US2016222389A1PendingUtilityA1

Modulators of complement factor b

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Assignee: IONIS PHARMACEUTICALS INCPriority: Sep 13, 2013Filed: Sep 12, 2014Published: Aug 4, 2016
Est. expirySep 13, 2033(~7.1 yrs left)· nominal 20-yr term from priority
Inventors:Tamar R. GrossmanMichael L. MccalebAndrew WattSusan M. Freier
A61P 43/00A61P 27/02A61P 13/12A61P 13/00C12N 15/1137C12Y 304/21047C12N 2310/315C12N 2310/3231C12N 2310/11C12N 2310/321C12N 2310/3341
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Claims

Abstract

The present embodiments provide methods, compounds, and compositions for treating, preventing, or ameliorating a disease associated with dysregulation of the complement alternative pathway by administering a Complement Factor B (CFB) specific inhibitor to a subject.

Claims

exact text as granted — not AI-modified
1 .- 94 . (canceled) 
     
     
         95 . A compound comprising a modified oligonucleotide consisting of 10 to 30 linked nucleosides having a nucleobase sequence comprising at least 8 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598. 
     
     
         96 . The compound of  claim 95 , wherein the modified oligonucleotide consists of 10 to 30 linked nucleosides having a nucleobase sequence comprising any of the nucleobase sequences of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598. 
     
     
         97 . The compound of  claim 96 , wherein the modified oligonucleotide consists of linked nucleosides having a nucleobase sequence consisting of any of the nucleobase sequences of SEQ ID NOs: 198, 228, 237, 440, 444, 448, 450, 453, 455, 549, and 598. 
     
     
         98 . The compound of  claim 95 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase. 
     
     
         99 . The compound of  claim 96 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase. 
     
     
         100 . The compound of  claim 97 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase. 
     
     
         101 . The compound of  claim 98 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         102 . The compound of  claim 99 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         103 . The compound of  claim 100 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         104 . The compound of  claim 98 , wherein the modified sugar is a bicyclic sugar. 
     
     
         105 . The compound of  claim 99 , wherein the modified sugar is a bicyclic sugar. 
     
     
         106 . The compound of  claim 100 , wherein the modified sugar is a bicyclic sugar. 
     
     
         107 . The compound of  claim 104 , wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA); 4′-(CH 2 ) 2 —O-2′ (ENA); and 4′-CH(CH 3 )—O-2′ (cEt). 
     
     
         108 . The compound of  claim 105 , wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA); 4′-(CH 2 ) 2 —O-2′ (ENA); and 4′-CH(CH 3 )—O-2′ (cEt). 
     
     
         109 . The compound of  claim 106 , wherein the bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA); 4′-(CH 2 ) 2 —O-2′ (ENA); and 4′-CH(CH 3 )—O-2′ (cEt). 
     
     
         110 . The compound of  claim 98 , wherein the modified sugar is 2′-O-methoxyethyl. 
     
     
         111 . The compound of  claim 99 , wherein the modified sugar is 2′-O-methoxyethyl. 
     
     
         112 . The compound of  claim 100 , wherein the modified sugar is 2′-O-methoxyethyl. 
     
     
         113 . The compound of  claim 98 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         114 . The compound of  claim 99 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         115 . The compound of  claim 100 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         116 . The compound of  claim 98 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase; wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage; the modified sugar is 2′-O-methoxyethyl or a bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA); 4′-(CH 2 ) 2 —O-2′ (ENA); and 4′-CH(CH 3 )—O-2′ (cEt); and the modified nucleobase is a 5-methylcytosine. 
     
     
         117 . The compound of  claim 99 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase; wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage; the modified sugar is 2′-O-methoxyethyl or a bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA); 4′-(CH 2 ) 2 —O-2′ (ENA); and 4′-CH(CH 3 )—O-2′ (cEt); and the modified nucleobase is a 5-methylcytosine. 
     
     
         118 . The compound of  claim 100 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar, or at least one modified nucleobase; wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage; the modified sugar is 2′-O-methoxyethyl or a bicyclic sugar is selected from the group consisting of: 4′-(CH 2 )—O-2′ (LNA); 4′-(CH 2 ) 2 —O-2′ (ENA); and 4′-CH(CH 3 )—O-2′ (cEt); and the modified nucleobase is a 5-methylcytosine. 
     
     
         119 . The compound of  claim 95 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         120 . The compound of  claim 96 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         121 . The compound of  claim 97 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         122 . The compound of  claim 98 , wherein the compound is single-stranded. 
     
     
         123 . The compound of  claim 99 , wherein the compound is single-stranded. 
     
     
         124 . The compound of  claim 100 , wherein the compound is single-stranded. 
     
     
         125 . The compound of  claim 98 , wherein the compound is double-stranded. 
     
     
         126 . The compound of  claim 99 , wherein the compound is double-stranded. 
     
     
         127 . The compound of  claim 100 , wherein the compound is double-stranded. 
     
     
         128 . The compound of  claim 97 , wherein the modified oligonucleotide consists of 20 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 198, 228, 237, 444, 448, 450, 453, or 455, and comprises:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides; and   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment,   wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar; wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine is a 5-methylcytosine.   
     
     
         129 . The compound of  claim 97 , wherein the modified oligonucleotide consists of 16 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 598, and comprises:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of three linked nucleosides; and   a 3′ wing segment consisting of three linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment;   
       wherein the 5′ wing segment comprises a 2′-O-methoxyethyl sugar, 2′-O-methoxyethyl sugar, and cEt sugar in the 5′ to 3′ direction; wherein the 3′ wing segment comprises a cEt sugar, cEt sugar, and 2′-O-methoxyethyl sugar in the 5′ to 3′ direction; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. 
     
     
         130 . The compound of  claim 97 , wherein the modified oligonucleotide consists of 16 linked nucleosides having a nucleobase sequence consisting of the sequence recited in SEQ ID NO: 549, and comprises:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of three linked nucleosides; and   a 3′ wing segment consisting of three linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment;   
       wherein each nucleoside of each wing segment comprises a cEt sugar; wherein each internucleoside linkage is a phosphorothioate linkage; and wherein each cytosine is a 5-methylcytosine. 
     
     
         131 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         132 . A compound consisting of a pharmaceutically acceptable salt of the compound of  claim 131 . 
     
     
         133 . The compound of  claim 132 , wherein the pharmaceutically acceptable salt is sodium. 
     
     
         134 . The compound of  claim 132 , wherein the pharmaceutically acceptable salt is potassium. 
     
     
         135 . A composition comprising the compound of  claim 131  and a pharmaceutically acceptable carrier or diluent. 
     
     
         136 . A composition comprising the compound of  claim 133  and a pharmaceutically acceptable carrier or diluent. 
     
     
         137 . A method of treating, preventing, or ameliorating a disease associated with dysregulation of the complement alternative pathway in a subject comprising administering to the subject the compound of  claim 131 , thereby treating, preventing, or ameliorating the disease. 
     
     
         138 . A method of treating, preventing, or ameliorating a disease associated with dysregulation of the complement alternative pathway in a subject comprising administering to the subject the compound of  claim 133 , thereby treating, preventing, or ameliorating the disease. 
     
     
         139 . The method of  claim 137 , wherein the disease is macular degeneration, age related macular degeneration (AMD), wet AMD, dry AMD, or Geographic Atrophy. 
     
     
         140 . The method of  claim 138 , wherein the disease is macular degeneration, age related macular degeneration (AMD), wet AMD, dry AMD, or Geographic Atrophy.

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