Use of factor b inhibitor in treatment of paroxysmal nocturnal hemoglobinuria

Abstract

The present disclosure relates to the use of a Factor B inhibitor in the treatment of paroxysmal nocturnal hemoglobinuria. Specifically, the present disclosure relates to the use of the Factor B inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a formulation for treating paroxysmal nocturnal hemoglobinuria (PNH) previously using a C5 complement inhibitor, wherein the Factor B inhibitor is represented by formula (I), (II) or (III).

Description

Use of Factor B inhibitors in the treatment of paroxysmal nocturnal hemoglobinuria Technical Field

[0001] This disclosure relates to the use of Factor B inhibitors in the treatment of paroxysmal nocturnal hemoglobinuria. Background Technology

[0002] Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disease of the red blood cell membrane caused by gene mutations in hematopoietic stem cells. It is a benign clonal disease. Clinically, it is characterized by chronic intravascular hemolysis with paroxysmal exacerbations, which may be accompanied by pancytopenia and recurrent venous thrombosis. The cause of PNH lies in a somatic mutation in the phosphatidylinositol glycan anchor biosynthesis class A (PIGA) gene, which encodes a protein product, glycosyltransferase, essential for the biosynthesis of glycophosphatidylinositol anchoring proteins (GPIs). GPIs are membrane-bound proteins that anchor to various functional proteins. Mutations in the PIGA gene in hematopoietic stem cells lead to partial or complete loss of GPIs in various blood cell lineages, subsequently resulting in partial or complete loss of GPI-anchored proteins. Among GPI anchoring proteins, CD55 (also known as decay accelerator factor [DAF]) and CD59 (also known as reactive membrane lysis inhibitor [MIRL]) are complement regulatory proteins. CD55 and CD59 deficiency, leading to complement-mediated intravascular hemolysis, is characteristic of PNH. While there are no precise statistics on the incidence of PNH, it is generally more common in northern regions than in southern regions. The overall incidence is likely similar to that of aplastic anemia, around 1-5 per million, and is more common in Europe and America. Due to its low incidence / prevalence, it has been included in the first batch of rare disease catalogs jointly released in May 2018 by five departments: the National Health Commission, the Ministry of Science and Technology, the Ministry of Industry and Information Technology, the National Medical Products Administration, and the State Administration of Traditional Chinese Medicine.

[0003] Current drug treatments for polycythemia vera (PNH) have limited efficacy. Before the introduction of complement inhibitors in my country, traditional treatments for PNH focused on protecting cells, reducing complement attack and damage, and alleviating hemolysis. The primary treatment was glucocorticoids, but their clinical efficacy was poor and long-term use resulted in significant side effects. Bone marrow transplantation was the only curative treatment, but high transplant-related complications and mortality rates limited its clinical application. Eculizumab was the first approved monoclonal antibody targeting complement C5 for the treatment of PNH. It prevents complement C5 from cleaving into C5a and C5b, thereby preventing the formation of membrane attack complexes, effectively controlling intravascular hemolysis, and prolonging patient survival. However, despite eculizumab treatment, approximately 70% of patients still experience persistent anemia, and 25% to 35% require red blood cell transfusions. Eculizumab blocks downstream complement activation, preventing intravascular hemolysis. However, upstream complement activation persists, with complement C3 cleaving into C3a and C3b. Erythrocytes deposited with C3 fragments are cleared by the mononuclear-macrophage system, leading to extravascular hemolysis. This may be the main mechanism underlying the persistent anemia in patients treated with complement C5 inhibitors. Given the limitations of terminal complement, new drug targets are being developed to improve current anticomplement therapy. Pegcetacoplan is the first complement C3 inhibitor that acts directly on complement C3, controlling both intravascular and extravascular hemolysis, providing more comprehensive control of hemolysis in PNH patients. However, because C3 inhibits all three complement activation pathways, there may be safety concerns associated with complete complement inhibition. Over a decade of experience with eculizumab treatment has enabled us to better understand the steps involved in the complement cascade in the pathophysiology of various human diseases. Many hemolytic diseases are caused by mutations that inactivate complement regulatory proteins and / or autoantibodies and mutations that directly activate the complement cascade. These mutations and antibodies mostly target the alternative complement pathway (APC), and C3, complement factor B (CFB), and complement factor D (CFD) are the main components of APC [4,6]. Oral small molecule inhibitors targeting CFB are currently under development. Iptacopan is a highly effective and selective factor B small molecule inhibitor developed by Novartis that targets complement AP. It treats related diseases by inhibiting factor B activity and blocking AP activation in the complement system. Factor B inhibitors can selectively bind to active factor B, effectively blocking AP activation at low concentrations, while not inhibiting the normal activation of the other two complement pathways, the classical pathway and the lectin pathway, at active concentrations. Therefore, by targeting factor B to inhibit AP, both intravascular and extravascular hemolysis can be controlled simultaneously, while preserving the innate immunity of other complement pathways, thereby minimizing the risk of infection. Summary of the Invention

[0004] This disclosure provides the use of a Factor B inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a treatment for paroxysmal nocturnal hemoglobinuria (PNH) previously treated with C5 complement inhibitors, wherein the Factor B inhibitor is as shown in formula (I), (II) or (III):

[0005] This disclosure also provides a method for treating paroxysmal nocturnal hemoglobinuria (PNH) previously treated with C5 complement inhibitors, comprising administering a therapeutically effective amount of a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof:

[0006] This disclosure also provides a method for treating paroxysmal nocturnal hemoglobinuria (PNH) with a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, in patients with a history of C5 complement inhibitor use:

[0007] In some embodiments, prior use of C5 complement inhibitors means at least 6 months of prior use; in some embodiments, prior use of C5 complement inhibitors means at least 6 months of prior use; in some embodiments, prior use of C5 complement inhibitors means at least 7 months of prior use; in some embodiments, prior use of C5 complement inhibitors means at least 8 months of prior use; and in some embodiments, prior use of C5 complement inhibitors means at least 8 months of prior use.

[0008] In some embodiments, the C5 complement inhibitor is eculizumab and / or kovarimab; in some embodiments, the C5 complement inhibitor is eculizumab; in some embodiments, the C5 complement inhibitor is kovarimab.

[0009] In some implementations, the PNH refers to PNH that remains anemic despite prior use of C5 complement inhibitors.

[0010] In some embodiments, the first administration of the compound represented by formula (I), (II), or (III) or its pharmaceutically acceptable salt must be performed on day 7 to 8 after the last infusion of eculizumab or on day 13 to 15 after the last infusion of kovarimab; in some embodiments, the first administration of the compound represented by formula (I), (II), or (III) or its pharmaceutically acceptable salt must be performed on day 7 to 8 after the last infusion of eculizumab; in some embodiments, the first administration of the compound represented by formula (I), (II), or (III) or its pharmaceutically acceptable salt must be performed on day 13 to 15 after the last infusion of kovarimab.

[0011] In some implementations, the timing of initiation of treatment with the compound of formula (I), (II) or (III) or its pharmaceutically acceptable salt should ensure a seamless transition from prior C5 complement inhibitor treatment, overlapping at least 1 week of prior eculizumab treatment or 2 weeks of kovarimab treatment.

[0012] In some implementations, the compound or its pharmaceutically acceptable salt represented by formula (I), (II) or (III) must be swallowed whole and cannot be left to sit or chewed before swallowing.

[0013] In some embodiments, the PNH is a PNH with a red blood cell or granulocyte clone size >5%, 10%, 15%, 20%, or 25% as detected by flow cytometry; in some embodiments, the PNH is a PNH with a red blood cell or granulocyte clone size >10% as detected by flow cytometry.

[0014] In some implementations, the PNH has at least one blood transfusion record within the 3 months prior to screening, or has a hemoglobin level that is consistently <12 g / dL, 11.5 g / dL, 11 g / dL, 10.5 g / dL, 10 g / dL, 9.5 g / dL, 9 g / dL, 8.5 g / dL, or 8 g / dL during eculizumab treatment within the 3 months prior to screening; in some implementations, the hemoglobin level is consistently <10 g / dL during eculizumab treatment within the 3 months prior to screening.

[0015] In some implementations, the average hemoglobin level of the PNH detected by two tests in the central laboratory during screening is <10 g / dL, and the Hb value of either test should be <10.5 g / dL.

[0016] In some embodiments, the PNH has no history of capsular bacterial infection and has been vaccinated against Neisseria meningitidis and Streptococcus pneumoniae at least 2 weeks prior to the first dose; in some embodiments, the capsular bacteria are Neisseria meningitidis and / or Streptococcus pneumoniae; in some embodiments, the Neisseria meningitidis is selected from type A, C, W, and Y; in some embodiments, the Streptococcus pneumoniae is a 23-valent pneumococcal polysaccharide vaccine [PPV23].

[0017] In some implementations, if treatment with the compound represented by formula (I), (II), or (III) or its pharmaceutically acceptable salt must be initiated less than two weeks after vaccination, then prophylactic antibiotic treatment must be initiated at least two weeks after vaccination.

[0018] In some embodiments, following administration of the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, at least three out of four measurements during weeks 18 to 24 show hemoglobin levels ≥10 g / dL, 10.5 g / dL, 11 g / dL, 11.5 g / dL, 12 g / dL, 12.5 g / dL, or 13 g / dL; in some embodiments, following administration of the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, at least three out of four measurements during weeks 18 to 24 show hemoglobin levels ≥12 g / dL; in some embodiments, following administration of the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, at least three out of four measurements ...0 g / dL; in some embodiments, following administration of the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, at least three out of four measurements show hemoglobin levels ≥12 g / dL; in some embodiments, following administration of the compound of formula Following administration of the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, three out of four measurements of hemoglobin level are ≥12 g / dL; in some embodiments, following administration of the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, four out of four measurements of hemoglobin level are ≥12 g / dL; in some embodiments, the absence of red blood cell transfusion means no red blood cell transfusion from week 2 to week 24; in some embodiments, the absence of red blood cell transfusion means no transfusion criteria and no RBC transfusion received from week 2 to week 24.

[0019] In some embodiments, following administration of the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, at least three out of four measurements during weeks 18 to 24 show an increase in hemoglobin levels ≥1.5 g / dL, 2 g / dL, 2.5 g / dL, 3 g / dL, 3.5 g / dL, 4 g / dL, or 4.5 g / dL from baseline; in some embodiments, following administration of the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, at least three out of four measurements during weeks 18 to 24 show an increase in hemoglobin levels ≥2 g / dL from baseline; in some embodiments, following administration of formula (I), (II), or (III), a pharmaceutically acceptable salt thereof, shows an increase in hemoglobin levels ≥2 g / dL from baseline; in some embodiments, following administration of formula (I), (II), or (III), a pharmaceutically acceptable salt thereof, shows an increase in hemoglobin levels ≥2 g / dL from baseline. Following administration of the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, three out of four measurements of hemoglobin level are ≥2 g / dL higher than baseline; in some embodiments, following administration of the compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, four out of four measurements of hemoglobin level are ≥2 g / dL higher than baseline; in some embodiments, the absence of red blood cell transfusion means no red blood cell transfusion from week 2 to week 24; in some embodiments, the absence of red blood cell transfusion means no transfusion criteria and no RBC transfusion received from week 2 to week 24. In some embodiments, treating PNH includes treating PNH-related hemolysis; in some embodiments, treating PNH includes normalizing the patient's intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH); in some embodiments, normalizing the patient's intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) includes increasing the patient's haptoglobin levels, decreasing reticulocyte levels, decreasing bilirubin levels, or decreasing lactate dehydrogenase (LDH) levels; in some embodiments, the bilirubin, reticulocyte, and LDH levels are reduced by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, and 70%, respectively. %, 75%, 80%, 85%, 90%; in some embodiments, the haptoglobin level increases by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%; in some embodiments, the treatment of PNH includes reducing C3 fragment deposition in the patient; in some embodiments, the reduction of C3 fragment deposition in the patient is about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%; in some embodiments, the treatment of PNH includes inhibiting the complement bypass pathway in the patient.

[0020] In some embodiments, the dosage of the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is 10-300 mg, in some embodiments 10-300 mg; in some embodiments 10-150 mg; in some embodiments 10 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg; in some embodiments 50 mg; in some embodiments 25 mg.

[0021] In some embodiments, the frequency of administration of the compound of formula (I), (II) or (III) or its pharmaceutically acceptable salt is selected from three times daily, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, or once weekly; in some embodiments, twice daily; in some embodiments, once daily; and in some embodiments, twice daily with an interval of about 12 hours between administrations.

[0022] In some embodiments, the treatment period described in this disclosure is 23, 24, 25, 26 or 27 weeks; in some embodiments, the treatment period is 24 weeks; in some embodiments, the treatment period is 25 weeks; and in some embodiments, the treatment period is 26 weeks.

[0023] In some embodiments, the compound of formula (I), (II) or (III) or its pharmaceutically acceptable salt is administered at 50 mg twice daily for 24 weeks during the treatment period, followed by a dose reduction period of 25 mg twice daily for 7 days and 25 mg once daily for 7 days.

[0024] In some embodiments, the compound represented by formula (I), (II) or (III) or its pharmaceutically acceptable salt is present in a unit dose formulation.

[0025] In some embodiments, the unit dose formulation contains at least 25 mg of a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof; in other embodiments, the unit dose formulation contains at least 15 mg of a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof; in some embodiments, the unit dose formulation contains 20 mg of a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof; in some embodiments, the unit dose formulation contains 30 mg of a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof; and in some embodiments, the unit dose formulation contains 25 mg of a compound of formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the pharmaceutically acceptable salts of formula (I), (II), or (III) are selected from maleates, phosphates, p-toluenesulfonates, sulfates, hydrochlorides, fumarates, tartrates, succinates, citrates, malates, methanesulfonates, and hydrobromic acids; in some embodiments, they are fumarates of formula (I), (II), or (III).

[0027] The term "no red blood cell transfusion" as used in this disclosure refers to not meeting the transfusion criteria and not receiving a red blood cell transfusion during the period from week 2 to week 24.

[0028] According to the relevant research data disclosed herein, compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts have outstanding efficacy in treating patients with paroxysmal nocturnal hemoglobinuria who still have anemia after previously using C5 complement inhibitors. They significantly increase the proportion of subjects who respond to treatment and are safe and controllable. Further development and application of this drug are expected to greatly change the current treatment status of PNH.

[0029] Terminology Definition

[0030] To facilitate understanding of this disclosure, certain techniques and scientific methods are specifically defined below. Unless otherwise expressly defined in this disclosure, all other techniques and scientific methods used in this disclosure have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0031] Unless the context clearly requires otherwise, throughout the specification and claims, the words “comprising,” “having,” “including,” etc., should be understood as having an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of “including but not limited to.”

[0032] The values ​​in this disclosure are instrument measurements or calculated values ​​after instrument measurement, and are subject to a certain degree of error. Generally speaking, ±10% is within the reasonable error range. Of course, the context in which the value is used needs to be considered. For example, the total impurity content, where the error variation after measurement does not exceed ±10%, can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, and in some embodiments, ±5%.

[0033] When the term "about" is applied to parameters such as pH, concentration, temperature, and range of variation, it indicates that the parameter can vary by ±10%, and sometimes within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0034] "Effective amount" includes an amount sufficient to improve or prevent the symptoms or condition of a medical condition. Effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount used on a subject may vary depending on factors such as the condition to be treated, the subject's overall health, the route and dosage of administration, and the severity of side effects. Effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity. Subjects in this disclosure may be animal or human subjects.

[0035] The term "pharmaceutical-acceptable excipient" or "pharmaceutical-acceptable excipient" includes any material that, when combined with an active ingredient, allows that ingredient to retain its biological activity and does not react with the subject's immune system. Examples include, but are not limited to, any standard pharmaceutical carrier, such as phosphate-buffered saline solution, water, emulsions such as oil / water emulsions, and various types of wetting agents. In some embodiments, the diluent for aerosol or parenteral administration is phosphate-buffered saline (PBS) or physiological (0.9%) saline. Compositions containing such carriers are formulated using well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, editor, Mack Publishing Co., Easton, PA, 1990; and R. Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000).

[0036] The terms “give,” “apply,” and “treat,” when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid, such as in therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular treatment includes contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cell. “Give,” “apply,” and “treat” also mean treatment, such as of cells, by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo. When applied to humans, veterinary, or research subjects, it refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0037] The term "treatment" means administering a therapeutic agent, such as a compound comprising any of the formulas (I), (II), or (III) of this disclosure or a pharmaceutically acceptable salt thereof, to a subject who has, is suspected of having, or is predisposed to have PNH, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, administering a therapeutic agent in a treated subject or population in an amount that effectively relieves symptoms of one or more diseases is done by preventing or delaying the onset of symptoms or complications, reducing symptoms or complications, or eliminating the disease, condition, or symptom to any clinically measurable degree. The amount of a therapeutic agent that effectively relieves symptoms of any specific disease (also referred to as a "therapeuticly effective amount") can vary depending on a variety of factors, such as the subject's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the subject. Whether the disease symptoms have been relieved can be evaluated using any clinical test that a physician or other healthcare professional typically uses to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating the symptoms of the target disease in a particular subject, they should alleviate the symptoms of the target disease in a statistically significant number of subjects, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test. The patients to be treated are mammals, and in some embodiments, are humans.

[0038] The term “prevention” refers to reducing the risk or incidence of one or more conditions, symptoms, complications or ailments, or eliminating or slowing the progression of one or more conditions, symptoms, complications or ailments.

[0039] The terms “subject” and “patient” refer to mammals, especially primates, and particularly humans.

[0040] ALP refers to alkaline phosphatase.

[0041] ALT refers to alanine aminotransferase.

[0042] eGFR refers to epidermal growth factor receptor.

[0043] ESA refers to erythropoietin.

[0044] FACIT refers to Functional Assessment for the Treatment of Chronic Diseases.

[0045] GGT refers to L-γ-glutamyltransferase.

[0046] Hb refers to hemoglobin.

[0047] HIF-PHI refers to hypoxia-inducible factor proline hydroxylase inhibitor.

[0048] LDH refers to lactate dehydrogenase.

[0049] MAVE(s) refers to major adverse vascular events.

[0050] PNH refers to paroxysmal nocturnal hemoglobinuria.

[0051] RBC refers to red blood cells. Detailed Implementation

[0052] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0053] Example 1. Efficacy and safety study of fumarate of formula (I) in treating patients with paroxysmal nocturnal hemoglobinuria who still have anemia despite prior stable use of C5 complement inhibitors.

[0054] I. Research on drugs

[0055] Test drug: Fumarate of formula (I), 25 mg / tablet, manufactured and supplied by Chengdu Shengdi Pharmaceutical Co., Ltd.

[0056] II. Inclusion and Exclusion Criteria

[0057] Patients must meet all of the following inclusion criteria to be enrolled in this study:

[0058] 1. Applicants must be at least 18 years old at the time of screening, regardless of gender;

[0059] 2. During screening, the patient was diagnosed with PNH, and flow cytometry analysis showed that the size of erythrocyte or granulocyte clones was >10%;

[0060] 3. Randomized patients received stable treatment with the C5 complement inhibitor eculizumab / kovarimab for the first 6 months (dosage and dosing intervals);

[0061] 4. At least one blood transfusion record within the 3 months prior to screening, or hemoglobin level consistently <10g / dL during eculizumab treatment within the 3 months prior to screening (medical history data, at least 2 test records with an interval of >4 weeks);

[0062] 5. The average hemoglobin level of two tests conducted by the central laboratory during screening should be <10g / dL, and the Hb value of any test should be <10.5g / dL (with an interval of ≥2 weeks between the two tests; if an RBC transfusion is received after the first test during the screening period, only the Hb value of the first test during the screening period needs to be <10g / dL).

[0063] 6. Meningococcal and pneumococcal vaccines must be administered at least 2 weeks before the first administration of fumarate in Formula (I) (if previously administered, proof of vaccination should be provided and determined by the investigator to be within the effective time frame); if fumarate treatment in Formula (I) must be initiated less than 2 weeks after vaccination, prophylactic antibiotic treatment must be initiated for at least 2 weeks after vaccination.

[0064] 7. Male and female subjects of childbearing age must agree to use highly effective contraception with their partners from signing the ICF until 30 days after the last dose (see Appendix 13.1), and must not have any plans to have children or donate sperm / eggs;

[0065] 8. Understand the research procedures and methods, voluntarily participate in this trial, and sign the ICF in writing.

[0066] Patients with any of the following conditions are ineligible for enrollment in this study:

[0067] 1. Except for C5 complement inhibitors (eculizumab / kovarimab), those who have participated in any other drug or medical device clinical trial within one month prior to screening and are expected to have residual effects of the experimental treatment (as determined by the investigator), or those who are still within the follow-up period of a clinical trial or within 5 half-lives of the investigational drug (whichever is longer) prior to screening.

[0068] 2. Known or suspected hereditary or acquired complement deficiency;

[0069] 3. Currently active primary or secondary immunodeficiency;

[0070] 4. Those with a history of splenectomy or those scheduled to undergo surgery during the trial period;

[0071] 5. History of bone marrow / hematopoietic stem cell or solid organ transplantation (such as heart, lung, kidney, liver);

[0072] 6. Diagnosed with a malignant tumor within the past 5 years (excluding radically excised basal cell carcinoma of the skin or cervical cancer in situ);

[0073] 7. Laboratory evidence of bone marrow failure (reticulocyte count <100×10⁻⁶) was present during screening. 9 / L, or platelets <30×10 9 / L [No platelet transfusion within 7 days prior to laboratory testing or no thrombopoietin-stimulating drugs such as recombinant human thrombopoietin and thrombopoietin receptor agonists within 14 days prior to the test], or neutrophils <0.5×10 9 / L [patients who have not received short-acting granulocyte colony-stimulating factor within 14 days or long-acting granulocyte colony-stimulating factor within 28 days prior to laboratory testing];

[0074] 8. History of infection with capsular bacteria (such as Neisseria meningitidis, Streptococcus pneumoniae, etc.);

[0075] 9. The presence or suspicion of an active systemic bacterial, viral, or fungal infection within 2 weeks prior to the first administration of the fumarate of formula (I) (as determined by the investigator);

[0076] 10. Fever (body temperature ≥38°C) occurs within 1 week prior to the first administration of fumarate of formula (I);

[0077] 11. Human immunodeficiency virus (HIV) infection (known history of HIV or positive HIV antibody screening);

[0078] 12. Positive for hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCVAb) at the time of screening, or abnormal liver function tests at the time of screening (defined as any one of alanine aminotransferase [ALT], gamma-glutamyl transferase [GGT], or alkaline phosphatase [ALP] exceeding 3 times the upper limit of normal).

[0079] 13. Use any of the following medications unless you have a stable treatment regimen during the following time periods prior to screening:

[0080] a) Erythropoietin (ESA), hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), or immunosuppressant for at least 8 weeks

[0081] b) Systemic use of glucocorticoids (≤15 mg / day of prednisone or equivalent dose of glucocorticoids) for at least 4 weeks.

[0082] c) Vitamin K antagonists (such as warfarin) have a stable international normalized ratio (INR) for at least 4 weeks.

[0083] d) Low molecular weight heparin, oral anticoagulants such as aspirin, rivaroxaban, apixaban, etc. for at least 4 weeks.

[0084] e) Iron supplements, vitamin B12, folic acid, or androgens for at least 4 weeks

[0085] 14. Those with severe comorbidities at the time of screening, such as severe kidney disease (e.g., eGFR < 30 mL / min / 1.73 mcg). 2 Individuals deemed unsuitable for participation in the study by the researchers include those who are undergoing dialysis, have advanced heart disease (such as NYHA Class IV), have severe lung disease such as severe pulmonary hypertension (WHO Class IV), or have liver disease (such as active hepatitis).

[0086] 15. Any medical condition that the investigators believe may affect a patient's participation in the trial, other possible causes of chronic anemia or unstable thrombotic events, or other circumstances that the investigators believe are unsuitable for participation in the trial;

[0087] 16. Individuals suspected of being allergic to the investigational drug or any component of the investigational drug;

[0088] 17. Screening visits for women with positive blood pregnancy tests and those who are breastfeeding.

[0089] III. Administration Method

[0090] Subjects were treated with formula (I) fumarate 50 mg bid for 24 weeks starting on day 1.

[0091] The first administration of fumarate of formula (I) must be performed on day 7 to 8 after the last infusion of eculizumab or on day 13 to 15 after the last infusion of kovarimab.

[0092] Subjects swallow the fumarate of formula (I) whole, without lingering or chewing the drug before swallowing.

[0093] Meal instructions: Formula (I) fumarate can be administered on an empty stomach or after a meal.

[0094] Dosage instructions: Subjects will be instructed to take the medication at approximately the same time each day (morning and evening), with an recommended interval of 12 hours between doses, and each dose should not exceed the prescribed amount.

[0095] Missed dose guidance: Subjects will be instructed that if they miss a dose of formula (I) fumarate on a certain day, they should not take an additional dose to compensate, but should take the prescribed dose of the medication on the next scheduled day.

[0096] Instructions for vomiting after medication: Subjects will be instructed that if they vomit after taking the medication, they should not take another dose, but should take the same dose as prescribed the following day.

[0097] Instructions for subjects who unintentionally overdose on medication: Subjects will be instructed not to take the next dose if they unintentionally overdose on a particular day. They should also proactively contact the investigator, who will conduct a comprehensive assessment and decide whether to adjust the dosing regimen. If necessary, communication with the sponsor's medical representative is required.

[0098] If a subject needs to suspend medication for more than 14 days during the trial, they will enter the safety follow-up phase. Based on the investigator's judgment, the suspension of fumarate dosage in formula (I) can last up to 14 days.

[0099] The medication administration of the subjects should be recorded in detail in the subject diary card.

[0100] IV. Clinical endpoint:

[0101] The primary efficacy endpoint of this trial was the proportion of participants with a hemoglobin level ≥12 g / dL at least three out of four measurements taken between weeks 18 and 24, in a transfusion-free period (defined as no red blood cell transfusions between weeks 2 and 24). Transfusion-free refers to not meeting the transfusion criteria and not receiving an RBC transfusion between weeks 2 and 24. Baseline Hb level was defined as the average of two central laboratory test values ​​during the screening period. If a participant received a transfusion after the first central laboratory test, the baseline Hb level was defined as the value of the first central laboratory test during the screening period.

[0102] Secondary efficacy endpoints were: the proportion of subjects whose hemoglobin levels increased by ≥2 g / dL from baseline in at least three out of four measurements during weeks 18 to 24 without red blood cell transfusion (defined as no red blood cell transfusion between week 2 and week 24); the mean change in hemoglobin from baseline during weeks 18 to 24; the mean percentage change in LDH levels from baseline during weeks 18 to 24; the mean change in reticulocyte count from baseline during weeks 18 to 24; the proportion of subjects who did not receive a transfusion during weeks 2 to 24; the mean change in FACIT-score from baseline during weeks 18 to 24; the incidence of breakthrough hemolysis during weeks 1 to 24; and the incidence of MAVEs (including thrombosis) during weeks 1 to 24.

[0103] Note: Weeks 2 onwards, specifically week 24, are from D15 (inclusive) to D169 (where D1 is the day of the first dose).

[0104] If a subject terminates the trial intervention prematurely, follow-up should be continued as much as possible, and the results of their efficacy indicators should be collected according to the original visits for efficacy evaluation.

[0105] For PNH patients, fumarate of formula (I) is significantly effective in increasing hemoglobin levels, reducing transfusion requirements and improving quality of life, with manageable safety and a good balance of risk and benefit.

Claims

1. Use of a Factor B inhibitor or a pharmaceutically acceptable salt thereof in the preparation of a treatment for paroxysmal nocturnal hemoglobinuria (PNH) previously treated with a C5 complement inhibitor, wherein the Factor B inhibitor is as shown in formula (I), (II) or (III):

2. The use according to claim 1, wherein prior use of C5 complement inhibitors means prior use of C5 complement inhibitors for at least 6 months.

3. The use according to claim 1 or 2, wherein the C5 complement inhibitor is eculizumab and / or kovarimab.

4. The use according to claims 1-3, wherein the PNH is a PNH that remains anemic despite prior use of C5 complement inhibitors.

5. The use according to any one of claims 1-4, wherein the PNH is a PNH with a red blood cell or granulocyte clone size >5%, 10%, 15%, 20%, or 25% as detected by flow cytometry; preferably >10%.

6. The use according to any one of claims 1-5, wherein the PNH has at least one blood transfusion record within 3 months prior to screening; or the hemoglobin level is consistently <12 g / dL, 11.5 g / dL, 11 g / dL, 10.5 g / dL, 10 g / dL, 9.5 g / dL, 9 g / dL, 8.5 g / dL, or 8 g / dL during eculizumab treatment within 3 months prior to screening; preferably, the hemoglobin level is consistently <10 g / dL.

7. The use according to any one of claims 1-6, wherein the average hemoglobin level of the PNH detected by the central laboratory in two separate tests during screening is <10 g / dL, and the Hb value of any one test is <10.5 g / dL.

8. The use according to any one of claims 1-7, wherein the pharmaceutically acceptable salt is selected from maleate, phosphate, p-toluenesulfonate, sulfate, hydrochloride, fumarate, tartrate, succinate, citrate, malate, methanesulfonate and hydrobromide.

9. The use according to any one of claims 1-8, wherein, Following administration of the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, at least three of the four measurements during weeks 18 to 24 show hemoglobin levels ≥10 g / dL, 10.5 g / dL, 11 g / dL, 11.5 g / dL, 12 g / dL, 12.5 g / dL or 13 g / dL, preferably at least three show ≥12 g / dL.

10. The use according to any one of claims 1-9, wherein, Following administration of the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, in the absence of red blood cell transfusion, at least three out of four measurements during weeks 18 to 24 show an increase in hemoglobin levels from baseline of ≥1.5 g / dL, 2 g / dL, 2.5 g / dL, 3 g / dL, 3.5 g / dL, 4 g / dL or 4.5 g / dL, preferably ≥2 g / dL.

11. The use according to any one of claims 1-10, wherein, The dosage of the compound of formula (I), (II) or (III) or its pharmaceutically acceptable salt is 10-300 mg, preferably 10-250 mg, more preferably 10-150 mg, and most preferably 10 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, or 90 mg.

12. The use according to any one of claims 1-11, wherein, The frequency of administration of the compound of formula (I), (II) or (III) or its pharmaceutically acceptable salt is selected from three times daily, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, or once weekly.

13. The use according to any one of claims 1-12, wherein the pharmaceutically acceptable salt is selected from maleate, phosphate, p-toluenesulfonate, sulfate, hydrochloride, fumarate, tartrate, succinate, citrate, malate, methanesulfonate and hydrobromide.

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