WO2025166342A1 - Combination of vanzacaftor, tezacaftor, deutivacaftor for use in treating cystic fibrosis - Google Patents

Abstract

This application describes methods of treating cystic fibrosis comprising administering vanzacaftor, tezacaftor, and deutivacaftor.

Description

10275-0230-00304 METHODS OF TREATMENT FOR CYSTIC FIBROSIS [0001] This application claims the benefit of U.S. Provisional Application No. 63/549,539, filed on February 4, 2024, the contents of which is incorporated by reference in its entirety. [0002] The present invention relates to methods of treating cystic fibrosis in a patient in need thereof (i.e., suffering from cystic fibrosis) using vanzacaftor, also known as (14S)-8- [3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia- 3,9,11,18,23-pentaazatetracyclo[17.3.1.1^11,14.0^5,10]tetracosa-1(22),5,7,9,19(23),20- hexaene-2,2,4-trione, in combination with tezacaftor, also known as (R)-1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2- methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, and in combination with deutivacaftor, also known as N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl- 1,1,1,3,3,3-d₆)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide. [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 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] 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 10275-0230-00304 phenylalanine at position 508 of the CFTR amino acid sequence and is commonly referred to as the F508del mutation. This mutation occurs in many of the cases of cystic fibrosis and is associated with severe disease. [0006] 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 (ER) 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: 12347-50). In addition to F508del, other disease-causing mutations in CFTR that result in defective trafficking, synthesis, and/or channel gating could be up- or down-regulated to alter anion secretion and modify disease progression and/or severity. [0007] 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 encode 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. [0008] 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 Cl- channels, resulting in a vectorial transport. Arrangement of Na⁺/2Cl-/K⁺ co-transporter, Na⁺-K⁺-ATPase pump and the basolateral membrane K⁺ 10275-0230-00304 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. [0009] A number of CFTR modulating compounds have recently been identified. Vanzacaftor ((14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12- dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.1^11,14.0^5,10]tetracosa- 1(22),5,7,9,19(23),20-hexaene-2,2,4-trione or vanzacaftor) and tezacaftor ((R)-1-(2,2- difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2- methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide) are both potent and selective CFTR correctors for treating mutant forms of human CFTR-mediated diseases, such as cystic fibrosis. Deutivacaftor (N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl- d₃)propan-2-yl-1,1,1,3,3,3-d₆)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide) is a potent and selective CFTR potentiator of wild-type and mutant forms of human CFTR and is useful in treating cystic fibrosis. [0010] TRIKAFTA, approved by the U.S. Food and Drug Administration (FDA) in 2019, is the current standard of care for the treatment of cystic fibrosis in patients aged at least 2 years who have at least one F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive based on in vitro data. TRIKAFTA is administered as a morning dose of elexacaftor/tezacaftor/ivacaftor and an evening dose of ivacaftor. KAFTRIO, approved by the European Medicines Agency (EMA) in 2020, is administered in the morning as elexacaftor/tezacaftor/ivacaftor, followed by evening administration of KALYDECO (ivacaftor). [0011] However, methods of providing statistically significant and clinically meaningful improvements in CFTR function in cystic fibrosis patients are still needed. Phase 3 data for TRIKAFTA supports a potential “ceiling effect” for improvement in ppFEV1, as demonstrated by the fact that CF participants with two responsive CFTR variants did not have greater improvements in ppFEV1 than CF participants with only one responsive CFTR variant, despite having greater improvements in CFTR function, as reflected in a larger drop in sweat chloride concentration. See: Edith T. Zemanick et al., Sweat chloride reflects CFTR function and correlates with clinical outcomes following CFTR modulator treatment, J. Cyst. Fibr., In Press; DOI:10.1016/j.jcf.2024.12.006. PpFEV1 is the percentage predicted forced expiratory volume in one second (a measure of 10275-0230-00304 lung function), and is the commonly used metric for patient CFTR function and level of clinical improvement. This lack of greater improvement in ppFEV1 highlights the need for more sensitive clinical measures that better reflect improvement in the underlying causal disease biology in CF to differentiate levels of efficacy as new CFTR modulators are developed. Patient sweat chloride levels provide such a metric, and lower sweat chloride levels may be associated with improved clinical outcomes. Specifically, CFTR modulators provide clinical benefit by restoring CFTR function towards normal, e.g., to patient sweat chloride levels of <60 mmol/L (below the diagnostic threshold for CF) and <30 mmol/L (normal levels). Thus, one aspect of the invention provides methods of treating cystic fibrosis in a patient aged at least 12 years for a duration sufficient to reduce sweat chloride levels in the patient to less than about 60 mmol/L. In some embodiments, the invention provides methods of treating cystic fibrosis in a patient aged at least 12 years for a duration sufficient to reduce sweat chloride levels in the patient to about 30 mmol/L or less. [0012] One aspect of the invention provides methods of treating cystic fibrosis in patients aged at least 12 years for a duration sufficient reduce sweat chloride levels below a threshold of 60 mmol/L in a proportion of the patients. In some embodiments, the proportion of patients aged at least 12 years that reach a reduced sweat chloride level below a threshold of 60 mmol/L is about 86%. In some embodiments, the invention provides methods of treating cystic fibrosis in patients aged at least 12 years for a duration sufficient to reduce sweat chloride levels to a threshold of 30 mmol/L or below in a proportion of the patients. In some embodiments, the proportion of patients aged at least 12 years that reach a reduced sweat chloride level to a threshold of 30 mmol/L or below is about 31%. [0013] In some embodiments, the cystic fibrosis patient aged at least 12 years has a CFTR genotype selected from F508del/F508del, F508del/residual function mutation, F508del/gating mutation, and elexacaftor/tezacaftor/ivacaftor-responsive mutation/non- F508del. In some embodiments, the cystic fibrosis patient aged at least 12 years has a CFTR genotype of F508del/minimal function mutation. [0014] Another aspect of the invention provides methods of treating cystic fibrosis in a patient aged 6 to less than 12 years for a duration sufficient to reduce sweat chloride levels in the patient to less than about 60 mmol/L. In some embodiments, the invention provides 10275-0230-00304 methods of treating cystic fibrosis in a patient aged 6 to less than 12 years for a duration sufficient to reduce sweat chloride levels in the patient to about 30 mmol/L or less. [0015] Yet another aspect of the invention provides methods of treating cystic fibrosis in patients aged 6 to less than 12 years for a duration sufficient to reduce sweat chloride levels below a threshold of 60 mmol/L in a proportion of the patients. In some embodiments, the proportion of patients aged 6 to less than 12 years that reach a reduced sweat chloride level below a threshold of 60 mmol/L is about 95%. In some embodiments, the invention provides methods of treating cystic fibrosis in patients aged 6 to less than 12 years for a duration sufficient to reduce sweat chloride levels to a threshold of 30 mmol/L or below in a proportion of the patients. In some embodiments, the proportion of patients aged 6 to less than 12 years that reach a reduced sweat chloride level to a threshold of 30 mmol/L or below is about 53%. [0016] In some embodiments, the cystic fibrosis patient aged 6 to less than 12 years has a CFTR genotype of F508del/minimal function mutation. In some embodiments, the cystic fibrosis patient aged 6 to less than 12 years has a cystic fibrosis genotype with at least one elexacaftor/tezacaftor/ivacaftor-responsive mutation. Brief Description of the Figures [0017] FIG.1 shows mean absolute change in subject sweat chloride levels over a 52- week period for patients aged at least 12 years with a CFTR F508del/minimal function mutation genotype receiving either elexacaftor/tezacaftor/ivacaftor or vanzacaftor/tezacaftor/deutivacaftor. Baseline was determined after a 4-week run-in period during which both groups received daily administration of elexacaftor/tezacaftor/ivacaftor. [0018] FIG.2 shows mean absolute change in subject sweat chloride levels over a 52- week period for patients aged at least 12 years with a CFTR genotype selected from F508del/F508del, F508del/residual function mutation, F508del/gating mutation, and elexacaftor/tezacaftor/ ivacaftor-responsive mutation/no F508del genotype receiving either elexacaftor/tezacaftor/ivacaftor or vanzacaftor/tezacaftor/deutivacaftor. Baseline was determined after a 4-week run-in period during which both patient groups received daily administration of elexacaftor/tezacaftor/ivacaftor. [0019] FIG.3 shows mean absolute change in subject sweat chloride levels over a 24- week period of treatment with vanzacaftor/tezacaftor/deutivacaftor in patients aged 6 to less than 12 years with cystic fibrosis having at least one elexacaftor/tezacaftor/ivacaftor- 10275-0230-00304 responsive mutation. Baseline was determined after a 4-week run-in period during which the patient group received daily administration of elexacaftor/tezacaftor/ivacaftor. Definitions [0020] As used herein, the term “active pharmaceutical ingredient” or “API” refers to a biologically active compound. APIs employed in the pharmaceutical compositions of the invention include two CF corrector compounds, (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7- yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo [17.3.1.1^11,14.0^5,10]tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione (vanzacaftor) and (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1- hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (tezacaftor), and a CF potentiator, N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d₃)propan-2-yl-1,1,1,3,3,3- d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (deutivacaftor). Vanzacaftor [0021] As used herein, the term “vanzacaftor” is used interchangeably with VNZ and (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H-pyrazol-1-yl]-12,12-dimethyl-2λ⁶- thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1^11,14.0^5,10]tetracosa-1(22),5,7,9,19(23),20- hexaene-2,2,4-trione, which has the following structure: . [0022] 2019/161078, WO 2020/102346, WO 2021/030554, WO 2021/030552, WO 2022/036060, WO 2022/125826, all of which are incorporated herein by reference. These publications also describe methods of making vanzacaftor and demonstrate that vanzacaftor is a CFTR corrector therapeutic. WO 2021/030552 also describes methods of making vanzacaftor crystalline calcium salt hydrate Form D. [0023] In some embodiments, vanzacaftor is a crystalline solid in the form of calcium salt hydrate Form D. In some embodiments, vanzacaftor calcium salt hydrate Form D is characterized by an X-ray powder diffractogram having signals at 6.1 ± 0.2 degrees two- theta, 16.2 ± 0.2 degrees two-theta, and 22.8 ± 0.2 degrees two-theta. In some 10275-0230-00304 embodiments, vanzacaftor calcium salt hydrate Form D is characterized by an X-ray powder diffractogram having signals at 6.1 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, and 22.8 ± 0.2 degrees two-theta, and 27.6 ± 0.2 degrees two-theta. In some embodiments, vanzacaftor calcium salt hydrate Form D is characterized by an X-ray powder diffractogram having signals at 6.1 ± 0.2 degrees two-theta, 15.5 ± 0.2 degrees two-theta, 16.2 ± 0.2 degrees two-theta, 19.7 ± 0.2 degrees two-theta, 22.8 ± 0.2 degrees two-theta, and 27.6 ± 0.2 degrees two-theta. [0024] In some embodiments, vanzacaftor calcium salt hydrate Form D is characterized as having a ¹³C solid state nuclear magnetic resonance (¹³C ssNMR) spectrum with one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) peaks selected from: 179.8 ± 0.2 ppm, 130.2 ± 0.2 ppm, 125.6 ± 0.2 ppm, 120.9 ± 0.2 ppm, 55.2 ± 0.2 ppm, 44.3 ± 0.2 ppm, 35.0 ± 0.2 ppm, and 1.6 ± 0.2 ppm. [0025] In some embodiments, vanzacaftor calcium salt hydrate Form D is characterized by a triclinic crystal system, a P1 space group, and the following unit cell dimensions measured at by 100 K on a Bruker diffractometer equipped with Cu K_α radiation (λ=1.5478 Å) and a Complementary metal-oxide-semiconductor (CMOS) detector: a 12.78 ± .01 Å α 64.93 ± .02 º b 16.64 ± .01 Å β 75.10 ± .02 º c 18.19 ± .01 Å γ 68.22 ± .02 º. [0026] One of ordinary skill in the art would recognize that the mass of a pharmaceutically acceptable salt form of a compound includes the mass of the compound alone (i.e., the mass of the free base form of the compound) plus the mass of the salt co- former(s). For example, 21.24 mg of vanzacaftor calcium salt hydrate Form D contains 20 mg of vanzacaftor. Similarly, 12.74 mg of vanzacaftor calcium salt hydrate Form D contains 12 mg of vanzacaftor; 10.6 mg of vanzacaftor calcium salt hydrate Form D contains 10 mg of vanzacaftor; and 4.24 mg of vanzacaftor calcium salt hydrate Form D contains 4 mg of vanzacaftor. Tezacaftor [0027] As used herein, the term “tezacaftor” is used interchangeably with TEZ and (R)- 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1- hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. Tezacaftor has the following structure: 10275-0230-00304 H O N F OH . Tezacaftor has been Publication US 2009/0131492, and WO 2015/160787, all of which are incorporated herein by reference. Deutivacaftor [0028] As used herein, the term “deutivacaftor” is used interchangeably with D-IVA and N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4- oxo-1,4-dihydroquinoline-3-carboxamide. Deutivacaftor has the following structure: . Deutivacaftor has been Nos. WO 2012/158885, WO 2017/053455, WO 2017/053711, WO 2018/080591, and WO 2019/109021, all of which are incorporated herein by reference. [0029] “Elexacaftor” or “ELX” as used herein, refers to N-(1,3-dimethylpyrazol-4- yl)sulfonyl-6-[3-(3,3,3-trifluoro-2,2-dimethyl-propoxy)pyrazol-1-yl]-2-[(4S)-2,2,4- trimethylpyrrolidin-1-yl]pyridine-3-carboxamide, which is depicted by the chemical structure: . Elexacaftor and in WO 2018/107100 and WO 2019/113476, each incorporated herein by reference. 10275-0230-00304 [0030] “Ivacaftor” or “IVA” as used throughout this disclosure refers to N-(5-hydroxy- 2,4-di-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide, which has the following structure: OH O O . Ivacaftor and methods of disclosed in WO 2006/002421, WO 2007/079139, WO 2010/108162, and WO 2010/019239, each incorporated herein by reference. [0031] 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 certain embodiments, the terms “about” and “approximately” mean within 1, 2, 3, or 4 standard deviations. In some embodiments, the terms “about” and “approximately” mean within 1 standard deviation. In some embodiments, the terms “about” and “approximately” mean within 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of a given value or range. In some embodiments, the terms “about” and “approximately” mean within 5% of a given value or range. In some embodiments, the terms “about” and “approximately” mean within 2% of a given value or range. As used herein, the symbol “~” appearing immediately before a numerical value has the same meaning as the “about” and “approximately.” [0032] As used herein, “CFTR” or “CFTR protein” stands for cystic fibrosis transmembrane conductance regulator protein. [0033] As used herein, the term “modulator” refers to a compound that increases the activity of a biological compound such as a protein. For example, a CFTR modulator is a compound that 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. [0034] 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 that augments or induces the channel activity of CFTR protein located at the cell surface, 10275-0230-00304 resulting in increased functional activity). Deutivacaftor and ivacaftor are CFTR potentiators. [0035] 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. Vanzacaftor, tezacaftor, and elexacaftor are CFTR correctors. [0036] The term “patient” refers to a human suffering from cystic fibrosis aged either 12 years or older or at least 6 years up to less than 12 years. [0037] 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, or a frame shift(s). [0038] The term “F508del” refers to a mutant CFTR protein which is lacking the amino acid phenylalanine at position 508. [0039] As used herein, “residual function mutations” refers to CFTR gene mutations associated with some remaining CFTR function. Some CFTR mutations reduce CFTR protein quantity or function to such an extent that there is little to no total CFTR activity. Other mutations result only in reduced protein quantity or function at the cell surface which can produce partial CFTR activity. These mutations are called residual function mutations. For example, some CFTR mutations that cause defective mRNA splicing, such as 2789+5G^A and E831X, result in reduced protein synthesis, but deliver some functional CFTR to the surface of the cell to provide residual function. Other CFTR mutations that reduce conductance and/or gating, such as R117H, result in a normal quantity of CFTR channels at the surface of the cell, but the functional level is low, resulting in residual function. Some mutations, such as F508del, result in multiple CFTR protein defects. Both CFTR alleles play a role in determining phenotype of disease severity. Common residual function mutations include E56K, P67L, R74W, D110E, D110H, R117C, R117H, G178R, E193K, L206W, R347H, R352Q, A455E, S549N, S549R, G551D, G551S, D579G, 711+3A^G, E831X, S945L, S977F, F1052V, K1060T, A1067T, R1070W, F1074L, D1152H, G1244E, S1251N, S1255P, D1270N, G1349D, 2789+5G^A, 3272-26A^G, and 3849+10kbC^T. Patients with residual function mutations may experience the symptoms of CFTR-mediated diseases later in life and 10275-0230-00304 symptoms may be less severe than in patients with other mutations. Patients with CFTR residual function mutations tend to have higher rates of pancreatic sufficiency, less elevated sweat chloride levels, and less severe pulmonary disease than patients with other mutations. However, patients with a residual function mutation generally have progressive lung function decline and other complications of CF that may still lead to a severe disease stage and cause premature death. [0040] As used herein, “gating mutations,” also known as “defective channel gating mutations,” refers to mutations associated with with severe defects in ability of the CFTR channel to open and close. [0041] As used herein, “minimal function mutations” refers to CFTR gene mutations associated with minimal CFTR function (little-to-no functioning CFTR protein) and include gating mutations; mutations associated with severe defects in the cellular processing of CFTR and its delivery to the cell surface; mutations associated with no (or minimal) CFTR synthesis; and mutations associated with severe defects in channel conductance. [0042] The terms “elexacaftor/tezacaftor/ivacaftor-responsive-mutation” or “ELX/TEZ/IVA-responsive” are used interchangeably with “mutation responsive to elexacaftor/tezacaftor/ivacaftor” and refers to CFTR mutations that respond to treatment with elexacaftor/tezacaftor/ivacaftor based on in vitro data. In one embodiment, the in vitro data is measured in Fischer rat thyroid (FRT) cells. [0043] As used herein, a patient who is “homozygous” for a particular gene mutation has the same mutation on each allele. [0044] As used herein, a patient who is “heterozygous” for a particular gene mutation has the particular mutation on one allele and a different mutation on the other allele. [0045] The term “F508del/F508del” refers to a CFTR genotype wherein the patient is homozygous for the F508del mutation. The term “F508del/residual function mutation” refers to a CFTR genotype wherein the patient is heterozygous, having an F508del mutation on one allele and a residual function mutation on the other allele. The term “F508del/gating mutation” refers to a CFTR genotype wherein the patient is heterozygous, having an F508del mutation on one allele and a gating mutation on the other allele. The term “F508del/residual function mutation” refers to a CFTR genotype wherein the patient is heterozygous, having an F508del mutation on one allele and a minimal function mutation on the other allele. The term “elexacaftor/tezacaftor/ivacaftor-responsive 10275-0230-00304 mutation/no F508del” refers to a CFTR genotype wherein the patient has at least one mutation responsive to elexacaftor/tezacaftor/ivacaftor on one allele and no F508del mutation on the other allele. [0046] 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 one or more of the symptoms of CF in a subject. “Treatment,” as used herein, includes, but is not limited to, the following: reduced sweat chloride levels, increased growth of the subject, increased weight gain, reduction of mucus in the lungs, improved pancreatic and/or liver function, reduction of chest infections, 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. [0047] 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, concurrently with, or subsequent to each other. [0048] As used herein, the terms “sweat chloride” and “SwCl” are used interchangeably and refer to the amount of chloride anion present 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., J. Pediatr.2007, 151(1):85-9; Farrell PM et al. J. Pediatr.2017, 181S:S4-S15.e1. [0049] As used herein, the term “baseline” refers to SwCl levels in a patient who has received treatment with elexacaftor/tezacaftor/ivacaftor prior to treatment with vanzacaftor/tezacaftor/deutivacaftor. In some embodiments “baseline” refers to SwCl levels in a patient who has received treatment with elexacaftor/tezacaftor/ivacaftor for at least 4 weeks prior to treatment with vanzacaftor/tezacaftor/deutivacaftor. [0050] 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 10275-0230-00304 are generally isotropic, i.e., exhibit similar properties in all directions and do not have definite melting points. [0051] In some embodiments, a solid material may comprise a mixture of crystalline solids and amorphous solids. The term “substantially amorphous” refers to a solid material having less than about 15% crystallinity (e.g., less than about 10% crystallinity or less than about 5% crystallinity). It is also noted that the term “substantially amorphous” includes the descriptor “amorphous,” which refers to materials having no (0%) crystallinity. In embodiments wherein the solid material contains a mixture of crystalline solids and amorphous solids, the characterizing data, such as XRPD, may contain indicators of both crystalline and amorphous solids. [0052] 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 multiple microns 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 this invention, 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 drug constituting the dispersed phase, and the polymer constitutes the continuous phase. [0053] 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 deutivacaftor). In some embodiments, the solid dispersion comprises two APIs (e.g., tezacaftor and deutivacaftor). 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 deutivacaftor) 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 10275-0230-00304 excipients (e.g., one or more surfactants) or nonfunctional excipients (e.g., one or more fillers). Another exemplary solid dispersion is a spray-dried dispersion, co-precipitate, or a co-melt of tezacaftor and/or deutivacaftor, optionally comprising at least one polymer. [0054] As used herein, “crystalline solid” refers to a solid material with a high degree of structural order (i.e., long-range order in the position of its molecules). A “substantially crystalline” material has less than about 15% amorphous solid, i.e., its solid-state structure is at least about 85% crystalline. In another example, a fully crystalline solid has zero (0%) amorphous material. In embodiments wherein the solid material contains a mixture of crystalline solids and amorphous solids, the characterizing data, such as XRPD, may contain indicators of both crystalline and amorphous solids. [0055] As used herein, the terms “X-ray powder diffractogram,” “X-ray powder diffraction pattern,” “XRPD pattern,” “XRPD spectrum” interchangeably refer to an experimentally obtained pattern plotting signal positions (on the abscissa) versus signal intensities (on the ordinate). For an amorphous material, an X-ray powder diffractogram may include one or more broad signals; and for a crystalline material, an X-ray powder diffractogram may include one or more signals, each identified by its angular value as measured in degrees 2^ (° 2^), depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as “a signal at … degrees two-theta,” “a signal at [a] two-theta value(s)of …” and/or “a signal at at least … two-theta value(s) selected from ….” [0056] A “signal” or “peak” as used herein refers to a point in an XRPD pattern where the intensity as measured in counts is at a local maximum. One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement. The repeatability of the measured angular values is in the range of ±0.2° 2^, i.e., the angular value can be at the recited angular value +0.2 degrees two-theta, the angular value -0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta). Detailed Description [0057] The present invention relates to methods of treating cystic fibrosis using vanzacaftor, also known as (14S)-8-[3-(2-{dispiro[2.0.2.1]heptan-7-yl}ethoxy)-1H- pyrazol-1-yl]-12,12-dimethyl-2λ⁶-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.1^11,14.0^5,10] 10275-0230-00304 tetracosa-1(22),5,7,9,19(23),20-hexaene-2,2,4-trione, in combination with tezacaftor, also known as (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6- fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide, and in combination with deutivacaftor, also known as N-(2-(tert-butyl)-5-hydroxy-4-(2- (methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3- carboxamide. [0058] One aspect of the invention provides methods of treating cystic fibrosis for a duration sufficient to reduce sweat chloride levels in the patient. [0059] One aspect of the invention provides methods of treating cystic fibrosis for a duration sufficient to reduce sweat chloride levels below a threshold in a proportion of the patients. In some embodiments, the threshold is less than 60 mmol/L. In some embodiments, the threshold is less than 30 mmol/L. [0060] One aspect of the invention provides methods of treating cystic fibrosis comprising administering about 20 mg of vanzacaftor, about 100 mg of tezacaftor, and about 250 mg of deutivacaftor. In some embodiments, vanzacaftor is in a crystalline solid the form of calcium salt hydrate form D. In some embodiments, tezacaftor is in amorphous or substantially amorphous form and is administered in a solid dispersion. In some embodiments, deutivacaftor is in amorphous or substantially amorphous form and is administered in a solid dispersion. In some embodiments, vanzacaftor, tezacaftor, and deutivacaftor are administered in a single pharmaceutical composition. [0061] In some embodiments, the patient is heterozygous and has an F508del mutation on one allele and a mutation on the other allele selected from Table 1: Table 1. CFTR mutations Mutation Q2X L218X Q525X R792X E1104X S4X Q220X G542X E822X W1145X W19X Y275X G550X W882X R1158X G27X C276X Q552X W846X R1162X Q39X Q290X R553X Y849X S1196X W57X G330X E585X R851X W1204X E60X W401X G673X Q890X L1254X R75X Q414X Q685X S912X S1255X 10275-0230-00304 Mutation L88X S434X R709X Y913X W1282X E92X S466X K710X Q1042X Q1313X Q98X S489X Q715X W1089X Q1330X Y122X Q493X L732X Y1092X E1371X E193X W496X R764X W1098X Q1382X W216X C524X R785X R1102X Q1411X 185+1G→T 711+5G→A 1717-8G→A 2622+1G→A 3121-1G→A 405+1G→A 1249-1G→A 1811+1.6kbA→G (G970R) 3850-1G→A 405+3A→C 1341+1G→A 1811+1643G→T 3120G→A 4005+1G→A 406-1G→A 1525-2A→G 1812-1G→A 3120+1G→A 4374+1G→T 621+1G→T 1525-1G→A 1898+1G→A 3121-2A→G 711+1G→T 1898+1G→C 306delTAGA 1138insG 1824delA 2869insG 3821delT 365-366insT 1154insTC 1833delT 2896insAG 3876delA 394delTT 1161delC 2043delG 2942insT 3878delG 442delA 1213delT 2143delT 2957delT 3905insT 444delA 1259insA 2183AA→G 3007delG 4016insT 457TAT→G 1288insTA 2184delA 3028delA 4021dupT 541delC 1343delG 2184insA 3171delC 4022insT 574delA 1471delA 2307insA 3171insC 4040delA 663delT 1497delGG 2347delG 3271delGG 4279insA 849delG 1548delG 2585delT 3349insT 4326delTC 935delA 1609del CA 2594delGT 3659delC CFTRdele1 CFTRdele16-17b 1461ins4 CFTRdele2 CFTRdele17a,17b 1924del7 CFTRdele2,3 CFTRdele17a-18 2055del9→A CFTRdele2-4 CFTRdele19 2105-2117del13insAGAAA 10275-0230-00304 Mutation CFTRdele3-10,14b-16 CFTRdele19-21 2372del8 CFTRdele4-7 CFTRdele21 2721del11 CFTRdele4-11 CFTRdele22-24 2991del32 CFTR50kbdel CFTRdele22,23 3667ins4 CFTRdup6b-10 124del23bp 4010del4 CFTRdele11 602del14 4209TGTT→AA CFTRdele13,14a 852del22 CFTRdele14b-17b 991del5 A46D V520F Y569D N1303K G85E A559T L1065P R347P R560T R1066C L467P R560S L1077P I507del A561E M1101K [0062] In some embodiments, the patient is heterozygous and has an F508del mutation on one allele and a mutation on the other allele selected from Table 2. Table 2. CFTR mutations 711+3A>G L206W K1060T 2789+5G>A R347H A1067T 3272-26A>G R352Q G1069R 3849+10kbC>T A455E R1070Q E56K S549N R1070W P67L S549R F1074L R74W G551D D1152H D110E G551S G1244E D110H D579G S1251N R117C E831X S1255P R117H S945L D1270N G178R S977F G1349D E193K F1052V 10275-0230-00304 [0063] In some embodiments, the patient has at least one mutation selected from Table 3 (see Example 4). In some embodiments, the patient has no F508del mutation and at least one mutation selected from Table 3. Table 3. CFTR mutations 3141del9 E822K G1244E 546insCTA F191V G1249R A46D F311del G1349D A120T F311L H139R A234D F508C H199Y A349V F508C;S1251N ^† H939R A455E F575Y H1054D A554E F1016S H1085P A1006E F1052V H1085R A1067T F1074L H1375P D110E F1099L I148T D110H G27R I175V D192G G85E I336K D443Y G126D I502T D443Y;G576A;R668C ^† G178E I601F D579G G178R I618T D614G G194R I807M D836Y G194V I980K D924N G314E I1027T D979V G463V I1139V D1152H G480C I1269N D1270N G551D I1366N E56K G551S K1060T E60K G576A L15P E92K G576A;R668C ^† L165S E116K G622D L206W E193K G628R L320V E403D G970D L346P 10275-0230-00304 E474K G1061R L453S E588V G1069R L967S L997F R117P S945L L1077P R170H S977F L1324P R258G S1159F L1335P R334L S1159P L1480P R334Q S1251N M152V R347H S1255P M265R R347L T338I M952I R347P T1036N M952T R352Q T1053I M1101K R352W V201M P5L R553Q V232D P67L R668C V456A P205S R751L V456F P574H R792G V562I Q98R R933G V754M Q237E R1066H V1153E Q237H R1070Q V1240G Q359R R1070W V1293G Q1291R R1162L W361R R31L R1283M W1098C R74Q R1283S W1282R R74W S13F Y109N R74W;D1270N ^† S341P Y161D R74W;V201M ^† S364P Y161S R74W;V201M;D1270N ^† S492F Y563N R75Q S549N Y1014C R117C S549R Y1032C R117G S589N R117H S737F R117L S912L 10275-0230-00304 † Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele. [0064] In some embodiments, the patient has at least one mutation selected from Table 4 (see Example 5). Table 4. CFTR mutations 3141del9 E822K G1069R L967S R117L S912L 546insCTA F191V G1244E L997F R117P S945L A46D F311del G1249R L1077P R170H S977F A120T F311L G1349D L1324P R258G S1159F A234D F508C H139R L1335P R334L S1159P F508C;S1251 A349V H199Y L1480P R334Q S1251N N ^† A455E F508del ^* H939R M152V R347H S1255P A554E F575Y H1054D M265R R347L T338I A1006E F1016S H1085P M952I R347P T1036N A1067T F1052V H1085R M952T R352Q T1053I D110E F1074L H1375P M1101K R352W V201M D110H F1099L I148T P5L R553Q V232D D192G G27R I175V P67L R668C V456A D443Y G85E I336K P205S R751L V456F D443Y;G57 † G126D I502T P574H R792G V562I 6A;R668C D579G G178E I601F Q98R R933G V754M D614G G178R I618T Q237E R1066H V1153E D836Y G194R I807M Q237H R1070Q V1240G D924N G194V I980K Q359R R1070W V1293G D979V G314E I1027T Q1291R R1162L W361R D1152H G463V I1139V R31L R1283M W1098C D1270N G480C I1269N R74Q R1283S W1282R E56K G551D I1366N R74W S13F Y109N 10275-0230-00304 R74W;D1 E60K G551S K1060T ^† S341P Y161D 270N R74W;V2 E92K G576A L15P S364P Y161S 01M ^† R74W;V2 G576A;R668C E116K ^† L165S 01M;D12 S492F Y563N 70N ^† E193K G622D L206W R75Q S549N Y1014C E403D G628R L320V R117C S549R Y1032C E474K G970D L346P R117G S589N E588V G1061R L453S R117H S737F * F508del is a responsive CFTR mutation based on both clinical and in vitro data † Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele. [0065] In some embodiments, the patient is aged at least 12 years. In some embodiments, the patient is aged 6 to less than 12 years. [0066] In some embodiments, the methods of treatment disclosed herein comprise administering vanzacaftor, tezacaftor, and deutivacaftor to the patient once daily. In some embodiments, the methods of treatment disclosed herein comprise administering 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor once daily to the patient aged at least 12 years. In some embodiments, the methods disclosed herein comprise daily administration of vanzacaftor, tezacaftor, and deutivacaftor (e.g., a daily dose of 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor) to patients in need thereof aged at least 12 years for a duration sufficient to result in about 86% of said patients with sweat chloride levels of <60 mmol/L. [0067] In some embodiments, the methods disclosed herein comprise daily administration of vanzacaftor, tezacaftor, and deutivacaftor (e.g., a daily dose of 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor) to a patient in need thereof aged at least 12 years for a duration sufficient to result in about 31% of said patients with sweat chloride levels of less than 30 mmol/L. 10275-0230-00304 [0068] In some embodiments, the methods of treatment disclosed herein comprise administering 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor to the patient aged at least 12 years once daily for at least 16 to 24 weeks. In some embodiments, the methods of treatment disclosed herein comprise administering 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor to the patient aged at least 12 years once daily for at least 24 to 52 weeks. In some embodiments, the methods of treatment disclosed herein comprise administering 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor to the patient aged at least 12 years once daily for at least 16 weeks. In some embodiments, the methods of treatment disclosed herein comprise administering 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor to the patient aged at least 12 years once daily for at least 24 weeks. In some embodiments, the methods of treatment disclosed herein comprise administering 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor to the patient aged at least 12 years once daily for at least 36 weeks. In some embodiments, the methods of treatment disclosed herein comprise administering 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor to the patient aged at least 12 years once daily for at least 52 weeks. [0069] In some embodiments, patient sweat chloride levels through week 24 are determined as an average of the patient’s sweat chloride levels at week 16 and week 24. In some embodiments, patient sweat chloride levels through week 52 are determined as an average of the patient’s sweat chloride levels at weeks 16, 24, 36, and 52. [0070] In some embodiments, the patient has received treatment for cystic fibrosis using elexacaftor/tezacaftor/ivacaftor prior to treatment with vanzacaftor/tezacaftor/deutivacaftor. In some embodiments, the patient has received treatment using elexacaftor/tezacaftor/ivacaftor for at least 4 weeks prior to treatment according to treatment with vanzacaftor/tezacaftor/deutivacaftor. [0071] In some embodiments, the methods disclosed herein comprise daily administration of vanzacaftor/tezacaftor/deutivacaftor (e.g., a daily dose of 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor for patients weighing 40 kg or more or a daily dose of 12 mg of vanzacaftor, 60 mg of tezacaftor, and 150 mg of deutivacaftor for patients weighing less than 40 kg) to a patient in need thereof aged 6 to less than 12 years for a duration sufficient to result in about 95% of said patients with sweat chloride levels of <60 mmol/L. 10275-0230-00304 [0072] In some embodiments, the methods disclosed herein comprise daily administration of vanzacaftor/tezacaftor/deutivacaftor (e.g., a daily dose of 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor for patients weighing 40 kg or more or a daily dose of 12 mg of vanzacaftor, 60 mg of tezacaftor, and 150 mg of deutivacaftor for patients weighing less than 40 kg) to a patient in need thereof aged 6 to less than 12 years for a duration sufficient to result in about 53% of said patients with sweat chloride levels of <30 mmol/L. [0073] In some embodiments, the methods disclosed herein comprise daily administration of vanzacaftor, tezacaftor, and deutivacaftor (e.g., a daily dose of 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor) to a patient in need thereof aged at least 12 years having a CFTR genotype of F508del/minimal function mutation for a duration sufficient to result in an absolute mean change in sweat chloride of about -7.5 mmol/L from baseline. [0074] In some embodiments, the methods disclosed herein comprise daily administration of vanzacaftor, tezacaftor, and deutivacaftor (e.g., a daily dose of 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor) to a patient in need thereof aged at least 12 years having a CFTR genotype selected from F508del/F508del, F508del/residual function mutation, F508del/gating mutation, elexacaftor/tezacaftor/ivacaftor-responsive mutation/non-F508del for a duration sufficient to result in an absolute mean change in sweat chloride of about -5.1 mmol/L from baseline. [0075] In some embodiments, the methods disclosed herein comprise daily administration of vanzacaftor/tezacaftor/deutivacaftor (e.g., a daily dose of 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor for patients weighing 40 kg or more or a daily dose of 12 mg of vanzacaftor, 60 mg of tezacaftor, and 150 mg of deutivacaftor for patients weighing less than 40 kg) to a patient in need thereof aged 6 to less than 12 years having a CFTR genotype with at least one elexacaftor/tezacaftor/ivacaftor responsive mutation for a duration sufficient to result in an absolute mean change in sweat chloride of about -8.6 mmol/L from baseline. [0076] 10275-0230-00304 Pharmaceutical Compositions [0077] Another aspect of this disclosure provides pharmaceutical compositions comprising vanzacaftor, tezacaftor, and/or deutivacaftor. In some aspects of the invention, vanzacaftor, tezacaftor, and deutivacaftor are administered as a single pharmaceutical composition. Exemplary pharmaceutical compositions comprising vanzacaftor/tezacaftor/deutivacaftor are disclosed in, for example, WO 2020/102346 and WO 2022/125826. In other aspects of the invention, vanzacaftor, tezacaftor, and deutivacaftor are administered as two or more separate pharmaceutical compositions. Exemplary compositions comprising each of these APIs are known in the art. [0078] In some embodiments, the pharmaceutical compositions are formulated for administration of the daily dose (for patients aged at least 12 years in need thereof) in a single composition comprising 20 mg of vanzacaftor, 100 mg of tezacaftor, and 250 mg of deutivacaftor. In some embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged at least 12 years in need thereof) in two compositions, each comprising 10 mg of vanzacaftor, 50 mg of tezacaftor, and 125 mg of deutivacaftor. [0079] In some embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged 6 to less than 12 years in need thereof and weighing less than 40 kg) in a single composition comprising 12 mg of vanzacaftor, 60 mg of tezacaftor, and 150 mg of deutivacaftor. In some embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged 6 to less than 12 years in need thereof and weighing less than 40 kg) in three compositions, each comprising 4 mg of vanzacaftor, 20 mg of tezacaftor, and 50 mg of deutivacaftor. [0080] In some embodiments, the vanzacaftor in the pharmaceutical compositions comprise the crystalline vanzacaftor calcium salt hydrate Form D. In some embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged at least 12 years in need thereof) in a single composition comprising about 21 to about 22 mg of vanzacaftor calcium salt hydrate Form D, 100 mg of tezacaftor, and 250 mg of deutivacaftor. In some embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged at least 12 years in need thereof) in a single composition comprising about 21.24 mg of vanzacaftor calcium salt hydrate Form D, 100 mg of tezacaftor, and 250 mg of deutivacaftor. In some 10275-0230-00304 embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged at least 12 years in need thereof) in two compositions, each comprising about 10 to about 11 mg of vanzacaftor calcium salt hydrate Form D, 50 mg of tezacaftor, and 125 mg of deutivacaftor. In some embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged at least 12 years in need thereof) in two compositions, each comprising about 10.6 mg of vanzacaftor calcium salt hydrate Form D, 50 mg of tezacaftor, and 125 mg of deutivacaftor. [0081] In some embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged 6 to less than 12 years in need thereof and weighing less than 40 kg) in a single composition comprise about 12 to about 13 mg of vanzacaftor calcium salt hydrate Form D, 60 mg of tezacaftor, and 150 mg of deutivacaftor. In some embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged 6 to less than 12 years in need thereof and weighing less than 40 kg) in a single composition comprise about 12.74 mg of vanzacaftor calcium salt hydrate Form D, 60 mg of tezacaftor, and 150 mg of deutivacaftor. In some embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged 6 to less than 12 years in need thereof and weighing less than 40 kg) in three compositions, each comprising about 4 to about 5 mg of vanzacaftor calcium salt hydrate Form D, 20 mg of tezacaftor, and 50 mg of deutivacaftor. In some embodiments, the pharmaceutical compositions are designed for administration of the daily dose (for patients aged 6 to less than 12 years in need thereof and weighing less than 40 kg) in three compositions, each comprising about 4.24 mg of vanzacaftor calcium salt hydrate Form D, 20 mg of tezacaftor, and 50 mg of deutivacaftor. [0082] In some embodiments, pharmaceutical compositions of the invention are administered with fat-containing meals or snacks once daily at approximately the same time each day. Non-limiting examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, peanut butter, cheeses, nuts, whole milk, or meats. Vanzacaftor exposure increases approximately 4- to 6-fold when administered with a fat-containing meal relative to fasted conditions. Deutivacaftor exposure increases approximately 3- to 4-fold when administered with fat-containing meals relative to fasted conditions. 10275-0230-00304 [0083] In some embodiments, the pharmaceutical compositions comprise tezacaftor in amorphous form. In some embodiments, the pharmaceutical compositions comprise amorphous tezacaftor in a solid dispersion. In some embodiments, the tezacaftor solid dispersion is a spray-dried dispersion. In some embodiments, the solid dispersion comprising amorphous tezacaftor also includes a polymer. [0084] In some embodiments, the pharmaceutical compositions comprise deutivacaftor in amorphous form. In some embodiments, the pharmaceutical compositions comprise amorphous deutivacaftor in a solid dispersion. In some embodiments, the deutivacaftor solid dispersion is a spray-dried dispersion. In some embodiments, the solid dispersion (e.g., spray-dried dispersion) comprising amorphous tezacaftor also comprises a polymer. In some embodiments, the amorphous tezacaftor solid dispersion also includes a surfactant, such as, e.g., sodium lauryl sulfate. [0085] Processes of making solid dispersions, including spray-dried dispersions, are well known in the art. Any suitable method known in the art may be used to prepare solid dispersions comprising tezacaftor and/or deutivacaftor. Solid dispersions of tezacaftor and methods of preparing thereof are disclosed in PCT Publication Nos. WO 2011/119984 and WO 2015/160787, incorporated herein by reference. Solid dispersions of ivacaftor and methods of preparing such dispersions are disclosed in PCT Publication No. WO 2007/079139, incorporated herein by reference. These same solid dispersions are suitable for use with deutivacaftor. [0086] In some embodiments, the pharmaceutical compositions comprise a first solid dispersion (e.g., a spray-dried dispersion) comprising amorphous tezacaftor and a second solid dispersion (e.g., a spray-dried dispersion) comprising amorphous deutivacaftor. In some embodiments, the pharmaceutical compositions comprise a single solid dispersion (e.g., a spray-dried dispersion) comprising both amorphous tezacaftor and amorphous deutivacaftor. [0087] Suitable polymers for use in a solid dispersion with comprising tezacaftor and/or deutivacaftor include cellulose derivative polymers such as, e.g., hypromellose acetate succinate, also known as hydroxypropylmethylcellulose acetate succinate (HPMCAS), hypromellose, also known as hydroxypropylmethylcellulose (HPMC), and ethylcellulose; pyrrolidone containing polymers such as, e.g., polyvinylpyrrolidone (PVP) and copolymer polyvinyl pyrrolidone/vinyl acetate (PVP/VA); enteric polymers that are preferentially soluble in the less acidic environment of the intestine relative to the more 10275-0230-00304 acid environment of the stomach; polyethylene glycols (PEGs), polyvinyl alcohols (PVAs); acrylates, such as, e.g., polymethacrylate; cyclodextrins, such as, e.g., β- cyclodestrin; and copolymers and derivatives thereof. [0088] In some embodiments, the pharmaceutical composition of the invention comprises a tezacaftor solid dispersion, wherein the solid dispersion comprises about 80 wt% tezacaftor and about 20 wt% hypromellose, by weight of the solid dispersion. [0089] In some embodiments, the pharmaceutical composition of the invention comprises a deutivacaftor solid dispersion, wherein the solid dispersion comprises about 80 wt% deutivacaftor, about 19.5 wt% hypromellose acetate succinate, and about 0.5 wt% sodium lauryl sulfate, by weight of the solid dispersion. [0090] In some embodiments, the pharmaceutical composition of the invention comprises a deutivacaftor solid dispersion wherein the solid dispersion comprises about 80 wt% deutivacaftor, about 19.5 wt% hypromellose acetate succinate, and about 0.5 wt% sodium lauryl sulfate, by weight of the solid dispersion, and is about about 39.9 wt% by weight of the composition; vanzacaftor calcium salt hydrate Form D, wherein the vanzacaftor calcium salt hydrate Form D is about 2.7 wt% by weight of the composition; and a tezacaftor solid dispersion, wherein the solid dispersion comprises about 80 wt% tezacaftor and about 20 wt% hypromellose, by weight of the solid dispersion and is about 16 wt% by weight of the composition. [0091] A pharmaceutical composition of the invention may further comprise at least one pharmaceutically acceptable carrier. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the at least one pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants. [0092] In some embodiments, the pharmaceutical compositions comprise, in addition to the doses of vanzacaftor or vanzacaftor calcium salt hydrate Form D, tezacaftor, and deutivacaftor, one or more additional ingredients selected from croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. In some embodiments, the pharmaceutical compositions comprise vanzacaftor (e.g., vanzacaftor calcium salt hydrate Form D), tezacaftor, deutivacaftor, croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. 10275-0230-00304 [0093] In some embodiments, the pharmaceutical compositions disclosed herein are in tablet form. In some embodiments, the tablet is film-coated. In some embodiments, the film coating comprises one or more ingredients selected from carmine, brilliant blue FCF aluminum lake/FD&C blue #1, hydroxypropyl cellulose, hypromellose, iron oxide red, talc, and titanium dioxide. In certain embodiments, the film coating on the tablets comprises carmine, brilliant blue FCF aluminum lake/FD&C blue #1, hydroxypropyl cellulose, hypromellose, iron oxide red, talc, and titanium dioxide. Non-limiting List of Exemplary Embodiments 1. A method of treating cystic fibrosis in patients aged 12 years or older in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients to result in 86% of said patients with sweat chloride levels of <60 mmol/L at 16 weeks of treatment. 2. A method of treating cystic fibrosis in patients aged 12 years or older in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients to result in 86% of said patients with sweat chloride levels of <60 mmol/L at 24 weeks of treatment. 3. A method of treating cystic fibrosis in patients aged 12 years or older in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients to result in 31% of said patients with sweat chloride levels of <30 mmol/L at 16 weeks of treatment. 4. A method of treating cystic fibrosis in patients aged 12 years or older in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; 10275-0230-00304 (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients to result in 31% of said patients with sweat chloride levels of <30 mmol/L at 24 weeks of treatment. 5. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg, to the patients to result in about 53% of said patients with sweat chloride levels of <30 mmol/L at 16 weeks of treatment. 6. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg to the patients to result in about 53% of said patients with sweat chloride levels of <30 mmol/L at 24 weeks of treatment. Other Embodiments [0094] The foregoing discussion discloses and describes merely exemplary embodiments of this disclosure. One skilled in the art will readily recognize from such discussion and from the accompanying drawings and claims, that various changes, modifications, and variations can be made therein without departing from the spirit and scope of this disclosure as defined in the following claims. 10275-0230-00304 Examples Abbreviations AE = adverse event AESI = adverse event of special interest CI = confidence interval CK = creatine kinase CPK = creatine phosphokinase ECG = electrocardiogram FRT = Fischer rat thyroid GEE = generalized estimating equation LFT = liver function test LS = least squares SAE = serious adverse event SD = standard deviation SDD = spray-dried dispersion SE = standard error qd = quaque die (once a day) [0095] In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. [0096] Vanzacaftor, tezacaftor, and deutivacaftor can be prepared by any suitable method in the art. Methods of making vanzacaftor and its pharmaceutically acceptable salts thereof are disclosed in WO 2019/161078 and PCT/US2020/046116; methods of making tezacaftor and pharmaceutically acceptable salts thereof are disclosed in WO 2011/119984 and WO 2011/133751; and methods of making deutivacaftor can be found in WO 2019/109021 and U.S. Patent 9,512,079, all of which are incorporated herein by reference. Example 1: Preparation of exemplary tablet formulation [0097] Vanzacaftor calcium salt hydrate Form D, tezacaftor spray-dried dispersion (SDD), deutivacaftor SDD, microcrystalline cellulose, and croscarmellose sodium (see 10275-0230-00304 Table 5. Exemplary Tablet Formulation Comprising 125 mg Deutivacaftor, 10.6 mg Vanzacaftor calcium salt hydrate Form D, and 50 mg Tezacaftor. for exemplary amounts) were weighed and sieved through a screen and placed in a bin blender. These components were blended and combined to prepare the intragranular powder blend. The intragranular powder blend was dry granulated using a roller compactor and then milled into granules. The extragranular microcrystalline cellulose was weighed, passed through a screen, and blended with the milled granules in a bin blender. Magnesium stearate was weighed and sieved, then added to the bin blender and blended. The blended components were compressed using a power-assisted rotary tablet press to prepare a tablet with the required core weight and hardness. The tablets were then placed in a coater to add a nonfunctional coating. Table 5. Exemplary Tablet Formulation Comprising 125 mg Deutivacaftor, 10.6 mg Vanzacaftor calcium salt hydrate Form D, and 50 mg Tezacaftor. I_{ngredient Amount per tablet (mg)} 10275-0230-00304 Example 2: Improvement of patient sweat chloride using vanzacaftor/tezacaftor/ deutivacaftor in patients at least 12 years [0098] Two studies were part of a Phase 3 program and were randomized, double- blind, active-controlled trials evaluating the efficacy of vanzacaftor (20 mg)/tezacaftor (100 mg)/deutivacaftor (250 mg) in patients with CF aged at least 12 years who have at least one F508del mutation or a mutation expected to be responsive to vanzacaftor/tezacaftor/deutivacaftor, compared to elexacaftor/tezacaftor/ivacaftor for 52 weeks of treatment. A first study included subjects with F508del mutation/minimal function mutations (Study 1), while a second study included subjects with other responsive genotypes; namely, F508del/F508del, F508del/residual function mutation, F508del/gating mutation, and elexacaftor/tezacaftor/ivacaftor-responsive mutation/no F508del mutation (Study 2). Both studies included a four-week run-in period where patients received elexacaftor/tezacaftor/ivacaftor. [0099] In both Study 1 and Study 2, the primary endpoint of change from baseline in percent predicted forced expiratory volume (ppFEV₁) through week 24 was met and treatment with vanzacaftor/tezacaftor/deutivacaftor was shown to be non-inferior to treatment with elexacaftor/tezacaftor/ivacaftor. [00100] As shown in Table 6, in Study 1 (patients with F508del/minimal function mutation genotype), the absolute mean change from baseline in SwCl through week 24 was -7.5 mmol/L for those taking vanzacaftor/tezacaftor/deutivacaftor, compared to an increase of 0.9 in those taking elexacaftor/tezacaftor/ ivacaftor, demonstrating a statistically significant and clinically meaningful improvement in CFTR function. This difference was maintained at week 52, which showed an absolute mean change from baseline in SwCl of -7.5 mmol/L for those taking vanzacaftor/tezacaftor/deutivacaftor, compared to an increase of 0.5 in those taking elexacaftor/tezacaftor/ivacaftor. See FIG.1.

10275-0230-00304 Table 6. Comparison of baseline and variations in SwCl (in mmol/L) in Study 1. ELX/TEZ/IVA VNZ/TEZ/D-IVA N=202 N=196 Baseline SwCl; Mean (SD) 54.3 (18.2) 53.6 (17.0) Absolute change through Week 24^*   LS Mean change (SE) 0.9 (0.8) -7.5 (0.8) LS Mean difference, 95% CI - -8.4 (-10.5, -6.3) 2-sided P value for superiority - <0.0001     Absolute change through Week 52^#   LS Mean change (SE) 0.5 (0.7) -7.5 (0.7) LS Mean difference, 95% CI - -8.0 (-9.9, -6.1) * average of weeks 16 and 24 # average of weeks 16, 24, 36, 52 [00101] As shown in Table 7 below, following treatment with vanzacaftor/tezacaftor/deutivacaftor, 81% of patients with CF in Study 1 had a SwCl level below the diagnostic threshold of 60 mmol/L through 24 weeks, compared to 59% of patients treated with elexacaftor/tezacaftor/ivacaftor. This difference was maintained through 52 weeks, where 78% of patients had a SwCl level below 60 mmol/L following treatment with vanzacaftor/tezacaftor/deutivacaftor, compared to 58% of patients treated with elexacaftor/tezacaftor/ivacaftor. Following treatment with vanzacaftor/tezacaftor/deutivacaftor through 24 weeks, 20% of patients across both trials had a SwCl of below 30 mmol/L, compared to 7% of patients treated with elexacaftor/tezacaftor/ivacaftor. This difference was maintained through 52 weeks, where 19% of patients had a SwCl level below 30 mmol/L following treatment with vanzacaftor/tezacaftor/deutivacaftor, compared to 7% of patients treated with elexacaftor/tezacaftor/ivacaftor. 10275-0230-00304 Table 7. Proportion of subjects with SwCl <60 or <30 mmol/L through weeks 24 and 52 in Study 1. ELX/TEZ/IVA VNZ/TEZ/D-IVA N=202 N=196 Baseline SwCl <60 mmol/L, Proportion 0.62 0.68 SwCl <60 mmol/L through Week 24^* Proportion 0.59 0.81 Odds Ratio^†, 95% CI - 4.28 (2.57, 7.11) SwCl <60 mmol/L through Week 52^# Proportion 0.58 0.78 Odds Ratio^†, 95% CI - 3.59 (2.39, 5.38)     Baseline SwCl <30 mmol/L, Proportion 0.10 0.09 SwCl <30 mmol/L through Week 24^* Proportion 0.07 0.20 Odds Ratio^†, 95% CI - 7.19 (3.54, 14.59) SwCl <30 mmol/L through Week 52^# Proportion 0.07 0.19 Odds Ratio^†, 95% CI - 5.77 (3.33, 9.99) * average of weeks 16 and 24; # average of weeks 16, 24, 36, 52 † Estimated by GEE model; odds ratio >1 favors VNZ/TEZ/D-IVA [00102] As shown in Table 8, in Study 2 (patients with cystic fibrosis caused by other responsive genotypes), the absolute mean change from baseline in SwCl through week 24 was -5.1 for those taking vanzacaftor/tezacaftor/deutivacaftor, compared to -2.3 for those on elexacaftor/tezacaftor/ivacaftor, again demonstrating statistically significant and clinically meaningful improvement in CFTR function. This difference was maintained at week 52, which showed an absolute mean change from baseline in SwCl of -5.0 mmol/L for those taking vanzacaftor/tezacaftor/deutivacaftor, compared to an increase of -2.2 in those taking elexacaftor/tezacaftor/ivacaftor. See FIG.2 10275-0230-00304 Table 8. Comparison of baseline and variations in SwCl (in mmol/L) in Study 2. ELX/TEZ/IVA VNZ/TEZ/D-IVA N=289 N=284 Baseline SwCl; Mean (SD) 42.1 (17.9) 43.4 (18.5) Absolute change through Week 24^*   LS Mean change (SE) -2.3 (0.7) -5.1 (0.7) LS Mean difference, 95% CI - -2.8 (-4.7, -0.9) 2-sided P value for superiority - 0.0034     Absolute change through Week 52^#   LS Mean change (SE) -2.2 (0.6) -5.0 (0.6) LS Mean difference, 95% CI - -2.8 (-4.6, -1.0) * ^{average of weeks 16 and 24 #} average of weeks 16, 24, 36, 52 [00103] As shown in Table 9, following treatment with vanzacaftor/tezacaftor/deutivacaftor, 90% of patients in Study 2 had a SwCl level below the diagnostic threshold of 60 mmol/L through 24 weeks, compared to 89% of patients treated with elexacaftor/tezacaftor/ivacaftor. Through 52 weeks, 90% of patients had a SwCl level below 60 mmol/L following treatment with vanzacaftor/tezacaftor/deutivacaftor, compared to 88% of patients treated with elexacaftor/tezacaftor/ivacaftor. Following treatment with vanzacaftor/tezacaftor/deutivacaftor through 24 weeks, 38% of patients across both trials had a SwCl of below 30 mmol/L, compared to 34% of patients treated with elexacaftor/tezacaftor/ivacaftor. Through 52 weeks, 37% of patients had a SwCl level below 30 mmol/L following treatment with vanzacaftor/tezacaftor/deutivacaftor, compared to 32% of patients treated with elexacaftor/tezacaftor/ivacaftor. 10275-0230-00304 Table 9. Proportion of subjects with SwCl <60 or <30 mmol/L through week 24 in Study 2. ELX/TEZ/IVA VNZ/TEZ/D-IVA N=289 N=284 Proportion 0.89 0.90 Odds Ratio^†, 95% CI - 1.10 (0.65, 1.87) SwCl <60 mmol/L through Week 52^# Proportion 0.88 0.90 Odds Ratio^†, 95% CI - 1.20 (0.78, 1.84)     Baseline SwCl <30 mmol/L, Proportion 0.28 0.26 SwCl <30 mmol/L through Week 24^* Proportion 0.34 0.38 Odds Ratio^†, 95% CI - (1.33, 3.18) SwCl <30 mmol/L through Week 52^# Proportion 0.32 0.37 Odds Ratio^†, 95% CI - (1.36, 2.88) * average of weeks 16 and 24; # average of weeks 16, † Estimated by GEE model; odds ratio >1 favors VNZ/TEZ/D-IVA [00104] As shown in Table 10, following treatment with vanzacaftor/tezacaftor/deutivacaftor, 86% of patients across both studies had a SwCl level below the diagnostic threshold of 60 mmol/L through 24 weeks, compared to 77% of patients treated with elexacaftor/tezacaftor/ivacaftor. Following treatment with vanzacaftor/tezacaftor/deutivacaftor through 24 weeks, 31% of patients across both trials had a SwCl of below 30 mmol/L, compared 23% of patients treated with elexacaftor/tezacaftor/ivacaftor. This means that for patients treated with 10275-0230-00304 vanzacaftor/tezacaftor/deutivacaftor, the odds of achieving a SwCl <60 mmol/L were more than twice that of those treated with elexacaftor/tezacaftor/ivacaftor through 24 weeks, and the odds of achieving a SwCl <30 mmol/L were nearly three times greater for those treated with vanzacaftor/tezacaftor/deutivacaftor compared to elexacaftor/tezacaftor/ivacaftor through 24 weeks. Table 10. Proportion of subjects with SwCl <60 or <30 mmol/L through week 24 compared (Pooled data from Study 1 and Study 2). ELX/TEZ/ VNZ/TEZ IVA /D-IVA † Estim # Average of weeks 16 and 24 10275-0230-00304 Example 3: Improvement of patient sweat chloride using vanzacaftor/tezacaftor/deutivacaftor in patients aged 6 to less than 12 years (Study 3) [00105] A third study Study 3 was part of a Phase 3 program as a multicohort, open- label study in patients aged 6 to less than 12 years with at least one mutation responsive to elexacaftor/tezacaftor/ivacaftor. The study evaluated safety, tolerability, and efficacy of vanzacaftor/tezacaftor/deutivacaftor in a total of 78 patients aged 6 to less than 12 years during a 24-week treatment period. All patients were administered elexacaftor/tezacaftor/ivacaftor for at least four weeks at the beginning of the study period. Patients aged 6 to less than 12 years weighing ≥ 40 kg at Day 1 received vanzacaftor 20 mg qd/tezacaftor 100 mg qd/deutivacaftor 250 mg qd. Patients weighing <40 kg at Day 1 received vanzacaftor 12 mg qd/tezacaftor 60 mg qd/deutivacaftor 150 mg qd. [00106] In Study 3, safety and tolerability were the primary endpoints. Efficacy endpoints included absolute change in ppFEV1, sweat chloride, Cystic Fibrosis Questionaire-Revised (CFQ-R) respiratory domain score, number of pulmonary exacerbations (PEx) and CF-related hospitalizations, measure of growth parameters (weight, height, BMI, and associated z scores) and measured as change from elexacaftor/tezacaftor/ivacaftor baseline. [00107] Vanzacaftor/tezacaftor/deutivacaftor and elexacaftor/tezacaftor/ivacaftor were generally safe and well-tolerated in patients aged 6 to less than 12 years. Patients in this study maintained their baseline level of lung function 99.7 % with absolute LS mean change from baseline of 0.0 and had an absolute mean change in sweat chloride of -8.6 mm/L from baseline levels of 40.4 mm/L on elexacaftor/tezacaftor/ivacaftor (See Table 11). Table 11. Absolute change in SwCl (in mmol/L) through week 24 in Study 3. VNZ/TEZ/D-IVA N=78 Baseline SwCl; Mean (SD) 40.4 (20.9) Absolute change through Week 24^# LS Mean, 95% CI -8.6 (-11.0, -6.3) # Average of measurements taken at weeks 16 and 24 10275-0230-00304 [00108] As shown in Table 12, following treatment with vanzacaftor/tezacaftor/deutivacaftor, 95% of patients in the study had a SwCl level below 60 mmol/L through 24 weeks and 53% of patients had a SwCl of below 30 mmol/L. See FIG.3. Table 12. Proportion of subjects with SwCl <60 mmol/L and <30 mmol/L through week 24 Study 3. VNZ/TEZ/D-IVA N=78 Baseline SwCl <60 mmol/L, Proportion 0.84 SwCl <60 mmol/L through Week 24^# 0.95 Proportion (0.87, 0.99) 95% CI Baseline SwCl <30 mmol/L, Proportion 0.39 SwCl <30 mmol/L through Week 24^# 0.53 Proportion (0.41, 0.64) 95% CI # Average of weeks 16 and 24 Example 4: CFTR Chloride Transport Assay of Elexacaftor/Tezacaftor/Ivacaftor in Fischer Rat Thyroid (FRT) Cells Expressing Mutant CFTR [00109] The chloride transport response of mutant CFTR protein to elexacaftor/tezacaftor/ivacaftor was determined in Ussing chamber electrophysiology studies using a panel of Fischer Rat Thyroid (FRT) cell lines transfected with individual CFTR mutations. Elexacaftor/tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR mutations that result in CFTR protein being delivered to the cell surface. [00110] The in vitro CFTR chloride transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive or reasonably expected to predict clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response. 10275-0230-00304 [00111] Table 3 lists responsive CFTR mutations based on in vitro data in FRT cells indicating that elexacaftor/tezacaftor/ivacaftor increases chloride transport to at least 10% of normal over baseline. Example 5: CFTR Chloride Transport Assay of Vanzacaftor/Tezacaftor/ Deutivacaftor in Fischer Rat Thyroid (FRT) Cells Expressing Mutant CFTR [00112] The chloride transport response of mutant CFTR protein to vanzacaftor/tezacaftor/deutivacaftor was determined using chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. vanzacaftor/tezacaftor/deutivacaftor increased chloride transport in FRT cells expressing select CFTR mutations. [00113] The in vitro CFTR chloride transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive of clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR mediated chloride transport in vitro is not correlated with the magnitude of clinical response. [00114] Clinical outcomes were consistent with in vitro results and indicate that a single responsive allele (including the F508del mutation) is sufficient to result in a significant clinical response. [00115] Table 4 lists responsive CFTR mutations based on in vitro data in FRT cells and/or clinical data indicating that vanzacaftor/tezacaftor/deutivacaftor increases chloride transport.

Claims

10275-0230-00304 CLAIMS 1. A method of treating cystic fibrosis in patients aged at least 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients for a duration sufficient to result in a majority of said patients with sweat chloride levels of <60 mmol/L. 2. A method of treating cystic fibrosis in patients aged at least 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients for a duration sufficient to result in about 86% of said patients with sweat chloride levels of <60 mmol/L. 3. A method of treating cystic fibrosis in patients aged 12 years or older in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients for at least 16 weeks to result in 86% of said patients with sweat chloride levels of <60 mmol/L. 4. A method of treating cystic fibrosis in patients aged 12 years or older in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients for at least 24 weeks to result in 86% of said patients with sweat chloride levels of <60 mmol/L. 10275-0230-00304 5. A method of treating cystic fibrosis in patients aged at least 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients for a duration sufficient to result in patient sweat chloride levels of <30 mmol/L. 6. A method of treating cystic fibrosis in patients aged at least 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients for a duration sufficient to result about 31% of said patients with sweat chloride levels of <30 mmol/L. 7. A method of treating cystic fibrosis in patients aged 12 years or older in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients for at least 16 weeks to result in 31% of said patients with sweat chloride levels of <30 mmol/L. 8. A method of treating cystic fibrosis in patients aged 12 years or older in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients for at least 24 weeks to result in 31% of said patients with sweat chloride levels of <30 mmol/L. 10275-0230-00304 9. The method of treating cystic fibrosis according to any one of claims 1 to 8, wherein the patients have a CFTR genotype selected from F508del/F508del, F508del/residual function mutation, F508del/gating mutation, elexacaftor/tezacaftor/ivacaftor-responsive mutation/non-F508del, and F508del/minimal function mutation. 10. A method of treating cystic fibrosis in patients aged at least 12 years having a CFTR genotype of F508del/minimal function mutation, comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients for a duration sufficient to result in an absolute mean change in sweat chloride of about -7.5 mmol/L from baseline. 11. A method of treating cystic fibrosis in patients aged at least 12 years having a CFTR genotype selected from F508del/residual function mutation, F508del/gating mutation, elexacaftor/tezacaftor/ivacaftor-responsive mutation/non-F508del, and F508del/F508del, comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patients for a duration sufficient to result in an absolute mean change in sweat chloride of about -5.1 mmol/L from baseline. 12. The method of treating cystic fibrosis according to any one of claims 1 to 11, wherein baseline is measured after administration of elexacaftor/tezacaftor/ivacaftor for at least 4 weeks and before administration of vanzacaftor/tezacaftor/deutivacaftor. 13. The method of treating cystic fibrosis according to any one of claims 1, 2, 5, and 6, wherein the duration is at least 36 weeks. 10275-0230-00304 14. The method of treating cystic fibrosis according to any one of claims 1, 2, 5, and 6, wherein the duration is at least 52 weeks. 15. The method of treating cystic fibrosis according to any one of claims 1, 2, 4, 5, and 6, and 8, wherein the sweat chloride level is evaluated as an average of measurements taken at weeks 16 and 24. 16. The method of treating cystic fibrosis according to claim 14, wherein the sweat chloride level is evaluated as an average of measurements taken at weeks 16, 24, 36, and 52. 17. The method of treating cystic fibrosis according to any one of claims 1 to 16, wherein the vanzacaftor is vanzacaftor calcium salt hydrate Form D. 18. The method of treating cystic fibrosis according to claim 17, wherein the amount of vanzacaftor calcium salt hydrate Form D is about 21.24 mg. 19. The method of treating cystic fibrosis according to any one of claims 1 to 18, wherein the tezacaftor is amorphous. 20. The method of treating cystic fibrosis according to claim 19, wherein the amorphous tezacaftor is in a solid dispersion with a polymer selected from cellulose derivatives, polyvinylpyrrolidones, polyethylene glycols, polyvinyl alcohols, acrylates, cyclodextrins, and copolymers and derivatives thereof. 21. The method of treating cystic fibrosis according to claim 20, wherein the polymer is selected from hydroxypropylmethylcellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone/vinyl acetate co-polymer (PVP/VA). 22. The method of treating cystic fibrosis according to claim 20, wherein the polymer is hydroxypropyl methyl cellulose (HPMC). 10275-0230-00304 23. The method of treating cystic fibrosis according to any one of claims 1 to 22, wherein the deutivacaftor is amorphous. 24. The method of treating cystic fibrosis according to claim 23, wherein the amorphous deutivacaftor is in a solid dispersion with a polymer selected from cellulose derivatives, polyvinylpyrrolidones, polyethylene glycols, polyvinyl alcohols, acrylates, cyclodextrins, and copolymers and derivatives thereof. 25. The method of treating cystic fibrosis according to claim 24, wherein the polymer is selected from hydroxypropylmethylcellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone/vinyl acetate co-polymer (PVP/VA). 26. The method of treating cystic fibrosis according to claim 24, wherein the polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS). 27. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg, for a duration sufficient to result in a majority of said patients with sweat chloride levels of <60 mmol/L. 28. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor 10275-0230-00304 to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg, for a duration sufficient to result in about 95% of said patients with sweat chloride levels of <60 mmol/L. 29. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg, for at least 16 weeks to result in about 95% of said patients with sweat chloride levels of <60 mmol/L. 30. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg, for at least 24 weeks to result in about 95% of said patients with sweat chloride levels of <60 mmol/L. 31. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof comprising daily administration of: 10275-0230-00304 (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg for a duration sufficient to result in a majority of said patients with sweat chloride levels of <30 mmol/L. 32. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg, for a duration sufficient to result in about 53% of said patients with sweat chloride levels of <30 mmol/L. 33. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg, to the patients for at least 16 weeks to result in about 53% of said patients with sweat chloride levels of <30 mmol/L. 10275-0230-00304 34. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg to the patients for at least 24 weeks to result in about 53% of said patients with sweat chloride levels of <30 mmol/L. 35. The method of treating cystic fibrosis according to any one of claims 27 to 34, wherein the patients have at least one elexacaftor/tezacaftor/ivacaftor-responsive mutation. 36. A method of treating cystic fibrosis in patients aged 6 to less than 12 years in need thereof having at least one elexacaftor/tezacaftor/ivacaftor-responsive mutation, comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to patients weighing ≥40 kg, or (a) 12 mg of vanzacaftor; (b) 60 mg of tezacaftor; and (c) 150 mg of deutivacaftor to patients weighing <40 kg for a duration sufficient to result in an absolute mean change in sweat chloride of about -8.6 mmol/L from baseline. 37. The method of treating cystic fibrosis according to claim 35 or claim 36, wherein the elexacaftor/tezacaftor/ivacaftor-responsive mutation is F508del. 10275-0230-00304 38. The method of treating cystic fibrosis according to claim 36 or claim 37, wherein the baseline is measured prior to administration of vanzacaftor/tezacaftor/deutivacaftor and after administration of elexacaftor/tezacaftor/ivacaftor for at least 4 weeks. 39. The method of treating cystic fibrosis according to claim 38, wherein the duration is at least 24 weeks. 40. The method of treating cystic fibrosis according to any one of claims 30, 34, and 36, wherein the sweat chloride level is evaluated as an average of measurements taken at weeks 16 and 24. 41. The method of treating cystic fibrosis according to any one of claims 27 to 40, wherein the vanzacaftor is in the form of vanzacaftor calcium salt hydrate Form D. 42. The method of treating cystic fibrosis according to claim 41, wherein the amount of vanzacaftor calcium salt hydrate Form D is about 21.24 mg for patients weighing ≥40 kg and about 12.74 mg for patients weighing <40 kg. 43. The method of treating cystic fibrosis according to any one of claims 27 to 42, wherein the tezacaftor is amorphous. 44. The method of treating cystic fibrosis according to claim 43, wherein the amorphous tezacaftor is in a solid dispersion with a polymer selected from cellulose derivatives, polyvinylpyrrolidones, polyethylene glycols, polyvinyl alcohols, acrylates, cyclodextrins, and copolymers and derivatives thereof. 45. The method of treating cystic fibrosis according to claim 44, wherein the polymer is selected from hydroxypropylmethylcellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone/vinyl acetate co-polymer (PVP/VA). 46. The method of treating cystic fibrosis according to claim 44 or claim 45, wherein the polymer is hydroxypropyl methyl cellulose (HPMC). 10275-0230-00304 47. The method of treating cystic fibrosis according to any one of claims 27 to 46, wherein the deutivacaftor is amorphous. 48. The method of treating cystic fibrosis according to claim 47, wherein the amorphous deutivacaftor is in a solid dispersion with a polymer selected from cellulose derivatives, polyvinylpyrrolidones, polyethylene glycols, polyvinyl alcohols, acrylates, cyclodextrins, and copolymers and derivatives thereof. 49. The method of treating cystic fibrosis according to claim 48, wherein the polymer is selected from hydroxypropylmethylcellulose (HPMC), hydroxypropyl methyl cellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone/vinyl acetate co-polymer (PVP/VA). 50. The method of treating cystic fibrosis according to claim 48 or claim 49, wherein the polymer is hydroxypropyl methyl cellulose acetate succinate (HPMCAS). 51. The method of treating cystic fibrosis according to any one of claims 1 to 50, wherein the vanzacaftor, tezacaftor, and deutivacaftor are administered in a single composition. 52. The method of treating cystic fibrosis according to any one of claims 1 to 26, wherein the vanzacaftor, tezacaftor, and deutivacaftor are administered in two tablets, each containing 10 mg of vanzacaftor, 50 mg of tezacaftor, and 125 mg of deutivacaftor. 53. The method of treating cystic fibrosis according to any one of claims 27 to 50, wherein the vanzacaftor, tezacaftor, and deutivacaftor are administered: (a) in three tablets for patients weighing <40 kg, each containing 4 mg of vanzacaftor, 20 mg of tezacaftor, and 50 mg of deutivacaftor; or (b) in two tablets for patients weighing ≥40 kg, each containing 10 mg of vanzacaftor, 50 mg of tezacaftor, and 125 mg of deutivacaftor. 54. The method of treating cystic fibrosis according to any one of claims 27 to 50, wherein the vanzacaftor, tezacaftor, and deutivacaftor are administered: 10275-0230-00304 (a) in three tablets for patients weighing <40 kg, each containing about 44.24 mg of vanzacaftor calcium salt hydrate Form D, 20 mg of tezacaftor, and 50 mg of deutivacaftor; or (b) in two tablets for patients weighing ≥40 kg, each containing 10.6 mg of vanzacaftor calcium salt hydrate Form D, 50 mg of tezacaftor, and 125 mg of deutivacaftor. 55. The method of treating cystic fibrosis according to any one of claims 1 to 54, wherein the vanzacaftor, tezacaftor, and deutivacaftor are administered together with fat- containing food once daily. 56. A method of treating cystic fibrosis in a patient aged at least 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patient to result in a sweat chloride level of <60 mmol/L at 16 weeks of treatment. 57. A method of treating cystic fibrosis in a patient aged at least 12 years in need thereof comprising daily administration of: (a) 20 mg of vanzacaftor; (b) 100 mg of tezacaftor; and (c) 250 mg of deutivacaftor to the patient to result in a sweat chloride level of <30 mmol/L at 24 weeks of treatment.