Claims for Patent: 12,186,306

Summary for Patent: 12,186,306

Title:	Methods of treatment for cystic fibrosis
Abstract:	This application describes methods of treating cystic fibrosis or a CFTR mediated disease comprising administering Compound I or a pharmaceutically acceptable salt thereof.The application also describes pharmaceutical compositions comprising Compound I or a pharmaceutically acceptable salt thereof and optionally comprising one or more additional CFTR modulating agents.
Inventor(s):	Bartlomiej Borek, Weichao George Chen, Rudy Gunawan, Eric HASELTINE, Nitin Nair, Porntula PANORCHAN, Patrick Sosnay
Assignee:	Vertex Pharmaceuticals Inc
Application Number:	US17/546,649
Patent Claims:	1. A method of treating cystic fibrosis comprising daily administration of: (a) 250 mg of Compound I: or an equivalent amount of a pharmaceutically acceptable salt thereof; and (b) 21.24 mg Compound II calcium salt hydrate Form D: and (c) 100 mg of Compound III: or an equivalent amount of a pharmaceutically acceptable salt thereof. 2. A method of treating cystic fibrosis comprising daily administration of: (a) 250 mg of Compound I: (b) 21.240 mg of Compound II calcium salt hydrate Form D: and (c) 100 mg of Compound III: (Compound III), to a patient in need thereof. 3. The method of claim 1 or claim 2, wherein Compounds I, II, and III are administered in separate compositions. 4. The method of claim 1 or claim 2, wherein Compounds I, II, and III are administered in a single composition. 5. The method of claim 1 or claim 2, wherein Compounds I, II, and III are administered as two compositions once daily, each composition comprising 125 mg of Compound I, 10.62 mg of Compound II calcium salt hydrate Form D, and 50 mg of Compound III. 6. The method of claim 1, wherein the patient is homozygous for the F508del cystic fibrosis transmembrane conductance regulator (CFTR) mutation or has an F508del/minimal function CFTR genotype, a F508del/gating CFTR genotype, or a F508del/residual function CFTR genotype. 7. The method of claim 1, wherein the patient has a heterozygous CFTR genotype and has one F508del CFTR mutation. 8. The method of claim 7, wherein the patient has one CFTR mutation selected from: 711 + 3A > G L206W K1060T 2789 + 5G > A R347H A1067T 3272 − 26A > G R352Q G1069R 3849 + 10 kb C > 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. 9. The method of claim 7, wherein the patient has one CFTR mutation selected from: 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 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 wherein D443Y; G576A; R668C, R74W; D1270N, R74W; V201M, R74W; V201M; D1270N, F508C; S1251N, and G576A; R668C are complex/compound mutations where a single allele of the CFTR gene has multiple mutations, existing independently of the presence of mutations on the other allele. 10. The method of claim 1, wherein the patient has at least one CFTR mutation selected from: 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 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 wherein D443Y: G576A; R668C, R74W; D1270N, R74W; V201M, R74W; V201M; D1270N, F508C; S1251N, and G576A; R668C are complex/compound mutations where a single allele of the CFTR gene has multiple mutations, existing independently of the presence of mutations on the other allele. 11. The method of claim 1, wherein the Compound II calcium salt hydrate Form D is characterized by an X-ray powder diffractogram (XRPD) 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. 12. The method of claim 11, wherein the Compound II calcium salt hydrate Form D is characterized by an XRPD having (a) 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 (b) one or more signals selected from 5.5±0.2 degrees two-theta, 15.5±0.2 degrees two-theta, 19.7±0.2 degrees two-theta, 21.5±0.2 degrees two-theta, 22.1±0.2 degrees two-theta, 23.0±0.2 degrees two-theta, and 27.6±0.2 degrees two-theta. 13. The method of claim 11, wherein the Compound II calcium salt hydrate Form D is characterized by an XRPD 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. 14. The method of claim 11, wherein the Compound II calcium salt hydrate Form D is characterized by an XRPD 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. 15. The method of claim 1, wherein the Compound II calcium salt hydrate Form D is characterized by an X-ray powder diffractogram substantially similar to FIG. 5 . 16. The method of claim 1, wherein the Compound II calcium salt hydrate Form D is characterized by a triclinic crystal system, a P1 space group, and unit cell dimensions measured at 100 K on a Bruker diffractometer equipped with Cu Kα radiation (λ=1.5478 Å) of a 12.78 ± .01 Å α 64.93 ± .02° b 16.64 ± .01 Å β 75.10 ± .02° c 18.19 ± .01 Å γ 68.22 ± .02°. 17. The method of claim 1, wherein the Compound II calcium salt hydrate Form D is characterized by a 13C solid state nuclear magnetic resonance (13C ss NMR) spectrum with one or more peaks selected from 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm. 18. The method of claim 17, wherein the Compound II calcium salt hydrate Form D is characterized by a 13C ss NMR spectrum with one or more 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. 19. The method of claim 17, wherein the Compound II calcium salt hydrate Form D is characterized by a 13C ss NMR spectrum with (a) one or more peaks selected from 130.2±0.2 ppm, 125.6±0.2 ppm, and 35.0±0.2 ppm; and (b) one or more peaks selected from 176.9±0.2 ppm, 160.9±0.2 ppm, 142.0±0.2 ppm, and 98.6±0.2 ppm. 20. The method of claim 1, wherein the Compound II calcium salt hydrate Form D is characterized by a 13C solid state nuclear magnetic resonance spectrum substantially similar to FIG. 6 . 21. The method of claim 1, wherein at least 85% of the Compound II is Compound II calcium salt hydrate Form D. 22. The method of claim 1, wherein at least 95% of the Compound II is Compound II calcium salt hydrate Form D.