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JP-7854774-B2 - Compositions and methods for inhibiting factor XII gene expression

JP7854774B2JP 7854774 B2JP7854774 B2JP 7854774B2JP-7854774-B2

Inventors

  • チェン リー
  • タオ ペイ
  • スティーブン ビー．カナー
  • ルイ チュー
  • ステイシー メルクイスト
  • ローレン ジェイ．アルメイダ

Assignees

  • アローヘッド ファーマシューティカルズ インコーポレイテッド

Dates

Publication Date
20260507
Application Date
20180130
Priority Date
20170130

Claims (4)

  1. An RNAi agent for inhibiting the expression of the factor XII (FXII) gene, The RNAi agent comprises a sense strand and an antisense strand. (i) AD05333 (SEQ ID NOs. 404 and 643) has a double-stranded structure in which the antisense strand is AM07041-AS usUfsusGfuAfcUfuAfuGfcUfcCfuUfgGfsc (SEQ ID NO: 404), and the sense strand is AM07044-SS (NAG37)gsccaaggaGfCfAfuaaguacaaaas(invAb) (SEQ ID NO: 643), which is at least partially complementary to the antisense strand; Or (ii) AD04625 (SEQ ID NOs. 375 and 611) having a double-stranded structure in which the antisense strand is AM05903-AS usUfsusGfuAfcUfuAfuGfcUfcCfuUfgGfsg (SEQ ID NO: 375), and the sense strand is AM05912-SS (NAG37)sscsccaaggaGfCfAfuaaguacaaaas(invAb) (SEQ ID NO: 611), which is at least partially complementary to the antisense strand; It is selected from, Here, unless otherwise indicated in the sequence, when present in an oligonucleotide, monomers are linked to each other by a 5'-3'-phosphodiester bond, where a is 2'-O-methyladenosine -3'-phosphate ; c is 2'-O-methylcytidine -3'-phosphate ; g is 2'-O-methylguanosine -3'-phosphate ; u is 2'-O-methyluridine -3'-phosphate ; Af is 2'-fluoroadenosine -3'-phosphate ; Cf is 2'-fluorocytidine -3'-phosphate ; Gf is 2'-fluoroguanosine -3'-phosphate ; Uf is 2'-fluorouridine -3'-phosphate ; s is a phosphorothioate bond; (invAb) is an inverted debased deoxyribose residue; (NAG37) is It has the structure of; and, (NAG37)s is, It has the structure of; RNAi agent.
  2. A pharmaceutical composition for use in the treatment of a pathological condition (including a state or disease) at least partially mediated by FXII expression, comprising the RNAi agent described in claim 1 and at least one pharmaceutically acceptable excipient, The aforementioned pathological condition is selected from hereditary angioedema (HAE), acquired angioedema (AAE), angioedema associated with ACE inhibitors, allergic angioedema, nonhistamine angioedema (INAE), idiopathic angioedema, thrombosis, venous thromboembolism (VTE), or thrombotic occlusive disease, and is a pharmaceutical composition.
  3. The pharmaceutical composition according to claim 2, further comprising a second therapeutic agent or therapeutic agent.
  4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is packaged in a kit, container, pack, dispenser, pre-filled syringe, or vial.

Description

This application, which cross-references related applications, claims priority to U.S. Provisional Patent Application No. 62/451,868, filed on 30 January 2017, the contents of which are incorporated herein by reference in their entirety. Disclosed herein are RNA interference (RNAi) agents for inhibiting factor XII gene expression, compositions comprising FXII RNAi agents, and methods of using them. Factor XII (also known as FXII, F12, or Hageman factor) is a serine protease primarily expressed in the liver and found in the blood. It has a dual function in both the endogenous coagulation pathway and the kinin-kallikrein system. The kinin-kallikrein system plays a role in inflammation, blood pressure regulation, coagulation, and pain. The active form of factor XII binds to and cleaves both factor XI in the coagulation cascade and prekallikrein in the kinin-kininogen system, producing active FXI and kallikrein, respectively. Patients who completely lose FXII do not exhibit bleeding disorders. Furthermore, mice lacking FXII through gene knockout have been shown to be protected from thrombosis (Renne et al JEM 2005, 202:271-281). Thromboprotective effects of FXII loss have also been observed in FXII-inhibiting antibody-treated mice, rabbits, and primates (Larsson et al. Science Trans Med, 2014 6:22ra17). Current treatments for thromboembolic events target downstream enzymes in the coagulation pathway crucial for controlling blood loss associated with fibrin formation; therefore, treatment with these drugs carries the drawback of potentially life-threatening bleeding. In particular, when factor Xa inhibitors are contraindicated, the administration of current anticoagulants increases the risk of major bleeding events. Hereditary angioedema (HAE) is a rare disease characterized by frequent episodes of severe swelling. The most common body parts affected are the limbs, face, intestines, and airways. Episodes can occur spontaneously or be triggered by physical trauma or stress. Laryngeal (airway) edema can be life-threatening due to the risk of death by suffocation. The primary treatment options for HAE involve administration during attacks, focusing on either C1INH replacement, kallikrein inhibition, or bradykinin 2 receptor-mediated signaling. Currently, the only long-term preventative treatment is C1INH replacement therapy. Previously discovered RNAi agents targeting FXII are, in particular, described in international patent application publication number WO2016/149331A2, which is incorporated herein by reference as if in its entirety. Furthermore, FXII iRNA compositions are disclosed in international patent applications publication numbers WO2016/179342 and WO2017/120397. However, the sequences and modifications of the FXII RNAi agents disclosed herein differ from those previously disclosed or known in the art. The FXII RNAi agents disclosed herein potently and efficiently inhibit the expression of the FXII gene. There is a need for novel FXII RNA interference (RNAi) agents (also referred to herein as RNAi agents, RNAi triggers, or triggers) that can selectively and efficiently inhibit FXII expression. Furthermore, there is a need for novel FXII-specific RNAi agent compositions. Since both thrombosis (including venous thromboembolism, VTE) and angioedema are thought to be caused by hyperactive signaling in their respective pathways, inhibition of FXII gene expression would be particularly useful as a prophylactic treatment for thrombosis and/or angioedema. In general, the disclosure herein features FXII RNA interference (RNAi) agents, compositions comprising FXII RNAi agents, and in vitro and/or in vivo methods for inhibiting the expression of the FXII gene using FXII RNAi agents and compositions comprising FXII RNAi agents. The FXII RNAi agents described herein can be used to treat conditions or diseases resulting from kinin kallikrein hyperactivation or intrinsic coagulation pathways, such as thrombosis and/or HAE. The FXII gene-specific RNAi agents described herein can selectively and efficiently reduce FXII expression. The FXII RNAi agents described herein can be used in methods for the therapeutic treatment (including prophylactic treatment) of diseases and conditions related to angioedema, including but not limited to hereditary angioedema (HAE), acquired angioedema (AAE), ACE inhibitor-associated angioedema, allergic angioedema, nonhistamine angioedema (INAE), idiopathic angioedema, thrombosis, venous thromboembolism (VTE), thromboembolic diseases, and perioperative venous occlusive disease prevention. The use of the FXII RNAi agents described herein provides methods for the treatment and prevention of venous occlusive diseases such as deep vein thrombosis or pulmonary embolism, and for the treatment and prevention of arterial thromboembolic diseases. Such methods include administering the FXII RNAi agents described herein to human or animal subjects by any appropriate means known in the art, such as subcu