Claims for Patent: 10,632,112

Summary for Patent: 10,632,112

Title:	Combination therapy for treatment of HBV infections
Abstract:	Provided herein is a combination therapy comprising a compound of Formula I and peginterferon alfa-2a, or another interferon analog. The combination therapy is useful for the treatment of HBV infection. Also provided herein are compositions comprising a compound of Formula I and peginterferon alfa-2a, or another interferon analog.
Inventor(s):	Hartman; George D. (Lansdale, PA)
Assignee:	NOVIRA THERAPEUTICS, INC. (Doylestown, PA)
Application Number:	16/235,210
Patent Claims:	1. A method of treating an HBV infection in a subject in need thereof, comprising administering to the subject a capsid assembly inhibitor and pegylated interferon, wherein the capsid assembly inhibitor is a compound of Formula I: ##STR00035## or a pharmaceutically acceptable salt thereof; wherein R.sup.4 is H or C.sub.1-C.sub.6 alkyl; wherein each R.sup.5 is independently selected at each occurrence from the group consisting of CH.sub.3, C.sub.1-C.sub.6 alkoxy, halo, --CN, --NO.sub.2, -(L).sub.m-SR.sup.9, -(L).sub.m-S(.dbd.O)R.sup.9, -(L).sub.m-S(.dbd.O).sub.2R.sup.9, -(L).sub.m-NHS(.dbd.O).sub.2R.sup.9, -(L).sub.m-C(.dbd.O)R.sup.9, -(L).sub.m-OC(.dbd.O)R.sup.9, -(L).sub.mCO.sub.2R.sup.8, -(L).sub.m-OCO.sub.2R.sup.8, -(L).sub.m-N(R.sup.8).sub.2, -(L).sub.m-C(.dbd.O)N(R.sup.8).sub.2, -(L).sub.m-OC(.dbd.O)N(R.sup.8).sub.2, -(L).sub.m-NHC(.dbd.O)NH(R.sup.8), -(L).sub.m-NHC(.dbd.O)R.sup.9, -(L).sub.m-NHC(.dbd.O)OR.sup.9, -(L).sub.m-C(OH)(R.sup.8).sub.2, -(L).sub.mC(NH.sub.2)(R.sup.8).sub.2, --C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.6 dihaloalkyl and --C.sub.1-C.sub.6 trihaloalkyl; L is independently, at each occurrence, a bivalent radical selected from --(C.sub.1-C.sub.3 alkylene)-, --(C.sub.3-C.sub.7 cycloalkylene)-, --(C.sub.1-C.sub.3 alkylene).sub.m-O--(C.sub.1-C.sub.3 alkylene).sub.m-, or --(C.sub.1-C.sub.3 alkylene).sub.m-NH--(C.sub.1-C.sub.3 alkylene).sub.m-; each R.sup.8 is independently, at each occurrence, H, C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.6 dihaloalkyl, --C.sub.1-C.sub.6 trihaloalkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 heterocycloalkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1-5 substituents selected from R.sup.2; R.sup.9 is C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.6 dihaloalkyl, --C.sub.1-C.sub.6 trihaloalkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.3-C.sub.10 cycloalkyl, a C.sub.3-C.sub.10 heterocycloalkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 0-5 substituents selected from R.sup.2; R.sup.10 is OH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-OH, --C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.6 dihaloalkyl, --C.sub.1-C.sub.6 trihaloalkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.3-C.sub.10 cycloalkyl, a C.sub.3-C.sub.10 heterocycloalkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R.sup.2; R.sup.11 is a bond or C.sub.1-C.sub.3 alkylene, wherein the C.sub.1-C.sub.3 alkylene is optionally substituted with 1-3 substituents selected from R.sup.2; R.sup.2 is independently selected at each occurrence from the group consisting of OH, halo, --CN, --NO.sub.2, --C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.6 dihaloalkyl, --C.sub.1-C.sub.6 trihaloalkyl, --C.sub.1-C.sub.6 heteroalkyl, and C(O) --C.sub.1-C.sub.6 alkyl; w is 0, 1 or 2; each occurrence of x is independently selected from the group consisting of 0, 1, 2, 3 and 4; each occurrence of y is independently selected from the group consisting of 1, 2, and 3; each occurrence of z is independently selected from the group consisting of 0, 1, 2, and 3; each occurrence of m is independently 0, 1 or 2. 2. The method of claim 1, wherein the pegylated interferon is selected from the group consisting of peginterferon-alpha 2a, peginterferon alpha-2b, peginterferon beta-1a, peginterferon lambda-1, DA-3021, and PEG-Infergen. 3. The method of claim 2, wherein the pegylated interferon is selected from the group consisting of peginterferon alpha-2a, peginterferon alpha-2b, peginterferon alpha-1a, and peginterferon lambda-1. 4. The method of claim 3, wherein the pegylated interferon is peginterferon alpha-2a. 5. The method of claim 1, wherein the pegylated interferon and compound of Formula I are in a single formulation or unit dosage form. 6. The method of claim 5, further comprising a pharmaceutically acceptable carrier. 7. The method of claim 1, wherein the pegylated interferon and compound of Formula I are administered separately. 8. The method of claim 1, wherein the subject is human. 9. The method of claim 1, wherein the treatment comprises administering the pegylated interferon and compound of Formula I at substantially the same time. 10. The method of claim 1, wherein the treatment comprises administering the pegylated interferon and compound of Formula I at different times. 11. The method of claim 10, wherein the pegylated interferon is administered to the subject, followed by administration of a compound of Formula I. 12. The method of claim 10, wherein the compound of Formula I is administered to the subject, followed by administration of the pegylated interferon. 13. The method of claim 10, wherein the pegylated interferon and compound of Formula I are in separate formulations or unit dosage forms. 14. The method of claim 1, wherein the pegylated interferon and compound of Formula I are administered at dosages that would not be effective when one or both of the pegylated interferon and compound of Formula I are administered alone, but which amounts are effective in combination. 15. A composition comprising pegylated interferon and a compound of Formula I: ##STR00036## or a pharmaceutically acceptable salt thereof; wherein R.sup.4 is H or C.sub.1-C.sub.6 alkyl; wherein each R.sup.5 is independently selected at each occurrence from the group consisting of CH.sub.3, C.sub.1-C.sub.6 alkoxy, halo, --CN, --NO.sub.2, -(L).sub.m-SR.sup.9, -(L).sub.m-S(.dbd.O)R.sup.9, -(L).sub.m-S(.dbd.O).sub.2R.sup.9, -(L).sub.m-NHS(.dbd.O).sub.2R.sup.9, -(L).sub.m-C(.dbd.O)R.sup.9, -(L).sub.m-OC(.dbd.O)R.sup.9, -(L).sub.mCO.sub.2R.sup.8, -(L).sub.m-OCO.sub.2R.sup.8, -(L).sub.m-N(R.sup.8).sub.2, -(L).sub.m-C(.dbd.O)N(R.sup.8).sub.2, -(L).sub.m-OC(.dbd.O)N(R.sup.8).sub.2, -(L).sub.m-NHC(.dbd.O)NH(R.sup.8), -(L).sub.m-NHC(.dbd.O)R.sup.9, -(L).sub.m-NHC(.dbd.O)OR.sup.9, -(L).sub.m-C(OH)(R.sup.8).sub.2, -(L).sub.mC(NH.sub.2)(R.sup.8).sub.2, --C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.6 dihaloalkyl and --C.sub.1-C.sub.6 trihaloalkyl; L is independently, at each occurrence, a bivalent radical selected from --(C.sub.1-C.sub.3 alkylene)-, --(C.sub.3-C.sub.7 cycloalkylene)-, --(C.sub.1-C.sub.3 alkylene).sub.m-O--(C.sub.1-C.sub.3 alkylene).sub.m-, or --(C.sub.1-C.sub.3 alkylene).sub.m-NH--(C.sub.1-C.sub.3 alkylene).sub.m-; each R.sup.8 is independently, at each occurrence, H, C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.6 dihaloalkyl, --C.sub.1-C.sub.6 trihaloalkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10 heterocycloalkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 1-5 substituents selected from R.sup.2; R.sup.9 is C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.6 dihaloalkyl, --C.sub.1-C.sub.6 trihaloalkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.3-C.sub.10 cycloalkyl, a C.sub.3-C.sub.10 heterocycloalkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 0-5 substituents selected from R.sup.2; R.sup.10 is OH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkyl-OH, --C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.6 dihaloalkyl, --C.sub.1-C.sub.6 trihaloalkyl, C.sub.1-C.sub.6 heteroalkyl, C.sub.3-C.sub.10 cycloalkyl, a C.sub.3-C.sub.10 heterocycloalkyl, aryl, heteroaryl, --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 cycloalkyl), --C.sub.1-C.sub.4 alkyl-(C.sub.3-C.sub.10 heterocycloalkyl), --C.sub.1-C.sub.4 alkyl-(aryl), or --C.sub.1-C.sub.4 alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 1-5 substituents selected from R.sup.2; R.sup.11 is a bond or C.sub.1-C.sub.3 alkylene, wherein the C.sub.1-C.sub.3 alkylene is optionally substituted with 1-3 substituents selected from R.sup.2; R.sup.2 is independently selected at each occurrence from the group consisting of OH, halo, --CN, --NO.sub.2, --C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6 alkoxy, --C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.6 dihaloalkyl, --C.sub.1-C.sub.6 trihaloalkyl, --C.sub.1-C.sub.6 heteroalkyl, and C(O)--C.sub.1-C.sub.6 alkyl; w is 0, 1 or 2; each occurrence of x is independently selected from the group consisting of 0, 1, 2, 3 and 4; each occurrence of y is independently selected from the group consisting of 1, 2, and 3; each occurrence of z is independently selected from the group consisting of 0, 1, 2, and 3; each occurrence of m is independently 0, 1 or 2. 16. A method of treating an HBV infection in a subject in need thereof comprising administering to the subject an effective amount of the composition of claim 15.

Details for Patent 10,632,112

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Kadmon Pharmaceuticals Llc	INFERGEN	interferon alfacon-1	Injection	103663	10/06/1997		2034-02-05
Biogen Inc.	PLEGRIDY	peginterferon beta-1a	Injection	125499	08/15/2014		2034-02-05