristics, including:

[0078] (ENCALS Risk Profile:) Patients with an ENCALS score of -6 or higher and -3 or lower are eligible for enrollment. The eligibility criteria exclude patients with very slow progression (long survival time) and very rapid progression (very short survival time). The ENCALS risk profile considers the prognostic impact of seven patient characteristics in a single score, providing a more accurate estimate of the patient's overall prognosis when determining eligibility for the trial (Westeneng et al., Lancet Neurol. 2018;17(5):423-433; van Eijk et al., Neurology. 2019;92(5):e451-e460; van Eijk et al., Neurology. 2021;97(11):528-536).

[0079] (Patient information may include): screening date, date of birth, date of diagnosis, date of symptom onset, El Escorial definitive classification, site of symptom onset, presence or absence of frontotemporal dementia, ALSFRS-R total score at screening, vital capacity at screening, and other patient information.

[0080] Study Design: ALS patients will be screened before participating in the study, and those meeting the eligibility criteria will be randomly assigned to one of three study groups: placebo, 150 mg of dazcholant per day, or 300 mg of dazcholant per day. The enrollment target is to enroll 198 ALS patients, and patient randomization will be stratified according to the following factors: use of the ALS treatment riluzole and / or edaravone (yes / no); and site of disease onset (bulbar palsy / other). Plasma samples will be collected from approximately 20% of patients at week 3 for pharmacokinetic analysis. Patients who complete the treatment period and meet the eligibility criteria for open-label extension (OLE) will be enrolled and may receive dazcholant for up to an additional 132 weeks.

[0081] Each of the three patient groups will receive the study drug daily for 24 weeks. During the initial 24-week treatment period, patients will be contacted every three weeks (by telephone or outpatient visit). Following the 24-week treatment period, a follow-up period of up to 132 weeks will be provided, during which patients will either a) remain on medication-free observation or b) receive 300 mg of dazkollant daily in an open-label continuation period of up to 132 weeks. Patients will be contacted by telephone every 8 to 24 weeks during the follow-up period without medication administration, or every 4, 12, or 16 weeks during the open-label continuation period (by telephone or outpatient visit).

[0082] The investigational drug administered to patients (Dazcorillant or placebo) is provided as a 75 mg softgel capsule. The investigational drug is administered orally once daily with food and water at approximately the same time each day.

[0083] The primary endpoints include the total score on the Revised ALS Functional Rating Scale-R (ALSFRS-R) (change from baseline to 24 weeks) and safety. Secondary endpoints include changes in % vital capacity, changes in muscle strength (using a handheld dynamometer), and changes in quality of life (5Q-5D-5L). Further secondary endpoints include time to event, which includes death from any cause, hospitalization due to an ALS-related event, tracheostomy (for respiratory failure, saliva management, or both), and the need for respiratory support for more than 22 hours per day for 7 days. A further secondary endpoint is the Combined Assessment of Function and Survival (CAFS). Key additional endpoints include pharmacokinetic measurements, ALS biomarkers (e.g., serum neurofilaments, IL-18, and / or IL-18-binding protein), and exploratory patient-reported outcome scales.

[0084] Summary: Dysregulation of cortisol levels in ALS patients and the inflammatory effects of cortisol in the central nervous system (CNS) provide strong evidence for the role of SGRMs such as dazacolinant in ALS treatment. DAZALS will be the first trial to evaluate whether GR modulation by dazacolinant can benefit ALS patients by mitigating the neurotoxic effects of cortisol activity and delaying functional loss (NCT05407324, EudraCT 2021-005611-31). Eligibility will be assessed using the ENCALS risk profile score, and a homogeneous patient population with similar predicted outcomes will be enrolled.

[0085] All patents, patent publications, publications, and patent applications cited herein are incorporated herein by reference in whole, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Furthermore, although the invention has been described in some detail by illustrations and examples for ease of understanding, it will be readily apparent to those skilled in the art that certain changes and modifications can be made in light of the teachings of the invention without departing from the spirit or scope of the appended claims.

Claims

1. A method for treating a person suffering from amyotrophic lateral sclerosis (ALS), The method involves applying an effective amount of dazucorilant, namely (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone: 【Chemistry 1】 This includes administering, The administration of Dazcolirant includes administering Dazcolirant daily for seven consecutive days or more. The method is effective in increasing the exposure to Dazcholant by approximately 1.7 times compared to the exposure to Dazcholant obtained by administering the effective amount of Dazcholant effective for treating ALS for only one day.

2. The method according to claim 1, wherein the Dazcolirant is administered together with food.

3. The method according to claim 1 or claim 2, wherein the effective amount of Dazzcolant is selected from approximately 75 mg, approximately 150 mg, approximately 300 mg, approximately 375 mg, approximately 450 mg, and approximately 500 mg of Dazzcolant.

4. The administration of Dazcolirant includes administering Dazcolirant daily for 14 consecutive days or more. The method according to any one of claims 1 to 3, which is effective in achieving a steady-state level of Dazcolirant exposure that is at least 1.6 times the Dazcolirant exposure obtained by administering the effective amount of Dazcolirant for only one day.

5. The method according to any one of claims 1 to 4, wherein the effective amount of Dazzcorrant is contained in one or more softgel capsules.

6. The method according to any one of claims 1 to 5, further comprising administering further treatment for ALS.

7. The method according to claim 6, wherein further treatment for ALS comprises the administration of riluzole or edaravone.

8. The method according to any one of claims 1 to 7, wherein the administration of Dazcolirant includes oral or enteral administration of Dazcolirant.

9. Use of heteroaryl ketone condensed azadecalindascorillant, namely (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone for use with food in the treatment of amyotrophic lateral sclerosis (ALS). 【Chemistry 2】

10. The use described above is the use with water and food, as described in claim 9.

11. The use according to claim 9 or 10, wherein the amount of Dazzcolant is selected from about 75 mg, about 150 mg, about 300 mg, about 375 mg, about 450 mg, and about 500 mg of Dazzcolant.

12. Use of heteroarylketone condensed azadecalindascorilant, namely (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone in the manufacture of a drug for use with food in the treatment of amyotrophic lateral sclerosis (ALS). 【Transformation 3】

13. The use according to claim 12, wherein the drug is used together with water and food.

14. The use according to claim 12 or 13, wherein the amount of Dazzcolant is selected from about 75 mg, about 150 mg, about 300 mg, about 375 mg, about 450 mg, and about 500 mg of Dazzcolant.

15. The use according to any one of claims 12 to 14, wherein the drug comprises Dazcorilant contained in a softgel capsule.

16. The use according to any one of claims 9 to 15 for use in combination with further treatment for ALS.

17. The use according to claim 16, wherein the further treatment for ALS includes the use of riluzole or edaravone.

18. A method for alleviating symptoms associated with amyotrophic lateral sclerosis (ALS) in subjects suffering from ALS, The method involves applying an effective amount of approximately 75 milligrams (mg) to approximately 500 mg of dazkolinant to the subject, namely (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone: 【Chemistry 4】 This includes administering, The administration of Dazcolirant includes administering Dazcolirant daily for seven consecutive days or more. A method that is effective in increasing the exposure to Dazcholant by approximately 1.7 times compared to the exposure to Dazcholant obtained by administering the effective amount of Dazcholant effective for treating ALS for only one day.

19. The method according to claim 18, wherein the Dazcolirant is administered together with food.

20. The method according to claim 18 or claim 19, wherein the effective amount of Dazzcolant is selected from approximately 75 mg, approximately 150 mg, approximately 300 mg, approximately 375 mg, approximately 450 mg, and approximately 500 mg of Dazzcolant.

21. The administration of Dazcolirant includes administering Dazcolirant daily for 14 consecutive days or more. The method according to any one of claims 18 to 20, which is effective in achieving a steady-state level of Dazcolirant exposure that is at least 1.6 times the Dazcolirant exposure obtained by administering the effective amount of Dazcolirant daily.

22. The method according to any one of claims 18 to 21, wherein the effective amount of Dazzcorilant is contained in one or more softgel capsules.

23. The method according to any one of claims 18 to 22, further comprising administering further treatment for ALS.

24. The method according to claim 23, wherein further treatment for ALS comprises the administration of riluzole or edaravone.

25. The method according to any one of claims 18 to 24, wherein the administration of Dazcolirant includes oral or enteral administration of Dazcolirant.

26. The method according to any one of claims 18 to 25, wherein the symptoms associated with ALS are selected from upper limb weakness, lower limb weakness, dysarthria, and dysphagia.

27. Use of heteroaryl ketone condensed azadecalindascorillant, namely (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone for use with food to alleviate symptoms associated with amyotrophic lateral sclerosis (ALS). 【Transformation 5】

28. The use described above is the use with water, as described in claim 27.

29. The use according to claim 27 or 28, wherein the amount of Dazzcolant is selected from about 75 mg, about 150 mg, about 300 mg, about 375 mg, about 450 mg, and about 500 mg of Dazzcolant.

30. The use according to any one of claims 27 to 29, wherein the symptoms associated with ALS are selected from upper limb weakness, lower limb weakness, dysarthria, and dysphagia.

31. Use of heteroarylketone condensed azadecalindascorillant, namely (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinoline-4a-yl)(pyridine-2-yl)methanone in the manufacture of a drug to be used with food to alleviate symptoms associated with amyotrophic lateral sclerosis (ALS). 【Transformation 6】

32. The use according to claim 31, wherein the drug is used together with water and food.

33. The use according to claim 31 or claim 32, wherein the amount of Dazzcolant is selected from about 75 mg, about 150 mg, about 300 mg, about 375 mg, about 450 mg, and about 500 mg of Dazzcolant.

34. The use according to any one of claims 31 to 33 for use in combination with further treatment for ALS.

35. The use according to claim 34, wherein the further treatment for ALS includes the use of riluzole or edaravone.

36. The use according to any one of claims 31 to 35, wherein the symptoms associated with ALS are selected from upper limb weakness, lower limb weakness, dysarthria, and dysphagia.

37. The use according to any one of claims 31 to 36, wherein the drug comprises Dazcorilant contained in a softgel capsule.

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