Bimonthly administration of FVIII mimetic bispecific antibodies

Abstract

To provide improved methods of administering particular bispecific FVIII mimetic antibodies to patients suffering from haemophilia A, such as haemophilia A with or without inhibitors.SOLUTION: The present invention generally relates to the use of bispecific FVIII mimetic antibodies in treatment of haemophilia such as haemophilia A with or without inhibitors and in particular methods for the treatment of diseases such as once every second month dosage regimens, and compositions for use in such methods.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method of administering a Factor VIII mimetic antibody to a hemophilia patient.

[0002] Incorporation by reference of sequence listing This application is submitted with an electronic Sequence Listing, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] In patients with blood clotting disorders, such as people with hemophilia A and B, various steps in the coagulation cascade malfunction, for example, due to the absence or insufficient presence of functional clotting factors. Malfunction of some parts of this coagulation cascade results in insufficient blood clotting and potentially life-threatening bleeding or damage to internal organs, such as joints.

[0004] Coagulation factor VIII (FVIII) deficiency, commonly referred to as hemophilia A, is a congenital bleeding disorder affecting approximately 420,000 people worldwide, of which approximately 105,000 are currently diagnosed. Hemophilia A has three severity grades, defined by FVIII plasma levels of 5 to <40%: ≤1% (severe), 2-5% (moderate), and 6-30% (mild) (Non-Patent Document 1), or according to Non-Patent Document 2. Bleeding can occur spontaneously or after trauma. Approximately half of patients with hemophilia A are classified as having severe hemophilia A, experiencing severe bleeding beginning in early childhood and frequent episodes of spontaneous or excessive bleeding later in life. Bleeding commonly occurs within joints and muscles, and without appropriate treatment, recurrent bleeding can lead to irreversible hemophilic arthropathy (Non-Patent Document 3).

[0005] Patients with hemophilia A may receive clotting factor replacement therapy, such as exogenous FVIII. Traditional treatment consists of replacement therapy, provided as prophylaxis or as demand treatment for bleeding episodes. Until recently, prophylactic treatment for patients with severe hemophilia A has consisted of intravenous injections up to three times a week with either plasma-derived or recombinant FVIII, or its long-acting variants.

[0006] However, such patients are at risk of developing neutralizing antibodies, so-called inhibitors, against these exogenous factors, rendering previously effective treatments ineffective. Hemophilia A patients with inhibitors are a non-limiting example of a blood clotting disorder that is partly congenital and partly acquired. Patients who develop inhibitors to FVIII cannot be treated with conventional replacement therapy.

[0007] Exogenous clotting factors may only be administered intravenously, which is quite inconvenient and uncomfortable for the patient. For example, infants and young children may need to have an intravenous catheter surgically inserted into a chest vein to ensure venous access. This greatly increases the risk of developing a bacterial infection.

[0008] The FVIII mimetic emicizumab (HEMLIBRA®), also known as ACE910, is approved for subcutaneous prophylactic treatment of hemophilia A with or without an inhibitor. Emicizumab is a humanized bispecific anti-FIX(a) / anti-FX(a) monoclonal antibody developed by Chugai Pharmaceuticals / Roche Pharmaceuticals for the treatment of hemophilia A. Emicizumab is designed to mimic FVIII cofactor function (see Non-Patent Document 4 and Patent Document 1).

[0009] US Patent Nos. 5,929,999 and 5,929,999 disclose dosing regimens described as being useful for administering emicizumab.

[0010] For example, US Pat. No. 6,299,499, US Pat. No. 6,299,499 and US Pat. No. 6,299,499 also disclose FVIII mimetic anti-FIX(a) anti-FX(a) bispecific antibodies and their use as procoagulants for the treatment of hemophilia A.

[0011] There is a need in the art for improved methods of administering certain bispecific FVIII mimetic antibodies to patients suffering from hemophilia A, for example, hemophilia A with or without inhibitors. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Publication No. 2012 / 067176 [Patent Document 2] International Publication No. 2015 / 194233 [Patent Document 3] International Publication No. 2018 / 047813 [Patent Document 4] International Publication No. 2018 / 021450 [Patent Document 5] International Publication No. 2020 / 025672 [Patent Document 6] International Publication No. 2021 / 152066 [Non-patent literature]

[0013] [Non-Patent Document 1] White et al. (2001) Thromb.Haemost.85:560 [Non-patent document 2] WFH “Guidelines for the management of haemophilia”2nd edition Haemophilia;Epub 6 JUL 2012 [Non-patent document 3] Manco-Johnson et al. (2007) N. Engl. J. Med. 357:535-44 [Non-patent document 4] Sampei et al.:(2013)PLoS One,8,e57479 Summary of the Invention

[0014] The present invention relates to methods of administering bispecific antibodies that function as substitutes for coagulation factor VIII (FVIII) in patients suffering from blood clotting disorders, in particular in patients lacking functional FVIII, such as hemophilia A patients, including hemophilia A patients with inhibitors. In particular, the bispecific antibodies are suitable for use in the treatment of hemophilia A with or without inhibitors, and are capable of binding to FIX (SEQ ID NO: 1) or its activated form, and FX (SEQ ID NO: 2) or its activated form.

[0015] In one aspect the invention provides a bispecific antibody for use in the treatment of hemophilia A, with or without an inhibitor, the bispecific antibody comprising: an anti-FIX(a) antibody or antigen-binding fragment thereof, which comprises a heavy chain and a light chain and is capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa); an anti-FX(a) antibody or antigen-binding fragment thereof, comprising a heavy chain and a light chain, capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa); the heavy chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 3, 4, and 5, respectively; the light chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 8, 9, and 10, respectively; the heavy chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 13, 14, and 15, respectively; the light chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 18, 19, and 20, respectively; the bispecific antibody is administered subcutaneously to a human patient in a composition comprising the bispecific antibody; a dose containing approximately 20 mg of the bispecific antibody administered once every two months to a patient weighing between 5 kg and less than 15 kg; or a dose containing approximately 46 mg of the bispecific antibody administered once every two months to a patient weighing between 15 kg and less than 45 kg; or - Concerning a bispecific antibody, wherein a dose comprising about 92 mg of the bispecific antibody is administered once every two months to a patient having a body weight of 45 kg or more.

[0016] In one embodiment, the dose administered to a patient weighing between 15 kg and less than 45 kg or more than 45 kg is a maintenance dose, and a loading dose is administered before the first maintenance dose. a loading dose containing about 49 mg of the bispecific antibody is administered to a patient weighing less than 15 kg to 45 kg; or a loading dose comprising approximately 112 mg of the bispecific antibody is administered to a patient weighing 45 kg or more; The first maintenance dose is administered two months after the loading dose.

[0017] In a preferred embodiment, the bispecific antibody comprises a first heavy chain comprising SEQ ID NO: 7 and a first light chain comprising SEQ ID NO: 12, and a second heavy chain comprising SEQ ID NO: 17 and a second light chain comprising SEQ ID NO: 22 (INN name: "denecimig", sometimes also called "Mim8").

[0018] In one embodiment, a mean plasma concentration of the bispecific antibody in the range of about 3 μg / mL to about 30 μg / mL, about 3 μg / mL to about 18 μg / mL, for example in the range of 3 to 9 μg / mL, for example 6.5 μg / mL, is provided.

[0019] In one embodiment, a patient receiving a denecimig loading dose suitable for a weekly, biweekly, or monthly dosing regimen as described in PCT / EP2023 / 055238, PCT / EP2023 / 055242, or PCT / EP2023 / 055240 is switched to a bimonthly dosing regimen as described herein.

[0020] In one embodiment, a patient being treated with a denesimig maintenance dose once weekly, once every two weeks, or once monthly as described in the publication is switched to a once every two months dosing regimen as described herein.

[0021] In one aspect, the invention relates to a pharmaceutical composition comprising a bispecific antibody as described herein.

[0022] In one embodiment, the bispecific antibody is administered subcutaneously to a human patient in a pharmaceutical composition comprising the bispecific antibody as described herein.

[0023] In some embodiments, the bispecific antibody is administered as disclosed herein in a loading dose followed by a maintenance dose.

[0024] In another aspect, the invention relates to a kit comprising a composition comprising a bispecific antibody, e.g., in an injection device, and instructions for use. [Brief explanation of the drawings]

[0025] [Figure 1] FIG. 1 shows SEQ ID NOs: 3 to 22 in a tabular format. [Figure 2] Figure 2 shows the mean profile of denesimig concentrations in patient plasma. Measurements below the lower limit of quantitation before administration were set to 0. Concentrations of 0 are reported as 1e-2 μg / mL due to the logarithmic scale. Vertical lines indicate two pharmacokinetic (PK) sessions. PK session days 56-63 were used for cohorts 1-3 and 5 (weekly), and days 56-84 were used for cohort 4 (weekly). Mean ± SEM. [Figure 3]Figure 3 shows a visual predictive check of the PK model fit to the observed data in the FRONTIER1 multiple ascending dose (MAD) portion. Data points are individual denesimig plasma concentrations over time. The solid line represents the median of the observed data, and the dashed line represents the model-predicted median denesimig plasma concentration versus time. The dotted lines represent the 5th (lower) and 95th (upper) percentiles of the model predictions from 1000 study simulations using the PK model. Across all cohorts, the model adequately captures the median trend line and the variability of the data. [Figure 4] Figure 4 shows peak thrombin levels in patients treated with escalating doses of denesimig and clinically recommended doses of emicizumab (emi). Plasma samples were collected at various time points throughout the treatment period from patients treated with different doses of denesimig (MAD cohort), who were initiating treatment with emicizumab or were on established emicizumab prophylaxis (MAD cohort). Latent FVIII activity was neutralized by the addition of anti-FVIII antibody, and thrombin generation studies were performed ex vivo. Solid lines represent in vitro samples of human plasma from healthy subjects induced with hemophilia A-like anti-FVIII antibody and spiked with different concentrations of denesimig or emicizumab. Dashed lines represent the mean denesimig plasma concentration (Cavg calculated based on PK analysis) for each designated cohort. [Figure 5] Figures 5a, 5b, and 5c show predicted typical PK profiles of denesimig in subjects with different body weights during steady-state dosing (weeks 0–12) at QM, Q2W, and QW, respectively, followed by transition to Q2M at week 13 at the doses illustrated in Table 8. PK simulations demonstrate that all subjects, regardless of body weight, should achieve denesimig plasma concentrations within the therapeutic range, as defined by a minimum concentration comparable to that in FRONTIER1 MAD Cohort 1 (C1) (1 μg / mL) and the individual maximum concentration observed in MAD Cohort 5 (34 μg / mL). This is demonstrated for both QW, Q2W, and QM dosing intervals. "ss" refers to the steady-state PK profile of denesimig before transition to Q2M dosing. [Figure 6] Figure 6 shows typical predicted PK profiles of denesimig in subjects with different body weights without previous denesimig exposure after multiple Q2M doses as illustrated in Table 8. The PK simulations demonstrate that all subjects, regardless of body weight, should achieve denesimig plasma concentrations within the therapeutic range as defined by a minimum concentration comparable to that in FRONTIER1 MAD Cohort 1 (C1) (1 μg / mL) and the individual maximum concentration observed in MAD Cohort 5 (34 μg / mL).

[0026] A brief description of the sequence SEQ ID NO: 1 represents the amino acid sequence of human coagulation factor IX.

[0027] SEQ ID NO: 2 represents the amino acid sequence of human coagulation factor X.

[0028] SEQ ID NOs: 3 to 22 represent the amino acid sequences of components of / from the bispecific antibody "Denesimig" referred to herein as follows: SEQ ID NOs: 3, 4, and 5 represent complementarity determining regions (CDRs) 1 to 3, respectively, of the heavy chain of the anti-FIX(a) antibody component of Denesimig. SEQ ID NO: 6 shows the heavy chain variable domain (V) of the anti-FIX(a) antibody component of Denesimig. H ) SEQ ID NO: 7 represents the full-length heavy chain of the anti-FIX(a) antibody component of Denesimig. SEQ ID NOs: 8, 9, and 10 represent CDRs 1 to 3, respectively, of the light chain of the Denesimig anti-FIX(a) antibody component. SEQ ID NO: 11 is the light chain variable domain (V) of the anti-FIX(a) antibody component of Denesimig. L ) SEQ ID NO: 12 represents the full-length light chain of the anti-FIX(a) antibody component of Denesimig. SEQ ID NOs: 13, 14, and 15 represent CDRs 1-3, respectively, of the heavy chain of the anti-FX(a) antibody component of Denesimig. SEQ ID NO: 16 is the heavy chain variable domain (V) of the anti-FX(a) antibody component of Denesimig. H ) SEQ ID NO: 17 represents the full-length heavy chain of the anti-FX(a) antibody component of Denesimig. SEQ ID NOs: 18, 19, and 20 represent CDRs 1-3, respectively, of the light chain of Denesimig's anti-FX(a) antibody component. SEQ ID NO: 21 is the light chain variable domain (V) of the anti-FX(a) antibody component of Denesimig. L ) SEQ ID NO: 22 represents the full-length light chain of the anti-FX(a) antibody component of Denesimig.

[0029] In addition to the electronic sequence listing provided herewith, Figure 1 shows SEQ ID NOS: 3-22 in tabular form. DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention relates to methods of administering bispecific antibodies that function as a substitute for coagulation factor VIII (FVIII) in patients suffering from blood clotting disorders, particularly in patients lacking functional FVIII, such as hemophilia A patients, including those with and without inhibitors, and compositions comprising such bispecific antibodies, particularly in a bimonthly dosing regimen.

[0031] In order that the present invention may be more readily understood, certain terms are first defined.

[0032] The terms "a" or "an" are intended to mean "one or more." When preceding a list of steps or elements, the word "comprise" and variations thereof, such as "comprises" and "comprising," are intended to mean that the addition of further steps or elements is optional and not excluded.

[0033] The term "about" is used herein to mean approximately, roughly, or in the region of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, the term about can modify numerical values ​​above and below the stated value by 10 percent above or below (higher or lower).

[0034] The term "annualized bleeding rate" (ABR) refers to the number of treated bleeding episodes (including spontaneous and traumatic bleeding) experienced by a patient during a defined period, extrapolated to one year. For example, two bleeding episodes in six months may indicate an ABR of 4.

[0035] The term antibody includes, but is not limited to, antibodies that are bivalent, such as bispecific antibodies. Full-length antibodies contain at least four polypeptide chains: two heavy chains (HC) and two light chains (LC) linked by disulfide bonds. One class of immunoglobulin with particular pharmaceutical interest is IgG. In humans, the IgG class can be divided into four subclasses, IgG1, IgG2, IgG3, and in a preferred embodiment, IgG4, based on the sequences of their heavy chain constant regions. Light chains can be divided into two types, kappa chains and lambda chains, based on differences in their sequence composition. IgG molecules are composed of two heavy chains linked by two or more disulfide bonds and two light chains, each attached to a heavy chain by a disulfide bond. IgG heavy chains contain a heavy chain variable domain (V H ) and up to three heavy chain constants (C H ) Domain: C H 1. C H 2, and C H 3. The light chain may comprise a light chain variable domain (V L ) and the light chain constant domain (C L ) may be included. V H and V LThe regions can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs) or hypervariable regions (HvRs), interspersed with more conserved regions, called framework regions (FRs). H and V L A domain typically consists of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The heavy and light chain variable domains, containing the hypervariable regions (CDRs), form a structure capable of interacting with an antigen, while the antibody constant region can mediate the binding of the immunoglobulin to host tissues or factors, including, but not limited to, various cells of the immune system (effector cells), Fc receptors, and C1q, the first component of the C1 complex of the classical complement system.

[0036] Antibodies or fragments thereof can be defined in terms of their complementarity-determining regions (CDRs). The term "complementarity-determining region" or "CDR," as used herein, refers to the region of an antibody in which the amino acid residues involved in antigen binding are located. CDRs can be identified as the regions of greatest variability in the amino acid alignment of antibody variable domains. Databases such as the Kabat database can be used to identify CDRs, which are defined as comprising, for example, amino acid residues 24-34 (L1), 50-56 (L2), and 89-97 (L3) of the light chain variable domain and amino acid residues 31-35 (H1), 50-65 (H2), and 95-102 (H3) of the heavy chain variable domain (Kabat et al. 1991; Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242). Typically, the numbering of amino acid residues in this region is performed according to the method described in Kabat et al., supra. As used herein, phrases such as "Kabat position," "Kabat residue," and "according to Kabat" refer to this numbering system for a heavy chain variable domain or a light chain variable domain, and the Kabat numbering is used herein unless contradicted by context.

[0037] As used herein, the term "bispecific antibody" refers to an antibody that can bind to two different antigens or two different epitopes on the same antigen.

[0038] The term "fixed dose" of a bispecific antibody refers to a dose administered to a patient having a weight that falls within a predetermined range (e.g., 15 kg to less than 45 kg). Thus, a fixed dose is provided as an absolute amount of bispecific antibody, rather than as a mg / kg dose.

[0039] As used herein, the term "human antibody" is intended to include antibodies having variable domains in which at least a portion of the framework regions and / or at least a portion of the CDR regions are derived from human germline immunoglobulin sequences. For example, a human antibody may have a variable domain in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region, or a portion thereof, is also derived from human germline immunoglobulin sequences. Preferably, a human antibody is a monoclonal antibody.

[0040] As used herein, "denesimig" refers to a bispecific antibody comprising an anti-FIX(a) antibody capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa), comprising a heavy chain and a light chain, and an anti-FX(a) antibody capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa), comprising a heavy chain and a light chain, wherein the heavy chain of the anti-FIX(a) antibody comprises SEQ ID NO: 7, the light chain of the anti-FIX(a) antibody comprises SEQ ID NO: 12, the heavy chain of the anti-FX(a) antibody comprises SEQ ID NO: 17, and the light chain of the anti-FX(a) antibody comprises SEQ ID NO: 22. The bispecific antibody comprises CDR sequences represented by SEQ ID NOs: 3, 4, 5, 8, 9, 10, 13, 14, 15, 18, 19, and 20.

[0041] The term "dosing regimen" or "dosing regimen" includes a treatment regimen based on a determined series of doses. For example, in one embodiment, the invention describes a dosing regimen for the treatment of hemophilia A, with or without an inhibitor, in which a bispecific antibody is administered initially in a loading dose, followed by maintenance doses comprising the same or a smaller amount of bispecific antibody as the loading dose.

[0042] The term "dosing" refers to the administration of a substance (eg, denecimig) to achieve a therapeutic goal (eg, treatment of hemophilia A with or without an inhibitor).

[0043] A "dose" can be administered in a single dose or in multiple sequential doses. For example, a 60 mg dose can be administered in a single 60 mg dose or in two sequential doses of 30 mg each, and a 120 mg dose can be administered in three sequential doses of, for example, 40 mg. Sequential administration of doses within one hour of administration of the first dose will total one dose (e.g., a loading dose that cannot be easily administered in a single dose).

[0044] The term "FIX (SEQ ID NO: 1) and / or its activated form (FIXa)" may also be referred to as "FIX / FIXa" or simply "FIX(a)".

[0045] The term "FX (SEQ ID NO: 2) and / or its activated form (FXa)" may also be referred to as "FX / FXa" or simply "FX(a)".

[0046] The term "heavy chain" includes a full-length heavy chain, which includes a variable region domain, V H , as well as three constant region domains, C H 1. C H 2, and C H Includes 3. V H The domain is located at the amino terminus of the polypeptide and is C H The domain is located at the carboxyl terminus and is C H 3 is closest to the -COOH terminus.

[0047] As used herein, the term "light chain" includes a full-length light chain. A full-length light chain includes a variable region domain, V L , and a constant region domain, C L The variable region domain of the light chain is at the amino-terminus of the polypeptide. Light chains as described herein include kappa chains and lambda chains.

[0048] The term "kit" refers to a packaged product containing components and instructions for administering a bispecific antibody (e.g., denesimig) for the treatment of a disorder. The kit preferably includes a box or container holding the kit components. The box or container is accompanied by a label or a Food and Drug Administration (or corresponding authority) approved protocol.

[0049] As used herein, the term "loading dose" refers to the initial dose of a bispecific antibody administered to a patient at the start of a treatment regimen. Generally, the loading dose is intended to achieve a therapeutically relevant plasma concentration of the bispecific antibody in the patient's body within a short period of time.

[0050] The term "loading period" refers to a period of treatment for a patient, including administering a bispecific antibody to the patient to induce a clinical response. The "loading period" is typically between one week and one month, depending on the desired administration frequency, and begins with the administration of a first loading dose. The loading period precedes the administration of the first maintenance dose.

[0051] As used herein, the term "maintenance dose" relates to a dose of a bispecific antibody administered to a patient at a time after administration of a loading dose.

[0052] “Maximum plasma concentration” (C max The term ) refers to the highest observed concentration of bispecific antibody in the patient's plasma after administration of the bispecific antibody to the patient.

[0053] "Mean plasma concentration" (or "C avg ") refers to the average plasma concentration of the bispecific antibody within the dosing interval at steady state.

[0054] "Denimig plasma concentration steady state C max " refers to a state in which the maximum plasma concentration after administration of denesimig remains unchanged from one dose to another. In one embodiment, the steady-state C maxIn another embodiment, the steady-state C of densimig plasma concentration is about 18 μg / mL. max is approximately 9 μg / mL.

[0055] "Denimig plasma concentration steady state C min " refers to a state in which the minimum plasma concentration after administration of denesimig remains unchanged from one dose to another. In one embodiment, the steady-state C min In another embodiment, the steady-state C of densimig plasma concentration is about 2 μg / mL. min is approximately 3 μg / mL.

[0056] The term "serum or plasma half-life" refers to the time required for half of the amount of a substance administered to a patient to be metabolized or removed from the patient's serum or plasma by normal biological processes.

[0057] The term "prophylactic treatment" refers to the administration of a therapy for the treatment of hemophilia A, with or without an inhibitor, where such treatment is intended to, for example, control, manage, prevent, or reduce the occurrence and / or severity of one or more symptoms of hemophilia A, with or without an inhibitor, e.g., bleeding episodes, e.g., one or more spontaneous bleeding episodes, and / or joint damage.

[0058] The term "treatment" or "treating" refers to a reduction in the frequency of one or more symptoms of hemophilia A, e.g., spontaneous or uncontrollable bleeding episodes, with or without an inhibitor. "Treatment," however, does not necessarily mean a cure.

[0059] "T max The term "maximum concentration of a substance in the plasma of a patient" refers to the observed time to reach a maximum concentration of a substance in the patient's plasma after administration of the substance to the patient.

[0060] The present invention relates to methods of administering bispecific antibodies that function as a substitute for coagulation factor VIII (FVIII) in patients suffering from blood clotting disorders, particularly in patients lacking functional FVIII, such as hemophilia A patients, including hemophilia A patients with and without inhibitors. In particular, the bispecific antibodies or antigen-binding fragments thereof can be used in the treatment of hemophilia A with or without inhibitors, and the antibodies can bind to FIX (SEQ ID NO: 1) or its activated form, and FX (SEQ ID NO: 2) or its activated form.

[0061] In one such embodiment, the heavy chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 3, 4, and 5, respectively; the light chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 8, 9, and 10, respectively; the heavy chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 13, 14, and 15, respectively; and the light chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 18, 19, and 20, respectively.

[0062] In one such embodiment, the anti-FIX(a) antibody or antigen-binding fragment thereof comprises a heavy chain variable domain identified by SEQ ID NO: 6 and a light chain variable domain identified by SEQ ID NO: 11, and the anti-FX(a) antibody or antigen-binding fragment thereof comprises a heavy chain variable domain identified by SEQ ID NO: 16 and a light chain variable domain identified by SEQ ID NO: 21.

[0063] In a preferred embodiment, the bispecific antibody is of the IgG4 isotype.

[0064] In a preferred embodiment, the bispecific antibody is a human antibody.

[0065] In one embodiment, the heavy chain of the anti-FIX(a) antibody comprises SEQ ID NO: 7, the light chain of the anti-FIX(a) antibody comprises SEQ ID NO: 12, the heavy chain of the anti-FX(a) antibody comprises SEQ ID NO: 17, and the light chain of the anti-FX(a) antibody comprises SEQ ID NO: 22 (also referred to herein as Denesimig).

[0066] In one embodiment, the heavy chain of the anti-FIX(a) antibody consists of SEQ ID NO: 7, the light chain of the anti-FIX(a) antibody consists of SEQ ID NO: 12, the heavy chain of the anti-FX(a) antibody consists of SEQ ID NO: 17, and the light chain of the anti-FX(a) antibody consists of SEQ ID NO: 22 (also referred to herein as Denesimig).

[0067] The properties of bispecific antibodies are described in WO 2020 / 025672, which is incorporated herein by reference.

[0068] Thus, as is clear from the above, a bispecific antibody can be characterized by reference to its CDR sequences, its variable domain sequences, or its complete heavy and light chain sequences. For the avoidance of doubt, reference to a desmig entails the presence of heavy and light chains defined by SEQ ID NOs: 7 and 12, and 17 and 22 herein.

[0069] The methods disclosed herein involve administering bi-monthly subcutaneous injections of the bispecific antibody to a patient. Preferably, the monthly administration scheme is preceded by the administration of one or more loading doses.

[0070] In a preferred embodiment, the loading dose and maintenance dose are selected based on the patient's weight, and in particular the patient's weight range (also referred to herein as "weight band").

[0071] In such an embodiment, patients weighing between 5 kg and less than 15 kg are grouped.

[0072] In another such embodiment, patients weighing between 15 kg and less than 45 kg are grouped.

[0073] In yet another such embodiment, patients weighing 45 kg or more are grouped.

[0074] In one embodiment, the doses disclosed herein are fixed doses suitable for use in patients weighing less than 5 kg to 15 kg.

[0075] In one embodiment, the loading dose and maintenance dose are each fixed doses suitable for use in patients weighing less than 15 kg to 45 kg.

[0076] In one embodiment, the loading dose and maintenance dose are each fixed doses suitable for use in patients weighing 45 kg or greater.

[0077] Thus, in one aspect of the invention there is provided a method of treating hemophilia A, with or without an inhibitor, comprising administering an effective amount of a bispecific antibody to a patient in need thereof, the method comprising at least one administration of the bispecific antibody to the patient, and wherein the patient has a body weight of less than 15 kg.

[0078] In another aspect of the invention, there is provided a method of treating hemophilia A, with or without an inhibitor, comprising administering to a patient in need thereof an effective amount of a bispecific antibody, said method comprising: a) administering at least one loading dose of a bispecific antibody to a patient, wherein the patient weighs at least 15 kg; b) administering at least one maintenance dose of the bispecific antibody to the patient after administering the final loading dose; A method is provided.

[0079] In a preferred embodiment, such a bispecific antibody is denesimig.

[0080] In one embodiment, the loading dose and the maintenance dose, measured in mg, are not the same in terms of the amount of bispecific antibody delivered.

[0081] The administration methods disclosed herein include monthly dosing regimens that accommodate specific patient weight ranges and dosages carefully designed by the inventors to allow for safe and effective treatment.

[0082] The long half-life of denecimig, combined with the limited intersubject variability in plasma concentrations determined by the inventors, a wide therapeutic window, and near-maximal dosing, may allow for simplified weight-band dosing instead of continuous weight-based dosing. In addition to providing a safe and effective hemostatic range, weight-band-based dosing with fixed-volume infusion is more convenient than dosing per kilogram of body weight, does not require dose calculations, and reduces the risk of dosing errors. This aims to simplify dosing while taking into account differences in plasma concentrations related to weight and formulation strength (see Example 1, Table 6). This dosing modality is suitable for, but not limited to, injection devices such as pre-filled pen syringes for subcutaneous administration of denecimig.

[0083] Bimonthly dosing regimen range In a preferred embodiment, a dose of about 16 mg to about 24 mg, e.g., 20 mg, of denecimig is administered every two months to patients weighing 5 kg to less than 15 kg, a dose of about 42 mg to 50 mg, e.g., 46 mg, of denecimig is administered to patients weighing 15 kg to less than 45 kg, and a dose of about 88 mg to about 96 mg, e.g., 92 mg, of denecimig is administered to patients weighing 45 kg or more.

[0084] In one embodiment, the above doses are maintenance doses.

[0085] In one embodiment, a loading dose is administered before the first maintenance dose.

[0086] In one embodiment, a loading dose of about 49 mg of the bispecific antibody is administered to a patient weighing less than 15 kg to 45 kg prior to administration of the first maintenance dose; or A loading dose containing approximately 112 mg of bispecific antibody is administered to patients weighing 45 kg or greater.

[0087] In one such embodiment, the first maintenance dose is administered 1 to 2 months after administration of the loading dose.

[0088] In one such embodiment, the first maintenance dose is administered one month after the administration of the loading dose.

[0089] In another embodiment, the first maintenance dose is administered two months after the administration of the loading dose.

[0090] In one embodiment, a patient being treated with denesimig on a weekly, biweekly, or monthly dosing regimen, as described in International Patent Application Nos. PCT / EP2023 / 055238, PCT / EP2023 / 055242, or PCT / EP2023 / 055240, respectively, is switched to a bimonthly dosing regimen, as described herein.

[0091] Switching to a 2-monthly dosing regimen a1) One week after the loading dose in a weekly dosing regimen, a2) 2 weeks after the loading dose in a once-every-2-week dosing regimen, or a3) 1 month after the loading dose has been administered in a monthly dosing regimen, or b) at the time of the first intended maintenance dose in a weekly, biweekly, or monthly dosing regimen; or c) May be administered at the time of the second or subsequent maintenance dose in a weekly, biweekly, or monthly dosing regimen.

[0092] In a preferred embodiment, administration of the maintenance dose every two months will continue for as long as treatment is required.

[0093] In one embodiment, there is provided a method for the treatment of hemophilia, e.g., hemophilia A, with or without inhibitors, the method comprising administering to the patient a composition comprising a bispecific antibody capable of binding to FIX(a) and FX(a), wherein said administration provides a mean plasma concentration of the bispecific antibody in the range of 2 μg / mL to about 30 μg / mL, 2 μg / mL to about 18 μg / mL, preferably about 3 μg / mL to about 9 μg / mL, for example, 6-7 μg / mL, for example, 6.5-7 μg / mL.

[0094] In a preferred embodiment, the bispecific antibody comprises an anti-FIX(a) antibody or antigen-binding fragment thereof, which comprises a heavy chain and a light chain and is capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa), and an anti-FX(a) antibody or antigen-binding fragment thereof, which comprises a heavy chain and a light chain and is capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa), wherein the heavy chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 3, 4, and 5, respectively; the light chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 8, 9, and 10, respectively; the heavy chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 13, 14, and 15, respectively; The light chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises the CDR1-3 sequences identified by SEQ ID NOs: 18, 19, and 20, respectively.

[0095] In a more preferred embodiment, the anti-FIX(a) antibody or antigen-binding fragment thereof comprises a heavy chain variable domain identified by SEQ ID NO: 6 and a light chain variable domain identified by SEQ ID NO: 11, and the anti-FX(a) antibody or antigen-binding fragment thereof comprises a heavy chain variable domain identified by SEQ ID NO: 16 and a light chain variable domain identified by SEQ ID NO: 21.

[0096] In the most preferred embodiment, the heavy chain of the anti-FIX(a) antibody comprises SEQ ID NO: 7, the light chain of the anti-FIX(a) antibody comprises SEQ ID NO: 12, the heavy chain of the anti-FX(a) antibody comprises SEQ ID NO: 17, and the light chain of the anti-FX(a) antibody comprises SEQ ID NO: 22 (Deneshimig).

[0097] Loading dose of denesimig in a bimonthly dosing regimen In one embodiment, a composition comprising a bispecific antibody is administered subcutaneously as a loading dose in a once every two months dosing regimen, which can be a loading dose of 48.5, 48.6, 48.7, 48.8, 48.9, 49, 49.1, 49.2, 49.3, 49.4, or 49.5 mg, preferably 49 mg, in a patient weighing between 15 kg and less than 45 kg.

[0098] In one embodiment, the composition comprising the bispecific antibody is administered subcutaneously as a loading dose in a bimonthly dosing regimen, which can be a loading dose of 111.5, 111.6, 111.7, 111.8, 111.9, 112, 112.1, 112.2, 112.3, 112.4 or 112.5 mg, preferably 112 mg, in a patient weighing 45 kg or greater.

[0099] In one embodiment, a loading dose is not administered to a patient weighing between 5 kg and 15 kg, and the first dose administered to the patient is a maintenance dose (i.e., 20 mg every two months).

[0100] Maintenance dose of denesimig in a bimonthly dosing regimen In one embodiment, a composition comprising a bispecific antibody is administered subcutaneously as a maintenance dose in a once every two months dosing regimen, which may be a dose of 19.5, 19.6, 19.7, 19.8, 19.9, 20, 20.1, 20.2, 20.3, 20.4, or 20.5 mg, preferably 20 mg, in a patient weighing 5 kg to less than 15 kg.

[0101] In one embodiment, a composition comprising a bispecific antibody is administered subcutaneously as a maintenance dose in a once every two months dosing regimen, which may be a dose of 45.5, 45.6, 45.7, 45.8, 45.9, 46, 46.1, 46.2, 46.3, 46.4, or 46.5 mg, preferably 46 mg, in a patient weighing between 15 kg and less than 45 kg.

[0102] In one embodiment, the composition comprising the bispecific antibody is administered subcutaneously as a maintenance dose in a bimonthly dosing regimen, which can be a dose of 91.5, 91.6, 91.7, 91.9, 92, 92.1, 92.2, 92.3, 92.4 or 92.5 mg, preferably 92 mg, in a patient weighing 45 kg or greater.

[0103] In one embodiment, the administration methods disclosed herein provide an ABR of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6 0.7, 0.8, 0.9, 1, 2, 3, 4, or 5, or in the range of 0-1, 0-2, 0-3, e.g., in the range of 1-3 or 2-3, or in the range of 1-5, e.g., in the range of 1-2, 1-3, 1-4, 2-3, 2-4, 2-5, 3-4, 3-5, or 4-5.

[0104] In one embodiment, the administration method includes administering one, two, or three additional loading doses, termed "extended loading doses" to distinguish them from the initial loading dose, if the patient does not achieve an adequate clinical response at the end of the initial loading period. The dose and dosing interval during the extended loading period are typically the same as those during the initial loading period, but may be changed if the attending medical professional has reason to believe that the patient may benefit from a change, such as an increased dose and more frequent dosing of the bispecific antibody.

[0105] In one embodiment, the first maintenance dose is administered one month after the loading dose is administered to the patient.

[0106] In one embodiment, T 1 / 2 is approximately 30.4 days.

[0107] In one embodiment, T max is approximately 9.1 days.

[0108] In a preferred embodiment, the treatment disclosed herein is a preventative treatment.

[0109] In one embodiment, the administration methods disclosed herein reduce spontaneous bleeding or bleeding episodes in patients susceptible to such spontaneous bleeding or bleeding episodes.

[0110] Pharmaceutical preparations In one aspect of the present invention, pharmaceutical compositions suitable for use in the administration methods disclosed herein are provided.

[0111] Such pharmaceutical compositions preferably comprise the bispecific antibody at a concentration of 10 mg / mL to 150 mg / mL, for example, 11.25 mg / mL to 140 mg / mL, for example, 11.25 mg / mL to 57.5 mg / mL, for example, 25 mg / mL to 57.5 mg / mL, and have a pH in the range of 5.5 to 7.5, preferably in the range of 6.0 to 6.5, for example, about 6.3. In more preferred embodiments, the concentration of the bispecific antibody is 11.25 mg / mL, 25 mg / mL, or 57.5 mg / mL.

[0112] Such pharmaceutical compositions are suitable for use in fixed dose injection devices, for example, but not limited to, injection devices configured to administer 0.8 ml per injection.

[0113] In a preferred embodiment, the pharmaceutical composition is an aqueous formulation. In one embodiment, the bispecific antibody is denesimig.

[0114] Pharmaceutical compositions can further comprise one or more of buffer system, preservative, isotonicity agent, chelating agent, stabilizer, or surfactant, and various combinations thereof.The use of preservative, isotonicity agent, chelating agent, stabilizer, and surfactant in pharmaceutical compositions is well known to those skilled in the art.Remington: The Science and Practice of Pharmacy, 19th edition, 1995 can be referred to.

[0115] In one embodiment, the pharmaceutical composition comprises 10 mg / mL to 150 mg / mL of the bispecific antibody, e.g., dexamethasone, L-arginine or L-arginine hydrochloride, L-histidine, and a surfactant, at a pH ranging from 5.5 to 7.0.

[0116] In one embodiment, the pharmaceutical composition comprises 10 mg / mL to 150 mg / mL of the bispecific antibody, e.g., denatured IgG, about 150 mM L-arginine hydrochloride, about 20 mM L-histidine, polysorbate 20, or polysorbate 80, at a pH ranging from 5.5 to 7.0.

[0117] In a preferred embodiment, the pharmaceutical composition comprises about 11.25 mg / mL, about 25 mg / mL, or about 57.5 mg / mL of the bispecific antibody Denesimig, about 150 mM L-arginine hydrochloride, about 20 mM L-histidine, about 0.02 w / v% polysorbate 20, at about pH 6.3.

[0118] In another preferred embodiment, the pharmaceutical composition comprises 11.25 mg / mL of the bispecific antibody Denesimig, 150 mM L-arginine hydrochloride, 20 mM L-histidine, 0.02 w / v% polysorbate 20 at pH 6.3.

[0119] In another preferred embodiment, the pharmaceutical composition comprises 25 mg / mL of the bispecific antibody Denesimig, 150 mM L-arginine hydrochloride, 20 mM L-histidine, 0.02 w / v% polysorbate 20 at pH 6.3.

[0120] In yet another preferred embodiment, the pharmaceutical composition comprises 57.5 mg / mL of the bispecific antibody Denesimig, 150 mM L-arginine hydrochloride, 20 mM L-histidine, 0.02 w / v% polysorbate 20, at pH 6.3.

[0121] A dose of 9 mg of denecimig is administered using a concentration of 11.25 mg / mL.

[0122] In one embodiment, a 20 mg dose of denesimig is administered using a pharmaceutical composition containing a denesimig concentration of 25 mg / mL.

[0123] In one embodiment, a 46 mg dose of denesimig is administered using a pharmaceutical composition containing a denesimig concentration of 57.5 mg / mL.

[0124] In some embodiments, the pharmaceutical compositions disclosed herein are intended to be used in and / or contained within an injection device.

[0125] In preferred embodiments, the injection device is a fixed dose device, such as one configured to deliver a single dose, or a device configured to deliver multiple predetermined doses of the pharmaceutical composition, the latter sometimes referred to as a multiple fixed dose device or a fixed dose multi-shot device. In some embodiments, the injection device is a disposable, pre-filled, multi-dose device. In some embodiments, the injection device is a disposable, pre-filled, single-dose device.

[0126] In one embodiment, the pharmaceutical compositions of the present invention are administered using an injection device equipped with a tube having a needle gauge in the range of 26-36.

[0127] In one embodiment, the pharmaceutical compositions of the present invention are administered using an injection device equipped with tubing having a needle gauge in the range of 28-34.

[0128] In one embodiment, the pharmaceutical compositions of the present invention are administered using an injection device equipped with tubing having a needle gauge in the range of 29-32.

[0129] In one embodiment, the loading dose and / or maintenance dose may each be administered as a single injection, and the entire loading dose and / or maintenance dose is administered as a single administration, i.e., the entire dose is administered all at once.

[0130] In some embodiments, the loading dose and / or maintenance dose are administered in multiple smaller doses, e.g., a total of 2, 3, or 4 smaller doses making up the full loading or maintenance dose. As a non-limiting example, a loading dose of 80 mg of a bispecific antibody may be administered in three smaller doses of 60 mg each. Alternatively, for example, two 50 mg doses and one 80 mg dose administered sequentially may also be contemplated.

[0131] The pharmaceutical composition can be administered as a subcutaneous injection of at least 0.05 mL of injection solution, thereby reaching the desired dose measured in mg.

[0132] As an example, for a pharmaceutical composition containing 100 mg / mL of the compound Denesimig, a volume of 100 μL is required to provide a 10 mg dose.

[0133] The volume required will depend on the concentration of the bispecific antibody in the pharmaceutical composition being administered, as lower volumes typically require additional injections and higher volumes may typically result in patient discomfort at the injection site. Typically, a volume of injection solution between 0.08 and 1.5 mL, preferably between 0.2 and 1 mL, more preferably between 0.6 and 0.9 mL, and more preferably 0.8 mL, is administered per injection.

[0134] Thus, the pharmaceutical compositions described above, as disclosed herein, can be used for multiple sequential administrations, allowing a specific dose to be administered using a (fixed) injection solution volume of 0.8 mL per injection. For example, two injections of 0.8 mL of a pharmaceutical composition containing 12.5 mg / mL of denecimig would allow a cumulative dose of 25 mg of denecimig. In another example, two injections of 0.8 mL of a pharmaceutical composition containing 57.5 mg, followed by one injection of 0.8 mL of a pharmaceutical composition containing 20 mg, would allow a cumulative dose of 112 mg of denecimig.

[0135] The pharmaceutical compositions may be administered at the same or different injection sites.

[0136] In another general aspect, the invention relates to a kit comprising an injection device containing a pharmaceutical composition comprising dexamethasone and one or more pharmaceutically acceptable carriers, the kit including instructions for subcutaneous administration of the pharmaceutical composition for the treatment of hemophilia A, with or without an inhibitor.

[0137] Further embodiments 1. A bispecific antibody for use in the treatment of hemophilia A, with or without an inhibitor, wherein the bispecific antibody comprises: an anti-FIX(a) antibody or antigen-binding fragment thereof, which comprises a heavy chain and a light chain and is capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa); an anti-FX(a) antibody or antigen-binding fragment thereof, comprising a heavy chain and a light chain, capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa); the heavy chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 3, 4, and 5, respectively; the light chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 8, 9, and 10, respectively; the heavy chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 13, 14, and 15, respectively; the light chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 18, 19, and 20, respectively; the bispecific antibody is administered subcutaneously to a human patient in a composition comprising the bispecific antibody; a dose containing approximately 20 mg of the bispecific antibody administered once every two months to a patient weighing between 5 kg and less than 15 kg; or a dose containing approximately 46 mg of the bispecific antibody administered once every two months to a patient weighing between 15 kg and less than 45 kg; or -A bispecific antibody for use in the treatment of hemophilia A, with or without an inhibitor, wherein a dose comprising approximately 92 mg of the bispecific antibody is administered once every two months to a patient weighing 45 kg or more. 2. The bispecific antibody for use according to embodiment 1, wherein the dose administered to a patient having a body weight of less than 15 kg to 45 kg or a body weight of more than 45 kg is a maintenance dose, and a loading dose has been administered before the first maintenance dose. 3. The bispecific antibody for use according to embodiment 1, wherein the doses are bimonthly maintenance doses, and wherein a loading dose and one or more weekly, biweekly, or monthly maintenance doses are administered before the first bimonthly maintenance dose is administered. 4. A loading dose containing about 49 mg of bispecific antibody is administered to a patient weighing less than 15 kg to 45 kg; or a loading dose comprising about 112 mg of the bispecific antibody is administered to a patient weighing 45 kg or greater; 3. The bispecific antibody for use according to embodiment 2, wherein the first maintenance dose is administered two months after the loading dose. 5. A loading dose containing approximately 9 mg of bispecific antibody was previously administered to a patient weighing between 5 kg and less than 15 kg; or A loading dose containing about 24 mg of the bispecific antibody was administered upfront to a patient weighing between 15 kg and less than 45 kg; or a loading dose comprising about 55 mg of the bispecific antibody is administered upfront to a patient weighing 45 kg or more; Approximately 1.6 mg of the bispecific antibody was administered upfront as a weekly maintenance dose to a patient weighing between 5 kg and less than 15 kg; or Approximately 4 mg of the bispecific antibody was administered upfront as a weekly maintenance dose to patients weighing 15 kg to less than 45 kg, or 4. The bispecific antibody of embodiment 3, wherein about 9 mg of the bispecific antibody has been previously administered as a weekly maintenance dose to a patient weighing 45 kg or more. 6. A loading dose containing approximately 9 mg of bispecific antibody has been previously administered to a patient weighing between 5 kg and less than 15 kg; or a loading dose containing about 29 mg of the bispecific antibody was administered upfront to a patient weighing between 15 kg and less than 45 kg; or a loading dose comprising about 66 mg of the bispecific antibody is administered upfront to a patient weighing 45 kg or more; Approximately 4 mg of the bispecific antibody was administered upfront as a maintenance dose once every two weeks to patients weighing between 5 kg and less than 15 kg, or Approximately 9 mg of the bispecific antibody was administered upfront as a maintenance dose once every two weeks to patients weighing 15 kg to less than 45 kg, or 4. The bispecific antibody for use according to embodiment 3, wherein about 20 mg of the bispecific antibody has been previously administered as a maintenance dose once every two weeks to a patient having a body weight of 45 kg or more. 7. A loading dose containing approximately 9 mg of bispecific antibody was previously administered to a patient weighing between 5 kg and less than 15 kg; or a loading dose containing about 40 mg of the bispecific antibody was administered upfront to a patient weighing between 15 kg and less than 45 kg; or a loading dose comprising about 92 mg of the bispecific antibody is administered upfront to a patient weighing 45 kg or more; A maintenance dose of 9 mg of bispecific antibody is administered monthly to patients weighing 5 kg to less than 15 kg, or Approximately 20 mg of the bispecific antibody was administered upfront as a monthly maintenance dose to patients weighing 15 kg to less than 45 kg, or 4. The bispecific antibody for use according to embodiment 3, wherein about 46 mg of the bispecific antibody has been previously administered as a monthly maintenance dose to a patient having a body weight of 45 kg or greater. 8. The bispecific antibody for use according to any one of embodiments 5 to 7, wherein the first bimonthly maintenance dose is administered 1 to 4 weeks after administration of the loading dose. 9. The bispecific antibody for use according to any one of embodiments 2 to 7, wherein the initial bimonthly maintenance doses are administered 1 to 2 months after administration of the loading dose. 10. The bispecific antibody for use according to embodiment 4 or 9, wherein the initial bimonthly maintenance dose is administered two months after administration of the loading dose. 11. The bispecific antibody for use according to any one of embodiments 5 to 7, wherein the initial bimonthly maintenance doses are administered more than two months after the administration of the loading dose. 12. The anti-FIX(a) antibody or antigen-binding fragment thereof comprises a heavy chain variable domain identified by SEQ ID NO: 6 and a light chain variable domain identified by SEQ ID NO: 11; 16. The bispecific antibody for use of any one of the preceding embodiments, wherein the anti-FX(a) antibody or antigen-binding fragment thereof comprises a heavy chain variable domain identified by SEQ ID NO: 16, and a light chain variable domain identified by SEQ ID NO: 21. 13. The heavy chain of the anti-FIX(a) antibody comprises SEQ ID NO: 7 and the light chain of the anti-FIX(a) antibody comprises SEQ ID NO: 12; 13. The bispecific antibody for use according to embodiment 12, wherein the heavy chain of the anti-FX(a) antibody comprises SEQ ID NO: 17 and the light chain of the anti-FX(a) antibody comprises SEQ ID NO: 22. 14. The heavy chain of the anti-FIX(a) antibody consists of SEQ ID NO: 7 and the light chain of the anti-FIX(a) antibody consists of SEQ ID NO: 12; 14. The bispecific antibody for use according to embodiment 13, wherein the heavy chain of the anti-FX(a) antibody consists of SEQ ID NO: 17 and the light chain of the anti-FX(a) antibody consists of SEQ ID NO: 22. 15. The bispecific antibody for use according to any one of the preceding embodiments, wherein there is provided a mean plasma concentration of the bispecific antibody in the range of about 2 μg / mL to about 30 μg / mL, about 2 μg / mL to about 18 μg / mL, such as 3 to 9 μg / mL, such as 6.5 μg / mL. 16. A bispecific antibody for use in the treatment of hemophilia A, with or without an inhibitor, wherein the bispecific antibody is: an anti-FIX(a) antibody capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa), comprising a heavy chain and a light chain; an anti-FX(a) antibody capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa), comprising a heavy chain and a light chain; the anti-FIX(a) antibody comprises a heavy chain identified by SEQ ID NO: 7 and a light chain identified by SEQ ID NO: 12; the anti-FX(a) antibody comprises a heavy chain identified by SEQ ID NO: 17 and a light chain identified by SEQ ID NO: 22; the antibody is administered subcutaneously to a human patient in a composition comprising the antibody; a loading dose containing 46 mg of the antibody is administered to a patient weighing less than 15 kg to 45 kg; or a loading dose comprising 92 mg of the antibody is administered to a patient having a body weight of 45 kg or greater; The loading dose is not administered to patients weighing less than 5 kg to 15 kg. a dose containing 20 mg of the antibody administered once every two months to a patient weighing between 5 kg and less than 15 kg; a maintenance dose containing 46 mg of the antibody administered once every two months to a patient weighing between 15 kg and less than 45 kg; or a maintenance dose comprising 92 mg of the antibody administered once every two months to patients weighing 45 kg or more; The first maintenance dose is administered 2 months after the loading dose, 10. A bispecific antibody for use in the treatment of hemophilia A, with or without an inhibitor, which provides a mean plasma concentration of the antibody in the range of 3 to 18 μg / mL, for example 6.5 μg / mL. 17. The bispecific antibody for use according to any one of the preceding embodiments, wherein the bispecific antibody is denesimig. 18. The dosing regimen of any one of the preceding embodiments, wherein the bispecific antibody is administered in a pharmaceutical composition comprising the bispecific antibody. 19. The bispecific antibody for use according to embodiment 18, wherein the composition comprises about 150 mM L-arginine hydrochloride or L-arginine, about 20 mM L-histidine and a surfactant, such as polysorbate 20 or polysorbate 80, at a pH of about 6.3. 20. The bispecific antibody for use according to embodiment 19, wherein the composition comprises about 150 mM L-arginine hydrochloride, about 20 mM L-histidine and about 0.02 w / v% polysorbate 20, at about pH 6.3. 21. The bispecific antibody for use according to embodiment 20, wherein the composition comprises 150 mM L-arginine hydrochloride, 20 mM L-histidine and 0.02 w / v% polysorbate 20, at a pH of about 6.3. 22. The bispecific antibody for use according to any one of embodiments 17 to 21, wherein the composition comprises about 11.25, about 25, or about 57.5 mg / ml of the bispecific antibody. 23. The bispecific antibody for use according to any one of the preceding embodiments, wherein the treatment provides an annualized bleeding rate (ABR) of 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3, or 4, or an ABR in the range of 0 to 5, such as in the range of 1 to 5. 24. The bispecific antibody for use according to any one of the preceding embodiments, wherein treatment provides an ABR of 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, or 2. 25. The bispecific antibody for use according to embodiment 1, wherein the patient has previously been treated with a maintenance dose of denecimig once a week, once every two weeks, or once a month. 26. The bispecific antibody for use according to any one of the preceding embodiments, wherein the treatment is a prophylactic treatment. 27. The bispecific antibody for use according to any one of the preceding embodiments, wherein the bispecific antibody is administered subcutaneously. 28. A kit comprising: a) a pharmaceutical composition comprising the bispecific antibody of any one of embodiments 12 to 14; and b) instructions for subcutaneous administration of the bispecific antibody or pharmaceutical composition for the treatment of hemophilia A, with or without an inhibitor of any one of claims 1 to 21. 29. A dosing regimen for use in the treatment of hemophilia A, with or without an inhibitor, comprising an anti-FIX(a) antibody or antigen-binding fragment thereof capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa), comprising a heavy chain and a light chain; and an anti-FX(a) antibody or antigen-binding fragment thereof, which antibody comprises a heavy chain and a light chain and is capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa), the heavy chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 3, 4, and 5, respectively; the light chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 8, 9, and 10, respectively; the heavy chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 13, 14, and 15, respectively; the light chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 18, 19, and 20, respectively; the bispecific antibody is administered subcutaneously to a human patient in a composition comprising the bispecific antibody; a dose containing approximately 20 mg of the bispecific antibody administered once every two months to a patient weighing between 5 kg and less than 15 kg; or a dose containing approximately 46 mg of the bispecific antibody administered once every two months to a patient weighing between 15 kg and less than 45 kg; or A dosing regimen in which a dose containing approximately 92 mg of the bispecific antibody is administered once every two months to patients weighing 45 kg or more. The dosing regimen of embodiment 29, wherein the dose administered to a patient having a body weight of 30.15 kg to less than 45 kg or a body weight of more than 45 kg is a maintenance dose, and a loading dose was administered before the first maintenance dose. 31. The dose is a maintenance dose every two months; The dosing regimen of embodiment 29, wherein a loading dose and one or more weekly, biweekly, or monthly maintenance doses are administered before the first of the bimonthly maintenance doses is administered. 32. A loading dose containing approximately 49 mg of bispecific antibody is administered to a patient weighing less than 15 kg to 45 kg; or a loading dose comprising about 112 mg of the bispecific antibody is administered to a patient weighing 45 kg or greater; The dosing regimen of embodiment 29 or 30, wherein the first maintenance dose is administered 2 months after the loading dose. 33.- A loading dose containing approximately 9 mg of bispecific antibody was administered upfront to patients weighing between 5 kg and less than 15 kg, or a loading dose containing approximately 24 mg of bispecific antibody was previously administered to a patient weighing between 15 kg and less than 45 kg; or a loading dose comprising about 55 mg of the bispecific antibody is administered upfront to a patient weighing 45 kg or more; Approximately 1.6 mg of the bispecific antibody was administered upfront as a weekly maintenance dose to a patient weighing 5 kg to less than 15 kg, or Approximately 4 mg of the bispecific antibody was administered upfront as a weekly maintenance dose to patients weighing 15 kg to less than 45 kg, or - The dosing regimen of embodiment 31, wherein about 9 mg of the bispecific antibody was previously administered as a weekly maintenance dose to a patient having a body weight of 45 kg or greater. 34.- A loading dose containing approximately 9 mg of bispecific antibody was administered upfront to patients weighing between 5 kg and less than 15 kg, or a loading dose containing approximately 29 mg of bispecific antibody was previously administered to a patient weighing between 15 kg and less than 45 kg; or - a loading dose comprising about 66 mg of the bispecific antibody is administered upfront to a patient weighing 45 kg or more; Approximately 4 mg of the bispecific antibody was administered upfront as a maintenance dose once every two weeks to patients weighing between 5 kg and less than 15 kg, or Approximately 9 mg of the bispecific antibody was administered upfront as a maintenance dose once every two weeks to patients weighing 15 kg to less than 45 kg, or - The dosing regimen of embodiment 31, wherein about 20 mg of the bispecific antibody was administered previously as a maintenance dose once every two weeks to a patient having a body weight of 45 kg or greater. 35.- A loading dose containing approximately 9 mg of bispecific antibody was administered upfront to patients weighing between 5 kg and less than 15 kg, or a loading dose containing approximately 40 mg of bispecific antibody was previously administered to a patient weighing between 15 kg and less than 45 kg; or - a loading dose comprising about 92 mg of the bispecific antibody is administered upfront to a patient weighing 45 kg or more; Approximately 9 mg of the bispecific antibody was administered upfront as a monthly maintenance dose to patients weighing between 5 kg and less than 15 kg, or Approximately 20 mg of the bispecific antibody was administered upfront as a monthly maintenance dose to patients weighing 15 kg to less than 45 kg, or - The dosing regimen of embodiment 31, wherein about 46 mg of the bispecific antibody was administered upfront as a monthly maintenance dose to patients weighing 45 kg or greater. 36. The dosing regimen of any one of embodiments 33-35, wherein the first bimonthly maintenance dose is administered 1 to 4 weeks after administration of the loading dose. 37. The dosing regimen of any one of embodiments 30-35, wherein the initial bimonthly maintenance dose is administered 1-2 months after administration of the loading dose. 38. The dosing regimen of embodiment 32 or 37, wherein the initial bimonthly maintenance dose is administered two months after administration of the loading dose. 39. The dosing regimen of any one of embodiments 33-35, wherein the initial bimonthly maintenance dose is administered more than two months after administration of the loading dose. 40. An anti-FIX(a) antibody or antigen-binding fragment thereof, comprising a heavy chain variable domain identified by SEQ ID NO: 6 and a light chain variable domain identified by SEQ ID NO: 11; An administration regimen described in any one of embodiments 29 to 39, wherein the anti-FX(a) antibody or antigen-binding fragment thereof comprises a heavy chain variable domain identified by SEQ ID NO: 16 and a light chain variable domain identified by SEQ ID NO: 21. 41. The heavy chain of the anti-FIX(a) antibody comprises SEQ ID NO: 7 and the light chain of the anti-FIX(a) antibody comprises SEQ ID NO: 12; 41. The administration regimen of any one of embodiments 40, wherein the heavy chain of the anti-FX(a) antibody comprises SEQ ID NO: 17 and the light chain of the anti-FX(a) antibody comprises SEQ ID NO: 22. 42. The heavy chain of the anti-FIX(a) antibody consists of SEQ ID NO: 7 and the light chain of the anti-FIX(a) antibody consists of SEQ ID NO: 12; 42. The administration regimen of any one of embodiments 41, wherein the heavy chain of the anti-FX(a) antibody consists of SEQ ID NO: 17 and the light chain of the anti-FX(a) antibody consists of SEQ ID NO: 22. 43. The dosing regimen of any one of embodiments 29-42, wherein a mean plasma concentration of the bispecific antibody in the range of about 2 μg / mL to about 18 μg / mL, such as about 3 to about 9 μg / mL, for example 6.5 μg / mL, is provided. 44. A dosing regimen for use in the treatment of hemophilia A, with or without an inhibitor, wherein a bispecific antibody is administered to a patient in need thereof, and the bispecific antibody: an anti-FIX(a) antibody capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa), comprising a heavy chain and a light chain; an anti-FX(a) antibody capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa), comprising a heavy chain and a light chain; the anti-FIX(a) antibody comprises a heavy chain identified by SEQ ID NO: 7 and a light chain identified by SEQ ID NO: 12; the anti-FX(a) antibody comprises a heavy chain identified by SEQ ID NO: 17 and a light chain identified by SEQ ID NO: 22; the antibody is administered subcutaneously to a human patient in a composition comprising the antibody; a loading dose containing 46 mg of the antibody is administered to a patient weighing between 15 kg and less than 45 kg; or a loading dose comprising 92 mg of the antibody is administered to a patient having a body weight of 45 kg or greater; The loading dose is not administered to patients weighing less than 5 kg to 15 kg. a dose containing 20 mg of the antibody administered once every two months to a patient weighing between 5 kg and less than 15 kg; a maintenance dose containing 46 mg of the antibody administered once every two months to a patient weighing between 15 kg and less than 45 kg; or a maintenance dose comprising 92 mg of the antibody administered once every two months to patients weighing 45 kg or more; The first maintenance dose is administered 2 months after the loading dose, A dosing regimen that provides a mean plasma concentration of the antibody in the range of 3 to 9 μg / mL, for example 6.5 μg / mL. 45. The dosing regimen of any one of embodiments 29 to 44, wherein the bispecific antibody is denesimig. 46. ​​The administration regimen of any one of embodiments 28 to 45, wherein the bispecific antibody is administered subcutaneously. 47. The administration regimen of any one of embodiments 29-45, wherein the bispecific antibody is administered in a pharmaceutical composition comprising the bispecific antibody. 48. The dosing regimen of embodiment 47, wherein the composition comprises about 150 mM L-arginine hydrochloride or L-arginine, about 20 mM L-histidine and a surfactant, such as polysorbate 20 or polysorbate 80, at about pH 6.3. 49. The dosing regimen of embodiment 48, wherein the composition comprises about 150 mM L-arginine hydrochloride, about 20 mM L-histidine, and about 0.02 w / v% polysorbate 20, at about pH 6.3. 50. The dosing regimen of embodiment 49, wherein the composition comprises 150 mM L-arginine hydrochloride, 20 mM L-histidine and 0.02 w / v% polysorbate 20 at a pH of about 6.3. 51. The dosing regimen of any one of embodiments 47-50, wherein the composition comprises about 11.25, about 25, or about 57.5 mg / ml of the bispecific antibody. 52. The dosing regimen of any one of embodiments 29-51, wherein the treatment provides an ABR of 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3, or 4, or an ABR in the range of 0 to 5, such as in the range of 1 to 5. 53. A dosing regimen according to any one of embodiments 29-52, wherein the treatment provides an ABR of 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, or 2. 54. The dosing regimen of embodiment 29, wherein the patient was previously treated with a maintenance dose of denecimig once a week, once every two weeks, or once a month. 55. The dosing regimen according to any one of embodiments 29-54, wherein the treatment is a preventative treatment. 56. A method for treating hemophilia A, with or without an inhibitor, wherein a bispecific antibody is administered subcutaneously to a patient in need thereof, and the bispecific antibody: an anti-FIX(a) antibody capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa), comprising a heavy chain and a light chain; an anti-FX(a) antibody capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa), comprising a heavy chain and a light chain; the heavy chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 3, 4, and 5, respectively; the light chain of the anti-FIX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 8, 9, and 10, respectively; the heavy chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 13, 14, and 15, respectively; the light chain of the anti-FX(a) antibody or antigen-binding fragment thereof comprises CDR1-3 sequences identified by SEQ ID NOs: 18, 19, and 20, respectively; the bispecific antibody is administered subcutaneously to a human patient in a composition comprising the bispecific antibody; a dose containing approximately 20 mg of the bispecific antibody administered once every two months to a patient weighing between 5 kg and less than 15 kg; or a dose containing approximately 46 mg of the bispecific antibody administered once every two months to a patient weighing between 15 kg and less than 45 kg; or -A method of treatment wherein a dose comprising approximately 92 mg of the bispecific antibody is administered once every two months to a patient weighing 45 kg or more. 57. The method of embodiment 56, wherein the dose administered to a patient having a body weight of less than 15 kg to 45 kg or a body weight of more than 45 kg is a maintenance dose, and a loading dose was administered before the first maintenance dose. 58. The dose is a maintenance dose every two months; The method of embodiment 56, wherein a loading dose and one or more weekly, biweekly, or monthly maintenance doses are administered before the first of the bimonthly maintenance doses is administered. 59. A loading dose containing approximately 49 mg of bispecific antibody is administered to a patient weighing less than 15 kg to 45 kg; or a loading dose comprising about 112 mg of the bispecific antibody is administered to a patient weighing 45 kg or greater; The dosing regimen of embodiment 57, wherein the first maintenance dose is administered 2 months after the loading dose. 60. a loading dose containing approximately 9 mg of bispecific antibody was previously administered to a patient weighing between 5 kg and less than 15 kg; or a loading dose containing approximately 24 mg of bispecific antibody was previously administered to a patient weighing between 15 kg and less than 45 kg; or a loading dose comprising about 55 mg of the bispecific antibody is administered upfront to a patient weighing 45 kg or more; Approximately 1.6 mg of the bispecific antibody was administered upfront as a weekly maintenance dose to a patient weighing 5 kg to less than 15 kg, or Approximately 4 mg of the bispecific antibody was administered upfront as a weekly maintenance dose to patients weighing 15 kg to less than 45 kg, or The method of embodiment 58, wherein about 9 mg of the bispecific antibody was previously administered as a weekly maintenance dose to a patient weighing 45 kg or more. 61. a loading dose containing approximately 9 mg of bispecific antibody was previously administered to a patient weighing between 5 kg and less than 15 kg; or a loading dose containing approximately 29 mg of bispecific antibody was previously administered to a patient weighing between 15 kg and less than 45 kg; or - a loading dose comprising about 66 mg of the bispecific antibody is administered upfront to a patient weighing 45 kg or more; Approximately 4 mg of the bispecific antibody was administered upfront as a maintenance dose once every two weeks to patients weighing between 5 kg and less than 15 kg, or Approximately 9 mg of the bispecific antibody was administered upfront as a maintenance dose once every two weeks to patients weighing 15 kg to less than 45 kg, or The method of embodiment 58, wherein about 20 mg of the bispecific antibody was previously administered as a maintenance dose once every two weeks to a patient weighing 45 kg or more. 62. a loading dose containing approximately 9 mg of bispecific antibody was previously administered to a patient weighing between 5 kg and less than 15 kg; or a loading dose containing approximately 40 mg of bispecific antibody was previously administered to a patient weighing between 15 kg and less than 45 kg; or - a loading dose comprising about 92 mg of the bispecific antibody is administered upfront to a patient weighing 45 kg or more; Approximately 9 mg of the bispecific antibody was administered upfront as a monthly maintenance dose to patients weighing between 5 kg and less than 15 kg, or Approximately 20 mg of the bispecific antibody was administered upfront as a monthly maintenance dose to patients weighing 15 kg to less than 45 kg, or The method of embodiment 58, wherein about 46 mg of the bispecific antibody was administered upfront as a monthly maintenance dose to a patient weighing 45 kg or more. 63. A method of treatment according to any one of embodiments 60-62, wherein the first bimonthly maintenance dose is administered 1 to 4 weeks after administration of the loading dose. 64. The method of treatment of embodiments 56-62, wherein the initial bimonthly maintenance dose is administered 1-2 months after administration of the loading dose. 65. The method of treatment of embodiment 59 or 64, wherein the first bimonthly maintenance dose is administered two months after administration of the loading dose. 66. A method of treatment according to any one of embodiments 56-62, wherein the initial bimonthly maintenance dose is administered more than two months after administration of the loading dose. 67. The anti-FIX(a) antibody comprises a heavy chain variable domain identified by SEQ ID NO: 6 and a light chain variable domain identified by SEQ ID NO: 11; A method of treatment according to any one of embodiments 59 to 66, wherein the anti-FX(a) antibody comprises a heavy chain variable domain identified by SEQ ID NO: 16 and a light chain variable domain identified by SEQ ID NO: 21. 68. The heavy chain of the anti-FIX(a) antibody comprises SEQ ID NO: 7 and the light chain of the anti-FIX(a) antibody comprises SEQ ID NO: 12; The method of treatment described in embodiment 67, wherein the heavy chain of the anti-FX(a) antibody comprises SEQ ID NO: 17 and the light chain of the anti-FX(a) antibody comprises SEQ ID NO: 22. 69. The heavy chain of the anti-FIX(a) antibody consists of SEQ ID NO: 7 and the light chain of the anti-FIX(a) antibody consists of SEQ ID NO: 12; The method of treatment described in embodiment 68, wherein the heavy chain of the anti-FX(a) antibody consists of SEQ ID NO: 17 and the light chain of the anti-FX(a) antibody consists of SEQ ID NO: 22. 70. A method of treatment according to any one of embodiments 56 to 69, wherein an average plasma concentration of the bispecific antibody in the range of about 2 μg / mL to about 18 μg / mL, such as about 3 to about 9 μg / mL, for example 6.5 μg / mL, is provided. 71. A method for treating hemophilia A, with or without an inhibitor, wherein a bispecific antibody is administered subcutaneously to a patient in need thereof, and the bispecific antibody: an anti-FIX(a) antibody capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa), comprising a heavy chain and a light chain; an anti-FX(a) antibody capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa), comprising a heavy chain and a light chain; the anti-FIX(a) antibody comprises a heavy chain identified by SEQ ID NO: 7 and a light chain identified by SEQ ID NO: 12; the anti-FX(a) antibody comprises a heavy chain identified by SEQ ID NO: 17 and a light chain identified by SEQ ID NO: 22; the antibody is administered subcutaneously to a human patient in a composition comprising the antibody; a loading dose containing 46 mg of the antibody is administered to a patient weighing less than 15 kg to 45 kg; or a loading dose comprising 92 mg of the antibody is administered to a patient having a body weight of 45 kg or greater; The loading dose is not administered to patients weighing less than 5 kg to 15 kg. a dose containing 20 mg of the antibody administered once every two months to a patient weighing between 5 kg and less than 15 kg; a maintenance dose containing 46 mg of the antibody administered once every two months to a patient weighing between 15 kg and less than 45 kg; or a maintenance dose comprising 92 mg of the antibody administered once every two months to patients weighing 45 kg or more; The first maintenance dose is administered 2 months after the loading dose, A method of treatment wherein a mean plasma concentration of the antibody in the range of 3-9 μg / mL, for example 6.5 μg / mL, is provided. 72. A method of treatment according to any one of embodiments 56 to 71, wherein the bispecific antibody is denesimig. 73. The method of treatment of any one of the embodiments, wherein the bispecific antibody is administered subcutaneously. 74. The method of treatment according to any one of embodiments 56 to 72, wherein the bispecific antibody is administered in a pharmaceutical composition comprising the bispecific antibody. 75. The method of treatment of embodiment 74, wherein the composition comprises about 150 mM L-arginine hydrochloride or L-arginine, about 20 mM L-histidine and a surfactant, such as polysorbate 20 or polysorbate 80, at about pH 6.3. 76. The method of treatment of embodiment 75, wherein the composition comprises about 150 mM L-arginine hydrochloride, about 20 mM L-histidine, and about 0.02 w / v% polysorbate 20, at about pH 6.3. 77. The method of treatment of embodiment 76, wherein the composition comprises 150 mM L-arginine hydrochloride, 20 mM L-histidine and 0.02 w / v% polysorbate 20 at a pH of about 6.3. 78. A method of treatment according to any one of embodiments 74 to 77, wherein the composition comprises about 11.25, about 25, or about 57.5 mg / ml of the bispecific antibody. 79. A method of treatment according to any one of embodiments 56-78, wherein the treatment provides an annualized bleeding rate (ABR) of 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3, or 4, or an ABR in the range of 0 to 5, for example in the range of 1 to 5. 80. The method of treatment of embodiment 79, wherein the treatment provides an ABR of 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, or 2. 81. The method of treatment of embodiment 56, wherein the patient was previously treated with a maintenance dose of denecimig once a week, once every two weeks, or once a month. 82. The method of treatment according to any one of embodiments 56-81, wherein the treatment is a preventative measure.

[0138] In a preferred embodiment, we describe a bimonthly dosing regimen for use in the treatment of hemophilia A, with or without an inhibitor, comprising: The method comprises subcutaneously administering a bispecific antibody comprising an anti-FIX(a) antibody comprising a heavy chain and a light chain and capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa), and an anti-FX(a) antibody comprising a heavy chain and a light chain and capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa), the heavy chain of the anti-FIX(a) antibody comprises SEQ ID NO: 7 and the light chain of the anti-FIX(a) antibody comprises SEQ ID NO: 12; the heavy chain of the anti-FX(a) antibody comprises SEQ ID NO: 17 and the light chain of the anti-FX(a) antibody comprises SEQ ID NO: 22; the bispecific antibody is administered in a pharmaceutical composition comprising the bispecific antibody, the pharmaceutical composition comprising 11.25 mg / mL, 25 mg / mL, or 57.5 mg / mL of the bispecific antibody, 150 mM L-arginine hydrochloride, 20 mM L-histidine, and 0.02% w / v polysorbate 20 at about pH 6.3; a loading dose of 40 mg of the bispecific antibody is administered to a patient weighing between 15 kg and less than 45 kg; or A loading dose of 92 mg of the bispecific antibody is administered to patients weighing 45 kg or more, The loading dose of the bispecific antibody is not administered to a patient weighing less than 5 kg to 15 kg; A dose of 9 mg of the bispecific antibody is administered once every two months to patients weighing between 5 kg and less than 15 kg; or A maintenance dose of 20 mg of the bispecific antibody is administered once every two months to patients weighing 15 kg to less than 45 kg, or A maintenance dose of 46 mg of the bispecific antibody is administered every two months to patients weighing 45 kg or more. The first maintenance dose is administered 2 months after the loading dose if a loading dose was administered; Plasma concentrations of the bispecific antibody in the range of about 2 μg / mL to about 18 μg / mL are provided.

[0139] Those skilled in the art will be familiar with the pharmacokinetics (e.g., but not limited to, C max , T max Those skilled in the art will understand various methods for measuring and calculating pharmacokinetic and pharmacodynamic parameters (e.g., serum half-life, serum half-life), and pharmacodynamic parameters. Additionally, those skilled in the art will understand various methods for performing statistical comparisons (e.g., but not limited to, comparisons of changes from baseline to post-treatment and / or comparisons between treatment groups) and / or analyses of the pharmacokinetic and pharmacodynamic parameters described herein. [Example]

[0140] List of Abbreviations CL: Full body clearance IIV: Inter-individual variability K a : Absorption rate constant MAD: Multiple Ascending Dose OFV: Objective function value PwHA: Patients with hemophilia A PK: Pharmacokinetics SAD: Single Ascending Dose SIA: sequence identical analogue Q: Inter-compartment clearance QW: Once a week Q2W: Once every two weeks Q4W: Once every 4 weeks QM: Once a month Q2M: Once every two months RSE: relative standard error V2: Median distribution volume V3: Peripheral distribution volume F: Relative bioavailability

[0141] Example 1: Dose Escalation Study An anti-FIX(a) / FX(a) bispecific antibody (Denesimig) comprising a first heavy chain comprising SEQ ID NO:7 and a first light chain comprising SEQ ID NO:12, and a second heavy chain comprising SEQ ID NO:17 and a second light chain comprising SEQ ID NO:22 is in development for patients with hemophilia A (PwHA) with or without inhibitors.

[0142] FRONTIER1 (EudraCT:2019-000465-20; NCT04204408) aims to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of a single ascending subcutaneous dose of denecimig (a bispecific antibody) in healthy participants and multiple ascending doses of denecimig with or without inhibitors in PwHA. Furthermore, this study aims to provide data for dose-finding in the subsequent FRONTIER trial.

[0143] Methods: In the single ascending dose (SAD) phase, healthy subjects received a single ascending dose of denesimig (targeting plasma concentrations of 0.05-3 μg / mL) or placebo. In the multiple ascending dose (MAD) phase, PwHA received multiple ascending doses of denesimig targeting mean plasma concentrations of 1 μg / mL (Cohort 1, QW dosing), 3 μg / mL (Cohort 2, QW dosing), 9 μg / mL (Cohort 3, QW dosing, and Cohort 4, Q4W dosing), or 16 μg / mL (Cohort 5, QW dosing).

[0144] Nonlinear mixed-effects modeling was used to analyze denesimig plasma concentration versus time data from FRONTIER1. Development of structure-based models for denesimig included one-compartment and two-compartment models. Denesimig plasma concentration-time profiles were analyzed using the absorption rate constant (k aThe model was best described by a two-compartment model with first-order elimination and absorption rates parameterized as: ), total body clearance (CL), intercompartmental clearance (Q), central volume of distribution (V2), marginal volume of distribution (V3), and relative bioavailability (F, fixed at 1). Random effects were investigated for interindividual variability (IIV, or intersubject variability) of the model's key parameters, as well as additive and / or proportional residual error. In addition to model stability and parameter precision, a minimal decrease in the objective function value (OFV) of 3.84 was considered for including random effects. The final model included CL, k a , and IIV with respect to F were included, and the residual error was described by proportional error.

[0145] Tables 1-5 list the dosing regimens for MAD cohorts 1-5. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0146] Results: Denesimig was well tolerated after both single and multiple dosing, and no related thromboembolic or serious adverse events were reported. No incidence of anti-denesimig antibodies was reported. Data from the SAD section showed an estimated T of 30.4 days. 1 / 2 , and T of 9.1 days max The highest densitidine concentration observed in MAD Cohort 5 was 18 μg / mL, which was assessed as safe and effective (Figure 2).

[0147] Population PK modeling analysis of the FRONTIER1 data suggested that the PK of denecimig was best described by a two-compartment PK model with first-order absorption and elimination. The main covariates affecting denecimig concentrations were baseline body weight and formulation strength. Parameter estimates from the population PK modeling analysis are collected in Table 6, and the model fit to the FRONTIER1 MAD data is shown in Figure 3. [Table 6]

[0148] During the 12-week observation period, 15 treated bleeds were reported in 8 patients, of which 13 bleeds (9 traumatic) were observed in 6 patients from the lowest-dose cohort. Two bleeds in patients from cohorts 2 and 3 were traumatic; therefore, no treated joint bleeds or spontaneous bleeding were observed beyond cohort 1 (Table 7).

[0149] Conclusions: The population PK model adequately explained median trends and variability in the data for the key covariates: baseline body weight and formulation strength. Denesimig was well tolerated, and no incidence of anti-denesimig antibodies was reported. FRONTIER1 provides promising data to support further clinical development using the dosing method / regimen described herein, derived by taking into account the effects of body weight and formulation strength. [Table 7]

[0150] Example 2: Thrombin generation after administration of densimig Factor VIII (FVIII) replacement is the standard of care for patients with hemophilia A (HA). Denesimig is a bispecific antibody that can combine factor IX(a) and FX(a) with enhanced hemostatic properties in vitro and in HA mouse models compared with emicizumab. FRONTIER1 (NCT04204408) is a phase 1 / 2 study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneously administered denesimig in healthy volunteers and patients with severe HA, regardless of FVIII inhibitor status.

[0151] Peak thrombin generation and laboratory markers in response to densimig or emicizumab were analyzed.

[0152] Methods: The Phase 2 portion of FRONTIER1 was open-label and administered densimig subcutaneously over 12 weeks across five ascending dose cohorts, targeting mean plasma concentrations of 1-18 μg / mL through weekly (Cohorts 1-3 and 5) or every 4 weeks (Cohort 4) dosing, with Cohorts 3 and 4 targeting the same plasma concentrations. For comparison, an additional exploratory cohort of subjects treated with emicizumab was included.

[0153] Results: Forty-two subjects were included in the denesimig group (Cohorts 1 [n=7], 2 [n=9], 3 [n=8], 4 [n=8], and 5 [n=10]) and 10 in the emicizumab group. Peak thrombin levels increased with denesimig dose. In vitro studies in which pre-dose FVIII-neutralized plasma samples were spiked with denesimig and emicizumab showed that denesimig reached maximum peak height at lower plasma concentrations than emicizumab, demonstrating greater potency for denesimig (see Figure 4). Mean peak thrombin levels were similar between patients receiving emicizumab and denesimig in Cohort 2. No dose-dependent changes in D-dimer, fibrinogen, platelets, or FIXa / FX antigen levels were observed, with most values ​​remaining within the normal range. Dose-dependent increases in prothrombin fragments 1 and 2 were observed in patients on denesimig and emicizumab (relative change [%]: 26.08, 93.99, 323.65, 606.41, and 315.62 for cohorts 1–5, respectively; 85.04 for emicizumab), which stabilized at steady state.

[0154] Conclusions: A dose-dependent increase in thrombin generation was observed in densimig patients, who reached higher peak thrombin levels than emicizumab patients. Laboratory parameters did not indicate any safety signals.

[0155] Example 3: Extrapolating the results from Examples 1 and 2 to new dosing regimens for different weight bands Based on certain novel learnings from the FRONTIER1 clinical trial as contained in Examples 1 and 2, the inventors have evaluated the patient response and observed characteristics (dose, T 1 / 2 , T maxBy carefully analyzing and using the novel data obtained in the study, including the therapeutic plasma concentrations, the administration methods disclosed herein, and in particular the specific dosing regimens (including the selection of weight bands / groups), were devised. The inventors have developed the dosing regimens necessary to reach therapeutic plasma concentrations in the range of, for example, about 1 μg / mL to about 30 μg / mL, preferably about 3 to about 18, more preferably 3 to 9 μg / mL, e.g., 5, 5.5, 6, 6.5, or 7 μg / mL, for specific weight bands by expanding the number of weight bands from 2 to 3 to cover body weights from 5 kg onwards, thereby also covering pediatric patients.

[0156] Using the population PK model described in Example 1, the inventors derived a dosing regimen used as a direct switch from a once-weekly (QW), once-every-two-weeks (Q2W), or once-monthly (QM) dosing regimen to a once-every-two-months (Q2M) dosing regimen, rapidly establishing steady-state denesimig plasma concentrations within the therapeutic range (1-30 μg / mL) for typical body weights within the hemophilia population.

[0157] Examples of such dosing regimens and weight bands are shown in Table 8. [Table 8]

[0158] Examples of the denesimig PK profile for a typical subject within each weight band and dosing frequency, along with a switch from either QW, Q2W, or QM to a Q2M dosing regimen, are shown in Figure 5. Figures 5a, 5b, and 5c show predicted typical PK profiles of denesimig in subjects with different body weights during steady-state dosing at QM, Q2W, and QW, respectively, and then transitioned directly to Q2M (exemplified at week 13 in the current figure) at the doses exemplified in Table 8. PK simulations demonstrate that all subjects, regardless of body weight, achieved a minimum concentration comparable to that in FRONTIER1 MAD Cohort 1 (C1) (1 μg / mL) and a C1 in MAD Cohort 5 (34 μg / mL). maxThis demonstrates that the QW, Q2W, and QM dosing intervals should achieve densimig plasma concentrations within the therapeutic range as defined by the maximum individual concentrations defined by:

[0159] Figure 6 shows typical predicted PK profiles of denesimig after multiple Q2M administrations, as illustrated in Table 8, in subjects with different body weights without previous denesimig exposure. PK simulations demonstrate that all subjects, regardless of body weight, should achieve denesimig plasma concentrations within the therapeutic range, as defined by a minimum concentration comparable to FRONTIER1 MAD Cohort 1 (C1) (1 μg / mL) and a maximum individual concentration observed in MAD Cohort 5 (34 μg / mL). Example 4: Stability of denesimig compositions.

[0160] The pharmaceutical composition analyzed in this example contained 1-100 mg / mL of the bispecific antibody dexamethasone, 150 mM L-arginine hydrochloride, 20 mM L-histidine, 0.02 w / v% polysorbate 20, at approximately pH 6.3.

[0161] Stability was assessed based on the following key parameters: appearance, high molecular weight protein (HMWP), monomer, and purity. Based on the stability results shown in Tables 9 through 22, no or only slight changes in trends are observed in the key parameters related to chemical stability (HMWP, monomer, and purity) and physical stability (appearance) during storage at long-term storage conditions (5°C ± 3°C) and accelerated storage conditions (25°C ± 2°C).

[0162] In summary, the results show that the composition is chemically and physically stable over time at 5°C and 25°C.

[0163] Analysis procedure 1. Compendial Analysis Procedures The following compendial analytical procedures are used to control the drug product:

[0164] exterior The appearance of the formulation is determined by visual inspection in accordance with Ph.Eur. and JP.

[0165] pH The pH is measured by potentiometric determination carried out according to Ph.Eur., USP, and JP.

[0166] 2. Non-Compendial Analytical Procedures The following non-comparative analytical procedures are employed to control the drug product:

[0167] 2.1 Content by SE-HPLC The content is determined by SE-HPLC using isocratic elution on a size exclusion column followed by UV detection. The content is calculated using the area of ​​the high molecular weight protein (HMWP) peak and the monomer peak relative to the area of ​​the HMWP peak and the monomer peak of a reference material with known content concentration, and is expressed in mg / ml.

[0168] 2.2 Monomers by SE-HPLC The content of monomer is determined by SE-HPLC using isocratic elution on a size exclusion column followed by UV detection. The monomer peak area relative to the total area is calculated and expressed as a percentage.

[0169] 2.3 High Molecular Weight Proteins (HMWP) by SE-HPLC The content of HMWP is determined by SE-HPLC using isocratic elution on a size exclusion column followed by UV detection. The HMWP peak area relative to the total area is calculated and expressed as a percentage.

[0170] 2.4 Purity by CE-SDS Purity is defined as the main peak area by capillary electrophoresis in the presence of sodium dodecyl sulfate (CE-SDS). Purity is determined by CE-SDS under non-reducing conditions with UV detection. Purity is calculated as the main peak area relative to the total area and expressed as a percentage.

[0171] Stability data for compositions containing Denesimig in the concentration range of 1 to 100 mg / ml The stability of compositions containing 1, 2, 5, 11.25, 57.5, and 100 mg / mL of denesimig was monitored under long-term storage conditions (5°C ± 3°C) and accelerated storage conditions (25°C ± 2°C).

[0172] Results for compositions containing denesimig in the range of 1 mg / ml to 100 mg / ml show comparable stability. The compositions are chemically and physically stable.

[0173] Stability data for 1mg / ml Denesimig Stability data for compositions containing 1 mg / ml of Denesimig are reported in Table 9 for long-term storage conditions and in Table 10 for accelerated storage conditions. [Table 9] [Table 10]

[0174] Stability data for 2.0mg / ml Denesimig Stability data for 2.0 mg / ml Denesimig is reported in Table 11 for long-term storage conditions and in Table 12 for accelerated storage conditions. [Table 11] [Table 12]

[0175] Stability data for 5.0mg / ml Denesimig Stability data for denesimig at 5.0 mg / ml is reported in Table 13 for long-term storage conditions and in Table 14 for accelerated storage conditions. [Table 13] [Table 14]

[0176] Stability data for 11.3mg / ml Denesimig Stability data for 11.3 mg / ml Denesimig is reported in Table 15 for long-term storage conditions and in Table 16 for accelerated storage conditions. [Table 15] [Table 16]

[0177] Stability data for 25.0 mg / ml Denesimig Stability data for 25.0 mg / ml Denesimig is reported in Table 17 for long-term storage conditions and in Table 18 for accelerated storage conditions. [Table 17] [Table 18]

[0178] Stability data for denesimig at 57.5mg / ml Stability data for denesimig at 57.5 mg / ml is reported in Table 19 for long-term storage conditions and in Table 20 for accelerated storage conditions. [Table 19] [Table 20]

[0179] Stability data for 100mg / ml Denesimig Stability data for 100 mg / ml Denesimig is reported in Table 21 for long-term storage conditions and in Table 22 for accelerated storage conditions. [Table 21] [Table 22]

[0180] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. It is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention.

Claims

1. 1. A medicament for use in the treatment of hemophilia A, with or without an inhibitor, comprising a bispecific antibody, said bispecific antibody comprising: an anti-FIX(a) antibody or antigen-binding fragment thereof, which comprises a heavy chain and a light chain and is capable of binding to FIX (SEQ ID NO: 1) and / or its activated form (FIXa); an anti-FX(a) antibody or antigen-binding fragment thereof, which comprises a heavy chain and a light chain and is capable of binding to FX (SEQ ID NO: 2) and / or its activated form (FXa); the heavy chain of the anti-FIX(a) antibody comprises SEQ ID NO: 7 and the light chain of the anti-FIX(a) antibody comprises SEQ ID NO: 12; the heavy chain of the anti-FX(a) antibody comprises SEQ ID NO: 17 and the light chain of the anti-FX(a) antibody comprises SEQ ID NO: 22; the bispecific antibody is administered subcutaneously to a human patient; a dose containing about 20 mg of said bispecific antibody administered once every two months to a patient having a body weight of 5 kg to less than 15 kg; or a dose containing about 46 mg of said bispecific antibody administered once every two months to a patient having a body weight of 15 kg to less than 45 kg; or - a medicament for use in the treatment of hemophilia A, with or without inhibitors, wherein a dose comprising about 92 mg of said bispecific antibody is administered once every two months to a patient having a body weight of 45 kg or more.

2. the heavy chain of the anti-FIX(a) antibody consists of SEQ ID NO: 7 and the light chain of the anti-FIX(a) antibody consists of SEQ ID NO: 12; The pharmaceutical composition of claim 1, wherein the heavy chain of the anti-FX(a) antibody consists of SEQ ID NO: 17 and the light chain of the anti-FX(a) antibody consists of SEQ ID NO:

22.

3. The method of claim 1, wherein an average plasma concentration of the bispecific antibody is provided in the range of about 2 μg / mL to about 18 μg / mL.

4. The pharmaceutical composition of claim 1, wherein the bispecific antibody is denesimig.

5. 2. The medicament of claim 1, comprising about 11.25, about 25, or about 57.5 mg / ml of the bispecific antibody, about 150 mM L-arginine hydrochloride, about 20 mM L-histidine, and about 0.02 w / v % polysorbate 20, at about pH 6.3.

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