Application of SR604 injection in preparation of medicine for preventing and / or treating human hemorrhagic diseases

Abstract

The invention relates to the field of biological medicines, in particular to application of an SR604 injection to preparation of a medicine for preventing and / or treating hemorrhagic diseases. The SR604 injection provided by the invention contains an SR604 antibody, and the injection dosage of the SR604 antibody in the SR604 injection is selected from 0.025 mg / kg to 0.8 mg / kg. The injection provided by the invention can be used for preventing and / or treating hemorrhagic diseases, the number of hemorrhagic events and the annual hemorrhagic rate of a patient are remarkably reduced by controlling the injection dosage and the injection frequency, and the injection has a relatively good treatment effect on hemophilia A, hemophilia B and congenital blood coagulation factor VII deficiency.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to the use of SR604 injection in the preparation of drugs for the prevention and / or treatment of human hemorrhagic diseases. Background Technology

[0002] Hemorrhagic disorders are a collective term for diseases caused by abnormalities in the hemostasis mechanism. They can be broadly classified into two categories: hereditary and acquired, with clinical manifestations primarily including bleeding in different sites. Hemorrhagic disorders are diverse in type and pathogenesis, requiring appropriate treatment based on their specific causes and mechanisms. These disorders include abnormalities in the blood vessel wall, platelets, the quantity and quality of coagulation factors, and abnormalities in anticoagulation and fibrinolysis. Hemophilia A and hemophilia B are X-linked recessive inherited bleeding disorders characterized by a deficiency of coagulation factor VIII (FVIII) or factor IX (FIX), leading to severe deficiencies in thrombin production, impaired hemostasis, and an increased risk of bleeding. Approximately 1 in 4,000 males has hemophilia A, while the incidence of hemophilia B is five times lower, approximately 1 in 20,000 males. The disease phenotypes of hemophilia A and hemophilia B are similar. Hemophilia is classified as mild (factor levels 6% to 30%), moderate (factor levels 1% to 5%), or severe (factor levels <1%) based on clotting factor activity relative to normal values ​​(50% to 150% of plasma factor levels in healthy, non-hemophilic individuals). Patients with mild hemophilia typically experience bleeding after severe injury or surgery. Patients with moderate hemophilia experience injury-related bleeding episodes and may experience spontaneous bleeding episodes. Patients with severe hemophilia experience massive bleeding upon injury and may experience frequent spontaneous bleeding episodes, leading to debilitating musculoskeletal damage that can severely impair mobility and quality of life (QOL).

[0003] The purpose of a hemostatic system is to maintain the integrity of the vascular system by preventing bleeding from vascular lesions and by combining various options to prevent thrombosis. This hemostatic balance is achieved by coordinating the regulation of both procoagulant factors (e.g., factor V (FV), factor VII (FVII), FVIII, FIX, factor X (FX)) and anticoagulant factors (e.g., antithrombin, protein C / protein S, and tissue factor pathway inhibitors).

[0004] Hemophilia A and Hemophilia B present with similar clinical manifestations, primarily involving bleeding in the joints, muscles, and deep tissues. Gastrointestinal, urinary tract, and central nervous system bleeding may also occur, as well as persistent bleeding after tooth extraction. Repeated bleeding without timely treatment can lead to joint deformities and / or pseudotumor formation, which can be life-threatening in severe cases. Patients with congenital factor VII deficiency exhibit greater clinical heterogeneity, ranging from life-threatening central nervous system bleeding and gastrointestinal bleeding to minor skin / mucous membrane bleeding, gingival bleeding, and nosebleeds. Bleeding can be traumatic or drug-induced, or spontaneous. Patients with severe FVII deficiency may experience joint and muscle bleeding after surgery, and are prone to bruising and bleeding. Women often experience severe menorrhagia; heavy and prolonged menstrual bleeding. The high bleeding risk associated with FVII deficiency significantly impacts the quality of life of patients.

[0005] The protein C (PC) pathway plays a crucial role in regulating coagulation and inflammation. Thrombin forms a complex with thrombin regulatory protein (TM) on vascular endothelial cells, thereby activating protein C. Activated protein C (APC) cleaves activated factors V and VIII, negatively downregulating thrombin formation and maintaining the balance between thrombus formation and hemostasis in the body. However, in most cases, bleeding episodes require hemostatic intervention using intravenously (IV) recombinant factor VIIa (rVIIa) or activated prothrombin complex concentrate (aPCC) as a preventative or on-demand treatment for bleeding episodes. Therefore, alternative therapies remain needed for subjects with hemophilia to effectively and safely prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B, while reducing the treatment burden, improving clinical outcomes, and enhancing quality of life. Summary of the Invention

[0006] In view of the shortcomings of the prior art described above, the object of the present invention is to provide the use of SR604 injection in the preparation of drugs for the prevention and / or treatment of hemorrhagic diseases.

[0007] To achieve the above and other related objectives, the first aspect of the present invention provides the use of SR604 injection in the preparation of drugs for the prevention and / or treatment of human hemorrhagic diseases, wherein the SR604 injection comprises SR604 antibody, and the effective dose of SR604 antibody in the SR604 injection is 0.025 mg / kg to 0.8 mg / kg.

[0008] Preferably, the SR604 antibody has the light chain amino acid sequence shown in SEQ ID No. 1 and the heavy chain amino acid sequence shown in SEQ ID No. 2.

[0009] A second aspect of the present invention provides a method for preventing and / or treating hemorrhagic diseases in humans, the method comprising: administering an effective amount of SR604 injection to a subject.

[0010] Compared with the prior art, the beneficial effects of the present invention include:

[0011] Compared to existing drugs for treating bleeding disorders, the SR604 injection of this application can reduce the frequency of bleeding within a 3-month treatment period. This product has a long half-life and stable absorption and elimination rates, significantly reducing the frequency of administration. Furthermore, it is conveniently administered via subcutaneous injection, requiring a low dosage and improving patient experience and acceptance. The SR604 injection of this application is indicated for hemophilia A / B patients with or without inhibitors, making it suitable for a wider range of patients and demonstrating good safety. Attached Figure Description

[0012] Figure 1 This is a schematic diagram of the dose escalation protocol for Part A.

[0013] Figure 2 The graph shows the plasma concentration-time of SR604 (Part A).

[0014] Figure 3 The graph is shown as a semi-logarithmic plot of SR604 plasma concentration versus time (Part A).

[0015] Figure 4 The graph shows the SR604 inhibition rate over time (Part A).

[0016] Figure 5 This is a schematic diagram of the experimental design for Part B.

[0017] Figure 6 Displayed as SR604 plasma concentration-time graph (Part B).

[0018] Figure 7 Displayed as a semi-logarithmic plot of SR604 plasma concentration versus time (Part B).

[0019] Figure 8 The graph shows the SR604 inhibition rate over time (Part B). Detailed Implementation

[0020] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0021] The present invention first provides the use of SR604 injection in the preparation of drugs for the prevention and / or treatment of human hemorrhagic diseases, wherein the SR604 injection comprises SR604 antibody, and the effective dose of SR604 antibody in the SR604 injection is 0.025 mg / kg to 0.8 mg / kg.

[0022] In this invention, the light chain amino acid sequence of the SR604 antibody is shown in SEQ ID No. 1, and its heavy chain amino acid sequence is shown in SEQ ID No. 2. The SR604 antibody is described in patent application 2023100629440, and is the anti-aPC monoclonal antibody SR604 in that patent.

[0023] SEQ ID No.1: DIQLTQSPSSSLSASVGDRVTITCRASESVDSFGATFMHWYQQKPGKAP KLLIYLASRLGSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNNEDPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0024] SEQ ID No.2: EVQLVESGGGLVQPGGSLRLSCAASGFTFSFYYLNWVRQAPGKGLEW VGDIRLKKNNYEKHYAESVKGRFTISRDDSKSITYLQMNSLRAEDTAVYYCAREGDYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQ VYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0025] In some embodiments of the present invention, the SR604 antibody content in the SR604 injection solution is 30–70 mg / ml. Preferably, the SR604 antibody content is 27–33, 45–55, or 63–77 mg / ml. More preferably, the SR604 antibody content is 30 mg / ml.

[0026] In some embodiments of the present invention, the SR604 injection solution further includes a buffer system. The buffer system is selected from histidine / histidine hydrochloride or acetate / sodium acetate; preferably, the buffer system is an L-histidine / L-histidine hydrochloride system. In some embodiments of the present invention, the buffer system is 10 mM L-histidine / L-histidine hydrochloride.

[0027] Furthermore, the SR604 injection also includes the following protective agents: a. sugar or sugar alcohol, wherein the sugar is selected from trehalose and sucrose, and the sugar alcohol is selected from sorbitol or mannitol; b. amino acid, wherein the amino acid is selected from arginine hydrochloride or aspartic acid.

[0028] In some embodiments of the present invention, the protective agent is selected from: 10% trehalose + 100 mmol / L L-arginine hydrochloride.

[0029] In some embodiments of the present invention, the SR604 injection further includes a surfactant selected from polysorbate 80 and / or P188. Preferably, the surfactant is selected from 200 ppm polysorbate 80.

[0030] As in some embodiments of the present invention, the SR604 injection solution contains 10 mM L-histidine / L-histidine hydrochloride, 10% trehalose, 100 mM L-arginine hydrochloride, 200 ppm polysorbate 80, and the SR604 antibody content is 30 mg / ml.

[0031] The SR604 injection is in liquid form. Preferably, the liquid form is a subcutaneous injection.

[0032] The liquid formulation is prepared using a solvent. The solvent can be one commonly used for preparing injectable formulations, such as water for injection (WFI), buffered saline solution, glucose solution, sodium chloride solution, or lactated Ringer's solution, with water for injection being preferred.

[0033] The liquid formulation can be prepared according to the prescription described in this invention using methods commonly used in the pharmaceutical field.

[0034] In this invention, the bleeding disorders are selected from hemophilia A, hemophilia B, and congenital factor VII deficiency.

[0035] The hemophilia A and hemophilia B mentioned are hemophilia A with inhibitors or hemophilia B without inhibitors.

[0036] In a preferred embodiment, the inhibitor is selected from one or more of FVIII inhibitors, FIX inhibitors, and FVII inhibitors.

[0037] In some embodiments of the present invention, the SR604 antibody injection dose in the SR604 injection is selected from 0.025 mg / kg to 0.8 mg / kg, and can be 0.025 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.4 mg / kg, or 0.8 mg / kg.

[0038] Preferably, the SR604 injection is administered at one or more of the following frequencies: once a week, once every two weeks, once every three weeks, and once every four weeks. More preferably, the SR604 injection is administered once every two weeks.

[0039] In a preferred embodiment, the initial dose of the SR604 injection is twice the weight of its subsequent doses.

[0040] In this invention, the drug has one or more of the following effects:

[0041] 1) Reduce the frequency of bleeding events;

[0042] 2) Reduce the annualized bleeding rate;

[0043] 3) Increase the drug's half-life;

[0044] 4) Regulate APC functional activity;

[0045] 5) Reduces thrombosis and adverse reactions at the injection site.

[0046] In this invention, prevention and / or treatment are routine preventative measures to prevent or reduce the frequency of bleeding episodes.

[0047] The present invention also provides a method for preventing and / or treating hemorrhagic diseases in humans, the method comprising: administering an effective amount of SR604 injection to the subject.

[0048] In a preferred embodiment, the effective dose of SR604 antibody in the SR604 injection solution is 0.025 mg / kg to 0.8 mg / kg, and can be 0.025 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.4 mg / kg, or 0.8 mg / kg.

[0049] In a preferred embodiment, the injection frequency of SR604 injection includes one or more of the following: once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every seven weeks, and once every eight weeks. More preferably, the injection frequency of SR604 injection is selected from once every two weeks, once every four weeks, once every six weeks, and once every eight weeks.

[0050] In a preferred embodiment, the initial dose of the SR604 injection is twice the weight of its subsequent doses.

[0051] In a preferred embodiment, the bleeding disorder is selected from hemophilia A, hemophilia B, and congenital factor VII deficiency.

[0052] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention; in the specification and claims of the present invention, unless otherwise expressly stated in the text, the singular forms "a", "an" and "this" include the plural forms.

[0053] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. In addition to the specific methods, apparatus, and materials used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description of this invention, any prior art methods, apparatus, and materials similar to or equivalent to those described, apparatus, and materials in the embodiments of this invention may be used to implement the present invention.

[0054] Unless otherwise stated, the experimental methods, detection methods, and preparation methods disclosed in this invention all employ conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related fields.

[0055] Example 1 - Clinical Trial Enrollment and Screening Criteria

[0056] 1. Selection Criteria

[0057] Applicants must be 18 years of age or older and 65 years of age or younger, clinically diagnosed with hemophilia A or B or congenital factor VII deficiency, and must meet the following criteria:

[0058] a) Hemophilia A or B patients with a previous or screening period of FⅧ activity level <1% or FⅨ activity level ≤2%;

[0059] Note: Hemophilia A or B patients with or without inhibitors can be included. Hemophilia A or B patients without inhibitors (inhibitor <0.6BU / ml) must have previously received coagulation factor therapy and have EDs >50 days.

[0060] b) Patients with congenital coagulation factor VII deficiency whose FVII activity is <10% in the past or during the screening period;

[0061] Part A: Patients who received FVIII, FIX, recombinant human coagulation factor VIIa (rFVIIa) or PCC as needed to treat bleeding events within one month prior to screening;

[0062] Part B / Part C phase: Patients with bleeding treatment records (factor replacement or bypass drug therapy) for at least 3 months prior to enrollment, patients with hemophilia A or B who received on-demand treatment within 3 months prior to enrollment and had ≥3 new bleeding events after treatment, and patients with congenital factor VII deficiency who had ≥2 new bleeding events after treatment within 3 months prior to enrollment.

[0063] There were no active bleeding symptoms before the first dose; the subject or impartial witness fully understood and could comply with the requirements of the trial protocol and was willing to complete the study as planned, and voluntarily cooperated in providing biological samples for testing as required by the protocol; the subject was able to understand the procedures and methods of this clinical trial, and after obtaining full informed consent, the patient voluntarily participated and signed the informed consent form.

[0064] 2. Exclusion Criteria

[0065] Patients with a known history of hypersensitivity to the investigational drug formulation or any of its components; subcutaneous injection intolerance or other local skin abnormalities or dermatitis affecting administration and safety assessment; or those meeting one of the following criteria during the screening period: a) hemoglobin < 60 g / L; b) platelet count < 100 × 10⁹ / L; c) abnormal liver or kidney function: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 times the upper limit of normal (ULN), or total bilirubin ≥ 1.5 times the ULN; or serum creatinine (Cr) ≥ 1.5 times the ULN; or hepatitis B surface antigen (HBsAg), anti-human immunodeficiency virus (HIV) antibody levels. Those who are positive for one or more of the following: antibodies and Treponema pallidum-specific antibodies; those clinically diagnosed with active hepatitis C; those with significantly abnormal coagulation indicators due to any bleeding disorder or other disease other than hemophilia A or B and congenital factor VII deficiency (such as platelet disorders, vitamin K deficiency, etc.); those with protein C deficiency or protein S deficiency; those with a history of thrombosis or a family history of thrombosis before signing the informed consent form or currently; those with a history of thrombotic disorders; those with intracranial hemorrhage due to hemophilia A or B or congenital factor VII deficiency within 2 years prior to screening; and those with severe heart disease, such as unstable angina or congestive heart failure (New York Heart Association). Contraindications include: grade III or higher; severe arrhythmias (QTc interval > 450 ms, corrected by Fridricia formula); uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 95 mmHg); administration of recombinant human coagulation factor VIIa (rFVIIa) within 48 hours prior to first administration; administration of any product containing FVIII within 72 hours prior to first administration; administration of any product containing FIX within 96 hours prior to first administration; long-acting products of the above drugs with less than 5 half-lives after elution; use of any anticoagulants, antifibrinolytics, or chemical or biological drugs affecting platelet function within 1 week prior to first administration or during the trial period. Patients who have taken or received traditional Chinese medicine products, including nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin; those who have received whole blood or plasma therapy within 2 weeks prior to the first dose; those who have received emecizumab therapy within 6 months prior to the first dose; those who have received or plan to receive a vaccine during the trial within 4 weeks prior to the first dose; those who have undergone major surgery (such as orthopedic surgery or abdominal surgery) within 1 month prior to the first dose, or those who plan to undergo surgery during the study; those who have been enrolled in other clinical trials within 1 month prior to the first dose; and those with a history of alcohol abuse (alcohol abuse criteria: a history of long-term alcohol consumption for more than 5 years, equivalent to ≥40g / day of ethanol, or a history of heavy drinking within 2 weeks, equivalent to >80g / day of ethanol).Ethanol content (g) conversion formula = alcohol consumption (mL) * ethanol content (%) × 0.8); those with mental illness or obvious mental disorders, or those who are incapacitated or cognitively incapacitated for other reasons; those who have plans to have children or donate sperm during the entire trial period and 6 months after the last dose, or those who do not wish to use effective physical contraception (such as condoms); those who have clinically significant diseases or other reasons that the researchers consider unsuitable for participation in the clinical trial (e.g., patients who cannot benefit from the clinical trial); those who the researchers consider to have poor subject compliance, will not be able to evaluate efficacy, or are unlikely to complete the course of treatment and follow-up.

[0066] Example 2 - Phase I Experimental Study on Single-Dose Escalation of SR604 Injection Part A

[0067] 1. Experimental Design

[0068] SR604 injection: SR604 antibody: 30 mg / mL, L-histidine: 0.761 mg / mL, L-histidine hydrochloride monohydrate: 1.067 mg / mL, polysorbate 80: 0.2 mg / mL, trehalose dihydrate: 100 mg / mL, L-arginine hydrochloride: 21.066 mg / mL, add WFI to a total volume of 1.0 mL.

[0069] Following the case screening process in Part A of Example 1, a total of 16 subjects were enrolled, all of whom were Han Chinese males with a mean age of 33.0 (7.90) years and a mean disease duration of 28.44 (10.438) years. All patients had moderate to severe hemophilia, and patients with inhibitors were not included. The trial was designed with 6 dose cohorts: 0.025 mg / kg (starting dose), 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.4 mg / kg, and 0.8 mg / kg. One patient was enrolled in the 0.025 mg / kg dose group, and three patients were enrolled in each of the other dose groups. Except for the 0.025 mg / kg group which enrolled one patient with hemophilia A, each of the other dose groups enrolled two patients with hemophilia A and one patient with hemophilia B. The safety, tolerability, pharmacokinetics, and pharmacodynamics of each dose cohort were evaluated sequentially.

[0070] The dosage was calculated based on the subject's weight and the selected dose group. Dosage (mg) = dose group (mg / kg) × weight (kg); administered subcutaneously, once.

[0071] Subjects in the 0.025 mg / kg dose group were followed up until day 57 after completing the D29 safety data review and assessment. Subjects in the other dose groups were followed up until day 85 after completing the D29 safety data review and assessment, and were discharged after undergoing immunogenicity and related safety tests and PK / PD collection. The dose escalation regimen is as follows: Figure 1 As shown.

[0072] Immunogenicity and SR604 were detected by ELISA; neutralizing antibodies were detected by MSD; Protac-APTT, protein C, protein S, FVIII:C or FIX:C or FVII:C, FVIII or FIX or FVII inhibitors were detected by HA; and TGA was detected by Fluorescence.

[0073] 2. Pharmacokinetic characteristics

[0074] 1) Blood collection point design

[0075] PK biological samples were collected from subjects in Cohort 1 (0.025 mg / kg, starting dose) at 1 hour before administration and at 2 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, 96 hours, 120 hours, 168 hours (D8), 240 hours (D11), 336 hours (D15), 504 hours (D22), and 672 hours (D29) after administration.

[0076] PK biological samples were collected from subjects in Cohort 2 at 15 time points, including 1 hour before drug administration and 2 hours, 8 hours, 24 hours (D2), 48 hours (D3), 96 hours (D5), 120 hours (D6), 168 hours (D8), 240 hours (D11), 336 hours (D15), 504 hours (D22), 672 hours (D29), 840 hours (D36), 1008 hours (D43), and 1344 hours (D57).

[0077] PK biological samples were collected from subjects in cohorts 3-6 at 17 time points: 1 hour before drug administration, and 2 hours, 8 hours, 24 hours (D2), 48 hours (D3), 96 hours (D5), 120 hours (D6), 168 hours (D8), 240 hours (D11), 336 hours (D15), 504 hours (D22), 672 hours (D29), 840 hours (D36), 1008 hours (D43), 1344 hours (D57), D71 (1680 hours), and D85 (2016 hours).

[0078] 2) SR604 blood drug concentration

[0079] Following administration, SR604 plasma concentrations gradually increased, reaching peak levels in 16 subjects between days 2 and 21. The pharmacokinetic (PK) curves were similar across cohorts, showing relatively stable absorption and elimination rates with an overall linear elimination pattern. The half-life ranged from 9.07 to 15.0 days, gradually increasing with the administered dose. For detailed SR604 plasma concentration-time and semi-logarithmic plasma concentration-time plots, please refer to... Figure 2 and Figure 3 .

[0080] 3) PK parameter

[0081] As shown in Table 1, one subject was enrolled in the 0.025 mg / kg dose group. max (ng / mL) was 170, AUC 0-t (h*ug / mL) was 114, AUC 0-∞ (h*ug / mL) is 116, T max (day) is 7.01, t 1 / 2z (day) is 9.07, V z / F (mL / kg) is 65.5, CL z / F(mL / h / kg) is 0.209, λ z (1 / h)0.003, MRT 0-t (h)447、MRT 0-∞ (h)469、AUC _％Extrap (%) 1.64;

[0082] Three subjects were enrolled in the 0.05 mg / kg dose group, with an average C... max (ng / mL) was 309 (45.0), with an average AUC 0-t (h*ug / mL) was 246 (69.9), and the average AUC was 0-∞ (h*ug / mL) was 261 (63.4), and the average T was... max (day) is 8.31 (2.90), average t 1 / 2z (day) is 14.6 (0.882), average V z / F (mL / kg) was 102 (27.6), and the average CL z / F (mL / h / kg) was 0.201 (0.046), and the average λ z (1 / h)0.002(0.000), average MRT 0-t (h) is 560(146), average MRT 0-∞ (h) is 649(112), average AUC _％Extrap (%) was 6.10 (3.73);

[0083] Three subjects were enrolled in the 0.1 mg / kg dose group, with an average C... max (ng / mL) was 602 (81.3), with an average AUC 0-t (h*ug / mL) was 419 (164), and the average AUC was 419 (164). 0-∞ (h*ug / mL) was 431 (173), and the average T was... max (day) is 7.98 (1.72), average t 1 / 2z (day) is 12.8 (4.13), average V z / F (mL / kg) was 109 (38.5), and the average CL z / F (mL / h / kg) was 0.257 (0.087), and the average λ z (1 / h)0.002(0.001), average MRT 0-t (h) is 527 (92.2), average MRT 0-∞ (h) is 571 (120), average AUC _％Extrap (%) was 2.46 (1.55);

[0084] Three subjects were enrolled in the 0.2 mg / kg dose group, with an average C... max (ng / mL) was 693 (42.8), with an average AUC of 0-t (h*ug / mL) was 625 (145), with an average AUC of 145. 0-∞ (h*ug / mL) was 671 (193), and the average T was... max (day) is 15.0 (5.60), average t 1 / 2z (day) is 16.1 (7.48), average V z / F (mL / kg) was 161 (39.0), and the average CL z / F (mL / h / kg) was 0.316 (0.093), and the average λ z (1 / h) is 0.002 (0.001), average MRT 0-t (h) is 650 (188), average MRT 0-∞ (h) is 764 (297), average AUC _％Extrap (%) was 5.80 (5.51);

[0085] Three subjects were enrolled in the 0.4 mg / kg dose group, with an average C... max (ng / mL) was 1713 (345), with an average AUC of 0-t (h*ug / mL) was 1568 (225), with an average AUC of 1568 (225). 0-∞ (h*ug / mL) was 1647 (265), and the average T was... max(day) is 8.66 (6.10), average t 1 / 2z (day) is 15.0 (9.05), average V z / F (mL / kg) was 124 (74.6), and the average CL z / F (mL / h / kg) was 0.246 (0.037), and the average λ z (1 / h) is 0.003 (0.003), average MRT 0-t (h) is 661 (38.9), average MRT 0-∞ (h) is 754(111), average AUC _％Extrap (%) was 4.60 (3.93);

[0086] Three subjects were enrolled in the 0.8 mg / kg dose group, with an average C... max (ng / mL) was 3897 (657), with an average AUC of 0-t (h*ug / mL) was 3386 (805), with an average AUC of 1000. 0-∞ (h*ug / mL) was 3534 (964), and the average T was... max (day) is 8.96 (1.72), average t 1 / 2z (day) is 14.4 (6.18), average V z / F (mL / kg) was 112 (31.8), and the average CL z / F (mL / h / kg) was 0.240 (0.063), and the average λ z (1 / h) is 0.002 (0.001), average MRT 0-t (h) is 634 (50.4), average MRT 0-∞ (h) is 706 (120), average AUC _％Extrap (%) was 3.61 (3.46).

[0087] Table 1. SR604 Plasma PK Parameters (Part A) (N represents the number of cases in the analysis set; n represents the actual number of subjects; SD = standard deviation; CV% = coefficient of variation (%); Q1 = 25th percentile; Q3 = 75th percentile; Min = minimum value; Max = maximum value; GM = geometric mean; GCV% = geometric coefficient of variation (%).)

[0088]

[0089]

[0090] Note: If any individual value used for calculation is 0, then GM and GCV% are displayed as "NA".

[0091] 4) Power function model analysis of linear PK determination of SR604 plasma

[0092] The exposure-dose relationship was inferred using a model based on the dose range of SR604 and Cmax, AUC0-t, and AUC0-∞. Considering that only one subject had the 0.025 mg / kg dose, this subject was not included in the analysis. The power function model yielded 95% CIs for Cmax (0.749–1.02), AUC0-t (0.799–1.11), and AUC0-∞ (0.790–1.11), indicating an overall linear trend between SR604 dose and exposure. See Table 2 for details.

[0093] Table 2 Power function model analysis of SR604 plasma PK linearity judgment

[0094]

[0095] 3. Pharmacodynamic evaluation

[0096] 1) Protac-APTT (Protac-induced protein C activation APTT assay)

[0097] Protac is a single-chain glycoprotein serine protease, a fast-acting protein C activator isolated from the venom of the copperhead viper. Protac-activated APCs sequentially inactivate FVIIIa (intrinsic pathway) and FVa (common pathway). APC activation due to the presence of Protac significantly prolongs the APTT clotting time. SR604 (an APC monoclonal antibody) can specifically bind to APCs, blocking the inactivation of FVIIIa and FVa, thereby correcting or shortening the prolonged clotting time. The Protac-APTT coagulation test can be used to detect SR604-specific inhibition of APC functional activity. When Protac is present in human plasma, the APTT time is negatively correlated with the plasma SR604 concentration.

[0098] The inhibition rate of SR604 was calculated by measuring the APTT in plasma with and without Protac, using the following formula: Among them, the blank mixed human plasma sample incubated with Protac was used as the Negative Control (NC), and the blank mixed human plasma sample not incubated with Protac was used as the Positive Control (PC).

[0099] With increasing PK concentration, the SR604 inhibition rate showed an increasing trend, reaching a peak and then gradually decreasing. The 0.025 mg / kg dose group reached its highest level (66.667%) on day 29; the 0.05 mg / kg dose group reached its highest level (73.432%) on day 6; the 0.1 mg / kg dose group reached its highest level (81.187%) on day 6; the 0.2 mg / kg dose group reached its highest level (85.460%) on day 22; the 0.4 mg / kg dose group reached its highest level (92.809%) on day 11; and the 0.8 mg / kg dose group reached its highest level (96.321%) on day 3. The SR604 inhibition rate increased with increasing dosage; for a detailed time-varying curve of the SR604 inhibition rate, see [link to relevant documentation]. Figure 4 .

[0100] According to the quantitative pharmacological modeling results, the inhibition rate of SR604 and the overall blood drug concentration conform to the Emax model, and there is a dose-response relationship with the blood drug concentration, with no delay compared to the blood drug concentration.

[0101] 2) Protein C, prothrombin time (PT), and total thrombin assay (TGA)

[0102] No significant changes were observed in protein C and PT as measured by PartA compared to pre-treatment levels, and no dose-related effects were observed.

[0103] Thrombin generation assays include peak thrombin concentration, delay time, time to peak concentration, generation potential, and rate index. No significant changes were observed in Part A of the assays compared to pre-administration values, and no dose-related effects were observed.

[0104] 4. Validity Evaluation

[0105] One subject was enrolled in the 0.025 mg / kg dose group, and the number of bleeding events treated with the drug from D1 to D29 was 2.0; three subjects were enrolled in the 0.05 mg / kg dose group, and the mean number of bleeding events treated with the drug from D1 to D29 was 1.3 (0.58); three subjects were enrolled in the 0.1 mg / kg dose group, and the mean number of bleeding events treated with the drug from D1 to D29 was 1.0 (1.00); three subjects were enrolled in the 0.2 mg / kg dose group, and the mean number of bleeding events treated with the drug from D1 to D29 was 0.7 (0.58); three subjects were enrolled in the 0.4 mg / kg dose group, and the mean number of bleeding events treated with the drug from D1 to D29 was 0; three subjects were enrolled in the 0.8 mg / kg dose group, and the mean number of bleeding events treated with the drug from D1 to D29 was 0.

[0106] The number of bleeding events after drug treatment in each dose group from D1 to D57 was statistically analyzed. The average number of bleeding events after drug treatment was 3.0 in the 0.025 mg / kg dose group, 2.7 (1.15) in the 0.05 mg / kg dose group, 1.7 (0.58) in the 0.1 mg / kg dose group, 1.3 (0.58) in the 0.2 mg / kg dose group, 0.7 (0.58) in the 0.4 mg / kg dose group, and 0.7 (1.15) in the 0.8 mg / kg dose group.

[0107] The number of bleeding events after drug treatment in each dose group from D1 to D85 was statistically analyzed. The number of bleeding events after drug treatment was 4.0 in the 0.025 mg / kg dose group, 3.0 (1.00) in the 0.05 mg / kg dose group, 2.0 (0) in the 0.1 mg / kg dose group, 1.7 (1.15) in the 0.2 mg / kg dose group, 2.3 (1.53) in the 0.4 mg / kg dose group, and 1.0 (1.73) in the 0.8 mg / kg dose group.

[0108] In summary, following a single dose of SR604, a decrease in the number of treated bleeding events was observed on days 1-29 and 57 post-dose, demonstrating a good dose-related effect. On days 1-85, all dose groups except the 0.4 mg / kg group also showed a good dose-related effect.

[0109] Statistical analysis of spontaneous bleeding events on days 1-29 after drug treatment showed that the number of spontaneous bleeding events decreased with increasing dosage, exhibiting a good dose-related effect. On days 1-57 and 1-85 after drug treatment, all dosage groups except the 0.4 mg / kg group also showed a good dose-related effect.

[0110] 5. Security Analysis

[0111] Of the 16 subjects enrolled in this phase, 13 (87.5%) experienced 21 TEAEs. Specifically, 1 subject in the 0.025 mg / kg dose group experienced 1 TEAE, 2 subjects in the 0.05 mg / kg dose group experienced 2 TEAEs, 3 subjects in the 0.1 mg / kg dose group experienced 6 TEAEs, 2 subjects in the 0.2 mg / kg dose group experienced 5 TEAEs, 3 subjects in the 0.4 mg / kg dose group experienced 4 TEAEs, and 3 subjects in the 0.8 mg / kg dose group experienced 3 TEAEs. All TEAEs were Grade 1 or 2; no Grade 3 or higher TEAEs occurred, no TEAEs led to withdrawal, and the relationship to the investigational drug was unrelated or possibly unrelated. No adverse reactions occurred. 18 TEAEs resolved, and 3 TEAEs remained unchanged / unrelieved / persistent. The three cases of TEAE that were classified as not improved / not relieved / persistent were hemophilic arthropathy, hypertriglyceridemia, and hyperuricemia.

[0112] TEAE is classified by SOC and PT. The most common SOC is various injuries, poisoning and procedural complications (37.5%), followed by infection and invasive diseases (18.8%) and metabolic and nutritional diseases (18.8%). Other SOCs are isolated cases. The PTs with an incidence of ≥10% are traumatic hemorrhage (37.5%) and hypertriglyceridemia (12.5%).

[0113] SR604 injection is safe and well-tolerated at all dose levels with a single dose. No TEAEs leading to withdrawal, no adverse events of particular concern (AESIs), no adverse drug reactions, no injection site reactions, no SAEs, and no reported thromboembolic events were observed.

[0114] 6. Immunogenicity analysis

[0115] Of the 16 subjects enrolled in Part A, all had negative baseline ADA (anti-drug antibody). Six subjects (37.5%) became ADA positive after medication, with titers ranging from 1:1 to 1:27. Three subjects (18.8%) were Nab positive. No impact was observed on pharmacokinetics, pharmacodynamics, safety, or efficacy. See Tables 3-4 for details, where N represents the number of cases in the analysis set; n represents the actual number of subjects; % represents the percentage calculated based on n as the denominator; post-medication positive means a positive result at any time after medication; any positive result means a positive result at any time before or after medication.

[0116] In the 0.025 mg / kg dose group, one subject had negative ADA levels both before and after medication; in the 0.05 mg / kg dose group, one subject had a negative result before medication but was positive on day 85 after medication, with an ADA titer of 1:1; in the 0.1 mg / kg dose group, two subjects had a negative result before medication but were positive on day 85 after medication, with the highest ADA titer of 1:3 in both cases; in the 0.2 mg / kg dose group, one subject had a negative result before medication but was positive on day 29 after medication, with the highest ADA titer of 1:1; in the 0.4 mg / kg dose group, one subject had a negative result before medication but was positive on day 57 after medication, with the highest ADA titer of 1:1; and in the 0.8 mg / kg dose group, one subject had a negative result before medication but was positive on day 57 after medication, with the highest ADA titer of 1:27.

[0117] Table 3 ADA Analysis (Part A)

[0118]

[0119] Table 9. Analysis of the first positive time for ADA (Part A)

[0120]

[0121] Table 4. List of ADA-positive patients (Part A)

[0122]

[0123] 7. Test Results

[0124] The Part A trial was designed with six dose cohorts: one patient was enrolled at 0.025 mg / kg, and three patients were enrolled at doses ranging from 0.05 mg / kg to 0.8 mg / kg, for a total of 16 subjects. Following a single administration of SR604 injection at doses ranging from 0.025 mg / kg to 0.8 mg / kg, the overall trend of dose and exposure was linear, with a long half-life. The inhibition rate of SR604 conformed to the Emax model, indicating a dose-response relationship with plasma concentration. Single administration of SR604 injection at all dose levels was safe and well-tolerated, with no TEAEs leading to withdrawal, no AESIs, no adverse drug reactions, no injection site reactions, no SAEs, and no reported thromboembolic events.

[0125] Example 3 - Phase IIa trial of two-dose, multiple-dose administration of SR604 injection Part B for preventive treatment efficacy exploration.

[0126] 1. Test Plan

[0127] SR604 injection: SR604 antibody: 30 mg / mL, L-histidine: 0.761 mg / mL, L-histidine hydrochloride monohydrate: 1.067 mg / mL, polysorbate 80: 0.2 mg / mL, trehalose dihydrate: 100 mg / mL, L-arginine hydrochloride: 21.066 mg / mL, add WFI to a total volume of 1.0 mL.

[0128] Following the case screening method in Example 1, a total of 24 subjects were enrolled, all of whom were male. 22 (91.7%) were Han Chinese, and 2 (8.3%) were from other ethnic groups. The mean disease duration was 25.63 (9.836) years. Except for one subject with moderate severity, all other subjects had severe severity. The number of new bleeding events in hemophilia A / B patients treated with on-demand therapy within the three months prior to enrollment was 8.0 (4.65). This phase was a Phase IIa trial exploring the efficacy of two-dose, open-label, multiple-dose prophylactic treatment. There were two dosage groups: 0.05 mg / kg (loading dose of 0.1 mg / kg for the first injection) and 0.1 mg / kg (loading dose of 0.2 mg / kg for the first injection). Each dosage group enrolled 12 cases. The 0.05 mg / kg dosage group included 1 patient with congenital factor VII deficiency, 4 patients with hemophilia B, and 7 patients with hemophilia A. The 0.1 mg / kg dosage group included 2 patients with hemophilia B and 10 patients with hemophilia A. No patients with inhibitors were enrolled in the 0.05 mg / kg dosage group. The 0.1 mg / kg dosage group included 6 patients with inhibitors (5 with FVIII inhibitors and 1 with FIX inhibitors). The inhibitor levels ranged from 0.6 to 3000 BU / ml.

[0129] The dosage was calculated based on the subject's weight and the selected dose group. Dosage (mg) = dose group (mg / kg) × weight (kg). The medication was administered subcutaneously once every 2 weeks for a total of 6 doses.

[0130] Eligible patients underwent a 3-month (12-week) treatment period, receiving dosing every 2 weeks for a total of 6 doses, during which PK / PD blood samples were collected. After 12 weeks, subjects could enter a 3-month (12-week) extended treatment period, receiving dosing every 2 weeks for a total of 6 doses, with PK / PD blood samples collected again. Patients were discharged after a safety assessment 56 days after the last dose. The trial design is as follows: Figure 5 As shown.

[0131] Immunogenicity and SR604 were detected by ELISA; neutralizing antibodies were detected by MSD; Protac-APTT, protein C, protein S, FVIII:C or FIX:C or FVII:C, FVIII or FIX or FVII inhibitors were detected by HA; and TGA was detected by Fluorescence.

[0132] 2. Pharmacokinetic Studies

[0133] 1) Blood collection point design

[0134] In Part B, both dosage groups (0.05 mg / kg and 0.1 mg / kg) were administered at the following times: D1 (before the first dose), D2 (24 h ± 20 min after the first dose), D3 (48 h ± 20 min after the first dose), D5 (96 h ± 1 h after the first dose), D8 (168 h ± 4 h after the first dose), D11 (240 h ± 4 h after the first dose), D15 (before the second dose), D57 (before the fifth dose), D71 (before the sixth dose), D72 (24 h ± 20 min after the sixth dose), and D73 (the sixth dose). PK biological samples were collected at a total of 20 time points: D75 (96h±1h after the 6th dose), D78 (168h±4h after the 6th dose), D81 (240h±4h after the 6th dose), D85 (336h after the 6th dose, before the 7th dose), D127 (before the 10th dose), D169 (336h-4d after the last dose), D183 (672h±1d after the last dose), D197 (1008h±2d after the last dose), and D211 (1344h±2d after the last dose).

[0135] 2) After administration, the plasma concentration of SR604 gradually increased. The average plasma concentration of the 0.1 mg / kg group before day 71 was generally higher than that of the 0.05 mg / kg group. See the SR604 plasma concentration-time plot and the SR604 plasma concentration-time semi-logarithmic plot for details. Figure 6 and Figure 7 .

[0136] 3) Plasma pharmacokinetic parameters after a single dose of SR604

[0137] In the 0.05 mg / kg dose group, after the first administration of SR604 (a loading dose of 0.1 mg / kg), the mean C max The average AUC was 519 (243) ng / mL. 0-336h (h*ug / mL) was 130 (69.6), and the average T was... max (day) was 11.1 (4.21); in the 0.1 mg / kg dose group, after the first administration of SR604 (loading dose of 0.2 mg / kg), the mean C max The average AUC was 987 (364) ng / mL. 0-336h (h*ug / mL) was 280 (115), and the average T was max The (day) is 9.06 (3.76). See Table 5 for details.

[0138] Table 5 Plasma p-values ​​for a single SR604 dose

[0139]

[0140] 4) Plasma pharmacokinetic parameters after multiple SR604 administrations

[0141] The pharmacokinetic parameters for multiple doses in the 0.05 mg / kg dosage group are as follows: mean C max,ss (ng / mL) was 886 (249), with an average AUC of 0-τ,ss (h*ug / mL) was 261 (74.9), and the average C min,ss (ng / mL) was 657 (215), average C av,ss The average concentration (ng / mL) was 778 (223), the average DF (%) was 29.9 (19.2), and the average S wing The value is 0.384 (0.295), and the average T is... max,ss The average AUC is 2.73 (2.45) for the day. 0-t (h*ug / mL) was 264 (74.8), and the average CL ss / F (mL / h / kg) is 0.210 (0.068).

[0142] The pharmacokinetic parameters for multiple doses in the 0.1 mg / kg dosage group are as follows: mean C max,ss (ng / mL) was 1485 (561), with an average AUC of 0-τ,ss (h*ug / mL) was 446 (166), and the average C min,ss (ng / mL) was 1094 (360), average C av,ss The concentration (ng / mL) was 1327 (494), the average DF (%) was 29.0 (15.8), and the S wing The average T is 0.376 (0.259). max,ss The average AUC is 3.48 (2.37) for the day. 0-t (h*ug / mL) was 450 (168), with an average CL ss / F (mL / h / kg) was 0.261 (0.124). See Table 6 for details, where N represents the number of cases in the analysis set; n represents the actual number of subjects; SD = standard deviation; CV% = coefficient of variation (%); Q1 = 25th percentile; Q3 = 75th percentile; Min = minimum value; Max = maximum value; GM = geometric mean; GCV% = geometric coefficient of variation (%); if any individual value used for calculation is 0, then GM and GCV% are displayed as "NA"; the blood drug concentration of subjects in the 0.05 mg / kg BA0202 group was BQL, with no PK parameters. For subjects BA0401 in the 0.05 mg / kg group and subjects BB0201 and BB0603 in the 0.1 mg / kg group, the actual sampling time at 336 h (D85) was less than 336 h, so AUC0-τ,ss could not be calculated. However, sampling was completed within 336 h and did not exceed the window. AUC0-t was used to fill AUC0-τ,ss, and the parameters Cav,ss, DF, and CLss / F were derived from this.

[0143] Table 6 Plasma pharmacokinetic parameters for multiple SR604 doses

[0144]

[0145]

[0146] 3. Pharmacodynamic evaluation

[0147] 1) Protac-APTT (Protac-induced protein C activation APTT assay)

[0148] The inhibition rate of SR604 was calculated by measuring the APTT in plasma with and without Protac, using the following formula: Among them, the blank mixed human plasma sample incubated with Protac was used as the Negative Control (NC), and the blank mixed human plasma sample not incubated with Protac was used as the Positive Control (PC).

[0149] After SR604 administration, the inhibition rate of SR604 gradually increased. The average SR604 inhibition rate in the 0.05 mg / kg dose group reached a peak of 83.436% on day 85, while in the 0.1 mg / kg dose group it reached a peak of 93.403% on day 71. The overall SR604 inhibition rate in the 0.1 mg / kg dose group was higher than that in the 0.05 mg / kg dose group. See details. Figure 8 .

[0150] 2) Protein C, prothrombin time (PT), and total thrombin assay (TGA)

[0151] No significant changes were observed in protein C and PT as measured by Part B compared to pre-treatment levels, and no dose-related effects were observed.

[0152] Thrombin generation assays include peak thrombin concentration, delay time, time to peak concentration, generation potential, and rate index. No significant changes were observed in Part B assays compared to pre-administration values, and no dose-related effects were observed.

[0153] 4. Validity Evaluation

[0154] After 12 weeks of treatment, the mean annualized total bleeding rate (95% CI) based on treatment in the 0.05 mg / kg dose group was 8.276 (4.484, 15.275), a decrease of 76.0% from baseline; the mean annualized total bleeding rate (95% CI) based on treatment in the 0.1 mg / kg dose group was 5.444 (2.820, 10.510), a decrease of 81.7% from baseline. After 12 weeks of treatment, the mean spontaneous bleeding rate (95% CI) based on treatment in the 0.05 mg / kg dose group was 5.520 (2.978, 10.231); the mean annualized spontaneous bleeding rate (95% CI) based on treatment in the 0.1 mg / kg dose group was 3.628 (1.813, 7.262). After 12 weeks of treatment, the mean annualized total joint bleeding rate (95% CI) based on treatment was 6.699 (3.758, 11.943) in the 0.05 mg / kg dose group and 2.176 (0.921, 5.142) in the 0.1 mg / kg dose group. These results demonstrate that 12 weeks of SR604 prophylactic treatment effectively reduces the annualized bleeding rate in patients. See Tables 7-9 for details, where N represents the number of subjects who used the investigational drug at least once; n represents the actual number of subjects; CI represents the confidence interval; and the baseline is defined as the last non-missing assessment (including unplanned measurements) before the first use of the investigational drug. The total annualized bleeding rate (times / year) over 12 weeks of treatment = number of treated bleeding episodes within 14 days after the first dose to the 6th dose / [(date of the 6th dose - date of the first dose + 14) / 365.25]. Total bleeding includes spontaneous bleeding and traumatic bleeding. Treated bleeding refers to bleeding for which factor replacement or bypass drug treatment was used. The statistical data were estimated based on a negative binomial model, in which the number of treated bleeding episodes during the exposure time is used as the response variable, and the offset is set as log(bleeding exposure time).

[0155] Table 7. Subgroup analysis of total annualized bleeding rate (FAS) after 12 weeks of treatment.

[0156]

[0157]

[0158] Table 8. Subgroup analysis of spontaneous annualized bleeding rate at 12 weeks of treatment.

[0159]

[0160] Table 9. Subgroup analysis of total annualized joint bleeding rate after 12 weeks of treatment.

[0161]

[0162] 5. Security Analysis

[0163] Of the 24 subjects enrolled in this phase, 17 (70.8%) experienced 39 TEAEs. Specifically, 8 subjects (66.7%) in the 0.05 mg / kg dose group experienced 22 TEAEs, and 9 subjects (75.0%) in the 0.01 mg / kg dose group experienced 17 TEAEs. All TEAEs were grade 1 or 2; no grade 3 or higher TEAEs occurred, no TEAEs led to withdrawal, no TEAEs led to dose adjustment, no TEAEs led to discontinuation of medication, no TEAEs led to death, and no SAEs occurred. 32 TEAEs resolved, and 7 TEAEs remained unchanged / unresolved / persistent (Part B continues with extended treatment; unresolved / unresolved / persistent AEs are still under further follow-up). 36 TEAEs were unrelated to or possibly unrelated to the medication, and 3 TEAEs were possibly related to the medication.

[0164] TEAEs were classified by SOC and PT. The most common SOCs were various injuries, poisoning and procedural complications (45.8%), followed by infections and invasive diseases (12.5%), metabolic and nutritional diseases (12.5%) and skin and subcutaneous tissue diseases (12.5%). The most common adverse events with an incidence of ≥5% were traumatic bleeding (41.7%), elevated uric acid (8.3%), upper respiratory tract infection (8.3%) and abnormal liver function (8.3%). Other TEAEs were isolated cases.

[0165] Three subjects (12.5%) experienced three episodes of AESI, with PTs of maculopapular rash, skin pain, and injection site erythema, respectively. All were in the 0.05 mg / kg dose group, with a severity of grade 1, and all outcomes were complete recovery.

[0166] Three subjects (12.5%) experienced three adverse drug reactions (ADRs), with PTs of maculopapular rash, skin pain, and injection site erythema, all in the 0.05 mg / kg dose group, all of which were grade 1 in severity and all of which resulted in recovery.

[0167] One subject (4.2%) experienced one injection site reaction.

[0168] SR604 injection was safe and well-tolerated at multiple doses (once every 2 weeks) at dose levels of 0.05 mg / kg and 0.1 mg / kg. No TEAEs leading to withdrawal occurred. Three ADRs occurred in 3 subjects (12.5%), and one subject (4.2%) experienced an injection site reaction. No SAEs or thromboembolic events occurred.

[0169] 6. Immunogenicity analysis

[0170] In Part B, among the 24 subjects enrolled, 2 subjects (8.3%) were negative for ADA (anti-drug antibody) at baseline but became positive after medication, with titers ranging from 1:1 to 1:6561. One subject (4.2%) was Nab-positive. No impact of ADA on safety was found. Details are shown in Table 10, where N represents the number of cases analyzed, % represents the percentage calculated based on N as the denominator, post-medication positive means any positive result after medication, and any positive result means any positive result before or after medication. Nab had a certain impact on the PK and SR604 inhibition rate and efficacy in one subject. The following is a detailed analysis of this subject:

[0171] The subject (BS0203 / BA0202, 0.05 mg / kg dose group, hemophilia B) first received the investigational drug on March 27, 2025 (D1), and received it every two weeks until the last dose on July 31, 2025 (D127), for a total of 10 injections. Treatment with the investigational drug was discontinued on August 11, 2025. The subject was negative for ADA before receiving the investigational drug on March 27, 2025 (D1). ADA was positive on April 24, 2025 (D29) with a titer of 1:27. The ADA titer was 1:243 on May 22, 2025 (D57). The titers were 1:6561 on June 19, 2025 (D85), July 31, 2025 (D127), and August 14, 2025 (D141). Further data are still being collected. Nab levels were also positive at D27, D57, D127, and D141. Starting at D57, both SR604 blood concentration and SR604 inhibition rate decreased sharply, and blood concentrations became undetectable at subsequent time points (D71-D141). The SR604 inhibition rate dropped to -31.017% at D57, recovered to 39.206% at D71, 45.906% at D73, 24.814% at D85, and -60.55% at D127, demonstrating that SR604 had lost its therapeutic effect. The ABR (Average Benefit Rate) for this subject after 12 weeks of treatment (D1-D85) was 8.696, while the preliminary ABR for D86-D140 was 26.089, indicating a decline in efficacy. As of September 25, 2025, the subject is still under safety follow-up and will be scheduled for a withdrawal visit at a later date. Immunogenicity will continue to be monitored until neutralizing antibodies are no longer detectable or the ADA titer is stable.

[0172] Table 10 ADA Analysis (Part B)

[0173]

[0174] Table 11 List of ADA-positive patients (Part B)

[0175]

[0176] 7. Test Results

[0177] Part A of the trial consisted of six dose cohorts: one patient was enrolled at 0.025 mg / kg, and three patients were enrolled at doses ranging from 0.05 mg / kg to 0.8 mg / kg, for a total of 16 subjects. Following a single administration of SR604 injection at doses ranging from 0.025 mg / kg to 0.8 mg / kg, the overall trend of dose and exposure was linear. The inhibition rate of SR604 conformed to the Emax model, indicating a dose-response relationship with plasma concentration. Single administration of SR604 injection at all dose levels was safe and well-tolerated, with no TEAEs leading to withdrawal, no AESIs, no adverse drug reactions, no injection site reactions, no SAEs, and no thromboembolic events.

[0178] Part B of the trial included two dosage groups: 0.05 mg / kg and 0.1 mg / kg. The initial dose was doubled, and prophylactic treatment was administered every two weeks. The planned enrollment was 24 subjects, and 24 subjects were actually enrolled. After 12 weeks of prophylactic treatment, the treatment-based annualized bleeding rate decreased by 76.0% from baseline in the 0.05 mg / kg group and by 81.7% in the 0.1 mg / kg group, both effectively reducing the annualized bleeding rate. Three subjects (12.5%) experienced three adverse drug reactions (ADRs), and one subject experienced one injection site reaction. No spontaneous aspiration encephalopathy (SAE) or thromboembolic events occurred. The safety profile was satisfactory and in line with expectations.

[0179] The above embodiments are for illustrating the implementation schemes disclosed in this invention and should not be construed as limiting the invention. Furthermore, various modifications listed herein, as well as variations in the methods and compositions of the invention, will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been specifically described in conjunction with various specific preferred embodiments, it should be understood that the invention should not be limited to these specific embodiments. In fact, various modifications as described above that are obvious to those skilled in the art to obtain the invention should be included within the scope of this invention.

Claims

1. The use of SR604 injection in the preparation of drugs for the prevention and / or treatment of human hemorrhagic diseases, wherein the SR604 injection comprises SR604 antibody, and the injection dose of SR604 antibody in the SR604 injection is selected from 0.025 mg / kg to 0.8 mg / kg.

2. The application as described in claim 1, characterized in that, The light chain amino acid sequence of the SR604 antibody is shown in SEQ ID No. 1, and its heavy chain amino acid sequence is shown in SEQ ID No. 2; And / or, the SR604 antibody content in the SR604 injection solution is 30-70 mg / ml; preferably, the SR604 antibody content is 27-33, 45-55, or 63-77 mg / ml.

3. The application as described in claim 1, characterized in that, The SR604 injection solution also includes a buffer system, which is selected from histidine / histidine hydrochloride or acetic acid / sodium acetate. And / or, the SR604 injection further comprises the following protective agents: a. sugars or sugar alcohols, wherein the sugars are selected from trehalose and sucrose, and the sugar alcohols are selected from sorbitol or mannitol; b. amino acids, wherein the amino acids are selected from arginine hydrochloride or aspartic acid; And / or, the SR604 injection solution further includes a surfactant selected from polysorbate 80 and / or P188.

4. The application as described in claim 3, characterized in that, The buffer system is 10 mM L-histidine / L-histidine hydrochloride; and / or, the protective agent is selected from 10% trehalose + 100 mmol / L L-arginine hydrochloride; and / or, the surfactant is selected from 200 ppm polysorbate 80.

5. The application as described in claim 1, characterized in that, The SR604 injection is for subcutaneous injection; And / or, the injection frequency of the SR604 injection includes one or more of once a week, once every two weeks, once every three weeks, and once every four weeks, preferably, the injection frequency of the SR604 injection is selected from once every two weeks.

6. The application as described in claim 1, characterized in that, The bleeding disorders mentioned are selected from hemophilia A, hemophilia B, and congenital factor VII deficiency.

7. The application as described in claim 1, characterized in that, The drug has one or more of the following effects: 1) Reduce the frequency of bleeding events; 2) Reduce the annualized bleeding rate; 3) Increase the drug's half-life; 4) Regulate APC functional activity; 5) Reduces thrombosis and adverse reactions at the injection site.

8. A method for preventing and / or treating hemorrhagic diseases in humans, the method comprising: Administer an effective amount of SR604 injection solution to the subject.

9. The method as described in claim 8, characterized in that, The effective dose of SR604 antibody in the SR604 injection solution is 0.025 mg / kg to 0.8 mg / kg; and / or, the SR604 injection is a subcutaneous injection; and / or, the injection frequency of the SR604 injection includes one or more of the following: once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, and once every eight weeks; and / or, the SR604 injection solution is the SR604 injection solution used in any one of claims 1 to 4.

10. The method as described in claim 8, characterized in that, The bleeding disorders mentioned are selected from hemophilia A, hemophilia B, and congenital factor VII deficiency.

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