Treatment of hemophilia A with phytosis

Abstract

This disclosure provides a method for using fitsiran to treat hemophilia A in patients who have previously received treatment with emicizumab.

Description

TECHNICAL FIELD

[0001] Cross-Reference to Related Applications This application claims priority to U.S. Patent Application No. 63 / 583,228 filed on September 15, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0002] Sequence Listing This application contains a sequence listing submitted electronically in XML format, which is incorporated herein by reference in its entirety. The XML copy created on September 12, 2024 has the file name 122548_WO022_SL.xml and a size of 26,873 bytes. BACKGROUND ART

[0003] Hemophilia A and Hemophilia B are X-linked recessive inherited bleeding disorders characterized by deficiency of coagulation factor VIII (FVIII) or factor IX (FIX), which causes severe defects in thrombin generation, impairs hemostatic function, and increases the risk of bleeding. Hemophilia A is found in approximately 1 in 4,000 males, while Hemophilia B occurs at one-fifth the frequency, affecting approximately 1 in 20,000 males. Hemophilia A and B have similar disease phenotypes.

[0004] Hemophilia is classified as mild (factor level 6% to 30%), moderate (factor level 1% to 5%), or severe (factor level less than 1%) based on coagulation factor activity compared to normal values (healthy non-hemophilic plasma factor levels are 50% to 150%). Patients with mild hemophilia typically experience bleeding after severe injury or surgery. Patients with moderate hemophilia experience trauma-related bleeding episodes and may have spontaneous bleeding episodes. Patients with severe hemophilia experience substantial bleeding from trauma and may have frequent spontaneous bleeding episodes, resulting in debilitating musculoskeletal damage that can significantly impair the patient's mobility and quality of life (QoL).

[0005] The hemostatic system aims to maintain vascular integrity by protecting against bleeding from vascular lesions, in combination with multiple options for preventing thrombosis. This hemostatic balance is achieved through the organized regulation of both procoagulation factors (e.g., factor V (FV), factor VII (FVII), FVIII, FIX, factor X (FX)) and anticoagulation factors (e.g., antithrombin, protein C / protein S, and tissue factor pathway inhibitors). Recent studies suggest that co-inheritance of deficiencies in natural anticoagulants may contribute to the mild phenotype in patients with hemophilia.

[0006] Antithrombin (AT) is a natural anticoagulant expressed in the liver that plays a crucial role in inhibiting thrombin. AT acts as an inhibitor of FVIIa and FXa, factors typically present at normal levels in patients with hemophilia A or B. Extensive preclinical in vitro and in vivo studies have described AT reduction as a potentially safe and effective method for correcting thrombin production and controlling microvascular and macrovascular traumatic bleeding episodes in both hemophilia A and B. Therefore, suppression of AT production is being studied as a potential hemophilia treatment.

[0007] For patients with hemophilia A and a severe bleeding phenotype, prophylactic administration is a recommended standard treatment. While replacement therapy with coagulation factor concentrates has established safety and efficacy, it is burdensome because it requires frequent intravenous administration (more than 2-3 times per week) to maintain hemostasis prophylactically. Prophylactic administration with bypass agents (BPA) is also burdensome as it may involve daily infusions, but it is likely impractical for patients with inhibitors due to cost, increased infusion frequency (e.g., recombinant activated factor VII [rFVIIa]), large infusion volume (aPCC), theoretical risk of thrombosis, and increased breakthrough bleeding due to insufficient improvement of hemostatic failure.

[0008] Emicizumab, a bispecific antibody that mimics the function of FVIIIa, is approved for hemophilia A patients regardless of age or the presence of inhibitors. While emicizumab shows promise in this population, clinical events such as thrombotic microangiopathy and thrombosis have been observed, particularly in combination with aPCC, and risk mitigation strategies are needed.

[0009] Hemophilia patients still need alternative therapies to prevent or reduce the frequency of bleeding episodes while reducing the treatment burden, improving clinical outcomes, and enhancing quality of life. [Overview of the project] [Means for solving the problem]

[0010] This disclosure provides a method for periodic prophylactic administration to prevent or reduce the frequency of bleeding episodes in human patients with hemophilia A receiving prophylactic treatment with emicizumab, comprising subcutaneously administering a first dose of fitsiran to human patients in need approximately 1 to 6 months after the completion of prophylactic treatment with emicizumab, wherein the first dose of fitsiran may be approximately 10 mg or approximately 20 mg, and subsequent doses of fitsiran may be approximately 10 to 80 mg, administered approximately once a month (QM), or once every 4 weeks (Q4W), or once every 1 month (Q2M), or once every 8 weeks (Q8W). The disclosure also provides a method for maintaining adequate thrombinogenesis (AG) capacity in human patients with hemophilia A, with or without inhibitors, who are receiving prophylactic treatment with emicizumab, comprising subcutaneously administering a first dose of fitsiran to human patients in need, approximately 1 to 6 months after the completion of prophylactic treatment with emicizumab, wherein the first dose of fitsiran may be approximately 10 mg or approximately 20 mg, and subsequent doses of fitsiran may be approximately 10 to 80 mg, administered approximately once a month (QM), or once every 4 weeks (Q4W), or once every 1 month (Q2M), or once every 8 weeks (Q8W).

[0011] In some embodiments, the patient is a hemophilia A patient with inhibitors. In some embodiments, the patient is a hemophilia A patient without inhibitors.

[0012] Patients may receive prophylactic treatment with emicizumab at a dose of approximately 1.5 mg / kg to approximately 6 mg / kg, once weekly (QW) to Q4W, or for about QM. In some embodiments, patients received prophylactic treatment with emicizumab at a dose of approximately 1.5 mg / kg for QW, or approximately 3 mg / kg every other week (Q2W). In some embodiments, patients received prophylactic treatment with emicizumab at a dose of approximately 6 mg / kg for about Q4W or QM.

[0013] In some embodiments, prophylactic emicizumab treatment in patients is completed approximately two months before the first dose of fitiran. In some embodiments, prophylactic emicizumab treatment in patients is completed approximately two and a half months before the first dose of fitiran.

[0014] In one embodiment, the patient is an adolescent or adult, and the first and second doses of fitsiran are approximately 20 mg each, administered at intervals of approximately 2 months or 8 weeks. In another embodiment, the patient is a pediatric patient, and the first and second doses of fitsiran are approximately 10 mg each, administered at intervals of approximately 2 months or 8 weeks.

[0015] In some embodiments, the method further includes obtaining a measurement of the antithrombin (AT) level after two doses of fitsiran or in the patient's steady state (SS); and performing one of the following steps: (i) if the AT level is between 15 and 35%, repeat the administration of fitsiran every Q2M or approximately every 8 weeks (Q8W); (ii) if the AT level is greater than 35%, administer approximately 50 mg of fitsiran subcutaneously to the patient at Q2M or Q8W; or (iii) if the AT level is less than 15%, discontinue or suspend fitsiran treatment.

[0016] In some embodiments, the method includes the following steps after step (ii): (a) if the patient has two SS measurements of AT level greater than 35%, administer approximately 50 mg of fitsiran subcutaneously to the patient at QM or approximately Q4W; then (a1) if there have been two instances where the SS measurement of AT level greater than 35%, administer approximately 80 mg of fitsiran subcutaneously to the patient at approximately QM or approximately Q4W; and if there have been two or more instances where the SS measurement of AT level less than 15%, gradually reduce the dosage regimen. Reduce the dose; or (a2) if there are two or more measurements of AT level less than 15%, gradually reduce to the administration regimen in (ii); (b) if there are two or more measurements of AT level less than 15%, administer approximately 20 mg of fitsiran subcutaneously to the patient, and then (b1) if the measured AT level is 22% or higher, repeat the administration of approximately 20 mg QM of fitsiran; or (b2) if there are two or more measurements of AT level less than 15%, discontinue fitsiran treatment.

[0017] In some embodiments, the method further comprises administering an effective dose of replacement factor VIII or bypass agent (BPA) to the patient to treat a bleeding episode occurring within 7 days after the initial administration of fitsilan, wherein the effective dose of replacement factor or BPA is administered according to the patient's previous administration regimen of replacement factor or BPA.

[0018] The method may also include administering an effective dose of supplemental factor VIII or bypass agent (BPA) to the patient to treat bleeding episodes occurring more than 8 days after the initial administration of fitisran, where the effective dose of supplemental factor or BPA is reduced compared to the recommended effective dose of supplemental factor or BPA for patients not receiving fitisran therapy. In some embodiments, the patient is a patient without a factor VIII inhibitor, the supplemental factor is factor VIII, the single dose of factor VIII is 20 IU / kg or less, optionally 10 IU / kg, and the administration of factor VIII may be repeated as needed after 24 hours or more. In another embodiment, the patient is a patient with a factor VIII inhibitor, the BPA is activated prothrombin complex concentrate (aPCC), the single dose of aPCC is 50 U / kg or less, optionally 30 U / kg, and the administration of aPCC may be repeated as needed after 24 hours or more. In some embodiments, aPCC is administered at least 6 months after the last dose of emicizumab or at least 4 months after the first dose of fitsiran to treat a bleeding episode. In some embodiments, the patient is a patient with factor VIII inhibitor, BPA is recombinant factor VIIa (rFVIIa), the single dose of rFVIIa is 45 μg / kg or less, and rFVIIa administration may be repeated at least 2 hours apart if necessary.

[0019] In another aspect, the Disclosure provides a phytotherane for use in the method of the Disclosure. The Disclosure also provides the use of phytotherane in the manufacture of a pharmaceutical product for use in the method of the Disclosure.

[0020] In one embodiment, the present disclosure provides a fitiran for use in periodic prophylactic administration to prevent or reduce the frequency of bleeding episodes, characterized in that a human patient with hemophilia A is receiving prophylactic treatment with emicizumab, and a first dose of fitiran is administered subcutaneously to a human patient who needs it within 1 to 6 months after the completion of prophylactic treatment with emicizumab, wherein the first dose of fitiran may be 10 or 20 mg, and subsequent doses of fitiran are 10 to 80 mg once a month (QM), once every four weeks (Q4W), once every two months (Q2M), or once every eight weeks (Q8W).

[0021] In another aspect, the Disclosure provides fitisran for use in the treatment of hemophilia A, characterized in that the treatment includes periodic prophylactic administration to prevent or reduce the frequency of bleeding episodes, the human patient having hemophilia A is receiving prophylactic treatment with emicizumab, and the first dose of fitisran is administered subcutaneously to the human patient in need within 1 to 6 months after the completion of prophylactic treatment with emicizumab, wherein the first dose of fitisran may be 10 or 20 mg, and subsequent doses of fitisran are 10 to 80 mg once a month (QM) or once every four weeks (Q4W), or once every two months (Q2M) or once every eight weeks (Q8W).

[0022] In another aspect, the disclosure provides a fitiran for use in the treatment of hemophilia A with or without inhibitors, characterized in that the treatment includes maintaining adequate thrombinogenesis (AG) ability, the human patient having hemophilia A is receiving prophylactic treatment with emicizumab, and a first dose of fitiran is administered subcutaneously to the human patient in need within 1 to 6 months after the completion of prophylactic treatment with emicizumab, wherein the first dose of fitiran may be 10 or 20 mg, and subsequent doses of fitiran are 10 to 80 mg once a month (QM) or once every four weeks (Q4W), or once every two months (Q2M) or once every eight weeks (Q8W).

[0023] Other features, objects, and advantages of the present invention will be apparent from the following detailed description. However, it should be understood that this detailed description, while indicating embodiments and aspects of the present invention, is given by way of illustration only and not by way of limitation. From this detailed description, various changes and modifications within the scope of the present invention will become apparent to those skilled in the art. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] [Figure 1] Shows the developed structural formula, chemical formula, and molecular weight of fitusiran sodium. [Figure 1-1] Same as above. [Figure 2] Shows the administration regimen of fitusiran. SS: Steady state. [Figure 3] This is a flowchart showing the dose escalation / de-escalation scheme of fitusiran for pediatric patients weighing from 22 kg to less than 45 kg. Participants start fitusiran at a dose of 10 mg every 4 weeks. AT: Antithrombin activity; QM = once monthly; SS = Steady state. *: Within a 12-month period; **: Dosing initiation after de-escalation from a higher dose is performed only after the centrally measured AT activity level is ≧22%. [Figure 4] This is a flowchart showing the dose escalation / de-escalation scheme of fitusiran for pediatric patients weighing from 8 kg to less than 22 kg. Participants start fitusiran at a dose of 5 mg every 4 weeks. Abbreviations and symbols are the same as those described for Figure 3 above. [Figure 5] Shows the clinical trial design for patients who received prophylactic treatment with emicizumab prior to the initiation of fitusiran therapy. AT: Antithrombin; D: Day; EOT: End of treatment; M: Month; QM: Monthly; Q2W: Every 2 weeks; QW: Weekly. [Figure 6] This is a series of line graphs showing the predicted proportion of FVIII-like activity in patients after emicizumab discontinuation (Panel A) and after initiation of fitusiran administration (Panel B). Additional emicizumab FVIII-like activity and fitusiran FVIII-like activity are shown in (Panel C). [Modes for carrying out the invention]

[0025] This disclosure provides a method for transitioning patients with hemophilia A from emicizumab prophylactic treatment to fitsiran prophylactic treatment, with or without the presence of inhibitors.

[0026] Emicizumab is a bispecific antibody that mimics activated factor VIII. In the United States, it is approved as routine prophylactic administration to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) from the neonatal stage onward, regardless of the presence or absence of factor VIII inhibitors. Difficulties associated with emicizumab treatment have been reported. Thrombotic microangiopathy and thrombosis have been observed in some patients, particularly those treated with emicizumab in combination with the bypass agent (BPA) activated prothrombin complex concentrate (aPCC), necessitating risk mitigation measures, and a black-bordered warning has been added to the prescribing information in the United States. There is also a risk that emicizumab may induce the development of neutralizing anti-drug antibodies. Furthermore, when emicizumab is administered every other week or once a month, the large volume of injections necessitates multiple injections, potentially increasing pain at the injection site (see, for example, Kruis et al., Haemophilia (2023) 29(2):689-91). Additionally, it has been reported that approximately 30-40% of patients treated with emicizumab continue to experience spontaneous bleeding episodes (see, for example, Callaghan et al., Blood. (2001) 137(16):2231-42).

[0027] Emicizumab is known to interfere with blood coagulation-based assays, and this effect persists for up to six months after the last dose of emicizumab, complicating the analysis of hemophilia patients attempting to transition to standard care (see, e.g., Pasi et al., N Engl J Med. (2017) 377(9):819-28). This six-month period is used as a wait period to switch to other hemostatic therapies if emicizumab becomes ineffective, but the risk of spontaneous bleeding episodes increases as emicizumab concentrations decrease. Currently, there is no data to explain how patients can switch from emicizumab to other non-factorial therapy options earlier than the six-month washout period after the last dose of emicizumab. Without guidance on how to safely switch from emicizumab to other therapies earlier than six months, clinical practice is limited and may be delayed in switching to what appears to be optimal prophylactic care.

[0028] This disclosure provides a method for switching patients from emicizumab prophylactic treatment to fitsiran prophylactic treatment without waiting for a 6-month washout period. Fitsiran is an N-acetyl-galactosamine (GalNAc) small molecular weight interfering ribonucleic acid (siRNA) conjugate that reduces antithrombin (AT) production and lowers plasma AT activity levels. By reducing plasma AT, fitsiran is designed to improve thrombin production and hemostasis in individuals with hemophilia, regardless of the type of hemophilia or the presence of inhibitor antibodies against FVIII or FIX. Fitsiran may be administered less frequently than emicizumab.

[0029] This method allows for the introduction of fitsiran prophylactic therapy in hemophilia A patients earlier than the 6-month waiting period after the last dose of emicizumab, enabling patients who are not effectively treated with emicizumab to switch treatments sooner without having to rely on more burdensome factors or BPA therapy for extended periods. The method of the present invention can maintain a good balance between benefits and risks for such patients. In some embodiments, the patient is an adult patient aged 18 years or older. In some embodiments, the patient is a young adult patient aged 12 to under 18 years. In some embodiments, the patient is a pediatric patient under 12 years of age (e.g., a patient aged 1 to under 12 years).

[0030] I. Physylane Pharmaceutical Composition Hemophilia results in a severe deficiency in thrombin production, and furthermore, the severity of hemophilia correlates with the inability to produce thrombin. Although not constrained by theory, a decrease in fitsiran-mediated antithrombin (AT) levels is thought to improve hemostasis in hemophilia patients by increasing thrombin production. Antithrombin is encoded by the SERPINC1 gene.

[0031] Phytsilane (whose structure is described herein) is a synthetically modified double-stranded small interfering RNA (siRNA) oligonucleotide that covalently binds to a tri-antennary N-acetyl-galactosamine (GalNAc) ligand targeting AT3 mRNA in the liver, thereby inhibiting antithrombin synthesis. The nucleosides in each chain of phytsilane are linked by either 3'-5' phosphodiester or phosphorothioate bonds to form the oligonucleotide's sugar-phosphate backbone.

[0032] The sense and antisense strands of phytsilane contain 21 and 23 nucleotides, respectively. The 3' end of the sense strand is conjugated to the GalNAc-containing moiety (also known as L96) via a phosphodiester bond. The sense strand contains two consecutive phosphorothioate bonds at its 5' end. The antisense strand contains four phosphorothioate bonds, two at its 3' end and two at its 5' end. The 21 nucleotides of the sense strand hybridize with the complementary 21 nucleotides of the antisense strand to form 21 nucleotide base pairs and a 2-base overhang at the 3' end of the antisense strand. See also U.S. Patent No. 9,127,274, U.S. Patent No. 11,091,759, and International Publication No. 2019 / 014187.

[0033] The two nucleotide strands of phytsilane are shown below: Sense chain: 5'Gf-ps-Gm-ps-Uf-Um-Af-Am-Cf-Am-Cf-Cf-Af-Um-Uf-Um-Af-Cm-Uf-Um-Cf-Am-Af-L96 3'(SEQ ID NO: 1), and Antisense chain: 5'Um-ps-Uf-ps-Gm-Af-Am-Gf-Um-Af-Am-Af-Um-Gm-Gm-Uf-Gm-Uf-Um-Af-Am-Cf-Cm-ps-Am-ps-Gm 3'(Sequence ID 2), During the ceremony, Af = 2'-fluoroadenosine (i.e., 2'-deoxy-2'-fluoroadenosine) Cf = 2'-fluorocytidine (i.e., 2'-deoxy-2'-fluorocytidine) Gf = 2'-fluoroguanosine (i.e., 2'-deoxy-2'-fluoroguanosine) Uf = 2'-fluorouridine (i.e., 2'-deoxy-2'-fluorouridine) Am=2'-O-methyladenosine Cm=2'-O-methylcytidine Gm = 2'-O-methylguanosine Um=2'-O-methyluridine "-" (hyphen) = 3'-5' phosphodiester bonded sodium salt "-ps-" = 3'-5' phosphorothioate bonded sodium salt, And L96 is given by the following formula: [ka] It has.

[0034] Figure 1 shows the expanded structural formula, molecular formula, and molecular weight of phytsilane (sodium form). As used herein, the term 2'-fluoroadenosine is synonymous with 2'-deoxy-2'-fluoroadenosine, the term 2'-fluorocytidine is synonymous with 2'-deoxy-2'-fluorocytidine, the term 2'-fluoroguanosine is synonymous with 2'-deoxy-2'-fluoroguanosine, and the term 2'-fluorouridine is synonymous with 2'-deoxy-2'-fluorouridine.

[0035] The structure of physsilane is shown in the following diagram: [ka] It can also be explained using (where X is O).

[0036] For use in this therapeutic method, fitsilane may be provided in a pharmaceutical composition comprising fitsilane and a pharmaceutically acceptable excipient. In certain embodiments, fitsilane is in the form of a sodium salt.

[0037] In some embodiments, phytsilane is provided in aqueous solution at concentrations of about 1 to about 200 mg / mL (e.g., about 50 to about 150 mg / mL, about 80 to about 110 mg / mL, or about 90 to about 110 mg / mL). Intermediate values ​​of the ranges and values ​​described herein are also intended to be part of this disclosure. In addition, ranges of values ​​are intended to be used with any combination of the described values ​​as upper and / or lower limits. In further embodiments, the pharmaceutical composition comprises phytsilane at concentrations of about 6.25, about 12.5, about 25, about 50, about 75, about 100, about 125, about 150, or about 200 mg / mL.

[0038] Unless otherwise specified, even if fitsiran is administered to the patient subcutaneously in its sodium form (in aqueous solution), the fitsiran weights listed in this disclosure refer to the weight of fitsiran free acid (active portion). For example, 100 mg / mL of fitsiran means 100 mg of fitsiran free acid per 1 mL (equivalent to 106 mg of fitsiran sodium active pharmaceutical ingredient).

[0039] In some embodiments, the pharmaceutical composition comprises phytosis in phosphate-buffered saline. The phosphate concentration in the solution may be about 1 to 10 mM (e.g., 2, 3, 4, 5, 6, 7, 8, or 9 mM) at a pH of 6.0 to 8.0. The pharmaceutical compositions herein may contain preservatives such as EDTA. Otherwise, the pharmaceutical compositions do not contain preservatives. In certain embodiments, the phytosis pharmaceutical composition is preservative-free and comprises, or essentially comprises, about 100 mg of phytosis per 1 mL of 5 mM phosphate-buffered saline (PBS) solution. The PBS solution consists of sodium chloride, dibasic sodium phosphate (heptahydrate), and monobasic sodium phosphate (monohydrate). The pH of this composition can be adjusted to 7.0 using a sodium hydroxide solution and dilute phosphoric acid.

[0040] The pharmaceutical composition may be provided in a container (e.g., a vial or syringe). The container may contain a single or multiple dose. In some embodiments, the container is a disposable container (e.g., a disposable ampoule or disposable syringe, e.g., a disposable pre-filled syringe), and each container contains about 10 to about 100 mg of fitsilane (e.g., about 10 mg, about 20 mg, about 25 mg, about 40 mg, about 50 mg, or about 80 mg). The fitsilane is provided in solid form in the container and may be reconstituted in an aqueous solution (e.g., PBS) before use, and the reconstituted solution contains about 1 to about 150 mg / mL (e.g., about 100 mg / mL) of fitsilane. In some embodiments, the fitsilane is provided in sodium salt form in a disposable glass vial or a disposable pre-filled syringe (e.g., one with a safety system). In further embodiments, each vial or syringe contains approximately 80 mg of fitsiran in approximately 0.8 mL of 5 mM phosphate-buffered saline (pH 7.0) (or approximately 50 mg of fitsiran in approximately 0.5 mL, approximately 20 mg of fitsiran in approximately 0.2 mL, or approximately 10 mg of fitsiran in approximately 0.1 mL), and this solution is administered to the patient by subcutaneous injection. The solution can be stored at 2 to 30°C (e.g., 2 to 8°C).

[0041] In certain embodiments, the fitsiran composition for subcutaneous injection comprises fitsiran in 5 mM phosphate-buffered saline at pH 7.0 containing 0.64 mM NaH2PO4, 4.36 mM Na2HPO4, and 84 mM NaCl. In a particular embodiment, the composition of the fitsiran solution for subcutaneous injection is shown in Table 1.

[0042] [Table 1]

[0043] In some embodiments, phytosis is packaged in a pre-filled pen containing 50 mg of phytosis (equivalent to 53 mg of phytosis sodium). In some embodiments, each single-use pre-filled pen contains 50 mg of phytosis in a 0.5 mL solution at a concentration of 100 mg / mL. In some embodiments, each pre-filled pen is designed to deliver 50 mg of phytosis in 0.5 mL, and this pen also contains sodium chloride (2.455 mg), disodium phosphate (0.585 mg), monosodium phosphate (0.044 mg), phosphoric acid (appropriate amount pH 7.0), sodium hydroxide (appropriate amount pH 7.0), and water for injection (appropriate amount 0.5 mL). Phytosis is supplied as a sterile clear solution for subcutaneous injection of 50 mg PFP. In some embodiments, the PFP includes a pre-filled syringe (PFS) containing a single dose of phytosis combined with an automated injection system (pen). The PFS is a 1 mL colorless, type 1 glass syringe with a one-piece 29 gauge (1 / 2 inch) stainless steel needle covered with a rigid needle shield. The syringe is closed with a rubber-coated (bromobutyl gray) plunger stopper.

[0044] In some embodiments, the phytosis is packaged in a vial containing 20 mg of phytosis (equivalent to 21 mg of phytosis sodium). In these embodiments, each single-use vial contains 20 mg of phytosis in a 0.2 mL solution at a concentration of 100 mg / mL. In some embodiments, each vial contains 20 mg of phytosis in 0.2 mL and also contains: sodium chloride (0.982 mg), disodium phosphate (0.234 mg), monosodium phosphate (0.018 mg), phosphoric acid (appropriate amount pH 7), sodium hydroxide (appropriate amount pH 7.0), and water for injection (appropriate amount 0.2 mL). The phytosis may be supplied as a sterile, clear solution for subcutaneous injection in a vial. The vial contains a single dose of phytosis in a 2 mL colorless type 1 glass vial with a bromobutyl rubber stopper and an aluminum polypropylene colored crimp cap.

[0045] In a particular embodiment, the composition of the phyturapine solution for subcutaneous injection is shown in Table 1B below.

[0046] [Table 2]

[0047] In this specification, the weight of the plantar silane dose refers to the weight of plantar silane free acid (active portion), but in this specification, the administration of plantar silane to a patient refers to the administration of plantar silane sodium (API) provided in a pharmaceutically appropriate aqueous solution (e.g., phosphate-buffered saline at physiological pH).

[0048] II. Therapeutic Use of Physirane Fitusiran can suppress hepatic production of antithrombin (AT). In its role as an anticoagulant, AT modulates hemostasis by directly targeting thrombin production or by inactivating FXa (which does not form a complex with AT, thus reducing thrombin production) (Quinsey et al., Int J Biochem Cell Biol. (2004) 36(3):386-9). Fitusiran may be used to treat individuals with impaired hemostasis. For example, fitusiran may be used to treat patients with hemophilia A, with or without inhibitors, for routine prophylactic administration to prevent or reduce the frequency of bleeding episodes. In certain embodiments, fitusiran is used to treat adult and adolescent patients (at least 12 years of age) with hemophilia A (congenital factor VIII deficiency), with or without inhibitors. The method involves administering a therapeutically effective amount of fitusiran to a hemophilia patient (e.g., a hemophilia A patient) in need of such treatment. "A therapeutically effective dose" refers to the amount of fitsiran that helps the patient achieve the desired clinical outcome.

[0049] In certain embodiments, the pharmaceutical composition is administered by subcutaneous injection at dose strengths of approximately 10 to 100 mg per dose (e.g., approximately 10 to 95 mg, approximately 40 to 90 mg, approximately 50 to 100 mg, approximately 50 to 90 mg, approximately 50 to 85 mg, or approximately 50 to 80 mg). In certain embodiments, phytsilan is administered subcutaneously in the PBS solution described above at a dose of approximately 10, approximately 20, approximately 50, or approximately 80 mg (weight of the active portion) per dose.

[0050] Multiple doses of fitsiran can be administered to a patient at intervals of approximately 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks, or approximately 1 month, 2 months, or 3 months. In certain embodiments, a fixed dose of fitsiran (e.g., approximately 50 or 80 mg subcutaneously) is administered to a hemophilia patient (e.g., a hemophilia A or hemophilia B patient aged 12 years or older with or without inhibitors).

[0051] In some embodiments, the method includes measuring AT levels in patients. AT measurement can be performed by well-established methods, including both kinetic and chromogenic assays. One commonly used method is the INNOVANCE® antithrombin assay (Siemens Healthineers, Malvern, PA; USFDA 510(k)#K081769). INNOVANCE® is a chromogenic assay that quantifies functionally active AT in human citrated plasma based on the inhibition of excess factor Xa by AT. The assay can be performed using an automated coagulation system (e.g., Siemens BCS® XP, Sysmex® CA-600 and CS Systems, or Atellica® COAG 360 System) and can be calibrated using Siemens standard human plasma (SHP) to a defined value of AT activity calibrated against World Health Organization (WHO) reference plasma. An equivalent assay is the Dade Behring Berichrom® Antithrombin III assay (Dade Behring Marburg GmbH, Marburg, Germany; USFDA 510(k)#K933125). Each measurement can be controlled by two independent controls (low and normal values) calibrated against WHO standards. AT activity (%) in plasma samples is calculated relative to WHO reference plasma. 100% AT level is defined as 1 unit of antithrombin activity in 1 mL of reference plasma sample. The detection limit of the INNOVANCE® assay is 6.0%, based on the assay's USFDA 510(k) determination summary. AT levels range from approximately 80% to 120% in the general population.

[0052] The risk of arterial thrombotic events among patients receiving fitiran has been observed to increase when AT levels are less than 10%. To reduce the risk of vascular thrombotic events while maintaining a favorable benefit-risk balance for patients receiving fitiran, fitiran therapy can be initiated in patients receiving prophylactic treatment with emicizumab, such as adult patients (18 years and older) or adolescent patients (12-17 years) receiving prophylactic treatment with emicizumab, by subcutaneous injection of approximately 20 mg of fitiran every two months (or every eight weeks). The patient's AT level may be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). If a patient has two AT measurements of less than 15% (e.g., less than 10%), the patient will discontinue fitiran treatment. In some embodiments, when the first AT level is less than 15%, the patient is given another sample of AT activity level within about one month (e.g., within about one or two weeks). If this result is less than 15%, this is considered a second AT of less than 15%. In patients receiving fitsiran at a dose of about 20 mg during Q2M, if the AT activity level is less than 15% two or more times (e.g., twice), the administration of fitsiran is discontinued.

[0053] However, if an adult or adolescent patient on 20 mg / Q2M (or Q8W) has two AT measurements exceeding 35%, the patient should escalate the medication regimen as shown in Figure 2. In the approach shown in Figure 2, the patient may receive approximately 50 mg of fitsiran every two months (or every eight weeks). If the patient has two AT measurements exceeding 35% under the 50 mg / Q2M (Q8W) regimen, the patient may receive approximately 50 mg of fitsiran every month (or every four weeks); if the patient has two AT measurements exceeding 35% under the 50 mg / QM (Q4W) regimen, the patient may receive approximately 80 mg of fitsiran every month (or every four weeks).

[0054] As shown in Figure 2, patients can gradually reduce their dose of fitsilan. For example, a patient who discontinued fitiran after their AT activity level fell below 15% on two or more occasions (e.g., twice) while receiving fitiran at a dose of 50 mg Q2 M can be administered fitiran at a dose of 20 mg Q2 M when their AT activity returns to 22% or higher; a patient who discontinued fitiran after their AT activity level fell below 15% on two or more occasions (e.g., twice) while receiving fitiran at a dose of approximately 50 mg QM (or approximately Q4W) can be administered fitiran at a dose of 50 mg Q2 M when their AT level returns to 22% or higher; and a patient who discontinued fitiran after their AT activity level fell below 15% on two or more occasions (e.g., twice) while receiving fitiran at a dose of 80 mg QM can be administered fitiran at a dose of approximately 50 mg QM (or approximately Q4W) when their AT activity returns to 22% or higher. Patients who have experienced AT activity levels below 15% on two or more occasions (e.g., twice) should discontinue fitiran treatment at a dose of 20 mg QM (or Q4W).

[0055] In the above dosage regimen, AT measurement for dosage determination is performed during the steady state (SS) of AT activity, i.e., after the patient's AT level has stabilized (in the low AT activity range) after fitiran treatment. SS is typically reached after two or three doses of fitiran. AT measurement for dosage determination is performed at appropriate intervals (e.g., every four weeks or every eight weeks). In the above dosage regimen, a starting dose of fitiran 20 mg Q2M is included as an example for illustrative purposes. For example, the starting dose of fitiran may be 50 mg Q2M, 20 mg Q2M, 20 mg QM, or 10 mg QM. Subsequently, dose increases and decreases can be performed accordingly from each starting dose. For example, a starting dose of fitiran 50 mg Q2M can be optionally sequentially increased to 50 mg QM or 80 mg QM in that order, or decreased to 20 mg QM or 20 mg Q2M.

[0056] Child patients with higher body weight Patients weighing between 22 kg and less than 45 kg receiving prophylactic treatment with emicizumab may be initiated with a starting dose of 10 mg of fitsiran monthly (or every four weeks). The patient's AT level may be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). An exemplary dose escalation and tapering scheme for pediatric patients is shown in Figure 3.

[0057] In some embodiments, patients treated with an initial dose of 10 mg of fitsiran monthly (or every four weeks) will have their fitsiran dosage regimen tapered. In some embodiments, when the first AT level is less than 15%, the patient is given a sample of another AT activity level within one month (e.g., within one or two weeks). If this result is less than 15%, this is considered to be a second AT of less than 15%. Patients receiving fitsiran at a dose of 10 mg QM with two or more (e.g., 2) AT activity levels less than 15% will have their dosage tapered to 2.5 mg of fitsiran monthly (or every four weeks). After the patient's AT level returns to above 15%, e.g., ≥22%, treatment with a lower dose of fitsiran may be initiated.

[0058] After gradually reducing the dose of fitsiran to 2.5 mg per month, the patient's AT level may again be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first AT level is less than 15%, the patient is given a sample of another AT activity level within one month (e.g., within one or two weeks). If this result is less than 15%, this is considered to be a second AT of less than 15%. Patients receiving fitsiran at a dose of 2.5 mg QM with two or more (e.g., 2) AT activity levels less than 15% may discontinue or pause fitsiran treatment.

[0059] In addition, after gradually reducing the dose of fitsiran to 2.5 mg per month, the patient's AT level is again monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level is greater than 35%, the patient has another AT activity level sample taken within one month (e.g., within one or two weeks). If this result is greater than 35%, this is considered to be a second steady-state AT greater than 35%. Patients receiving fitsiran at a dose of 2.5 mg QM with two or more (e.g., 2) steady-state AT activity levels greater than 35% may be gradually increased to a dose of 5 mg fitsiran once a month (or every four weeks).

[0060] In other embodiments, patients treated with an initial dose of 10 mg of fitsiran monthly (or every four weeks) may have their fitsiran dose escalated. The patient's AT level may be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level is greater than 35%, the patient has another steady-state AT activity level sample taken within one month (e.g., within one or two weeks). If this result is greater than 35%, this is considered to be a second steady-state AT greater than 35%. Patients receiving fitsiran at a dose of 10 mg QM with two or more (e.g., 2) steady-state AT activity levels greater than 35% may have their fitsiran dose escalated to 20 mg of fitsiran monthly (or every four weeks).

[0061] After gradually increasing the dose of fitsiran to 20 mg per month, the patient's AT level may again be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level is greater than 35%, the patient has another steady-state AT activity level sample taken within one month (e.g., within one or two weeks). If this result is greater than 35%, this is considered to be a second steady-state AT greater than 35%. Patients receiving fitsiran at a dose of 20 mg QM with two or more (e.g., 2) steady-state AT activity levels greater than 35% may be gradually increased to a dose of 30 mg of fitsiran once a month (or every four weeks).

[0062] In some embodiments, the gradual increase is performed after the steady-state AT activity level remains above 35% (see, for example, Figure 3).

[0063] Pediatric patients with lower body weight Patients weighing between 8 kg and less than 22 kg receiving prophylactic treatment with emicizumab may be initiated with a starting dose of 5 mg of fitsiran monthly (or every 4 weeks). A dose escalation and tapering scheme for pediatric patients is shown in Figure 4. The patient's AT level may be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months).

[0064] In some embodiments, patients treated with an initial dose of 5 mg of fitsiran monthly (or every four weeks) may have their fitsiran dose gradually reduced. In some embodiments, when the first AT level is less than 15%, the patient is given a sample of another AT activity level within one month (e.g., within one or two weeks). If this result is less than 15%, this is considered to be a second AT of less than 15%. Patients receiving fitsiran at a dose of 5 mg QM with two or more (e.g., 2) AT activity levels less than 15% may have their fitsiran dose gradually reduced to 1.25 mg of fitsiran monthly (or every four weeks). After the patient's AT level returns to above 15%, e.g., ≥22%, they may be started with a lower dose of fitsiran.

[0065] After gradually reducing the dose of fitsiran to 1.25 mg per month, the patient's AT level may again be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first AT level is less than 15%, the patient is given a sample of another AT activity level within one month (e.g., within one or two weeks). If this result is less than 15%, this is considered to be a second AT of less than 15%. Patients receiving fitsiran at a dose of 1.25 mg QM with two or more (e.g., 2) AT activity levels less than 15% may discontinue or pause fitsiran treatment.

[0066] In addition, after gradually reducing the dose of fitsiran to 1.25 mg per month, the patient's AT level may again be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level is greater than 35%, the patient has another steady-state AT activity level sample taken within one month (e.g., within one or two weeks). If this result is greater than 35%, this is considered to be a second steady-state AT greater than 35%. Patients receiving fitsiran at a dose of 1.25 mg QM with two or more (e.g., 2) steady-state AT activity levels greater than 35% may be gradually increased to a dose of 2.5 mg of fitsiran once a month (or every four weeks).

[0067] In other embodiments, patients treated with an initial dose of 5 mg of fitsiran monthly (or every four weeks) may have their fitsiran dose escalated. The patient's AT level may be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level is greater than 35%, the patient has another steady-state AT activity level sample taken within one month (e.g., within one or two weeks). If this result is greater than 35%, this is considered to be a second steady-state AT greater than 35%. Patients receiving fitsiran at a dose of 5 mg QM with two or more (e.g., 2) steady-state AT activity levels greater than 35% may have their fitsiran dose escalated to 10 mg of fitsiran monthly (or every four weeks).

[0068] After gradually increasing the dose of fitsiran to 10 mg per month, the patient's AT level may again be monitored regularly (e.g., every 1, 2, 3, 4, 5, 6, 7, or 8 weeks, or every 1, 2, 3, 4, 5, or 6 months). In some embodiments, when the first steady-state AT level is greater than 35%, the patient has another steady-state AT activity level sample taken within one month (e.g., within one or two weeks). If this result is greater than 35%, this is considered to be a second steady-state AT greater than 35%. Patients receiving fitsiran at a dose of 10 mg QM with two or more (e.g., 2) steady-state AT activity levels greater than 35% may be gradually increased to a dose of 20 mg of fitsiran once a month (or every four weeks).

[0069] In some embodiments, the gradual increase is performed after the steady-state AT activity level remains above 35% (see, for example, Figure 4).

[0070] In some embodiments, the AT activity level used to determine whether to escalate the dose or frequency of fitsiran is measured at a steady state (SS), i.e., when the patient's AT level stabilizes after fitsiran treatment. SS is typically reached after two or three doses of fitsiran. AT measurements for dose determination are performed at appropriate intervals (e.g., every four or eight weeks).

[0071] In the above-mentioned pediatric dosage regimen, the starting doses of 10 mg of fitsiran QM or 5 mg of fitsiran QM are considered as illustrative examples. For example, the starting dose of fitsiran may be 20 mg QM, 10 mg Q2M, 7.5 mg Q2M, 5 mg Q2M, or 2.5 mg QM. Subsequently, dose increases and decreases can be carried out accordingly from each starting dose. For example, the starting dose of 2.5 mg QM fitsiran can be increased sequentially to 5 mg QM, 10 mg QM, 20 mg QM, 30 mg QM, or 50 mg QM in any order, or it can be decreased to 2.5 mg Q2M or 1.25 QM.

[0072] An AT level of 10–35% (e.g., 10–25%, 15–35%, or 15–25%) is targeted to reduce the risk of vascular thrombotic events while maintaining a favorable benefit-risk balance for patients regularly using fitiran. In some embodiments, the target AT level is 15–35%. Therefore, as long as the patient reaches this target AT level, there is no need for the patient to receive higher fitiran doses or more frequent administrations. That is, the patient can remain on their current treatment regimen (i.e., maintenance regimen). For example, once the desired AT level is reached, the patient may be treated with subcutaneous doses of fitiran (e.g., 40–90 mg per dose) at intervals of approximately 1, 2, 3, 4, 5, 6, 7, or 8 weeks or approximately 1, 2, 3, 4, 5, or 6 months. In some embodiments, if a patient receives fitsiran at a dose of 50 mg in a Q2M regimen and both AT measurements fall below 35%, the regimen will be maintained without further dose or frequency increases. In another example, if a patient receives 80 mg Q2M or 50 mg QM and both AT measurements fall below 35%, the regimen will remain unchanged without further dose or frequency increases (e.g., to 80 mg QM). However, as a measure to mitigate the risk of vascular thrombotic events, fitsiran treatment should be discontinued if AT measurements fall below 15% (e.g., less than 10%) two or more times. Alternatively, the patient may resume treatment with a lower dose of fitsiran after their AT levels return to above 15%, e.g., 22% or higher. In some embodiments of the maintenance regimen, adult or adolescent patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 50 mg of fitsiran every two months (or every eight weeks). In other embodiments, adult or adolescent patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 50 mg of fitsiran every month (or every four weeks). In yet another embodiment, adult or adolescent patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 80 mg of fitsiran every two months (or every eight weeks).In yet another embodiment, adult or adolescent patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 80 mg of fitsiran approximately every month (or approximately every four weeks). In yet another embodiment, adult or adolescent patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 20 mg of fitsiran approximately every two months (or approximately every eight weeks). In yet another embodiment, adult or adolescent patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 20 mg of fitsiran approximately every month (or approximately every four weeks). In yet another embodiment, adult or adolescent patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 10 mg of fitsiran approximately every month (or approximately every four weeks).

[0073] Pediatric patients with hemophilia A, with or without inhibitors (i.e., patients between 1 and 12 years of age), can be treated with a subcutaneous maintenance dose of approximately 150 mg of fitsiran every month (or every four weeks). In some embodiments of the maintenance regimen, pediatric patients with hemophilia A, with or without inhibitors, are treated with a subcutaneous dose of approximately 50 mg of fitsiran every month (or every four weeks). In some embodiments of the maintenance regimen, pediatric patients with hemophilia A, with or without inhibitors, are treated with a subcutaneous dose of approximately 30 mg of fitsiran every month (or every four weeks). In other embodiments, pediatric patients with hemophilia A, with or without inhibitors, are treated with a subcutaneous dose of approximately 20 mg of fitsiran every month (or every four weeks). In other embodiments, pediatric patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 10 mg of fitsiran approximately every month (or approximately every four weeks). In some embodiments of the maintenance regimen, pediatric patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 7.5 mg of fitsiran approximately every month (or approximately every four weeks). In other embodiments, pediatric patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 5 mg of fitsiran approximately every month (or approximately every four weeks). In other embodiments, pediatric patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 2.5 mg of fitsiran approximately every month (or approximately every four weeks). In other embodiments, pediatric patients with hemophilia A, with or without inhibitors, are treated with subcutaneous administration of approximately 1.25 mg of fitsiran approximately every month (or approximately every four weeks). AT monitoring in pediatric patients is similar to that described for adolescents and adults, with a desirable AT level of 15–35%. In some embodiments, patients may be treated based on their AT level, starting with a dose of approximately 10 mg (approximately Q2M or approximately Q8W), and then escalating to a stronger dosing regimen (higher dose and / or frequency), or de-escalating to a weaker dosing regimen (lower dose and / or frequency), or discontinuing treatment, as described above for adolescents and adults.

[0074] In some embodiments, patients may receive periodic AT monitoring (e.g., approximately every month or every four weeks) for approximately 12 months after a change in the fitsiran administration regimen.

[0075] In some embodiments, once a patient remains on a maintenance regimen (e.g., 10 mg QM or Q4W, 20 mg Q2M or Q8W, 20 mg QM or Q4W, 50 mg Q2M or Q8W, 50 mg QM or Q4W, 80 mg QM or Q4W, or 80 mg Q2M or Q8W), the frequency of AT monitoring can be reduced. For example, AT levels can be monitored approximately every month, every two months, every three months, every four months, every six months, every year, or every two years.

[0076] This method involves administering a therapeutically effective dose of fitsiran to hemophilia A patients who require it. “Therapeutally effective dose” refers to the amount of fitsiran that helps the patient achieve the desired clinical endpoint.

[0077] In some embodiments, patients with hemophilia A, with or without inhibitors, are treated with a subcutaneous dose of approximately 50 mg of fitsiran every two months (or every eight weeks). In other embodiments, patients with hemophilia A, with or without inhibitors, are treated with a subcutaneous dose of approximately 50 mg of fitsiran every month (or every four weeks). In yet another embodiment, patients with hemophilia A, with or without inhibitors, are treated with a subcutaneous dose of approximately 80 mg of fitsiran every two months (or every eight weeks). In yet another embodiment, patients with hemophilia A, with or without inhibitors, are treated with a subcutaneous dose of approximately 80 mg of fitsiran every month (or every four weeks). In yet another embodiment, patients with hemophilia A, with or without inhibitors, are treated with approximately 20 mg of fitsiran subcutaneously every two months (or every eight weeks). In yet another embodiment, patients with hemophilia A, with or without inhibitors, are treated with approximately 20 mg of fitsiran subcutaneously every month (or every four weeks). In yet another embodiment, patients with hemophilia A, with or without inhibitors, are treated with approximately 10 mg of fitsiran subcutaneously every month (or every four weeks).

[0078] III. Prophylactic administration of emicizumab In this method, the patient receives prophylactic treatment with emicizumab. Emicizumab is administered by subcutaneous injection approximately once a week, once every two weeks, or once a month, according to a typical dosage regimen based on body weight. The treatment method of the present invention is for use in patients receiving prophylactic treatment with emicizumab. In some embodiments, prophylactic treatment with emicizumab includes administering emicizumab at a dose of approximately 1.5 mg / kg to approximately 6 mg / kg once a week (approximately QW), once every two weeks (approximately Q2W), once a month (approximately QM), or once every four weeks (approximately Q4W). In some embodiments, prophylactic treatment with emicizumab includes administration of approximately 1.5 mg / kg QW, approximately 3 mg / kg Q2W, or approximately 6 mg / kg Q4W.

[0079] In some embodiments, patients receive prophylactic treatment with emicizumab at a dose of approximately 1.5 mg / kg once a week. In some embodiments, patients receive prophylactic treatment with emicizumab at a dose of approximately 1.5 mg / kg Q2W. In some embodiments, patients receive prophylactic treatment with emicizumab at a dose of approximately 1.5 mg / kg about once a month or about once every four weeks.

[0080] In some embodiments, patients receive prophylactic treatment with emicizumab at a dose of approximately 3 mg / kg once a week. In some embodiments, patients receive prophylactic treatment with emicizumab at a dose of approximately 3 mg / kg Q2W. In some embodiments, patients receive prophylactic treatment with emicizumab at a dose of approximately 3 mg / kg about once a month or about once every four weeks.

[0081] In some embodiments, patients receive prophylactic treatment with emicizumab at a dose of approximately 6 mg / kg once a week. In some embodiments, patients receive prophylactic treatment with emicizumab at a dose of approximately 6 mg / kg Q2W. In some embodiments, patients receive prophylactic treatment with emicizumab at a dose of approximately 6 mg / kg about once a month or about once every four weeks.

[0082] In some embodiments, patients receive prophylactic treatment with emicizumab once weekly at a dose of approximately 3 mg / kg for the first four weeks, followed by prophylactic treatment with emicizumab once weekly at a dose of approximately 1.5 mg / kg. In some embodiments, prophylactic emicizumab treatment in patients is terminated approximately 1 to 3 months or 4 to 12 weeks before the first dose of fitsiran.

[0083] In some embodiments, prophylactic emicizumab treatment in patients is completed approximately two months or eight weeks before the first dose of fitsiran. In further embodiments, the prior treatment for this prophylactic emicizumab therapy is 1.5 mg / kg emicizumab Q1W, 3 mg / kg emicizumab Q1W, or 3 mg / kg emicizumab Q2W.

[0084] In some embodiments, prophylactic emicizumab treatment in patients is completed approximately 2.5 months or 10 weeks before the first dose of fitsiran. In further embodiments, this prior prophylactic emicizumab treatment is 6 mg / kg of emicizumab Q1M.

[0085] In some embodiments, prophylactic emicizumab treatment in patients is terminated approximately 6 months or 6.5 months before the dose of fitsiran is escalated.

[0086] IV. Recommendations for the Management of Bleeding Episodes The pre-fitsiran treatment period begins at the time of the final dose of emicizumab. During the pre-fitsiran treatment period, participants switch from emicizumab to prophylactic or on-demand therapy with factor VIII / rFVIIa. Prophylactic CFC / rFVIIa therapy is discontinued approximately one week after the start of prophylactic fitiran therapy, or approximately 7 days later.

[0087] During the pre-fitsiran treatment period, hemophilia A patients transitioning from emicizumab may receive bleeding management therapy with FVIII concentrate (CFC) or recombinant factor VIIa (rFVIIa).

[0088] During the treatment period with fitisran, the factor or BPA dosage required to safely and effectively treat breakthrough bleeding episodes in patients receiving fitisran is lower than that prescribed by standard. Patients can continue the standard factor or BPA regimen for the first few days after starting fitisran, and then reduce the factor or BPA dosage from day 8 onward to implement protocol-specific bleeding management guidelines (Table 2).

[0089] [Table 3]

[0090] More specifically, during days 1-7 of the fitiran treatment period, the patient may continue with the standard factor or BPA regimen. From day 7 onward of the fitiran treatment period, the patient should not use factor, BPA, or other hemostatic agents as prophylactic doses for bleeding episodes. From day 8 onward, if the patient experiences symptoms consistent with a bleeding episode, follow these steps: - Single doses should be administered according to the guidelines in Table 2. - Patients should be instructed to reassess their symptoms 24 hours after bleeding treated with FVIII, FIX, or aPCC, and 2-3 hours after bleeding treated with rFVIIa (the interval between doses should be 5-7 days or more to allow for the extended half-life of FIX). - The dosing interval should be 24 hours or longer (except for rFVIIa shown in Table 2). - The dosage should not exceed the maximum recommended dosage shown in Table 2 of the protocol. - Antifibrinolytic agents should not be used in combination with factors or BPA.

[0091] The bleeding management guidelines in Table 2 may also be used for perioperative prophylactic administration (e.g., for perioperative bleeding management of minor or major surgery). Minor surgery is defined as any invasive procedure in which only the skin, mucous membrane, or superficial connective tissue is manipulated and which does not meet the criteria for major surgery (e.g., extraction of fewer than three non-molar teeth). Major surgery is defined as any invasive procedure requiring any of the following: - Opening to major body cavities (e.g., abdomen, chest, skull), - Joint surgery, - Removal of organs, - Extraction of molars or three or more non-molars, or implant treatment. - Surgical modification of normal anatomical structures, - Cross-section of the mesenchymal barrier (e.g., pleura, peritoneum, dura mater).

[0092] In participants undergoing surgery, perioperative prophylactic administration may be carried out as described above, according to Table 2.

[0093] V. Patient population This treatment can be used for prophylactic treatment of hemophilia A patients who have previously received prophylactic treatment with emicizumab, with or without inhibitors. In some embodiments, the patient is male. In some embodiments, the patient (e.g., male) is adolescent or an adult aged 12 years or older. In some embodiments, the patient is an adult (e.g., male) aged 18 years or older with severe hemophilia A. The diagnosis of severe hemophilia A is based on a factor VIII level of less than 1%. In some embodiments, the patient has experienced one or more bleeding episodes (e.g., two or more, four or more, or six or more) requiring factor or BPA treatment within the six months prior to treatment.

[0094] In some embodiments, the patient has inhibitor antibodies against factor VIII (i.e., is a patient with inhibitors). A patient is defined as having inhibitors if they meet at least one of the following Nijmegen-modified Bethesda assay result criteria: a. The inhibitor titer before treatment is 0.6 BU / mL or higher, or b. There is medical record evidence that the inhibitor titer before treatment was less than 0.6 BU / mL and that the titer was 0.6 BU / mL or higher for two consecutive measurements, or c. The inhibitor titer before treatment is less than 0.6 BU / mL, and there is evidence of a medical record of a past reaction.

[0095] In some embodiments, the patient does not have inhibitor antibodies against factor VIII (i.e., is an inhibitor-free patient). A patient is defined as inhibitor-free if they meet at least one of the following Nijmegen-modified Bethesda assay result criteria: a. The inhibitor titer of the modified Nijmegen Bethesda assay prior to treatment is less than 0.6 BU / mL. b. No bypass agents have been used to treat bleeding episodes in the six months prior to treatment, and c. No history of immune tolerance induction therapy within the past three years prior to treatment.

[0096] The patient had received prophylactic treatment with emicizumab to manage bleeding episodes prior to the initiation of fitisiran treatment. In some embodiments, the patient received prophylactic treatment with emicizumab at a dose of approximately 6 mg / kg, approximately once a week, approximately once every two weeks, or approximately once a month (or approximately once every four weeks). In some embodiments, the patient received prophylactic treatment with emicizumab at a dose of approximately 3 mg / kg, approximately once a week, approximately once every two weeks, or approximately once a month (or approximately once every four weeks). In some embodiments, the patient received prophylactic treatment with emicizumab at a dose of approximately 1.5 mg / kg, approximately once a week, approximately once every two weeks, or approximately once a month (or approximately once every four weeks).

[0097] In some embodiments, the patient does not have any known co-existing bleeding disorders other than hemophilia A, such as hemophilia B, von Willebrand disease, further factor deficiencies, acquired hemophilia, or platelet disorders.

[0098] In some embodiments, the patient has no history of antiphospholipid antibody syndrome, or arterial or venous thromboembolism, atrial fibrillation, significant valvular heart disease, myocardial infarction, angina pectoris, transient ischemic attack, or stroke. Patients experiencing thrombosis related to indwelling venous access can be treated with this method.

[0099] In some embodiments, the patient has not had any malignant tumors within the past two years, except for basal cell carcinoma or squamous cell carcinoma of the skin that has been successfully treated.

[0100] In some embodiments, the patient does not have a clinically significant liver disease, such as (i) a history of cirrhosis, portal hypertension, esophageal varices, hepatic fibrosis, or hepatic encephalopathy; or (ii) the presence of ascites on physical examination.

[0101] In some embodiments, patients did not have an AT activity of less than 60% before treatment.

[0102] In some embodiments, the patient does not have a pre-existing thrombotic disorder, as determined by the presence of any of the following: a. FV Leiden mutation (homozygous or heterozygous), b. Protein S deficiency, c. Protein C deficiency, or d. Prothrombin mutation (G20210A; homozygous and heterozygous).

[0103] In some embodiments, the patient's ALT and / or AST levels do not exceed 1.5 times the upper limit of the normal reference range (ULN).

[0104] In some embodiments, patients' total bilirubin levels do not exceed 1.5 × ULN (or 2.0 × ULN in patients with Gilbert's syndrome).

[0105] In some embodiments, the patient is not positive for hepatitis C virus antibodies. A patient who is positive for hepatitis C virus antibodies may be treated with this method if the patient has the following: a. Curative treatment has been completed at least 12 weeks prior to registration, and a sustained virological response has been achieved as demonstrated by negative HCV RNA prior to treatment, or the infection has been spontaneously cleared as demonstrated by negative HCV RNA prior to treatment, and b. No evidence of cirrhosis by FibroScan (if available) less than 12.5 kPa, or a FibroTest score less than 0.75, and an APRI score less than 2 (if FibroScan is unavailable).

[0106] In some embodiments, the patient does not have acute hepatitis, i.e., hepatitis A or E.

[0107] In some embodiments, the patient does not have acute or chronic hepatitis B infection (positive for IgM anti-HBc antibody or positive for hepatitis B serum antigen).

[0108] In some embodiments, the patient's platelet count is not less than 100,000 / μL.

[0109] In some embodiments, the patient is not an HIV-positive patient with a CD4 count of less than 200 cells / μL.

[0110] In some embodiments, the patient has an estimated glomerular filtration rate of 45 mL / min / 1.73 m³. 2 The following (based on the Modified Diet in Renal Disease (MDRD) formula) is not applicable.

[0111] In some embodiments, the patient meets one or more of the inclusion criteria and one or more of the exclusion criteria detailed in Example 1 below.

[0112] VI. Treatment Outcomes and Evaluation In some embodiments, this treatment method reduces the frequency of bleeding episodes in patients. A bleeding episode is defined as any occurrence of bleeding (e.g., joint bleeding, muscle bleeding, or mucosal bleeding) that requires the infusion of replacement factors or BPA. The definitions of bleeding episode types described below are based on the unified view of the International Society on Thrombosis and Haemostasis (ISTH) (Blanchette et al., J Thromb Haemost. (2014) 12(11):1935-9).

[0113] The onset time of a bleeding episode is defined as the time when the symptoms of the bleeding episode first appear. Any bleeding at this site, or any symptoms of bleeding at this site that occur within 72 hours of the last injection used to treat a bleeding episode at this site, is considered part of the original bleeding event and counted as one bleeding episode for ABR. Any bleeding symptoms that begin more than 72 hours after the last injection used to treat a bleeding episode at this site constitute a new bleeding event.

[0114] A spontaneous bleeding episode refers to a bleeding event that occurs without apparent or known cause, particularly in the joints, muscles, and soft tissues. Joint bleeding episodes are characterized by an abnormal sensation in the joint ("aura"), combined with 1) increased swelling or warmth of the skin over the joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty of use of the limb compared to baseline. Muscle bleeding may be characterized by pain, swelling, and loss of movement in the affected muscle group. A target joint is defined as a joint in which three or more spontaneous bleeding episodes have occurred within a continuous six-month period. If a joint has had two or fewer bleeding episodes within a continuous twelve-month period, it is no longer considered a target joint. A traumatic bleeding episode is an episode caused by a known injury or trauma. Bleeding episodes that persist during sports and recreation are counted as traumatic bleeding episodes.

[0115] In some embodiments, the therapeutic method of the present invention results in a reduction in the annualized bleeding rate (ABR) and / or the annualized spontaneous bleeding rate (AsBR) in the treated population compared to the population treated with prophylactic administration (e.g., replacement factors, BPA, or emicizumab) compared to the population treated with other prophylactic administrations.

[0116] In some embodiments, the treatment methods of the present invention result in improvements in patient-reported outcomes (PROs) or quality of life (QoL), as further described below. Hemophilia directly impacts patients' health-related quality of life (HRQoL) through its associated symptoms, functional limitations, and treatment burden. Improving HRQoL is an important aspect of disease management for hemophilia. The methods improve patients' HRQoL, as determined by well-designed, detailed questionnaires.

[0117] In some embodiments, HRQoL is measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) v2.0 Pain Intensity 3a. PROMIS v2.0 Pain Intensity 3a is a reliable and accurate system for measuring health status reported by adolescent and adult (12 years and older) participants (Cella et al., Med Care. (2007) 45(5 Suppl 1):S3-S11). PROMIS v2.0 Pain Intensity 3a is a psychometrically and clinically validated scale for assessing how much pain a person experiences. The scale consists of three items that measure the worst, mean, and current pain intensity over a 7-day recall period. Each question has a 5-point scale ranging from 1 ("no pain") to 5 ("very severe"). The raw score is converted to a T-score (item-level calibrated). A higher PROMIS T score indicates a greater number of measured concepts (pain intensity). The questionnaire can be administered after the last dose of emicizumab and after one or more doses (e.g., two or more, three or more, four or more, five or more, or six or more) of fitsiran (e.g., 50 mg subcutaneously once every four weeks or once a month). For example, the questionnaire can be taken at 6, 12, and 18 months after the start of fitsiran treatment. In some embodiments, the treatment method of the present invention reduces the PROMIS T score compared to treatment with another prophylactic dose.

[0118] In some embodiments, improvements in PRO or QoL are measured using the Therapeutic Quality Meter (TSQM-9), a 9-item questionnaire that assesses participants' satisfaction with their treatment. The TSQM-9 is a psychometrically validated tool that can generally measure participants' satisfaction with their pharmacotherapy (Atkinson et al., Health Qual Life Outcomes. (2004) 2:12). The questionnaire consists of nine items relating to overall patient satisfaction or dissatisfaction with the medication administered in the clinical trial, measured by patient assessments of the medication's effectiveness, side effects, and convenience over the preceding 2-3 weeks. Each question has seven response options, ranging from 1 ("very dissatisfied") to 7 ("very satisfied"). A higher score indicates better health. The questionnaire can be completed after the final dose of emicizumab and after one or more doses (e.g., two, three, four, five, or six) of fitsiran (e.g., approximately 50 mg subcutaneously once every four weeks or once every month). For example, questionnaires can be collected at 6, 12, and 18 months after the start of fitsiran treatment. In some embodiments, this treatment method increases the TSQM-9 score compared to treatment with another prophylactic dose.

[0119] In some embodiments, improvements in PRO or QoL are measured using a Preference Questionnaire. The Preference Questionnaire is a three-item questionnaire that measures participants' preference for fitsiran compared to standard care. The Preference Questionnaire assesses respondents' preferred treatment, reasons for preference, and willingness to continue treatment. The questionnaire consists of three items directed at the patient's preference for fitsiran over emicizumab, the main reasons for the indicated preference, and the respondent's willingness to continue the preferred treatment. Respondents indicated whether they preferred emicizumab (before fitsiran treatment), fitsiran treatment administered during the clinical trial, or neither treatment. Respondents selected and ranked three main reasons for wanting treatment from the following: shorter treatment time, fewer doses, ease of use, greater flexibility in treatment administration, higher quality of life, and lower risk of bleeding. The respondent's willingness to continue the preferred treatment is indicated by a five-option response range from "I would not like to continue" to "I would definitely like to continue." The questionnaire can be administered 12 months after the start of treatment with fitsiran. In some embodiments, the treatment method of the present invention enhances the reported palatability of fitsiran prophylactic administration compared to treatment with other prophylactic administrations.

[0120] In some embodiments, improvements in PRO or QoL are measured using the International Physical Activity Questionnaire (IPAQ). The IPAQ measures the physical activity level of adult participants (18 years and older) by collecting information on household chores, gardening, occupational activities, self-mobility, leisure physical activity, and sedentary activity (Craig et al., Med Sci Sports Exerc. (2003) 35(8):1381-95). The questionnaire consists of 27 items regarding the number of days and hours spent sitting, walking, and moderate and vigorous physical activity in the last 7 days or last normal week. Overall and domain scores can be calculated with higher scores indicating higher physical activity. The questionnaire can be completed after the last dose of emicizumab and after treatment with one or more doses (e.g., two, three, four, five, or six) of fitsiran (e.g., 50 mg subcutaneously once every four weeks or once every month). For example, questionnaires can be collected at 6, 12, and 18 months after the start of Fitsiran treatment. In some embodiments, the treatment method of the present invention increases the IPAQ score compared to treatment with another prophylactic dose.

[0121] In some embodiments, improvements in PRO or QoL are measured by qualitative interviews with participants. These qualitative interviews record the patient's experience with treatment and trial participation from their perspective. Specifically, they capture: 1) their experience living with hemophilia, 2) their treatment experience prior to participating in the trial, and 3) their expectations of and experiences during the trial. Interviews can be conducted within two weeks after participant screening and within two weeks after the end of the trial. Dominant trends can be identified in each interview and compared across other interview results to derive themes and patterns in how participants describe their experience with their disease, treatment, and clinical trials. In some embodiments, the treatment method of the present invention results in a better experience with prophylactic administration of fitsiran compared to treatment with other prophylactic administrations.

[0122] In some embodiments, the therapeutic methods of the present invention improve joint health in hemophilia patients. The efficacy of fitsilan in improving joint health is measured using the Hemophilia Joint Health Score (HJHS). The HJHS is a clinician-reported outcome tool for assessing joint health in hemophilia participants. The HJHS assesses impairment in six joints (left and right elbows, knees, and ankles) and includes a global gait score assessed by a trained physician or trained healthcare professional using 11 score items (swelling, duration of swelling, axial alignment, muscle atrophy, crepitus, flexion loss, extension loss, joint pain, instability, gait, and intensity). The total score ranges from 0 to 148, with lower scores indicating less functional limitation (reduced functional impairment). HJHS assessment may be performed after the final dose of emicizumab, at the time of the first dose of prophylactic fittingan, and after treatment with one or more doses of fittingan (e.g., 2 or 3 or 4 or 5 or 6 or 6 doses) (e.g., 50 mg administered subcutaneously approximately once every four weeks or approximately once every month). In some embodiments, the treatment method of the present invention reduces the HJHS score of patients treated with prophylactic fittingan compared to treatment with another prophylactic administration.

[0123] According to the International Conference on Harmonisation (ICH) E2A guideline Definitions and Standards for Expedited Reporting, and Code of Federal Regulations (CFR) 312.32, IND Safety Reporting, an adverse event (AE) is any adverse medical event in a patient receiving a drug or in a clinical trial that is not necessarily causally related to the treatment. Since bleeding episodes are recorded as part of the efficacy evaluation of fitsilan, they are not considered AEs unless they meet one of the severe adverse event (SAE) criteria listed below.

[0124] SAEs can be administered at any dose. a. to bring death, b. Is it life-threatening? (An event that, if it occurs, exposes the patient to a risk of immediate death. This does not include events that, if they occurred in a more severe form, could have caused death.) c. Whether hospitalization of an inpatient or extension of existing hospitalization is necessary, d. To cause permanent or serious impairment or incapacity, e. Whether it is a congenital anomaly or congenital defect, f. A significant medical event that does not immediately threaten life, cause death, or result in hospitalization, but which may endanger the patient and may require intervention to prevent one of the other outcomes listed in the definition above (for example, events such as allergic bronchospasm, blood disorder, seizures, or the onset of drug addiction or abuse requiring intensive care in the emergency room or at home). This is any adverse medical event.

[0125] VII. Products and Kits The present invention also provides a kit comprising a pharmaceutical composition for use in the therapeutic method. Such a kit includes one or more vials or one or more pre-filled syringes or injectors (e.g., pens) containing the pharmaceutical composition of the present invention and instructions for use, for example, instructions for administering a therapeutically effective amount of fitsilan.

[0126] In some embodiments, fitsilane is packaged in a drug delivery device. In some embodiments, this may include a needle-based infusion system, such as those described in Table 1 of Section 5.2 of ISO 11608-1:2014(E). As described in ISO 11608-1:2014(E), needle-based infusion systems can be broadly classified into multi-dose container systems and single-dose (with partial or full discharge) container systems. The containers may be replaceable or integrated non-replaceable containers.

[0127] As further described in ISO 11608-1:2014(E), a multi-dose container system may involve a needle-based infusion device with replaceable containers. In such a system, each container holds multiple doses, and its size may be fixed or variable (pre-set by the user). Another multi-dose container system may involve a needle-based infusion device with an integrated non-replaceable container. In such a system, each container holds multiple doses, and its size may be fixed or variable (pre-set by the user).

[0128] As further described in ISO 11608-1:2014(E), a single-dose container system may be accompanied by a needle-based infusion device having a replaceable container. As also described in ISO 11608-1:2014(E), a single-dose container system may be accompanied by a needle-based infusion device having an integrated, non-replaceable container. In some embodiments, each container holds a single dose so that the entire deliverable amount is dispensed (full discharge). In other embodiments, each container holds a single dose so that a portion of the deliverable amount is dispensed (partial discharge).

[0129] An exemplary sleeve-trigger autoinjector with manual needle insertion is described in International Publication No. 2015 / 004052. An exemplary audible end-of-administration feedback mechanism is described in International Publication Nos. 2016 / 193346 and International Publication Nos. 2016 / 193348. An exemplary needle safety mechanism after use of an autoinjector is described in International Publication No. 2016 / 193352. An exemplary needle sheath removal mechanism for a syringe autoinjector is described in International Publication No. 2016 / 193353. An exemplary support mechanism for supporting the axial position of a syringe is described in International Publication No. 2016 / 193355.

[0130] Phytsilane can be supplied in single-use vials containing 20 mg of Phytsilane (equivalent to 21 mg of Phytsilane sodium) at a concentration of 100 mg / mL in 0.2 mL of solution. Phytsilane can also be supplied in pre-filled pens containing 50 mg of Phytsilane (equivalent to 53 mg of Phytsilane sodium) at a concentration of 100 mg / mL in 0.5 mL of solution.

[0131] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have meanings generally understood by those skilled in the art. Exemplary methods and materials are described below, but similar or equivalent methods and materials may also be used in the practice or testing of this disclosure. In case of any conflict, this specification, including definitions, shall prevail. Generally, the nomenclature and techniques used in relation to hematology, medicine, pharmaceutical and pharmaceutical chemistry, and cell biology described herein are well known and commonly used in those arts. Furthermore, unless otherwise required by context, singular terms shall include plurals, and plural terms shall include singulars. All publications and other references referenced herein are incorporated by reference as a whole. While several documents are cited herein, such citations do not constitute an endorsement that any of those documents form part of the common technical knowledge in the art. Where used herein, the terms “approximately” or “about” refer to a value similar to the reference value described when applied to one or more values ​​of interest. In certain embodiments, unless otherwise noted or evident from the context, the term refers to a range of values ​​that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less than (greater than or less than) 10% in either direction of the given reference value.

[0132] According to this disclosure, backreferences in dependent claims mean abbreviated notation to any direct and obvious disclosure of any combination of claims indicated by that backreference. Furthermore, the headings in this specification are provided for ease of organization and are not intended to limit in any way the scope of the claimed invention.

[0133] Examples are provided below to help the present invention be better understood. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way. [Examples]

[0134] Example 1: Clinical trial protocol for an open-label, single-arm study to investigate the safety and tolerability of switching from emicizumab to fitsiran prophylactic therapy in male participants aged 18 years or older with severe hemophilia A, with or without inhibitors. This example describes an open-label, single-arm phase 1 trial to investigate the safety and tolerability of fitisran prophylactic therapy in adult male patients with severe hemophilia A who have previously received emicizumab prophylactic therapy and who may or may not have inhibitor antibodies against factor VIII (FVIII). The primary objective of this trial was to characterize the safety of initiating fitisran approximately two months or two and a half months after discontinuation of emicizumab therapy.

[0135] Approximately two months after discontinuing emicizumab treatment, prophylactic treatment with fitiran is initiated with a 20 mg Q2M regimen to gradually increase thrombin production (TG) while residual emicizumab levels continue to decrease. This treatment regimen is chosen to maintain TG function until the next fitiran administration and to enhance protection against bleeding after fitiran introduction. The 20 mg fitiran Q2M dose is the lowest dose investigated in adults who are likely to reach the desired AT activity level range of 15%–35%.

[0136] Dosage appropriateness To identify a dosing regimen that can maintain AT activity levels between 15% and 35% as a strategy to mitigate the risk of vascular thrombotic events, we developed a population pharmacokinetic / pharmacodynamic (pop PK / PD) model describing the dynamics of AT activity levels in participants treated with fitsiran. The model was characterized using AT activity data from phase 1, phase 2, and phase 3 trials. Using the model, which included estimated parameters, we simulated steady-state AT activity levels under different dosing scenarios in a hypothetical population of 1000 participants.

[0137] The starting dose for all participants in this study is 20 mg Q2M. Four months after the first dose of fitsiran, participants whose AT level exceeds 35% or who require dose escalation for clinical reasons are eligible for dose escalation to 50 mg Q2M. Based on simulation results, it is expected that approximately 45.7% of hypothetical participants will have AT activity less than 15% in the 50 mg Q2M regimen and therefore may require dose escalation. According to the protocol, these participants should be tapered from 50 mg Q2M to 20 mg Q2M.

[0138] Simulations of low-dose regimens in 1000 new hypothetical participants (20 mg Q2M and 20 mg QM) predicted that 3.8% and 23.4% of participants, respectively, would have AT activity levels below 15%. Therefore, based on the simulations, 20 mg Q2M was considered an appropriate tapering regimen for 45.7% of participants who could have AT activity levels below 15% at 50 mg Q2M. When tapering to 20 mg Q2M, approximately 8% of the tapering group may have AT activity levels below 15%, and approximately 7% may have AT activity levels above 35%, but the remaining 84% to 85% of the tapering group are predicted to have AT activity levels within the target AT window of 15% to 35%.

[0139] Treatment period The treatment duration with fitisran is 18 months. The estimated total duration of the study is up to 28 months. The estimated total duration includes a 2-month screening period, a 2-month washout period after the last dose of emicizumab, an 18-month treatment period with fitisran, and a 6-month follow-up period after the last dose of fitisran to monitor AT activity levels. For participants receiving emicizumab on a QW or Q2W schedule, the washout period will be 2 months. For participants receiving emicizumab monthly, the washout period will be 2.5 months.

[0140] Test objectives and evaluation items The primary objective of this study is to clarify the safety and tolerability of switching from prophylactic emicizumab to prophylactic fitisiran after a transition period.

[0141] The secondary objectives of this test are as follows: - Evaluate the peak thrombin generation (TG) profile and antithrombin (AT) levels during prophylactic treatment with fitisiran over a 6-month period following the final dose; - Evaluate emicizumab levels up to 6 months after the last dose of emicizumab; - To clarify the safety and tolerability of switching from emicizumab prophylactic therapy to fitsiran prophylactic therapy after the transition period; - Characterize the change from baseline in the following outcomes regarding health-related quality of life (HRQoL) of participants after switching to fitsilan: - Overall satisfaction with Fitsilan among participants, and assessment of injection pain from both therapies to measure treatment and injection burden. - Participants' preferences for treatment, - Participant pain intensity, and - Participants' physical function and physical activity; -Characterization of the joint health status of participants after switching to Fitsilan, as assessed by physicians; and Characterization of the frequency of treated bleeding episodes during prophylactic treatment with fitsiran.

[0142] The exploratory objective is to characterize the participants' overall experience.

[0143] The primary endpoint of this study is to evaluate the incidence, severity, and severity of adverse events (AEs) from D1 to M4 of fitsiran treatment.

[0144] Secondary outcome measures include evaluating the following: - Peak TG and AT values ​​from the last dose of emicizumab to the first day of the washout period before the administration of fitisran, and from D1 to M4 of the fitisran treatment period; - Plasma emicizumab concentration until complete washout of Fitusiran treatment (approximately M4); - Incidence, severity, and severity of adverse events (AEs) during D1-M18 of Fitsiran treatment: - Changes in overall satisfaction among participants during the period of fitsiran treatment, as assessed by the Therapeutic Satisfaction Questionnaire (TSQM-9) over time from baseline to end-of-situation (EOS). - Participants' treatment preferences (via Preference Questionnaire), - Changes in pain intensity in participants during the period of Fitsiran treatment (as measured by the PROMIS Pain Intensity 3a questionnaire) over time from baseline to end-of-situation, and - Changes in participants' physical function and physical activity over time (via IPAQ) during the period of Fitsiran treatment from baseline to end-of-situation (EOS); - Changes in participants' joint health status over time during the period of fitsiran treatment from baseline to end-of-situation (as measured by the Hemophilia Joint Health Score [HJHS]); and - Annualized bleeding rate (ABR) during the 14-month extension period while receiving prophylactic treatment with fitisiran.

[0145] The exploratory endpoint is the characterization of the participants' overall experience, obtained through interviews with participants at their exit point.

[0146] Test design This study evaluates male patients aged 18 years or older with severe hemophilia A who have or do not have inhibitor antibodies against FVIII, and who have switched from previous standard treatment with emicizumab prophylactic therapy.

[0147] Participants complete screening during a maximum screening period of two months. Following this, three trial periods are established: approximately two months of pre-fitsiran treatment, an 18-month fitsiran treatment period, and an antithrombin follow-up (ATFU) period (Figure 5).

[0148] During the pre-fitsiran treatment period of approximately two months from the last dose of emicizumab, participants will continue their prior regimen with CFC or BPA. For participants who were receiving emicizumab QM at the start of the study, the pre-fitsiran treatment period will begin with the last dose of emicizumab on day -70 (-2.5 months) and end on day -1. For participants who were receiving emicizumab Q2W or QW at the start of the study, the pre-fitsiran treatment period will begin with the last dose of emicizumab on day -56 (-2 months) and end on day -1. Participants who were receiving emicizumab (hemlibra) at the time of screening will not be able to receive emicizumab after day -70 or day -56 (depending on the emicizumab administration schedule), and therefore the pre-fitsiran treatment period will be switched to CFC / BPA prophylactic administration or on-demand therapy. For participants who received emicizumab, data on bleeding and administration will be collected from medical records for the six months prior to screening.

[0149] During the 18-month period of fitsiran treatment, participants will receive prophylactic fitsiran doses (from day 1 to day 505). Participants may need adjustments to their fitsiran regimen (dosage / frequency) based on their individual responses. Dosage adjustments can be made as summarized in Figure 3. The primary treatment period is from day 1 to day 113. The period of extended efficacy will occur between day 114 and day 533 or day 561 (depending on the fitsiran administration frequency in QM or Q2M).

[0150] Following the completion of the treatment period or early, permanent discontinuation of prophylactic treatment with fituiran, participants will enter an antithrombin follow-up (ATFU) period during which their AT activity levels will be monitored (approximately monthly after the final fituiran dose and / or ET visit) until the AT activity level returns to at least 60% by central laboratory testing. Participants who continue fituiran prophylactic treatment immediately after the trial, if applicable, will not be required to visit for AT follow-up.

[0151] Breakdown bleeding events, including the doses of CFC and BPA administered after enrollment, will be recorded. Safety, quality of life (QoL), and disease progression (PD) data will also be collected.

[0152] During the pre-fitsiran treatment period, participants who had previously received emicizumab (hemlibra) will be switched to prophylactic or on-demand treatment with CFC / BPA. Throughout the study, all participants will be able to receive incidental / on-demand treatment with CFC or BPA for breakthrough bleeding episodes as needed. A summary of the study period is shown in Table 3.

[0153] [Table 4]

[0154] Test group Participants are eligible to take this exam if they meet all of the following criteria: I01. Male participants must be 18 years of age or older at the time of signing the informed consent form. I02. Diagnosis of severe congenital hemophilia A (FVIII <1%) as evidenced by measurements taken in the central laboratory at the time of screening or by documented medical records. Inhibitor titer of 0.6 BU / mL or higher at screening, or medical records showing inhibitor titer of less than 0.6 BU / mL at screening followed by two consecutive measurements of 0.6 BU / mL or higher. Alternatively, there is a medical record indicating an anamnetic reaction with an inhibitor titer of less than 0.6 BU / mL at the time of screening. I03. Participants currently receiving prophylactic emicizumab (6 mg / kg), regardless of whether they have inhibitors. I04. Participants willing to use or switch to rFVIIa as the primary BPA for the treatment of breakthrough bleeding from day -56 of the initiation of Fitusiran treatment up to M4. I05. Male.

[0155] Participants will be excluded from this study if they meet any of the following criteria:

[0156] Health condition E01. Other co-existing bleeding disorders besides congenital hemophilia A are known, namely hemophilia B, von Willebrand disease, further factor deficiencies, acquired hemophilia, or platelet disorders. E02. History of antiphospholipid antibody syndrome. E03. History of arterial or venous thromboembolism, atrial fibrillation, severe valvular heart disease, myocardial infarction, angina pectoris, transient ischemic attack, or stroke. Participants who have experienced thrombosis associated with intravenous catheterization are also eligible to register. E04. A history of malignant tumors within two years prior to screening, excluding basal cell carcinoma or squamous cell carcinoma of the skin that was successfully treated. E05. Individuals who have completed surgery within 14 days prior to screening, or who have received additional CFC or BPA injections for postoperative hemostasis. E06. If surgery is anticipated to be necessary during the trial, or if surgery is scheduled during the trial, at the time of screening. History of intolerance to E07.1 or multiple SC injections. E08. History of alcohol abuse within 12 months prior to screening. In this study, alcohol abuse is defined as regular consumption of more than 14 units per week (1 unit = 1 glass of wine [approx. 125 mL] = 1 major (approx. 1 fluid ounce) of spirits = 1 / 2 pint (approx. 284 mL) of beer). E09. Presence of clinically significant liver disease or any of the following conditions: - A history of cirrhosis, portal hypertension, esophageal varices, hepatic fibrosis, or hepatic encephalopathy, - Presence of ascites (fluid in the abdomen) on physical examination. Past therapies / combination therapies E11. Bleeding was well controlled with emicizumab administration, and the patient was well-tolerated (no side effects). E12. Currently participating in immune tolerance induction therapy. E13. Past gene therapies. Past / concurrent clinical trial experience E14. Current or past participation in the Fitsilan trial. E15. Participation in current or past gene therapy clinical trials. E16. The patient received the investigational drug or device within 30 days prior to the screening visit or within the longer of the following half-lives of the investigational drug (or device containing the investigational drug [IMP]) prior to the screening visit. Diagnostic evaluation E17. AT activity at the time of screening must be less than 60%, as determined by measurements taken in the central laboratory. E18. Coexisting thrombotic disorders determined by the presence of any of the following, identified in the central laboratory (or via past results, if available): - Factor V Leiden mutation (homozygous or heterozygous). - Protein S deficiency. - Protein C deficiency. - Prothrombin mutation (G20210A; homozygous or heterozygous). E19. ALT and / or AST > 1.5 × Upper limit of normal reference range (ULN). E20. Total bilirubin > 1.5 × ULN (in participants with Gilbert's syndrome, > 2.0 × ULN). E21. Participants who are positive for hepatitis C virus (HCV) antibodies, except for those with a history of HCV infection meeting both of the following conditions: - Completion of therapeutic treatment at least 12 weeks prior to registration, achieving a sustained virological response as demonstrated by negative HCV ribonucleic acid (RNA) at screening, or spontaneous clearing of infection as demonstrated by negative HCV RNA at screening. - No cirrhosis is detected by any of the following assessments: - FibroScan less than 12.5kPa (if available), or - FibroTest score less than 0.75 and AST to platelet ratio index (APRI) less than 2 (if FibroScan is unavailable). E22. The presence of acute hepatitis, i.e., hepatitis A and hepatitis E. E23. Presence of acute or chronic hepatitis B infection (positive for IgM anti-HBc antibody or positive for hepatitis B serum antigen (HBs Ag)). E24. Platelet count 100,000 / μL or less. E25. Presence of acute, severe, or serious infection at the time of screening. It is known that E26.CD4 counts of less than 200 cells / μL indicate HIV positivity. E27. Estimated glomerular filtration rate: 45 mL / min / 1.73 m 2 The following (using the Modification of Diet in Renal Disease formula):

[0157] Trial intervention All study interventions are pre-specified investigational and non-investigational drugs, medical devices, and other interventions (e.g., surgical and behavioral) intended to be administered to study participants during the study. Study participants receive their final dose of emicizumab on D-56 and initiate prophylactic treatment with fitsiran on D1. The study treatments and administration methods are summarized in Table 4 below.

[0158] [Table 5]

[0159] [Table 6]

[0160] Administration regimens and formulations Fitsilan is formulated as a 100 mg / mL sterile solution in a vial for subcutaneous injection in phosphate-buffered saline (PBS). Patients are administered 20 mg of Q2M or QM, 50 mg of Q2M or QM, or 80 mg of QM for a total of 18 months.

[0161] Dosage change All trial participants will begin treatment with a dose of 20 mg Q2M of fitsiran. The first dose will be administered on day 1. Participants may be escalated to 50 mg Q2M starting at month 4, and may switch to monthly doses according to the criteria for dose reduction or increase, targeting an AT activity range of 15% to 35% (as determined by the central laboratory). Clinical criteria will also be defined for dose adjustments based on the investigator's judgment regarding bleeding prevention achieved at each dose level.

[0162] If an adverse event (AE) occurs in a participant that the principal investigator determines presents a potential risk to the participant for further administration, the principal investigator may, at their discretion, withhold the administration of fitsiran and contact the medical monitoring team.

[0163] Antithrombin criteria for dosage adjustment: Trial participants whose AT activity level falls outside the target range (less than 15% or greater than 35% as determined by the central laboratory) must follow the instructions outlined below.

[0164] Gradual reduction in antithrombin concentration below 15%: If a study participant experiences multiple AT activity levels (as determined by the central laboratory) below 15% within 12 months at the current dose level, fitsiran must be gradually reduced or discontinued.

[0165] At each dosage level, if the first AT activity level is less than 15% (by central laboratory), the participant must have another AT measurement taken within one week of the location where the results are received. If the result is less than 15% (by central laboratory), this will be considered a second AT level of less than 15%. Participants with one AT level of less than 15% should not be administered fitsiran in the current regimen until a second AT activity level is obtained and provides guidance for management.

[0166] Participants who received fitsiran once every two months (Q2M): Participants receiving 20 mg Q2M of fitsiran who experience an AT activity level of less than 15% (as determined by the central laboratory) two or more times within a 12-month period must permanently discontinue treatment with fitsiran. Participants receiving fitsiran at a dose of 50 mg Q2M who experience an AT activity level of less than 15% (as determined by the central laboratory) on two or more occasions within a 12-month period must be tapered to 20 mg QM. Participants may resume medication at their monthly visits immediately after their AT activity level recovers to 22% or higher (as determined by the central laboratory).

[0167] Participants (QM) receiving Fitsiran once a month: - Participants who have been increased to 50 mg QM or 80 mg QM due to AT activity of 35% or higher, and who have experienced AT activity levels of less than 15% (as determined by the central laboratory) at least twice within the past 12 months at their current dose escalation level: - Permanently discontinue the treatment with Physirane, or - The dose will be gradually reduced to the previous dose level, i.e., 50 mg Q2M (from 50 mg QM) or 50 mg QM (from 80 mg QM). Further dose increases will not be permitted for these participants. Administration at the low dose level may be resumed according to the visit schedule Q2M or QM when the participant's AT activity level recovers to 22% or higher (as determined by the central laboratory). - Participants receiving fitsiran at a dose of 20 mg QM who experience an AT activity level of less than 15% (by central laboratory) two or more times within 12 months at the current dose escalation level must permanently discontinue fitsiran treatment. - Participants who experience an AT activity level of less than 15% (by central laboratory) two or more times within 12 months at the current dose escalation level, or who have been increased to 50 mg QM or 80 mg QM based on clinical criteria, must permanently discontinue fitsiran treatment.

[0168] Gradual increase when AT exceeds 35% Participants are eligible for dose escalation in the following cases: - If you have administered Fitusiran at the current dosage level at least four times, and - Based on the measurement of AT activity at the third dose at the current dosage level, at least two instances of AT activity levels exceeding 35% (by central laboratory) have been experienced (however, if the 20 mg Q2M dosage regimen is initiated, it can be gradually increased after two doses of fitsiran, so it should be started from the fourth month), and fitsiran administration and AT activity evaluation are being carried out as planned at the current dosage level.

[0169] Participants who received fitsiran under the following conditions are eligible. Gradually increase from -20mg Q2M to 50mg Q2M. Gradually increase from -50mg Q2M to 50mg QM. Gradually increase the dose from -50mg QM to 80mg QM.

[0170] In a dose escalation schedule from Q2M to QM (50 mg), the final dose of Q2M is considered the first dose of QM.

[0171] Clinical criteria for dose adjustment: The investigator may increase the dose of fitsiran to a higher dose if the participant has received at least two doses of fitsiran at the current dose, despite an AT activity level of 35% or less, and the investigator determines that bleeding control is not optimal, defined as two or more bleeding episodes treated with CFC or BPA within 12 weeks. For participants treated with QM, bleeding episodes during the first 8 weeks at the current dose level are not considered in this determination. For participants treated with Q2M, bleeding episodes during the first 12 weeks at the current dose level are not considered in this determination.

[0172] Antithrombin activity levels, and, where applicable, additional clinical data, will be considered in dose escalation for individual participants.

[0173] Test evaluation A bleeding episode is defined as any occurrence of bleeding requiring the administration of CFC or BPA, such as joint bleeding, muscle bleeding, or mucosal bleeding. The definitions of bleeding episode types described below are based on the consensus of the International Society on Thrombosis and Haemostasis (ISTH) (Irio et al., Ann Intern Med (2019) 171(8):540-6).

[0174] The onset time of a bleeding episode is considered to be the time when the symptoms of the bleeding episode first appear. Any bleeding at this site, or any symptoms of bleeding at this site that occur within 72 hours of the last injection used to treat a bleeding episode at the same site, is considered part of the original bleeding event and counted as one bleeding episode for ABR. Any bleeding symptoms that begin more than 72 hours after the last injection used to treat a bleeding episode at this site constitute a new bleeding event.

[0175] A spontaneous bleeding episode is a bleeding event that occurs without apparent or known cause, particularly in the joints, muscles, and soft tissues.

[0176] An episode of joint bleeding is characterized by an abnormal sensation in the joint ("aura"), combined with 1) increased swelling or warmth of the skin over the joint, 2) increased pain, or progressive loss of range of motion or difficulty of use of the limb compared to baseline 30.

[0177] Muscle bleeding may be characterized by pain, swelling, and loss of movement in the affected muscle group.

[0178] A target joint is defined as a joint in which three or more spontaneous bleeding episodes have occurred within a continuous six-month period; if a joint has two or fewer bleeding episodes within a continuous twelve-month period, it is no longer considered a target joint.

[0179] A traumatic bleeding episode is an episode caused by a known injury or trauma. Bleeding that occurs during sports or recreation is counted as a traumatic bleeding episode, and participants are asked to record any bleeding that occurred during such activities in their eDiary.

[0180] This study will use patient-reported outcomes (PROs) to evaluate health-related quality of life (HRQOL), physical activity, and treatment satisfaction.

[0181] Management of bleeding episodes during the pre-fitsiran treatment period During the pre-treatment period with Fitsiran, all participants must receive bleeding management therapy with locally approved FVIII concentrate (CFC) or rFVIIa. When treating participants with a history of prior emicizumab treatment, local prescribing information must be followed.

[0182] Management of breakthrough bleeding episodes during Fitsiran treatment Participants receiving fitsiran will be provided with a breakthrough bleeding management plan outlining the appropriate dosage of CFC or rFVIIa from day 1 to day 7, and the dosage from day 8 onward. This plan will be reviewed and updated at each monthly visit, and if medication changes, a new written plan will be provided to the participant.

[0183] After day 7, participants receiving prophylactic treatment with fitsiran according to the protocol should not use CFC, BPA (e.g., FVIIa), or other hemostatic agents for prophylactic treatment or bleeding episode prevention, including doses associated with anticipated hemostatic difficulties such as those related to physical activity.

[0184] Management of bleeding episodes after discontinuation of phytosis To monitor AT recovery (AT activity of 60% or more as measured by the central laboratory), an AT follow-up (AT FU) will be conducted monthly after end-of-surgery (EOS) or discontinuation of Fitusiran treatment.

[0185] If a participant's AT activity level returns to at least 60% (as determined by the central laboratory) after EOS or discontinuation of Fitsiran, the participant can resume local standard management of bleeding episodes due to CFC or BPA. Prior to AT recovery, bleeding management administration guidelines must be followed.

[0186] Example 2: Model and simulation analysis for determining the initiation of treatment and dosage level with prophylactic administration of fitsiran. In patients treated with emicizumab, it is impossible to detect the hemostatic effect of emicizumab using standard coagulation assays. According to manufacturer guidance, the effect of emicizumab may persist for up to 6 months after the last dose. This study aims to explain the safety of initiating fitsiran when emicizumab is still present approximately 2 months after discontinuation of emicizumab. The level of residual emicizumab from the last dose will likely still provide a significant preventive effect against spontaneous bleeding approximately 2 months after discontinuation, even if optimal bleeding prevention is not expected at 2 months post-discontinuation (see, for example, Chuansumrit et al., Blood (2021) 138:2116).

[0187] The scientific rationale for the switching strategy was developed based on the equivalence of thrombin generation (TG) and FVIII-like activity, theoretical concerns, and considerations of appropriate clinical practice, and is partly based on pharmacokinetic and pharmacokinetic (PKDM) simulations in a Fitsiran quantitative system pharmacology (QSP) model. Modeling analysis suggests that a washout period of 2–2.5 months is appropriate before initiating Fitsiran administration, supporting a practical approach. This washout period is substantially shorter than the 6-month washout period currently recommended for emicizumab.

[0188] The switch is planned as a cross-tapering-like design, where the PD effect from the last dose of emicizumab gradually decreases while the PD effect of fitsiran accumulates simultaneously. The objective and expected benefit of this strategy is to avoid unacceptable break-in bleeding after the last dose of emicizumab while avoiding unnecessary excessive coagulation after the initiation of fitsiran.

[0189] After approximately two months, with the aim of gradually increasing the potential for TG, the Q2M regimen is initiated with 20 mg of fitsiran, the lowest dose studied in adults that may reach AT activity levels within the desired range of 15% to 35%. Meanwhile, to ensure the potential for sustained TG before the next fitsiran administration and to enhance protection against bleeding after fitsiran introduction, emicizumab residual levels continue to decrease after a two-month interruption.

[0190] Modeling and simulation analyses were developed to predict the total FVIII-like activity during the proposed emicizumab washout period and initiation of fitsiran treatment. Published population PK (popPK) models for emicizumab and reported emicizumab-FVIII equivalence data were analyzed to consider FVIII-like activity during the washout period. Two complementary approaches, consisting of internally developed population PK / PD (popPK / PD) and QSP models, were employed to predict fitsiran-derived FVIII-like activity. This analysis utilized the popPK / PD model to simulate AT levels at the initiation of a 20 mg fitsiran Q2M regimen, and previously established QSP-based hemostatic equivalence between AT reduction and FVIII-like activity (see, e.g., Kaddi et al., Blood. (2022) 140(Suppl 1):5606-7) to predict FVIII-like activity in patients with severe hemophilia A.

[0191] We assumed that the combined FVIII-like activity derived from emicizumab and fitsiran was additive. This analysis suggests that when 20 mg of Q2M fitsiran was administered 2 months after the final dose of emicizumab (3 mg / kg QW for 4 weeks, followed by 3 mg / kg Q2M), the total FVIII-like activity remained below 35% FVIII (Figure 6).

[0192] The dose of fitsiran should not be escalated until four months prior to (i.e., completion of complete emicizumab lavage). In addition to a balanced switching strategy and risk mitigation measures, participants will be closely monitored for bleeding. Bleeding management guidance with reduced factor / BPA doses and regular, appropriate laboratory examinations will be implemented. Treatment of breakthrough bleeding with aPCC is permitted only after complete emicizumab clearance.

[0193] All PK / PD modeling described below was performed with the aim of finding dosing regimens that maintain AT activity levels between 15% and 35% as a risk reduction strategy for vascular thrombotic events.

[0194] To identify a dosing regimen that can maintain AT activity levels between 15% and 35% as a risk reduction strategy for vascular thrombotic events, we developed a population pharmacokinetic / pharmacodynamic (pop PK / PD) model describing the dynamics of AT activity levels in participants treated with fitsiran. This model was characterized based on AT activity data obtained from clinical trials. Using the model, which included estimated parameters, we simulated steady-state AT activity levels under different dosing scenarios in a hypothetical population of 1000 participants.

[0195] The simulation results are shown in Table 5. Every two months (Q2M) and every one month (QM) refer to the administration of fitsiran every 8 weeks and every 4 weeks, respectively. TroughAT and PeakAT represent the trough and peak levels of AT activity, while 5th, median, and 95th percentiles represent the 5th, median, and 95th percentiles, respectively.

[0196] [Table 7]

[0197] The starting dose for all participants in this study is 20 mg Q2M. Four months after the first dose of fitsiran, participants whose AT level exceeds 35% or who require dose escalation for clinical reasons are eligible for dose escalation to 50 mg Q2M. Based on simulation results, it is expected that approximately 45.7% of hypothetical participants will have AT activity less than 15% in the 50 mg Q2M regimen and therefore may require dose escalation. According to the protocol, these participants should be tapered from 50 mg Q2M to 20 mg Q2M.

[0198] Simulations of low-dose regimens in 1000 new hypothetical participants (20 mg Q2M and 20 mg QM) predicted that 3.8% and 23.4% of participants, respectively, would have AT activity levels below 15%. Therefore, based on the simulations, 20 mg Q2M was considered an appropriate tapering regimen for 45.7% of participants who could have AT activity levels below 15% at 50 mg Q2M. When tapering to 20 mg Q2M, approximately 8% of the tapering group may have AT activity levels below 15%, and approximately 7% may have AT activity levels above 35%, but the remaining 84% to 85% of the tapering group are predicted to have AT activity levels within the target AT window of 15% to 35%.

Claims

1. A method for providing a regular prophylactic dose to prevent or reduce the frequency of bleeding episodes in a human patient with hemophilia A who has been receiving prophylactic treatment with emicizumab, comprising subcutaneous administration to the human patient in need thereof, The first dose of fitsiran is administered approximately one to six months after the completion of the aforementioned prophylactic treatment with emicizumab, and the amount of fitsiran administered in the first dose may be approximately 10 mg or approximately 20 mg, and The subsequent dosage of phyturanc is approximately 10-80 mg, administered approximately once a month (QM), or approximately once every four weeks (Q4W), or approximately once every month (Q2M), or approximately once every eight weeks (Q8W).

2. A method for maintaining appropriate thrombin production (AG) ability in human patients with hemophilia A, regardless of whether or not they had inhibitors that had been treated prophylactically with emicizumab, the method comprising subcutaneous administration to the human patient in need thereof, The first dose of fitsiran is administered approximately one to six months after the completion of the aforementioned prophylactic treatment with emicizumab, and the amount of fitsiran administered in the first dose may be approximately 10 mg or approximately 20 mg, and The subsequent dosage of phyturanc is approximately 10-80 mg, administered approximately once a month (QM), or approximately once every four weeks (Q4W), or approximately once every month (Q2M), or approximately once every eight weeks (Q8W).

3. The method according to claim 1 or 2, wherein the patient is a hemophilia A patient with an inhibitor.

4. The method according to claim 1 or 2, wherein the patient is a hemophilia A patient without inhibitors.

5. The method according to any one of claims 1 to 4, wherein the patient is receiving prophylactic treatment with emicizumab at a dose of approximately 1.5 mg / kg to approximately 6 mg / kg about once a week (QW) to about Q4W, or about QM.

6. The method according to claim 5, wherein the patient was receiving prophylactic treatment with emicizumab at a dose of approximately 1.5 mg / kg quarterly (QW) or approximately 3 mg / kg every other week (Q2W).

7. The method according to claim 6, wherein the prophylactic emicizumab treatment in the patient is terminated approximately two months before the first dose of fitsiran.

8. The method according to claim 5, wherein the patient is receiving prophylactic treatment with emicizumab at a dose of approximately 6 mg / kg at approximately Q4W or QM.

9. The method according to claim 8, wherein the prophylactic emicizumab treatment in the patient is completed about two and a half months before the first dose of fitisiran.

10. The method according to any one of claims 1 to 9, wherein the patient is an adolescent or adult, and the first and second doses of fitsiran are each about 20 mg, administered at intervals of about 2 months or about 8 weeks.

11. The method according to any one of claims 1 to 9, wherein the patient is a pediatric patient, the first and second doses of fitsiran are each about 10 mg, and are administered at intervals of about 2 months or about 8 weeks.

12. After administering fitsilan twice, or at steady state (SS) in the patient, measure the antithrombin (AT) level; (i) If the AT level is 15-35%, the administration of the first dose of fitsilan shall be repeated approximately every 2 months (Q2M) or every 8 weeks (Q8W); (ii) If the AT level exceeds 35%, administer approximately 50 mg of fitsilan subcutaneously to the patient at Q2M or Q8W, or (iii) If the AT level is less than 15%, discontinue or interrupt the treatment with Fitsilan. The method according to any one of claims 1 to 11, further comprising performing any one of the steps of:

13. After step (ii), (a) If the patient has two SS measurements with an AT level exceeding 35%, administer approximately 50 mg of fitsilan subcutaneously to the patient at QM or approximately Q4W, then (a1) If the patient has two SS measurements with an AT level of 35%, administer 80 mg of fitsilan subcutaneously to the patient at approximately QM or approximately Q4W, and if the patient has two or more measurements with an AT level of less than 15%, reduce the dose to the aforementioned administration regimen; or (a2) If the patient has two or more measurements in which the AT level is less than 15%, gradually reduce the dosage regimen to (ii); (b) If the patient has two or more measurements showing an AT level of less than 15%, administer approximately 20 mg of phytsialan subcutaneously to the patient, (b1) If the patient has one or more measurements showing an AT level of 22% or higher, administer approximately 20 mg QM of fitsilan repeatedly; and (b) If the patient has two or more measurements showing an AT level of less than 15%, discontinue treatment with Fitsilan; The method according to claim 12, including the method described in claim 12.

14. The method according to any one of claims 1 to 13, comprising administering to the patient an effective amount of replacement factor VIII or bypass agent (BPA) to treat a bleeding episode occurring within seven days following the first administration of fitsilan, wherein the effective amount of replacement factor or BPA is administered in accordance with the patient's previous administration regimen of the replacement factor or BPA.

15. The method according to any one of claims 1 to 13, comprising administering to the patient an effective dose of replacement factor VIII or bypass agent (BPA) to treat a bleeding episode occurring more than eight days after the first administration of fitisran, wherein the effective dose of the replacement factor or BPA is reduced compared to the recommended effective dose of the replacement factor or BPA for a patient not receiving fitisran therapy.

16. The method according to claim 15, wherein the patient is a patient without a factor VIII inhibitor, the supplement factor is factor VIII, the single dose of factor VIII is 20 IU / kg or less, optionally 10 IU / kg, and the administration of factor VIII may be repeated at intervals of 24 hours or more if necessary.

17. The method according to claim 15, wherein the patient is a patient having a factor VIII inhibitor, the BPA is activated prothrombin complex concentrate (aPCC), the single dose of aPCC is 50 U / kg or less, optionally 30 U / kg, and if administration of aPCC is necessary, it may be repeated at intervals of 24 hours or more.

18. The method according to claim 17, wherein aPCC is administered at least six months after the last dose of emicizumab, or at least four months after the first dose of fitsiran, in order to treat a bleeding episode.

19. The method according to claim 14 or 15, wherein the patient is a patient having a factor VIII inhibitor, the BPA is recombinant factor VIIa (rFVIIa), the single dose of rFVIIa is 45 μg / kg or less, and the administration of rFVIIa may be repeated after 2 hours or more if necessary.

20. A physylane for use in the method according to any one of claims 1 to 19.

21. Use of fitsilane in the manufacture of a pharmaceutical product for use in the method according to any one of claims 1 to 19.

22. A type of physalilan for use in regular prophylactic administration to prevent or reduce the frequency of bleeding episodes, Human patients with hemophilia A are receiving prophylactic treatment with emicizumab. This includes subcutaneous administration to the aforementioned human patient who requires it, The first dose of fitsiran is administered between one and six months after the completion of the aforementioned prophylactic treatment with emicizumab, and the amount of fitsiran in the first dose may be 10 mg or 20 mg, and A type of physiran characterized in that the subsequent dose of physiran is 10 to 80 mg, administered once a month (QM), once every four weeks (Q4W), once every month (Q2M), or once every eight weeks (Q8W).

23. Fitsilan for use in the treatment of hemophilia A, The aforementioned treatment includes periodic prophylactic administration to prevent or reduce the frequency of bleeding episodes. Human patients with hemophilia A are receiving prophylactic treatment with emicizumab. This includes subcutaneous administration to the aforementioned human patient who requires it, The first dose of fitsiran is administered between one and six months after the completion of the aforementioned prophylactic treatment with emicizumab, and the amount of fitsiran in the first dose may be 10 mg or 20 mg, and A type of physiran characterized in that the subsequent dose of physiran is 10 to 80 mg, administered once a month (QM), once every four weeks (Q4W), once every month (Q2M), or once every eight weeks (Q8W).

24. Fitusiran for use in the treatment of hemophilia A with or without inhibitors, The aforementioned treatment includes maintaining appropriate thrombin production (AG) ability, In the aforementioned human patient suffering from hemophilia A, who is receiving prophylactic treatment with emicizumab, This includes subcutaneous administration to the aforementioned human patient who requires it, The first dose of fitsiran is administered between one and six months after the completion of the aforementioned prophylactic treatment with emicizumab, and the amount of fitsiran in the first dose may be 10 mg or 20 mg, and A type of physiran characterized in that the subsequent dose of physiran is 10 to 80 mg, administered once a month (QM), once every four weeks (Q4W), once every month (Q2M), or once every eight weeks (Q8W).

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