Combination comprising exacaftor / tezacaftor / ivacaftor for use in treating cystic fibrosis where the patient has at least one CFTR mutation

Abstract

The present disclosure relates to methods of treating cystic fibrosis comprising administering elexacaftor, tezacaftor, and ivacaftor to a patient with certain mutations.

Description

COMBINATION COMPRISING EXACAFTOR / TEZACAFTOR / IVACAFTOR FOR USE IN TREATING CYSTIC FIBROSISWHERE THE PATIENT HAS AT LEAST ONE CFTR MUTATION

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 665,338, filed June 28, 2024; the contents of which are herein incorporated by reference in their entirety.

[0002] This application describes methods of treating cystic fibrosis in patients with rare incidence of mutations using elexacaftor, tezacaftor, and ivacaftor (TRIKAFTA®).

[0003] Cystic fibrosis (CF) is a recessive genetic disease that affects approximately 92,000 children and adults worldwide. Despite progress in the treatment of CF, there is no cure.

[0004] In patients with CF, mutations in cystic fibrosis transmembrane conductance regulator (CFTR) endogenously expressed in respiratory epithelia lead to reduced apical anion secretion causing an imbalance in ion and fluid transport. The resulting decrease in anion transport contributes to enhanced mucus accumulation in the lung and accompanying microbial infections that ultimately cause death in CF patients. In addition to respiratory disease, CF patients typically suffer from gastrointestinal problems and pancreatic insufficiency that, if left untreated, result in death. In addition, the majority of males with cystic fibrosis are infertile, and fertility is reduced among females with cystic fibrosis.

[0005] CFTR is a cAMP / ATP-mediated anion channel that is expressed in a variety of cell types, including absorptive and secretory epithelia cells, where it regulates anion flux across the membrane, as well as the activity of other ion channels and proteins. In epithelial cells, normal functioning of CFTR is critical for the maintenance of electrolyte transport throughout the body, including respiratory and digestive tissue. CFTR is composed of approximately 1480 amino acids that constitute a protein which is made up of a tandem repeat of transmembrane domains, each containing six transmembrane helices and a nucleotide binding domain. The two transmembrane domains are linked by a large, polar, regulatory (R)-domain with multiple phosphorylation sites that regulate channel activity and cellular trafficking.

[0006] Chloride transport takes place by the coordinated activity of ENaC and CFTR present on the apical membrane and the Na+-K+-ATPase pump and Cl' channels expressed on the basolateral surface of the cell. Secondary active transport of chloride from the luminal side leads to the accumulation of intracellular chloride, which can then passively leave the cell via CF channels, resulting in a vectorial transport. Arrangement of Na+ / 2C17K+co-transporter, Na+-K+-ATPase pump and the basolateral membrane K+channels on the basolateral surface and CFTR on the luminal side coordinate the secretion of chloride via CFTR on the luminal side. Because water is probably never actively transported itself, its flow across epithelia depends on tiny transepithelial osmotic gradients generated by the bulk flow of sodium and chloride.

[0007] Sequence analysis of the CFTR gene has revealed a variety of disease-causing mutations (Cutting, G. R. et al. (1990) Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863-870; and Kerem, B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc. Natl. Acad. Sci. USA 87:8447-8451). To date, greater than 2000 mutations in the CF gene have been identified. Currently, the CFTR2 database contains information on only 804 of these identified mutations, with sufficient evidence to define 719 mutations as disease-causing. The most prevalent disease-causing mutation is a deletion of phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the F508del mutation. This mutation occurs in many CF cases and is associated with severe disease.

[0008] The deletion of residue 508 in CFTR prevents the nascent protein from folding correctly. This results in the inability of the mutant protein to exit the endoplasmic reticulum and traffic to the plasma membrane. As a result, the number of CFTR channels for anion transport present in the membrane is far less than observed in cells expressing wild- type CFTR, i.e., CFTR having no mutations. In addition to impaired trafficking, the mutation results in defective channel gating. Together, the reduced number of channels in the membrane and the defective gating lead to reduced anion and fluid transport across epithelia. (Quinton, P. M. (1990), FASEB J. 4:2709-2727). The channels that are defective because of the F508del mutation are still functional, albeit less functional than wild-type CFTR channels. (Dalemans et al. (1991), Nature Lond. 354:526-528; Pasyk and Foskett (1995), J. Cell. Biochem. 270:12347-12350). In addition to F508del, other disease-causing mutations in CFTR that result in defective trafficking, synthesis, and / or channel gating can alter anion secretion and modify disease progression and / or severity.

[0009] In the recent decade, the U.S. Food and Drug Administration (FDA) has approved several therapies for treating cystic fibrosis by correcting and / or potentiating CFTR function (modulator therapy). In 2019, the FDA approved elexacaftor / tezacaftor / ivacaftor under the trade name TRIKAFTA® for treating patients with CF with at least one F508del mutation. In August 2023, TRIKAFTA®’s indicationwas broadened to include treatment of people with CF with 178 additional CFTR gene mutations that are responsive to TRIKAFTA®.

[0010] In 2017, the FDA allowed the use of well-controlled in vitro assays to determine the drug-responsiveness of certain CFTR mutations. This change paved the way for more people with rare mutations to be treated with modulator therapy. Since 2017, the FDA has approved additional indications for KALYDECO®, SYMDEKO®, and TRIKAFTA® based on in vitro data. However, many patients with certain rare mutations remain ineligible for modulator therapy.

[0011] There are over 65,000 patients with CF with an F508del mutation in the CFTR2 database. By contrast, for some rare mutations, there are fewer than ten patients with the rare mutations in the CFTR2 database. The rarity of these mutations makes it highly challenging to assess the responsiveness of patients with certain rare mutations to modulator therapy due to a lack of clinical data, since large numbers of patients with each mutation are not available to conduct traditional clinical studies. In certain cases, ex-vivo cellular models for correcting CFTR dysfunction have been developed to predict clinical response (e.g., with nasal epithelial cells or nasal / rectal organoids), although this requires the use of samples from patients with each individual mutation, making this a time-intensive and iterative process. For certain rare mutations cellular models are not available, and thus there is an unmet medical need for methods of treatment for cystic fibrosis patients with certain rare mutations.

[0012] Thus, one aspect of the disclosure provides methods of treating cystic fibrosis in patients with at least one CFTR mutation comprising administering elexacaftor or a pharmaceutically acceptable salt thereof, tezacaftor or a pharmaceutically acceptable salt thereof, and ivacaftor or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the CFTR mutation is selected from 5T;TG12, 5T;TG13, 296+28A^G, 2752-26A^G, 3600G^A, and 3849+4A— >G. In some embodiments, the CFTR mutation is selected from 5T;TG12, 5T;TG13, 3600G^A, and 3849+4A— >G.

[0014] In one embodiment, the patient is heterozygous for at least one mutation selected from 5T;TG12, 5T;TG13, 296+28A^G, 2752-26A^G, 3600G^A, and 3849+4A^G on one allele and a second CFTR gene mutation on the other allele.Definitions

[0015] As used herein, “CFTR” means cystic fibrosis transmembrane conductance regulator.

[0016] As used herein, “mutations” can refer to mutations in the CFTR gene or the CFTR protein. A “CFTR gene mutation” refers to a mutation in the CFTR gene, and a “CFTR protein mutation” refers to a mutation in the CFTR protein. A genetic defect or mutation, or a change in the nucleotides in a gene in general results in a mutation in the CFTR protein translated from that gene.

[0017] As used herein, “splice mutation,” “splicing mutation,” and “splice site mutation” are used interchangeably and refer to a mutation in the CFTR gene (one or more insertions, deletions, frame shifts, and / or nucleotide changes) at a site where splicing takes place during the processing of precursor mRNA into mature mRNA. Splicing mutations can be canonical (Class I) where a highly truncated non-functional CFTR protein is made, or non- canonical, where a longer yet still incomplete CFTR protein is made. The CFTR protein made from a non-canonical splicing mutation is long enough to have the binding sites of elexacaftor, tezacaftor and ivacaftor present so it is hypothesized that the mutant CFTR protein is responsive to elexacaftor, tezacaftor and ivacaftor. The rare mutations 5T;TG12, 5T;TG13, 296+28A^G, 2752-26A^G, 3600G^A, and 3849+4A^G described herein are non-canonical splicing mutations.

[0018] As used herein, a patient who is “homozygous” for a particular gene mutation has that same mutation on each allele. The term “heterozygous” as used herein, refers to a patient having a particular gene mutation on one allele, and a different mutation on the other allele. Patients that may benefit from the methods of treatment of the disclosure and from pharmaceutical compositions for use in treating CFTR-mediated diseases described herein include patients who have homozygous or heterozygous mutations in the CFTR gene selected from 5T;TG12, 5T;TG13, 296+28A^G, 2752-26A^G, 3600G^A, and 3849+4 A— >G.

[0019] As used herein, the term “modulator” refers to a compound that alters or increases the activity of a biological compound such as a protein. For example, a CFTR modulator is a compound that generally increases the activity of CFTR. The increase in activity resulting from a CFTR modulator includes but is not limited to compounds that correct, potentiate, stabilize, and / or amplify CFTR.

[0020] As used herein, a “CFTR potentiator"” refers to a compound that exhibits biological activity characterized by increasing gating functionality of the mutant CFTR protein present in the cell surface to approximately wild- type levels (i.e., a compound thataugments or induces the channel activity of CFTR protein located at the cell surface, resulting in increased functional activity).

[0021] As used herein, the term “CFTR corrector” refers to a compound that augments or induces the amount of functional CFTR protein to the cell surface, resulting in increased functional activity.

[0022] The terms “about” and “approximately”, when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent. The terms “about” and “approximately” may refer to an acceptable error for a particular value as determined by one of skill in the art, which depends in part on how the values is measured or determined. In some embodiments, the terms “about” and “approximately” mean within 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. As used herein, the symbolappearing immediately before a numerical value has the same meaning as the terms “about” and “approximately.”

[0023] As used herein, the term “active pharmaceutical ingredient” or “API” refers to a biologically active compound.

[0024] The term “patient” or “subject” is used interchangeably and refers to an animal including humans.

[0025] The terms “effective dose” or “effective amount” are used interchangeably herein and refer to that amount of a compound that produces the desired effect for which it is administered (e.g., the treatment of CF, improvement in CF or a symptom of CF, or lessening the severity of CF or a symptom of CF). The exact amount of an effective dose will depend on the patient and the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0026] As used herein, the terms “treatment,” “treating,” and the like generally mean the improvement of CF or its symptoms or lessening the severity of CF or its symptoms in a subject. “Treatment,” as used herein, includes, but is not limited to, the following: increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and / or liver function, reduction of chest infections, increase in FEVi (forced expiratory volume in one second), decreases in sweat chloride, reductions inpulmonary exacerbations, increased life span, decreased progression of disease, and / or reductions in coughing or shortness of breath. Improvements in or lessening the severity of any of these symptoms can be readily assessed according to standard methods and techniques known in the art.

[0027] As used herein, the term “in combination with” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other. The terms “about” and “approximately,” when used in connection with doses, amounts, or weight percent of ingredients of a composition or a dosage form, include the value of a specified dose, amount, or weight percent, or a range of the dose, amount, or weight percent that is recognized by one of ordinary skill in the art to provide a pharmacological effect equivalent to that obtained from the specified dose, amount, or weight percent.

[0028] As used herein, the term “ppFEVi” refers to percent predicted forced expiratory volume in one second, a widely used measure of lung function, as determined by spirometry.

[0029] As used herein, “lung clearance index” or “LCI” refers to an index derived from a multiple breath washout test (MBW). LCI is a marker of overall lung ventilation inhomogeneity. See, e.g., Lombardi, E et al. (2019), Ital. J. Pediatr. 45:56.

[0030] As used herein, “sweat chloride” refers to the concentration of chloride anion in the sweat of a patient. Sweat chloride is a marker of underlying CFTR dysfunction that causes CF, and greater improvement in sweat chloride is associated with greater restoration of CFTR function. A sweat chloride level of 60 mmol / L is a diagnostic threshold for CF. Patients with a sweat chloride level below 30 mmol / L are unlikely to have CF, and this level is seen in CF carriers who do not have the disease. Methods for testing sweat chloride are well known in the art and have been reported in, e.g., LeGrys VA et al. (2007), J.Pediatr. 15 l(l):85-89; Farrell PM et al. (2017), J. Pediatr. 181S:S4-S15.el.Elexacaftor

[0031] As used herein, the term “elexacaftor” is used interchangeably with A-(l,3- dimethylpyrazol-4-yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-l-yl]-2- [(4S)-2,2,4-trimethylpyrrolidin-l-yl]pyridine-3-carboxamide, which has the following structure:Elexacaftor is described in International Patent Publications WO 2018 / 107100 andWO 2019 / 018395, each of which are incorporated herein by reference. WO 2018 / 107100 and WO 2019 / 018395 also describe methods of making elexacaftor, methods of making crystalline Form A of elexacaftor, and demonstrate that elexacaftor is a CFTR corrector therapeutic. In some embodiments, elexacaftor is in the form of a pharmaceutically acceptable salt.Tezacaftor

[0032] As used herein, the term “tezacaftor” is used interchangeably with (R)-l-(2,2- difluorobenzo[d] [ 1 ,3]dioxol-5-yl)-A-(l -(2,3-dihydroxypropyl)-6-fluoro-2-(l -hydroxy-2 - mcthylpropan-2-yl)- 1 / / -mdol-5-yl)cyclopropanccarboxamidc. Tezacaftor can be depicted as having the following structure:Tezacaftor has been previously described in United States Patent PublicationUS 2009 / 0131492, and International Patent Publications WO 2011 / 119984 andWO 2015 / 160787, all of which are incorporated herein by reference.Ivacaftor

[0033] As used herein, the term “ivacaftor” is used interchangeably with A-(5 -hydroxy - 2,4-di- / e / 7-butyl-phcnyl)-4-oxo-l / / -quinolinc-3-carboxamidc and A-[2,4-bis(l,l-dimethylethyl)-5-hydroxyphenyl]- 1 ,4-dihydro-4-oxoquinoline-3-carboxamide. Ivacaftor has the following structure:Ivacaftor has been previously described in International Patent PublicationsWO 2006 / 002421, WO 2007 / 079139, and WO 2013 / 130669, all of which are incorporated herein by reference.

[0034] As used herein, the term “active pharmaceutical ingredient” or “API” refers to a biologically active compound.

[0035] As used herein, the term “amorphous” refers to a solid material having no long- range order in the position of its molecules. Amorphous solids are generally supercooled liquids in which the molecules are arranged in a random manner so that there is no well- defined arrangement, e.g., molecular packing, and no long-range order. Amorphous solids are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. For example, an amorphous material is a solid material having no sharp characteristic crystalline peak(s) in its X-ray power diffraction (XRPD) pattern (i.e., is not crystalline as determined by XRPD). Instead, one or several broad peaks (e.g., halos) appear in its XRPD pattern. Broad peaks are characteristic of an amorphous solid. See US 2004 / 0006237 for a comparison of XRPDs of an amorphous material and crystalline material.

[0036] As used herein, the term “substantially amorphous” refers to a solid material having little or no long-range order in the position of its molecules. For example, substantially amorphous materials have less than 15% crystallinity (e.g., less than 10% crystallinity or less than 5% crystallinity). It is also noted that the term “substantially amorphous” includes the descriptor, “amorphous,” which refers to materials having no (0%) crystallinity.

[0037] As used herein, the term “dispersion” refers to a disperse system in which one substance, the dispersed phase, is distributed, in discrete units, throughout a second substance (the continuous phase or vehicle). The size of the dispersed phase can vary considerably (e.g., single molecules, colloidal particles of nanometer dimension, to multiplemicrons in size). In general, the dispersed phases can be solids, liquids, or gases. In the case of a solid dispersion, the dispersed and continuous phases are both solids. In pharmaceutical applications, a solid dispersion can include: an amorphous drug in an amorphous polymer; an amorphous drug in crystalline polymer; a crystalline drug in an amorphous polymer; or a crystalline drug in crystalline polymer. In this disclosure, a solid dispersion can include an amorphous drug in an amorphous polymer or an amorphous drug in crystalline polymer. In some embodiments, a solid dispersion includes the polymer constituting the dispersed phase, and the drug constitutes the continuous phase. Or, a solid dispersion includes the drug constituting the dispersed phase, and the polymer constitutes the continuous phase.

[0038] As used herein, the term “solid dispersion” generally refers to a solid dispersion of two or more components. In some embodiments a solid dispersion comprises a single API, (e.g., tezacaftor or ivacaftor). In some embodiments, the solid dispersion comprises two APIs (e.g., tezacaftor and ivacaftor). In some embodiments, the solid dispersion contains a polymer, but possibly containing other components such as surfactants or other pharmaceutical excipients, where the drug(s) (e.g., tezacaftor and / or ivacaftor) is substantially amorphous (e.g., having about 15% or less (e.g., about 10% or less, or about 5% or less)) of crystalline drug or amorphous (i.e., having no crystalline drug), and the physical stability and / or dissolution and / or solubility of the substantially amorphous or amorphous drug is enhanced by the other components. Solid dispersions typically include a compound dispersed in an appropriate carrier medium, such as a solid-state carrier. For example, a carrier comprises a polymer (e.g., a water-soluble polymer or a partially water- soluble polymer) and can include optional excipients such as functional excipients (e.g., one or more surfactants) or nonfunctional excipients (e.g., one or more fdlers). Another exemplary solid dispersion is a co-precipitate or a co-melt of tezacaftor and / or ivacaftor, optionally comprising at least one polymer.

[0039] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this disclosure that, upon administration to a recipient, is capable of providing,either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.

[0040] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.

[0041] Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, edisylate (ethanedisulfonate), ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(CI-4 alkyl)4 salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0042] As used herein, the term “granule” or “oral granule” refers to solid particulate pharmaceutical compositions suitable for administration to patients who have difficulty swallowing large tablets or capsules such as, e.g., pediatric patients. As used herein, “granule” is equivalent to similar terms such as minitablets, sprinkles, pellets, beads,particles, particulates, and troches, a plurality of which can be contained in capsules, pouches, packets, sachets, bottles, or blister packs to provide a unit dosage form.Pharmaceutical Compositions

[0043] A pharmaceutical composition for use in the methods of the disclosure comprises, in addition to elexacaftor, tezacaftor, and ivacaftor or a pharmaceutically acceptable salt of any of the foregoing, one or more of a vehicle, adjuvant, or carrier, such as a filler, a disintegrant, a surfactant, a binder, a lubricant, or combinations thereof.

[0044] Compositions comprising elexacaftor, tezacaftor, and ivacaftor are described in U.S. Patent 11,179,367 and WO 2024 / 031081, each of which is incorporated herein by reference.

[0045] In some embodiments, the pharmaceutical compositions comprise 100 mg of elexacaftor, 50 mg of tezacaftor, and 75 mg of tezacaftor.

[0046] In some embodiments, the pharmaceutical compositions comprise 50 mg of elexacaftor, 25 mg of tezacaftor, and 37.5 mg of tezacaftor.

[0047] In some embodiments, the pharmaceutical compositions are in the form of a plurality of oral granules. In some embodiments, the pharmaceutical compositions are formulated into a unit dosage form comprising a plurality of oral granules.

[0048] In some embodiments, the pharmaceutical compositions are in the form of one or more tablets. In some embodiments, the pharmaceutical compositions are formulated into a unit dosage form comprising one or more tablets.

[0049] In one embodiment, the pharmaceutical compositions used herein comprise: a. about 19.9 percent elexacaftor by weight, b. about 12.43 percent by weight of a first solid dispersion, wherein the first solid dispersion comprises 80 percent amorphous tezacaftor and 20 percent HPMC by weight of the solid dispersion, c. about 18.6 percent by weight of a second solid dispersion, wherein the second solid dispersion comprises 80 percent amorphous ivacaftor, and 19.5 percent HPMC AS and 0.5% percent SLS by weight of the solid dispersion, d. about 5.83 percent croscarmellose sodium by weight, e. about 39.31 percent microcrystalline cellulose by weight, and f. about 0.97 percent magnesium stearate by weight.

[0050] In one embodiment, the pharmaceutical compositions are formulated into a unit dosage form comprising one or more tablets, wherein the unit dosage form comprises: a. about 19.9 percent elexacaftor by weight, b. about 12.43 percent by weight of a first solid dispersion, wherein the first solid dispersion comprises 80 percent amorphous tezacaftor and 20 percent HPMC by weight of the solid dispersion, c. about 18.6 percent by weight of a second solid dispersion, wherein the second solid dispersion comprises 80 percent amorphous ivacaftor, and 19.5 percent HPMC AS and 0.5% percent SLS by weight of the solid dispersion, d. about 5.83 percent croscarmellose sodium by weight, e. about 39.31 percent microcrystalline cellulose by weight, and f. about 0.97 percent magnesium stearate by weight, wherein the unit dosage form comprises 50 mg of elexacaftor, 25 mg of tezacaftor, and 37.5 mg of ivacaftor.

[0051] In one embodiment, the pharmaceutical compositions are formulated into a unit dosage form comprising one or more tablets, wherein the unit dosage form comprises: a. about 19.9 percent elexacaftor by weight, b. about 12.43 percent by weight of a first solid dispersion, wherein the first solid dispersion comprises 80 percent amorphous tezacaftor and 20 percent HPMC by weight of the solid dispersion, c. about 18.6 percent by weight of a second solid dispersion, wherein the second solid dispersion comprises 80 percent amorphous ivacaftor, and 19.5 percent HPMC AS and 0.5% percent SLS by weight of the solid dispersion, d. about 5.83 percent croscarmellose sodium by weight, e. about 39.31 percent microcrystalline cellulose by weight, and f. about 0.97 percent magnesium stearate by weight, wherein the unit dosage form comprises 100 mg of elexacaftor, 50 mg of tezacaftor, and 75 mg of ivacaftor.Methods of Treatment

[0052] In certain embodiments, the methods of the disclosure are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibitresidual CFTR activity in the apical membrane of respiratory and non-respiratory epithelia. The presence of residual CFTR activity at the epithelial surface can be readily detected using methods known in the art, e.g., standard electrophysiological, biochemical, or histochemical techniques. Such methods identify CFTR activity using in vivo or ex vivo electrophysiological techniques, measurement of sweat or salivary CF concentrations, or ex vivo biochemical or histochemical techniques to monitor cell surface density of CFTR protein. Using such methods, residual CFTR activity can be readily detected in patients heterozygous or homozygous for a variety of different mutations, including patients homozygous or heterozygous for the most common mutation, F508del. In certain embodiments, the methods of the disclosure are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit residual CFTR activity. In certain embodiments, the methods of the disclosure are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients who exhibit little to no residual CFTR activity in the apical membrane of respiratory epithelia.

[0053] In certain embodiments, the methods of the disclosure are useful for treating, lessening the severity of, or symptomatically treating cystic fibrosis in patients within certain clinical phenotypes, e.g., a moderate to mild clinical phenotype that typically correlates with the amount of residual CFTR activity in the apical membrane of epithelia. Such phenotypes include patients exhibiting pancreatic sufficiency.

[0054] The exact amount of a pharmaceutical composition(s) comprising elexacaftor, tezacaftor, and ivacaftor required in the methods of the disclosure will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Elexacaftor, tezacaftor, and ivacaftor may be formulated into a unit dosage form for ease of administration and uniformity of dosage. The expression “unit dosage form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of this disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, genetic profile, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specificcompound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0055] Thus, one aspect of the disclosure provides a method of treating or lessening the severity of cystic fibrosis in a patient, comprising administering to the patient an effective amount of elexacaftor or pharmaceutically acceptable salt thereof, an effective amount of tezacaftor or a pharmaceutically acceptable salt thereof, and an effective amount of ivacaftor or a pharmaceutically acceptable salt thereof. Another aspect of the disclosure provides a method of treating cystic fibrosis in a patient, comprising administering to the patient an effective amount of elexacaftor or pharmaceutically acceptable salt thereof an effective amount of tezacaftor or a pharmaceutically acceptable salt thereof, and an effective amount of ivacaftor or a pharmaceutically acceptable salt thereof. Another aspect provides the method of lessening the severity of cystic fibrosis in a patient, comprising the step of administering to the patient an effective amount of elexacaftor or pharmaceutically acceptable salt thereof, an effective amount of tezacaftor or a pharmaceutically acceptable salt thereof, and an effective amount of ivacaftor or a pharmaceutically acceptable salt thereof.

[0056] One aspect of the disclosure provides a method of treating cystic fibrosis by administering elexacaftor, tezacaftor, and ivacaftor in a patient with a mutation selected from 5T;TG12, 5T;TG13, 296+28A^G, 2752-26A^G, 3600G^A, and 3849+4A^G.

[0057] Another aspect of the disclosure provides a method of treating cystic fibrosis by administering elexacaftor, tezacaftor, and ivacaftor in a patient with a mutation selected from 5T;TG12, 5T;TG13, 3600G^A, and 3849+4A^G.

[0058] In one embodiment, the patient is heterozygous for at least one mutation selected from 5T;TG12, 5T;TG13, 296+28A^G, 2752-26A^G, 3600G^A, and 3849+4A^G on one allele and a second CFTR gene mutation on the other allele. In another embodiment, the patient is heterozygous for at least one mutation selected from 5T;TG12, 5T;TG13, 296+28A— >G, 2752-26A^G, 3600G^A, and 3849+4A^G on one allele and a F508del mutation on the other allele. In another embodiment, the patient is heterozygous for at least one mutation selected from 5T;TG12, 5T;TG13, 296+28A^G, 2752-26A^G, 3600G^A, and 3849+4A^G on one allele and a F508del mutation on the other allele.

[0059] In one embodiment, the patient is heterozygous for at least one mutation selected from 5T;TG12, 5T;TG13, 3600G^A, and 3849+4A^G on one allele and a second CFTRgene mutation on the other allele. In another embodiment, the patient is heterozygous for at least one mutation selected from 5T;TG12, 5T;TG13, 3600G^A, and 3849+4A^G on one allele and a F508del mutation on the other allele. In another embodiment, the patient is heterozygous for at least one mutation selected from 5T;TG12, 5T;TG13, 3600G^A, and 3849+4A^G on one allele and a F508del mutation on the other allele.

[0060] In one embodiment, the patient has at least one mutation selected from 5T;TG12, 5T;TG13, 296+28A^G, 2752-26A^G, 3600G^A, and 3849+4A^G and no other CFTR mutation known to be responsive to modulator therapy.

[0061] In some embodiments, the patient has no F508del mutation.

[0062] In some embodiments, the patient has a 5T;TG12 CFTR mutation.

[0063] In some embodiments, the patient has a 5T;TG13 CFTR mutation.

[0064] In some embodiments, the patient has a 296+28 A^G CFTR mutation.

[0065] In some embodiments, the patient has a 2752-26 A— >G CFTR mutation.

[0066] In some embodiments, the patient has a 3600G^A CFTR mutation.

[0067] In some embodiments, the patient has a 3849+4A^G CFTR mutation.

[0068] In certain embodiments, the patient is at least 2 years of age. In some embodiments, the patient is 2 to less than 6 years of age. In some embodiments, the patient is 6 to less than 12 years of age. In some embodiments, the patient is 12 years or older.

[0069] In some embodiments, the patient weighs less than 14 kg. In some embodiments, the patient weighs 14 kg or more. In some embodiments, the patient weighs less than 30 kg. In some embodiments, the patient weighs 30 kg or more.

[0070] One aspect of the disclosure provides a method of treating cystic fibrosis in a patient 2 to less than 6 years of age and weighing less than 14 kg by administering 80 mg of elexacaftor, 40 mg tezacaftor, and 60 mg of ivacaftor, followed about 12 hours later by 59.5 mg of ivacaftor once daily.

[0071] One aspect of the disclosure provides a method of treating cystic fibrosis in a patient 2 to less than 6 years of age and weighing 14 kg or more by administering 100 mg of elexacaftor, 50 mg tezacaftor, and 75 mg of ivacaftor, followed about 12 hours later by 75 mg of ivacaftor once daily.

[0072] One aspect of the disclosure provides a method of treating cystic fibrosis in a patient 6 to less than 12 years of age and weighing less than 30 kg by administering 100 mg of elexacaftor, 50 mg tezacaftor, and 75 mg of ivacaftor, followed about 12 hours later by 75 mg of ivacaftor once daily.

[0073] One aspect of the disclosure provides a method of treating cystic fibrosis in a patient 6 to less than 12 years of age and weighing 30 kg or more by administering 200 mg of elexacaftor, 100 mg tezacaftor, and 150 mg of ivacaftor, followed about 12 hours later by 150 of ivacaftor once daily.

[0074] One aspect of the disclosure provides a method of treating cystic fibrosis in a patient 12 years and older by administering 200 mg of elexacaftor, 100 mg tezacaftor, and 150 mg of ivacaftor, followed about 12 hours later by 150 mg of ivacaftor once daily.

[0075] In some embodiments, the methods of treating cystic fibrosis disclosed herein result in a decrease in patient sweat chloride.

[0076] In some embodiments, the methods of treating cystic fibrosis result in an increase in patient ppFEVi.

[0077] In some embodiments, the methods of treating cystic fibrosis result in an increase in patient lung clearance index.

[0078] In some embodiments, the methods of treating cystic fibrosis result in a reduction in patient pancreatic insufficiency.

[0079] In some embodiments, the methods of treating cystic fibrosis result in an increase in patient Body Mass Index (BMI).

[0080] In some embodiments, the methods of treating cystic fibrosis result in an increase in patient weight.Exemplary EmbodimentsEmbodiment 1 : A method of treating cystic fibrosis in a patient by administering to the patient an effective amount of elexacaftor or a pharmaceutically acceptable salt thereof, tezacaftor or a pharmaceutically acceptable salt thereof, and ivacaftor or a pharmaceutically acceptable salt thereof, wherein the patient has at least one cystic fibrosis transmembrane conductance regulator (CFTR) mutation selected from 5T;TG12, 5T;TG13, 296+28A^G, 2752-26 A^G, 3600G^A, and 3849+4A^G.Embodiment 2: The method according to embodiment 1, wherein the patient has at least one CFTR mutation selected from 5T;TG12, 5T;TG13, 3600G^A, and 3849+4A^G.Embodiment 3: The method according to embodiment 1, wherein the patient has a 5T;TG12 mutation.Embodiment 4: The method according to embodiment 1, wherein the patient has a 5T;TG13 mutation.Embodiment 5: The method according to embodiment 1, wherein the patient has a 296+28 A^G mutation.Embodiment 6: The method according to embodiment 1, wherein the patient has a 2752- 26A^G mutation.Embodiment 7: The method according to embodiment 1, wherein the patient has a 3600G^A mutation.Embodiment 8: The method according to embodiment 1, wherein the patient has a 3849+4A^G mutation.Embodiment 9: The method according to any one of embodiments 1 to 8, wherein the effective amounts are 200 mg of elexacaftor, 100 mg of tezacaftor, and 150 mg of ivacaftor once daily, followed about 12 hours later by 150 mg of ivacaftor.Embodiment 10: The method according to embodiment 9, wherein the 200 mg of elexacaftor, 100 mg of tezacaftor, and 150 mg of ivacaftor are administered as two tablets comprising 100 mg of elexacaftor, 50 mg of tezacaftor, and 75 mg of ivacaftor each.Embodiment 11 : The method according to any one of embodiments 1 to 8, wherein the effective amounts are 100 mg of elexacaftor, 50 mg of tezacaftor, and 75 mg of ivacaftor once daily, followed about 12 hours later by 75 mg of ivacaftor.Embodiment 12: The method according to embodiment 11, wherein the 100 mg of elexacaftor, 50 mg of tezacaftor, and 75 mg of ivacaftor are administered as two tablets comprising 50 mg of elexacaftor, 25 mg of tezacaftor, and 37.5 mg of ivacaftor each.Embodiment 13: The method according to any one of embodiments 1 to 8, wherein the effective amounts are 80 mg of elexacaftor, 40 mg of tezacaftor, and 60 mg of ivacaftor once daily, followed about 12 hours later by 60 mg of ivacaftor once daily.Embodiment 14: The method according to embodiment 13, wherein elexacaftor, tezacaftor, and ivacaftor are administered in the form of oral granules.ExampleExemplary Pharmaceutical CompositionsMethods for preparing elexacaftor are disclosed in WO 2018 / 107100 andWO 2019 / 018395. Methods for preparing tezacaftor are disclosed in WO 2011 / 119984 andWO 2015 / 160787. Methods for preparing ivacaftor are disclosed in WO 2006 / 002421,WO 2007 / 079139, and WO 2013 / 130669. Compositions comprising elexacaftor, tezacaftor, and ivacaftor are described in U.S. Patent 11,179,367 and WO 2024 / 031081, each of which is incorporated herein by reference.

Claims

CLAIMS1. A method of treating cystic fibrosis in a patient by administering to the patient an effective amount of elexacaftor or a pharmaceutically acceptable salt thereof, tezacaftor or a pharmaceutically acceptable salt thereof, and ivacaftor or a pharmaceutically acceptable salt thereof, wherein the patient has at least one cystic fibrosis transmembrane conductance regulator (CFTR) mutation selected from 5T;TG12, 5T;TG13, 296+28A^G, 2752-26A^G, 3600G^A, and 3849+4A^G.

2. The method according to claim 1, wherein the patient has at least one CFTR mutation selected from 5T;TG12, 5T;TG13, 3600G^A, and 3849+4A^G.

3. The method according to claim 1, wherein the patient has a 5T;TG12 mutation.

4. The method according to claim 1, wherein the patient has a 5T;TG13 mutation.

5. The method according to claim 1, wherein the patient has a 296+28 A— >G mutation.

6. The method according to claim 1, wherein the patient has a 2752-26A^G mutation.

7. The method according to claim 1, wherein the patient has a 3600G^A mutation.

8. The method according to claim 1, wherein the patient has a 3849+4A^G mutation.

9. The method according to any one of claims 1 to 8, wherein the effective amounts are 200 mg of elexacaftor, 100 mg of tezacaftor, and 150 mg of ivacaftor once daily, followed about 12 hours later by 150 mg of ivacaftor.

10. The method according to claim 9, wherein the 200 mg of elexacaftor, 100 mg of tezacaftor, and 150 mg of ivacaftor are administered as two tablets comprising 100 mg of elexacaftor, 50 mg of tezacaftor, and 75 mg of ivacaftor each.

11. The method according to any one of claims 1 to 8, wherein the effective amounts are 100 mg of elexacaftor, 50 mg of tezacaftor, and 75 mg of ivacaftor once daily, followed about 12 hours later by 75 mg of ivacaftor.

12. The method according to claim 11, wherein the 100 mg of elexacaftor, 50 mg of tezacaftor, and 75 mg of ivacaftor are administered as two tablets comprising 50 mg of elexacaftor, 25 mg of tezacaftor, and 37.5 mg of ivacaftor each.

13. The method according to any one of claims 1 to 8, wherein the effective amounts are 80 mg of elexacaftor, 40 mg of tezacaftor, and 60 mg of ivacaftor once daily, followed about 12 hours later by 60 mg of ivacaftor once daily.

14. The method according to claim 13, wherein elexacaftor, tezacaftor, and ivacaftor are administered in the form of oral granules.

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