IP Library › Granted Patent US 12,186,306
Granted Patent B2
US 12,186,306 · App. 17/546,649 · Granted Jan 7, 2025

Methods of treatment for cystic fibrosis

Inventors: Bartlomiej Borek (San Diego, CA); Weichao George Chen (San Diego, CA); Rudy Gunawan (Apex, NC); Eric Haseltine (Melrose, MA); Nitin Nair (Hopkinton, MA); Porntula Panorchan (Orlando, FL); Patrick Sosnay (West Roxbury, MA)
Assignee: Vertex Pharmaceuticals Incorporated
A61K31/4375A61K9/2054A61K31/4045A61K31/47
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Quick Facts
Patent No.
US 12,186,306
App. No.
17/546,649
Granted
Jan 7, 2025
Kind
B2
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.

Claims (440)

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 K α 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 13 C solid state nuclear magnetic resonance ( 13 C 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 13 C 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 13 C 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 13 C 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.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2022
From: SOSNAY, PATRICK; BOREK, BARTLOMIEJ; CHEN, WEICHAO GEORGE; HASELTINE, ERIC; NAIR, NITIN
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 060348/0907 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2022
From: GUNAWAN, RUDY
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 060348/0943 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2022
From: PANORCHAN, PORNTULA
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 060348/0951 →
Continuity (4)
Provisional Application 63150434 · Feb 17, 2021
Provisional Application 63124575 · Dec 11, 2020
Provisional Application 63123928 · Dec 10, 2020
Related Publication 20220184049A1 · Jun 16, 2022
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