Methods of treating hemophilia a

Abstract

This disclosure provides a method for treating hemophilia A in a human individual in need, the method comprising administering a chimeric polypeptide to the individual at dosing intervals, the chimeric polypeptide comprising (i) factor VIII (FVIII) protein, and (ii) a von Willebrand factor (VWF) fragment comprising the D' domain and the D3 domain of VWF.

Description

[Technical Field] Citation of priority claims This application claims the benefit of priority to U.S. Provisional Application No. 62 / 673,670, filed May 18, 2018; U.S. Provisional Application No. 62 / 712,880, filed July 31, 2018; U.S. Provisional Application No. 62 / 773,785, filed November 30, 2018; and U.S. Provisional Application No. 62 / 801,576, filed February 5, 2019, each of which is incorporated herein by reference in its entirety. Reference to the electronically submitted sequence list The contents of the sequence list (name: SA9-461PC_SeqListing; size: 922 kilobytes; creation date: May 14, 2019) submitted electronically as an ASCII text file are incorporated herein by reference in their entirety. This application provides a method for treating hemophilia A in a human individual in need, the method comprising administering a chimeric polypeptide to the individual at dosing intervals, the chimeric polypeptide comprising (i) factor VIII (FVIII) protein, and (ii) a von Willebrand factor (VWF) fragment comprising the D' domain and the D3 domain of VWF. [Previous Technology] Background Technology Hemophilia A is a bleeding disorder caused by a defect in the gene encoding coagulation factor VIII (FVIII), affecting 1-2 out of every 10,000 male births. Graw et al., Nat. Rev. Genet. 6(6): 488-501 (2005). Patients affected by hemophilia A can be treated with infusions of purified or recombinant FVIII. Many commercially available FVIII products are known to have a half-life of approximately 8-12 hours, requiring frequent intravenous administration to patients. See Weiner MA and Cairo MS, Pediatric Hematology Secrets, Lee, MT, 12. Disorders of Coagulation, Elsevier Health Sciences, 2001; Lillicrap, D. Thromb. Res. 122 Supplement 4: S2-8 (2008). In addition, many methods have been explored to prolong the half-life of FVIII. For example, methods under development to prolong the half-life of clotting factors include pegylation, glycopegylation, and conjugation to albumin. See Dumont et al., Blood. 119(13): 3024-3030 (2012). Consistent results have been demonstrated in humans; for example, rFVIIIFc has been reported to improve the half-life by up to ~1.7 times compared to ADVATE® in patients with hemophilia A. See Powell et al., Blood. 119(13): 3031-3037 (2012). Therefore, although the improvement is small, the increase in half-life indicates the presence of other half-life limiting factors. See Liu, T. et al., 2007 ISTH Conference, Abstract #PM-035; Henrik, A. et al., 2011 ISTH Conference, Abstract #P=MO-181; Liu, T. et al., 2011 ISTH Conference Abstract #P-WE-131. The current recommended standard of care involves regular administration of FVIII (routine prophylaxis) to minimize the number of bleeding events. Routine prophylaxis is associated with improved long-term outcomes, but it is a demanding regimen limited by the need for frequent intravenous (IV) administration. See Manco-Johnson et al., N Engl J Med. 357(6): 535-44 (2007). Extended-half-life FVIII products have reduced the frequency of FVIII administration for prophylaxis; however, all of these products interact with von Willebrand factor (VWF) and have comparable circulating half-lives, consistent with the upper limit of the half-life of rFVIII variants due to the half-life of endogenous VWF. See, for example, Pipe et al., Blood. 128(16): 2007-16 (2016). Prophylactic administration of these FVIII products is every 3 to 5 days. Next-generation FVIII products with extended half-life that prevent and control bleeding events for longer periods (leading to less frequent administration) could potentially address the challenges of adhering to demanding prophylactic regimens, thereby improving the quality of life for hemophilia patients. [Summary of the Invention] Certain aspects of this disclosure relate to a method of treating hemophilia A in a human individual in need, the method comprising administering multiple doses of a chimeric polypeptide to the individual at dosing intervals, the chimeric polypeptide comprising (i) factor VIII (FVIII) protein and (ii) a von Willebrand factor (VWF) fragment comprising the D' domain and the D3 domain of VWF, wherein at least one of the multiple doses is from about 15 IU / kg to about 100 IU / kg, and the dosing interval is at least about every 7 days. In some embodiments, the multiple doses include at least two doses, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, at least eleven doses, at least twelve doses, at least thirteen doses, at least fourteen doses, at least fifteen doses, at least sixteen doses, at least seventeen doses, at least eighteen doses, at least nineteen doses, at least twenty doses, or more. In some embodiments, treatment of hemophilia A includes controlling or reducing the incidence or frequency of bleeding events in the individual in need. In some embodiments, treatment of hemophilia A includes preventing or treating bleeding events in the individual in need. In some embodiments, at least one of the multiple doses is about 20 IU / kg to about 95 IU / kg, about 20 IU / kg to about 90 IU / kg, about 20 IU / kg to about 85 IU / kg, about 20 IU / kg to about 80 IU / kg, about 20 IU / kg to about 75 IU / kg, about 20 IU / kg to about 70 IU / kg, about 20 IU / kg to about 65 IU / kg, about 20 IU / kg to about 60 IU / kg, about 20 IU / kg to about 55 IU / kg, about 20 IU / kg to about 50 IU / kg, about 20 IU / kg to about 45 IU / kg, about 20 IU / kg to about 40 IU / kg, about 20 IU / kg to about 35 IU / kg, about 20 IU / kg to about 30 IU / kg, or about 20 IU / kg to about 25 IU / kg. In some embodiments, at least one of the multiple doses is about 20 IU / kg to about 100 IU / kg, about 25 IU / kg to about 100 IU / kg, about 30 IU / kg to about 100 IU / kg, about 35 IU / kg to about 100 IU / kg, about 40 IU / kg to about 100 IU / kg, about 45 IU / kg to about 100 IU / kg, about 50 IU / kg to about 100 IU / kg, Approximately 55 IU / kg to approximately 100 IU / kg, approximately 60 IU / kg to approximately 100 IU / kg, approximately 65 IU / kg to approximately 100 IU / kg, approximately 70 IU / kg to approximately 100 IU / kg, approximately 75 IU / kg to approximately 100 IU / kg, approximately 80 IU / kg to approximately 100 IU / kg, approximately 85 IU / kg to approximately 100 IU / kg, or approximately 90 IU / kg to approximately 100 IU / kg. In some embodiments, at least one of the multiple doses is about 20 IU / kg to about 80 IU / kg, about 25 IU / kg to about 75 IU / kg, about 30 IU / kg to about 70 IU / kg, about 35 IU / kg to about 65 IU / kg, about 40 IU / kg to about 60 IU / kg, or about 45 IU / kg to about 55 IU / kg. In some embodiments, at least one of the multiple doses is about 25 IU / kg to about 65 IU / kg. In some embodiments, at least one of the multiple doses is about 20 IU / kg, about 25 IU / kg, about 30 IU / kg, about 35 IU / kg, about 40 IU / kg, about 45 IU / kg, about 50 IU / kg, about 55 IU / kg, about 60 IU / kg, about 65 IU / kg, about 70 IU / kg, about 75 IU / kg, about 80 IU / kg, about 85 IU / kg, about 90 IU / kg, about 95 IU / kg, or about 100 IU / kg. In some embodiments, at least one of the multiple doses is about 25 IU / kg. In some embodiments, at least one of the multiple doses is about 50 IU / kg. In some embodiments, at least one of the multiple doses is about 65 IU / kg. In some embodiments, at least one of the multiple doses is about 80 IU / kg. In some embodiments, the dosing interval is at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, at least about 12 days, at least about 13 days, at least about 14 days, at least about 15 days, at least about 16 days, at least about 17 days, at least about 18 days, at least about 19 days, at least about 20 days, at least about 21 days, at least about 22 days, at least about 23 days, at least about 24 days, at least about 25 days, at least about 26 days, at least about 27 days, at least about 28 days, at least about 29 days, at least about 30 days, or at least about 31 days. In some embodiments, the dosing frequency is at least once a week, at least once every two weeks, at least once every three weeks, or at least once every four weeks. In some embodiments, the dosing interval is at least once a week. In some embodiments, the dosing interval is at least once every two weeks. In some embodiments, the chimeric polypeptide system is administered as a preventative treatment. In some embodiments, the FVIII protein is associated with the VWF fragment via a covalent bond. In some embodiments, the covalent bond is a peptide bond or a disulfide bond. In some embodiments, the FVIII protein comprises an FVIII polypeptide and a first extended half-life portion. In some embodiments, the first extended half-life portion is fused to the C-terminus or N-terminus of the FVIII polypeptide. In some embodiments, the first extended half-life portion is inserted into the FVIII polypeptide. In some embodiments, the first extended half-life portion is inserted into the B domain of the FVIII polypeptide. In some embodiments, the first extended half-life portion is inserted into the FVIII polypeptide immediately downstream of amino acid residue 745 corresponding to SEQ ID NO: 65. In some embodiments, the first extended half-life portion is fused to the FVIII polypeptide via a linker. In some embodiments, the VWF fragment includes a portion with a second extended half-life. In some embodiments, the portion with the second extended half-life is fused to the C-terminus or N-terminus of the VWF fragment. In some embodiments, the portion with the second extended half-life is inserted within the VWF fragment. In some embodiments, the portion with the second extended half-life is fused to the C-terminus of the VWF fragment. In some embodiments, the portion with the second extended half-life is fused to the VWF fragment via a connector. In some embodiments, the first extended half-life portion, the second extended half-life portion, or both are selected from the group consisting of: albumin, immunoglobulin Fc region, XTEN sequence, C-terminal peptide (CTP) of the β subunit of human chorionic gonadotropin, PAS sequence, HAP sequence, transferrin, albumin-binding moiety, or any fragment, derivative, variant, or combination thereof. In some embodiments, the portion of the first extended half-life includes a first XTEN. In some embodiments, the first XTEN is inserted into the FVIII polypeptide, immediately downstream of the amino acid corresponding to amino acid residue 745 of SEQ ID NO: 65. In some embodiments, the portion of the second extended half-life includes a second XTEN. In some embodiments, the second XTEN is fused to the C-terminus of the VWF fragment. In some embodiments, the FVIII protein comprises a first immunoglobulin (Ig) constant region or a portion thereof. In some embodiments, the first Ig constant region or a portion thereof is fused to the C-terminus or N-terminus of the FVIII polypeptide. In some embodiments, the first Ig constant region or a portion thereof is inserted into the FVIII polypeptide. In some embodiments, the first Ig constant region or a portion thereof is fused to the C-terminus of the FVIII polypeptide. In some embodiments, the first Ig constant region or a portion thereof is fused to the FVIII polypeptide via a linker. In some embodiments, the first Ig constant region or a portion thereof comprises a first Fc domain or a portion thereof. In some embodiments, the VWF segment includes a second Ig constant region or a portion thereof. In some embodiments, the second Ig constant region or a portion thereof is fused to the C-terminus or N-terminus of the VWF segment. In some embodiments, the second Ig constant region or a portion thereof is inserted within the VWF segment. In some embodiments, the second Ig constant region or a portion thereof is fused to the C-terminus of the VWF segment. In some embodiments, the second Ig constant region or a portion thereof is fused to the VWF segment via a connector. In some embodiments, the connector is a slittable connector. In some embodiments, the second Ig constant region or a portion thereof includes a second Fc domain or a portion thereof. In some embodiments, the FVIII protein and the VWF fragment are associated with each other via a covalent bond between the first Fc domain and the second Fc domain. In some embodiments, the FVIII protein and the VWF fragment are further associated with each other via a non-covalent interaction between the FVIII protein and the VWF fragment. In one aspect, this document discloses a method for treating hemophilia A in an individual human being, the method comprising administering multiple doses of a chimeric polypeptide to the individual in need at dosing intervals, wherein the chimeric polypeptide comprises: (i) an FVIII protein comprising a first FVIII polypeptide fragment comprising an amino acid sequence comprising SEQ ID NO: 215; a first XTEN sequence comprising an amino acid sequence comprising SEQ ID NO: 8 (AE288); a second FVIII polypeptide fragment comprising an amino acid sequence comprising SEQ ID NO: 216; and a first Fc region comprising an amino acid sequence comprising SEQ ID NO: 217; and (ii) a VWF protein comprising: a D' domain of VWF comprising an amino acid sequence comprising SEQ ID NO: 210; a D3 domain of VWF comprising an amino acid sequence comprising SEQ ID NO: 214; a second XTEN sequence comprising an amino acid sequence comprising SEQ ID NO: 58 (AE144_5A); and a second Fc region ...iii) a FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII polypeptide fragment comprising: an FVIII The a2 linker of the amino acid sequence NO: 88; and the second Fc region containing the amino acid sequence of SEQ ID NO: 217, wherein the first Fc region is covalently linked to the second Fc region by a disulfide bond. In some embodiments, the chimeric polypeptide comprises an FVIII protein, the FVIII protein comprising an FVIII polypeptide, a first XTEN sequence, a first Fc region, and a VWF protein, the VWF protein comprising a D' domain of VWF, a D3 domain of VWF, a second XTEN sequence, an a2 linker of FVIII, and a second Fc region, wherein the FVIII polypeptide comprises the amino acid sequence of SEQ ID NO: 215, the first XTEN sequence comprises the amino acid sequence of AE288 (SEQ ID NO: 8) and is fused to the C-terminus of SEQ ID NO: 215, the FVIII polypeptide further comprises the amino acid sequence of SEQ ID NO: 216, the first Fc region comprises the amino acid sequence of SEQ ID NO: 217 and is fused to the C-terminus of SEQ ID NO: 216; the D' domain of VWF comprises the amino acid sequence of SEQ ID NO: 210; the D3 domain of VWF comprises the amino acid sequence of SEQ ID NO: 214, and the second XTEN sequence comprises AE144_5A (SEQ ID NO: 8). The first Fc region contains the amino acid sequence of SEQ ID NO: 58 and is fused to the C-terminus of the D3 domain of the VWF; the second Fc region contains the amino acid sequence of SEQ ID NO: 88 and is fused to the C-terminus of the second XTEN sequence; the second Fc region contains the amino acid sequence of SEQ ID NO: 217 and is fused to the C-terminus of the second Fc region; and the first Fc region is connected to the second Fc region by a disulfide bond. In some embodiments, the chimeric polypeptide comprises an FVIII protein containing an FVIII signal peptide, the FVIII signal peptide containing the amino acid sequence of SEQ ID NO: 64. In some embodiments, the chimeric polypeptide comprises a VWF protein containing a VWF signal peptide, the VWF signal peptide containing the amino acid sequence of SEQ ID NO: 208. In some embodiments, the chimeric polypeptide comprises a VWF protein containing the D1D2 domain of VWF, the D1D2 domain containing the amino acid sequence of SEQ ID NO: 209. In some embodiments, the chimeric polypeptide comprises an FVIII protein containing an amino acid sequence that is at least about 80%, 90%, 95%, or 100% identical to that of SEQ ID NO: 201, SEQ ID NO: 203, or SEQ ID NO: 207; and the VWF protein contains an amino acid sequence that is at least about 80%, 90%, 95%, or 100% identical to that of SEQ ID NO: 202 or SEQ ID NO: 205. In one embodiment, the chimeric polypeptide comprises an FVIII protein comprising the amino acid sequence of SEQ ID NO: 203 and a VWF protein comprising the amino acid sequence of SEQ ID NO: 205. In another embodiment, the chimeric polypeptide comprises an FVIII protein comprising the amino acid sequence of SEQ ID NO: 201 and a VWF protein comprising the amino acid sequence of SEQ ID NO: 202. In yet another embodiment, the chimeric polypeptide comprises an FVIII protein comprising the amino acid sequence of SEQ ID NO: 207 and a VWF protein comprising the amino acid sequence of SEQ ID NO: 202. In some embodiments, the chimeric polypeptide comprises an FVIII protein containing an amino acid sequence that is at least about 80%, 90%, 95%, or 100% identical to a sequence selected from the following: FVIII-161 (SEQ ID NO: 69), FVIII-169 (SEQ ID NO: 70), FVIII-170 (SEQ ID NO: 71), FVIII-173 (SEQ ID NO: 72); FVIII-195 (SEQ ID NO: 73); FVIII-196 (SEQ ID NO: 74), FVIII-199 (SEQ ID NO: 75), FVIII-201 (SEQ ID NO: 76); FVIII-203 (SEQ ID NO: 77), FVIII-204 (SEQ ID NO: 78), FVIII-205 (SEQ ID NO: 79), FVIII-266 (SEQ ID NO: 80), FVIII-267 (SEQ ID NO: 78). FVIII-268 (SEQ ID NO: 82), FVIII-269 (SEQ ID NO: 83), FVIII-271 (SEQ ID NO: 84), FVIII-272 (SEQ ID NO: 85), FVIII-312 (SEQ ID NO: 173), or FVIII-312A (SEQ ID NO: 203); and the VWF protein contains at least about 80%, 90%, 95%, or 100% identical amino acid sequences to sequences selected from the following: VWF031 (SEQ ID NO: 86), VWF034 (SEQ ID NO: 87), VWF059 (SEQ ID NO: 197), VWF059A (SEQ ID NO: 202), or VWF036. In some embodiments, the chimeric polypeptide is administered via a route selected from the group consisting of: intravenous injection, intravenous infusion, subcutaneous administration, intramuscular administration, oral administration, nasal administration, and pulmonary administration. In some embodiments, after administration, the chimeric peptide results in an FVIII plasma activity level of at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10%. In some embodiments, the FVIII plasma activity level is at least about 3%. In some embodiments, the FVIII plasma activity level is at least about 5%. In some embodiments, after administration, the chimeric peptide results in FVIII plasma activity levels of at least about 1 IU / dL, at least about 2 IU / dL, at least about 3 IU / dL, at least about 4 IU / dL, at least about 5 IU / dL, at least about 6 IU / dL, at least about 7 IU / dL, at least about 8 IU / dL, at least about 9 IU / dL, or at least about 10 IU / dL. In some embodiments, the FVIII plasma activity level is at least about 3 IU / dL. In some embodiments, the FVIII plasma activity level is at least about 5 IU / dL. In some embodiments, the FVIII plasma activity level is at least about 10 IU / dL at least about 5 days after administration of the chimeric peptide. In some embodiments, the FVIII plasma activity level is at least about 5 IU / dL at least about 7 days after administration of the chimeric peptide. In some embodiments, the FVIII plasma activity level is at least about 3 IU / dL at least about 8 days after administration of the chimeric peptide. In some embodiments, the FVIII plasma activity level is at least about 1 IU / dL at least about 10 days after administration of the chimeric peptide. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 80 IU / kg. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 65 IU / kg. In some embodiments, at least one of the multiple doses is about 65 IU / kg to about 80 IU / kg. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 80 IU / kg, and the dosing interval is at least about 7 days. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 65 IU / kg, and the dosing interval is at least about 5 days. In some embodiments, at least one of the multiple doses is about 65 IU / kg to about 80 IU / kg, and the dosing interval is at least about 5 days. In some embodiments, at least one of the multiple doses is about 50 IU / kg. In some embodiments, the multiple doses are about 50 IU / kg, and the dosing interval is about 5 days. In some embodiments, the multiple doses are about 50 IU / kg, and the dosing interval is about 7 days. In some embodiments, the multiple doses are about 50 IU / kg, and the dosing interval is about 14 days. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 80 IU / kg. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 65 IU / kg. In some embodiments, at least one of the multiple doses is about 65 IU / kg to about 80 IU / kg. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 80 IU / kg, and the dosing interval is at least about 7 days. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 65 IU / kg, and the dosing interval is at least about 7 days. In some embodiments, at least one of the multiple doses is about 65 IU / kg to about 80 IU / kg, and the dosing interval is at least about 7 days. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 80 IU / kg, and the dosing interval is at least about 10 days. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 65 IU / kg, and the dosing interval is at least about 10 days. In some embodiments, at least one of the multiple doses is about 65 IU / kg to about 80 IU / kg, and the dosing interval is at least about 10 days. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 80 IU / kg, and the dosing interval is at least about 14 days. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 65 IU / kg, and the dosing interval is at least about 14 days. In some embodiments, at least one of the multiple doses is about 65 IU / kg to about 80 IU / kg, and the dosing interval is at least about 14 days. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 80 IU / kg, and the dosing interval is at least about 1 week. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 65 IU / kg, and the dosing interval is at least about 1 week. In some embodiments, at least one of the multiple doses is about 65 IU / kg to about 80 IU / kg, and the dosing interval is at least about 1 week. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 80 IU / kg, and the dosing interval is at least about 2 weeks. In some embodiments, at least one of the multiple doses is about 50 IU / kg to about 65 IU / kg, and the dosing interval is at least about 2 weeks. In some embodiments, at least one of the multiple doses is about 65 IU / kg to about 80 IU / kg, and the dosing interval is at least about 2 weeks. In some embodiments, the dosing interval is at least about 5 days. In some embodiments, the dosing interval is at least about 7 days. In some embodiments, the dosing interval is about 5 days to about 14 days. In some embodiments, the dosing interval is about 7 days to about 14 days. In some embodiments, the dosing interval is at least about 10 days. In some embodiments, the dosing interval is about 10 days to about 21 days. In some embodiments, the dosing interval is about 14 days to about 21 days. In some embodiments, the dosing interval is about 14 days. In some embodiments, the individual human being is female. In some embodiments, the individual human being is a child. In some embodiments, the individual human being is a child who is less than or equal to about 12 years old, less than about 11 years old, less than about 10 years old, less than about 9 years old, less than about 8 years old, less than about 7 years old, less than about 6 years old, less than about 5 years old, less than about 4 years old, less than about 3 years old, less than about 2 years old, or less than about 1 year old. In some embodiments, the administration induces immune tolerance to FVIII in the individual human individual. In some embodiments, the administration reduces the suppressive immune response to FVIII in the individual human individual. In some embodiments, the suppressive immune response to FVIII comprises a high-titer anti-FVIII antibody in the individual human individual. In some embodiments, administration of the chimeric peptide does not induce FVIII inhibitory factor approximately 7, 10, 11, 12, 13, 14, 15, 20, 24, 25, 28, 30, or 35 days after administration. In some embodiments, administration of the chimeric peptide does not induce FVIII inhibitory factor approximately 28 days after administration. [Simplified Explanation of the Diagram] Figure 1 is a schematic diagram of rFVIIIFc-VWF-XTEN. FVIII: Factor VIII; VWF: Von Willerich factor; A1, A2, A3, C1, C2: Domains of FVIII; D'D3: Domain of VWF; Fc: Fc region of the immunoglobulin constant region. Figures 2A and 2B show the procedures for testing the safety and efficacy of rFVIIIFc-VWF-XTEN in human patients administered 25 IU / kg rFVIIIFc-VWF-XTEN in a low-dose cohort (Figure 2A) and in human patients administered 65 IU / kg rFVIIIFc-VWF-XTEN in a high-dose cohort (Figure 2B). Figures 3A-3B are illustrations of corrected baseline FVIII activity levels based on activated partial thromboplastin time (aPTT) measurements in individuals with severe hemophilia A. Systems were administered 25 IU / kg rFVIII, followed by a washout period, and then 25 IU / kg rFVIIIFc-VWF-XTEN (Figure 3A; low-dose cohort), or 65 IU / kg rFVIII, followed by a washout period, and then 65 IU / kg rFVIIIFc-VWF-XTEN (Figure 3B; high-dose cohort). Dashed lines indicate 3%, 5%, 10%, and 20% FVIII activity. Figure 4 is a schematic diagram of the clinical study design, which is used to evaluate the safety and tolerability of rFVIIIFc-VWF-XTEN in adult males aged 18-25 years with severe hemophilia A and prior treatment (PTP). rFVIIIFc-VWF-XTEN was administered once weekly at a dose of 50 IU / kg or 65 IU / kg for a total of four doses. EOS = End of Study; ET = Early Termination; PK = Pharmacokinetics.

Implementation Method

Claims

1. Use of a chimeric polypeptide for the preparation of a medicament for the treatment of hemophilia A in human individuals in need, wherein the chimeric polypeptide comprises: (i) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 207; and (ii) a second polypeptide comprising the amino acid sequence of SEQ ID NO: 202, wherein the chimeric polypeptide is administered intravenously in multiple doses of 45 IU / kg to 55 IU / kg at intervals of at least about 7 days, wherein the individual is at least 12 years old, and wherein the first polypeptide is covalently associated with the second polypeptide.

2. The use as described in claim 1, wherein the covalent bond is a disulfide bond.

3. The use as described in claim 1 or 2, wherein each of the multiple doses is 50 IU / kg and the dosing interval is at least 7 days.

4. The use as described in claim 1 or 2, wherein the chimeric polypeptide is administered for prophylactic treatment.

5. The use as described in claim 1 or 2, wherein the individual has severe hemophilia A.

6. The use as described in claim 1 or 2, wherein the individual has previously received any recombinant FVIII, plasma-derived FVIII, or cryoprecipitate for at least 150 exposure days (ED) to treat hemophilia A.

7. The use as described in claim 1 or 2, wherein the individual: (a) has used the prophylactic treatment method of a commercially available FVIII product and has had at least 4 bleeding events within 12 months prior to the administration of the chimeric peptide; or (b) has used the on-demand treatment method of a commercially available FVIII product and has had at least 12 bleeding events within 12 months prior to the administration of the chimeric peptide.

8. The use as described in claim 1 or 2, wherein the individual has a platelet count of at least 100,000 cells / µL.

9. The use as described in claim 1 or 2, wherein the individual does not have any other coagulation disorder other than hemophilia A.

10. The use as described in claim 1 or 2, wherein the individual does not have a history of developing an inhibitor of FVIII products.

11. The use as described in claim 1 or 2, wherein the multiple doses are administered for at least 3 months.

12. The use as described in claim 1 or 2, wherein the multiple doses are administered for at least 6 months.

13. Use of a chimeric polypeptide for the preparation of a medicament for the prophylactic treatment of severe hemophilia A in human individuals in need, wherein the chimeric polypeptide comprises: (i) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 207; and (ii) a second polypeptide comprising the amino acid sequence of SEQ ID NO: 202, wherein the system is at least 12 years old; and wherein the chimeric polypeptide is administered intravenously once weekly at a dose of 50 IU / kg.

14. The use as described in claim 13, wherein the multiple doses are administered for at least 6 months.

15. The use as described in claim 13, wherein the multiple doses are administered for at least 52 weeks.

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