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CN-122005597-A - Methods and compositions for treating hemophilia

CN122005597ACN 122005597 ACN122005597 ACN 122005597ACN-122005597-A

Abstract

The present invention relates to methods and compositions for treating hemophilia, providing novel therapies using double-stranded oligonucleotide compounds as agents for improving quality of life and joint function in hemophilia a and B patients.

Inventors

  • MEI BAISONG
  • S. ANDERSON
  • YU QIFENG
  • P. Dasmahapatra

Assignees

  • 建新公司

Dates

Publication Date
20260512
Application Date
20210622
Priority Date
20200622

Claims (10)

  1. 1. A method for improving joint function in a hemophilia patient comprising subcutaneously administering filaggrin (fitusiran) to a hemophilia patient in need thereof, optionally wherein the patient is a hemophilia a or B patient with or without an inhibitor.
  2. 2. The method according to claim 1, wherein the administration reduces walking difficulty or increases mobility.
  3. 3. A method of ameliorating joint symptoms in a hemophilia patient comprising subcutaneously administering filofilachlor to a hemophilia patient in need thereof, wherein the joint symptoms are selected from joint swelling, motor pain, and joint pain, and optionally wherein the patient is a hemophilia a or B patient with or without an inhibitor.
  4. 4. A method of improving the patient's self-outcome (PRO) in a hemophilia patient, comprising subcutaneously administering filoplumet to a hemophilia patient in need thereof, optionally wherein the patient is a hemophilia a patient of type a or type B with or without an inhibitor, and optionally wherein PRO is improved in one or more quality of life categories.
  5. 5. A method of improving quality of life (QoL) in a hemophilia patient comprising subcutaneously administering filoplumet to a hemophilia patient in need thereof, wherein QoL is improved in one or more QoL categories, and optionally wherein the patient is a hemophilia a or B patient with or without an inhibitor.
  6. 6. The method according to any one of claims 1 to 5, wherein filplaces are administered at 40 to 90 milligrams per dose.
  7. 7. The method according to claim 4 or 5, wherein the one or more QoL categories are categories in a QoL questionnaire, optionally wherein the QoL questionnaire is an adult hemophilia quality of life questionnaire (Haem-a-QoL).
  8. 8. The method according to claim 7, wherein the administration results in a clinically significant improvement as represented by a reduction of 7 or more units (optionally 8 or more, 9 or more, or10 or more units) in one or more of the overall score, the exercise and leisure category score, and the body health category score of the questionnaire.
  9. 9. The method according to any one of claims 1 to 8, wherein the patient is an adult or teenager patient over twelve years of age with or without an inhibitor of haemophilia a or B.
  10. 10. The method according to any one of claims 1 to 9, wherein the patient has haemophilia a.

Description

Methods and compositions for treating hemophilia The application is a divisional application of Chinese patent application with the application date of 2021, 6-month and 22-date, chinese application number of 202180044790.1 and the application name of 'method and composition for treating hemophilia'. Cross Reference to Related Applications The present application claims priority from U.S. patent application Ser. No. 63/042390, filed on 6/22 of 2020, the disclosure of which is incorporated herein by reference in its entirety. Sequence listing The present application comprises a sequence listing in electronically submitted ASCII format and is incorporated herein by reference in its entirety. An ASCII text file was created at 2021, month 6, 21, named 022548.Tw080_sl. Txt and file size 774 bytes. Technical Field The present invention uses double-stranded oligonucleotide compounds as novel therapies for improving quality of life and joint function in patients with hemophilia a and hemophilia B. Background Maintenance of normal hemostasis depends on a set of simultaneous procoagulant and anticoagulant processes in which thrombin plays a central role. Hemophilia a and B are hereditary hemorrhagic diseases characterized by an inability of the body to control blood clotting. Which are caused by the deficiency of factor VIII and factor IX, respectively. Bleeding from haemophilia a and B is caused by insufficient thrombin generation (PEYVANDI ET al., lancet (2016) 388 (10040): 187-97). Without effective treatment, hemophiliacs can experience recurrent bleeding, which can lead to severe disability due to chronic hemorrhagic arthropathy (hemarthropathy) and severe pain, and can be life threatening (Pipe et al, haemophilia (2007) 13 Suppl 4:1-16). Despite advances in treatment, significant unmet needs and administrative challenges remain for all hemophilia populations. While prevention based on factor VIII or factor IX replacement therapy is considered a cornerstone of hemophilia management, it has significant limitations. For example, prevention by injection of factor replacement is cumbersome and impractical, often requiring multiple intravenous infusions per week (Peyvandi, together with the limitation that factor replacement ;Ljung and Andersson, Br J Haematol. (2015) 169(6):777-86;Srivastava et al., Haemophilia (2013) 19(1):e1-47;Bauer, Am J Manag Care (2015) 21(6 Suppl):S112-22;Mannucci and Franchini, Blood Transfus. (2013) 11(Suppl 4):s77-81). is also limited by venous access difficulty and risk of infection (Balkaransingh and Young, Ther Adv Hematol. (2018) 9(2):49-61;Valentino et al., Blood Rev. (2011) 25(1):11-5). to provide factor replacement also results in a significant portion of the world's hemophilia population not first receiving prophylactic treatment (Hemophilia, w.f.o. TREATMENT SAFETY AND supply 2020). Furthermore, treatment with factor replacement products may result in the production of inhibitory alloantibodies (alloantibodies), disabling factor treatment (Morfini et al., haemophilia (2007) 13 (5): 606-12). Those inhibitors (which typically occur during childhood) limit the treatment options and significantly worsen the prognosis of hemophilia. Furthermore, those with persistent inhibitors generally have lower quality of life, more severe joint disease, greater surgical risk, and higher mortality, including bleeding complications associated with hemophilia, when compared to patients without inhibitors (Morfini, supra; oladapo et al., orphanet J Rare dis. (2018) 13 (1): 198). Current therapeutic strategies for individuals with sustained inhibitory factors include immune tolerance induction (immune tolerance induction, ITI) therapies and detour drug (bypassing agents, BPAs) preventative therapies, such as activated procoagulant complex concentrates (ACTIVATED PROTHROMBIN COMPLEX CONCENTRATE, aPCC) and recombinant activated factor VII (rFVIIa)(Benson et al., Eur J Haematol. (2012) 88(5):371-79;Collins et al., Br J Haematol. (2013) 160(2):153-70;Kempton et al., Blood (2014) 124(23):3365-72;Astermark et al., Haemophilia (2007) 13(1):38-45;Eichinger et al., Eur J Clin Invest. (2009) 39(8):707-13). There remains an urgent and unmet need in the development of therapeutic agents and methods of treatment to prevent recurrent bleeding in hemophiliacs and improve overall quality of life. Disclosure of Invention The present invention provides methods and compositions for treating hemophilia patients. In one aspect, the invention provides a method of improving joint function in a hemophilia patient (e.g., a hemophilia a or B patient with or without an inhibitor) in need thereof, comprising administering (e.g., subcutaneously) 40 to 90 milligrams of filoplumet (fitusiran) per dose to the patient. In some embodiments, the treatment reduces walking difficulty or increases mobility. In one aspect, the invention provides a method of ameliorating a joint symptom (e.g., joint swelling, motor pain, and joint pain) in a