Inhbe RNA interference agents

Abstract

The present invention relates to novel therapeutic compounds, known as RNAi agents, that decrease expression of the INHBE receptor (expressed by the INHBE gene), thereby decreasing expression of mRNA and protein expression. Such RNAi agents are useful in the treatment of diseases involving the regulation of INHBE expression and function, such as obesity or cardiometabolic disorders.

Description

INHBE RNA INTERFERENCE AGENTSSEQUENCE LISTING

[0001] The present application is being filed along with a Sequence Listing in ST.26 XML format. The Sequence Listing is provided as a file titled 30978_WO.xml created June 9, 2025, and is 2.33 megabytes in size. The Sequence Listing information in the ST.26 XML format is incorporated herein by reference in its entirety.BACKGROUND

[0002] Increased volume of abdominal adipose tissue is associated with multiple cardiometabolic diseases including type 2 diabetes (T2D) and coronary heart disease (CHD). It is also associated with impaired glycemic control, dyslipidemia, high blood pressure, and increased risk of death. The relationship has been found to be independent of overall weight as measured by BMI and some studies have deemed it a causal relationship. INHBE is a proprotein mostly expressed in hepatocytes, with multiple potential functions including activin rearrangement. Increased levels of INHBE have recently been found to correlate with obesity and conditions characterized by insulin resistance. Conversely, decreased levels of INHBE have been found to correlate with decreased abdominal adipose tissue distribution, although some studies have reached the opposite conclusion. (Deaton, A.M., Dubey, A., Ward, L.D. et al. Rare loss of function variants in the hcpatokinc gene INHBE protect from abdominal obesity. Nat Commim 13, 4319 (2022)).

[0003] RNA interference (RNAi) is a highly conserved regulatory mechanism in which RNA molecules are involved in sequence- specific suppression of gene expression by double-stranded RNA molecules (dsRNA) (Fire et al., Nature 391:806-811, 1998). RNAi agents targeting INHBE have been disclosed, for example in International Patent Publications No. WO2022 / 132666 and W02023 / 003922.

[0004] There remains a need for therapeutic agents that can inhibit or adjust the expression of INHBE for treating INHBE associated metabolic disorders, e.g., by utilizing RNAi.SUMMARY OF INVENTION

[0005] In one aspect, the present invention provides an INHBE RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex RNA, wherein:(i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 2, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 49;(ii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 50;(iii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 4, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 51;(iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 52;(v) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 6, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 53;(vi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 54;(vii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 8, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 55;(viii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 56;(ix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 10, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 57;(x) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58;(xi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 12, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 59;(xii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 60;(xiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 14, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 61;(xiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 62;(xv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 16, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 63;(xvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 64;(xvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 18, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 65;(xviii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 66;(xix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 20, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 67;(xx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 68;(xxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 22, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 69;(xxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 70;(xxiii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 24, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 71;(xxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 72;(xxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 26, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 73;(xxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 74;(xxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 75;(xxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 76;(xxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 30, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 77;(xxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 78;(xxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 32, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 79;(xxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 80;(xxxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 81;(xxxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 82;(xxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 36, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 83;(xxxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 84;(xxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 38, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 85;(xxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 86;(xxxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 87;(xl) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 88;(xli) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 42, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 89;(xlii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 90;(xliii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 44, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 91;(xliv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 92;(xlv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 46, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 93;(xlvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 94;(xlvii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 48, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 95;(xlviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 190, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 230;(xlix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 191 , and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 231;(1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 192, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 232;(li) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 193, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 233;(lii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 194, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 234;(liii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 195, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 235;(liv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 196, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 236;(Iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 197, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 237;(Ivi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 198, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 238;(Ivii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 199, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 239;(Iviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 200, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 240;(lix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 201, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 241;(lx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 202, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 242;(Ixi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 203, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 243;(Ixii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 204, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 244;(Ixiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 205, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 245;(Ixiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 206, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 246;(Ixv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 207, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 247;(Ixvi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 208, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 248;(Ixvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 209, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 249;(Ixviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 210, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 250;(Ixix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 211, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 251;(Ixx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 212, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 252;(Ixxi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 213, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 253;(Ixxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 214, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 254;(Ixxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 215, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 255;(Ixxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 216, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 256;(Ixxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 217, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 257;(Ixxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 218, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 258;(Ixxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 219, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 259;(Ixxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 220, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 260;(Ixxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 221, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 261;(Ixxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 222, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 262;(Ixxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 223, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 263;(Ixxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 224, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 264;(Ixxxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 225, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 265;(Ixxxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 226, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 266;(Ixxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 227, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 267;(Ixxxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 228, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 268;(Ixxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 18, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 363;(Ixxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 360, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 364;(Ixxxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 2, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 365;(xc) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 361, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 366;(xci) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 362, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 367;(xcii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 368;(xciii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 369;(xciv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 4, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 370; or (xcv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 12, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 371.

[0006] In one aspect, the present invention provides an INHBE RNAi agent, comprising the formula R-L-D, wherein R is duplex RNA; L is a bond or a linker; and D is a delivery moiety.

[0007] In one embodiment, the present invention provides an INHBE RNAi agent, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of:(i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 96, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 143;(ii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 97, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 144;(iii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 98, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 145;(iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 99, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 146;(v) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 100, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 147;(vi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 148;(vii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 102, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 149;(viii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 103, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 150;(ix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 104, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 151;(x) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 105, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 152;(xi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 106, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 153;(xii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 107, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 154;(xiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 108, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 155;(xiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 109, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 156;(xv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 110, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 157;(xvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 111, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 158;(xvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 112, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 159;(xviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 113, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 160;(xix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 114, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 161;(xx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 115, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 162;(xxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 116, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 163;(xxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 117, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 164;(xxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 118, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 165;(xxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 166;(xxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 120, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 167;(xxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 121, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 168;(xxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 122, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 169;(xxviii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 123, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 170;(xxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 124, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 171;(xxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 125, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 172;(xxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 126, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 173;(xxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 127, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 174;(xxxiii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 128, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 175;(xxxiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 129, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 176;(xxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 130, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 177;(xxxvi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 131, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 178;(xxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 132, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 179;(xxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 133, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 180;(xxxix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 134, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 181;(xl) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 135, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 182;(xli) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 136, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 183;(xlii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 137, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 184;(xliii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 138, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 185;(xliv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 139, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 186;(xlv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 140, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 187;(xlvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 141, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 188;(xlvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 142, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 189;(xlviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 190, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 189;(xlix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 270, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 310;(1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 271, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 311;(li) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 106, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 312;(lii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 272, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 313;(liii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 273, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 314;(liv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 97, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 315;(Iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 274, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 316;(Ivi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 275, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 317;(Ivii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 276, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 318;(Iviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 98, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 319;(lix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 105, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 320;(lx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 277, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 321;(Ixi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 278, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 322;(Ixii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 279, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 323;(Ixiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 280, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 324;(Ixiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 281, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 325;(Ixv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 326;(Ixvi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 282, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 327;(Ixvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 283, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 328;(Ixviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 284, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 329;(Ixix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 285, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 330;(Ixx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 286, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 331;(Ixxi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 287, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 332;(Ixxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 288, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 333;(Ixxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 334;(Ixxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 289, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 335;(Ixxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 290, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 336;(Ixxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11 1 , and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 337;(Ixxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 291, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 338;(Ixxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 292, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 339;(Ixxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 293, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 340;(Ixxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 294, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 341;(Ixxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 295, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 342;(Ixxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 296, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 343;(Ixxxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 297, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 344;(Ixxxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 298, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 345;(Ixxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 299, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 346;(Ixxxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 300, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 347;(Ixxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 301, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 348;(Ixxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 302, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 349;(Ixxxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 303, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 350;(xc) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 304, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 351;(xci) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 305, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 352;(xcii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 306, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 353;(xciii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 134, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 354;(xciv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 184, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 355;(xcv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 307, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 356;(xcvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 308, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 357;(xcvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 104, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 358; (xcviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 372, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 377;(xcix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 373, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 378;(c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 374, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 379;(ci) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 375, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 380;(cii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 376, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 381;(ciii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 373, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 382;(civ) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 383, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 384;(cv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 376, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 385;(cvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 386, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 387;(cvii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 388, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 389;(cviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 376, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 390; and (eix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 391, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 392.DETAILED DESCRIPTION

[0008] The present invention relates to novel therapeutic compounds, known as RNAi agents, that decrease expression of Inhibin Subunit Beta E (INHBE, expressed by the INHBE gene), thereby decreasing expression of INHBE mRNA and INHBE protein. Such RNAi agents are useful in the treatment of diseases involving the regulation of INHBE expression and function.

[0009] The INHBE RNAi agents disclosed herein may be used to decrease expression of INHBE and can be employed, e.g., to treat obesity, in patients in need thereof. Such siRNAs may exhibit one or more of, e.g., as compared to other liver targeted siRNAs such as INHBE siRNAs comprising a different delivery ligand, a different sequence, a differently modified sequence, or as compared to treatment with a vehicle control: improved knockdown in the liver; improved tissue exposure, improved exposure in liver hepatocytes; an improved durable response: an improved pharmacokinetic profile: fewer off target effects; and / or an improved toxicity profile. Other embodiments of the INHBE RNAi agents herein may include one or more of fewer side effects as compared to statins or other standard of care; an improved toxicity profile: an improved safety profile; improved tolerability or compliance; and / or improved liver function tests. Still other siRNAs herein may have other benefits, e.g., in combination with any of the preceding or as a stand-alone benefit, including improved and / or simplified synthesis, synthetic processes with fewer degradation products; or any combination thereof.

[0010] As used herein, the terms “a,” “an,” “the,” and similar terms used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

[0011] As used herein, the term “alkyl” means saturated linear or branched-chain monovalent hydrocarbon radical, containing the indicated number of carbon atoms. For example, “C1-C20 alkyl” means a radical having 1-20 carbon atoms in a linear or branched arrangement.

[0012] As used herein, “RNAi” refers to RNA interference, a process that results in sequence-specific degradation of a messenger RNA (mRNA), such as via the RNA-induced silencing complex (RISC) pathway. RNAi is achieved through the use of an “RNAi agent,” also referred to interchangeably herein as “iRNA,” “iRNA agent,” and “RNA interference agent,” each of which means an agent that mediates sequence-specific degradation of a target mRNA by RNA interference. In some embodiments, the RNAi agent has a sense strand and an antisense strand, and the sense strand and the antisense strand form a duplex (e.g., a double stranded RNA). In some embodiments, the RNAi agent includes a delivery moiety for targeting various cells or tissues. In some instances, the sense strand has a delivery moiety conjugated to the 3’ end of the sense strand or a nucleotide of the sense strand.

[0013] The RNAi agents herein comprise a sense strand and an antisense strand, wherein each is an oligonucleotide. As used herein, “nucleotide” means an organic compound having a nucleoside (a nucleobase such as, for example, adenine, cytosine, guanine, thymine, or uracil; and a pentose sugar such as, for example, ribose or 2'-deoxyribose) and a phosphate group. A “nucleotide” can serve as a monomeric unit of nucleic acid polymers such as deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).

[0014] As used herein, “modified nucleotide” refers to a nucleotide having one or more chemical modifications when compared with a corresponding reference nucleotide selected from: adenine ribonucleotide, guanine ribonucleotide, cytosine ribonucleotide, uracil ribonucleotide, adenine deoxyribonucleotide, guanine deoxyribonucleotide, cytosine deoxyribonucleotide, and thymidine deoxyribonucleotide. A modified nucleotide can be a non-naturally occurring nucleotide. A modified nucleotide can have, for example, one or more chemical modification in its sugar, nucleobase, and / or phosphate group. Additionally, or alternatively, a modified nucleotide can have one or more chemical moieties conjugated to a corresponding reference nucleotide.

[0015] As used herein, “oligonucleotide” means a polymer of linked nucleotides, each of which can be modified or unmodified. Typically, an oligonucleotide is a short nucleic acid compound, less than about 100 nucleotides in length. An oligonucleotide may be, but is notlimited to, a small interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), Dicer substrate interfering RNA (DsiRNA), or antisense oligonucleotide (ASO).

[0016] As used herein, “ribonucleotide” means a nucleotide having a ribose as its pentose sugar, which contains a hydroxyl group at its 2' position. A modified ribonucleotide is a ribonucleotide having one or more modifications or substitutions of atoms other than hydrogen at the 2' position, including modifications or substitutions in or of the nucleobase, sugar, or phosphate group.

[0017] As used herein, “strand” refers to a single, contiguous sequence of nucleotides linked together through intemucleotide linkages (e.g., phosphodiester linkages or phosphorothioate linkages). A strand can have two free ends (e.g., a 5’ end and a 3’ end).

[0018] As used herein, INHBE refers to an INHBE mRNA transcript. The nucleic acid sequence of human INHBE mRNA can be found at NM_031479.5 (SEQ ID NO: 1). The amino acid sequence of human INHBE protein can be found at NP_113667.1.

[0019] As used herein, “modified internucleotide linkage” means an internucleotide linkage having one or more chemical modifications when compared with a reference intemucleotide linkage having a phosphodiester bond. A modified intemucleotide linkage can be a non-naturally occurring linkage.

[0020] As used herein, “duplex,” in reference to nucleic acids or oligonucleotides, means a structure formed through complementary base pairing of two antiparallel sequences of nucleotides (i.e., in opposite directions, whether formed by two separate nucleic acid strands or by a single, folded strand (such as via a hairpin). In some instances, a duplex will arise by pairing of a sense strand to an antisense strand. A duplex may form despite not having full complementarity between the two strands, or when an abasic nucleotide is present. A Duplex No:, as shown herein, e.g., in Table 4, corresponds to a specific sense and antisense strand that comprise a given RNAi agent.

[0021] As used herein, “complementary” means a structural relationship between two nucleotides (e.g., on two opposing nucleic acids or on opposing regions of a single nucleic acid strand, e.g., a hairpin) that permits the two nucleotides to form base pairs with one another. For example, a purine nucleotide of one nucleic acid that is complementary to apyrimidine nucleotide of an opposing nucleic acid may base pair together by forming hydrogen bonds with one another. Complementary nucleotides can base pair in the Watson- Crick manner or in any other manner that allows for the formation of stable duplexes. Likewise, two nucleic acids may have regions of multiple nucleotides that are complementary with each other to form regions of complementarity, as described herein.

[0022] As used herein, “region of complementarity” means a nucleotide sequence of a nucleic acid (e.g., a double stranded oligonucleotide) that is sufficiently complementary to an antiparallel nucleotide sequence to permit hybridization between the two sequences of nucleotides under appropriate hybridization conditions (e.g., in a phosphate buffer, in a cell, etc.). In some embodiments, an oligonucleotide herein includes a targeting sequence having a region of complementary to a mRNA target sequence.

[0023] As used herein, “antisense strand” means a single- stranded oligonucleotide that is complementary to a region of a target sequence. Likewise, and as used herein, “sense strand” means a single-stranded oligonucleotide that is complementary to a region of an antisense strand.

[0024] As used herein, “overhang” means the unpaired nucleotide or nucleotides that protrude from the duplex structure of a double stranded oligonucleotide. An overhang may include one or more unpaired nucleotides extending from a duplex region at the 5’ terminus or 3’ terminus of a double stranded oligonucleotide. The overhang can be a 3’ or 5’ overhang on the antisense strand or sense strand of a double stranded oligonucleotide. For example, the sense strand and the antisense strand may have 5’ or 3’ overhangs of 1 to 5 nucleotides.

[0025] The term “percentage sequence identity” with respect to a reference nucleic acid sequence is defined as the percentage of nucleotides, nucleosides, or nucleobases in a candidate sequence that are identical with the nucleotides, nucleosides, or nucleobases in the reference nucleic acid sequence, after optimally aligning the sequences and introducing gaps or overhangs, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent nucleic acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software programs, for example, those described in Current Protocols in Molecular Biology(Ausubel et al., eds., 1987, Supp. 30, section 7.7.18, Table 7.7.1), and including BLAST, BLAST-2, ALIGN, Clustal W2.0 or Clustal X2.0 or Megalign (DNASTAR) software. In one embodiment herein, sequence identity is calculated use Clustal W2.0 or Clustal X2.0. In another embodiment, sequence identity is calculated using Clustal W2.0. In another embodiment, sequence identity is calculated using Clustal X2.0. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. Percentage of “sequence identity” can be determined by comparing two optimally aligned sequences over a comparison window, where the fragment of the nucleic acid sequence in the comparison window may comprise additions or deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions at which the identical nucleotide, nucleoside, or nucleobase occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity. The output is the percent identity of the subject sequence with respect to the query sequence. In some embodiments, percent sequence identity is the percent of nucleotide residues that arc identical between two strands using the PID3 calculation, which is the number of identical nucleotide residues divided by the total number of nucleotides of the shortest of the two sequences, multiplied by 100. See, e.g., Raghava, G., Barton, G.J. Quantification of the variation in percentage identity for protein sequence alignments. BMC Bioinformatics 7, 415 (2006).

[0026] As used herein, “phosphate analog” means a chemical moiety that mimics the electrostatic and / or steric properties of a phosphate group. In some embodiments, a phosphate analog is positioned at the 5' terminal nucleotide of an oligonucleotide in place of a 5'-phosphate. A 5' phosphate analog can include a phosphatase-resistant linkage. Examples of phosphate analogs include, but are not limited to, 5' phosphonates, such as 5' methylene phosphonate (5'-MP) and 5'-(E)-vinylphosphonate (5'- VP). An oligonucleotide can have a phosphate analog at a 4’-carbon position of the sugar (referred to as a “4'-phosphate analog”)at a 5'-terminal nucleotide. An example of a 4’-phosphate analog is oxymethylphosphonate, in which the oxygen atom of the oxymethyl group is bound to the sugar' moiety (e.g., at its 4'- carbon) or analog thereof. See, e g., Inti. Patent Application Publication No. WO 2018 / 045317. Other modifications have been developed for the 5' end of oligonucleotides (see, e.g., Inti. Patent Application No. WO 2011 / 133871; US Patent No. 8,927,513; and Prakash et al. (2015) Nuc. Acids Res. 43:2993-3011).

[0027] As used herein, a “delivery moiety” refers to a chemical moiety that facilitates the entry of an oligonucleotide or RNAi agent into a cell. The delivery moiety can be lipid, cholesterol, vitamin E, carbohydrate (e.g., GalNAc), amino sugar, or polypeptide.

[0028] The term “knockdown” or “expression knockdown” refers to reduced mRNA or protein expression of a gene after treatment of a reagent, e.g., a RNAi agent.

[0029] As used herein, “subject” means a mammal, including cat, dog, mouse, rat, chimpanzee, ape, monkey, and human. Preferably the subject is human.

[0030] The term “patient,” as used herein, refers to a human patient.

[0031] As used herein, “treatment” or “treating” refers to all processes wherein there may be a slowing, controlling, delaying, or stopping of the progression of the disorders or disease disclosed herein, or ameliorating disorder or disease symptoms, but does not necessarily indicate a total elimination of all disorder or disease symptoms. Treatment includes administration of a protein, nucleic acid, or vector, or pharmaceutical composition thereof, for treatment of a disease or condition in a patient, particularly a human.

[0032] An “effective amount” refers to an amount necessary (for periods of time and for the means of administration) to achieve the desired therapeutic result. An effective amount of a RNAi agent may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the RNAi agent to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the RNAi agent are outweighed by the therapeutically beneficial effects.

[0033] As used herein, the term “control agent” refers to an RNAi agent which does not appreciably decrease levels of INHBE transcripts or expression.

[0034] In one aspect, the present disclosure provides an INHBE RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex RNA, wherein:(i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 2, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 49;(ii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 50;(iii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 4, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 51;(iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 52;(v) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 6, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 53;(vi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 54;(vii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 8, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 55;(viii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 56;(ix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 10, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 57;(x) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58;(xi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 12, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 59;(xii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 60;(xiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 14, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 61;(xiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 62;(xv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 16, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 63;(xvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 64;(xvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 18, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 65;(xviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 66;(xix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 20, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 67;(xx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 68;(xxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 22, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 69;(xxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 70;(xxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 24, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 71;(xxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 72;(xxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 26, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 73;(xxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 74;(xxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 75;(xxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 76;(xxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 30, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 77;(xxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 78;(xxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 32, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 79;(xxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 80; (xxxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 81;(xxxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 82;(xxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 36, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 83;(xxxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 84; (xxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 38, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 85; (xxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 86;(xxxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 87; (xl) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 88; (xli) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 42, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 89;(xlii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 90;(xliii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 44, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 91;(xliv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 92;(xlv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 46, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 93;(xlvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 94;(xcvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 48, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 95;(xcvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 190, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 230;(xlvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 191, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 231;(xlviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 192, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 232;(xlix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 193, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 233;(1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 194, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 234;(li) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 195, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 235;(lii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 196, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 236;(liii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 197, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 237;(liv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 198, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 238;(Iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 199, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 239;(Ivi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 200, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 240;(Ivii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 201, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 241;(Iviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 202, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 242;(lix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 203, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 243;(lx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 204, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 244;(Ixi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 205, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 245;(Ixii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 206, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 246;(Ixiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 207, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 247;(Ixiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 208, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 248;(Ixv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 209, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 249;(Ixvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 210, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 250;(Ixvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 211, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 251;(Ixviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 212, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 252;(Ixix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 213, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 253;(Ixx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 214, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 254;(Ixxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 215, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 255;(Ixxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 216, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 256; (Ixxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 217, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 257;(Ixxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 218, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 258;(Ixxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 219, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 259;(Ixxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 220, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 260; (Ixxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 221, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 261;(Ixxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 222, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 262;(Ixxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 223, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 263;(Ixxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 224, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 264;(Ixxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 225, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 265;(Ixxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 226, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 266; (Ixxxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 227, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 267; (Ixxxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 228, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 268; (Ixxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 18, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 363; (Ixxxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 360, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 364; (Ixxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 2, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 365;(Ixxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 361, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 366;(Ixxxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 362, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 367; (xc) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 368;(xci) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 369; (xcii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 4, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 370; or (xciii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 12, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 371.

[0035] In one aspect of the INHBE RNAi agent, one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides.

[0036] In one embodiment, at least one intemucleotide linkage of the sense strand and the antisense strand are modified internucleotide linkages.

[0037] In one embodiment, the INHBE RNAi agent may include a delivery moiety.

[0038] In one aspect, the INHBE RNAi agent may include a delivery moiety includingN-acetylgalactosamine. In one aspect, GalNAc has the following structure:

[0039] In one embodiment, the INHBE RNAi agent includes a delivery moiety which comprises:wherein E is a connection point at which the duplex RNA is conjugated.

[0040] In one embodiment, the delivery moiety is conjugated to the sense strand via a linker. In one embodiment, the delivery moiety is conjugated to the 3’ terminal nucleotide of the sense strand via a linker.

[0041] In one embodiment of the INHBE RNAi agent, the linker comprises formula:wherein A and B are connection points, the delivery moiety is conjugated to the linker at connection point A, and the duplex RNA is conjugated to the linker at connection point B.

[0042] In another embodiment of the INHBE RNAi agent, the linker comprises formula:wherein X and Y are connection points, the delivery moiety is conjugated to the linker at connection point X, and the duplex RNA is conjugated to the linker at connection point Y.

[0043] In one embodiment of the INHBE RNAi agent, the antisense strand is 23 to 50 nucleotides in length. In one embodiment, the sense strand is 21 to 50 nucleotides in length. In one embodiment, the antisense strand is between 21 and 23 nucleotides in length. In one embodiment, the sense strand is 21 nucleotides in length. In one embodiment, the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length. In one embodiment, a region of complementarity between the sense strand and the antisense strand is at least 18 nucleotides in length.

[0044] In one embodiment of the INHBE RNAi agent the sense strand or the antisense strand each independently comprise one or more modified nucleotides, and the modified nucleotides are each independently selected from 2 ’-fluoro modified nucleotides or 2’-O- methyl modified nucleotides. In one embodiment, each nucleotide of the sense strand and each nucleotide of the antisense strand is a modified nucleotide.

[0045] In one embodiment of the INHBE RNAi agent, the antisense strand is 23 nucleotides in length and wherein each nucleotide of the antisense strand is a modified nucleotide, and 2’ -fluoro modified nucleotides are present at a. Positions 2, 3, 7, 14, and 16 from the 5’ end of the antisense strand; or b. Positions 2, 5, 7, 14, and 16 from the 5’ end of the antisense strand; or c. Positions 2, 3, 8, 14, and 16 from the 5’ end of the antisense strand; or d. Positions 2, 5, 8, 14, and 16 from the 5’ end of the antisense strand; or e. Positions 2, 6, 14, and 16 from the 5’ end of the antisense strand; orf. Positions 2, 14, and 16 from the 5’ end of the antisense strand.

[0046] In one embodiment of the INHBE RNAi agent, the sense strand and antisense strand each independently comprise one or more modified internucleotide linkages, and wherein each modified internucleotide linkage is a phosphorothioate linkage. In one embodiment, the sense strand and antisense strand each independently comprise four phosphorothioate linkages. In one embodiment, the first two intemucleotide linkages and the last two internucleotide linkages of either or both of the sense strand and the antisense strand are phosphorothioate linkages; that is, the two internucleotide linkages closest to the 5’ end and closest to the 3’ end of the oligonucleotide, respectively. In one embodiment, the first two internucleotide linkages and the last two internucleotide linkages of the sense strand and the antisense strand are phosphorothioate linkages.

[0047] In certain embodiments, the delivery moiety may instead be a compound comprising Formula VI:wherein Formula VI may be conjugated to an oligonucleotide directly or via a linker, wherein the linker or oligonucleotide is conjugated to the delivery moiety at connection point E.

[0048] In an embodiment, the linker comprises a linker of Formula VII having connection points A and B; or of Formula VIII having connection points C and D; or of Formula IX having connection points E and F:wherein connection point A or connection point C or connection point E are conjugated to Formula VI.

[0049] In another aspect, the delivery moiety may comprise a compound of Formula X:

[0050] In one embodiment, the delivery moiety may comprise a compound of Formula

[0051] In another embodiment, the delivery moiety may comprise a compound ofFormula XI:

[0052] In another embodiment, the delivery moiety may comprise a compound ofFormula XII:

[0053] In another embodiment, the delivery moiety may comprise a compound ofFormula XIII:

[0054] In another embodiment, the delivery moiety may comprise a compound ofFormula XIV:

[0055] In another embodiment, the delivery moiety may comprise a compound ofFormula XV:

[0056] In another embodiment, the delivery moiety may comprise a compound ofFormula XVI:

[0057] In another embodiment, the delivery moiety may comprise a compound ofFormula XVII:

[0058] In another embodiment, the delivery moiety may comprise a compound ofFormula XVIII:

[0059] It will be appreciated that any of the delivery moieties disclosed herein may be conjugated to an oligonucleotide directly, via any linker disclosed herein, by any combination of linkers disclosed herein, and by other linkers.

[0060] For example, the delivery moiety D of Formula Xa may be conjugated to the linker of Formula IX, to yield a linker-delivery moiety L-D of Formula XIX:

[0061] In some embodiments, the linker-delivery moiety L-D of Formula XIX may be conjugated to a nucleic acid, such as via a phosphate group at the 3’ end of the nucleic acid, at connection point F. For example the oxygen at connecting point

[0062] In another embodiment, the delivery moiety of Formula VI may be conjugated to the linker of Formula VIII, to yield a linker-delivery moiety L-D of Formula XX:

[0063] In some embodiments, the linker-delivery moiety L-D of Formula XX may be conjugated to a nucleic acid, such as via a phosphate group at the 3’ end of the nucleic acid, at connection point F.

[0064] It will be appreciated that the linkers as shown herein may be depicted in different ways, and will form covalent bonds with the delivery moiety and / or the nucleic acid of the RNAi agent in conventional ways. For example, when a linker is depicted with an oxygen atom at the connection point, and is to be conjugated to a phosphate group of a nucleic acid, it will be understood that the oxygen of the linker will take the place of an oxygen atom of the nucleic acid. When a linker is not shown with an oxygen atom at the connection point, an oxygen atom of the nucleic acid may in some embodiments covalently bind the linker at the depicted position, and so forth.

[0065] 2-propyl nucleotides (PrON) were incorporated into oligonucleotides using standard phosphoramidite chemistry and standard synthetic methods. The compounds of Preparations 12 and 13 above were used in CPG methods described herein.

[0066] In one embodiment of the INHBE RNAi agent, the 5’ terminal nucleotide of the antisense strand comprises an OH group, a phosphate group or a phosphate analog. In one embodiment, the 5’ terminal nucleotide of the antisense strand comprises a vinyl phosphonate, a phosphate, or a hydroxyl group.

[0067] In one embodiment of the INHBE RNAi agent, the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of:(i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 96, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 143;(ii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 97, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 144;(iii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 98, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 145;(iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 99, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 146;(v) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 100, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 147;(vi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 148;(vii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 102, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 149;(viii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 103, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 150;(ix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 104, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 151;(x) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 105, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 152;(xi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 106, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 153;(xii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 107, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 154;(xiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 108, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 155;(xiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 109, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 156;(xv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 110, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 157;(xvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 111, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 158;(xvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 112, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 159;(xviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 113, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 160;(xix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 114, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 161;(xx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 115, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 162;(xxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 116, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 163;(xxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 117, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 164;(xxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 118, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 165;(xxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 166;(xxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 120, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 167;(xxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 121, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 168;(xxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 122, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 169;(xxviii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 123, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 170;(xxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 124, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 171;(xxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 125, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 172;(xxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 126, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 173;(xxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 127, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 174;(xxxiii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 128, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 175;(xxxiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 129, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 176;(xxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 130, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 177;(xxxvi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 131, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 178;(xxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 132, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 179;(xxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 133, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 180;(xxxix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 134, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 181;(xl) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 135, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 182;(xli) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 136, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 183;(xlii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 137, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 184;(xliii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 138, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 185;(xliv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 139, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 186;(xlv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 140, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 187;(xlvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 141, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 188; and(xlvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 142, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 189.

[0068] In one embodiment of the INHBE RNAi agent, the INHBE RNAi agent comprises a formula R-L-D, wherein:R is a duplex RNA comprising a sense strand and an antisense strand, wherein:(i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 2, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 49;(ii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 50;(iii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 4, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 51;(iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 52;(v) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 6, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 53;(vi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 54;(vii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 8, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 55;(viii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 56;(ix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 10, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 57;(x) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58;(xi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 12, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 59;(xii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 60;(xiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 14, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 61;(xiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 62;(xv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 16, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 63;(xvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 64;(xvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 18, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 65;(xviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 66;(xix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 20, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 67;(xx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 68;(xxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 22, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 69;(xxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 70;(xxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 24, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 71;(xxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 72;(xxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 26, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 73;(xxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 74;(xxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 75;(xxviii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 76;(xxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 30, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 77;(xxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 78;(xxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 32, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 79;(xxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 80;(xxxiii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 81;(xxxiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 82;(xxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 36, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 83;(xxxvi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 84;(xxxvii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 38, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 85;(xxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 86;(xxxix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 87;(xl) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 88;(xli) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 42, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 89;(xlii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 90;(xliii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 44, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 91;(xliv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 92;(xlv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 46, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 93;(xlvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 94; or(xlvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 48, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 95;L is a bond or a linker; and D is a delivery moiety.This embodiment may be combined with any of the previous embodiments.

[0069] In one embodiment, the INHBE RNAi agent decreases expression of the INHBE gene in a liver cell, as compared to a control agent.

[0070] In one embodiment, the INHBE RNAi agent may be for use in therapy.

[0071] In one embodiment, the INHBE RNAi agent is for use in the treatment of obesity.

[0072] In one embodiment, the present disclosure provides a pharmaceutical composition comprising the INHBE RNAi agent, and one or more pharmaceutically acceptable excipients.

[0073] In one embodiment, the present disclosure provides a use of an INHBE RNAi agent, in the manufacture of a medicament for the treatment of obesity.

[0074] In one embodiment, the present disclosure provides a method of treating obesity in a patient in need thereof, comprising administering the INHBE RNAi agent, or a pharmaceutical composition comprising the same.

[0075] In one embodiment, the present disclosure provides a method of decreasing INHBE expression in a cell, comprising contacting the cell with the INHBE RNAi agent.

[0076] In one embodiment, the method further comprises incubating the cell for a time sufficient for decreasing the level of INHBE mRNA by at least 50% as compared to a cell treated with a control agent or an untreated cell.

[0077] Disclosed herein are RNAi agents for reducing INHBE gene expression, wherein the RNAi agents comprise a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex region, and wherein the antisense strand comprises aregion of complementarity of at least 15 nucleotides to the sequence as set forth in SEQ ID NO: 1, and wherein the sense strand and / or the antisense strand each optionally comprise one or more modified nucleotides and / or modified intemucleotide linkages. In further embodiments, the antisense strand comprises at least 15 nucleotides of a sequence in the antisense column of Table 2. In further embodiments, the antisense strand comprises at least 18 nucleotides of a sequence in the antisense column of Table 2. In further embodiments, the antisense strand comprises one of the sequences in the antisense column of Table 2. In further embodiments, the RNAi agent reduces INHBE gene expression by about 50% or greater in a cell expressing INHBE, as compared to a control. In further embodiments, the RNAi agent reduces INHBE gene expression by reducing the level of INHBE mRNA transcript, the level of INHBE protein, or both.

[0078] In further embodiments, the antisense strand is 15 to 50 nucleotides in length, and / or the sense strand is 15 to 50 nucleotides in length. In further embodiments, the sense and / or sense strand is independently 15 to 30 nucleotides in length. In further embodiments, the antisense strand is between 18 and 23 nucleotides in length. In further embodiments, the antisense strand is between 21 and 23 nucleotides in length. In further embodiments, the sense strand is between 18 and 21 nucleotides in length.

[0079] In further embodiments, the RNAi agent comprises an antisense strand that comprises at least 15 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 49 to 95. In still further embodiments, the antisense strand comprises at least 18 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 49 to 95.

[0080] In other further embodiments, the antisense strand comprises at least 18 contiguous nucleotides of a sequence selected from the group consisting of 18 contiguous nucleotides of a sequence selected from the group consisting of SEQ ID NOs: 49 to 95.

[0081] In further embodiments, the antisense strand of the RNAi agent is 23 nucleotides in length. In still further embodiments, the sense strand is 21 nucleotides in length. In another embodiment, the sense and antisense strand comprise a sequence selected from thesequences set forth in Table 2. In other embodiments, the antisense strand comprises a sequence selected from the group consisting of SEQ ID NO:s 143 to 189.

[0082] The sense strand and the antisense strand of the RNAi agents disclosed herein do not require full complementarity. Accordingly, in the RNAi agents disclosed herein, the duplex region between the sense strand and the antisense strand comprises 0, 1, 2, or 3 mismatches between the sense strand and the antisense strand. In further embodiments, the duplex region between the sense strand and the antisense strand consists of 0, 1, 2, or 3 mismatches between the sense strand and the antisense strand. In other embodiments, the sense strand comprises a sequence selected from the group consisting of SEQ ID NO:s 2 to 48. In some embodiments, the sense strand comprises a sequence selected from the group consisting of SEQ ID NO:s 96 to 142.

[0083] In further embodiments, the sense strand and the antisense strand each independently comprise one or more modified nucleotides, such as 2’-fluoro modified nucleotides, 2’-O-methyl modified nucleotides, 2’ deoxy nucleotide (DNA), or 2'-O-alkyl modified nucleotide. In still further embodiments of the RNAi agents disclosed herein, each nucleotide of the sense strand and each nucleotide of the antisense strand is a modified nucleotide. In further embodiments, each nucleotide is a 2’-fluoro modified nucleotide or a 2’-O-mcthyl modified nucleotide.

[0084] In further embodiments of the RNAi agents disclosed herein, the antisense strand is 23 nucleotides in length, each nucleotide of the antisense strand is a modified nucleotide, and 2’ -fluoro modified nucleotides are present at b. Positions 2, 3, 7, 14, and 16 from the 5’ end of the antisense strand; or c. Positions 2, 5, 7, 14, and 16 from the 5’ end of the antisense strand; or d. Positions 2, 3, 8, 14, and 16 from the 5’ end of the antisense strand; or e. Positions 2, 5, 8, 14, and 16 from the 5’ end of the antisense strand; or f. Positions 2, 6, 14, and 16 from the 5’ end of the antisense strand; or g. Positions 2, 14, and 16 from the 5’ end of the antisense strand.

[0085] In further embodiments, the nucleotides specified in the enumerated examples above are modified by a combination of 2’ -fluoro and 2’-O-methyl.

[0086] In further embodiments of the RNAi agents disclosed herein, the sense strand and antisense strand each independently comprise one or more modified intemucleotide linkages, and each modified internucleotide linkage is a phosphorothioate linkage. In further embodiments, the sense strand and antisense strand each independently comprise four phosphorothioate linkages. In still further embodiments, the two terminal nucleotides at each of the 5’ and 3’ ends of each of the sense and antisense strand are phosphorothioate linkages.

[0087] In certain embodiments, the 5’ nucleotide of the antisense strand comprises a phosphate group or a phosphate analog.

[0088] In some embodiments, at least one of the sense strand and the antisense strand can include at least one abasic moiety of the formula:wherein “5”’ and “3”’ indicate the direction of the sequences.

[0089] In some embodiments, at least one of the sense strand and the antisense strand can include at least one inverted abasic (iAb) moiety of the formula:wherein “5”’ and “3”’ indicate the direction of the sequences.

[0090] In some embodiments, at least one of the sense strand and the antisense strand can include at least one “hmpT” moiety of the formula:

[0091] In further embodiments of the RNAi agents disclosed herein, the antisense strand comprises a sequence selected from the group consisting of SEQ ID NOs: 49 to 95, or a sequence having at least 90% sequence identity thereto, wherein the 5’ terminal nucleotide of the antisense strand may comprise a further modification, wherein a 5’ a vinyl phosphonate, a phosphate, or a hydroxyl group. In other embodiments, the phosphate group listed at the 5’ end of the recited SEQ ID NO: is removed and replaced with an OH. In other embodiments, the phosphate group listed at the 5’ end of the recited SEQ ID NO: is replaced with a 5’ vinylpho sphonate. In other embodiments, an abasic moiety or iAb moiety may be present at the 5’ end or the 3’ end of the antisense strand.

[0092] In further embodiments of the RNAi agents disclosed herein, the antisense strand comprises a sequence selected from the group consisting of SEQ ID NOs: 143 to 189, or a sequence having at least 90% sequence identity thereto, wherein the 5’ terminal nucleotide of the antisense strand may comprise a further modification, wherein a 5’ a vinyl phosphonate, a phosphate, or a hydroxyl group. In other embodiments, the phosphate group listed at the 5’ end of the recited SEQ ID NO: is removed and replaced with an OH. In other embodiments, the phosphate group listed at the 5’ end of the recited SEQ ID NO: is replaced with a 5’ vinylphosphonate. In other embodiments, an abasic moiety or iAb moiety may be present at the 5’ end or the 3’ end of the antisense strand.

[0093] In further embodiments the sense strand comprises a sequence selected from the group consisting of SEQ ID NOs: 2 to 48, or a sequence having at least 90% sequence identity thereto. The 5’ terminal nucleotide of the sense strand may comprise a further modification, wherein a 5’ a vinyl phosphonate, a phosphate, or a hydroxyl group. In other embodiments, the phosphate group listed at the 5’ end of the recited SEQ ID NO: is removedand replaced with an OH. In other embodiments, the phosphate group listed at the 5’ end of the recited SEQ ID NO: is replaced with a 5’ vinylpho sphonate. In other embodiments, an abasic moiety or iAb moiety may be present at the 5’ end or the 3’ end of the sense strand.

[0094] In further embodiments the sense strand comprises a sequence selected from the group consisting of SEQ ID NOs: 96 to 142, or a sequence having at least 90% sequence identity thereto. The 5’ terminal nucleotide of the sense strand may comprise a further modification, wherein a 5’ a vinyl phosphonate, a phosphate, or a hydroxyl group. In other embodiments, the phosphate group listed at the 5’ end of the recited SEQ ID NO: is removed and replaced with an OH. In other embodiments, the phosphate group listed at the 5’ end of the recited SEQ ID NO: is replaced with a 5’ vinylpho sphonate. In other embodiments, an abasic moiety or iAb moiety may be present at the 5’ end or the 3’ end of the sense strand.

[0095] In still further embodiments of the RNAi agents disclosed herein, the sense strand and antisense strand are a pair of oligonucleotide sequences selected from Table 1 or Table 2, or a sequence that is at least 80, 85, 90, or 95, percent identical to a sequence therein. In further embodiments, 1, 2, or 3 mismatches are introduced into the sense strand of the pair in Table 1 or Table 2. In further embodiments, 1, 2, or both terminal nucleotides of 5’ end of the antisense strand are changed.

[0096] In some embodiments of the RNAi agents herein, the antisense strand comprises a first nucleic acid sequence that has at least 90% sequence identity to an antisense sequence corresponding to a Duplex NO: in Table 1 or Table 2, and the sense strand comprises a second nucleic acid sequence that has at least 90% sequence identity to a sense sequence corresponding to the same Duplex No: in the corresponding table. For example, in one embodiment, the antisense strand comprises a first nucleic acid sequence that has at least 90% sequence identity to an antisense sequence corresponding to a Duplex NO: 52 in Table 2, that is, a first nucleic acid sequence that has at least 90% sequence identity to SEQ ID NO: 147, and the sense strand comprises a second nucleic acid sequence that has at least 90% sequence identity to a sense sequence corresponding to Duplex No: 52 in Table 2, that is, SEQ ID NO: 100. In further embodiments, the 5’ phosphate of the antisense strand is furthermodified / replaced, and is a 5’ vinylphophonate or an OH group. In other embodiments, an abasic moiety or iAb moiety may be present at the 5 ’ end or the 3 ’ end of the sense strand.

[0097] In further embodiments, the 5’ terminal nucleotide of the antisense strand is substituted such that the final sequence contains a vinylphosphonate, a phosphate group, an abasic moiety, an iAb moiety, or an OH group. For example, for the antisense sequences as set forth in SEQ ID NOs 143-189, or a sequence having at least 90% sequence identity thereto, the 5’ phosphate group is replaced with an OH group.

[0098] The sense strand and antisense strand of an INHBE RNAi agent can be synthesized using any nucleic acid polymerization methods known in the art, for example, solid-phase synthesis by employing phosphoramidite chemistry methodology (e.g., Current Protocols in Nucleic Acid Chemistry, Beaucage, S.L. et al. (Edrs.), John Wiley & Sons, Inc., New York, NY, USA), H-phosphonate, phosphortriester chemistry, or enzymatic synthesis. Automated commercial synthesizers can be used, for example, MerMade™ 12 from LGC Biosearch Technologies, or other synthesizers from BioAutomation or Applied Biosystems. Phosphorothioate linkages can be introduced using a sulfurizing reagent such as phenylacetyl disulfide or DDTT (((dimethylaminomethylidene) amino)-3H-l,2,4-dithiazaoline-3-thione). It is well known to use similar techniques and commercially available modified amidites and controllcd-porc glass (CPG) products to synthesize modified oligonucleotides or conjugated oligonucleotides.

[0099] Purification methods can be used to exclude the unwanted impurities from the final oligonucleotide product. Commonly used purification techniques for single stranded oligonucleotides include reverse-phase ion pair high performance liquid chromatography (RP-IP-HPLC), capillary gel electrophoresis (CGE), anion exchange HPLC (AX-HPLC), and size exclusion chromatography (SEC). After purification, oligonucleotides can be analyzed by mass spectrometry and quantified by spectrophotometry at a wavelength of 260 nm. The sense strand and antisense strand can then be annealed to form a duplex.[000100] In other embodiments disclosed herein are INHBE RNAi agents having a Formula I of R-L-D, wherein R is a double stranded RNA (dsRNA) comprising a sense strand and an antisense strand, wherein the antisense strand is complementary to INHBEmRNA (SEQ ID NO: 1), wherein L is a bond or a linker, and wherein D is a delivery moiety of Formula II:In some embodiments, the sense strand and antisense strand may be selected from Tables 1 and 2.[000101] In some embodiments, the RNAi agent disclosed herein comprises a linker. In further embodiments, R is conjugated to Formula II via a linker. In other further embodiments R is conjugated to Formula II via a linker. In a further embodiment, the linker comprises a linker of Formula III having connection points A and B. In another embodiment, the linker comprises Formula IV having connection points X and Y, and wherein:Formula IV ; a. the RNAi agent comprises Formula II conjugated to Formula III at connection point A and Formula III is conjugated to a phosphate group at connection point B, and the phosphate group is conjugated to R; or b. the RNAi agent comprises Formula II conjugated to Formula IV at connection point X and Formula IV is conjugated to a phosphate group at connection point Y, and the phosphate group is further conjugated to R.[000102] In an embodiment in which the RNAi agent of Formula I includes a linker, and the linker is of or comprises Formula IV, -L-D has the structure of Formula V :wherein dsRNA R is connected to Formula V at connection point Y via a phosphate or phosphate analog.[000103] In a further aspect, provided herein are methods of reducing INHBE expression in a cell, such methods can include introducing a INHBE RNAi agent described herein into the cell; and incubating the cell for a time sufficient for degradation of INHBE mRNA, therebyreducing INHBE expression in the cell. The INHBE RNAi agent can be introduced into the cell using a method known in the art, e.g., transfection, electroporation, microinjection, or uptake by the cell via natural transport mechanisms.[000104] In another aspect, provided herein are methods of treating a INHBE associated metabolic disorder, such as obesity and CHD, in a patient in need thereof, and such method comprises administering to the patient an effective amount of a INHBE RNAi agent or a pharmaceutical composition described herein. In some embodiments, the INHBE RNAi agent or the pharmaceutical composition is administered to the patient intravenously or subcutaneously.[000105] In still other embodiments, the RNAi agent is capable of decreasing expression of the INHBE gene in a liver cell. In other embodiments, the RNAi agents disclosed herein are for use in therapy. In further embodiments, the use is for the treatment of obesity. In other embodiments, the use for the reduced distribution of adipose tissue in the abdomen. In other embodiments, the use is for the treatment of dyslipidemia. In further embodiments, the dyslipidemia is hypercholesteremia. In another embodiment, the use is for the treatment of insulin resistance or T2D. In other embodiments, the use is to reduce the risk of one or more of myocardial infarction (MI), stroke, revascularization procedures, and angina. In further embodiments, the use is for any of the preceding uses, after alteration of diet failed to control one or more symptoms. In other further embodiments, the use is for any of the preceding uses, as an adjunct therapy to diet.[000106] Dosage values may vary with the type and severity of the condition to be alleviated. It is further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. [000107] The RNAi agents may be formulated into pharmaceutical compositions.Accordingly, disclosed herein are pharmaceutical compositions comprising the RNAi agent disclosed herein, and one or more pharmaceutically acceptable excipients. In other embodiment are uses of the RNAi agents herein for the manufacture of a medicament for the treatment of obesity or any of the uses recited in the preceding paragraph.[000108] In other embodiments are methods of treating obesity, in patients in need thereof, comprising administering an RNAi agent disclosed herein, or a pharmaceutical composition thereof. In other embodiments are methods of treating obesity, or any of the uses recited above, in patients in need thereof, or a pharmaceutical composition thereof. In other embodiments are methods of treating a patient unable to achieve lipid levels following statin and / or diet therapy, comprising administering to the patient an RNAi agent disclosed herein, or a pharmaceutical composition thereof.[000109] In other embodiments are methods of decreasing INHBE expression in a cell, comprising contacting the cell with an RNAi agent disclosed herein, and incubating the cell for a time sufficient for decreasing the level of INHBE mRNA by at least 50% as compared to an untreated or control treated cell.[000110] Certain abbreviations used herein include: “1,2-DCE” refers to 1,2- dichloroethane; “Ac” refers to acetyl; “DCM” refers to dichloromethane; “DIEA” refers to N,N-diisopropylethylamine; “DMF” refers to N,N-dimethylformamide; “DMAP” refers to 4- dimethylaminopyridine; “DMTC1” refers to 4,4’-dimethoxytrityl chloride; “DPP4” refers to dipeptidyl peptidase; “EDC” refers to l-ethyl-3-(3-dimethylaminopropyl)carbodiimide; “EtOAc” refers to ethyl acetate; “GalNAc” refers to N-acetylgalactosamine; “HATU” refers to l-[bis(dimcthylamino)mcthylcnc]- 1H- l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; “HBTU” refers to O-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate; “HOBt” refers to 1 -hydroxybenzotriazole hydrate; “HPRT” refers to hypoxanthine-guanine phosphoribosyltransferase; “IP A” refers to isopropanol and isopropyl alcohol; “LDHA” refers to lactate dehydrogenase-A; “MeCN” refers to acetonitrile; “MeOH” refers to methanol and methyl alcohol; “MWCO” refers to molecular weight cut-off; “NHS” refers to N-hydroxysuccinimide; “OD” refers to optical density; “PBS” refers to phosphate-buffered saline; “PhSiH3” refers to phenylsilane; “PTS” refers to portable endotoxin testing system; “siRNA” refers to small interfering ribonucleic acid; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “THF” refers to tetrahydrofuran; “TLC” refers to thin line chromatography; and “TMP” refers to 2, 2,6,6- tetramethy Ipiperidine .[000111] A delivery moiety comprising Formula I may be made by synthetic steps and schemes as described in United States Patent Application No. 18 / 573,794, filed December 22, 2023, or International Patent Publication No. WO2022 / 271806, each of which is incorporated herein by reference in its entirety.[000112] Briefly, for the synthesis of GalNAc-conjugated sense strands, a sense strand with a 3’ C6-NH2 functional group is first synthesized using standard phosphoramidite chemistry. A stock solution of the desired GalNAc ligand-NHS ester (10 mmol / L in acetonitrile; 1 eq) is prepared. Borate buffer (10% v / v; 20x) is added to oligonucleotide C6-NH2 sense strand in an Eppendorf tube, then GalNAc ligand (5 eq) is added. The mixture is shaken at ambient temperature for 16 hours. After this time, the mixture is transferred to a 15 mL falcon tube, ammonium hydroxide (28 mass%) is added, and the mixture is shaken at ambient temperature for 2 hours. The ammonia is then removed in vacuo. The residue is purified by ion-exchange chromatography. Conditions; Solvent A; 15% MeCN / 20 mM NaH2PO4, Solvent B: 15%MeCN / 20mM NaH2PO4, IM NaBr; 35-55%B over 5 CV at 8 mL / min, column temperature 60 °C. The desired fractions are pooled and desalted by spin-filtration using an Eppendorf centrifuge or desalting column. After desalting, the material is recovered and OD and volume are measured to obtain concentration.[000113] Alternatively, and particularly in the case of a delivery moiety including a linker of Formula IV, oligo synthesis may be conducted on a MerMade™ 12 instrument using phosphoramidite chemistry. Sense strands are synthesized from the prefunctionalized GalNAc solid support and antisense strands are synthesized using standard support preloaded with the first nucleotide of the oligo sequence. Antisense strands are prepared using CPG with a universal support or linker. Oligos are cleaved and deprotected using concentrated ammonium hydroxide solution (28% by mass) and purified by ion exchange chromatography using conditions described above. Such deprotection likewise converts the OAc precursor groups of the galactose moieties to hydroxyl groups. Desalting, annealing, and endotoxin testing are conducted.[000114] To generate the siRNA duplexes of a sense and antisense strand, the following procedures may be performed. To a tube (such as a Falcon tube) containing oligonucleotidesense strand-GalNAc conjugate, the corresponding antisense oligonucleotide (1 eq) is added and vortexed for 10 seconds before spin-filtering through 100K MWCO Amicon filter unit to remove particulates. The filtrate is recovered and concentrated in vacuo on a Genevac evaporator. The residue is reconstituted in lx PBS, filtered through 0.2 p filter, and OD and volume are measured to obtain concentration.[000115] An endotoxin test is performed using a Limulus amebocyte lysate on an EndosafeO-nexgen PTS instrument.Homo sapiens Inhibin Subunit Beta E (INHBE) transcript,SEQ ID NO: 12221 aagaagggtt agggtgatgg tccagagcaa cagttcttca agtgtactct gtaggcttct2281 gggaggtccc ttttcagggg tgtccacaaa gtcaaagcta ttttcataat aatactaaca2341 tgttatttgc cttttgaatt ctcattatct taaaattgta ttgtggagtt ttccagaggc2401 cgtgtgacat gtgattacat catctttctg acatcattgt taatggaatg tgtgcttgta[000116] Exemplary RNA duplexes of unmodified sequence, including their constituent sense and antisense strand sequences, are shown in Table 1 below. It will be appreciated that these sequences form a basis for RNAi agents useful for practicing the invention and may be optionally further modified with alternative intemucleotide linkages, nucleobases, and / or other moieties as described herein.Table 1Exemplary unmodified full-length sense and antisense strands of INHBE RNAi agentsAbbreviations - “m” indicates 2’-0Me; “f” indicates 2’-fluoro; indicates phosphorothioate linkage; “iAb” indicates an inverted abasic moiety; “SProN(U)” indicates (S) 2-propyl-o-uridine; “hmpT” indicates the hmpT nucleotide. Unless otherwise noted, the 5’ position of the AS can include 5’-phosphate or 5’-vinylphosphonate (VP).PREPARATIONS

[0001] The compounds of the present disclosure may be prepared by following the schemes and preparations detailed below. These schemes and preparations are not limiting in their scope.

[0002] Certain abbreviations are defined as follows: “AS” refers to antisense strand; “CT” refers to cycle threshold; “DCM” refers to dichloromethane; “DMF” refers to dimethylformamide; “DIEA” refers to N,N-diisopropylethylamine; “PE” refers to petroleum ether; “TFA” refers to trifluoroacetic acid; “DMT” refers to dimethoxy trityl; “DMTQ” refers to dimethoxytrityl chloride; “DMSO” refers to dimethyl sulfoxide; “dsRNA” refers to double stranded ribonucleic acid; “EtOH” refers to ethanol; “EtOAc” refers to ethyl acetate;“hiPSC” refers to human induced pluripotent stem cell; “McCN” refers to acetonitrile; “MeOH” refers to methanol and methyl alcohol; “PBS” phosphate-buffered saline; “PCR” refers to polymerase chain reaction; “RT-PCR” refers to reverse transcription polymerasechain reaction; “siRNA” refers to small interfering RNA; “SS” refers to sense strand; “TEA” refers to triethylamine; “IBX” refers to 2-iodoxybenzoic acid “9-BBN” refers to 9- borabicyclo[3.3.1]nonane; “2, 4, 6 TMP” refers to 2, 4, 6 trimethylpyridine; “TBAF” refers to tetra-butylammonium fluoride; “TBDMSC1” refers to tert-butyldimethylsilyl chloride; “9- BBN” refers to 9-borabicyclo[3.3.1]nonane; “CAP A” refers to capping agent; “CPG” refers to controlled pore glass; “CV” refers to column volume; “1,2-DCE” refers to 1,2- dichloroethane; “DIEA” refers to N,N-diisopropylethylamine; “DMAP” refers to 4- dimethylaminopyridine; “DMF” refers to N,N-dimethylformamide; “EDCI HQ” refers to 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; “ES / MS” refers to electrospray mass spectrometry; “Et2O” refers to diethyl ether; “GalNAc” refers to N- acetylgalactosamine; “HATU” refers to l-fbis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; “HBTU” refers to O-(benzotriazol-l- yl)-A,A,A',AAtetramethyhironium hexafluorophosphate; “HOBt” refers to 1- hydroxybenzotriazole hydrate; “IBX” refers to 2-iodoxybenzoic acid; “LDHA” refers to lactate dehydrogenase-A; “MeCN” refers to acetonitrile; “MWCO” refers to molecular weight cut-off; “NHS” refers to N-hydroxy succinimide; “NMR” refers to nuclear magnetic resonance; “OD” refers to optical density; “PBS” refers to phosphate-buffered saline; “PE” refers to petroleum ether; “TFA” refers to trifluoroacctic acid; “THF” refers to tetrahydrofuran; “TLC” refers to thin line chromatography; and “TMP” refers to 2, 2,6,6- tetramethylpiperidine; and “TBDMS” refers to tert-butyldimethylsilyl.Scheme 1

[0003] Scheme 1, step A depicts the cyclization of compound (1) using trimethylsilyl trifluoromethanesulfonate in a solvent such as 1,2-DCE to give compound (2).

[0004] Scheme 2, Step A depicts the condensation of compound (3) with compound (4) using a suitable base such as NaOH in a solvent such as DMSO to give compound (5). Step B shows the protection of compound (5) with benzyl chloroformate using a base such assodium carbonate in a solvent such as DCM to give compound (6). Step C shows the hydrolysis of compound (6) with formic acid to give triacid compound (7).Scheme 3

[0005] Scheme 3, Step A depicts the protection of compound (8) with benzyl bromide using a base such as potassium carbonate in a solvent such as acetone to give compound (9). Step B shows the O-alkylation of compounds (9) and (10) using tetrabutylammonium sulfate and sodium hydroxide to give compound (11). Step C shows the debenzylation of compound (11) using a suitable catalyst such as palladium hydroxide on carbon and hydrogen gas in a solvent such as MeOH to give compound (12).

[0006] Scheme 4, Step A depicts the amide coupling between compounds (7) and (12) using HBTU and a base such as DIEA in a solvent such as DMF to give compound (13). Step B shows the acidic deprotection of compound (13) with p-toluenesulfonic acid monohydrate in a solvent such as MeOH to give compound (14). Step C shows the addition of compound (14) to compound (2) using trimethylsilyl trifluoromethanesulfonate in a solvent such as 1,2- DCE to give compound (15). Step D shows the deprotection of compound (15) using a catalyst such as palladium on carbon and a gas such as hydrogen in a solvent such as MeOH to give compound (16). Step E shows the amide coupling between compounds (16) and (17) using HBTU and a base such as DIEA in a solvent such as DMF to give compound (18). Step F shows the hydrogenation of compound (18) using palladium on carbon in a solvent such as MeOH to give compound (19).Scheme 5[W07] Scheme 5, step A depicts the protection of compound (20) using DMTC1 with a suitable base such as DIEA in a solvent such as DCM to give compound (21). Step B shows an amide coupling between compound (21) and piperidin-4-yl methanol using HBTU and HOBt with TMP in a solvent such as DCM to give compound (22). The deprotection of compound (22) with 20% piperidine in DMF to give compound (23) is shown in step C.Scheme 6

[0008] Scheme 6, step A depicts an amide coupling between compounds (19) and (23) using HBTU and HOBt with an appropriate base such as DIEA in a solvent such as DMF to give compound (24). Step B shows the formation of compound (25) by adding succinic anhydride to compound (24) in an appropriate solvent such as DCM with a base system of TEA and DMAP. Step C depicts the loading of compound (25) onto resin with 2-(lH-benzotriazol-l- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate and a base such as DIEA in a solvent system such as MeCN and DCM to give compound (26).Scheme 7

[0009] Scheme 7, Step A depicts a coupling reaction between compounds (19) and (27) using a reagent such as EDCI HC1 in a solvent such as DCM to give compound (28).

[0010] Scheme 8, step A depicts the synthesis of compound (30) by DMT protection of compound (29), the conditions of which will be known by one skilled in the art. Step B shows the conversion of compound (30) to compound (31) by protection of the 3’ alcohol using TBDMSC1 in an appropriate solvent such as DMF. For step C, the DMT group was removed from compound (31) to give compound (32), the conditions of which will be known by one skilled in the ait. Step D depicts the oxidation of compound (32), using IBX in an appropriate solvent such as EtOAc, to provide compound (33). Conversion of compound (33) to compound (34) via a Wittig reaction, in step E, was accomplished using methyltriphenylphosphonium bromide in an appropriate solvent such as THF.Hydroboration of compound (34) in step F, using 9-BBN in an appropriate solvent such as THF, gave compound (35) which was then oxidized in step G, using IBX and an appropriatesolvent such as MeCN, to provide compound (36). A Grignard reaction, depicted in step H, was used to convert compound (36) to compound (37) using methylmagnesium bromide in an appropriate solvent such as THF. DMT protection of compound (37), depicted in Step I, provided compound (38) using DMTC1, 2, 4, 6-TMP, and AgNCh in an appropriate solvent such as DCM. The TBDMS group was removed from compound (38) to provide compound (39), the conditions of which will be known by one skilled in the art.Scheme 9

[0011] Scheme 9, step A depicts the SFC purification of compound (39) to give compounds (40) and (41) as diastereomers. In step B, the 3’ alcohol of compound (40) was phosphitylated with 3-((chloro(diisopropylamino)phosphaneyl)oxy)propanenitrile in an appropriate solvent such as DCM to provide compound (42). Step C, using the same conditions as step B, provided compound (43) from compound (41).Scheme 10

[0012] Scheme 10, steps A-C depict the formation of compound (47) through several steps beginning with compounds (19) and (44). The steps are essentially analogous to those found in Scheme 6, steps A-C.Scheme 11

[0013] Scheme 11, step A depicts the synthesis of compound (2) by DMT protection of compound (1), the conditions of which will be known by one skilled in the ait. Step B shows the conversion of compound (2) to compound (3) by protection of the 3’ alcohol using TBDMSC1 in an appropriate solvent such as DMF. For step C, the DMT group was removed from compound (3) to give compound (4), the conditions of which will be known by one skilled in the ait. Step D depicts the oxidation of compound (4), using IBX in an appropriate solvent such as EtOAc, to provide compound (5). Conversion of compound (5) to compound (6) via a Wittig reaction, in step E, was accomplished using methyltriphenylphosphonium bromide in an appropriate solvent such as THF. Hydroboration of compound (6) in step F, using 9-BBN in an appropriate solvent such as THF, gave compound (7) which was then oxidized in step G, using IBX and an appropriate solvent such as ACN, to provide compound(8). A Grignard reaction, depicted in step H, was used to convert compound (8) to compound (9) using methylmagnesium bromide in an appropriate solvent such as THF. DMT protection of compound (9), depicted in Step I, provided compound (10) using DMTC1, 2, 4, 6-TMP, and AgNCh in an appropriate solvent such as DCM. The TBDMS group was removed from compound (10) to provide compound (11), the conditions of which will be known by one skilled in the art.Scheme 12

[0014] Scheme 12, step A depicts the SFC purification of compound (11) to give compounds (12) and (13) as diastereomers. In step B, the 3’ alcohol of compound (12) was phosphitylated with 3-((chloro(diisopropylamino)phosphaneyl)oxy)propanenitrile in an appropriate solvent such as dichloromethane to provide compound (14). Step C, using the same conditions as step B, provided compound (15) from compound (13).Preparation 1 l-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxy-3- methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione

[0015] DIEA (50.1 g, 67.5 mL, 387 mmol) and l-[Chloro-(4-methoxyphenyl)-phenyl- methyl]-4- methoxy-benzene (72.2 g, 213 mmol) were added to a solution of 1- ((2R,3R,4R,5R)-4-hydroxy-5-(hydroxymethyl)-3-methoxytetrahydrofuran-2-yl)pyrimidine- 2,4(lH,3H)-dione (50.0 g, 194 mmol) dissolved in DCM (500 mL). The mixture was stirred at ambient temperature for 15 hours. The reaction mixture was quenched with water (500 ml) and the organic layer was removed. The aqueous layer was extracted three times with DCM (200 ml). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography, eluting with 0% to 100% EtOAc / PE, to give the title compound (100 g, 82%) as a yellow solid. ES / MS (m / z): 583.3 (M+23).Preparation 2 l-((2R,3R,4R,5R)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((tert- butyldimethylsilyl)oxy)-3-methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione

[0016] Imidazole (216 g, 3.18 mol) and tert-butyldimethylchlorosilane (47.96 g, 52.9 mL, 318 mmol) were added to a solution of l-((2R,3R,4R,5R)-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxy-3-methoxytetrahydrofuran-2- yl)pyrimidine- 2,4(lH,3H)-dione (100.0 g, 159 mmol) in DMF (500 mL). The mixture was stirred under nitrogen at 50 °C for 15 hours. After cooling to ambient temperature, the mixture was quenched with water (I L). The aqueous layer was extracted three times with EtOAc (800 ml). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography, eluting with 0% to 100% EtOAc / PE, to give the title compound (99 g, 86%) as a yellow solid. ES / MS (m / z): 697.4 (M+23).Preparation 3 l-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)-3- methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione

[0017] TFA (59.0 g, 40 ml, 520 mmol) was added to a solution of l-((2R,3R,4R,5R)-5- ((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((tert-butyldimethylsilyl)oxy)-3- methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (99.0 g, 136 mmol) dissolved in DCM (1000 mL). The mixture was stirred under nitrogen at ambient temperature for 2 hours, cooled to 0 °C in an ice bath, and then quenched by the addition of aqueous sodium bicarbonate (300 mL). The aqueous was then extracted 3 times with DCM (200 mL) and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography, eluting with 0% to 80% EtOAc / PE, to give the title compound (30 g, 57%) as a yellow solid. ES / MS (m / z): 373.1 (M+l).Preparation 4(2S,3S,4R,5R)-3-((tcrt-butyldimcthylsilyl)oxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)-4-methoxytetrahydrofuran-2-carbaldehyde

[0018] IBX (43.8 g, 156 mmol) was added to a solution of l-((2R,3R,4R,5R)-4-((tert- butyldimethylsilyl)oxy)-5-(hydroxymethyl)-3-methoxytetrahydrofuran-2-yl)pyrimidine- 2,4(1H,3H)- dione (30.0 g, 78.1 mmol) in EtOAc (400 mL). The mixture was stirred undernitrogen at 80 °C for 5 hours. The reaction mixture was then cooled to ambient temperature, filtered, and concentrated under reduced pressure to give to give the title compound (33 g, 86%) as a pink solid. ES / MS (m / z): 371.1 (M+l).Preparation 5 l-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-3-methoxy-5-vinyltetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione

[0019] N-Butyllithium (14.6 g, 91 . 1 mL, 228 mmol, 2.5M in hexane) was added to a solution of methyltriphenylphosphonium bromide (81.4 g, 228 mmol) in THF (600 mL) under nitrogen at -70 °C. The solution was warmed to 0 °C, stirred for 30 minutes, and (2S,3S,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)- yl)-4-methoxytetrahydrofuran-2-carbaldehyde (37.5 g, 75.9 mmol) dissolved in THF (300 mL) was then added. The mixture was then warmed to ambient temperature and stirred under nitrogen for 16 hours. After quenching with saturated ammonium chloride (1200 ml) the mixture was further diluted with water (500 ml). The aqueous was extracted 3 times with EtOAc (1000 ml) and the organic layers were combined, washed with brine (800 ml), dried over sodium sulfate, and then reduced to residue. The residue was purified by silica gel flash chromatography, eluting with 0% to 50% EtOAc / PE, to give the title compound (16 g, 56%) as a white solid. ES / MS (m / z): 369.6 (M+l).Preparation 6 l-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(2-hydroxyethyl)-3- methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione

[0020] l-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-3-methoxy-5- vinyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (11.1 g, 28.6 mmol) was dissolved in THF (200 mL) under nitrogen and the solution was cooled to 0 °C. 9-BBN in THF (45.2 g, 143 mmol, 0.5M in THF) was added to the solution and it was stirred at 0 °C for 30 minutes. The mixture was then warmed to ambient temperature. After stirring for 16 hours, the solution was cooled to 0 °C and MeOH (12 mL) was added dropwise. When gas evolution had ceased, water (6.0 mL) was added followed by a mixture of sodium hydroxide (2.29 g, 28.6 mL, 57.2 mmol) and hydrogen peroxide (22.7 g, 20.5 ml, 200 mmol). The ice bath was then removed, and the mixture was stirred vigorously at ambient temperature for 2 hours. Aqueous sodium sulfite (400 mL) was then added, and the mixture was extracted 3 times with EtOAc (500 mL). The organic layers were then combined, washed 2 times with brine (200 ml), dried over sodium sulfate, and then reduced to residue. The residue was purified by silica gel flash chromatography, eluting with 0% to 50% EtOAc / PE, to give the title compound (8.6 g, 78%) as a colorless oil. ES / MS (m / z): 387.2 (M+l).Preparation 72-((2R,3R,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-5-(2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)-4-methoxytetrahydrofuran-2-yl)acetaldehyde

[0021] l-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(2-hydroxyethyl)-3- methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)- dione (12.0 g, 22.4 mmol) was dissolved in MeCN (150 mL) and IBX (12.5 g, 44.7 mmol) was added. After stirring at 80 °C for 1 hour, the mixture was filtered through a Celite pad and concentrated to residue. The residue was purified by silica gel flash chromatography, eluting with 0% to 60% EtOAc / PE, to give the title compound (8.4 g, 86%) as a white solid. ES / MS (m / z): 385.1 (M+l).Preparation 8 l-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(2-hydroxypropyl)-3- mcthoxytctrahydrofuran-2-yl)pyrimidinc-2,4(lH,3H)-dionc

[0022] Methylmagnesium bromide (3.49 g, 9.77 mL, 29.3 mmol, 3M in THF) was added to a solution of 2-((2R,3R,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-4-methoxytetrahydrofuran-2- yl)acetaldehyde (3.20 g, 7.32 mmol) in THF (100 mL) at 0 °C under nitrogen. The solution was stirred at 0 °C for 1 hour. The reaction mixture was quenched by the addition of aqueous saturated ammonium chloride (150 mL) and then diluted with water (100 mL). The aqueous was extracted with EtOAc(200 mL). The organic layer was washed with brine (100 mL), dried over sodium sulfate, filtered, and then reduced to residue. The residue was purified by silica gel flash chromatography, eluting with 20% to 60% EtOAc / PE to give the title compound (1.8 g, 61%) as a colorless oil. ES / MS (m / z): 401.1 (M+l).Preparation 9 l-((2R,3R,4R,5R)-5-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-4-((tert- butyldimethylsilyl)oxy)-3-methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione

[0023] Silver nitrate (15.2 g, 89.2 mmol), 2,4,6-trimethylpyridine (14.6 g, 15.9 mL, 119 mmol), and 4,4'-(chloro(phenyl)methylene)bis(methoxybenzene) (20.2 g, 59.7 mmol) were added to a solution of l-((2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-((RS)-2- hydroxypropyl)-3-methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (5.90 g, 11.9 mmol) in DCM (120 mL) at 0 °C. The ice bath was removed, and the mixture was stirred at ambient temperature for 16 hours under nitrogen. The reaction mixture was quenched by the addition of water (200 mL) and the aqueous was then extracted three times with EtOAc (200 mL). The organic layers were then combined, washed 2 times with brine (200 ml), dried over sodium sulfate, and then reduced to residue. The residue was purified by silica gel flash chromatography, eluting with 0% to 70% EtOAc / PE, to give the title compound (11 g, 74%) as an orange solid. ES / MS (m / z): 725.3 (M+23).Preparation 10 l-((2R,3R,4R,5R)-5-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-4-hydroxy-3- methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione

[0024] Tetrabutylammonium fluoride (2.50 g, 9.70 mL 9.70 mmol, IM in THF) was added to a solution of l-((2R,3R,4R,5R)-5-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-4- ((tcrt-butyldimcthylsilyl)oxy)-3-mcthoxytctrahydrofuran-2-yl)pyrimidinc-2,4(lH,3H)-dionc (10.0 g, 9.70 mmol) in THF (100 mL) and the mixture was stirred at ambient temperature under nitrogen. After 30 minutes of stirring, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography, eluting with 0% to 100% EtOAc / PE, to give the title compound (5.0 g, 80%) as a white solid. ES / MS (m / z): 587.2 (M-l).Preparation 11 l-((2R,3R,4R,5R)-5-((S)-2-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-4-hydroxy-3- methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione and l-((2R,3R,4R,5R)-5-((R)-2- (bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-4-hydroxy-3-methoxytetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione

[0025] l-((2R,3R,4R,5R)-5-(2-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-4-hydroxy- 3-methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (5.00 g, 8.15 mmol) was purified by SFC (Condition: CCh-EtOH; Column: Daicel Chiralpak IBN 250 mm X 50 mm X 10 um; Begin B: 50%; End B: 50%; Gradient Time(min): 150 min; Flowrate: 200mL / min.) to give l-((2R,3R,4R,5R)-5-((S)-2-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-4- hydroxy-3-methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (first eluting isomer, 1.85 g, 38%) and l-((2R,3R,4R,5R)-5-((R)-2-(bis(4- methoxyphenyl)(phenyl)methoxy)propyl)-4-hydroxy-3-methoxytetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione (second eluting isomer, 3.01 g, 61%) as white solids.ES / MS (m / z): 587.2 (M-l). Relative stereochemistry was verified by x-ray crystallography.Preparation 12(2R,3R,4R,5R)-2-((S)-2-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-4-methoxytetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite

[0026] l-((2R,3R,4R,5R)-5-((S)-2-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-4- hydroxy-3-methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (1.85 g, 3.14 mmol) was dissolved in a mixture of DIEA (1.22 g, 1.64 mL, 9.43 mmol) in DCM (25 mL) and the solution was chilled to 0 °C in an ice bath. 3- ((chloro(diisopropylamino)phosphaneyl)oxy)propanenitrile (1.64 g, 1.54 mL, 6.91 mmol) was then added dropwise and the ice bath was removed. The mixture was stirred at ambient temperature for 1.5 hours and the solvent was then removed under vacuum at 25 °C to leave a residue. The residue was purified by silica gel flash chromatography, eluting with 0% to 100% EtOAc / hexanes (eluents contain 1% TEA) to give the title compound (1.54 g, 62%) as an off-white foam.31P NMR (DMSO) 5 148.90, 148.80; ES / MS (m / z): 789.4 (M+l).Preparation 13(2R,3R,4R,5R)-2-((R)-2-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-5-(2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)-4-methoxytetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite

[0027] l-((2R,3R,4R,5R)-5-((R)-2-(bis(4-methoxyphenyl)(phenyl)methoxy)propyl)-4- hydroxy-3-methoxytetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (3.01 g, 5.11 mmol) was dissolved in a mixture of DIEA (1.98 g, 2.67 mL, 15.3 mmol) in DCM (40 mL) and the solution was chilled to 0 °C in an ice bath. 3- ((chloro(diisopropylamino)phosphaneyl)oxy)propanenitrile (2.66 g, 2.51 mL, 11.2 mmol) was then added dropwise and the ice bath was removed. The mixture was stirred at ambient temperature for 1.5 hours and the solvent was then removed under vacuum at 25 °C to leave a residue. The residue was purified by silica gel flash chromatography, eluting with 0% to 100% EtOAc / hexanes (eluents contain 1% TEA) to give the title compound (3.8 g, 95%) as an off-white foam.31P NMR (DMSO) 5 149.06, 148.99; ES / MS (m / z): 789.4 (M+l).Preparation 14(6,7-Diacetoxy-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]oxazol-5-yl)methyl acetate

[0028] To a suspension of (5-acetamido-3,4,6-triacetoxy-tetrahydropyran-2-yl)methyl acetate (25.0 g, 62.9 mmol) in 1,2-DCE (120 mL) was added trimethylsilyl trifluoromethanesulfonate (18.4 mL, 94.3 mmol). The mixture was heated to 50 °C and stirred for 16 hours under nitrogen atmosphere. After this time, the cooled mixture was poured into cold saturated aqueous NaHCCL and extracted three times with DCM. The organic layer was washed successively with saturated aqueous NaHCCh solution and saturated aqueous NaCl solution, dried over MgSCL, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography, eluting with 0-5% MeOH / DCM, to give the title compound as thick, yellow oil (12.7 g, 61%). ES / MS m / z: 330 (M+H).Preparation 15Di-tert-butyl 3,3'-((2-amino-2-((3-(tert-butoxy)-3-oxopropoxy)methyl)propane-l,3- diy l)bi s (oxy ) )dipropionate

[0029] Tris(hydroxymethyl)aminomethane (7.0 g, 57 mmol) was dissolved in fresh dimethyl sulfoxide (11 mL) and cooled to 15 °C under a nitrogen atmosphere. While stirring, 5N sodium hydroxide (1.2 mL, 6.0 mmol) was added, followed by tert-butyl acrylate (30 mL, 203 mmol) as a slow stream. The mixture was stirred at ambient temperature. After 8 hours, an additional 5N sodium hydroxide (1.2 mL, 6.0 mmol) and tert-butyl acrylate (15 mL, 101 mmol) were added and stirring continued for another 8 hours. The mixture was concentrated under reduced pressure (50 °C and 2 mbar) for 1 hour. The residue was diluted with water and saturated aqueous NaCl solution, then extracted three times with EtOAc. The organic layer was dried over MgSCU, filtered, and concentrated in vacuo to give the title compound as a colorless, viscous oil (24.72 g, 85%). ES / MS m / z: 506 (M+H).Preparation 16Di-terz-butyl 3,3'-((2-(((benzyloxy)cai’bonyl)amino)-2-((3-(?e77-butoxy)-3- oxopropoxy)methyl)propane- 1 ,3-diyl)bis(oxy ))dipropionate

[0030] To di-tert-butyl 3,3'-((2-amino-2-((3-(tert-butoxy)-3-oxopropoxy)methyl)propane- l,3-diyl)bis(oxy))dipropionate (24.7 g, 48.9 mmol) and sodium carbonate (25% aqueous, 180 mL) in DCM (300 mL) was added benzyl chloroformate (22 mL, 151 mmol) as a slow stream. The mixture was stirred at ambient temperature for 4 hours. After this time, the mixture wasdiluted with water, stirred for 5 minutes and the layers separated. The aqueous layer was extracted two times with DCM. The combined organic layer was washed with saturated aqueous NaCl solution, dried over Na2SC>4, filtered and concentrate in vacuo. The crude residue was purified by silica gel flash chromatography, eluting with 0-60% EtOAc in hexanes to give the title compound as thick, colorless oil (19.1 g, 61.1%). ES / MS m / z: 640 (M+H).Preparation 173,3'-((2-(((Benzyloxy)carbonyl)amino)-2-((2-carboxyethoxy)methyl)propane-l,3- diyl)bis(oxy))dipropionic acid

[0031] Di-terZ-butyl 3, 3'-((2-(( (benzyloxy )carbonyl)amino)-2-((3-(tcrt-butoxy)-3- oxopropoxy)methyl)propane-l,3-diyl)bis(oxy))dipropionate (19.1 g, 29.9 mmol) was stirred in formic acid (100 mL) at ambient temperature for 16 hours. After this time, the mixture was concentrated in vacuo (50 °C and 2 mbar) to give the title compound as a thick oil (15.07 g, 94.2%). ES / MS m / z: 472 (M+H).Preparation 183-(Dibenzylamino)propan-l-ol

[0032] To a mixture of benzyl bromide (16.5 mL, 136 mmol) and 3-amino-l -propanol (5.00 mL, 64.7 mmol) in acetone (200 mL) was added potassium carbonate (45.0 g, 322.3 mmol). The mixture was stirred for 16 hours under nitrogen atmosphere. After this time, the mixture was filtered and the filter cake washed with acetone. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel flash chromatography, eluting with 0-80% EtOAc in hexanes to give the title compound as light, yellow liquid (7.9 g, 48%). ES / MS m / z: 256 (M+H).Preparation 19N,N-Dibcnzyl-3-(3-((tctrahydro-2H-pyran-2-yl)oxy)propoxy)propan-l-aminc

[0033] Tetrabutylammonium sulfate (50 mass% in H2O) (42 mL, 36 mmol) was added to a mixture of 3-(dibenzylamino)propan-l-ol (7.9 g, 31 mmol) and 2-(3- bromopropoxy)tetrahydro-2H-pyran (6.5 mL, 38 mmol) in 5N sodium hydroxide (120 mL). The mixture was stirred at 70 °C for 24 hours. Additional tetrabutylammonium sulfate (50 mass% in H2O) (42 mL, 36 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (6.5 mL, 38 mmol) were added and stirred for a further 24 hours. After cooling to ambient temperature, the mixture was diluted with saturated aqueous NaCl solution and extracted three times with EtOAc. The organic layer was washed with saturated aqueous NaCl solution, dried overN £12.804. filtered and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography, eluting with 0-50% EtOAc in hexanes to give the title compound as yellow liquid (7.6 g, 62%). ES / MS m / z: 398 (M+H).Preparation 203-(3-((Tetrahydro-2H-pyran-2-yl)oxy)propoxy)propan-l -amine

[0034] Palladium hydroxide on carbon (20% wet) was suspended in MeOH (225 mL) in a Parr shaker. A solution of N,N-dibenzyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)propan-l- amine in MeOH (225 mL) was added. The shaker was sealed and purged with nitrogen gas, followed by hydrogen gas. The mixture was stirred at ambient temperature under 60 psi of hydrogen gas. After 8 hours, the mixture was filterd over a small pad of diatomaceous earth and the filter cake washed with MeOH. The filtrate was concentrated in vacuo to give the title compound as a yellow liquid (3.95 g, 96%). GC / MS m / z: 218.Preparation 21Benzyl (9,19-dioxo-14-((3-oxo-3-((3-(3-((tetrahydro-2H-pyran-2- yl)oxy)propoxy)propyl)amino)propoxy)methyl)-l,27-bis((tetrahydro-2H-pyran-2-yl)oxy)- 4,12,16,24-tetraoxa-8,20-diazaheptacosan-14-yl)carbamate

[0035] 3,3'-((2-(((Benzyloxy)carbonyl)amino)-2-((2-carboxyethoxy)methyl)propane-l,3- diyl)bis(oxy))dipropionic acid (2.00 g, 4.20 mmol) and 3-(3-((tetrahydro-2H-pyran-2- yl)oxy)propoxy)propan-l -amine (3.95 g, 18.2 mmol) were dissolved in DMF (50 mL). HBTU (4.90 g, 13.0 mmol) and DIEA (5.00 mL, 27.3 mmol) were added and the mixture stirred at ambient temperature. After 16 hours, the mixture was diluted with ice water and extracted two times with DCM. The organic layer was washed with saturated aqueous NaCl, dried over MgSCL filtered, and concentrated in vacuo. The crude residue was purified by silica gel flash chromatography, eluting with 0-20% MeOH in DCM to give the title compound as a thick, yellow oil (3.5 g, 77%). ES / MS m / z: 1092 (M+23).Preparation 22Benzyl (l,27-dihydroxy-14-((3-((3-(3-hydroxypropoxy)propyl)amino)-3- oxopropoxy)methyl)-9,19-dioxo-4,12,16,24-tetraoxa-8,20-diazaheptacosan-14-yl)carbamate

[0036] p-Toluenesulfonic acid monohydrate (0.12 g, 0.68 mmol) was added to a solution of benzyl (9,19-dioxo-14-((3-oxo-3-((3-(3-((tetrahydro-2H-pyran-2- yl)oxy)propoxy)propyl)amino)propoxy)methyl)-l,27-bis((tetrahydro-2H-pyran-2-yl)oxy)- 4,12,16,24-tetraoxa-8,20-diazaheptacosan-14-yl)carbamate (3.5 g, 3.3 mmol) in MeOH (50 mL). The mixture was stirred at 60 °C for 30 minutes, cooled to ambient temperature then concentrated in vacuo. The residue was diluted with saturated aqueous NaHCOi solution and extracted three times with chloroform. The organic layer was washed successively with saturated aqueous NaHCOs and saturated aqueous NaCl solution, dried over MgSO4, filteredand concentrated in vacuo to give the title compound as a thick, yellow oil (2.57 g, 96%).ES / MS m / z: 409 ([M+2H] / 2).Preparation 23[5-Acetamido-6-[3-[3-[3-[3-[3-[3-[3-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo-propoxy]-2-[[3-[3-[3-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxypropoxy]propylamino]-3-oxo-propoxy]methyl]-2-(benzyloxycarbonylamino)propoxy]propanoylamino]propoxy]propoxy]-3,4-diacetoxy- tetrahydropyran-2-yl]methyl acetate

[0037] To a mixture of benzyl (l,27-dihydroxy-14-((3-((3-(3- hydroxypropoxy)propyl)amino)-3-oxopropoxy)methyl)-9,19-dioxo-4,12,16,24-tetraoxa-8,20- diazaheptacosan-14-yl)carbamate (2.5 g, 3.1 mmol) in 1,2-dichloroethane (30 mL) was added 4 A molecular sieves (3 g), (6,7-diacetoxy-2-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]oxazol-5-yl)methyl acetate (0.3M in 1,2-dichloroethane, 30 mL, 9 mmol) and trimethylsilyl trifluoromethanesulfonate (0.2 mL, 1.02 mmol). The mixture was stirred for 16 hours at ambient temperature under nitrogen atmosphere. After this time, the mixture was diluted with saturated aqueous NaHCCL solution and extracted three times with chloroform. The organic layer was dried over MgSCL. filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluting with 0-20% MeOH in DCM, to give the title compound as colorless foam (850 mg, 15%). ES / MS m / z: 903 ([M+2H] / 2).Preparation 24 [5-Acetamido-6-[3-[3-[3-[3-[3-[3-[3-[3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo-propoxy]-2-[[3-[3-[3- [3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxypropoxy]propylamino]-3-oxo-propoxy]methyl]-2-amino- propoxy]propanoylamino]propoxy]propoxy]-3,4-diacetoxy-tetrahydropyran-2-yl]methyl acetate

[0038] [5-Acetamido-6-[3-[3-[3-[3-[3-[3-[3-[3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo-propoxy]-2-[[3-[3-[3- [3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxypropoxy]propylamino]-3-oxo-propoxy]methyl]-2- (benzyloxycarbonylamino)propoxy]propanoylamino]propoxy]propoxy]-3,4-diacetoxy- tetrahydropyran-2-yl]methyl acetate (0.85 g, 0.47 mmol) was combined with palladium on carbon (50% wet) (0.1 g, 0.047 mmol) in MeOH (10 mL). Two drops of glacial acetic acid was added. The mixture was stirred under 1 atmosphere of hydrogen gas. After 2 hours, the mixture was filtered over a small pad of diatomaceous earth and the cake washed with MeOH. The filtrate was concentrated in vacuo to give the title compound as a colorless foam (726 mg, 92%). ES / MS m / z: 836 ([M+2H] / 2).Preparation 25Benzyl 12-[[2-[3-[3-[3-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo-propoxy]-l,l-bis[[3-[3-[3-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo- propoxy]methyl]ethyl]amino]-12-oxo-dodecanoate

[0039] To 12-benzyloxy-12-oxo-dodecanoic acid (0.100 g, 0.312 mmol) in DMF (2 mL) was added HBTU (0.121 g, 0.313 mmol) and D1EA (0.18 mL, 0.982 mmol). The mixture was stirred for 5 minutes then [5-acetamido-6-[3-[3-[3-[3-[3-[3-[3-[3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo-propoxy]-2-[[3-[3-[3- [3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxypropoxy]propylamino]-3-oxo-propoxy]methyl]-2-amino- propoxy]propanoylamino]propoxy]propoxy]-3,4-diacetoxy-tetrahydropyran-2-yl]methyl acetate (0.400 g, 0.239 mmol) in DMF (2 mL) was added. The mixture was stirred at ambient temperature for 2 hours. After this time, the mixture was diluted with water and extracted three times with chloroform. The organic layer was washed successively with saturated aqueous NaHCCL and saturated aqueous NaCl solution, dried over MgSCU, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography, eluting with 0-30% MeOH in DCM, to give the title compound as a colorless foam (176 mg, 37%). ES / MS m / z: 988 ([M+2H] / 2).Preparation 2612-[[2-[3-[3-[3-[3-Acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxypropoxy]propylamino]-3-oxo-propoxy]-l,l-bis[[3-[3-[3-[3-acetamido-4,5-diacetoxy- 6-(acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo-propoxy]methyl]ethyl]amino]- 12-oxo-dodecanoic acid

[0040] Palladium on carbon (50% wet) (0.0200 g, 0.00939 mmol) was added to a solution of benzyl 12-[[2-[3-[3-[3-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxypropoxy]propylamino]-3-oxo-propoxy]-l,l-bis[[3-[3-[3-[3-acetamido-4,5-diacetoxy- 6-(acetoxymethyl)tetrahydropyran-2-ylJoxypropoxyJpropylamino]-3-oxo- propoxy]methyl]ethyl] amino] -12-oxo-dodecanoate (0.176 g, 0.0892 mmol) in MeOH (3 mL). The mixture was stirred under 1 atmosphere of hydrogen gas. After 18 hours, the mixture was filtered through a short pad of diatomaceous earth and the filter cake rinsed with MeOH. The filtrate was concentrated in vacuo to give the title compound as a colorless foam (158 mg, 94%). ES / MS m / z: 943 ([M+2H] / 2).Preparation 27N-(((9H-Fhioren-9-yl)methoxy)carbonyl)-O-(bis(4-methoxyphenyl)(phenyl)methyl)-L-serine

[0041] To a stirring solution of (2S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-hydroxy- propanoic acid (40 g, 0.122 mol) in dry DCM (400 mL) was added DIEA (64 mL, 0.366 mol)at 0 °C under inert atmosphere. To this, a solution of DMTC1 (49.6 g, 0.146 mol) in DCM (200 mL) was added slowly. The resulting mixture was brought to ambient temperature and stirred for 16 hours. After this time, the reaction mixture was diluted with water (12.5 vol) and extracted with DCM (25 vol). The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The crude obtained was washed with 10% EtOAc / hexane (12.5 vol) and dried under vacuum to give the title compound as a pale brown solid (62 g, crude). This material was taken to next step without any further purification. TLC: 5% MeOH / DCM (Rf. 0.5) UV, 254 nM.Preparation 28(9H-Fluoren-9-yl)methyl (S)-(3-(bis(4-methoxyphenyl)(phenyl)methoxy)-l-(4-(hydroxymethyl)piperidin- 1 -yl)- 1 -oxopropan-2-y l)carbamate

[0042] To a stirring solution of N-(((9H-fluoren-9-yl)methoxy)carbonyl)-O-(bis(4- methoxyphenyl)(phenyl)methyl)-L-serine (62 g, 0.103 mol) in DCM (750 mL) was added slowly HBTU (78.3 g, 0.206 mol), HOBt (27.9 g, 0.206 mol), and piperidin-4-yl methanol (15.4 g, 0.134 mol) followed by TMP (15 mL, 0.113 mol) at 0 °C under inert atmosphere. The resulting mixture was brought to ambient temperature and stirred for 4 hours. After this time, the reaction mixture was diluted with water (8 vol) and extracted with DCM (15 vol). The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography, eluting with 20-40% EtOAc / hexane and 1% MeOH / DCM, to give the title compound (40 g, 52% over two steps).*H NMR (DMSO-d6) 57.88 (br d, J = 7.5 Hz, 2H), 7.79 - 7.59 (m, 3H), 7.45 - 7.12 (m, 13H), 6.92 - 6.76 (m, 4H), 4.79 - 4.44 (m, 2H), 4.32 (br d, 7 = 11.4 Hz, 2H), 4.20 (br s, 2H), 3.71 (s, 6H), 3.21 (br s, 4H), 2.99 - 2.79 (m, 1H), 2.69 ( br s, 2H), 1.81 - 1.43 (m, 3H), 1.08 - 0.73 (m, 2H).Preparation 29(S)-2-Amino-3-(bis(4-methoxyphenyl)(phenyl)methoxy)-l-(4-(hydroxymethyl)piperidin-l- yl)propan-l-one

[0043] A solution of 20% piperidine in DMF (400 mL) was added slowly to (9H-fluoren-9- yl)methyl (S)-(3-(bis(4-methoxyphenyl)(phenyl)methoxy)- l-(4-(hydroxymethyl)piperidin- 1- yl)-l-oxopropan-2-yl)carbamate (40 g, 0.055 mol) at 0 °C under inert atmosphere. The resulting reaction mixture was stirred at ambient temperature for 1 hour. After this time, the mixture was diluted with water (15 vol) and extracted with EtOAc (30 vol). The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography, eluting with 1-8% MeOH / DCM, to give the title compound as an off-white solid (13 g, 47%). ES / MS m / z 1009.5 (2M+H).Preparation 30N~1 — { l,27-Bis[(2-Acetamido-3,4,6-tri-o-acetyl-2-deoxyhexopyranosyl)oxy]-14-({3-[(3-{3-[(2-acetamido-3,4,6-tri-o-acetyl-2-deoxyhexopyranosyl)oxy]propoxy}propyl)amino]-3-oxopropoxy }methyl)-9,19-dioxo-4, 12, 16, 24-tetraoxa-8,20-diazaheptacosan-14-yl}-n~ 12 — {(2s)-3-[bis(4-methoxyphenyl)(phenyl)methoxy]-l-[4-(hydroxymethyl)piperidin-l-yl]-l- oxopropan-2-yl} dodecanediamide

[0044] 12-[[2-[3-[3-[3-[3-Acctamido-4,5-diacctoxy-6-(acctoxymcthyl)tctrahydropyran-2- yl]oxypropoxy]propylamino]-3-oxo-propoxy]-l,l-bis[[3-[3-[3-[3-acetamido-4,5-diacetoxy- 6-(acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo- propoxy]methyl]ethyl] amino] -12-oxo-dodecanoic acid (500 mg, 266 pmol) was added to a solution of (Z)-2-(lH-benzo[d][l,2,3]triazol-l-yl)-l,l,3-trimethylisouronium hexafluorophosphate(V) (107 mg, 292 pmol), 1 -hydroxy- IH-benzotriazole (39.5 mg, 292 pmol), and DIEA (228 μL, 1.33 mmol) dissolved in DMF (6 ml). The solution was stirred at ambient temperature for 15 minutes, (S)-2-amino-3-(bis(4-methoxyphenyl)(phenyl)methoxy)- l-(4-(hydroxymethyl)piperidin-l-yl)propan-l-one (147 mg, 292 pmol) was then added, and stirring at ambient temperature was continued for 16 hours. The mixture was diluted with EtOAc and the organic was washed with saturated aqueous NaCl, dried over sodium sulfate, and concentrated in vacuo to give an oil. The oil was purified by silica gel flash chromatography, using 0-20% MeOH / EtOAc (w / 1% triethylamine added), to give the title compound as an off-white foam (418 mg, 66%). ES / MS m / z: 1183.8 ([M-2H] / 2).Preparation 314-((l-((S)-30-(((2S,3S,4S,5S,6S)-3-Acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-17,17-bis((3-((3-(3-(((2S,3S,4S,5S,6S)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)propoxy)propyl)amino)-3- oxopropoxy)methyl)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4,15,22-trioxo- 19,27-dioxa-3,16,23-triazatriacontanoyl)piperidin-4-yl)methoxy)-4-oxobutanoic acid

[0045] Succinic anhydride (118 mg, 1.18 mmol) was added to a solution of N~l~-{ 1,27- bis[(2-acetamido-3,4,6-tri-o-acetyl-2-deoxyhexopyranosyl)oxy]-14-({3-[(3-{3-[(2- acetamido-3,4,6-tri-o-acetyl-2-deoxyhexopyranosyl)oxy]propoxy}propyl)amino]-3- oxopropoxy }methyl)-9, 19-dioxo-4,l 2, 16,24-tetraoxa-8,20-diazaheptacosan- 14-yl }-n~l 2 — { (2s)-3- [bis(4-methoxyphenyl)(phenyl)methoxy ] - 1 - [4-(hydroxy methyl)piperidin- 1 -yl] - 1 - oxopropan-2-yl}dodecanediamide (1.40 g, 591 pmol), 4-dimethylaminopyridine (217 mg, 1.77 mmol), and triethylamine (412 p.L, 2.95 mmol) dissolved in DCM (20 ml). The mixture was stirred at ambient temperature for 16 hours then purified directly by silica gel flash chromatography, eluting with 0-10% MeOH / DCM (w / 1% triethylamine added), to give the title compound as an off-white foam (1.23 g, 84%). ES / MS m / z: 1234.0 ([M-2H] / 2).Preparation 32Resin loading

[0046] In a resin loading cartridge, 4-((l-((S)-30-(((2S,3S,4S,5S,6S)-3-acetamido-4,5- diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-17,17-bis((3-((3-(3- (((2S,3S,4S,5S,6S)-3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2- yl)oxy)propoxy)propyl)amino)-3-oxopropoxy)methyl)-2-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-4, 15,22-trioxo- 19,27-dioxa-3, 16,23- triazatriacontanoyl)piperidin-4-yl)methoxy)-4-oxobutanoic acid (1.23 g, 499 pmol) was added to a solution of 2-(lH-benzo[d][1 ,2,3]triazol-l-yl)-l ,l ,3,3-tetramethylisouronium hexafluorophosphate(V) (391 mg, 1.030 mmol) and DIEA (264 μL, 1.52 mmol) in acetonitrile (50 ml) and the mixture was shaken at ambient temperature for 15 minutes. After this time, native amino LCAA 500 A controlled-pore glass (CPG) resin (3.91 g, 123 pmol / g loading, purchased from ChemGenes) was added and the mixture was shaken at ambient temperature for 16 hours. The cartridge was drained by suction filtration and the CPG was washed by shaking with DCM (50 mL) for 10 minutes. The cartridge was drained and the washing and draining procedure was repeated with 10% MeOH / DCM (50 mL) and EtiO (50 mL). After draining, a solution of CAP A (50 ml) was added to the cartridge and shaken at ambient temperature for 2 hours. The cartridge was then drained and the washing and draining procedure above was repeated using DCM (50 mL), 10% MeOH / DCM (50 mL) and diethyl ether (50 mL). The cartridge was drained one final time, and the resin dried under vacuum for 30 minutes. The resin loading was determined using a standard trityl assay. The resin loading was calculated to be 64.1 pmol / g.Preparation 33(2,5-Dioxopyrrolidin-l-yl) 12-[[2-[3-[3-[3-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo-propoxy]-l,l-bis[[3-[3-[3-[3-acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxypropoxy]propylamino]-3-oxo-propoxy]methyl]ethyl]amino]-12-oxo-dodecanoate

[0047] 12-[[2-[3-[3-[3-[3-Acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxypropoxy]propylamino]-3-oxo-propoxy]-l,l-bis[[3-[3-[3-[3-acetamido-4,5-diacetoxy- 6-(acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo- propoxy]methyl]ethyl] amino] -12-oxo-dodecanoic acid (158 mg, 0.0839 mmol) and N- hydroxysuccinimide (15 mg, 0.128 mmol) were dissolved in DCM (1 mL). EDCI HC1 (25 mg, 0.128 mmol) was added and the resulting mixture stirred at ambient temperature for 6 hours. The mixture was loaded directly on a column and purified by silica gel flash chromatography, eluting with 0-40% MeOH in DCM. The desired fractions were concentrated in vacuo. The residue was dissolved in DCM and filtered through glass wool to remove insoluble particulates. The filtrate was concentrated in vacuo to give the title compound as a colorless foam (114 mg, 69%). ES / MS m / z: 990 ([M+2H] / 2).Preparation 3419-[(2-Acetamido-3,4,6-tri-o-acetyl-2-deoxyhexopyranosyl)oxy]-n-(3-{3-[(2-acetamido- 3,4,6-tri-o-acetyl-2-deoxyhexopyranosyl)oxy]propoxy}propyl)-6-({3-[(3-{3-[(2-acetamido- 3,4,6-tri-o-acetyl-2-deoxyhexopyranosyl)oxy]propoxy}propyl)amino]-3-oxopropoxy }methyl)-6-{ 12-[(2s,4r)-2-{ [bis(4-methoxyphenyl)(phenyl)methoxy]methyl}-4- hydroxypyiTolidin- 1-yl]- 12-oxododecanamido}- ll-oxo-4,8, 16-trioxa-12-azanonadecan-l- amide

[0048] 12-[[2-[3-[3-[3-[3-Acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydropyran-2- yl]oxypropoxy]propylamino]-3-oxo-propoxy]-l,l-bis[[3-[3-[3-[3-acetamido-4,5-diacetoxy- 6-(acetoxymethyl)tetrahydropyran-2-yl]oxypropoxy]propylamino]-3-oxo- propoxy]methyl]ethyl] amino] -12-oxo-dodecanoic acid (500 mg, 266 pmol) was added to a solution of (Z)-2-( lH-benzo[d] [ l,2,3]triazol- 1-yl)- 1 , 1 ,3-trimethylisouronium hexafluorophosphate(V) (1 11 mg, 292 pmol), 1 -hydroxy- 1 H-benzotriazole (39.5 mg, 292 pmol), and diisopropylethylamine (172 mg, 228 μL, 1.33 mmol) dissolved in DMF (6 mL). The solution was stirred at ambient temperature for 15 minutes, (3R,5S)-5-((bis(4- methoxyphenyl) (phenyl)methoxy)methyl)pyrrolidin-3-ol (123 mg, 292 pmol) was then added, and stirring at ambient temperature was continued for 16 hours. The mixture was diluted with EtOAc and the organic was washed with saturated aqueous NaCl, dried over sodium sulfate, and concentrated in vacuo to give an orange foam. The foam was purified by silica gel flash chromatography, using 0-20% MeOH / EtOAc (w / 1% triethylamine added), to give the title compound as tan foam (313 mg, 52%). ES / MS (m / z): 11414 (M-2H / 2).Preparation 354-(((3R,5S)-l-(l-(((2R,3R,4R,5R,6R)-3-Acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-14,14-bis((3-((3-(3-(((2R,3R,4R,5R,6R)-3- acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2- yl)oxy)propoxy)propyl)amino)-3-oxopropoxy)methyl)-9,16-dioxo-4,12-dioxa-8,15- diazaheptacosan-27-oyl)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)pyrrolidin-3- yl)oxy)-4-oxobutanoic acid

[0049] Succinic anhydride (27.4 mg, 274 pmol) was added to a solution of 19-[(2-acetamido- 3,4,6-tri-o-acetyl-2-deoxyhexopyranosyl)oxy]-n-(3-{3-[(2-acetamido-3,4,6-tri-o-acetyl-2- deoxyhexopyranosyl)oxy]propoxy}propyl)-6-({3-[(3-{3-[(2-acetamido-3,4,6-tri-o-acetyl-2- deoxyhexopyranosyl)oxy]propoxy}propyl)amino]-3-oxopropoxy}methyl)-6-{ 12-[(2s,4r)-2- { [bis(4-methoxyphenyl)(phenyl)methoxy]methyl } -4-hydroxypyrrolidin- 1 -yl] - 12- oxododecanamido}-l l-oxo-4,8,16-trioxa-12-azanonadecan-l-amide (313 mg, 137 pmol), 4- dimethylaminopyridine (50.1 mg, 410 pmol), and triethylamine (13.8 mg, 19.1 μL, 137 pmol) dissolved in DCM (5 mL) and the mixture was stirred at ambient temperature for 16 hours. The mixture was purified directly by silica gel flash chromatography, using 0- 10% MeOH / DCM (w / 1% triethylamine added), to give the title compound as an off-white foam (274 mg, 84%). ES / MS (m / z): 1191.2 (M-2H / 2).Preparation 36CPG loading

[0050] In a resin loading cartridge, 2-(lH-benzo[d][l,2,3]triazol-l-yl)-l,l,3,3- tetramethylisouronium hexafluorophosphate(V) (87.3 mg, 230 pmol) and N,N- diisopropylethylamine (44.6 mg, 60.1 μL, 345 pmol) were added to a solution of 4- (((3R,5S)-l-(l-(((2R,3R,4R,5R,6R)-3-acetamido-4,5-diacetoxy-6- (acetoxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-14,14-bis((3-((3-(3-(((2R,3R,4R,5R,6R)-3- acetamido-4,5-diacetoxy-6-(acetoxymethyl)tetrahydro-2H-pyran-2- yl)oxy)propoxy)propyl)amino)-3-oxopropoxy)mcthyl)-9,16-dioxo-4,12-dioxa-8,15- diazaheptacosan-27-oyl)-5-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)pyrrolidin-3- yl)oxy)-4-oxobutanoic acid (274 mg, 115 pmol) dissolved in a mixture of acetonitrile (10 mL) and DMF (1 mL). The mixture was shaken at ambient temperature for 15 minutes. After this time, Native amino LCAA 500A CPG (1.15 g, 123 pmol / g loading, purchased from ChemGenes) was added and the mixture was shaken at ambient temperature for 16 hours. The cartridge was drained by suction filtration and the CPG was washed by shaking with DCM (10 mL) for 10 minutes. The cartridge was drained and the washing and draining procedure was repeated with 10% MeOH / DCM (10 mL) and EtoO (10 mL). After draining, a solution of CAP A (10 mL) was added to the cartridge, and it was shaken at ambient temperature for 2 hours. The cartridge was then drained and the washing and draining procedure above was repeated using DCM (10 mL), 10% MeOH / DCM (10 mL) and diethylether (10 mL). The cartridge was drained one final time, and the CPG was dried under vacuum for 45 minutes. The resin loading was determined using a standard trityl assay. The resin loading was calculated to be 42.9 pmol / g.EXAMPLE 1A:In vitro knockdown of human INHBE in Hep3B cells with GalNAc-conjugated INHBE siRNA by transfection[000117] For Hep3B (ATCC, Part #: HB-8064) cells, transfection was carried out by adding 24.8 μL of Opti-MEM™ (Gibco, Part #: 31985062) plus 0.2 μL of Lipofectamine™ RNAiMAX (Life Technologies, Part #: 13778-150) per well to 25 μL of each INHBE- GalNAc siRNA duplex to an individual well in a 96-well collagen I-coated plate (Coming, Part #: 354649). The mixture was then incubated at room temperature for 20 minutes. Fifty microliters of complete growth media without antibiotic containing Hep3B at 200,000 cells / mL were then added to the INHBE-GalNAc siRNA mixture (the GalNAc of Formula II was employed in this experiment.) For single point screening, 2.5nM of siRNA was used. Dose response experiments were done at 100, 30, 9, 2.7, 0.81, 0.243, 0.073, 0.022, 0.007, 0.002, and 0.0006 nM final siRNA duplex concentration. Cells were incubated for 24-48 hours prior to RNA isolation.[000118] Treated cells were lysed directly into the 96 well cell plate and RNA was isolated using the Quick-RNA 96 Kit (Zymo Research, Part #: R1052). The eluted RNA was used immediately or stored frozen. cDNA was synthesized using Fast Advanced RT Master Mix (Invitrogen, Part #: A39110) and using the following steps in a thermocycler: 37°C for 30 minutes, 95°C for 5 minutes, and 4°C hold. Polymerase Chain Reaction (PCR) was performed via TaqMan™ RT PCR (Life Technologies, Pail #: 4326708) using the following cycles temperatures and times: 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles of 95°C for 15 seconds and 60°C for 1 minute.[000119] The human INHBE levels were normalized to human RPLP0 (Life Technologies) and represented the relative knockdown of human INHBE mRNA expression as compared tovehicle-treated control cells. IC50 values were calculated using a 4-parameter fit model using XLFit®. Results are provided in Table 3A below.Table 3ASingle dose and concentration related curve (CRC) screen for dsRNA agents targeting INHBE in Hep3B cellsEXAMPLE IB:In vitro knockdown of human INHBE in Hep3B cells with INHBE siRNA by transfection[000120] For Hep3B (ATCC, Part #: HB-8064) cells, transfection was carried out by adding 24.7 μL of Opti-MEMTM (Gibco, Part #: 31985062) plus 0.3 μL of LipofcctamincTTW RNAiMAX (Life Technologies, Part #: 13778-150) per well to 25 μL of each INHBE siRNA duplex to an individual well in a 96-well plate (Coming, Pail #: 354649). The mixture was then incubated at room temperature for 20 minutes. Fifty microliters of complete growth media without antibiotic containing Hep3B at 150,000 cells / mL were then added to the INHBE siRNA mixture. For single point screening, InM of siRNA was used. Cells were incubated for 24 hours prior to RNA isolation.[000121] Treated cells were lysed directly into the 96 well cell plate using the Cells-to-CT Fast Advanced Lysis Kit, (Part #: A35377). The eluted RNA was used immediately or stored frozen. cDNA was synthesized using Fast Advanced RT Master Mix (Invitrogen, Part #: A39110) and using the following steps in a thermocycler: 37°C for 30 minutes, 95°C for 5 minutes, and 4°C hold. Polymerase Chain Reaction (PCR) was performed via TaqManTM RT PCR (Life Technologies, Part #: 4326708) using the following cycles temperatures and times: 50°C for 2 minutes, 95 °C for 10 minutes, 40 cycles of 95°C for 15 seconds and 60°C for 1 minute. Results are presented as percent remaining in Table 3B.Table 3BSingle dose INHBE in Hep3B cellsExample 2In vitro knockdown of human INHBE in human iPSC-hepatocytes with GalN Ac-conjugated INHBE siRNA by transfection[000122] For human iPSC-hepatocytes (FUJIFILM Cellular Dynamics, Part #: 01434.1028), transfection was carried out by adding 24.8 μL of Opti-MEM™ (Gibco, Pail #: 31985062) plus 0.2 μL of Eipofectamine™ RNAiMAX (Fife Technologies, Part #: 13778- 150) per well to 25 μL of each INHBE-GalNAc siRNA duplex to an individual well in a 96- well collagen Lcoated plate (Coming, Part #: 354649). The GalNAc of Formula II was employed in this experiment. The mixture was then incubated at room temperature for 20 minutes. Fifty microliters of complete growth media without antibiotic containing human iPSC-hepatocytes at 300,000 cells / mL were then added to the INHBE-GalNAc siRNA mixture. Dose response experiments were done at 100, 30, 9, 2.7, 0.81, 0.243, 0.073, 0.022,0.007, 0.002, and 0.0006 nM final siRNA duplex concentration. Cells were incubated for 24- 48 hours prior to RNA isolation.[000123] Treated cells were lysed directly into the 96 well cell plate and RNA was isolated using the Quick-RNA 96 Kit (Zymo Research, Part #: R1052). The eluted RNA was used immediately or stored frozen. cDNA was synthesized using Fast Advanced RT Master Mix (Invitrogen, Part #: A39110) and using the following steps in a thermocycler: 37°C for 30 minutes, 95°C for 5 minutes, and 4°C hold. Polymerase Chain Reaction (PCR) was performed via TaqMan™ RT PCR (Life Technologies, Pail #: 4326708) using the following cycles temperatures and times: 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles of 95°C for 15 seconds and 60°C for 1 minute.[000124] The human INHBE levels were normalized to human RPLP0 (Life Technologies) and represented the relative knockdown of human INHBE mRNA expression as compared to vehicle-treated control cells. IC50 values were calculated using a 4-parameter fit model using XLFit®. Results are provided in Table 4 below.Table 4CRC screen for dsRNA agents targeting INHBE in human iPSC-hepatocytesExample 3In vitro knockdown of monkey INHBE in cynomolgus monkey primary hepatocytes with GalNAc-conjugated INHBE siRNA by transfection[000125] For cynomolgus monkey primary hepatocytes (BIOIVT, part #: M003055-P; Lot #: WNY), transfection was carried out by adding 24.9 μL of Opti-MEM™ (Gibco, Part #: 31985062) plus 0.1 μL of Lipofectamine™ RNAiMAX (Life Technologies, Part #: 13778- 150) per well to 25 μL of each INHBE-GalNAc siRNA duplex to an individual well in a 96- well collagen I-coated plate (Coming, Part #: 354649). The mixture was then incubated at room temperature for 20 minutes. Fifty microliters of complete growth media without antibiotic containing monkey primary hepatocytes at 1,180,000 cells / mL were then added to the INHBE-GalNAc siRNA mixture. The GalNAc of Formula II was employed in this experiment. Dose response experiments were done at 100, 30, 9, 2.7, 0.81, 0.243, 0.073, 0.022, 0.007, 0.002, and 0.0006 nM final siRNA duplex concentration. Cells were incubated for 24-48 hours prior to RNA isolation.[000126] Treated cells were lysed directly into the 96 well cell plate and RNA was isolated using the Quick-RNA 96 Kit (Zymo Research, Part #: R1052). The eluted RNA was used immediately or stored frozen. cDNA was synthesized using Fast Advanced RT Master Mix (Invitrogen, Pail #: A39110) and using the following steps in a thermocycler: 37°C for 30minutes, 95°C for 5 minutes, and 4°C hold. Polymerase Chain Reaction (PCR) was performed via TaqMan™ RT PCR (Life Technologies, Part #: 4326708) using the following cycles temperatures and times: 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles of 95°C for 15 seconds and 60°C for 1 minute.[000127] The monkey INHBE levels were normalized to monkey RPLP0 (Life Technologies) and represented the relative knockdown of monkey INHBE mRNA expression as compared to vehicle-treated control cells. IC50 values were calculated using a 4-parameter fit model using XLFit®. Results are provided in Table 5 below.Table 5CRC screen for dsRNA agents targeting INHBE in cynomolgus monkey primary hepatocytesExample 4In vitro knockdown of human INHBE in human primary hepatocytes with GalNAc- conjugated INHBE siRNA by transfection[000128] For human primary hepatocytes (IV AT, part #: 82006; Lot #: HH1181), transfection was earned out by adding 24.9 μL of Opti-MEM™ (Gibco, Part #: 31985062) plus 0.1 μL of Lipofectamine™ RNAiMAX (Life Technologies, Part #: 13778-150) per well to 25 μL of each INHBE-GalNAc siRNA duplex to an individual well in a 96-well collagen I-coated plate (Corning, Part #: 354649). The mixture was then incubated at room temperature for 20 minutes. Fifty microliters of complete growth media without antibiotic containing human primary hepatocytes at 572,000 cells / mL were then added to the INHBE- GalNAc siRNA mixture. The GalNAc of Formula II was employed in this experiment. Dose response experiments were done at 100, 30, 9, 2.7, 0.81, 0.243, 0.073, 0.022, 0.007, 0.002, and 0.0006 nM final siRNA duplex concentration. Cells were incubated for 24-48 hours prior to RNA isolation.[000129] Treated cells were lysed directly into the 96 well cell plate and RNA was isolated using the Quick-RNA 96 Kit (Zymo Research, Part #: R1052). The eluted RNA was used immediately or stored frozen. cDNA was synthesized using Fast Advanced RT Master Mix (Invitrogen, Part #: A39110) and using the following steps in a thermocycler: 37°C for 30 minutes, 95°C for 5 minutes, and 4°C hold. Polymerase Chain Reaction (PCR) was performed via TaqMan™ RT PCR (Life Technologies, Part #: 4326708) using the following cycles temperatures and times: 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles of 95°C for 15 seconds and 60°C for 1 minute.[000130] The human INHBE levels were normalized to human RPLPO (Life Technologies) and represented the relative knockdown of human INHBE mRNA expression as compared to vehicle-treated control cells. IC50 values were calculated using a 4-parameter fit model using XLFit®. Results are presented in Table 6 below.Table 6CRC screen for dsRNA agents targeting INHBE in human primary hepatocytesExample 5 Human INHBE siRNA Screen in Humanized INHBE Mice[000131] A cohort of male and female C57Bl / 6N-Inhbetml(hINHBE)Cgen mice (Cyagen, catalog number: C001533, homozygous x homozygous strain maintained at Taconic), aged 9-13 weeks old were used in the following study. These mice express the human INHBE ortholog in place of the mouse gene. Animals were individually housed in a temperature- controlled facility (20-22°C) facility with 12-hour light / dark cycle (lights on at 0600 hours). Animals were maintained on a standard chow diet (LabDiet, ProLab Isopro RMH 30005P75, catalog number: 0006972) and given ad libitum access to diet and water. After 72 hours of acclimation to the facility, mice were randomized into treatment groups according to their body weight, regardless of sex, into 7 groups of 5 mice each (N=35 mice total; average body weight of 24.7 grams).[000132] Vehicle (Gibco, lx PBS, pH7.4, catalog number: 10010023) or Lilly siRNA compounds diluted in vehicle were administered to mice by a single subcutaneous injection at 5 mg / kg concentration (1 mL BD Tuberculin Syringe with Detachable 27 G x 1 / 2 inch needle, 250 uL dose volume). Six days post subcutaneous injection, animals were fasted for approximately 18 hours overnight in clean cage bottoms with diet removed. The next morning, animals were euthanized via CO2 asphyxiation. Liver samples were collected using 4mm biopsy punches (Integra Miltex Biopsy Punch with Plunger System, catalog number: 12-460-410) and placed in MPBio Lysing Tubes (MPBio, Lysing Matrix D, catalog number: 6913500), flash frozen in liquid nitrogen, and stored at -80°C.[000133] To analyze hepatic gene expression, liver tissue was analyzed by RT-qPCR and fold change of human inhibin E gene was calculated (hINHBE; Applied Biosystems TaqMan Gene Expression Assay, Assay ID: Hs00368884_gl).[000134] Constructs tested in the study described in Example 5 are listed in Table 7. Results are provided in Table 8.Table 7: RNAi agent constructs used in Example 5Table 8: Knockdown of INHBE mRNA in liverExample 6In vitro knockdown of monkey INHBE in cynomolgus monkey and human primary hepatocytes with GalNAc-conjugated INHBE siRNA by self-uptake1000135] Plateable cryopreserved cynomolgus monkey primary hepatocytes (CPH) (iVAL, part #: A75245) and human primary hepatocytes (HPH) (Gibco, Part #HMCPTS) were platedon collagen-I 96-well plates (Coming, Part #: 354649) at 60,000 cells per well (CPH) or 40,000 cells per well (HPH).[000136] For the CPH, various concentrations of GalNAc-conjugated INHBE siRNA with chemical modification were added in 10 μL of 10X siRNA duplexes in Opti-MEM per well. Dose response experiments were done at 10,000, 3,000, 900, 270, 81, 24.3, 7.29, 2.19, 0.656, 0.197, and 0.059 nM final siRNA duplex concentration. Cells were incubated for 48 hours prior to RNA isolation.[000137] For the HPH, cells were plated in rich media for three hours before refed with serum-free media with various concentration of LYGal2-conjugated INHBE siRNA with chemical modification were added in 10 μL of 10X siRNA duplexes in Opti-MEM per well. Dose response experiments were done at 3,000, 900, 270, 81, 24.3, 7.29, 2.19, 0.656, 0.197, 0.059, & 0.018 nM final siRNA duplex concentration. Cells were incubated for 48 hours prior to RNA isolation.[000138] RNAi agent constructs used are described in Table 7 above. Treated cells were lysed directly into the 96 well cell plate and RNA was isolated using the Quick-RNA 96 Kit (Zymo Research, Pail #: R1052). The eluted RNA was used immediately or stored frozen. cDNA was synthesized using Fast Advanced RT Master Mix (Invitrogen, Part #: A39110) and using the following steps in a thcrmocyclcr: 37°C for 30 minutes, 95°C for 5 minutes, and 4°C hold. Polymerase Chain Reaction (PCR) was performed via TaqMan RT PCR (Life Technologies, Part #: 4326708) using the following cycles temperatures and times: 50°C for 2 minutes, 95°C for 10 minutes, 40 cycles of 95°C for 15 seconds and 60°C for 1 minute.[000139] The respective monkey or human INHBE levels were normalized to monkey RPLP0 (Life Technologies) and represented the relative knockdown of INHBE mRNA expression as compared to vehicle-treated control cells. IC50 values were calculated using a 4-parameter fit model using XLFit. Results are shown in Table 9. In the table, “nd” denotes “not determined.”Table 9: IC50 for dsRNA agents targeting INHBE in cynomolgus monkey primary hepatocytesWhat is claimed is:1. An INHBE RNAi agent comprising a sense strand and an antisense strand, wherein the sense strand and the antisense strand form a duplex RNA, wherein:(i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 18, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 65;(ii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 2, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 49;(iii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 50;(iv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 4, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 51 ;(v) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 52;(vi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 6, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 53;(vii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 54;(viii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 8, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 55;(ix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 56;(x) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 10, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 57;(xi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58;(xii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 12, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 59;(xiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 60;(xiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 14, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 61;(xv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 62;(xvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 16, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 63;(xvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 64;(xviii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 66;(xix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 20, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 67;(xx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 68;(xxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 22, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 69;(xxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 70;(xxiii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 24, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 71;(xxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 72;(xxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 26, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 73;(xxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 74;(xxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 75;(xxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 76;(xxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 30, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 77;(xxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 78;(xxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 32, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 79;(xxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 80;(xxxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 81;(xxxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 82;(xxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 36, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 83;(xxxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 84;(xxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 38, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 85;(xxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 86;(xxxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 87;(xl)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 88;(xli) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 42, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 89;(xlii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 90;(xliii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 44, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 91;(xliv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 92;(xlv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 46, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 93;(xlvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 94;(xlvii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 48, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 95;(xlviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 191, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 231;(xlix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 192, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 232;(1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 193, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 233;(li) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 194, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 234;(lii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 195, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 235;(liii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 196, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 236;(liv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 197, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 237;(Iv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 198, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 238;(Ivi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 199, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 239;(Ivii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 200, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 240;(Iviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 201, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 241;(lix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 202, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 242;(Ix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 203, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 243;(Ixi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 204, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 244;(Ixii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 205, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 245;(Ixiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 206, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 246;(Ixiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 207, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 247;(Ixv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 208, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 248;(Ixvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 209, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 249;(Ixvii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 210, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 250;(Ixviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 211 , and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 251;(Ixix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 212, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 252;(Ixx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 213, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 253;(Ixxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 214, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 254;(Ixxii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 215, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 255;(Ixxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 216, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 256;(Ixxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 217, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 257;(Ixxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 218, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 258;(Ixxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 219, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 259;(Ixxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 220, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 260;(Ixxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 221, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 261;(Ixxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 222, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 262;(Ixxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 223, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 263;(Ixxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 224, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 264;(Ixxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 225, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 265;(Ixxxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 226, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 266;(Ixxxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 227, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 267;(Ixxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 228, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 268;(Ixxxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 18, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 363;(Ixxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 360, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 364;(Ixxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 2, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 365;(Ixxxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 361, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 366;(xc) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 362, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 367;(xci) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 368;(xcii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 369;(xciii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 4, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 370; or(xciv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 12, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 371. he INHBE RNAi agent of claim 1 , wherein one or more nucleotides of the sense strand and the antisense strand arc independently modified nucleotides. he INHBE RNAi agent of claim 1 or claim 2, wherein at least one internucleotide linkage of the sense strand and the antisense strand are modified internucleotide linkages. he INHBE RNAi agent of any one of claims 1 -3, further comprising a delivery moiety. he INHBE RNAi agent of claim 4, wherein the delivery moiety comprises a GalNAc. he INHBE RNAi agent of claim 5, wherein the delivery moiety comprises:

Claims

1. wherein E is a connection point at which the duplex RNA is conjugated.

7. The INHBE RNAi agent of claim 5, wherein the delivery moiety comprises:wherein E is a connection point at which the duplex RNA is conjugated.

8. The INHBE RNAi agent of claim 6 or claim 7, wherein the delivery moiety is conjugated to the sense strand via a linker.

9. The INHBE RNAi agent of claim 8, wherein the delivery moiety is conjugated to the 3’ terminal nucleotide of the sense strand via a linker.

10. The INHBE RNAi agent of any one of claims 4-9, wherein the linker comprises formula:wherein A and B arc connection points, the delivery moiety is conjugated to the linker at connection point A, and the duplex RNA is conjugated to the linker at connection point B.

11. The INHBE RNAi agent of any one of claims 4-9, wherein the linker comprises formula:wherein X and Y are connection points, the delivery moiety is conjugated to the linker at connection point X, and the duplex RNA is conjugated to the linker at connection point Y.

12. The INHBE RNAi agent of any one of claims 1 to 11, wherein the antisense strand is23 to 50 nucleotides in length.

13. The INHBE RNAi agent of any one of claims 1 to 12, wherein the sense strand is 21 to 50 nucleotides in length.

14. The INHBE RNAi agent of any one of claims 1 to 13, wherein the antisense strand is between 21 and 23 nucleotides in length.

15. The INHBE RNAi agent of any one of claims 1 to 14, wherein the sense strand is 21 nucleotides in length.

16. The INHBE RNAi agent of any one of claims 1 to 15, wherein the antisense strand is 23 nucleotides in length and the sense strand is 21 nucleotides in length.

17. The INHBE RNAi agent of any one of claims 1 to 16, wherein a region of complementarity between the sense strand and the antisense strand is at least 18 nucleotides in length.

18. The INHBE RNAi agent of any one of claims 1-17, wherein the sense strand or the antisense strand each independently comprise one or more modified nucleotides, and the modified nucleotides are each independently selected from 2’ -fluoro modified nucleotides or 2’-O-methyl modified nucleotides.

19. The INHBE RNAi agent of claim 18, wherein each nucleotide of the sense strand and each nucleotide of the antisense strand is a modified nucleotide.

20. The INHBE RNAi agent of claim 18 or claim 19, wherein the antisense strand is 23 nucleotides in length and wherein each nucleotide of the antisense strand is a modified nucleotide, and 2’ -fluoro modified nucleotides are present at a. Positions 2, 3, 7, 14, and 16 from the 5’ end of the antisense strand; or b. Positions 2, 5, 7, 14, and 16 from the 5’ end of the antisense strand; or c. Positions 2, 3, 8, 14, and 16 from the 5’ end of the antisense strand; or d. Positions 2, 5, 8, 14, and 16 from the 5’ end of the antisense strand; or e. Positions 2, 6, 14, and 16 from the 5’ end of the antisense strand; or f. Positions 2, 14, and 16 from the 5’ end of the antisense strand.

21. The INHBE RNAi agent of any one of claims 1 to 20, wherein the sense strand and antisense strand each independently comprise one or more modified intemucleotide linkages, and wherein each modified intemucleotide linkage is a phosphorothioate linkage.

22. The INHBE RNAi agent of claim 21, wherein the sense strand and antisense strand each independently comprise four phosphorothioate linkages.

23. The INHBE RNAi agent of claim 21 or claim 22, wherein the first two intemucleotide linkages and the last two intemucleotide linkages of either or both of the sense strand and the antisense strand arc phosphorothioate linkages.

24. The INHBE RNAi agent of any one of claims 21 to 23, wherein the first two intemucleotide linkages and the last two intemucleotide linkages of the sense strand and the antisense strand are phosphorothioate linkages.

25. The INHBE RNAi agent of any one of claims 1 to 24, wherein the 5’ terminal nucleotide of the antisense strand comprises an OH group, a phosphate group or a phosphate analog.

26. The INHBE RNAi agent of any one of claims 1 to 25, wherein the 5’ terminal nucleotide of the antisense strand comprises a vinyl phosphonate, a phosphate, or a hydroxyl group.

27. The INHBE RNAi agent of any one of claims 1-26, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of:(i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 96, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 143;(ii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 97, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 144;(iii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 98, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 145;(iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 99, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 146;(v) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 100, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 147;(vi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 148;(vii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 102, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 149;(viii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 103, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 150;(ix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 104, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 151;(x) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 105, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 152;(xi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 106, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 153;(xii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 107, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 154;(xiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 108, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 155;(xiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 109, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 156;(xv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 110, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 157;(xvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 111, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 158;(xvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 112, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 159;(xviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 113, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 160;(xix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 114, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 161;(xx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 115, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 162;(xxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 116, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 163;(xxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 117, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 164;(xxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 118, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 165;(xxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 166;(xxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 120, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 167;(xxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 121, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 168;(xxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 122, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 169;(xxviii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 123, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 170;(xxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 124, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 171;(xxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 125, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 172;(xxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 126, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 173;(xxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 127, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 174;(xxxiii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 128, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 175;(xxxiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 129, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 176;(xxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 130, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 177;(xxxvi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 131, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 178;(xxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 132, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 179;(xxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 133, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 180;(xxxix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 134, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 181;(xl) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 135, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 182;(xli) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 136, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 183;(xlii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 137, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 184;(xliii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 138, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 185;(xliv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 139, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 186;(xlv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 140, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 187;(xlvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 141, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 188;(xlvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 142, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 189;(xlviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 270, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 310;(xlix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 271, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 311;(1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 106, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 312;(li) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 272, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 313;(lii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 273, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 314;(liii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 97, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 315;(liv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 274, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 316;(Iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 275, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 317;(Ivi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 276, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 318;(Ivii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 98, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 319;(Iviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 105, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 320;(lix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 277, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 321;(lx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 278, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 322;(Ixi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 279, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 323;(Ixii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 280, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 324;(Ixiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 281, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 325;(Ixiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 326;(Ixv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 282, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 327;(Ixvi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 283, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 328;(Ixvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 284, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 329;(Ixviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 285, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 330;(Ixix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 286, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 331;(Ixx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 287, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 332;(Ixxi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 288, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 333;(Ixxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 334;(Ixxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 289, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 335;(Ixxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 290, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 336;(Ixxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 111, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 337;(Ixxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 291, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 338;(Ixxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 292, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 339;(Ixxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 293, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 340;(Ixxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 294, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 341;(Ixxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 295, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 342;(Ixxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 296, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 343;(Ixxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 297, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 344;(Ixxxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 298, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 345;(Ixxxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 299, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 346;(Ixxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 300, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 347; (Ixxxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 301, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 348;(Ixxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 302, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 349; (Ixxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 303, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 350;(Ixxxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 304, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 351;(xc) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 305, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 352; the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 306, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 353;(xci) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 134, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 354;(xcii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 184, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 355;(xciii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 307, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 356; (xciv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 308, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 357;(xcv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 104, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 358;(xcvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 309, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 359; (xcvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 372, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 377;(xcviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 373, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 378;(xcix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 374, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 379;(c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 375, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 380;(ci) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 376, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 381;(cii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 373, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 382;(ciii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 383, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 384;(civ) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 376, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 385;(cv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 386, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 387;(cvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 388, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 389;(cvii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 376, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 390; and (cviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 391, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 392.

28. An INHBE RNAi agent comprising formula R-L-D, wherein:R is a duplex RNA comprising a sense strand and an antisense strand, wherein:(i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 2, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 49;(ii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 3, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 50;(iii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 4, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 51;(iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 52;(v) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 6, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 53;(vi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 7, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 54;(vii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 8, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 55;(viii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 9, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 56;(ix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 10, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 57;(x) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 11, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 58;(xi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 12, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 59;(xii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 13, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 60;(xiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 14, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 61;(xiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 62;(xv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 16, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 63;(xvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 17, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 64;(xvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 18, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 65;(xviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 19, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 66;(xix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 20, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 67;(xx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 21, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 68;(xxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 22, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 69;(xxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 23, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 70;(xxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 24, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 71;(xxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 25, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 72;(xxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 26, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 73;(xxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 27, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 74;(xxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 28, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 75;(xxviii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 29, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 76;(xxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 30, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 77;(xxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 31, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 78;(xxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 32, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 79;(xxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 33, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 80;(xxxiii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 34, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 81;(xxxiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 35, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 82;(xxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 36, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 83;(xxxvi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 37, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 84;(xxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 38, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 85;(xxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 39, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 86;(xxxix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 40, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 87;(xl) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 41, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 88;(xli) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 42, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 89;(xlii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 43, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 90;(xliii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 44, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 91;(xliv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 45, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 92;(xlv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 46, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 93;(xlvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 47, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 94;(xlvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 48, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 95;(xlviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 190, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 230;(xlix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 191, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 231;(1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 192, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 232;(li) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 193, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 233;(lii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 194, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 234;(liii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 195, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 235;(liv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 196, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 236;(Iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 197, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 237;(Ivi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 198, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 238;(Ivii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 199, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 239;(Iviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 200, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 240;(lix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 201, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 241;(lx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 202, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 242;(Ixi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 203, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 243;(Ixii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 204, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 244;(Ixiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 205, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 245;(Ixiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 206, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 246;(Ixv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 207, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 247;(Ixvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 208, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 248;(Ixvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 209, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 249;(Ixviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 210, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 250;(Ixix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 211, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 251;(Ixx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 212, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 252;(Ixxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 213, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 253;(Ixxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 214, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 254;(Ixxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 215, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 255;(Ixxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 216, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 256;(Ixxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 217, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 257;(Ixxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 218, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 258;(Ixxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 219, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 259;(Ixxviii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 220, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 260;(Ixxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 221, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 261;(Ixxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 222, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 262;(Ixxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 223, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 263;(Ixxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 224, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 264;(Ixxxiii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 225, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 265;(Ixxxiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 226, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 266;(Ixxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 227, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 267;(Ixxxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 228, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 268;(Ixxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 229, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 269;(Ixxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 18, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 363;(Ixxxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 360, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 364;(xc) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 2, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 365;(xci) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 361, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 366;(xcii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 362, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 367;(xciii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 5, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 368;(xciv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 15, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 369;(xcv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 4, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 370; or (xcvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 12, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 371;L is a bond or a linker; and D is a delivery moiety.

29. The INHBE RNAi agent of claim 28, wherein one or more nucleotides of the sense strand and the antisense strand are independently modified nucleotides.

30. The INHBE RNAi agent of claim 28 or claim 29, wherein at least one internucleotide linkage of the sense strand and the antisense strand are modified internucleotide linkages.

31. The INHBE RNAi agent of any one of claims 28-30, wherein the delivery moiety comprises a GalNAc.

32. The INHBE RNAi agent of claim 31, wherein the delivery moiety comprises:wherein E is a connection point at which the duplex RNA is conjugated.

33. The INHBE RNAi agent of claim 31, wherein the delivery moiety comprises: wherein E is a connection point at which the duplex RNA is conjugated.

34. The INHBE RNAi agent of claim 32 or claim 33, wherein the delivery moiety is conjugated to the sense strand via L.

35. The TNHBE RNAi agent of claim 34, wherein the delivery moiety is conjugated to the 3’ terminal nucleotide of the sense strand via L.

36. The INHBE RNAi agent of any one of claims 27-35, wherein the linker comprises formula: wherein A and B are connection points, the delivery moiety is conjugated to the linker at connection point A, and the duplex RNA is conjugated to the linker at connection point B.

37. The INHBE RNAi agent of any one of claims 27-35, wherein the linker comprises formula: wherein X and Y are connection points, the delivery moiety is conjugated to the linker at connection point X, and the duplex RNA is conjugated to the linker at connection point38. The INHBE RNAi agent of any one of claims 27-37, wherein the sense strand or the antisense strand each independently comprise one or more modified nucleotides, and the modified nucleotides are each independently selected from 2’-fluoro modified nucleotides or 2’-O-methyl modified nucleotides.

39. The INHBE RNAi agent of claim 38, wherein each nucleotide of the sense strand and each nucleotide of the antisense strand is a modified nucleotide.

40. The INHBE RNAi agent of claim 38 or claim 39, wherein the antisense strand is23 nucleotides in length and wherein each nucleotide of the antisense strand is a modified nucleotide, and 2 ’-fluoro modified nucleotides are present at a. Positions 2, 3, 7, 14, and 16 from the 5’ end of the antisense strand; or b. Positions 2, 5, 7, 14, and 16 from the 5’ end of the antisense strand; or c. Positions 2, 3, 8, 14, and 16 from the 5’ end of the antisense strand; ord. Positions 2, 5, 8, 14, and 16 from the 5’ end of the antisense strand; or e. Positions 2, 6, 14, and 16 from the 5’ end of the antisense strand; or f. Positions 2, 14, and 16 from the 5’ end of the antisense strand.

41. The INHBE RNAi agent of any one of claims 27 to 40, wherein the sense strand and antisense strand each independently comprise one or more modified intemucleotide linkages, and wherein each modified intemucleotide linkage is a phosphorothioate linkage.

42. The INHBE RNAi agent of claim 41, wherein the sense strand and antisense strand each independently comprise four phosphorothioate linkages.

43. The INHBE RNAi agent of claim 41 or claim 42, wherein the first two intemucleotide linkages and the last two intemucleotide linkages of either or both of the sense strand and the antisense strand are phosphorothioate linkages.

44. The INHBE RNAi agent of any one of claims 41 to 43, wherein the first two intemucleotide linkages and the last two intemucleotide linkages of the sense strand and the antisense strand are phosphorothioate linkages.

45. The INHBE RNAi agent of any one of claims 27 to 44, wherein the 5’ terminal nucleotide of the antisense strand comprises an OH group, a phosphate group or a phosphate analog.

46. The INHBE RNAi agent of any one of claims 27 to 45, wherein the 5’ terminal nucleotide of the antisense strand comprises a vinyl phosphonate, a phosphate, or a hydroxyl group.

47. The INHBE RNAi agent of any one of claims 27 to 46, wherein the sense strand and the antisense strand comprise a pair of nucleic acid sequences selected from the group consisting of:(i) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 96, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 143;(ii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 97, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 144;(iii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 98, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 145;(iv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 99, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 146;(v) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 100, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 147;(vi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 148;(vii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 102, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 149;(viii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 103, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 150;(ix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 104, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 151;(x) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 105, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 152;(xi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 106, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 153;(xii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 107, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 154;(xiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 108, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 155;(xiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 109, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 156;(xv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 110, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 157;(xvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 111, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 158;(xvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 112, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 159;(xviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 113, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 160;(xix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 114, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 161;(xx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 115, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 162;(xxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 116, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 163;(xxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 117, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 164;(xxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 118, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 165;(xxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 166;(xxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 120, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 167;(xxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 121, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 168;(xxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 122, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 169;(xxviii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 123, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 170;(xxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 124, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 171;(xxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 125, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 172;(xxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 126, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 173;(xxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 127, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 174;(xxxiii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 128, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 175;(xxxiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 129, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 176;(xxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 130, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 177;(xxxvi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 131, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 178;(xxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 132, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 179;(xxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 133, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 180;(xxxix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 134, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 181;(xl) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 135, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 182;(xli) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 136, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 183;(xlii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 137, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 184;(xliii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 138, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 185;(xliv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 139, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 186;(xlv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 140, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 187;(xlvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 141, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 188;(xlvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 142, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 189;(xlviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 270, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 310;(xlix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 271, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 311;(1) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 106, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 312;(li) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 272, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 313;(lii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 273, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 314;(liii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 97, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 315;(liv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 274, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 316;(Iv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 275, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 317;(Ivi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 276, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 318;(Ivii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 98, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 319;(Iviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 105, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 320;(lix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 277, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 321;(Ix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 278, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 322;(Ixi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 279, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 323;(Ixii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 280, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 324;(Ixiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 281, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 325;(Ixiv)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 119, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 326;(Ixv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 282, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 327;(Ixvi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 283, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 328;(Ixvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 284, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 329;(Ixviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 285, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 330;(Ixix)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 286, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 331;(Ixx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 287, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 332;(Ixxi)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 288, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 333;(Ixxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 101, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 334;(Ixxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 289, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 335;(Ixxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 290, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 336;(Ixxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 111, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 337;(Ixxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 291, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 338;(Ixxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 292, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 339;(Ixxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 293, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 340;(Ixxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 294, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 341;(Ixxx) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 295, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 342;(Ixxxi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 296, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 343;(Ixxxii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 297, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 344;(Ixxxiii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 298, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 345;(Ixxxiv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 299, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 346;(Ixxxv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 300, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 347;(Ixxxvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 301, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 348;(Ixxxvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 302, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 349;(Ixxxviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 303, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 350;(Ixxxix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 304, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 351;(xc) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 305, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 352; the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 306, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 353;(xci) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 134, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 354;(xcii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 184, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 355;(xciii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 307, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 356;(xciv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 308, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 357;(xcv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 104, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 358;(xcvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 309, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 359;(xcvii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 372, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 377;(xcviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 373, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 378;(xcix) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 374, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 379;(c) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 375, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 380;(ci) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 376, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 381;(cii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 373, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 382;(ciii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 383, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 384;(civ) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 376, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 385;(cv) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 386, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 387;(cvi) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 388, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 389;(cvii)the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 376, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 390; and (cviii) the sense strand comprises a first nucleic acid sequence of SEQ ID NO: 391, and the antisense strand comprises a second nucleic acid sequence of SEQ ID NO: 392.

48. The INHBE RNAi agent of any one of claims 1 to 47, wherein the RNAi agent decreases expression of the INHBE gene in a liver cell, as compared to a control agent.

49. The INHBE RNAi agent of any one of claims 1 to 47, for use in therapy.

50. The INHBE RNAi agent of any one of claims 1 to 47, for use in the treatment of obesity.

51. A pharmaceutical composition comprising the INHBE RNAi agent of any one of claims 1 to 47, and one or more pharmaceutically acceptable excipients.

52. Use of the INHBE RNAi agent of any one of claims 1 to 47, in the manufacture of a medicament for the treatment of obesity.

53. A method of treating obesity in a patient in need thereof, comprising administering the INHBE RNAi agent of any one of claims 1 to 47, or the pharmaceutical composition of claim 51.

54. A method of decreasing INHBE expression in a cell, comprising contacting the cell with the INHBE RNAi agent of any one of claims 1 to 47.

55. The method of claim 53, wherein the method further comprises incubating the cell for a time sufficient for decreasing the level of INHBE mRNA by at least 50% as compared to a cell treated with a control agent or an untreated cell.