US2019038623A1PendingUtilityA1
Therapeutic regimens for treatment of paroxysmal nocturnal hemoglobinuria
Assignee: ACHILLION PHARMACEUTICALS INCPriority: Aug 2, 2017Filed: Aug 2, 2018Published: Feb 7, 2019
Est. expiryAug 2, 2037(~11 yrs left)· nominal 20-yr term from priority
C07K 2317/76A61P 7/00C07K 16/18A61K 2039/505A61K 39/3955A61K 31/506
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Claims
Abstract
Provided herein are methods for treating a subject with PNH comprising administering to a subject a therapeutically effective amount of complement component C5 (C5) inhibitor, complement component C3 (C3) inhibitor, or complement factor B (CFB) inhibitor in combination with a therapeutically effective amount of small molecule complement factor D (CFD) inhibitor of Formula I or Formula II, or a pharmaceutically acceptable salt thereof.
Claims
exact text as granted — not AI-modified1 . A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a complement 5 (C5) inhibitor in combination with a therapeutically effective amount of a complement factor D (CFD) inhibitor;
wherein the CFD inhibitor is selected from a compound of Formula I or Formula II:
or a pharmaceutically acceptable salt thereof;
wherein:
X is selected from N and CH;
R 1 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 2 is selected from hydrogen and C 1 -C 3 alkyl;
R 3 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 4 is selected from hydrogen, C 1 -C 3 alkyl, and halogen; and
R 5 is selected from hydrogen, C 1 -C 3 alkyl, halogen, and cyano.
2 . The method of claim 1 , wherein the CFD inhibitor is selected from the group consisting of a compound of formula:
3 . The method of claim 1 , wherein the CFD inhibitor is selected from the group consisting of a compound of formula:
4 . The method of claim 1 , wherein the CFD inhibitor is a compound of the formula:
5 . The method of claim 1 , wherein the C5 inhibitor is eculizamab.
6 . The method of claim 1 , wherein the C5 inhibitor is selected from the group consisting of a recombinant human minibody, coversin, Tesidolumab/LFG316, ARC-1905, RA101348, RA101495, SOBI002, ARC1005, a SOMAmer for C5, SSL7, MEDI7814, aurin tricarboxylic acid, an aurin tricarboxylic acid derivative, RG6107/SKY59, ALXN1210, ALXN5500, TT30, ABP959, Anti-05 siRNA, Erdigna, avacincaptad pegol/Zimura®, SOBI005, ISU305, and REGN3918.
7 . A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a complement factor D (CFD) inhibitor selected from a compound of Formula I or Formula
or a pharmaceutically acceptable salt thereof;
wherein:
X is selected from N and CH;
R 1 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 2 is selected from hydrogen and C 1 -C 3 alkyl;
R 3 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 4 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 5 is selected from hydrogen, C 1 -C 3 alkyl, halogen, and cyano;
wherein the subject at the time of administration of the CFD inhibitor has been receiving or is currently receiving a therapeutic regimen comprising the administration of a complement 5 (C5) inhibitor; and,
wherein the subject is experiencing extravascular hemolysis.
8 . The method of claim 7 , wherein the CFD inhibitor is selected from the group consisting of a compound of formula:
9 . The method of claim 7 , wherein the CFD inhibitor is selected from the group consisting of a compound of formula:
10 . The method of claim 7 , wherein the CFD inhibitor is a compound of the formula:
11 . The method of claim 7 , wherein the C5 inhibitor is eculizamab.
12 . The method of claim 7 , wherein the C5 inhibitor is selected from the group consisting of a recombinant human minibody, coversin, Tesidolumab/LFG316, ARC-1905, RA101348, RA101495, SOBI002, ARC1005, a SOMAmer for C5, SSL7, MEDI7814, aurin tricarboxylic acid, an aurin tricarboxylic acid derivative, RG6107/SKY59, ALXN1210, ALXN5500, TT30, ABP959, Anti-05 siRNA, Erdigna, avacincaptad pegol/Zimura®, SOBI005, ISU305, and REGN3918.
13 . The method of claim 7 , wherein the subject has a hemoglobin level of less than about 10 g/dL at the time of administration of the CFD inhibitor.
14 . The method of claim 7 , wherein the subject has an LDH level within a normal range.
15 . The method of claim 7 , wherein the subject has a LDH level of less than 250 U/L at the time of administration of the CFD inhibitor.
16 . The method of claim 7 , wherein the subject has received one or more blood transfusions within the twelve months prior to administration of the CFD inhibitor.
17 . The method of claim 7 , wherein the subject has been on a C5 therapeutic regimen for at least three months prior to administration of the CFD inhibitor.
18 . The method of claim 7 , wherein upon administration of the CFD inhibitor, the C5 inhibitor also continues to be administered.
19 . The method of claim 7 , wherein upon administration of the CFD inhibitor, the C5 inhibitor is no longer administered.
20 . A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a complement factor D (CFD) inhibitor selected from a compound of Formula I or Formula
or a pharmaceutically acceptable salt thereof;
wherein:
X is selected from N and CH;
R 1 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 2 is selected from hydrogen and C 1 -C 3 alkyl;
R 3 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 4 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 5 is selected from hydrogen, C 1 -C 3 alkyl, halogen, and cyano;
wherein the subject at the time of administration of the CFD inhibitor has been receiving or is currently receiving a therapeutic regimen comprising the administration of a complement 5 (C5) inhibitor; and
wherein the subject is experiencing residual intravascular hemolysis.
21 . The method of claim 20 , wherein the CFD inhibitor is selected from the group consisting of a compound of formula:
22 . The method of claim 20 , wherein the CFD inhibitor is selected from the group consisting of a compound of formula:
23 . The method of claim 20 , wherein the CFD inhibitor is a compound of the formula:
24 . The method of claim 20 , wherein the C5 inhibitor is eculizamab.
25 . The method of claim 20 , wherein the C5 inhibitor is selected from the group consisting of a recombinant human minibody, coversin, Tesidolumab/LFG316, ARC-1905, RA101348, RA101495, SOBI002, ARC1005, a SOMAmer for C5, SSL7, MEDI7814, aurin tricarboxylic acid, an aurin tricarboxylic acid derivative, RG6107/SKY59, ALXN1210, ALXN5500, TT30, ABP959, Anti-05 siRNA, Erdigna, avacincaptad pegol/Zimura®, SOBI005, ISU305, and REGN3918.
26 . The method of claim 20 , wherein the subject has a hemoglobin level of less than about 10 g/dL at the time of administration of the CFD inhibitor.
27 . The method of claim 20 , wherein the subject has a LDH level greater than the upper level of normal.
28 . The method of claim 20 , wherein the subject has a LDH level of greater than 250 U/L at the time of administration of the CFD inhibitor.
29 . The method of claim 20 , wherein the subject has received one or more blood transfusions within the twelve months prior to administration of the CFD inhibitor.
30 . The method of claim 20 , wherein the subject has been on a C5 therapeutic regimen for at least three months prior to administration of the CFD inhibitor.
31 . The method of claim 20 , wherein upon administration of the CFD inhibitor, the C5 inhibitor also continues to be administered.
32 . The method of claim 20 , wherein upon administration of the CFD inhibitor the C5 inhibitor is no longer administered.
33 . A method for treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a complement factor D (CFD) inhibitor selected from a compound of Formula I or Formula
or a pharmaceutically acceptable salt thereof;
wherein:
X is selected from N and CH;
R 1 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 2 is selected from hydrogen and C 1 -C 3 alkyl;
R 3 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 4 is selected from hydrogen, C 1 -C 3 alkyl, and halogen;
R 5 is selected from hydrogen, C 1 -C 3 alkyl, halogen, and cyano;
wherein the subject at the time of administration of the CFD inhibitor has been receiving or is currently receiving a therapeutic regimen comprising the administration of a complement 5 (C5) inhibitor; and
wherein the subject has a hemoglobin level of less than about 10 g/dL.
34 . The method of claim 33 , wherein the CFD inhibitor is selected from a compound of formula:
35 . The method of claim 33 , wherein the CFD inhibitor is selected from a compound of formula:
36 . The method of claim 33 , wherein the CFD inhibitor is a compound of the formula:
37 . The method of claim 33 , wherein the C5 inhibitor is eculizamab.
38 . The method of claim 33 , wherein the C5 inhibitor is selected from a recombinant human minibody, coversin, Tesidolumab/LFG316, ARC-1905, RA101348, RA101495, SOBI002, ARC1005, a SOMAmer for C5, SSL7, MEDI7814, aurin tricarboxylic acid, an aurin tricarboxylic acid derivative, RG6107/SKY59, ALXN1210, ALXN5500, TT30, ABP959, Anti-C5 siRNA, Erdigna, avacincaptad pegol/Zimura®, SOBI005, ISU305, and REGN3918.
39 . The method of claim 33 , wherein the subject has a hemoglobin level of less than about 8 g/dL at the time of administration of the CFD inhibitor.
40 . The method of claim 33 , wherein the subject has a LDH level greater than the upper level of normal.
41 . The method of claim 33 , wherein the subject has a LDH level of greater than about 250 U/L at the time of administration of the CFD inhibitor.
42 . The method of claim 33 , wherein the subject has a LDH level within a normal range.
43 . The method of claim 33 , wherein the subject has a LDH level of less than about 250 U/L at the time of administration of the CFD inhibitor.
44 . The method of claim 33 , wherein the subject has received one or more blood transfusions within the twelve months prior to administration of the CFD inhibitor.
45 . The method of claim 33 , wherein the subject has been on a C5 therapeutic regimen for at least three months prior to administration of the CFD inhibitor.
46 . The method of claim 33 , wherein upon administration of the CFD inhibitor, the C5 inhibitor also continues to be administered.
47 . The method of claim 33 , wherein upon administration of the CFD inhibitor the C5 inhibitor is no longer administered.Join the waitlist — get patent alerts
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