COMBINATION THERAPIES COMPRISING APREMILAST AND TYK2 INHIBITORS

POLYTHERAPIES COMPRENANT DE L'APREMILAST ET DES INHIBITEURS DE TYK2

English Abstract

Provided herein are methods of treating diseases and disorder responsive to the inhibition of PDE4 comprising administering apremilast and a Tyk2 inhibitor to a subject. Also provided herein are pharmaceutical compositions comprising apremilast and a Tyk2 inhibitor.

French Abstract

L'invention concerne des méthodes de traitement de maladies et de troubles sensibles à l'inhibition de PDE4 qui consistent à administrer de l'aprémilast et un inhibiteur de Tyk2 à un sujet. L'invention concerne également des compositions pharmaceutiques comprenant de l'aprémilast et un inhibiteur de Tyk2.

Claims

Claims
1. A method of treating a disease or disorder responsive to the inhibition
of
phosphodiesterase type 4 (PDE4) in a subject, comprising administering to the
subject a
therapeutically effective amount of N-[2-[( 1S)- 1 -(3-ethoxy-4-methoxypheny1)-
2-
(methylsulfonyl)ethyl[-2,3-dihydro- 1,3-dioxo- 1H-isoindo1-4-yl[acetamide, or
a
pharmaceutically acceptable salt thereof; and a therapeutically effective
amount of a tyrosine
kinase 2 (Tyk2) inhibitor or a pharmaceutically acceptable salt thereof.
2. The method of Claim 1, wherein the Tyk2 inhibitor is of the formula:
<IMG>
or a pharmaceutically acceptable salt thereof, wherein
R1 is Ci_3a1ky1 optionally substituted by 0-7 Rla;
Rla at each occurrence is independently hydrogen, deuterium, F, Cl, Br, CF3 or
CN;
R2 is Ci_olkyl or-(CH2),-3-14 membered carbocycle, each group substituted with
0-4
R2a;
R2a at each occurrence is independently hydrogen,=0, halo, OCF3, CN, NO2, -
(CH2),ORb, -(CH2),SRb, -(CH2),C(0)Rb, -(CH2),C(0)0Rb, -(CH2),OC(0)Rb, -
(CH2),NR11R11,
-(CH2),C(0)NR11R11, -(CH2),NRbC(0)RC, -(CH2),NRbC(0)ORC, -NRbC(0)NR11R11, -
S(0)pNR11R11, -NRbS(0)pRc, -S(0)pRc, Ci_6 alkyl substituted with 0-3 Ra, Ci_6
haloalkyl, C2_
6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl substituted with 0-3 Ra, -
(CH2),-3-14 membered
carbocycle substituted with 0-1 Ra or a -(CH2),-5-7 membered heterocycle
comprising carbon
atoms or 1-4 heteroatoms selected from N, 0, and S(0)p substituted with 0-2
Ra;
R3 is C3_10 cycloalkyl, C6_10 aryl, or a 5-10 membered heterocycle containing
1-4
heteroatoms selected from N, 0, and S, each group substituted with 0-4 R3';
R3' at each occurrence is independently hydrogen, =0, halo, OCF3, CF3, CHF2,
CN,
NO2, -(CH2),ORb, -(CH2),SRb, -(CH2),C(0)Rb, -(CH2),C(0)0Rb, -(CH2),OC(0)Rb, -
(CH2),NR11R11, -(CH2),C(0)NR11R11, -(CH2),NRbC(0)RC, -(CH2),NRbC(0)ORC, -
NRbC(0)NR1lRll, -S(0)pNR11R11, -NRbS(0)pRc, -S(0)pRc, C1_6 alkyl substituted
with 0-3 Ra,
C2_6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl substituted with 0-3 Ra,
C1_6 haloalkyl, -
46

(CH2)r-3-14 membered carbocycle substituted with 0-3 Ra or a -(CH2)r-5-10
membered
heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, 0,
and
S(0)p substituted with 0-3 Ra;
or two R3a, together with the atoms to which they are attached, combine to
form a
fused ring wherein said ring is selected from phenyl and a 5-7 membered
heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N, S or 0 said fused
ring further
substituted by Ral;
R4 and R5 are independently hydrogen, C1_4 alkyl substituted with 0-1 Rf,
(CH2)r-
phenyl substituted with 0-3 Rd, or a -(CH2)-5-7 membered heterocycle
comprising carbon
atoms and 1-4 heteroatoms selected from N, 0, and S(0)p;
R11 at each occurrence is independently hydrogen, C1_4 alkyl substituted with
0-3 Rf,
CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-
3 Rd, or -
(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms
selected
from N, 0, and S(0)p substituted with 0-3 Rd;
Ra and Ral at each occurrence are independently hydrogen, F, Cl, Br, OCF3,
CF3,
CHF2, CN, NO2, -(CH2)rORb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -
(CH2)r0C(0)Rb,
-(CH2)rNR11R11, -(CH2),C(0)NR11R11, -(CH2)rNRbC(0)RC, -(CH2)rNRbC(0)ORC, -
NRbC(0)NR11R11, -S(0)pNR11R11, _NRI:s(c)pRc, _sow,K _s(0.)2,-, c,
C1_6 alkyl substituted
with 0-3 Rf, C1_6haloa1kyl, C2_6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl
substituted with
0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle
comprising
carbon atoms and 1-4 heteroatoms selected from N, 0, and S(0)p substituted
with 0-3 Rf;
Rb at each occurrence is independently hydrogen, C1-6 alkyl substituted with 0-
3 Rd,
C1_6haloa1kyl, C3_6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7
membered heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N, 0, and S(0)p
substituted with
0-3 Rfor (CH2)r-phenyl substituted with 0-3 Rd;
Rc is C1_6 alkyl substituted with 0-3 Rf, (CH2)r-C3_6cycloa1kyl substituted
with 0-3 Rf,
(CH2)r-phenyl substituted with 0-3 Rf; or
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO2, -
ORe, -(CH2)rC(0)12c, -NReRe, -NReC(0)0Rc, C1_6 alkyl, or (CH2)r-phenyl
substituted with 0-3
Rf;
Re at each occurrence is independently selected from hydrogen, C1_6 alkyl, C3_
6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 Rf;
47

Rf independently at each occurrence is hydrogen, halo, CN, NH2, OH,
C3_6cyc1oa1ky1,
CF3, 0(C1-6alkyl), or a -(CH2)r-5-7 membered heteroaryl comprising carbon
atoms and 1-4
heteroatoms selected from N, 0, and S(0)p;
p is 0, 1, or 2; and
r is 0, 1, 2, 3, or 4
3. The method of Claim 1, wherein the Tyk2 inhibitor is of the formula:
<IMG>
or a pharmaceutically acceptable salt thereof, wherein
R1 is C i3a1kyi optionally substituted by 0-7 [Zia
Ria at each occurrence is independently hydrogen, deuterium, F, CI, Br, C13 or
CN;
R2 is C1,6 alkyl substituted with 0-4 R2a, C3_6 cycloalkyl substituted with 0-
4 R2a,
C6_10 aryl substituted with 0-4 R2a, a 5-14 membered heterocycle containing 1-
4
heteroatoms selected from N, 0, and S, substituted with 0-4 R2a, NR6R6 or ORb;
R2a at each occurrence is independently hydrogen, =0, halo, OCF3, CN, NO2,
-(CH2),ORb, -(CHASRb, -(CHAC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)r0C(0)Rb,
(CH2)rNR11R11, -(CH2)rC(0)NR11R11, -(CH2)rNRbC(0)12C, -(CH2)rNRbC(0)ORC,
-NRbC(0)NR11R11, _S(0)pNR11R11, _NRbs(c)pRc, _soyK p-c,
) C1,6 alkyl substituted with
0-3 Ra, C1,6 halo alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-1
Ra or
a-(CH2)r-5-7 membered heterocycle comprising carbon atoms or 1-4 heteroatoms
selected
from N, 0, and S(0)p substituted with 0-2 Ra;
or one R2a and another R2a, together with the atoms to which they are
attached,
combine to form a fused 5-6 membered ring wherein said fused ring may be
substituted
with 0-2 Ra;
R3 is -(CH2)r-3-14 membered carbocycle substituted 0-5 R3a;
R3a at each occurrence is independently hydrogen, =0, halo, OCF3, CN, NO2,
-(CH2)r0Rb, -(CHASRb, -(CHAC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)r0C(0)Rb,
(CH2)rNR11R11, -(CH2)rC(0)NR11R11, -(CHANRbC(0)RC, -(CHANRbC(0)ORC,
-NRbC(0)NR11R11, _S(0)pNR11R11, _NRbs(c)pRc, _soyK p-c,
) C1,6 alkyl substituted with
0-3 Ra, C1,6 halo alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-3
Ra or
48

a-(CH2),-5-10 membered heterocycle comprising carbon atoms or 1-4 heteroatoms
selected
from N, 0, and S(0)p substituted with 0-3 Ra;
or two R3a, together with the atoms to which they are attached, combine to
form a
fused ring wherein said ring is selected from phenyl and a 5-7 membered
heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N, S or 0, said
fused ring
may be further substituted by Ra;
R4 and R5 are independently hydrogen, C 1_4 alkyl substituted with 0-1 Rf,
(CH2),-phenyl substituted with 0-3 Rd, or a -(CH2)-5-7 membered heterocycle
comprising
carbon atoms and 1-4 heteroatoms selected from N, 0, and S(0)p;
R6 and R11 at each occurrence are independently hydrogen, C 1_4 alkyl
substituted
with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl
substituted with
0-3 Rd, or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4
heteroatoms selected from N, 0, and S(0)p substituted with 0-3 Rd;
Ra at each occurrence is hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2,
-(CH2),ORb, -(CHASRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)r0C(0)Rb,
-(CH2)rNR11R11, -(CH2)rC(0)NR11R11, -(CH2)rNRbC(0)12c, -(CH2)rNRbC(0)012c,
-NRbC(0)NR11,-.t(, -11 S(0)pNR11R11, -NRbS(0)pRc, -S(0)12c, -S(0)212c,
Ci_olkyl
substituted with 0-3 Rf, Ci_6haloalkyl, -(CH2)r-3-14 membered carbocycle, or -
(CH2)r-5-7
membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from
N, 0,
and S(0)p substituted with 0-3 Rf;
Rb at each occurrence is hydrogen, C1_6 alkyl substituted with 0-3 Rd,
C1_6 halo alkyl, C3_6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7
membered
heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, 0,
and S(0)p
substituted with 0-3 Rf, or (CH2)r-phenyl substituted with 0-3 Rd;
Rc is C1_6 alkyl substituted with 0-3 Rf, (CH2)r-C3_6 cycloalkyl substituted
with 0-3
Rf or (CH2)r-phenyl substituted with 0-3 Rf;
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO2,
ORe, -(CH2)rC(0)12c, NReRe, -NReC(0)0Rc, C1_6 alkyl or (CH2)r-phenyl
substituted
with 0-3 Rf;
Re at each occurrence is independently selected from hydrogen, C1_6 alkyl,
C3_6 cycloalkyl and (CH2)r-phenyl substituted with 0-3 Rf;
Rf independently at each occurrence is hydrogen, halo, CN, NH2, OH,
C3_6 cycloalkyl, CF3, 0(Ci_6a1ky1) or a -(CH2)r-5-7 membered heteroaryl
comprising
carbon atoms and 1-4 heteroatoms selected from N, 0, and S(0)p;
49

p is 0, 1, or 2; and
r is 0,1,2,3, or 4.
4. The method of Claim 1, wherein the Tyk2 inhibitor is of the formula:
<IMG>
or a pharmaceutically acceptable salt thereof, wherein
Y is N or CR6;
R1 is H, Ci_3a1ky1 or C3_6cyc1oa1ky1, each optionally substituted by 0-7 Rla;
Ria at each occurrence is independently hydrogen, deuterium, F, Cl, Br or CN;
R2 is Ci_olkyl, -(CH2),-3-14 membered carbocycle substituted with 0-1 R2a or a
5-14
membered heterocycle containing 1-4 heteroatoms selected from N, 0, and S,
each group
substituted with 0-4 R2a (for the sake of clarity, R2is intended to include
substituted methyl
groups such as
R2a at each occurrence is independently hydrogen, =0, halo, OCF3, CN, NO2, -
(CH2),ORb, -(CH2),SRb, -(CH2),C(0)Rb, -(CH2),C(0)0Rb, -(CH2),OC(0)Rb,
CH2),NR11R11, -
(CH2),C(0)NR11R11, -(CH2),NRbC(0)RC, -(CH2),NRbC(0)ORC, -NRbC(0)NR11R11, -
S(0)pNR11R11, -NRbS(0)pRc, -S(0)pRc, Ci_6 alkyl substituted with 0-3 Ra,
Ci_6haloalkyl, C2_
6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl substituted with 0-3 Ra, -
(CH2),-3-14 membered
carbocycle substituted with 0-1 Ra or a -(CH2),-5-7 membered heterocycle
comprising carbon
atoms or 1-4 heteroatoms selected from N, 0, and S(0)p substituted with 0-2
Ra;
R3 is C3_10 cycloalkyl, C6_10 aryl or a 5-10 membered heterocycle containing 1-
4
heteroatoms selected from N, 0, and S, each group substituted with 0-4 R3a;
R3a at each occurrence is independently hydrogen, =0, halo, OCF3, CF3, CHF2,
CN,
NO2, -(CH2),ORb, -(CH2),SRb, -(CH2),C(0)Rb, -(CH2),C(0)0Rb, -(CH2),OC(0)Rb, -
(CH2),NR11R11, -(CH2),C(0)NR11R11, -(CH2),NRbC(0)RC, -(CH2),NRbC(0)ORC, -
NRbC(0)NR11R11, -S(0)pNR11R11, -NRbS(0)pRc, -S(0)pRc, Ci_6 alkyl substituted
with 0-3 Ra,
C2_6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl substituted with 0-3 Ra,
C1_6haloa1kyl, -
(CH2),-3-14 membered carbocycle substituted with 0-3 Ra or a -(CH2),-5-10
membered
heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, 0,
and
S(0)p substituted with 0-3 Ra;

or two R3a, together with the atoms to which they are attached, combine to
form a
fused ring wherein said ring is selected from phenyl and a heterocycle
comprising carbon
atoms and 1-4 heteroatoms selected from N, 0, and S(0)p, each fused ring
substituted with 0-
3 Ral;
R4 and R5 are independently hydrogen, C1_4 alkyl substituted with 0-1 Rf,
(CH2)r-
phenyl substituted with 0-3 Rd or a -(CH2)-5-7 membered heterocycle comprising
carbon
atoms and 1-4 heteroatoms selected from N, 0, and S(0)p;
R6 is hydrogen, halo, Ci_4a1ky1, Ci4haloalkyl, OCi_4ha1oa1ky1, OCi_4a1ky1, CN,
NO2 or
OH;
R11 at each occurrence is independently hydrogen, C1_4 alkyl substituted with
0-3 Rf,
CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-
3 Rd or -(CH2)r-
5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected
from N, 0,
and S(0)p substituted with 0-3 Rd;
Ra and Rai at each occurrence are independently hydrogen, F, Cl, Br, OCF3,
CF3,
CHF2, CN, NO2, -(CH2)r0Rb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -
(CH2)r0C(0)Rb,
-(CH2)rNR11R11, -(CH2)rC(0)NR11R11, -(CH2)rNRbC(0)12c, -(CH2)rNRbC(0)012c, -
NRbC(0)NR11R11, -S(0)pNR"R", -NRbS(0)pRc, -S(0)12c, -S(0)212c, C1,6 alkyl
substituted
with 0-3 Rf, C1,6 haloalkyl, C2_6 alkenyl substituted with 0-3 Ra, C2_6
alkynyl substituted with
0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle
comprising
carbon atoms and 1-4 heteroatoms selected from N, 0, and S(0)p substituted
with 0-3 Rf;
Rb is hydrogen, C1_6 alkyl substituted with 0-3 Rd, C1_6 haloalkyl, C3_6
cycloalkyl
substituted with 0-2 Rd, or -(CH2)r-5-7 membered heterocycle comprising carbon
atoms and
1-4 heteroatoms selected from N, 0, and S(0)p substituted with 0-3 Rfor (CH2)r-
phenyl
substituted with 0-3 Rd;
Rc is C1,6 alkyl substituted with 0-3 Rf, (CH2)r-C3,6 cycloalkyl substituted
with 0-3
Rfor (CH2)r-phenyl substituted with 0-3 Rf;
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO2, -
ORe, -(CH2)rC(0)12c, -NReRe, -NReC(0)0Rc, C1,6 alkyl or (CH2)r-phenyl
substituted with 0-3
Rf;
Re at each occurrence is independently selected from hydrogen, C1,6 alkyl, C3_
6cyc10a1ky1 and (CH2)r-phenyl substituted with 0-3 Rf;
Rf independently at each occurrence is hydrogen, halo, CN, NH2, OH, C3_6
cycloalkyl,
CF3, 0(Ci_6a1ky1) or a -(CH2)r-5-7 membered heterocycle comprising carbon
atoms and 1-4
heteroatoms selected from N, 0, and S(0)p;
51

p is 0, 1, or 2; and
r is 0, 1, 2, 3, or 4.
5. The method of Claim 1 or 4, wherein the Tyk2 inhibitor is of the
formula:
<IMG>
or a pharmaceutically acceptable salt thereof.
6. The method of any one of Claims 1 to 5, wherein the effective amount of
the Tyk2
inhibitor, or the pharmaceutically acceptable salt ranges from about 0.1
mg/day to about 250
mg/day.
7. The method of any one of Claims 1 to 6, wherein the effective amount of
the Tyk2
inhibitor, or the pharmaceutically acceptable salt ranges from about 0.2
mg/day to about 100
mg./day, about 0.5 mg/ day to about 50 mg/day, and about 1.0 mg to about 24
mg/day.
8. The method of any one of Claims 1 to 7, wherein the effective amount of
the Tyk2
inhibitor, or the pharmaceutically acceptable salt ranges from about 1 mg/day
to about 15
mg/day, about 1 mg/day to about 14 mg/day, about 2 mg/day to about 14 mg/day,
about 2
mg/day to about 12 mg/day, or about 3 mg/day to about 12 mg/day.
9. The method of any one of Claims 1 to 8, wherein the effective amount of
the Tyk2
inhibitor is about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day,
about 6
mg/day, about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about
11 mg/day,
or about 12 mg/day.
10. The method of any one of Claims 1 to 9, wherein the effective amount of
the Tyk2
inhibitor is about 6 mg/day.
52

11. The method of any one of Claims 1 to 10, wherein the N42-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is greater than 95% stereomerically pure.
12. The method of any one of Claims 1 to 11, wherein the N42-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is greater than 99% stereomerically pure.
13. The method of any one of Claims 1 to 12, wherein the N-[2-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is greater than 99.5% stereomerically pure.
14. The method of any one of Claims 1 to 13, wherein the N-[2-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is greater than 99.9% stereomerically pure.
15. The method of any one of Claims 1 to 14, wherein the N-[2-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is a single crystalline form.
16. The method of any one of Claims 1 to 15, wherein the N-[2-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is a single crystalline Form B characterized by X-ray powder diffraction peaks
at 2 angles
selected from 10.1 , 13.5 , 20.7 , and 26.9 .
17. The method of any one of Claims 1 to 16, wherein the N-[2-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is a single crystalline Form B characterized by X-ray powder diffraction peaks
at 2 angles
selected from 10.1 , 13.5 , 15.7 , 18.1 , 20.7 , 24.7 , and 26.9 .
18. The method of any one of Claims 1 to 17, wherein the N-[2-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is a single crystalline Form B characterized by X-ray powder diffraction peaks
at 2 angles
selected from 10.1 , 13.5 , 15.7 , 16.3 , 18.1 , 20.7 , 22.5 , 24.7 , 26.2 ,
26.9 , and 29.1 .
53

19. The method of any one of Claims 1 to 18, wherein the N-[2-R1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl] -2,3 -dihydro- 1,3-dio xo - 1H- iso
indo1-4- yl] acetamide
is at least 90% single crystalline Form B.
20. The method of any one of Claims 1 to 19, wherein the N42-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl] -2,3 -dihydro- 1,3-dio xo - 1H- iso
indo1-4- yl] acetamide
is at least 95% single crystalline Form B.
21. The method of any one of Claims 1 to 20, wherein the N42-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl] -2,3 -dihydro- 1,3-dio xo - 1H- iso
indo1-4- yl] acetamide
is at least 99% single crystalline Form B.
22. The method of any one of Claims 1 to 20, wherein the effective amount
of N42-[(1S)-
1-(3 -etho xy-4- metho xypheny1)-2-(methylsulfo nyl) ethyl] -2,3 -dihydro -
1,3 -dio xo - 1H-iso indo I-
4-yl]acetamide, or the pharmaceutically acceptable salt thereof, ranges from
about 0.5 mg to
about 1000 mg per day, about 1 mg to about 1000 mg per day, about 5 mg to
about 500 mg
per day, about 10 mg to about 200 mg per day, about 10 mg to about 100 mg per
day, about
40 mg to about 100 mg per day, about 20 mg to about 40 mg per day, about 0.1
mg to about
mg per day, about 0.5 mg to about 5 mg per day, about 1 mg to about 20 mg per
day, and
about 1 mg to about 10 mg per day, about 1 mg to about 100 mg per day, about 1
mg to about
80 mg per day, about 5 mg to about 70 mg per day, and about 10 mg to about 60
mg per day.
23. The method of any one of Claims 1 to 22, wherein the effective amount
of N42-[(1S)-
1-(3 -etho xy-4- metho xypheny1)-2-(methylsulfo nyl) ethyl] -2,3 -dihydro -
1,3 -dio xo - 1H-iso indo I-
4-yl]acetamide, or the pharmaceutically acceptable salt thereof, ranges from
about 10 mg to
about 60 mg per day.
24. The method of any one of Claims 1 to 23, wherein the effective amount
of N42-[(1S)-
1-(3 -etho xy-4- metho xypheny1)-2-(methylsulfo nyl) ethyl] -2,3 -dihydro -
1,3 -dio xo - 1H-iso indo I-
4-yl]acetamide, or the pharmaceutically acceptable salt thereof, ranges from
about 10 mg to
about 40 mg per day.
25. The method of any one of Claims 1 to 24, wherein the effective amount
of N42-[(1S)-
1-(3 -etho xy-4- metho xypheny1)-2-(methylsulfo nyl) ethyl] -2,3 -dihydro -
1,3 -dio xo - 1H-iso indo I-
4-yl]acetamide, or the pharmaceutically acceptable salt thereof, is about 10
mg administered
once or twice a day.
54

26. The method of any one of Claims 1 to 24, wherein the effective amount
of N42-[(1S)-
1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-1,3-dioxo-1H-
isoindol-
4-yl[acetamide, or the pharmaceutically acceptable salt thereof, is about 20
mg administered
once or twice a day.
27. The method of any one of Claims 1 to 23, wherein the effective amount
of N42-[(1S)-
1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-1,3-dioxo-1H-
isoindol-
4-yl[acetamide, or the pharmaceutically acceptable salt thereof, is about 10
mg per day, about
15 mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day,
about 35 mg
per day, about 40 mg per day, about 45 mg per day, about 50 mg per day, about
55 mg per
day, or about 60 mg per day.
28. The method of any one of Claims 1 to 23 and 27, wherein the effective
amount of N-
[2-[(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-1,3-
dioxo-1H-
isoindo1-4-yl[acetamide, or the pharmaceutically acceptable salt thereof, is
about 30 mg per
day or about 60 mg per day.
29. The method of any one of Claims 1 to 23, 27, and 28, wherein the
effective amount of
N-[2-[(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-
1,3-dioxo-
1H-isoindo1-4-yl[acetamide is about 30 mg administered once daily.
30. The method of any one of Claims 1 to 23, 27, and 28, wherein the
effective amount of
N-[2-[(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-
1,3-dioxo-
1H-isoindo1-4-yl[acetamide is about 30 mg administered twice daily.
31. The method of any one of Claims 1 to 23, 27, and 28, wherein the N42-
[(1S)-1-(3-
ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-1,3-dioxo-1H-
isoindo1-4-
yl[acetamide is titrated to a dosage of about 30 mg administered twice daily
using the
following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: about 30 mg twice daily.

32. The method of any one of Claims 1 to 22, wherein the effective amount
of N42-[(1S)-
1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-
isoindo1-
4-yl]acetamide, or the pharmaceutically acceptable salt thereof, ranges from
about 40 mg to
about 100 mg per day.
33. The method of any one of Claims 1 to 22 and 32, wherein the N42-[(1S)-1-
(3-ethoxy-
4-methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide is titrated to a dosage of between about 40 mg/day to between
about 100
mg/day using the following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: between about 40 mg/day to between about 100 mg/day.
34. The method of any one of Claims 1 to 22, wherein the effective amount
of N42-[(1S)-
1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-
isoindo1-
4-yl]acetamide, or the pharmaceutically acceptable salt thereof, is about 20
mg administered
twice daily.
35. The method of any one of Claims 1 to 22 and 34, wherein the N42-[(1S)-1-
(3-ethoxy-
4-methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide is titrated to a dosage of about 20 mg administered twice daily
using the
following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: about 20 mg twice daily.
36. The method of any one of Claims 1 to 22, wherein the effective amount
of N42-[(1S)-
1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-
isoindol-
56

4-yl]acetamide, or the pharmaceutically acceptable salt thereof, ranges from
about 4 mg to
between about 10 mg per day.
37. The method of any one of Claims 1 to 22 and 36, wherein the N42-[(1S)-1-
(3-ethoxy-
4-methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide is titrated to a dosage of between about 4 mg/day to between
about 10 mg/day
using the following titration schedule:
Day 1: about 1 mg in morning;
Day 2: about 1 mg in morning and about 1 mg in evening;
Day 3: about 1 mg in morning and about 2 mg in evening;
Day 4: about 2 mg in morning and about 2 mg in evening;
Day 5: about 2 mg in morning and about 3 mg in evening; and
Day 6 and thereafter: between about 4 mg/day to between about 10 mg/day.
38. The method of any one of Claims 1 to 22, wherein the effective amount
of N42-[(1S)-
1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-
isoindo1-
4-yl]acetamide, or the pharmaceutically acceptable salt thereof, is about 3
mg/day.
39. The method of any one of Claims 1 to 22 and 38, wherein the N42-[(1S)-1-
(3-
ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-
isoindo1-4-
yl]acetamide is titrated to a dosage of 3 mg administered twice daily using
the following
titration schedule:
Day 1: about 1 mg in morning;
Day 2: about 1 mg in morning and about 1 mg in evening;
Day 3: about 10 mg in morning and about 2 mg in evening;
Day 4: about 2 mg in morning and about 2 mg in evening;
Day 5: about 2 mg in morning and about 3 mg in evening; and
Day 6 and thereafter: about 3 mg twice daily.
40. The method of any one of Claims 1 to 39, wherein the N42-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is formulated as part of a pharmaceutical composition comprising a
pharmaceutically
acceptable carrier.
57

41. The method of any one of Claims 1 to 40, wherein the N42-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is administered parenterally, transdermally, mucosally, nasally, buccally,
sublingually, or
orally.
42. The method of any one of Claims 1 to 41, wherein the N42-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is administered orally.
43. The method of any one of Claims 1 to 42, wherein the N42-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is administered orally in the form of a tablet or a capsule.
44. The method of any one of Claims 40 to 43, wherein the N42-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is formulated as an extended release form.
45. The method of any one of Claims 40 to 43, wherein the N42-[(1S)-1-(3-
ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yl]acetamide
is formulated as an immediate release form.
46. The method of any one of Claims 1 to 45, wherein the disease or
disorder is selected
from a viral, genetic, inflammatory, allergic, and autoimmune disease.
47. The method of any one of Claims 1 to 46, wherein the disease or
disorder is selected
from chronic obstructive pulmonary disease, asthma, chronic pulmonary
inflammatory
disease, hyperoxic alveolar injury, inflammatory skin disease, psoriasis,
psoriatic arthritis,
rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, atopic
dermatitis, rheumatoid
spondylitis, depression, osteoarthritis, contact dermatitis, ankylo sing
spondylitis, lupus, lupus
nephritis, cutaneous lupus erythematosus, systemic lupus erythrematosus,
erythema nodosum
leprosum, Sjögren's syndrome, inflammatory bowel disease, Crohn's Disease,
Behget's
Disease, and ulcerative colitis.
48. The method of any one of Claims 1 to 47, wherein the disease or
disorder is selected
from psoriasis, psoriatic arthritis, contact dermatitis, systemic lupus
erythrematosus,
cutaneous lupus erythematosus, and ulcerative colitis.
58

49. The method of any one of Claims 1 to 48, wherein the disease or
disorder is psoriasis.
50. The method of any one of Claims 1 to 49, wherein the disease or
disorder is plaque
psoriasis.
51. The method of any one of Claims 1 to 50, wherein the disease or
disorder is moderate
to severe plaque psoriasis.
52. The method of any one of Claims 49 to 51, wherein the subject is a
candidate for
phototherapy or systematic therapy.
53. The method of any one of Claims 1 to 48, wherein the disease or
disorder is psoriatic
arthritis.
54. A pharmaceutical composition comprising a therapeutically effective
amount of N42-
[(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-1,3-
dioxo-1H-
isoindo1-4-yl[acetamide, or a pharmaceutically acceptable thereof, as defined
in any one of
Claims 11 to 21; and a therapeutically effective amount of a Tyk2 inhibitor as
defined in any
one of Claims 2 to 5.
55. The pharmaceutical composition of Claim 54, wherein the Tyk2 inhibitor
is of the
formula:
<IMG>
or a pharmaceutically acceptable salt thereof.
56. The pharmaceutical composition of Claims 54 or 55, wherein the
composition is
formulated for administration of from about 1 mg/day to about 15 mg/day, about
1 mg/day to
about 14 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day to about 12
mg/day, or
about 3 mg/day to about 12 mg/day, of the Tyk inhbitor.
59

57. The pharmaceutical composition of any one of Claims 54 to 56, wherein
the
composition is formulated for administration of about 2 mg/day, about 3
mg/day, about 4
mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about 8 mg/day, about
9 mg/day,
about 10 mg/day, about 11 mg/day, or about 12 mg/day of the Tyk inhibitor.
58. The pharmaceutical composition of any one of Claims 54 to 57, wherein
the
composition is formulated for administration of about 6 mg/day of the Tyk
inhibitor.
59. The pharmaceutical composition of any one of Claims 54 to 58, wherein
the
composition is formulated for administration of from about 1 mg to about 1000
mg per day,
about 5 mg to about 500 mg per day, about 10 mg to about 200 mg per day, about
10 mg to
about 100 mg per day, about 40 mg to about 100 mg per day, about 20 mg to
about 40 mg per
day, about 0.1 mg to about 10 mg per day, about 0.5 mg to about 5 mg per day,
about 1 mg to
about 20 mg per day, and about 1 mg to about 10 mg per day, about 1 mg to
about 100 mg
per day, about 1 mg to about 80 mg per day, about 5 mg to about 70 mg per day,
and about
mg to about 60 mg per day of N42-[(1S)-1-(3-ethoxy-4-methoxypheny1)-2-
(methylsulfonyl)ethyl[-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-yl[acetamide, or
the
pharmaceutically acceptable salt thereof.
60. The pharmaceutical composition of any one of Claims 54 to 59, wherein
the
composition is formulated for administration of from about 10 mg to about 60
mg per day of
N-[2-[(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-
1,3-dioxo-
1H-isoindo1-4-yl[acetamide, or the pharmaceutically acceptable salt thereof.
61. The pharmaceutical composition of any one of Claims 54 to 60, wherein
the
composition is formulated for administration of about 10 mg per day, about 15
mg per day,
about 20 mg per day, about 25 mg per day, about 30 mg per day, about 35 mg per
day, about
40 mg per day, about 45 mg per day, about 50 mg per day, about 55 mg per day,
or about 60
mg per day of N-[2-[(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-
2,3-
dihydro-1,3-dioxo-1H-isoindo1-4-yl[acetamide, or the pharmaceutically
acceptable salt
thereof.
62. The pharmaceutical composition of any one of Claims 54 to 61, wherein
the
composition is formulated for administration of about 30 mg per day or about
60 mg per day
of N- [2- [(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-
dihydro-1,3-
dioxo-1H-isoindo1-4-yl[acetamide, or the pharmaceutically acceptable salt
thereof.

63. The pharmaceutical composition of any one of Claims 54 to 62, wherein
the
composition is formulated for administration of about 30 mg once daily of N42-
[(1S)-1-(3-
ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-1,3-dioxo-1H-
isoindo1-4-
yl[acetamide, or the pharmaceutically acceptable salt thereof.
64. The pharmaceutical composition of any one of Claims 54 to 61, wherein
the
composition is formulated for administration of about 30 mg twice daily of N42-
[(1S)-1-(3-
ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-1,3-dioxo-1H-
isoindo1-4-
yl[acetamide, or the pharmaceutically acceptable salt thereof.
65. The pharmaceutical composition of any one of Claims 54 to 60, wherein
the
composition is formulated for administration of from about 10 mg to about 40
mg per day of
N-[2-[(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-
1,3-dioxo-
1H-isoindo1-4-yl[acetamide, or the pharmaceutically acceptable salt thereof.
66. The pharmaceutical composition of any one of Claims 54 to 60 and 65,
wherein the
composition is formulated for administration of from about 10 mg once or twice
daily of N-
[2-[(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-1,3-
dioxo-1H-
isoindo1-4-yl[acetamide, or the pharmaceutically acceptable salt thereof.
67. The pharmaceutical composition of any one of Claims 54 to 60 and 65,
wherein the
composition is formulated for administration of from about 20 mg once or twice
daily of N-
[2-[(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyl[-2,3-dihydro-1,3-
dioxo-1H-
isoindo1-4-yl[acetamide, or the pharmaceutically acceptable salt thereof.
68. The pharmaceutical composition of any one of Claims 54 to 67, wherein
the
pharmaceutical composition is in the form of a tablet or a capsule.
69. The pharmaceutical composition of any one of Claims 54 to 68, wherein
the
pharmaceutical composition is formulated for extended release.
70. The pharmaceutical composition of any one of Claims 54 to 68, wherein
the
pharmaceutical composition is formulated for immediate release.
61

Description

CA 03138686 2021-10-29
WO 2020/223431 PCT/US2020/030608
COMBINATION THERAPIES COMPRISING APREMILAST AND TYK2
INHIBITORS
RELATED APPLICATIONS
[0001] This application claims priority to International Application No.
PCT/US2019/029772, filed April 30, 2019, the entire contents of which are
incorporated
herein by reference.
BACKGROUND
[0002] N-[2-R1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyll-2,3-
dihydro-
1,3-dioxo-1H-isoindo1-4-yllacetamide (apremilast), marketed as Otezla , is a
phosphodiesterase type 4 (PDE4) inhibitor currently approved for treating both
moderate to
severe plaque psoriasis and active psoriatic arthritis. PDE4 inhibition by
apremilast elevates
cyclic adenosine monophosphate (cAMP) levels in immune cells. This in turn
down-regulates
inflammatory responses by reducing the expression of pro-inflammatory
mediators such as
TNF-a, IL-23, IL-17, and other inflammatory cytokines, and increases the
production of
anti-inflammatory mediators. Studies have shown that a 75% reduction in plaque
psoriasis is
achievable in some patients in as little as just over 4 months of treatment.
[0003] Tyrosine kinase 2 (Tyk2), an intracellular signaling enzyme, activates
signal
transducer and activator of transcription (STAT)¨dependent gene expression and
functional
responses of IL-12, IL-23, and type I and III interferon receptors. Amongst
other conditions,
tyrosine kinase inhibitors (TKIs) have recently gained attention as effective
agents for
treating psoriasis and related conditions. The TM inhibitor BMS-986165, for
example,
recently showed positive results in phase 2 clinical trials in subjects with
moderate to severe
plaque psoriasis. See Kim Papp, M.D., Phase 2 Trial of Selective Tyrosine
Kinase 2
Inhibition in Psoriasis, The New England Journal of Medicine, Sept. 12, 2018.
SUMMARY
[0004] It has now been found that the combination of apremilast and the Tyk2
inhibitor 6-
(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methy1-1H-1,2,4-triazol-3-
yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165)
synergistically
reduces pro-inflammatory cytokines expressed in a whole blood assay under
conditions that
stimulate Th17 cells. For example, there was over a 2-fold increase in the
inhibition of IL-
17F expression using the combination of 0.01 04 BMS-986165 and 1 04 apremilast
when
compared to the use of each drug alone. See e.g., Table 5 in the
Exemplification section.
1

CA 03138686 2021-10-29
WO 2020/223431 PCT/US2020/030608
Similar results were seen at 0.1 (1M concentrations of BMS-986165 with 1 (1M
apremilast.
See e.g., Table 5. The combination of BMS-986165 with 1 (.04 apremilast also
reduced
cytokine expression for IL-17A and IL-22 at values of 2-fold or greater over
the use of each
drug alone. See e.g., Table 5.
[0005] It was also found that the combination of apremilast and BMS-986165
elicit
complementary effects against certain pro-inflammatory cytokines. BMS-986165,
for
example, increased TNF-a and GM-CSF cytokine in whole blood assay, while
apremilast
inhibited the production of these cytokines. See e.g., Table 5 where the %
control for 1 (.04
apremilast was 10.7 and the % control for 0.01 (.04 BMS-986165 was 143.1
against TNF-a.
When administered in combination, however, apremilast corrected the deficiency
of BMS-
986165 thereby producing a complementary effect of 13.5% inhibition against
TNF-a. See
e.g., Table 5. This trend was also established at 0.1 (1M concentrations of
BMS-986165 and
against cytokine GM-CSF. See e.g., Table 5. These results illustrate the
synergistic and
complementary pharmacological effects of BMS-986165 and apremilast.
[0006] In addition to whole blood assay, the combination of BMS-986165 and
apremilast
elicit complementary effects against certain pro-inflammatory cytokines in LPS
stimulated
PBMCs as well. BMS-986165 increased IL-23, IL-12 and TNF-a, while apremilast
inhibited
the production of these cytokines. See e.g., Table 6 in the Exemplification
section. These
results further support the advantage of combining BMS-986165 and apremilast
in treatment
of Th17 related diseases.
[0007] Provided herein, therefore are methods of treating diseases or
disorders responsive
to the inhibition of PDE4 in a subject using an effective amount of
apremilast, or a
pharmaceutically acceptable salt thereof, and an effective amount of a Tyk2
inhibitor such as
BMS-986165. Such diseases and disorders include e.g., inflammatory diseases
such as
psoriasis, psoriatic arthritis, and ulcerative colitis.
[0008] Also provided herein are pharmaceutical compositions comprising an
effective
amount of apremilast, or a pharmaceutically acceptable salt thereof, and an
effective amount
of a Tyk2 inhibitor such as BMS-986165.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 illustrates interleukin-17a (IL-17a) cytokine production
(percent of control)
by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-
CD28, IL-113,
IL-6 and IL-23 (Th17) stimulated whole blood ¨ TruCulture tube assay.
2

CA 03138686 2021-10-29
WO 2020/223431 PCT/US2020/030608
[0010] FIG. 2 illustrates interleukin-17A (IL-17A) cytokine production by
apremilast and
BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-113, IL-6 and
IL-23
(Th17) stimulated whole blood ¨ TruCulture tube assay.
[0011] FIG. 3 illustrates interleukin-17F (IL-17F) cytokine production
(percent of control)
by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-
CD28, IL-113,
IL-6 and IL-23 (Th17) stimulated whole blood ¨ TruCulture tube assay.
[0012] FIG. 4 illustrates interleukin-17F (IL-17F) cytokine production by
apremilast and
BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-113, IL-6 and
IL-23
(Th17) stimulated whole blood ¨ TruCulture tube assay.
[0013] FIG. 5 illustrates interleukin-22 (IL-22) cytokine production (percent
of control) by
apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28,
IL-113,
IL-6 and IL-23 (Th17) stimulated whole blood ¨ TruCulture tube assay.
[0014] FIG. 6 illustrates interleukin-22 (IL-22) cytokine production by
apremilast and
BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28, IL-113, IL-6 and
IL-23
(Th17) stimulated whole blood ¨ TruCulture tube assay.
[0015] FIG. 7 illustrates tumor necrosis factor alpha (TNF-a) cytokine
production (percent
of control) by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-
CD3/anti-
CD28, IL-113, IL-6 and IL-23 (Th17) stimulated whole blood ¨ TruCulture tube
assay.
[0016] FIG. 8 illustrates tumor necrosis factor alpha (TNF-a) cytokine
production by
apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28,
IL-113,
IL-6 and IL-23 (Th17) stimulated whole blood ¨ TruCulture tube assay.
[0017] FIG. 9 illustrates granulocyte-macrophage colony-stimulating factor (GM-
CSF)
cytokine production (percent of control) by apremilast and BMS-986165 in anti-
CD3/anti-
CD28 (Th0) or anti-CD3/anti-CD28, IL-113, IL-6 and IL-23 (Th17) stimulated
whole blood ¨
TruCulture tube assay.
[0018] FIG. 10 illustrates granulocyte-macrophage colony-stimulating factor
(GM-CSF)
cytokine production by apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0)
or anti-
CD3/anti-CD28, IL-113, IL-6 and IL-23 (Th17) stimulated whole blood ¨
TruCulture tube
assay.
[0019] FIG. 11 illustrates interleukin-23 (IL-23) cytokine production by
apremilast in
Lipopolysaccharide (_,PS) stimulated peripheral blood mononuclear cells
(PBMCs).
[0020] FIG. 12 illustrates interleukin-23 (IL-23) cytokine production by
apremilast and
Tyk2i (BMS-986165) in LPS stimulated PBMCs.
3

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[0021] FIG. 13 illustrates interleukin-12p40 (IL-12p40) cytokine production by
apremilast
and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
[0022] FIG. 14 illustrates interleukin-12p'70 (IL-12p'70) cytokine production
by apremilast
and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
[0023] FIG. 15 illustrates tumor necrosis factor alpha (TNF-a) cytokine
production by
apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
[0024] FIG. 16 illustrates interferon gamma (IFN-y) cytokine production by
apremilast and
Tyk2i (BMS-986165) in LPS stimulated PBMCs.
[0025] FIG. 17 illustrates monocyte chemoattractant protein-1 (MCP-1) cytokine
production by apremilast and Tyk2i (BMS-986165) in LPS stimulated PBMCs.
[0026] FIG. 18 illustrates fixed dose combination effects of apremilast and
Tyk2i (BMS-
986165) in IL-17A whole blood.
[0027] FIG. 19 illustrates fixed dose combination effects of apremilast and
Tyk2i (BMS-
986165) in IL-17F whole blood.
[0028] FIG. 20 illustrates fixed dose combination effects of apremilast and
Tyk2i (BMS-
986165) in IL-22 whole blood.
[0029] FIG. 21 illustrates fixed dose combination effects of apremilast and
Tyk2i (BMS-
986165) in TNF-a whole blood.
DETAILED DESCRIPTION
[0030] In a first embodiment, provided herein are methods for treating a
disease or disorder
responsive to the inhibition of cyclic nucleotide phosphodiesterase isoenzyme
IV (PDE4), the
method comprising administering to a subject an effective amount of N42-[(1S)-
1-(3-ethoxy-
4-methoxypheny1)-2-(methylsulfonyl)ethyll-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yllacetamide (apremilast), or a pharmaceutically acceptable salt thereof, and
an effective
amount of a Tyk2 inhibitor.
[0031] Alternatively, as part of a first embodiment, provided is the use of an
effective
amount of N- [2- [(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyll-
2,3-dihydro-
1,3-dioxo-1H-isoindo1-4-yllacetamide (apremilast), or a pharmaceutically
acceptable salt
thereof, and an effective amount of a Tyk2 inhibitor, in the manufacture of a
medicament for
treating a disease or disorder responsive to the inhibition of cyclic
nucleotide
phosphodiesterase isoenzyme IV (PDE4).
[0032] In another alternative, as a part of a first embodiment, provided is an
effective
amount of N- [2- [(1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyll-
2,3-dihydro-
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1,3-dioxo-1H-isoindo1-4-yl[acetamide (apremilast), or a pharmaceutically
acceptable salt
thereof, and an effective amount of a Tyk2 inhibitor, for use in treating a
disease or disorder
responsive to the inhibition of cyclic nucleotide phosphodiesterase isoenzyme
IV (PDE4).
1. Definitions
[0033] N-[2-R1S)-1-(3-ethoxy-4-methoxypheny1)-2-(methylsulfonyl)ethyll-2,3-
dihydro-
1,3-dioxo-1H-isoindo1-4-yllacetamide (apremilast) is disclosed in U.S. Patent
No. 6,962,940,
the contents of which are incorporated herein by reference, and refers to the
compound
having the following chemical structure:
ocH3
ocH2cH3
o
z
H
SO2CH3
H3C NH 0
II
0 .
[0034] Apremilast has a chiral center designated as (S) in the chemical
structure and name.
As used herein, this designation means that apremilast is optically enriched
as the (S)
enantiomer at this position in an amount of at least 80%, 90%, 95%, 98%, 99%,
or 99.9%
relative to the corresponding (R) enantiomer. Thus, when apremilast is
referred to herein as
being stereomerically or enantiomerically pure at a specified amount, it means
that the (S)
enantiomer is enriched in that amount. For example, N42-[(1S)-1-(3-ethoxy-4-
methoxypheny1)-2-(methylsulfonyl)ethyll-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-
yllacetamide
that is at least 95% stereomerically pure means that the compound contains
greater than or
equal to 95% of the (S) enantiomer and 5% or less of the (R) enantiomer.
[0035] Unless otherwise indicated, the administrations described herein
include
administering apremilast prior to, concurrently with, or after administration
of the Tyk2
inhibitor described herein. Thus, simultaneous administration is not necessary
for therapeutic
purposes. In one aspect, apremilast and a disclosed Tyk2 inhibitor are
administered together.
In another aspect, apremilast and a disclosed Tyk2 inhibitor are administered
at different
times on the same day. In another aspect, apremilast and a disclosed Tyk2
inhibitor are
administered at different times as separate tablets or capsules. In another
aspect, apremilast
and a disclosed Tyk2 inhibitor are administered in a fixed dose combination in
the same
tablet or capsule.

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[0036] The terms "treatment," "treat," and "treating" refer to reversing,
alleviating, or
inhibiting the progress of a disease or disorder responsive to the inhibition
of PDE4, or one or
more symptoms thereof, as described herein.
[0037] The term "subject" means an animal, such as a mammal, and such as a
human. The
terms "subject" and "patient" may be used interchangeably.
[0038] The term "effective amount" or "therapeutically effective amount"
refers to an
amount of a compound described herein that will elicit a biological or medical
response of a
subject e.g., a dosage of between 0.001 - 100 mg/kg body weight/day.
[0039] The term "pharmaceutically acceptable carrier" refers to a non-toxic
carrier,
adjuvant, or vehicle that does not adversely affect the pharmacological
activity of the
compound with which it is formulated, and which is also safe for human use.
Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used
in the
compositions of this disclosure include, but are not limited to, ion
exchangers, alumina,
aluminum stearate, magnesium stearate, lecithin, serum proteins, such as human
serum
albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium
sorbate,
partial glyceride mixtures of saturated vegetable fatty acids, water, salts or
electrolytes, such
as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen
phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, cellulose-
based substances (e.g., microcrystalline cellulose, hydroxypropyl
methylcellulose, lactose
monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene
glycol,
sodium carboxymethylcellulo se, polyacrylates, waxes, polyethylene-
polyoxypropylene-block
polymers, polyethylene glycol and wool fat.
[0040] The term "pharmaceutically acceptable salts" refer to salts prepared
from
pharmaceutically acceptable non-toxic acids or bases including inorganic acids
and bases and
organic acids and bases. Suitable pharmaceutically acceptable base addition
salts for the
compounds described herein include, but are not limited to include metallic
salts made from
aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic
salts made
from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine,
ethylene diamine, meglumine (N-methylglucamine) and procaine. Suitable non-
toxic acids
include, but are not limited to, inorganic and organic acids such as acetic,
alginic, anthranilic,
benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic,
fumaric, furoic,
galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic,
hydrochloric, isethionic,
6

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lactic, maleic, malic, mandelic, methane sulfonic, mucic, nitric, pamoic,
pantothenic,
phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,
sulfuric, tartaric
acid, and p-toluenesulfonic acid.
[0041] "Crystalline" refers to a solid form of a compound wherein there exists
long-range
atomic order in the positions of the atoms. The crystalline nature of a solid
can be confirmed,
for example, by examination of the X-ray powder diffraction pattern. A "single
crystalline
form" means that the recited compound, i.e., N-[2-[(1S)-1-(3-ethoxy-4-
methoxypheny1)-2-
(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindo1-4-yllacetamide, is
present as a
single crystal or a plurality of crystals in which each crystal has the same
crystal form (e.g.,
crystalline Form B). When the crystal form is defined as a specified
percentage of one
particular single crystalline form of the compound, the remainder is made up
of amorphous
form and/or crystalline forms other than the one or more particular forms that
are specified.
In one aspect, e.g., a disclosed crystalline form is at least 80% a single
crystalline form, at
least 90% a single crystalline form, at least 95% a single crystalline form,
or at least 99% a
single crystalline form by weight. Percent by weight of a particular crystal
form is determined
by the weight of the particular crystal form divided by the sum weight of the
particular crystal,
plus the weight of the other crystal forms present plus the weight of
amorphous form present
multiplied by 100%.
[0042] The term "amorphous" refers to a solid that is present in a non-
crystalline state or
form. Amorphous solids are disordered arrangements of molecules and therefore
possess no
distinguishable crystal lattice or unit cell and consequently have no
definable long range
ordering. Solid state ordering of solids may be determined by standard
techniques known in
the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning
calorimetry (DSC).
Amorphous solids can also be differentiated from crystalline solids e.g., by
birefringence
using polarized light microscopy.
[0043] The 2-theta values of the X-ray powder diffraction patterns for the
crystalline forms
described herein may vary slightly from one instrument to another and also
depending on
variations in sample preparation and batch to batch variation due to factors
such as
temperature variation, sample displacement, and the presence or absence of an
internal
standard. Therefore, unless otherwise defined, the XRPD patterns / assignments
recited
herein are not to be construed as absolute and can vary 0.2 degrees. It is
well known in the
art that this variability will account for the above factors without hindering
the unequivocal
identification of a crystal form.
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2. Tyk2 Inhibitors
[0044] Tyk2 inhibitors used in the disclosed methods and compositions include
compounds
which block the action of tyrosine kinase 2, a non-receptor tyrosine-protein
kinase encoded
by the Tyk2 gene.
[0045] In a second embodiment, the disclosed Tyk2 inhibitors include, but are
not limited
to, those described in Xingrui He et al., Expert Opinion on Therapeutics
Patents 2019, Vol.
29, No. 2, 137-149, the entire contents of which are incorporated herein by
reference.
[0046] In a third embodiment, the disclosed Tyk2 inhibitors may be selected
from those
having the formula:
R5 Q1-A¨R1
R4 gibi R6 =
R3 0 (F)n
R7 .,....
NH2
0 =
,
[0047] or a pharmaceutically acceptable salt thereof, wherein the variables
are as described
in WO 2015/032423, the entire contents of which are incorporated herein by
reference.
Exemplary compounds having this formula as part of the third embodiment
include, but are
not limited to, those having the formula:
o o /¨
NH N 0
e
\ F l F . ( iN H 4111
.
0 0
CI N / NH CI NI / NH
0 0
H2N . H2N .
0 0
NH = N_H
I 0 7H K CI
= \
ci
0 0 N
CI Ni.....(NH CI
0 0
H2N ;or H2N =
,
or a pharmaceutically acceptable salt thereof. Other Tyk2 inhibitors as part
of the third
embodiment include those in WO 2008/139161, and WO 2010/055304, the entire
contents of
each of which are incorporated herein by reference.
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[0048] In a fourth embodiment, the disclosed Tyk2 inhibitors may be selected
from those
having the formula:
NR
HN N NH
Xt
)2
N¨N X5,x4 X3
R,1
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2013/174895, the entire contents of which are incorporated herein by
reference. Exemplary
compounds having this formula as part of the fourth embodiment include, but
are not limited
to, those having the formula:
NX
HN N NH F HN N NH
cra¨NH N¨N )--NH N_N = Oy F
0 ;or 0 =
or a pharmaceutically acceptable salt thereof. Other Tyk2 inhibitors include
those in WO
2012/062704, the entire contents of which are incorporated herein by
reference.
[0049] In a fifth embodiment, the disclosed Tyk2 inhibitors may be selected
from those
having the formula:
R3õ Ny N ,Ri
x2 xl
R2 =
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2012/062704, the entire contents of which are incorporated herein by
reference.
[0050] In a sixth embodiment, the disclosed Tyk2 inhibitors may be selected
from those
having the formulae:
R1 R1 R1
,R2 N R2 R
,¨X ( R2
N R3 N s R3 N R3
R4, R4,
,or =
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2015/091584, the entire contents of which are incorporated herein by
reference. Exemplary
9

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compounds having this formula as part of the sixth embodiment include, but are
not limited
to, those having the formula:
CN
/
I ,¨N/ I ,¨N
N \ N \ __ /
H2N NH CN H2N NH CN
N N
;or =
or a pharmaceutically acceptable salt thereof.
[0051] In a seventh embodiment, the disclosed Tyk2 inhibitors may be selected
from those
having the formula:
Fl
(H2C)J
R1
A X R5
(H2C)(
)
m N n
R2
I 11
,
R- N NR4
H ;
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2016/027195, the entire contents of which are incorporated herein by
reference. Exemplary
compounds having this formula as part of the seventh embodiment include, but
are not
limited to, those having the formula:
FvF
A
)N ,--N
N N
=
or a pharmaceutically acceptable salt thereof.
[0052] In an eighth embodiment, the disclosed Tyk2 inhibitors may be selected
from those
having the formula:

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,R2
NC\4
N-N R4
__
R 1 ___
Ro
R-&---- N
-..--
A"
R5 .
/
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in US
2017/0240552, the entire contents of which are incorporated herein by
reference. Exemplary
compounds having this formula as part of the eighth embodiment include, but
are not limited
to, those having the formula:
\
p
NC
\i,P
N-N
C------- \N
N ' N
N----
Ni =
,
or a pharmaceutically acceptable salt thereof.
[0053] In a ninth embodiment, the disclosed Tyk2 inhibitors may be selected
from those
having the formula:
R3
N R2 0
H,
N N6(CN
1
R5 R4 R1 ;
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2015/016206, the entire contents of which are incorporated herein by
reference.
[0054] In a tenth embodiment, the disclosed Tyk2 inhibitors may be selected
from those
having the formula:
R3
N// i_R1
)=N
H-N
'IR2 .
/
11

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or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2013/146963, the entire contents of which are incorporated herein by
reference.
[0055] In an eleventh embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
H2 N 0
LN-R1
Nb jy
R2 .
/
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2016/047678, the entire contents of which are incorporated herein by
reference.
[0056] In a twelfth embodiment, the disclosed Tyk2 inhibitors may be selected
from those
described in US 2015/0299139; WO 2015/069310; US 9,505,748; WO 2018/0162889;
US
2013/0178478; or WO 2015/123453, the entire contents of each of which are
incorporated
herein by reference.
[0057] In a thirteenth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
R5, c-) - R4
Li N 0
X
K NH
R3 Y 7 R1
R- =
,
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2015/131080 or WO 2016/138352, the entire contents of which are incorporated
herein by
reference.
[0058] In a fourteenth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
(R7),õ
R5,Li 0
0
X
K NH
R3 Y 7 R1
R- =
,
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2017/040757, the entire contents of which are incorporated herein by
reference.
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[0059] In a fifteenth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
R5Li N, ,R4 R5Li N
, ,R4
0 0
N
,k NH NH
R3 N or R3 N =
,
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2015/131080, WO 2016/138352, and WO 2017/040757, the entire contents of which
are
incorporated herein by reference.
[0060] In a sixteenth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
H
R2 N
=-=õõ..,--rx
Cy' 1
Ll Cy'&
0 L1
R3 2(1
R2 Cy
,k
Z--N
N N 1 /
or Cy --Li =
, ,
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2018/071794, the entire contents of which are incorporated herein by
reference.
[0061] In a seventeenth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
R2N EN-I
II j ¨R1
X / N
i Ll
,
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2018/075937, the entire contents of which are incorporated herein by
reference.
[0062] In an eighteenth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
NH2
N, 00
HN N [XL,
H
n[Y]-0 =
,
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in US
2013/0178478, the entire contents of which are incorporated herein by
reference.
13

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[0063] In a nineteenth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
(R1 a)0_3
ND
Ls1,
NH 0
(R2a)o-4 N H2
R'
, - N N A..,-;.N
-
H =
,
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2015/123453, the entire contents of which are incorporated herein by
reference.
[0064] In a twentieth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
R1
N-----T---- R3
.._.....¨N,NNH
R2H N
0 Zi
X R- =
,
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2015/089143, the entire contents of which are incorporated herein by
reference.
[0065] In a twenty-first embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
R1
N,---z
\ N R4
.NN-
R3H N 145
0 =
/
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2015/089143, the entire contents of which are incorporated herein by
reference.
[0066] In a twenty-second embodiment, the disclosed Tyk2 inhibitors may be
selected
from those having the formula:
H N, R1
N-.... R3
\ E
N ,
N NA yN-I R-
A
H
R2H N 0
0 =
,
14

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or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2018/067432, the entire contents of which are incorporated herein by
reference.
[0067] In a twenty-third embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
R1
R2 N R-
N
143 0
=
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2018/093968, the entire contents of which are incorporated herein by
reference.
[0068] In a twenty-fourth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
R2,NH
YLrX ,-R1
R3,NN N
=
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2018/081488, the entire contents of which are incorporated herein by
reference.
[0069] In a twenty-fifth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
0 R4,N,R3
Rt
N N
H I R2
145 ;
or a pharmaceutically acceptable salt thereof, wherein
R' is Ci_3alkyl optionally substituted by 0-7 Ria;
Ria at each occurrence is independently hydrogen, deuterium, F, Cl, Br, CF3or
CN;
R2 is Ci_6alkyl or-(CH2),-3-14 membered carbocycle, each group substituted
with 0-4
R2a ;
R2a at each occurrence is independently hydrogen,=0, halo, OCF3, CN, NO2, -
(CH2)r0Rb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)rOC(0)Rb, -
(CH2)rNR11R11,
-(CH2)rC(0)NR11-rsK11
-(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)012c, -NRbC(0)NR11Rii,
S(0)pNRi iRii, _NRbs(o)pRc, _soyKc p ,
) C 1_6 alkyl substituted with 0-3 Ra, C 1_6 halo alkyl, C2-

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6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl substituted with 0-3 Ra, -
(CH2)r-3-14 membered
carbocycle substituted with 0-1 Ra or a -(CH2),-5-7 membered heterocycle
comprising carbon
atoms or 1-4 heteroatoms selected from N, 0, and S(0)p substituted with 0-2
Ra;
R3 is C3_10 cycloalkyl, C6_10 aryl, or a 5-10 membered heterocycle containing
1-4
heteroatoms selected from N, 0, and S, each group substituted with 0-4 R3a;
R3a at each occurrence is independently hydrogen, =0, halo, 0CF3, CF3, CHF2,
CN,
NO2, -(CH2)r0Rb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)r0C(0)Rb, -
(CH2)rNRi iRii, -(CH2)rC(0)NR11R11, -(CH2)rNRbC(0)12c, -(CH2)rNRbC(0)012c, -
NRbC(0)NR11-ii,
S(0)pNR11Rii, _NRbs(o)pRc,
) K Ci_6 alkyl substituted with 0-3 Ra,
C2_6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl substituted with 0-3 Ra,
Ci_6haloalkyl, -
(CH2)r-3-14 membered carbocycle substituted with 0-3 Ra or a -(CH2)r-5-10
membered
heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, 0,
and
S(0)p substituted with 0-3 Ra;
or two R3a, together with the atoms to which they are attached, combine to
form a
fused ring wherein said ring is selected from phenyl and a 5-7 membered
heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N, S or 0 said fused
ring further
substituted by Rai;
R4 and R5 are independently hydrogen, Ci_4 alkyl substituted with 0-1 Rf,
(CH2)r-
phenyl substituted with 0-3 Rd, or a -(CH2)-5-7 membered heterocycle
comprising carbon
atoms and 1-4 heteroatoms selected from N, 0, and S(0)p;
R" at each occurrence is independently hydrogen, Ci_4 alkyl substituted with 0-
3 Rf,
CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-
3 Rd, or -
(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms
selected
from N, 0, and S(0)p substituted with 0-3 Rd;
Ra and Rai at each occurrence are independently hydrogen, F, Cl, Br, OCF3,
CF3,
CHF2, CN, NO2, -(CH2)r0Rb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -
(CH2)r0C(0)Rb,
-(CH2)rNR11R11, -(CH2)rC(0)NR11R11, -(CH2)rNRbC(0)12c, -(CH2)rNRbC(0)012c, -
NRbC(0)NR11,-.K11,
S(0)pNR11R11, _NRbs(o)pRc, _s(0)Rc,
K Ci_6 alkyl substituted
with 0-3 Rf, C1_6haloalkyl, C2_6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl
substituted with
0-3 Ra, -(CH2)r-3-14 membered carbocycle or -(CH2)r-5-7 membered heterocycle
comprising
carbon atoms and 1-4 heteroatoms selected from N, 0, and S(0)p substituted
with 0-3 Rf;
Rb at each occurrence is independently hydrogen, C1-6 alkyl substituted with 0-
3 Rd,
C1_6haloalkyl, C3_6 cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7
membered heterocycle
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comprising carbon atoms and 1-4 heteroatoms selected from N, 0, and S(0)p
substituted with
0-3 Rf or (CH2),-pheny1 substituted with 0-3 Rd;
Re is C 1_6 alkyl substituted with 0-3 Rf, (CH2),-C3_6cycloalkyl substituted
with 0-3 Rf,
(CH2),-pheny1 substituted with 0-3 Rf; or
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO2, -
ORe, -(CH2),C(0)Re, -NReRe, -NReC(0)012e, C 1_6 alkyl, or (CH2),-pheny1
substituted with 0-3
Rf;
Re at each occurrence is independently selected from hydrogen, C1_6 alkyl, C3_
6 cycloalkyl, and (CH2),-pheny1 substituted with 0-3 Rf;
Rf independently at each occurrence is hydrogen, halo, CN, NH2, OH,
C3_6cycloa1kyl,
CF3, 0(C1-6alkyl), or a -(CH2),-5-7 membered heteroaryl comprising carbon
atoms and 1-4
heteroatoms selected from N, 0, and S(0)p;
p is 0, 1, or 2; and
r is 0, 1, 2, 3, or 4, wherein additional definitions and specific compounds
can be
found e.g., in US 2015/0299139, the entire contents of which are incorporated
herein by
reference.
[0070] In a twenty-sixth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
0 WIN
,R3
Rt
N
H I R2
145 ;
or a pharmaceutically acceptable salt thereof, wherein
R1 is C 1_3a1icyl optionally substituted by 0-7 lei
RI' at each occurrence is independently hydrogen, deuterium, F, CI, Br, CF3 or
CN;
R2 is C1_6 alkyl substituted with 0-4 R2a, C3_6 cycloalkyl substituted with 0-
4 R2a,
C6_10 aryl substituted with 0-4 R2a, a 5-14 membered heterocycle containing 1-
4
heteroatoms selected from N, 0, and S, substituted with 0-4 R2a, NR6R6 or ORb;
R2a at each occurrence is independently hydrogen, =0, halo, OCF3, CN, NO2,
-(CH2),ORb, -(CHASRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)r0C(0)Rb,
(CH2)rNR11R11, -(CH2)rC(0)NR11R11, -(CH2)/NRbC(0)RC, -(CH2)/NRbC(0)ORC,
-NRbC(0)NR11R11, _5(0)pNRi iRii, _NRbs(o)pRc, _soyK p- C,
) C1_6 alkyl substituted with
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0-3 Ra, C1_6 halo alkyl, -(CH2),-3-14 membered carbocycle substituted with 0-1
Ra or
a-(CH2),-5-7 membered heterocycle comprising carbon atoms or 1-4 heteroatoms
selected
from N, 0, and S(0)p substituted with 0-2 Ra;
or one R2a and another R2a, together with the atoms to which they are
attached,
combine to form a fused 5-6 membered ring wherein said fused ring may be
substituted
with 0-2 Ra;
R3 is -(CH2),-3-14 membered carbocycle substituted 0-5 R3a;
R3a at each occurrence is independently hydrogen, =0, halo, 0CF3, CN, NO2,
-(CH2),ORb, -(CHASRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)r0C(0)Rb,
(CH2)rNRi1R11, -(CH2)rC(0)NR11RH, -(CH2)rNRbC(0)12c, -(CH2)rNRbC(0)012c,
-NRbC(0)NR11-ii,
- S(0)pNR11Rii, _NRbs(o)pRc, _soyK p-C,
) Ci_6 alkyl substituted with
0-3 Ra, C1_6 halo alkyl, -(CH2)r-3-14 membered carbocycle substituted with 0-3
Ra or
a-(CH2)r-5-10 membered heterocycle comprising carbon atoms or 1-4 heteroatoms
selected
from N, 0, and S(0)p substituted with 0-3 Ra;
or two R3a, together with the atoms to which they are attached, combine to
form a
fused ring wherein said ring is selected from phenyl and a 5-7 membered
heterocycle
comprising carbon atoms and 1-4 heteroatoms selected from N, S or 0, said
fused ring
may be further substituted by Ra;
R4 and R5 are independently hydrogen, C 1_4 alkyl substituted with 0-1 Rf,
(CH2)r-pheny1 substituted with 0-3 Rd, or a -(CH2)-5-7 membered heterocycle
comprising
carbon atoms and 1-4 heteroatoms selected from N, 0, and S(0)p;
R6 and RH at each occurrence are independently hydrogen, C 1_4 alkyl
substituted
with 0-3 Rf, CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl
substituted with
0-3 Rd, or -(CH2)r-5-7 membered heterocycle comprising carbon atoms and 1-4
heteroatoms selected from N, 0, and S(0)p substituted with 0-3 Rd;
Ra at each occurrence is hydrogen, F, Cl, Br, OCF3, CF3, CHF2, CN, NO2,
-(CH2)r0Rb, -(CHASRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)r0C(0)Rb,
-(CH2)rNR111211, -(CH2)rC(0)NR11R11, -(CH2)rNRbC(0)12c, -(CH2)rNRbC(0)012c,
-NRbC(0)NR11,-.11,
- S(0)pNR11R11, -NRbS(0)pRc, -S(0)12c, -S(0)212c, Ci_6a1kyl
substituted with 0-3 Rf, C1_6haloalkyl, -(CH2)r-3-14 membered carbocycle, or -
(CH2)r-5-7
membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from
N, 0,
and S(0)p substituted with 0-3 Rf;
Rb at each occurrence is hydrogen, C1,6 alkyl substituted with 0-3 Rd,
C1_6 halo alkyl, C3_6cycloalkyl substituted with 0-2 Rd, or -(CH2)r-5-7
membered
18

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heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, 0,
and S(0)p
substituted with 0-3 Rf, or (CH2),-pheny1 substituted with 0-3 Rd;
Rc is Ci_6 alkyl substituted with 0-3 Rf, (CH2),-C3,6 cycloalkyl substituted
with 0-3
Rf or (CH2),-pheny1 substituted with 0-3 Rf;
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO2,
ORe, -(CH2),C(0)Rc, NReRe, -NReC(0)0Rc, Ci_6 alkyl or (CH2),-pheny1
substituted
with 0-3 Rf;
Re at each occurrence is independently selected from hydrogen, Ci_6 alkyl,
C3_6 cycloalkyl and (CH2),-pheny1 substituted with 0-3 Rf;
Rf independently at each occurrence is hydrogen, halo, CN, NH2, OH,
C3_6 cycloalkyl, CF3, 0(Ci_6a1kyl) or a -(CH2),-5-7 membered heteroaryl
comprising
carbon atoms and 1-4 heteroatoms selected from N, 0, and S(0)p;
p is 0, 1, or 2; and
r is 0,1,2,3, or 4.
[0071] In a twenty-seventh embodiment, the disclosed Tyk2 inhibitors may be
selected
from those having the formula:
0 R1N,R3
Rt J.
N 1 0
H I
N N AR-
,
R5 =
,
or a pharmaceutically acceptable salt thereof, wherein the variables are as
described in WO
2015/069310, the entire contents of which are incorporated herein by
reference.
[0072] In a twenty-eighth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formula:
0 R1N,R3
Rtk.p)y,,
1 i
N ,N'N, R2
R5 ;
or a pharmaceutically acceptable salt thereof, wherein
Y is N or CR6;
R' is H, Ci_3a1kyl or C3_6cycloa1kyl, each optionally substituted by 0-7 Ria;
Ria at each occurrence is independently hydrogen, deuterium, F, Cl, Br or CN;
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R2 is Ci_6a1ky1, -(CH2)r-3-14 membered carbocycle substituted with 0-1 R2a or
a 5-14
membered heterocycle containing 1-4 heteroatoms selected from N, 0, and S,
each group
substituted with 0-4 R2a (for the sake of clarity, R2 is intended to include
substituted methyl
groups such as -C(0)R21);
R2a at each occurrence is independently hydrogen, =0, halo, 0CF3, CN, NO2, -
(CH2)r
ORb, -(CHASRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)rOC(0)Rb, CH2)rNR11RH, _
(CH2)rC(0)NR11R1 1, -(CH2)rNRbC(0)Rc, -(CH2)rNRbC(0)0Rc, -NRbC(0)NR11R11,
S (0)pNR11R11, _NRbs(o)pRc, _soyK p- c,
) C 1_6
alkyl substituted with 0-3 Ra, C 1_6 haloalkyl, C2-
6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl substituted with 0-3 Ra, -
(CH2)r-3-14 membered
carbocycle substituted with 0-1 Ra or a -(CH2)r-5-7 membered heterocycle
comprising carbon
atoms or 1-4 heteroatoms selected from N, 0, and S(0)p substituted with 0-2
Ra;
R3 is C3_10 cycloalkyl, C6_10 aryl or a 5-10 membered heterocycle containing 1-
4
heteroatoms selected from N, 0, and S, each group substituted with 0-4 R3a;
R3a at each occurrence is independently hydrogen, =0, halo, OCF3, CF3, CHF2,
CN,
NO2, -(CH2)r0Rb, -(CH2)rSRb, -(CH2)rC(0)Rb, -(CH2)rC(0)0Rb, -(CH2)r0C(0)Rb, -
(CH2)rNR11R11, -(CH2)rC(0)NR11R11, -(CH2)rNRbC(0)12c, -(CH2)rNRbC(0)012c, -
NRbC(0)NR11-ii,
S(0)pNR11Rii, _NRbs(o)pRc,
) K C
1_6 alkyl substituted with 0-3 Ra,
C2_6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl substituted with 0-3 Ra, C
1_6 haloalkyl, -
(CH2)r-3-14 membered carbocycle substituted with 0-3 Ra or a -(CH2)r-5-10
membered
heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, 0,
and
S(0)p substituted with 0-3 Ra;
or two R3a, together with the atoms to which they are attached, combine to
form a
fused ring wherein said ring is selected from phenyl and a heterocycle
comprising carbon
atoms and 1-4 heteroatoms selected from N, 0, and S(0)p, each fused ring
substituted with 0-
3 Ral
R4 and R5 are independently hydrogen, C1_4 alkyl substituted with 0-1 Rf,
(CH2)r-
phenyl substituted with 0-3 Rd or a -(CH2)-5-7 membered heterocycle comprising
carbon
atoms and 1-4 heteroatoms selected from N, 0, and S(0)p;
R6 is hydrogen, halo, Ci_4alkyl, Ci_4haloalkyl, OCi_4haloalkyl, OCi_4alkyl,
CN, NO2 or
OH;
Ril at each occurrence is independently hydrogen, C1_4 alkyl substituted with
0-3 Rf,
CF3, C3-10 cycloalkyl substituted with 0-1 Rf, (CH)r-phenyl substituted with 0-
3 Rd or -(CH2)r-
5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected
from N, 0,
and S(0)p substituted with 0-3 Rd;

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Ra and Rai at each occurrence are independently hydrogen, F, Cl, Br, OCF3,
CF3,
CHF2, CN, NO2, -(CH2),ORb, -(CH2),SRb, -(CH2),C(0)Rb, -(CH2),C(0)0Rb, -
(CH2),OC(0)Rb,
-(CH2),NRiiRii, -(CH2),C(0)NR11R11, -(CH2),NRbC(0)Rc, -(CH2),NRbC(0)0Re, -
NRbC(0)NR11,-.K11, _
S(0)pNR"R", -NRbS(0)pRe, -S(0)Re, -S(0)2Re, Ci_6 alkyl substituted
with 0-3 Rf, C1-6haloalkyl, C2_6 alkenyl substituted with 0-3 Ra, C2_6 alkynyl
substituted with
0-3 Ra, -(CH2),-3-14 membered carbocycle or -(CH2),-5-7 membered heterocycle
comprising
carbon atoms and 1-4 heteroatoms selected from N, 0, and S(0)p substituted
with 0-3 Rf;
Rb is hydrogen, Ci_6 alkyl substituted with 0-3 Rd, Ci_6haloalkyl,
C3_6cycloalkyl
substituted with 0-2 Rd, or -(CH2),-5-7 membered heterocycle comprising carbon
atoms and
1-4 heteroatoms selected from N, 0, and S(0)p substituted with 0-3 Rf or
(CH2),-pheny1
substituted with 0-3 Rd;
Re is Ci_6 alkyl substituted with 0-3 Rf, (CH2),-C3_6cycloalkyl substituted
with 0-3
Rf or (CH2),-pheny1 substituted with 0-3 Rf;
Rd at each occurrence is independently hydrogen, F, Cl, Br, OCF3, CF3, CN,
NO2, -
ORe, -(CH2),C(0)Re, -NReRe, -NReC(0)012e, Ci_6 alkyl or (CH2),-phenyl
substituted with 0-3
Rf;
Re at each occurrence is independently selected from hydrogen, Ci_6 alkyl, C3_
6cyc10a11cy1 and (CH2),-pheny1 substituted with 0-3 Rf;
Rf independently at each occurrence is hydrogen, halo, CN, NH2, OH,
C3_6cycloalkyl,
CF3, 0(Ci_6a1kyl) or a -(CH2),-5-7 membered heterocycle comprising carbon
atoms and 1-4
heteroatoms selected from N, 0, and S(0)p;
p is 0, 1, or 2; and
r is 0, 1, 2, 3, or 4, wherein additional definitions and specific compounds
are as
described in US 9,505,748 and WO 2018/0162889, the entire contents of each of
which are
incorporated herein by reference.
[0073] In a twenty-ninth embodiment, the disclosed Tyk2 inhibitors may be
selected from
those having the formulae:
-
o HNR1
D3C,
N)Y
H I
N, ,R2
N N
H ;
or a pharmaceutically acceptable salt thereof, wherein:
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N/
x
N , N
0
II
0 P
110 I
' '
R1 is or' N-
;and
F
0 N N N N)
I
R2 is , , , or .
[0074] In a thirtieth embodiment, the Tyk2 inhibitor described herein is 6-
(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methy1-1H-1,2,4-triazol-3-
yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (BMS-986165), having
the
following chemical structure:
/
N
x
N N
0
0
0 HN
D3C,N)Cri 0
H 1\1,NN)/
H =
,
or a pharmaceutically acceptable salt thereof.
[0075] The specific dosage and treatment regimen for a disclosed Tyk2
inhibitor to be used
in combination with apremilast will depend upon a variety of factors,
including age, body
weight, general health, sex, diet, time of administration, rate of excretion,
drug combination,
the judgment of the treating physician, and the severity of the particular
disease being treated.
[0076] In a thirty-first embodiment, the effective amount of a disclosed Tyk2
inhibitor (e.g.,
as in any one of the second to thirtieth embodiment) to be used in combination
with
apremilast ranges from 0.001 to 50 mg/kg body weight/day. For example, as part
of a thirty-
first embodiment, the effective amount of a disclosed Tyk2 inhibitor (e.g., as
in any one of
the second to thirtieth embodiment) to be used in combination with apremilast
ranges from
about 0.1 mg/day to about 250 mg/day, e.g., from about 0.2 mg/day to about 100
mg./day,
about 0.5 mg/ day to about 50 mg/day, and about 1.0 mg to about 24 mg/day.
[0077] In a thirty-second embodiment, the Tyk2 inhibitor described herein is
BMS-986165,
or a pharmaceutically acceptable salt thereof, and the effective amount of BMS-
986165, or a
22

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pharmaceutically acceptable salt thereof, ranges from about 0.1 mg/day to
about 250 mg/day,
about 0.1 mg/day to about 100 mg/day, about 0.1 mg/day to about 50 mg/day,
about 0.1
mg/day to about 25 mg/day 0.1 mg/day to about 15 mg/day, about 0.1 mg/day to
about 10
mg/day, about 0.5 mg/day to about 15 mg/day, about 0.5 mg/day to about 10
mg/day, about
0.1 mg/day to about 5 mg/day, about 0.5 mg/day to about 5 mg/day, about 1
mg/day to about
25 mg/day, about 2 mg/day to about 14 mg/day, about 2 mg/day to about 12
mg/day, or about
3 mg/day to about 12 mg/day. Alternatively, as part of a thirty-second
embodiment, the
effective amount of BMS-986165, or a pharmaceutically acceptable salt thereof
ranges from
about 1 mg/day to about 15 mg/day, about 1 mg/day to about 14 mg/day, about 2
mg/day to
about 14 mg/day, about 2 mg/day to about 12 mg/day, or about 3 mg/day to about
12 mg/day.
[0078] In a thirty-third embodiment, the Tyk2 inhibitor described herein is
BMS-986165,
or a pharmaceutically acceptable salt thereof, and the effective amount of BMS-
986165, or a
pharmaceutically acceptable salt thereof, is about 0.1 mg/day, about 0.5
mg/day, about 1.0
mg/day, about 2 mg/day, about 3 mg/day, about 4 mg/day, about 5 mg/day, about
6 mg/day,
about 7 mg/day, about 8 mg/day, about 9 mg/day, about 10 mg/day, about 11
mg/day, or
about 12 mg/day. Alternatively, as part of a thirty-third embodiment, the
effective amount of
BMS-986165, or a pharmaceutically acceptable salt thereof, is about 2 mg/day,
about 3
mg/day, about 4 mg/day, about 5 mg/day, about 6 mg/day, about 7 mg/day, about
8 mg/day,
about 9 mg/day, about 10 mg/day, about 11 mg/day, or about 12 mg/day. In
another
alternative, as part of a thirty-third embodiment, the effective amount of BMS-
986165, or a
pharmaceutically acceptable salt thereof, is about 6 mg/day. In another
alternative, as part of
a thirty-third embodiment, the effective concentration of BMS-986165, or a
pharmaceutically
acceptable salt thereof, is about 1 nM to about 1 i.t.M (e.g., from about 0.01
i.t.M to about 0.1
IJM).
3. Apremilast
[0079] As described above, apremilast is optically enriched as the (S)
enantiomer. In a
thirty-fourth embodiment, the stereomeric purity of apremilast in the methods
and
compositions described herein is greater than 90%, wherein the Tyk2 inhibitor
and related
features are as described herein e.g., as in any one of the first to thirty-
third embodiments.
Alternatively, as part of a thirty-fourth embodiment, the stereomeric purity
of apremilast in
the methods and compositions described herein is greater than 95%, wherein the
Tyk2
inhibitor and related features are as described herein e.g., as in any one of
the first to thirty-
third embodiments. In another alternative, as part of a thirty-fourth
embodiment, the
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stereomeric purity of apremilast in the methods and compositions described
herein is greater
than 97%, wherein the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-third embodiments. In another alternative, as
part of a thirty-
fourth embodiment, the stereomeric purity of apremilast in the methods and
compositions
described herein is greater than 98%, wherein the Tyk2 inhibitor and related
features are as
described herein e.g., as in any one of the first to thirty-third embodiments.
In another
alternative, as part of a thirty-fourth embodiment, the stereomeric purity of
apremilast in the
methods and compositions described herein is greater than 99%, wherein the
Tyk2 inhibitor
and related features are as described herein e.g., as in any one of the first
to thirty-third
embodiments. In another alternative, as part of a thirty-fourth embodiment,
the stereomeric
purity of apremilast in the methods and compositions described herein is
greater than 99.5%,
wherein the Tyk2 inhibitor and related features are as described herein e.g.,
as in any one of
the first to thirty-third embodiments. In another alternative, as part of a
thirty-fourth
embodiment, the stereomeric purity of apremilast in the methods and
compositions described
herein is greater than 99.9%, wherein the Tyk2 inhibitor and related features
are as described
herein e.g., as in any one of the first to thirty-third embodiments.
[0080] Polymorphic forms of apremilast are included in the disclosed methods
and
compositions and include e.g., those described in US 9,018,243, the entire
contents of which
are incorporated herein by reference. In a thirty-fifth embodiment, apremilast
in the disclosed
methods and compositions is a single crystalline form, wherein additional
features for
apremilast as well as the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-fourth embodiments.
[0081] In a thirty-sixth embodiment, apremilast in the disclosed methods and
compositions
is a single crystalline Form B characterized by X-ray powder diffraction peaks
at 20 angles
selected from 10.1 , 13.5 , 20.7 , and 26.9 , wherein additional features for
apremilast as
well as the Tyk2 inhibitor and related features are as described herein e.g.,
as in any one of
the first to thirty-fourth embodiments. Alternatively, as part of a thirty-
sixth embodiment,
apremilast in the disclosed methods and compositions is a single crystalline
Form B
characterized by X-ray powder diffraction peaks at 20 angles selected from
10.10, 13.5 ,
15.7 , 18.1 , 20.7 , 24.7 , and 26.9 , wherein additional features for
apremilast as well as the
Tyk2 inhibitor and related features are as described herein e.g., as in any
one of the first to
thirty-fourth embodiments. In another alternative, as part of a thirty-sixth
embodiment,
apremilast in the disclosed methods and compositions is a single crystalline
Form B
characterized by X-ray powder diffraction peaks at 20 angles selected from
10.1 , 13.5 ,
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15.7 , 16.3 , 18.1 , 20.7 , 22.5 , 24.7 , 26.2 , 26.9 , and 29.1 , wherein
additional features
for apremilast as well as the Tyk2 inhibitor and related features are as
described herein e.g.,
as in any one of the first to thirty-fourth embodiments.
[0082] In a thirty-seventh embodiment, apremilast in the disclosed methods and
compositions is at least 90% single crystalline Form B, wherein additional
features for
apremilast as well as the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-sixth embodiments. Alternatively, apremilast in
the disclosed
methods and compositions is at least 95% single crystalline Form B, wherein
additional
features for apremilast as well as the Tyk2 inhibitor and related features are
as described
herein e.g., as in any one of the first to thirty-sixth embodiments. In
another alternative,
apremilast in the disclosed methods and compositions is at least 99% single
crystalline Form
B, wherein additional features for apremilast as well as the Tyk2 inhibitor
and related
features are as described herein e.g., as in any one of the first to thirty-
sixth embodiments.
[0083] The specific dosage and treatment regimen of apremilast, or a
pharmaceutically
acceptable salt thereof, to be used in combination with a disclosed Tyk2
inhibitor will depend
upon a variety of factors, including age, body weight, general health, sex,
diet, time of
administration, rate of excretion, drug combination, the judgment of the
treating physician,
and the severity of the particular disease being treated.
[0084] For example, in a thirty-eighth embodiment, the effective amount of
apremilast, or
the pharmaceutically acceptable salt thereof, ranges from about 0.5 mg to
about 1000 mg per
day, about 1 mg to about 1000 mg per day, about 5 mg to about 500 mg per day,
about 10 mg
to about 200 mg per day, about 10 mg to about 100 mg per day, about 40 mg to
about 100 mg
per day, about 20 mg to about 40 mg per day, about 0.1 mg to about 10 mg per
day, about 0.5
mg to about 5 mg per day, about 1 mg to about 20 mg per day, and about 1 mg to
about 10
mg per day, about 1 mg to about 100 mg per day, about 1 mg to about 80 mg per
day, about 5
mg to about 70 mg per day, about 10 mg to about 60 mg per day, and about 10 mg
to about
40 mg per day, wherein additional features for apremilast as well as the Tyk2
inhibitor and
related features are as described herein e.g., as in any one of the first to
thirty-seventh
embodiments. Alternatively, as part of a thirty-eighth embodiment, the
effective amount of
apremilast, or the pharmaceutically acceptable salt thereof, ranges from about
10 mg to about
60 mg per day, wherein additional features for apremilast as well as the Tyk2
inhibitor and
related features are as described herein e.g., as in any one of the first to
thirty-seventh
embodiments. In another alternative, as part of a thirty-eighth embodiment,
the effective
amount of apremilast, or the pharmaceutically acceptable salt thereof, ranges
from about 40

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mg to about 100 mg per day, wherein additional features for apremilast as well
as the Tyk2
inhibitor and related features are as described herein e.g., as in any one of
the first to thirty-
seventh embodiments. In another alternative, as part of a thirty-eighth
embodiment, the
effective amount of apremilast, or the pharmaceutically acceptable salt
thereof, ranges from
between about 40 mg to between about 100 mg per day, wherein additional
features for
apremilast as well as the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-seventh embodiments. In another alternative, as
part of a thirty-
eighth embodiment, the effective amount of apremilast, or the pharmaceutically
acceptable
salt thereof, ranges from about 4 mg to about 10 mg per day, wherein
additional features for
apremilast as well as the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-seventh embodiments. In another alternative, as
part of a thirty-
eighth embodiment, the effective amount of apremilast, or the pharmaceutically
acceptable
salt thereof, ranges from between about 4 mg to between about 10 mg per day,
wherein
additional features for apremilast as well as the Tyk2 inhibitor and related
features are as
described herein e.g., as in any one of the first to thirty-seventh
embodiments. In another
alternative, as part of a thirty-eighth embodiment, the effective amount of
apremilast, or the
pharmaceutically acceptable salt thereof, ranges from about 10 mg to about 40
mg per day,
wherein additional features for apremilast as well as the Tyk2 inhibitor and
related features
are as described herein e.g., as in any one of the first to thirty-seventh
embodiments. In
another alternative, as part of a thirty-eighth embodiment, the effective
amount of apremilast,
or the pharmaceutically acceptable salt thereof, is about 1 mg per day, about
2 mg per day,
about 3 mg per day, about 4 mg per day, about 5 mg per day, about 10 mg per
day, about 15
mg per day, about 20 mg per day, about 25 mg per day, about 30 mg per day,
about 35 mg
per day, about 40 mg per day, about 45 mg per day, about 50 mg per day, about
55 mg per
day, or about 60 mg per day, wherein additional features for apremilast as
well as the Tyk2
inhibitor and related features are as described herein e.g., as in any one of
the first to thirty-
seventh embodiments. In another alternative, as part of a thirty-eighth
embodiment, the
effective amount of apremilast, or the pharmaceutically acceptable salt
thereof, is about 30
mg per day or about 60 mg per day, wherein additional features for apremilast
as well as the
Tyk2 inhibitor and related features are as described herein e.g., as in any
one of the first to
thirty-seventh embodiments. In another alternative, as part of a thirty-eighth
embodiment,
apremilast is administered at a dose of about 30 mg once daily, wherein
additional features
for apremilast as well as the Tyk2 inhibitor and related features are as
described herein e.g.,
as in any one of the first to thirty-seventh embodiments. In another
alternative, as part of a
26

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thirty-eighth embodiment, apremilast is administered at a dose of about 30 mg
twice daily,
wherein additional features for apremilast as well as the Tyk2 inhibitor and
related features
are as described herein e.g., as in any one of the first to thirty-seventh
embodiments. In
another alternative, as part of a thirty-eighth embodiment, the effective
amount of apremilast,
or the pharmaceutically acceptable salt thereof, is about 10 mg per day or
about 40 mg per
day, wherein additional features for apremilast as well as the Tyk2 inhibitor
and related
features are as described herein e.g., as in any one of the first to thirty-
seventh embodiments.
In another alternative, as part of a thirty-eighth embodiment, apremilast is
administered at a
dose of about 10 mg once or twice daily, wherein additional features for
apremilast as well as
the Tyk2 inhibitor and related features are as described herein e.g., as in
any one of the first
to thirty-seventh embodiments. In another alternative, as part of a thirty-
eighth embodiment,
apremilast is administered at a dose of about 20 mg once or twice daily,
wherein additional
features for apremilast as well as the Tyk2 inhibitor and related features are
as described
herein e.g., as in any one of the first to thirty-seventh embodiments. In
another alternative, as
part of a thirty-eighth embodiment, the effective concentration of apremilast
is about 100 nM
to about 10 i.t.M (e.g., from about 0.1 i.t.M to about 1 t.M), wherein
additional features for
apremilast as well as the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-seventh embodiments.
[0085] In a thirty-ninth embodiment, apremilast is titrated to a dosage of
about 30 mg
administered twice daily using the following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: about 30 mg twice daily, wherein additional features for
apremilast as well as the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-seventh embodiments. Alternatively, apremilast
is titrated to a
dosage of between about 40 mg/day to between about 100 mg/day using the
following
titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
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Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: between about 40 mg/day to between about 100 mg/day,
wherein additional features for apremilast as well as the Tyk2 inhibitor and
related features
are as described herein e.g., as in any one of the first to thirty-seventh
embodiments. In
another alternative, apremilast is titrated to a dosage of about 20 mg
administered twice daily
using the following titration schedule:
Day 1: about 10 mg in morning;
Day 2: about 10 mg in morning and about 10 mg in evening;
Day 3: about 10 mg in morning and about 20 mg in evening;
Day 4: about 20 mg in morning and about 20 mg in evening;
Day 5: about 20 mg in morning and about 30 mg in evening; and
Day 6 and thereafter: about 20 mg twice daily, wherein additional features for
apremilast as well as the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-seventh embodiments. In yet another
alternative, apremilast is
titrated to a dosage of between about 4 mg/day to between about 10 mg/day
using the
following titration schedule:
Day 1: about 1 mg in morning;
Day 2: about 1 mg in morning and about 1 mg in evening;
Day 3: about 1 mg in morning and about 2 mg in evening;
Day 4: about 2 mg in morning and about 2 mg in evening;
Day 5: about 2 mg in morning and about 3 mg in evening; and
Day 6 and thereafter: between about 4 mg/day to between about 10 mg/day,
wherein
additional features for apremilast as well as the Tyk2 inhibitor and related
features are as
described herein e.g., as in any one of the first to thirty-seventh
embodiments. In yet another
alternative, apremilast is titrated to a dosage of about 3 mg administered
twice daily using the
following titration schedule:
Day 1: about 1 mg in morning;
Day 2: about 1 mg in morning and about 1 mg in evening;
Day 3: about 10 mg in morning and about 2 mg in evening;
Day 4: about 2 mg in morning and about 2 mg in evening;
Day 5: about 2 mg in morning and about 3 mg in evening; and
Day 6 and thereafter: about 3 mg twice daily, wherein additional features for
apremilast as well as the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-seventh embodiments.
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3. Compositions and Administration
[0086] Also provided herein are pharmaceutical compositions comprising a
therapeutically
effective amount of apremilast, or a pharmaceutically acceptable salt thereof;
and a
therapeutically effective amount of a Tyk2 inhibitor (e.g., BMS-986165).
Features for the
disclosed pharmaceutical compositions include elements described above e.g.,
as in any one
of the first to thirty-eighth embodiments.
[0087] Further provided are pharmaceutical compositions comprising a
therapeutically
effective amount of apremilast, or a pharmaceutically acceptable thereof; and
a
therapeutically effective amount of a Tyk2 inhibitor (e.g., BMS-986165), for
use in treating a
disease or disorder responsive to the inhibition of PDE4. Features for the
disclosed
pharmaceutical compositions include elements described above e.g., as in any
one of the first
to thirty-eighth embodiments.
[0088] Pharmaceutical compositions and single unit dosage forms comprising
apremilast
and a Tyk2 inhibitor (e.g., BMS-986165) alone or together in a fixed dose for
administration
as described above (e.g., as in any one of the first to thirty-eighth
embodiments) is included.
Single unit dosage forms of the disclosed methods and compositions are
suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal),
parenteral (e.g.,
Subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial),
or transdermal
administration to a patient. Examples of dosage forms include, but are not
limited to: tablets;
caplets; capsules, such as soft elastic gelatin capsules; cachets; troches;
lozenges; dispersions;
suppositories; ointments; cataplasms (poultices); pastes; powders; dressings;
creams; plasters;
solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid
dosage forms suitable
for oral or mucosal administration to a patient, including suspensions (e.g.,
aqueous or non-
aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid
emulsions),
solutions, and elixirs; liquid dosage forms suit able for parenteral
administration to a patient;
and sterile solids (e.g., crystalline or amorphous solids) that can be
reconstituted to provide
liquid dosage forms suitable for parenteral administration to a patient.
[0089] The composition, shape, and type of dosage forms of the will typically
vary
depending on their use. For example, a dosage form used in the acute treatment
of
inflammation or a related disorder may contain larger amounts of one or more
of the active
ingredients it comprises than a dosage form used in the chronic treatment of
the same disease.
Similarly, a parenteral dosage form may contain smaller amounts of one or more
of the active
ingredients it comprises than an oral dosage form used to treat the same
disease or
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disorder. These and other ways in which specific dosage forms encompassed by
this
invention will vary from one another will be readily apparent to those skilled
in the art. See,
e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton
Pa. (1990).
[0090] In a thirty-ninth embodiment, apremilast in the disclosed methods and
compositions
is administered parenterally, transdermally, mucosally, nasally, buccally,
sublingually, or
orally, wherein additional features for apremilast as well as the Tyk2
inhibitor and related
features are as described herein e.g., as in any one of the first to thirty-
eighth embodiments.
Alternatively, as part of a thirty-ninth embodiment, apremilast in the
disclosed methods and
compositions is administered orally, wherein additional features for
apremilast as well as the
Tyk2 inhibitor and related features are as described herein e.g., as in any
one of the first to
thirty-eighth embodiments.
[0091] In a fortieth embodiment, apremilast in the disclosed methods and
compositions is
administered orally in the form of a tablet or a capsule, wherein additional
features for
apremilast as well as the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-ninth embodiments.
[0092] In a forty-first embodiment, apremilast in the disclosed methods and
compositions
is formulated as an extended release form, wherein additional features for
apremilast as well
as the Tyk2 inhibitor and related features are as described herein e.g., as in
any one of the
first to thirty-ninth embodiments.
[0093] In a forty-second embodiment, apremilast in the disclosed methods and
compositions is formulated as an immediate release form, wherein additional
features for
apremilast as well as the Tyk2 inhibitor and related features are as described
herein e.g., as in
any one of the first to thirty-ninth embodiments.
[0094] In a forty-third embodiment, both the apremilast and the Tyk2 inhibitor
in the
disclosed methods and compositions are administered in fixed dosage
combination as a once
a day formulation, wherein additional features for apremilast as well as the
Tyk2 inhibitor
and related features are as described herein e.g., as in any one of the first
to forty-second
embodiments.
4. Conditions Treated by the Methods and Compositions Disclosed Herein
[0095] Diseases or disorders that are responsive to the inhibition of PDE4
using the
methods and compositions disclosed herein include e.g., viral, genetic,
inflammatory, allergic,
and autoimmune conditions.

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[0096] In one aspect, the disease or disorder responsive to the inhibition of
PDE4 is
selected from chronic obstructive pulmonary disease, asthma, chronic pulmonary
inflammatory disease, hyperoxic alveolar injury, inflammatory skin disease,
psoriasis,
psoriatic arthritis, rheumatoid arthritis, rheumatoid spondylitis,
osteoarthritis, atopic
dermatitis, rheumatoid spondylitis, depression, osteoarthritis, contact
dermatitis, ankylo sing
spondylitis, lupus, lupus nephritis, cutaneous lupus erythematosus, systemic
lupus
erythrematosus, erythema nodo sum lepro sum, Sjogren's syndrome, inflammatory
bowel
disease, Crohn's Disease, Behget's Disease, and ulcerative colitis.
[0097] In one aspect, the disease or disorder responsive to the inhibition of
PDE4 is
selected from psoriasis, psoriatic arthritis, contact dermatitis, systemic
lupus erythrematosus,
cutaneous lupus erythematosus, and ulcerative colitis.
[0098] In one aspect, the disease or disorder responsive to the inhibition of
PDE4 is
psoriasis. In another aspect, the disease or disorder responsive to the
inhibition of PDE4 is
psoriasis and the subject being treated is a candidate for phototherapy or
systematic therapy.
[0099] In one aspect, the disease or disorder responsive to the inhibition of
PDE4 is plaque
psoriasis. In another aspect, the disease or disorder responsive to the
inhibition of PDE4 is
plaque psoriasis and the subject being treated is a candidate for phototherapy
or systematic
therapy.
[00100] In
one aspect, the disease or disorder responsive to the inhibition of PDE4 is
moderate to severe plaque psoriasis. In another aspect, the disease or
disorder responsive to
the inhibition of PDE4 is severe plaque psoriasis and the subject being
treated is a candidate
for phototherapy or systematic therapy.
[00101] In
one aspect, the disease or disorder responsive to the inhibition of PDE4 is
psoriatic arthritis.
[00102] In
one aspect, the disease or disorder responsive to the inhibition of PDE4 is
active psoriatic arthritis.
[00103] In
one aspect, the disease or disorder responsive to the inhibition of PDE4 is
heart disease, such as congestive heart failure, cardiomyopathy, pulmonary
edema,
endotoxin-mediated septic shock, acute viral myocarditis, cardiac allograft
rejection, and
myocardial infarction.
[00104] In
one aspect, the disease or disorder responsive to the inhibition of PDE4 is
HIV, hepatitis, adult respiratory distress syndrome, bone-resorption diseases,
cystic fibrosis,
septic shock, sepsis, endotoxic shock, hemodynamic shock, sepsis syndrome,
post ischemic
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reperfusion injury, meningitis, fibrotic disease, cachexia, graft rejection,
osteoporosis,
multiple sclerosis, and radiation damage.
[00105] In one aspect, the disease or disorder responsive to the
inhibition of PDE4 is
cancer of the head, thyroid, neck, eye, skin, mouth, throat, esophagus, cheat,
bone, blood,
bone marrow, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries,
kidney, liver,
pancreas, brain, intestine, heart, adrenal, subcutaneous tissue, lymph nodes,
heart, and
combinations thereof.
[00106] In one aspect, the disease or disorder responsive to the
inhibition of PDE4 is
multiple myeloma, malignant melanoma, malignant glioma, acute lymphoblastic
leukemia,
acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia,
acute
myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic
leukemia, acute
erythroleukemic leukemia, acute megakaryoblastic leukemia, acute
myelomonocytic
leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia,
chronic
myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia,
multiple myeloma
and acute, lymphoblastic leukemia, myelogenous leukemia, lymphocytic leukemia,
and
myelocytic leukemia.
[00107] In one aspect, the disease or disorder responsive to the
inhibition of PDE4 is a
solid tumor, such as sarcoma, fibrosarcoma, myxosarcoma, liposarcoma,
chondrosarcoma,
osteogenic sarcoma, chordoma, angiosarcoma, endothelio sarcoma, lymphangio
sarcoma,
lymphangioendothelio sarcoma, syn-ovioma, mesothelioma, Ewing's tumor, leiomyo
sarcoma,
rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian
cancer,
prostate cancer, squamous cell carcinoma, basal cell carcinoma,
adenocarcinoma, sweat gland
carcinoma, sebaceous gland carcinoma, papillary car-cinoma, papillary
adenocarcinomas,
cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell
carcinoma,
hepatoma, bile duct carcinoma, choriocarci-noma, seminoma, embryonal
carcinoma, Wilms'
tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung
carcinoma, bladder
carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma,
craniopharyngioma,
ependymoma, Kaposi's sarcoma, pinealoma, hemangioblas-toma, acoustic neuroma,
oligodendroglioma, menangioma, melanoma, neuroblastoma, and retinoblastoma.
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EXEMPLIFICATION
1. Materials
Table 1: Whole blood assay: Study Materials and Reagents.
Name of Material Vendor Catalog#/Lot#
Null TruCulture Tube Myriad RBM 782-001086/11437E0
CD3/CD28 TruCulture Tube Myriad RBM 782-001125/11761EQ
IL-1(3, IL-6 and IL-23 recombinant proteins R&D Systems 201-
LB/206-IL/1290-IL
Magpix Kit with Th17 Cytokines Millipore HT17MG-14K-PX25
Abcam Simplestep IL-22 ELISA kit Abcam ab216170
Table 2: LPS stimulated PBMCs assay: Study Materials and Reagents
Name of Material Vendor Catalog#
SepMate PBMC Isolation Tube Stemcell 85450
Ficoll-Paque PLUS GE Healthcare 17-1440-03
RPMI Top of Form Gibco 11875
RPMI Medium 1640Bottom of Form
Fetal bovine serum (FBS) Gibco 10082-147
PBS Gibco 10010-023
40 p.m cell strainer Falcon 352340
RBC lysis buffer eBioscience 00-4333-57
96 well plates Corning Costar 3610
96 well plates for supernatants Corning Costar 3363
Lipopolysaccharides (LPS) Sigma L4391
Bio-Plex ProTM Human Th17 Cytokine IL-23 Bio-Rad 171BA009M
Set
Bio-Plex ProTM Human Inflammation Panel 1 Bio-Rad 171BL015M
IL-12 (p40) Set
Bio-Plex ProTM Human Cytokine 27-plex Assay Bio-Rad M500KCAFOY
Table 3: Test Articles for Studies
Compound Lot# Company
Apremilast Celgene
PDE4i 61983-04 Corporation
Available from Medkoo (555349)
or MedChemExpress (HY- Celgene
BMS- 986165 117287) Corporation
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2. General Methods
[00108] Whole blood was received through the Celgene Donor program after
informed
consent and donor deidentification. All volunteers were healthy and were not
on any
medications for at least 72 hours prior to the blood draw. Blood was collected
in sodium
heparin tubes. The assay was started within 2 hours of the blood draw.
[00109] An ex-vivo stimulation of healthy donor human whole blood was
performed
under two different stimulation conditions. Condition Th0 was a stimulation
with
TruCulture tubes containing anti-CD3/anti-CD28. Condition Th17 was a
stimulation with
TruCulture tubes containing anti-CD3/anti-CD28 plus IL-113, IL-6 and IL-23.
Whole blood
was separated into 15 milliliter conical tubes and pre-treated with DMSO,
apremilast alone,
BMS-986165 alone or BMS-986165 combined with apremilast. Final concentrations
were
0.2% DMSO, 1 M for apremilast alone, 1 M, 0.1 M, 0.01 M and 0.001 M BMS-
986165 alone and in combination with 1 04 apremilast. Blood was mixed well and
then
incubated in a 37 C/5 %CO2 incubator for 1 hour.
[00110] The anti-CD3/anti-CD28 (200 ng/ml and 330 ng/ml final
concentrations
respectively) TruCulture tubes were thawed on the bench top for 30 minutes
and then
labeled. Plungers were pressed and then broken off. TruCulture tubes were
placed in a rack
standing upright such that the plunger side is pointing down in the rack and
the tube-cap is
pointing up. While blood was incubating with compound Human recombinant IL-6,
IL-1f3
and IL-23 were added to all Th17 tubes in the following concentrations: 120 ng
IL-6, 120 ng
IL-lb and 150 ng IL-23. One ml of the pre-treated whole blood was placed in
each tube,
using sterile pyrogen-free pipette tips. The cap was replaced and the contents
of the tube were
mixed by inverting 3 times. The tubes were immediately placed in a 37 C heat
block and
incubated for 42 hours (tube-cap end). After the 42 hours the tubes were
removed from the
heat block, tops were unscrewed and 250 1 of the supernatant was removed and
transferred
into three 96-well polypropylene plates. Samples were immediately frozen at -
80 C. The
supernatants were then thawed at room temperature and tested neat for cytokine
production
by Luminex Multi-Plex MagPix technology (Millipore) or IL-22 by ELISA (Abcam).
The
manufacturer's procedures were followed accordingly.
[00111] Peripheral blood mononuclear cells (PBMCs) isolation: Whole blood
was
received through the Celgene Donor program after informed consent and donor
deidentification. All volunteers were healthy and were not on any medications
for at least 72
hours prior to the blood draw. Blood was collected in Sodium Heparin tubes and
were used
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within 2 hours of the blood draw for PBMCs isolation. Before PBMCs isolation,
whole blood
was diluted 1:1 with PBS solution containing 2%FBS (2%FBS-PBS). 13m1 of Ficoll-
Paque
solution was loaded in the SepMate tube and 25m1 of diluted blood was loaded
on top of
the Ficoll-Paque. Centrifugation at 1200g for 15 minutes with the brake on for
cell separation,
after which isolated PBMCs were transferred into a new tube. PBMCs were washed
with
2%FBS-PBS and centrifuged at 800g 10 minutes. Pellets were resuspended in
2%FBS-PBS
and filtered through a 40i.tm cell strainer to obtain single-cell suspension.
3m1 of RBC lysis
buffer were used to eliminate red blood cells in the isolated population.
Isolated PBMCs
were washed with 2%FBS-PBS and were resuspended in RPMI growth medium
containing
10%FBS and antibiotics.
[00112] For Example 6-11, PBMCs from 9 healthy donors were isolated and
LPS-
stimulated ex-vivo for IL-23, IL-12p40, IL-12p70, TNF-a, IFNI, and MCP-1
cytokine
analysis. PBMCs were plated in 96 well plate at a density of 200,000 cells per
well in 200 ill
of RPMI growth medium containing 10%FBS followed by treatment with DMSO and
compounds. Each well received the same amount of DMSO, which is 0.3% v/v as
final
concentration. Series dilutions of compound treatment was performed according
to Table 4
shown below. After two hours of compound treatment, LPS 100 ng/ml as final
concentration
was used as the stimulator. PBMCs were then incubated in a 37 C/5%CO2
incubator for 16
hours.
Table 4: Compound treatment conditions for PBMC assays
Treatment Stiniulatioti
DMSO No
DMSO LPS 100 ng/ml
Single compound: LPS 100 ng/ml
Tyk2i (BMS-986165): 21.4.M max, 8 point, 3 fold dilution series
(Final concentration were 2 p,M, 0.66 p,M, 0.22 p,M, 0.07 p.M, 0.02
p.M, 0.008 p.M, 0.002 p.M, 0.000911M)
Single compound: LPS 100 ng/ml
Apremilast (CC-10004): 31.4.M max, 8 point, 3 fold dilution series
(Final concentration were 3 p,M, 1 p,M, 0.33 p,M, 0.11 p.M, 0.037
p,M, 0.012 p,M, 0.004 p.M, 0.00111M)
Combination of Tyk2i and Apremilast: LPS 100 ng/ml
Tyk2i (BMS-986165): 21.4.M max, 8 point, 3 fold dilution series
Apremilast CC-10004: fixed concentration at 111M
Combination of Tyk2i and Apremilast: LPS 100 ng/ml
Tyk2i (BMS-986165): 21.4.M max, 8 point, 3 fold dilution series
Apremilast CC-10004 : fixed concentration at 0.311M
Combination of Tyk2i and Apremilast: LPS 100 ng/ml
Tyk2i (BMS-986165): 21.4.M max, 8 point, 3 fold dilution series

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Apremilast CC-10004 : fixed concentration at 0.111M
Combination of Tyk2i and Apremilast: LPS 100 ng/ml
Tyk2i (BMS-986165): 21.4.M max, 8 point, 3 fold dilution series
Apremilast CC-10004 : fixed concentration at 0.037 11M
[00113] After 16 hours incubation, supernatants were collected into new 96-
well
polypropylene plates and centrifuged at 4000 rpm for 10 minutes to get rid of
cell debris.
Cytokine production was measured by Luminex Bio-Plex Multiplex Immunoassay
(Bio-Rad)
according to the manufacturer's procedures. To ensure that supernatant level
was within the
range of the standard cytokine for the assay, samples were diluted 5 fold for
IL-12p40 and
27-plex assays, and used neat for IL-23 assay.
3. Data Analysis
[00114] Data processing for the cytokine analysis was done using Milliplex
Analyst
(Millipore), and raw data was exported to Excel template for the cytokine
analysis. Data from
the template was plotted using GraphPad Prism 7.0 (GraphPad Software, Inc., La
Jolla, CA)
and expressed as pg/ml or % of control. Statistical analysis was also
performed using One
Way Anova and Dunnett's Post Test.
[00115] Data processing for PBMCs assays was done using Bio-plex manager,
and raw
data was exported to Excel template for the cytokine analysis. Data was
plotted using
GraphPad Prism 7.0 (GraphPad Software, Inc., La Jolla, CA) and expressed as %
of DMSO
control. Statistical analysis was performed using One Way ANOVA and Tukey's
multiple
comparisons test.
[00116] To evaluate the combinatory effect of apremilast and BMS-986165,
data from
the two independent treatments were analyzed by comparing the combinatory
response
against the theoretical additive response of the two agents. The expected
additive effect of
two agents (A and B) was calculated using the fractional product method:
(fu)A,B = (fu)A x
(fu)B; where fu = fraction unaffected by treatment. A synergism of a
combination is
determined when the observed fraction unaffected in combination is less than
(fu)A,B,
whereas an additive effect is determined when the observed fraction unaffected
in
combination equals (fu)A,B. A partially additive effect is indicated when the
observed
fraction unaffected in combination is greater than (fu)A,B.
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Example 1
Interleukin 17A Cytokine Production by Apremilast and BMS-986165 in anti-
CD3/anti-
CD28 (Th0) or anti-CD3/anti-CD28, IL-1(3, IL-6 and IL-23 (Th17) Stimulated
Whole
Blood
[00117] Whole blood from 4 healthy donors were analyzed for IL-17A, IL-
17F, IL-22,
TNF-a and GM-CSF cytokine production in both Th0 and Th17 conditions. The
blood was
pre-treated with apremilast and Tyk2 inhibitor BMS-986165 both alone and in
combination
using the TruCulture Tube System. The IL-17A results located in FIG. 1 show
the IL-
17A% of control and all data is normalized to the Th17 DMSO control.
Apremilast inhibited
28% of IL-17A cytokine expression under Th0 conditions and had no effect in
Th17
conditions. BMS-986165 had a similar effect under both stimulation conditions
and inhibited
10-25% of IL-17A expression at 0.001-1 p.M. When apremilast was combined with
BMS-
986165 under Th0 conditions there was synergy seen with 1 1.tM BMS-986165 with
a 65%
reduction in IL-17A. Under Th17 conditions there was synergy with the
combination of 1
1.tM apremilast and 0.01 p,M, 0.111M and 11.tM BMS-986165 with inhibition of
24%, 44%
and 85% of IL-17A respectively. FIG. 2 shows the picograms per milliliter
levels of IL-17A.
Levels of IL-17A increased in the Th17 stimulation conditions by 387% compared
to the Th0
stimulation. In Th0 conditions apremilast reduced IL-17A levels from 138 pg/mL
to
93 pg/mL. BMS-986165, at 11.tM reduced IL-17A levels to 97 pg/mL. The
combination of
apremilast with 11.tM BMS-986165 further reduced IL-17A levels to 24pg/mL with
the Th0
stimulation. Under Th17 conditions the stimulation control measured 532 pg/mL
and
apremilast did not inhibit IL-17A levels. BMS-986165 reduced IL-17A levels to
519 pg/mL
at 0.01 p,M, 428 pg/mL at 0.111M and 383 pg/mL at 1 p.M. The combination of
11.tM
apremilast with BMS-986165 reduced IL-17A levels to 379 pg/mL at 0.01 p,M, 328
pg/mL at
0.111M and 68 pg/mL at 11.tM BMS-986165.
Example 2
Interleukin 17F Cytokine Production by Apremilast and BMS-986165 in anti-
CD3/anti-
CD28 (Th0) or anti-CD3/anti-CD28, IL-1(3, IL-6 and IL-23 (Th17) Stimulated
Whole
Blood
[00118] IL-17F cytokine expression data is in FIG. 3 and FIG. 4.
Apremilast inhibited
69% of IL-17F production under Th0 conditions and 49% under Th17 conditions.
BMS-
986165 had a similar effect on IL-17F with both the Th0 and Th17 stimulation.
There was
31% inhibition at the lowest concentration of 0.001 1.tM and a dose response
with 34%
inhibition at 0.01 p,M, 70% inhibition at 0.111M and 95% inhibition of IL-17F
expression at 1
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1.tM (Th17 results). The combination of 11.tM apremilast with BMS-986165 under
Th0
conditions was partially additive with inhibition ranging from 60% at 0.001 to
95% at 1 p.M.
Under Th17 conditions lower concentrations of BMS-986165 combined with
apremilast
showed synergy. Apremilast combined with BMS-986165 at 0.00111M inhibited 68%
of IL-
17F, 0.0111M inhibited 70%, 0.111M inhibited 94% and 11.tM inhibited 99% of IL-
17F
production under Th17 stimulation conditions. Levels of IL-17F in the Th0
stimulation
control were 1085 pg/mL and increased to 6524 pg/mL in the Th17 stimulation.
Apremilast
reduced IL-17F to 368 pg/mL in the Th0 stimulation and to 3643 pg/mL in the
Th17
stimulation. BMS-986165 significantly reduced IL-17F at 0.1 and 11.tM in both
stimulation
conditions. There was significant inhibition of IL-17F at all concentrations
of BMS-986165
when combined with apremilast and under both stimulation conditions.
Example 3
Interleukin 22 Cytokine Production by Apremilast and BMS-986165 in anti-
CD3/anti-
CD28 (Th0) or anti-CD3/anti-CD28, IL-1(3, IL-6 and IL-23 (Th17) Stimulated
Whole
Blood
[00119] IL-22
cytokine expression data is in FIG. 5 and FIG. 6. Apremilast inhibited
85% of IL-22 cytokine expression under Th0 conditions and 41% under Th17
conditions.
Under Th0 stimulation condition BMS-986165 inhibited 16% of IL-22 at 0.01 p,M,
86% at
0.111M and 91% at 1 p.M. Under Th17 stimulation conditions BMS-986165 had no
effect on
IL-22 cytokine expression at 0.00111M but inhibited 17% at 0.01 p,M, 60% at
0.111M and
70% at 1 p.M. Under Th0 conditions the combination had similar effects to
apremilast alone
with ¨90% inhibition at all concentrations of BMS-986165. The combination
under Th17
conditions was synergist at 0.0111M with 60% inhibition and at 0.111M with 90%
inhibition
of IL-22 cytokine expression. The Th0 stimulation control had 1085 pg/mL of IL-
22 and the
Th17 control was 6524 pg/mL. Apremilast significantly lowered IL-22 levels to
368 pg/mL
in the Th0 conditions and 3643 pg/mL in the Th17 conditions. BMS-986165
significantly
lowered IL-22 cytokine expression in both stimulation conditions at 0.111M and
1 p.M. There
was significant inhibition of IL-22 at all concentrations of BMS-986165 when
combined with
apremilast and under both stimulation conditions.
38

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Example 4
TNF-a Cytokine Production by Apremilast and BMS-986165 in anti-CD3/anti-CD28
(Th0) or anti-CD3/anti-CD28, IL-1(3, IL-6 and IL-23 (Th17) Stimulated Whole
Blood
[00120] TNF-a cytokine expression data is located in FIG. 7 and FIG. 8.
Apremilast
inhibited 90% of TNF-a levels in Th0 conditions and 94% in Th17 conditions. In
the Th0
stimulation BMS-986165 increased TNF-a expression by 21% at 0.001 p,M, 43% at
0.0111M
and 61% at 0.1 p.M. At the highest concentration of 11.tM BMS-986165 inhibited
66% of
TNF-a cytokine expression. There was a similar increase in TNF-a production
seen with
BMS-986165 under Th17 conditions with a 19% increase at 0.01 1.tM and a 77%
increase at
0.1 p.M. There was also inhibition of TNF-a (68%) with 11.tM BMS-986165 under
Th17
stimulation conditions. The combination of 1 1.tM apremilast with BMS-986165
reduced
levels of TNF-a by 80-95% (Th0) and 93-96% (Th17), a similar effect to single
agent
apremilast. Both stimulation conditions had a similar effect on levels of TNF-
a with the Th0
stimulation control of 1380 pg/mL and the Th17 stimulation control of 1436
pg/mL.
Apremilast significantly inhibited TNF-a by reducing levels to 148 pg/mL in
Th0 conditions
and 91 pg/mL in Th17 conditions. The increase in TNF-a levels by BMS-986165
was
significant in Th17 conditions at 0.1 p.M. The inhibition of TNF-a levels with
11.tM BMS-
986165 was significant under both stimulation conditions. The combination of
apremilast
with BMS-986165 significantly inhibited TNF-a levels with all concentrations
and in both
stimulation conditions.
Example 5
Granulocyte-Macrophage Colony-Stimulating Factor Cytokine Production by
Apremilast and BMS-986165 in anti-CD3/anti-CD28 (Th0) or anti-CD3/anti-CD28,
IL-
113, IL-6 and IL-23 (Th17) Stimulated Whole Blood
[00121] Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) cytokine
expression results are in FIG. 9 and FIG. 10. GM-CSF cytokine expression was
reduced
80% by apremilast under Th0 conditions and by 66% under Th17 conditions. BMS-
986165
increased GM-CSF cytokine expression under both conditions. BMS-986165
increased GM-
CSF by 19% at 0.001 p.M, 36% at 0.01 p,M, 110% at 0.111M and 31% at 1 p.M in
the Th0
conditions. When apremilast (0.111M) was added to BMS-986165 there was
inhibition 60-
80% of GM-CSF cytokine expression. In the Th17 stimulation BMS-986165
increased GM-
CSF by 41% at 0.01 p,M, 139% at 0.111M and 104% at 1 p.M. When apremilast was
added
there was 40-73% inhibition of GM-CSF cytokine expression. Total pg/mL of GM-
CSF in
39

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the Th0 and Th17 stimulation controls were 409 and 637 respectively.
Apremilast
significantly inhibited GM-CSF under both stimulation conditions. The increase
of GM-CSF
by BMS-986165 was significant at 0.111M (both Th0 and Th17) and 111M (Th17).
The
combination of apremilast and BMS-986165 significantly reduced GM-CSF cytokine
levels
at all concentrations and under both stimulation conditions.
Example 6
IL-23 production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-
986165)
Treatment
[00122] PBMCs from 9 healthy donors were analyzed for cytokine production
in LPS
stimulation condition (FIG. 11 to FIG. 17). Results in FIG. 11 and FIG. 12
showed the level
of IL-23. FIG. 11 showed that Apremilast decreased IL-23 production in LPS
stimulated
PBMCs. IL-23 level from DMSO treated LPS stimulated PBMCs was set as 100%
(control),
cytokine levels were shown as normalized value in % compared to control. In
contrast to
decreasing IL-23 level by Apremilast, FIG. 12 showed that BMS-986165 induces
IL-23 level
in LPS stimulated PBMCs. At the range of 0.2 11M ¨2 p,M, BMS-986165 induced a
20 fold
increases of IL-23 compared to DMSO group. The combination of apremilast with
BMS-
986165 was able to decrease the induction of IL-23 by BMS-986165. With
increased level of
apremilast, there is significant reduction of IL-23 level. Statistical
analysis using ANOVA
and Turkey's multiple comparisons were performed to compare each treatment
with BMS-
986165 alone. There is significant reduction of IL-23 when combining BMS-
986165 with
low level of apremilast, which is at the concentration of 0.03711M (****
p<0.001). When
combined with 111M apremilast, the induction of IL-23 was 90% inhibited, and
almost
reached a similar level as apremilast alone. Thus, the curve of combination
treatment with 1
04 apremilast has no significant difference compared to apremilast treatment
alone.
Example 7
IL-12p40 Production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-
986165) Treatment
[00123] Results in FIG. 13 showed the normalized level of IL-12p40
compared to
DMSO treated LPS stimulated PBMCs group. Apremilast decreased IL-12p40 in a
dose
dependent manner, whereas BMS-986165 increased it. The combination of BMS-
986165
with apremilast significantly decreased the induction of IL-12p40 by BMS-
986165. With
111M apremilast, the increased IL-12p40 induced by BMS-986165 was 85%
inhibited, and
almost reached a similar level as Apremilast alone. Statistical analysis using
ANOVA and

CA 03138686 2021-10-29
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Turkey's multiple comparisons were performed to compare each treatment with
BMS-
986165 alone. **** p<0.001
Example 8
IL-12p70 Production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-
986165) Treatment
[00124] Results in FIG. 14 showed the normalized level of IL-12p70
compared to
DMSO treated LPS stimulated PBMCs group. Apremilast decreased IL-12p'70 in a
dose
dependent manner, whereas BMS-986165 increased it. The combination of BMS-
986165
with apremilast significantly decreased the induction of IL-12p70 by BMS-
986165. In
combination treatment, both 0.3 M and 1 M significantly reduced IL-12p'70
level induced
by BMS-986165 and have no significant difference compared to apremilast alone.
Statistical
analysis using ANOVA and Turkey's multiple comparisons were performed to
compare each
treatment with BMS-986165 alone. **** p<0.001
Example 9
TNF-a Production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-
986165) Treatment
[00125] Results in FIG. 15 showed the normalized level of TNF-a compared
to
DMSO treated LPS stimulated PBMCs group. Apremilast decreased TNF- a level in
a dose
dependent manner, however, BMS-986165 induced 1.2-1.5 fold increase of TNF-a.
The
combination of BMS-986165 and apremilast significantly decreased the level of
TNF-a.
Statistical analysis using ANOVA and Turkey's multiple comparisons were
performed to
compare each treatment with BMS-986165 alone. **** p<0.001
Example 10
IFN-y Production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-
986165)
Treatment
[00126] Results in FIG. 16 showed the normalized level of IFN-y compared
to DMSO
treated LPS stimulated PBMCs group. Both apremilast alone and BMS-986165 alone
decreased IFN-y in a dose dependent manner. The combination of BMS-986165 and
apremilast has synergistic effect in reducing IFN-y level which significantly
decreased IFN-
y level compared to single compound treatment. Statistical analysis using
ANOVA and
Turkey's multiple comparisons were performed to compare each treatment with
BMS-
986165 alone. **** p<0.001.
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Example 11
MCP-1 Production in LPS Stimulated PBMCs with Apremilast and Tyk2i (BMS-
986165) Treatment
[00127] Results in FIG. 17 showed the normalized level of MCP-1 compared
to
DMSO treated LPS stimulated PBMCs group. Both apremilast alone and BMS-986165
alone
decreased MCP-1 in a dose dependent manner. The combination of BMS-986165 and
Apremilast has synergistic effect in reducing MCP-1 level. Statistical
analysis using ANOVA
and Turkey's multiple comparisons were performed to compare each treatment
with BMS-
986165 alone. **** p<0.001.
Data Summary
[00128] Table
5 below provides a summary of the cytokine effects of apremilast and
BMS-986165 on stimulated whole blood in the Ex-Vivo TruCulture Assay.
Synergistic
effects are shown in bold and complementary effects are underlined.
[00129] Four
healthy donors' whole blood was tested in the Tru-culture assay in Th0
(anti-CD3/anti-CD28) or Th17 (anti-CD3/anti-CD28 + IL-113, IL-6 and IL-23)
conditions for
48 hours with the Tyk2 inhibitor BMS-986165 +/- apremilast. BMS-986165
inhibited IL-17A,
IL-17F, and IL-22 cytokine expression under Th0 and Th17 conditions. When
combined with
apremilast these cytokines were further reduced with a synergistic effect on
IL-17A, IL-17F
and IL-22 under Th17 conditions. BMS-986165 increased TNF-a and GM-CSF
production,
while apremilast inhibited production of these cytokines. When BMS-986165 was
combined
with apremilast there was a complementary effect on TNF-a and GM-CSF cytokine
expression, with apremilast correcting the defect of BMS-986165. These
combined effect
provide means for treating diseases or disorders responsive to the inhibition
of PDE4 such as
for the treatment inflammatory diseases (e.g., psoriasis, psoriatic arthritis,
and ulcerative
colitis).
Table 5
IL-17F IL-17A IL-22 TNF-a IL-23 GM-CSF IFN-y IL-10
Stim. Treatment % of % of % of % of % of % of % of %
of
Control Control Control Control Control Control Control Control
1 [EM
31.8 71.6 14.8 10.7 82.1 20.3 9.3 41.6
apremilast
0.01 [EM
BMS- 68.5 83.5 84.1 143.1 101.8 136.3 100.2
101.5
Th0
9896165
0.1 [EM
BMS- 28.3 73.0 13.4 160.7 89.9 210.5 80.9
33.8
9896165
42

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0.01 !LEM
BMS-
33.8 84.0 11.2 13.5 79.3 27.4 12.2 42.0
9896165
+ apr
0.1 !LEM
BMS-
21.0 90.0 9.3 21.9 77.0 41.6 12.9 34.8
9896165
+ apr
1 !LEM
59.7 102.4 57.5 5.8 94.3 33.8 18.7 32.6
apremilast
0.01 !LEM
BMS- 73.6 97.7 83.3 118.5 93.8 141.1 114.2
78.4
9896165
0.1 !LEM
BMS- 30.0 79.2 39.8 177.4 96.3 239.3 74.7
46.6
9896165
Th17
0.01 !LEM
BMS-
34.1 76.1 39.5 6.7 92.7 37.8 16.8 29.9
9896165
+ apr
0.1 !LEM
BMS-
11.5 66.1 9.2 8.2 84.2 60.8 8.4 45.4
9896165
+ apr
CCL20 IL-13 IL-10 IL-2 IL-21 IL-4 IL-5 IL-6
Stim. Treatment % of % of % of % of % of % of % of % of
Control Control Control Control Control Control Control Control
1 !LEM
59.5 15.3 16.4 17.9 62.9 30.3 6.2 52.8
apremilast
0.01 !LEM
BMS- 82.7 146.9 113.5 120.1 107.6 122.8
153.1 149.3
9896165
0.1 !LEM
BMS- 106.4 205.9 113.2 187.4 94.5 114.7 178.6
124.0
9896165
Th0
0.01 !LEM
BMS-
9896165 73.1 25.0 30.4 18.2 62.9 33.1 9.1
112.6
+ apr
0.1 !LEM
BMS-
9896165 97.0 45.1 41.6 22.9 68.9 37.6 16.6
210.0
+ apr
1 !LEM
220.3 22.1 98 14.4 76.2 36.7 4.8 95.3
apremilast
0.01 !LEM
BMS- 121.7 158.1 94.2 128.5 91.5 126.5 144.3
96.8
9896165
0.1 !LEM
BMS- 157.8 287.5 89.0 250.3 86.3 161.9 249.9
112.7
Th17
9896165
0.01 !LEM
BMS-
270.3 26.1 88.7 15.9 72.8 27.4 6.4 108.9
9896165
+ apr
0.1 !LEM
340.1 46.2 82.8 21.9 54.5 28.7 8.0 101.1
BMS-
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WO 2020/223431 PCT/US2020/030608
9896165
+ apr
[00130] Table 6 below provides a summary of the cytokine effects of
apremilast and
BMS-986165 on LPS stimulated PBMCs. Red arrows indicate induction and green
arrows
indicate decrease of the production of cytokines.
[00131] PBMCs from 9 healthy donors were tested in LPS stimulated condition
with or
without BMS-986165 or apremilast or the combination of both. BMS-986165
treatment alone
induced IL-23, IL-12p40, IL-12p70 and TNF-a, whereas apremilast treatment
alone
decreased these cytokines. When BMS-986165 was combined with apremilast, these
cytokines were either unchanged or reduced compared to DMSO control group.
These results
indicate that apremilast could inhibit the induction of these cytokines by BMS-
986165. Both
apremilast and BMS-986165 reduced IFN-y and MCP-1 production, and the
combination of
both further reduced these two cytokines with a synergistic effect. BMS-986165
inhibits
Th17 lineage cytokines, which provide a means for treating diseases where Th17
cytokines
are implicated in the pathogenesis. However, the induction of some
proinflammatory
cytokines, such as IL-23, IL-12 and TNF-a, by BMS-986165 could be a
disadvantage in
disease treatment. The combined effects of apremilast and BMS-986165 in which
IL-23, IL-
12 and TNF-a were decreased showed an advantage of combining these two
compounds in
treating inflammatory diseases such as psoriasis, psoriatic arthritis, and
ulcerative colitis.
Table 6
51435-U9451 titr = II
I =
kggwai
gm:mg! ,..; :mom
E:gool:E:4:Ag:: m:**:EN:Rogs: mAtom:
FMS-9861er.5
Induced
____________ No change
Reduced
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Example 12
Apremilast and Tyk2i (BMS-986165) Fixed Dose Combinations in Whole Blood
[00132] Apremilast and BMS-986165 were tested in IL-17A, IL-17F, IL-22,
and TNF-
a whole blood at the following fixed dosages: 2 mg BID BMS-986165, 6 mg QD BMS-
986165, 6 mg BID BMS-986165, 10 mg BID apremilast, 20 mg BID apremilast, and
30 mg
BID apremilast. These concentrations were derived from average plasma
concentrations
observed or extrapolated from clinical PK data.
[00133] As shown by FIGs. 18-21, the 6 mg QD dose concentration of BMS-
986165
did not maximally inhibit IL-17A, IL-17F, or IL-22, and it elevated TNF-alpha.
See FIGs.
18-21. The addition of apremilast, however, at the 10 to 30 mg BID dose
concentrations
compensated for this, and prevented the TNF-alpha elevation. See FIGs. 18-21.
Even low
concentrations of apremilast where shown to be effective. For example, the 20
mg BID dose
of apremilast compensated for the suboptimal inhibition of IL-17F, and the 10
mg BID dose
of apremilast compensated for the suboptimal inhibition of IL-22, and to
prevent the increase
of TNF-alpha. This data supports the synergistic use of BMS-986165 (e.g., at 6
mg QD) and
apremilast (e.g., 10-20 mg QD or BID) to inhibit IL-17 and IL-22, and reduce
TNF-alpha
production for the treatment of inflammatory diseases driven by these
cyotkines such as
psoriasis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis,
Crohn's disease,
hidradenitis suppurativa, and Behcet's disease.