Method for using B factor inhibitor

Abstract

To provide a pharmaceutical composition for use in treating complement driven diseases, in particular, paroxysmal nocturnal hemoglobinuria (PNH).SOLUTION: Described herein are methods of treating paroxysmal nocturnal hemoglobinuria (PNH) with the Factor B inhibitor LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to a method for treating complement-driven diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), with LNP023, a factor B inhibitor, or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride.

Background Art

[0002] Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hemolytic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure (BMF), and a severe thrombotic diathesis (Risitano AM (2012). Paroxysmal nocturnal hemoglobinuria and other complement-mediated hematological disorders. Immunology; 217: 1080 - 1087). It begins with the clonal expansion of hematopoietic stem cells that have acquired somatic mutations in the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) gene (Brodsky RA (2014) Paroxysmal nocturnal hemoglobinuria. Blood; 124: 2804 - 2811). As a result, PNH blood cells lack the glycosylphosphatidylinositol (GPI) anchor protein and are deficient in the membrane-bound complement inhibitory proteins CD55 and CD59. As a result, PNH-type red blood cells (RBCs) are attacked by complement, leading to complement-mediated lysis. no AM(2012).Paroxysmal nocturnal hemoglo binuria and other complement-mediated he matological disorders.Immunology;217:108

[0003] The clinical spectrum of PNH is diverse, and the signs and symptoms include anemia, thrombosis, smooth muscle Examples include dystonia, fatigue, hemoglobinuria, chronic kidney disease, and pulmonary hypertension. Clin ical symptoms are driven by uncontrolled complement activation on CD55- and CD59-deficient PNH-type RBCs, leading to hemolysis and release of free hemoglobin, and platelet activation (Hill A, et al.(2013). Thrombosis in paroxysmal noc turnal hemoglobinuria. Blood;121:4985-499 6). Hemolysis results in the release of intracellular hemoglobin and lactate dehydrogenase (LDH) into the circulation. Irreversible binding and inactivation of nitric oxide (NO) by hemoglobin and inhibition of NO synthesis, resulting in vasoconstriction and tissue ischemia, cause abdominal pain, dysphagia, erectile dysfunction, platelet activation, and a prothrombotic state (Hill et al 2013, B rodsky 2014). Thromboembolism is a major cause of morbidity and mortality in PNH patients and can occur at any site; veins are more common (80 - 85%), but arterial events can also occur (15 - 20%) (Hillmen P, et al.(2007). Eff ect of the complement inhibitor eculizum ab on thromboembolism in patients with p aroxysmal nocturnal hemoglobinuria. Blood ;110:4123-4128).

[0004] Eculizumab and ravulizumab (engineered from eculizumab with an extended dosing interval) are approved anti-C5 antibody therapies for the treatment of PNH and are the current standard of care (SoC) available.

Summary of the Invention

Problems to be Solved by the Invention

[0005] Anti-C5 antibody therapy is generally effective in the treatment of intravascular hemolysis (IVH), but there are still high unmet medical needs for PNH. Various authors have reported the heterogeneous hematological responses to eculizumab and the fact that a significant proportion of patients do not achieve normal or nearly normal hemoglobin levels (Risitano AM, et al (2009) C omplement fraction 3 binding on erythroc ytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria p atients treated by eculizumab. Blood; 113: 4094-4100; Hill A, et al. (2010). Eculizumab prevents intravascular hemolysis in pat ients with paroxysmal nocturnal hemoglob inuria and unmasks low-level extravascul ar hemolysis occurring through C3 opsoni zation. Haematologica; 95:567-573; DeZern A E, et al. (2013). Predictors of hemoglobin response to eculizumab therapy in paroxy smal nocturnal hemoglobinuria. Eur J Hae matol; 95:567-573; DeZern AE, et al. (2013). Predictors of hemoglobin response to eculizumab therapy in paroxy smal nocturnal hemoglobinuria. Eur J Hae Matol; 90:16 - 24; McKinley C. (2017) Extravas cular Hemolysis Due to C3 - Loading in Pat ients with PNH Treated with Eculizumab: D efining the Clinical Syndrome. ASH meetin g abstract. Blood; 130(Supplement1):3471). Heterogeneous responses to eculizumab or other anti - C5 antibody therapies can be explained to some extent by their mechanism of action, which inhibits only the terminal portion of the complement cascade. Thus, the deposition of C3 fragments on the cell surface of PNH - type red blood cells lacking CD55 is not affected, and the cells are more prone to extravascular hemolysis. Extravascular hemolysis can be a major mechanism of hemolysis in patients treated with eculizumab (Risitano et al 2009), and C3 - mediated extravascular hemolysis represents an unmet medical need. LNP023 is a novel oral small - molecule compound that inhibits factor B (FB) and is in clinical development for the treatment of PNH. Factor B (FB) is an important protease of the alternative pathway (AP) of complement. Inhibition of FB by oral LNP023 or its pharmaceutically acceptable salts, such as LNP023 hydrochloride, may prevent both intravascular and extravascular hemolysis and thus provide therapeutic benefits beyond current standard of care (SoC). Furthermore, the oral administration route offers advantages to patients compared to the intravenous administration route of current SoC.

[0006] Means for Solving the Problems

[0007] ​​​​​​​​​​The present disclosure relates to a method of treating complement-driven diseases such as paroxysmal nocturnal hemoglobinuria (PNH) with LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. LNP023 belongs to the class of factor B inhibitors of the complement pathway and acts by inhibiting or suppressing the amplification of the complement system caused by C3 activation, regardless of the initial mechanism of activation. LNP023 hydrochloride is currently in clinical development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). LNP023 hydrochloride is chemically designated as 4-(((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the following chemical structure: It relates to a method of treating complement-driven diseases such as paroxysmal nocturnal hemoglobinuria (PNH) with LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. LNP023 belongs to the class of factor B inhibitors of the complement pathway and acts by inhibiting or suppressing the amplification of the complement system caused by C3 activation, regardless of the initial mechanism of activation. LNP023 hydrochloride is currently in clinical development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). LNP023 hydrochloride is chemically designated as 4-(((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the following chemical structure: It relates to a method of treating complement-driven diseases such as paroxysmal nocturnal hemoglobinuria (PNH) with LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. LNP023 belongs to the class of factor B inhibitors of the complement pathway and acts by inhibiting or suppressing the amplification of the complement system caused by C3 activation, regardless of the initial mechanism of activation. LNP023 hydrochloride is currently in clinical development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). LNP023 hydrochloride is chemically designated as 4-(((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the following chemical structure: It relates to a method of treating complement-driven diseases such as paroxysmal nocturnal hemoglobinuria (PNH) with LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. LNP023 belongs to the class of factor B inhibitors of the complement pathway and acts by inhibiting or suppressing the amplification of the complement system caused by C3 activation, regardless of the initial mechanism of activation. LNP023 hydrochloride is currently in clinical development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). LNP023 hydrochloride is chemically designated as 4-(((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the following chemical structure: It relates to a method of treating complement-driven diseases such as paroxysmal nocturnal hemoglobinuria (PNH) with LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. LNP023 belongs to the class of factor B inhibitors of the complement pathway and acts by inhibiting or suppressing the amplification of the complement system caused by C3 activation, regardless of the initial mechanism of activation. LNP023 hydrochloride is currently in clinical development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). LNP023 hydrochloride is chemically designated as 4-(((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the following chemical structure: It relates to a method of treating complement-driven diseases such as paroxysmal nocturnal hemoglobinuria (PNH) with LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. LNP023 belongs to the class of factor B inhibitors of the complement pathway and acts by inhibiting or suppressing the amplification of the complement system caused by C3 activation, regardless of the initial mechanism of activation. LNP023 hydrochloride is currently in clinical development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). LNP023 hydrochloride is chemically designated as 4-(((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the following chemical structure: ((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the following chemical structure: ((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the following chemical structure: ((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the following chemical structure:

Chemical formula

[0008] LNP023 hydrochloride and its preparation method are incorporated herein by reference in their entirety, see WO 2015 / 009616 pamphlet (see Example 26d). LNP023 hydrochloride and its preparation method are incorporated herein by reference in their entirety, see WO 2015 / 009616 pamphlet (see Example 26d). LNP023 hydrochloride and its preparation method are incorporated herein by reference in their entirety, see WO 2015 / 009616 pamphlet (see Example 26d).

[0009] In one aspect, the present disclosure provides a method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject, such as a patient in need thereof, the method comprising, for example, orally administering to the subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of about 200 mg twice a day (b.i.d.) every about 12 hours, whereby, for example, the subject, such as a patient, is treated (where the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the subject, such as a patient, is treated In one aspect, the present disclosure provides a method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject, such as a patient in need thereof, the method comprising, for example, orally administering to the subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of about 200 mg twice a day (b.i.d.) every about 12 hours, whereby, for example, the subject, such as a patient, is treated (where the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the subject, such as a patient, is treated In one aspect, the present disclosure provides a method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject, such as a patient in need thereof, the method comprising, for example, orally administering to the subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of about 200 mg twice a day (b.i.d.) every about 12 hours, whereby, for example, the subject, such as a patient, is treated (where the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the subject, such as a patient, is treated In one aspect, the present disclosure provides a method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject, such as a patient in need thereof, the method comprising, for example, orally administering to the subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of about 200 mg twice a day (b.i.d.) every about 12 hours, whereby, for example, the subject, such as a patient, is treated (where the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the subject, such as a patient, is treated In one aspect, the present disclosure provides a method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject, such as a patient in need thereof, the method comprising, for example, orally administering to the subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of about 200 mg twice a day (b.i.d.) every about 12 hours, whereby, for example, the subject, such as a patient, is treated (where the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the subject, such as a patient, is treated In one aspect, the present disclosure provides a method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject, such as a patient in need thereof, the method comprising, for example, orally administering to the subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of about 200 mg twice a day (b.i.d.) every about 12 hours, whereby, for example, the subject, such as a patient, is treated (where the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the subject, such as a patient, is treated can be.

[0010] In another aspect, the present disclosure provides a method for treating PNH-related disorders in a subject, e.g., a patient in need thereof. The present invention provides a method of treating hemolysis, the method comprising administering the drug twice daily, e.g., about every 12 hours. d.) at a dose of about 200 mg of LNP023 or its salts, such as, for example, LNP023 hydrochloride. to a subject, e.g., a patient, As a result, a subject, e.g., a patient, may be treated (wherein the dosage is a 0.1 mg / kg / day dose of LNP023 hydrochloride). water free base), so that a subject, such as a patient, is treated.

[0011] In another aspect, the present disclosure provides a method for treating intravascular lysis in a subject, e.g., a patient in need thereof. The present invention provides a method for normalizing intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH), the method comprising, for example: For example, LNP023 may be administered at a dose of approximately 200 mg twice daily (bid), such as approximately every 12 hours. or orally administering to the subject a pharma- ceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. (wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride), As a result, IVH and / or EVH in a subject, such as a patient, is normalized.

[0012] In another aspect, the disclosure provides a method for reducing the incidence of PNH-associated hemolysis in a patient population. and the method includes administering about 200 mg twice a day (bid), such as about every 12 hours. LNP023 or a pharma- ceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, orally administering to a patient an anhydrous salt of LNP023 hydrochloride, refers to the free base), resulting in a reduced incidence.

[0013] In another aspect, the present disclosure provides a method of treating intravascular hemolysis (IVH) in a subject such as a patient in need thereof, the method comprising orally administering LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to the subject at a dose of about 200 mg twice daily (b.i.d.), such as every about 12 hours (wherein the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the subject such as a patient is treated. In another aspect, the present disclosure provides a method of treating extravascular hemolysis (EVH) in a subject such as a patient in need thereof, the method comprising orally administering LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to the subject at a dose of about 200 mg twice daily (b.i.d.), such as every about 12 hours (wherein the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the subject such as a patient is treated. In another aspect, the present disclosure provides a method of normalizing hemoglobin levels in a subject such as a patient in need thereof, the method comprising orally administering LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to the subject at a dose of about 200 mg twice daily (b.i.d.), such as every about 12 hours (wherein the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the hemoglobin levels in the subject such as a patient are normalized. In another aspect, the present disclosure provides a method of reducing C3 deposition in a subject in need thereof. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated.

[0014] In another aspect, the present disclosure provides a method of treating extravascular hemolysis (EVH) in a subject such as a patient in need thereof, the method comprising orally administering LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to the subject at a dose of about 200 mg twice daily (b.i.d.), such as every about 12 hours (wherein the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the subject such as a patient is treated. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated. In another aspect, the present disclosure provides a method of normalizing hemoglobin levels in a subject such as a patient in need thereof, the method comprising orally administering LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to the subject at a dose of about 200 mg twice daily (b.i.d.), such as every about 12 hours (wherein the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the hemoglobin levels in the subject such as a patient are normalized. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated.

[0015] In another aspect, the present disclosure provides a method of normalizing hemoglobin levels in a subject such as a patient in need thereof, the method comprising orally administering LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to the subject at a dose of about 200 mg twice daily (b.i.d.), such as every about 12 hours (wherein the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, the hemoglobin levels in the subject such as a patient are normalized. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated. (This dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated.

[0016] In another aspect, the present disclosure provides a method of reducing C3 deposition in a subject in need thereof. administered, for example, at a dose of about 200 mg twice daily (b.i.d.), such as every about 12 hours, to a subject, such as a patient, an LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, wherein the dose refers to the anhydrous free base of LNP023 hydrochloride, and as a result, C3 deposition in a subject, such as a patient, is reduced.

[0017] In another aspect, the present disclosure provides a method for increasing the survival rate of red blood cells (RBCs), such as increasing the lifespan of RBCs, in a subject, such as a patient in need thereof, the method comprising administering, for example, at a dose of about 200 mg twice daily (b.i.d.), such as every about 12 hours, an LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, to a subject, wherein the dose refers to the anhydrous free base of LNP023 hydrochloride, and as a result, the RBC survival rate in a subject, such as a patient, is increased.

[0018] In another aspect, the present disclosure provides a method for inhibiting the alternative complement pathway, such as sustained inhibition, in a subject, such as a patient in need thereof, the method comprising administering, for example, at a dose of about 200 mg twice daily (b.i.d.), such as every about 12 hours, an LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, to a subject, wherein the dose refers to the anhydrous free base of LNP023 hydrochloride, and as a result, the alternative complement pathway in a subject, such as a patient, is suppressed.

[0019] In another aspect, the present disclosure provides, for example, fragments in a subject, such as a patient in need thereof, ​​​​​To provide a method for reducing the level of fragment Bb, the method is, for example, twice a day, such as every about 12 hours at a dose of about 200 mg (b.i.d.), orally administer LNP023 or its pharmaceutically acceptable salts such as, for example, LNP023 hydrochloride salt (where the dose refers to the anhydrous free base of LNP023 hydrochloride), as a result, fragment Bb in a subject such as a patient is reduced.

[0020] The treatment method described herein may further include various evaluation steps before and / or subsequent to treatment with LNP023 or its pharmaceutically acceptable salts such as, for example, LNP023 hydrochloride. In one embodiment, before and / or after administration of LNP023 or its pharmaceutically acceptable salts such as, for example, LNP023 hydrochloride, the method further includes the step of evaluating PK and PD parameters (e.g., the plasma concentration of LNP023 or its pharmaceutically acceptable salts such as, for example, LNP023 hydrochloride, C3, fragment Bb, or sC5B). The evaluation may be achieved by analyzing a sample of body fluid such as blood or plasma by mass spectrometry such as, for example, LC-MS. BRIEF DESCRIPTION OF THE DRAWINGS

[0021]

Figure 1

Figure 2-1

Figure 2-2

Figure 3

[0022] Described herein is a method for treating PNH in patients in need thereof, which method comprises orally administering to the patient, for example, LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, in capsule form, for example, twice daily, such as every about 12 hours (wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride). Also described herein are methods of selecting a target patient population, monitoring the treatment of a target patient population, and evaluating the safety and efficacy of the treatment of a target patient population. The details of the present disclosure are set forth in the following accompanying description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In the specification and the appended claims, unless the context clearly dictates otherwise, the singular forms also include the plural forms. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated herein by reference in their entirety. a Phase III clinical trial for determining the safety and efficacy of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, in patients with PNH who exhibit refractory anemia despite treatment with anti-C5 therapy. Accordingly,

[0023] The details of the present disclosure are set forth in the following accompanying description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In the specification and the appended claims, unless the context clearly dictates otherwise, the singular forms also include the plural forms. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated herein by reference in their entirety. Similar or equivalent methods and materials may be used in the practice or testing of the present disclosure, but exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In the specification and the appended claims, unless the context clearly dictates otherwise, the singular forms also include the plural forms. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated herein by reference in their entirety.

[0024] Definitions Unless otherwise provided with specific definitions, the analytical chemistry, synthetic organic chemistry, and pharmaceutical ​​​​​​​​​​​​​The nomenclature, procedures, and techniques used in connection with pharmaceutical chemistry are well known in the art and are generally employed. Standard techniques are used for chemical syntheses and chemical analyses as may be appropriate. Specific such techniques and procedures are, for example, incorporated herein by reference for all purposes from “Remington’s Pharmaceutical S ciences,” Mack Publishing Co., Easton, Pa., 21st edition, 2005. All patents, applications, published applications, and other publications, and other data mentioned throughout this disclosure are incorporated herein by reference in their entirety to the extent that their contents are relevant.

[0025] Unless otherwise indicated, the following terms have the following meanings: As used herein, “about” means within ±10% of a value

[0026] As used herein, “administer” or “administration” means providing a pharmaceutical to an individual and includes, but is not limited to, administration by a medical professional and self-administration The administration of a pharmaceutical to an individual can be continuous, chronic, short-term, or intermittent

[0027] As used herein, the terms “acquire” or “acquiring” as used herein mean obtaining ownership of a physical entity or value either “directly acquire” or “indirectly acquire” a physical entity (e.g., a sample such as a blood sample or a plasma sample) or a value (e.g., a numerical value) by “directly acquire” means performing a process (e.g., an analytical method) for acquiring a physical entity or value ​​This means. "Indirectly obtaining" refers to receiving a physical entity or value from another party or source (e.g., a physical entity or a third-party research institute that directly obtained the value). Directly obtaining a value includes, for example, performing an analysis process that includes physical changes in a substance such as a sample such as, for example, LC-MS, such as by mass spectrometry such as LC-MS / MS, performing an analysis method such as the method described herein by analyzing a sample of a body fluid such as blood including performing a process that includes physical changes in a sample or another substance. is included.

[0028] In the usage of this specification, "dose" means a predetermined amount of a pharmaceutical provided during a single administration or within a specified period. In certain embodiments, the dose can be administered in a capsule. In the usage of this specification, the dosage refers to the anhydrous free base of LNP023 hydrochloride. In the usage of this specification, "individual", "patient", "participant", or "subject" means a human selected for treatment or therapy.

[0029] In the usage of this specification, "pharmaceutically acceptable salt" means a physiologically and pharmaceutically acceptable salt of LNP023, i.e., a salt that retains the desired biological activity of LNP023 and does not impart undesired toxicological effects. The term "pharmaceutically acceptable salt" or "salt" includes salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and bases. The "pharmaceutically acceptable salt" of LNP023

[0030] may be prepared by methods well known in the art. A review of pharmaceutically acceptable salts is provided. This means a salt that retains the desired biological activity of LNP023 and does not impart undesired toxicological effects. The term "pharmaceutically acceptable salt" or "salt" includes salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and bases. The "pharmaceutically acceptable salt" of LNP023 may be prepared by methods well known in the art. A review of pharmaceutically acceptable salts is provided. For more information, see Stahl and Wermuth, Handbook of Phar maceutical Salts:Properties,Selection an d Use (Wiley-VCH, Weinheim, Germany, 2002). LNP023 hydrochloride and methods for its preparation are incorporated herein by reference in their entirety. WO 2015 / 009616 (see Example 26d), which is incorporated by reference. The information is disclosed in the "Company Information on the Transaction" (hereinafter referred to as "the Company") at http: / / www.company.jp / en / about / .

[0031] As used herein, the term "treat" refers to treating a disorder or disease, such as, for example, PNH. By "reducing, inhibiting, attenuating, decreasing, halting, or stabilizing the onset or progression of a disease or condition" is meant reducing, inhibiting, attenuating, decreasing, halting, or stabilizing the onset or progression of a disease or condition.

[0032] Unless otherwise indicated, conventional definitions are provided for all formulas and groups. Future stable valences are predicted and achieved.

[0033] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (e.g., For example, "an element" is used to refer to at least one "ent" means one element or more than one element.

[0034] How to use Provided herein are methods for treating seizure disorders in a subject, e.g., a patient in need thereof. A method for treating nocturnal hemoglobinuria (PNH), the method comprising administering, for example, about every 12 hours and the like, at a dose of about 200 mg twice daily (bid), LNP023 or, e.g., LN P023 can be administered orally to a subject, such as a patient, in the form of a pharma- ceutical acceptable salt thereof, such as hydrochloride. (wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride), As a result, a subject such as a patient is treated.

[0035] In one embodiment, for example, a subject such as a patient is being treated with anti-C5 therapy.

[0036] In one embodiment, for example, a subject such as a patient is, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride, treated with anti-C5 therapy for at least about 8 months. therapy.

[0037] In one embodiment, for example, a subject such as a patient is, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride, treated with anti-C5 therapy for at least about 6 months. therapy.

[0038] In one embodiment, the anti-C5 therapy is an anti-C5 monoclonal antibody therapy.

[0039] In one embodiment, the anti-C5 therapy is eculizumab or ravulizumab.

[0040] In one embodiment, for example, a subject such as a patient has refractory anemia.

[0041] In one embodiment, for example, a subject such as a patient is vaccinated prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride.

[0042] In one embodiment, for example, a subject such as a patient is, prior to treatment, vaccinated against Neisseria meningitidis (serogroups A, C, Y and W-135).

[0043] In one embodiment, treating PNH comprises one or more red blood cell (RBC) transfusions In the absence, for example, of increasing hemoglobin levels in a subject such as a patient comprises.

[0044] In one embodiment, for example, a subject such as a patient is, for example, at least once about 6 months prior to administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride receives a concentrated RBC transfusion.

[0045] In one embodiment, for example, the hemoglobin level in a subject such as a patient is evaluated prior to administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride is.

[0046] In one embodiment, for example, the hemoglobin level, haptoglobin level of a subject such as a patient, reticulocyte level, and / or bilirubin level are evaluated prior to administration of a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride is.

[0047] In one embodiment, for example, the hemoglobin level of a subject such as a patient is, prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride, about 12 g / dL or less, about 11.5 g / dL or less, about 11 g / dL or less, about 10.5 g / dL or less, about 10 g / d or less L, about 9.5 g / dL or less, about 9 g / dL or less, about 8.5 g / dL or less or about 8 g / dL or less. is.

[0048] In one embodiment, for example, the hemoglobin level of a subject such as a patient is about 10 g / dL or less prior to administration of LNP023 hydrochloride is.

[0049] In one embodiment, for example, compared to baseline, for example, LNP023 or for example 、 The hemoglobin level in a subject such as a patient, compared to before treatment with a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride, is, for example, increased by, for example, about 1 g / dL or more, about 1.5 g / dL, 2 g / dL, about 2.5 g / dL or more, or about 3 g / dL or more after treatment with a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride. / dL or more, about 1.5 g / dL, 2 g / dL, about 2.5 g / dL or more, or about 3 g / dL or more after treatment with a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride.

[0050] In one embodiment, for example, compared to baseline, the hemoglobin level in a subject such as a patient, compared to the hemoglobin level before treatment with a pharmaceutically acceptable salt thereof such as LNP023 or, for example, LNP023 hydrochloride, is increased by, for example, about 2 g / dL or more. In one embodiment, for example, compared to baseline, the hemoglobin level in a subject such as a patient, compared to the hemoglobin level before treatment with a pharmaceutically acceptable salt thereof such as LNP023 or, for example, LNP023 hydrochloride, is increased by, for example, about 2 g / dL or more.

[0051] In one embodiment, treating PNH comprises, for example, normalizing intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) in a subject such as a patient. In one embodiment, normalizing IVH and / or EVH hemolysis comprises, for example, increasing the haptoglobin level, decreasing the reticulocyte level, or decreasing the bilirubin level in a subject such as a patient, compared to baseline, for example, compared to the levels of haptoglobin, reticulocytes, or bilirubin in a subject such as a patient before administration of a pharmaceutically acceptable salt thereof such as LNP023 or, for example, LNP023 hydrochloride. bilirubin in a subject such as a patient before administration of a pharmaceutically acceptable salt thereof such as LNP023 or, for example, LNP023 hydrochloride. bilirubin in a subject such as a patient before administration of a pharmaceutically acceptable salt thereof such as LNP023 or, for example, LNP023 hydrochloride. In one embodiment, treating PNH comprises treating PNH-related hemolysis. In one embodiment, treating PNH comprises treating PNH-related hemolysis. In one embodiment, treating PNH comprises treating PNH-related hemolysis.

[0052] In one embodiment, treating PNH comprises treating PNH-related hemolysis. In one embodiment, treating PNH comprises treating PNH-related hemolysis.

[0053] In one embodiment, treating PNH comprises, for example, reducing C3 deposition in a subject such as a patient. In one embodiment, C3 deposition is, for example, compared to a baseline, for example, compared to the level of C3 deposition in a subject such as a patient before administration of LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride, and is reduced by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or about 99%.

[0054] In one embodiment, treating PNH comprises, for example, increasing the survival rate of red blood cells (RBCs) in a subject such as a patient.

[0055] In one embodiment, treating PNH comprises, for example, inhibiting the complement alternative pathway in a subject such as a patient.

[0056] In one embodiment, treating PNH comprises, for example, reducing the level of fragment Bb in a subject such as a patient.

[0057] In one embodiment, treating PNH comprises, for example, increasing the hemoglobin level in a subject such as a patient by, for example, about 2 g / dL or more compared to the hemoglobin level in the subject such as a patient before administration of LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride compared to a baseline.

[0058] In one embodiment, treating PNH results in a sustained increase in hemoglobin level. comprises achieving. In one embodiment, treating PNH is about 10 g / d L, greater than about 10.5 g / dL, greater than about 11 g / dL, greater than about 11.5 g / dL exceeding, greater than about 12 g / dL, greater than about 12.5 g / dL, or greater than about 13 g / dL, comprises achieving a sustained increase in hemoglobin level. In one embodiment , treating PNH comprises achieving a sustained increase in hemoglobin level of about 12 g / dL or higher.

[0059] In one embodiment, treating PNH is, for example, with LNP023 or, for example, LNP 023 hydrochloride or its pharmaceutically acceptable salts, etc., a sustained increase in hemoglobin level of about 1.5 g / dL or higher, about 2 g / dL or higher , about 2.5 g / dL or higher, about 3 g / dL or higher, about 3.5 g / dL or higher, about 4 g / dL or higher , about 4.5 g / dL or higher, or about 5 g / dL or higher compared to the hemoglobin level in a patient, for example, before treatment with LNP023 or, for example, LNP 023 hydrochloride or its pharmaceutically acceptable salts, etc., comprises achieving.

[0060] In one embodiment, treating PNH is, for example, with LNP023 or, for example, LNP 023 hydrochloride or its pharmaceutically acceptable salts, etc., a sustained increase in hemoglobin level of about 2 g / dL or higher compared to the hemoglobin level in a patient, for example, before treatment with LNP023 or, for example, LNP 023 hydrochloride or its pharmaceutically acceptable salts, etc., comprises achieving.

[0061] In one embodiment, the increase in hemoglobin level is about 1 week, about 2 weeks, about 3 weeks after administration of LNP023 or, for example, LNP02 3 hydrochloride or its pharmaceutically acceptable salts, etc., , about 4 weeks later, about 6 weeks later, about 8 weeks later, about 10 weeks later, about 12 weeks later, about 14 weeks later, maintained at about 16 weeks later, about 18 weeks later, about 20 weeks later, about 22 weeks later, or about 24 weeks later .

[0062] In one embodiment, the increase in hemoglobin level is maintained about 18 - 24 weeks after administration of LNP023 or its pharmaceutically acceptable salts such as, for example, LNP02 3 hydrochloride.

[0063] In one embodiment, the increase in hemoglobin level is maintained about 18 or 24 weeks after administration of LNP023 or its pharmaceutically acceptable salts such as, for example, LNP02 3 hydrochloride.

[0064] In one embodiment, the effectiveness of the treatment is determined by measuring the hemoglobin level in a subject such as a patient, for example, compared to the baseline and, for example, before administration of LNP 023 or its pharmaceutically acceptable salts such as, for example, LNP023 hydrochloride. For example, compared to the hemoglobin level in a subject such as a patient before administration of LNP 023 or its pharmaceutically acceptable salts such as, for example, LNP023 hydrochloride.

[0065] In one embodiment, the hemoglobin level increases by about 1.5 g / dL or more, about 2 g / dL or more, about 2.5 g / dL or more, about 3 g / dL or more, about 3.5 g / dL or more, about 4 g / dL or more, about 4.5 g / dL or more, or about 5 g / dL or more compared to the hemoglobin level in a subject such as a patient before administration of LNP023 or its pharmaceutically acceptable salts such as, for example, LNP02 3 hydrochloride.

[0066] In one embodiment, the hemoglobin level is, for example, compared to the baseline and, for example, before administration of LNP023 or its pharmaceutically acceptable salts such as, for example, LNP023 hydrochloride For example, it increases by about 2 g / dL or more compared to the hemoglobin level in a subject such as a patient. Increase.

[0067] In another aspect, the present disclosure provides a method for normalizing intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) in a subject such as a patient in need thereof, the method comprising, for example, administering LNP023 hydrochloride orally to a subject such as a patient at a dose of about 200 mg twice a day (b.i.d.) such as every about 12 hours (where the dose refers to the anhydrous free base of LNP023 hydrochloride), resulting in normalization of IVH and / or EVH in a subject such as a patient. Hemolysis (IVH) and / or extravascular hemolysis (EVH), the method comprising, for example, At a dose of about 200 mg twice a day (b.i.d.) such as every about 12 hours, for example, Administering LNP023 hydrochloride orally to a subject such as a patient (where the dose refers to the anhydrous free base of LNP023 hydrochloride), and as a result, IVH and / or EVH in a subject such as a patient is normalized. IVH and / or EVH is normalized.

[0068] In one embodiment, a subject such as a patient has or is diagnosed with PNH. Is diagnosed.

[0069] In one embodiment, normalizing IVH and / or EVH hemolysis comprises, for example, increasing the haptoglobin level, decreasing the reticulocyte level, or decreasing the bilirubin level in a subject such as a patient compared to, for example, the levels of haptoglobin, reticulocytes, or bilirubin in the subject such as a patient prior to administration of LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride compared to the baseline. In one embodiment, the haptoglobin level increases by about 10%, about 15%, about 20%, about 25 %, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65 %, about 70%, about 75%, about 80%, about 85%, or about 90%. In one embodiment, the haptoglobin level increases by about 10%, about 15%, about 20%, about 25% %, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.

[0070] In one embodiment, the haptoglobin level increases by about 10%, about 15%, about 20%, about 25 %, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65 %, about 70%, about 75%, about 80%, about 85%, or about 90%.

[0071] In one embodiment, the level of bilirubin or reticulocytes is reduced by about 10%, about 15%, about 20 %, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60 %, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.

[0072] In one embodiment, for example, the haptoglobin level, reticulocyte level, or bilirubin level in a subject such as a patient is obtained by analyzing a sample of a body fluid such as blood or plasma.

[0073] In another aspect, the present disclosure provides a method of treating PNH-related hemolysis in a subject such as a patient in need thereof, the method comprising, for example, orally administering to the subject such as a patient LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride at a dose of about 200 mg twice daily (b.i. d.) such as every about 12 hours, whereby, for example, the subject such as a patient is treated. wherein the dose refers to the anhydrous free base of LNP023 hydrochloride),

[0074] In one embodiment, the PNH-related hemolysis is breakthrough hemolysis (BTH) as defined, for example, in Table 2.

[0075] In another aspect, the present disclosure provides a method of reducing the incidence of PNH-related hemolysis in a patient population, the method comprising, for example, LNP023, or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride, or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride at a dose of about 200 mg twice daily (b.i.d.) such as every about 12 hours, or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride, orally administering to, for example, a patient ​​​​​​comprising oral administration to a subject such as, wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride), as a result, the incidence rate is reduced. and the incidence rate is reduced.

[0076] In one embodiment, PNH-related hemolysis is, for example, breakthrough hemolysis (BTH) as defined in Table 2. is hemolysis (BTH).

[0077] In one embodiment, the incidence rate is reduced by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%.

[0078] In another aspect, the present disclosure provides a method of treating intravascular hemolysis (IVH), such as suppressing IVH, in a subject such as a patient in need thereof, the method comprising, for example, administering LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, at a dosage of about 200 mg twice daily (b.i.d.), such as every about 12 hours, to a subject such as a patient, wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride), as a result, the subject such as the patient is treated. hours, to a subject such as a patient, wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride), as a result, the subject such as the patient is treated. hours, to a subject such as a patient, wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride), as a result, the subject such as the patient is treated. hours, to a subject such as a patient, wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride), as a result, the subject such as the patient is treated. ), as a result, the subject such as the patient is treated.

[0079] In one embodiment, a subject such as a patient has or is diagnosed with PNH. is diagnosed with it.

[0080] In one embodiment, treating IVH, such as controlling IVH, is, for example, compared to the baseline, for example, compared to the level of LDH in a subject such as a patient before administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride compared to the level of LDH in a subject such as a patient before administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride , for example, reducing the level of lactate dehydrogenase (LDH) in a subject such as a patient comprising.

[0081] In one embodiment, for example, the LDH level in a subject such as a patient is obtained by analysis of a sample of a body fluid such as blood or plasma .

[0082] In one embodiment, for example, the LDH level in a subject such as a patient is reduced by at least about 40 %, at least about 45%, at least about 50%, at least about 55%, at least about 60 %, at least about 65%, at least about 70%, at least about 75%, or at least about 80%. In one embodiment, for example, the LDH level in a subject such as a patient is reduced by at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%. In one embodiment, for example, the LDH level in a subject such as a patient is reduced by at least about 60 %.

[0083] In another aspect, the present disclosure provides a method of treating extravascular hemolysis (EVH) in a subject such as a patient in need thereof, for example, suppressing EVH, the method comprising, for example, administering to a subject such as a patient orally at a dose of about 200 mg twice a day (b.i.d.) such as every about 12 hours, LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride (where the dose refers to the anhydrous free base of LNP023 hydrochloride) , whereby, for example, a subject such as a patient is treated. ).

[0084] In one embodiment, for example, the subject such as a patient has or is diagnosed as having PNH.

[0085] ​​ In one embodiment, for example, the treatment of EVH, such as controlling EVH, is, for example, in a subject such as a patient to reduce the level of bilirubin or reticulocytes, or, for example, compared to baseline, to increase the level of haptoglobin in a subject such as a patient prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. This includes increasing the level of haptoglobin compared to the level of bilirubin or reticulocytes in the subject.

[0086] In one embodiment, the level of bilirubin or reticulocytes is reduced by about 10%, about 15%, about 20 %, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60 %, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.

[0087] In one embodiment, the level of haptoglobin is increased by about 10%, about 15%, about 20%, about 25 %, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65 %, about 70%, about 75%, about 80%, about 85%, or about 90%.

[0088] In one embodiment, for example, the value of the level of bilirubin, reticulocytes, or haptoglobin in a subject such as a patient is obtained by analyzing a sample of a body fluid such as blood or plasma. .

[0089] In another aspect, the present disclosure provides a method for normalizing hemoglobin levels in a subject such as a patient in need thereof, the method comprising orally administering to the subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, at a dose of about 200 mg twice a day (b.i.d.), for example, every about 12 hours. .i.d.) ​ Li (where the dosage refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, the hemoglobin level in a subject such as a patient is normalized.

[0090] In one embodiment, the hemoglobin level exceeds about 10 g / dL, exceeds about 10.5 g / dL exceeds about 11 g / dL, exceeds about 11.5 g / dL, exceeds about 12 g / dL, exceeds about 12.5 g / dL, or exceeds about 13 g / dL and is normalized.

[0091] In one embodiment, the hemoglobin level is normalized to about 12 g / dL or higher.

[0092] In one embodiment, for example, a subject such as a patient has PNH or is diagnosed as having it. It has been diagnosed.

[0093] In one embodiment, normalizing the hemoglobin level is performed in the absence of red blood cell transfusion. It is performed.

[0094] In another aspect, the present disclosure provides a method for reducing C3 deposition in a subject such as a patient in need thereof, the method comprising, for example, orally administering LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride to the subject such as a patient at a dose of about 200 mg twice a day (b.i.d. ) (where the dosage refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient ) of about 200 mg, and as a result, for example, a subject such as a patient is treated. The dosage refers to the anhydrous free base of LNP023 hydrochloride), and as a result, for example, a subject such as a patient is treated.

[0095] In one embodiment, for example, a subject such as a patient has PNH or is diagnosed as having it. It has been diagnosed.

[0096] In one embodiment, C3 deposition is reduced by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or about 99%.

[0097] In one embodiment, C3 deposition is completely reversed. In one embodiment, C3 deposition is quantified by flow cytometry as C3 fragment deposition on red blood cells.

[0098] In another aspect, the present disclosure provides a method for increasing the erythrocyte survival rate in a subject, such as a patient in need thereof. The method comprises orally administering LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to the subject, such as a patient, at a dose of about 200 mg twice a day (b.i.d.), for example, every about 12 hours (wherein the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby a subject, such as a patient, is treated.

[0099] In one embodiment, a subject, such as a patient, has or is diagnosed with PNH.

[0100] In another aspect, the present disclosure provides a method for inhibiting the alternative complement pathway, such as achieving sustained inhibition, in a subject, such as a patient in need thereof. The method comprises orally administering LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to the subject, such as a patient, at a dose of about 200 mg twice a day (b.i.d.), for example, every about 12 hours (wherein the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby a subject, such as a patient, is treated. ​

[0101] In one embodiment, for example, a subject such as a patient has, or is diagnosed as having, PNH. It has been.

[0102] In one embodiment, sustained inhibition of the alternative complement pathway is achieved at about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, or about 24 weeks after administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP02 3 hydrochloride. It is achieved.

[0103] In one embodiment, sustained inhibition of the alternative complement pathway is achieved about 18 - 24 weeks after administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP02 3 hydrochloride.

[0104] In one embodiment, sustained inhibition of the alternative complement pathway is achieved about 18 or 24 weeks after administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP02 3 hydrochloride.

[0105] In another aspect, the present disclosure provides a method of reducing fragment Bb in a subject such as, for example, a patient in need thereof, the method comprising orally administering to the subject such as, for example, a patient LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride at a dose of about 200 mg twice daily (b.i .d.) such as, for example, every about 12 hours, wherein the dose refers to the anhydrous free base of LNP023 hydrochloride, whereby fragment Bb in the subject such as, for example, a patient is reduced. It consists of. Here, the dose refers to the anhydrous free base of LNP023 hydrochloride), as a result, fragment Bb in a subject such as, for example, a patient is reduced. It is.

[0106] In one embodiment, a subject, e.g., a patient, has or is diagnosed with PNH. It has been done.

[0107] In one embodiment, fragment Bb is about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or is reduced by approximately 90%.

[0108] In another aspect, the present disclosure provides a method for treating paroxysmal nocturnal episodes in a subject, e.g., a patient in need thereof. LNP023 or e.g. LNP023 for use in the treatment of parahemoglobinuria (PNH). and a pharma- ceutically acceptable salt thereof, such as 023 hydrochloride, and the treatment may be, for example, about every 12 hours. and the like, at a dose of about 200 mg twice daily (bid), LNP023 or, e.g., LN P023 can be administered orally to a subject, such as a patient, in the form of a pharma- ceutical acceptable salt thereof, such as hydrochloride. (wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride), As a result, the subject, e.g., a patient, is treated.

[0109] In another aspect, the present disclosure provides a method for treating intravascular lysis in a subject, e.g., a patient in need thereof. and / or for use in the treatment of LN, such as the inhibition of intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH). and providing P023 or a pharma- ceutical acceptable salt thereof, such as, for example, LNP023 hydrochloride, Treatment may be, for example, at a dose of about 200 mg twice daily (bid), such as about every 12 hours, with L NP023 or a pharma- ceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, can be administered, for example, orally administering to a subject, such as a patient, an amount of LNP023 hydrochloride (referring to the anhydrous free base of EVH is normalized.

[0110] In one embodiment, for example, a subject such as a patient has or is diagnosed with PNH. being

[0111] In another aspect, the present disclosure provides LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, for use in the treatment of PNH-related hemolysis in a subject such as a patient in need thereof, the treatment comprising orally administering to the subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), such as, for example, every about 12 hours (where the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby a subject such as a patient is treated.

[0112] In another aspect, the present disclosure provides the use of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, in the manufacture of a medicament for treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject such as a patient in need thereof, the treatment comprising orally administering to the subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), such as, for example, every about 12 hours (where the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby a subject such as a patient is treated.

[0113] In another aspect, the present disclosure provides a medicament for treating, for example, suppression of intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) in a subject such as a patient in need thereof. ​​​​​​​​​​​​ Provided is the use of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, in the manufacture of The treatment comprises, for example, orally administering to a subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), such as, for example, every about 12 hours ) (wherein the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, IVH and / or EVH in a subject, such as a patient, is normalized. In one embodiment, a subject, such as a patient, has or is diagnosed with PNH.

[0114]

[0115] In another aspect, the present disclosure provides the use of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, in the manufacture of a medicament for treating PNH-related hemolysis in a subject, such as a patient, in need thereof, the treatment comprising, for example, orally administering to a subject, such as a patient, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), such as, for example, every about 12 hours wherein the dose refers to the anhydrous free base of LNP023 hydrochloride), whereby, for example, a subject, such as a patient, is treated.

[0116] Patient Selection and Monitoring In a Phase III trial, subjects who have experienced residual anemia defined as hemoglobin of 10 g / dL or less, with or without regular red blood cell transfusions in the past 6 months, while being treated with SoC (eculizumab or ravulizumab) ​​​​​​​​​​​Register PNH patients diagnosed by flow cytometry (clone size of 10% or more). PNH blood cells lack glycosylphosphatidylinositol (GPI) anchor protein (GPI-AP) and are deficient in the membrane-bound complement inhibitory proteins CD55 and CD59. The absence of these two GPI-APs, CD55 and CD59, leads to uncontrolled complement activation, which explains hemolysis and other manifestations of PNH. The rationale for selecting this patient population is that these patients have unmet medical needs despite standard of care (SoC) treatment.

[0117] LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, can suppress complement activation. Thus, for example, a patient is first evaluated to determine whether a subject, such as a patient, has GPI-AP-deficient blood cells, such as peripheral blood cells. Thereby, a subject, such as a patient, can be selected for treatment with LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. For example, if a subject, such as a patient, is determined to have GPI-AP-deficient peripheral blood cells, then, for example, a subject, such as a patient, is optionally administered LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride.

[0118] In one embodiment, high-sensitivity flow cytometry is used to determine whether a patient has GPI-AP-deficient peripheral blood cells in, for example, about two or more cell lineages.

[0119] In one embodiment, a subject, such as a patient, is LNP023 or, for example, LNP023 ​​​​​​​The levels of its pharma- ceutically acceptable salts, such as the hydrochloride salt, the levels of LDH, and the levels of hemoglobin. By assessing specific PK / PD parameters such as the pharmacokinetics, pharmacokinetics, and PNH clone size. can be monitored.

[0120] Efficacy evaluation As used herein, at a dose of about 200 mg twice a day (bid), such as about every 12 hours, Treated with LNP023 or a pharma- ceutical acceptable salt thereof, such as, for example, LNP023 hydrochloride. Also provided is a method for assessing the efficacy of a treatment in a selected patient population, the method comprising, for example, Patients who achieve an increase, such as a sustained increase, in hemoglobin levels compared to baseline determining a percentage of the population to assess the efficacy of the treatment; The indole is LNP023 or a pharma- ceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. and hemoglobin levels in a patient population prior to administration of the compound.

[0121] In one embodiment, the patient is at increased risk of developing a pulmonary syndrome, e.g., a sustained increase in hemoglobin levels from baseline. The increases were approximately 1.5 g / dL or more, approximately 2 g / dL or more, approximately 2.5 g / dL or more, and approximately 3 g / dL or more. dL or more, about 3.5 g / dL or more, about 4 g / dL or more, about 4.5 g / dL or more, or about 5 In one embodiment, e.g., LNP023 or e.g., LNP023 For example, the hemoglobin level in a patient prior to treatment with a pharma- ceutical acceptable salt thereof, such as the hydrochloride salt. Increases such as sustained increases in hemoglobin levels compared to baseline levels are The average serum glucose level is approximately 2 g / dL or higher.

[0122] In one embodiment, the increase in hemoglobin levels is determined by, for example, administering LNP023 or then, after administration of a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride, it is maintained for at least about 18 weeks is maintained. In one embodiment, the increase in hemoglobin level is, for example, after administration of LNP0 23 or, for example, a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride, at least about 24 weeks is maintained.

[0123] In one embodiment, the increase in hemoglobin level is LNP023 or, for example, LN after administration of a pharmaceutically acceptable salt thereof such as P023 hydrochloride, for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months for at least about 6 months, at least about 8 months, at least about 10 months, or at least about 12 months is maintained.

[0124] In one embodiment, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% of the patient population has achieved an increase, such as a sustained increase in hemoglobin level, compared to the hemoglobin level in the patients before treatment with LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride. level compared to the hemoglobin level in the patients before treatment with LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride. level compared to the hemoglobin level in the patients before treatment with LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride.

[0125] In one embodiment, the patient has PNH or is diagnosed as having it.

[0126] In another aspect, the present disclosure provides a method for evaluating the efficacy of treatment in a patient population treated with LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, at a dose of about 200 mg twice a day (b.i.d.), such as every about 12 hours. The method includes, for example, determining the percentage of the patient population that achieves a hemoglobin level of about 12 g / dL or higher, and thereby evaluating the efficacy of the treatment. In one embodiment, the patient has, or is diagnosed as having, PNH. In one embodiment, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% of the patient population has achieved an increase, such as a sustained increase in hemoglobin level, compared to the hemoglobin level in the patients prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. In one embodiment, the increase in hemoglobin level is maintained for at least about 18 weeks, for example, after administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride.

[0127]

[0128]

[0129] ​​​​​​​​​​​​​​It is maintained for at least about 24 weeks.

[0130] In one embodiment, the increase in hemoglobin level is maintained for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, or at least about 12 months after administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride. It is maintained for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, or at least about 12 months.

Examples

[0131] The present disclosure should not be construed as limiting the disclosure in scope or spirit to the specific procedures described herein, and is further illustrated by the following examples and synthetic schemes. It is to be understood that the examples are provided to illustrate specific embodiments and are not intended to limit the scope of the present disclosure. It should also be further understood that various other embodiments, modifications, and equivalents that may suggest themselves to those skilled in the art without departing from the spirit and / or scope of the present disclosure or the appended claims may have to be relied upon.

[0132]

Table 1

[0133]

Table 2

[0134]

Table 3

[0135]

Table 4

[0136]

Table 5

[0137]

Table 6

[0138]

Table 7

[0139]

Table 8

[0140] Example 1. Despite treatment with intravenous anti-C5 antibody, the efficacy and safety of LNP023 hydrochloride were evaluated in adult patients with PNH and residual anemia who were administered orally twice a day in a randomized, multi-center, active-controlled, open-label trial Purpose The purpose of this Phase I-II trial in PNH patients with residual anemia despite treatment with anti-C5 antibody is to determine whether LNP023 hydrochloride is effective and safe for treating PNH by demonstrating its superiority compared to anti-C5 antibody therapy. This Phase III trial is a randomized, active-controlled, open-label trial with a 24-week treatment period and a 24-week open-label extension period. Efficacy is evaluated by the proportion of participants achieving the primary hemoglobin response criteria in the absence of red blood cell transfusions, as well as other hematological response assessment items, transfusion avoidance, breakthrough hemolysis rate, and fatigue score (FACIT-Fatigue, patient-reported outcome questionnaire). Despite treatment with anti-C5 antibody, the purpose of this Phase I-II trial in PNH patients with residual anemia is to determine whether LNP023 hydrochloride is effective and safe for treating PNH by demonstrating its superiority compared to anti-C5 antibody therapy. This Phase III trial is a randomized, active-controlled, open-label trial with a 24-week treatment period and a 24-week open-label extension period. Efficacy is evaluated by the proportion of participants achieving the primary hemoglobin response criteria in the absence of red blood cell transfusions, as well as other hematological response assessment items, transfusion avoidance, breakthrough hemolysis rate, and fatigue score (FACIT-Fatigue, patient-reported outcome questionnaire). The purpose of this Phase I-II trial in PNH patients with residual anemia despite treatment with anti-C5 antibody is to determine whether LNP023 hydrochloride is effective and safe for treating PNH by demonstrating its superiority compared to anti-C5 antibody therapy. This Phase III trial is a randomized, active-controlled, open-label trial with a 24-week treatment period and a 24-week open-label extension period. Efficacy is evaluated by the proportion of participants achieving the primary hemoglobin response criteria in the absence of red blood cell transfusions, as well as other hematological response assessment items, transfusion avoidance, breakthrough hemolysis rate, and fatigue score (FACIT-Fatigue, patient-reported outcome questionnaire). The purpose of this Phase I-II trial in PNH patients with residual anemia despite treatment with anti-C5 antibody is to determine whether LNP023 hydrochloride is effective and safe for treating PNH by demonstrating its superiority compared to anti-C5 antibody therapy. This Phase III trial is a randomized, active-controlled, open-label trial with a 24-week treatment period and a 24-week open-label extension period. Efficacy is evaluated by the proportion of participants achieving the primary hemoglobin response criteria in the absence of red blood cell transfusions, as well as other hematological response assessment items, transfusion avoidance, breakthrough hemolysis rate, and fatigue score (FACIT-Fatigue, patient-reported outcome questionnaire). The purpose of this Phase I-II trial in PNH patients with residual anemia despite treatment with anti-C5 antibody is to determine whether LNP023 hydrochloride is effective and safe for treating PNH by demonstrating its superiority compared to anti-C5 antibody therapy. This Phase III trial is a randomized, active-controlled, open-label trial with a 24-week treatment period and a 24-week open-label extension period. Efficacy is evaluated by the proportion of participants achieving the primary hemoglobin response criteria in the absence of red blood cell transfusions, as well as other hematological response assessment items, transfusion avoidance, breakthrough hemolysis rate, and fatigue score (FACIT-Fatigue, patient-reported outcome questionnaire). The purpose of this Phase I-II trial in PNH patients with residual anemia despite treatment with anti-C5 antibody is to determine whether LNP023 hydrochloride is effective and safe for treating PNH by demonstrating its superiority compared to anti-C5 antibody therapy. This Phase III trial is a randomized, active-controlled, open-label trial with a 24-week treatment period and a 24-week open-label extension period. Efficacy is evaluated by the proportion of participants achieving the primary hemoglobin response criteria in the absence of red blood cell transfusions, as well as other hematological response assessment items, transfusion avoidance, breakthrough hemolysis rate, and fatigue score (FACIT-Fatigue, patient-reported outcome questionnaire). The purpose of this Phase I-II trial in PNH patients with residual anemia despite treatment with anti-C5 antibody is to determine whether LNP023 hydrochloride is effective and safe for treating PNH by demonstrating its superiority compared to anti-C5 antibody therapy. This Phase III trial is a randomized, active-controlled, open-label trial with a 24-week treatment period and a 24-week open-label extension period. Efficacy is evaluated by the proportion of participants achieving the primary hemoglobin response criteria in the absence of red blood cell transfusions, as well as other hematological response assessment items, transfusion avoidance, breakthrough hemolysis rate, and fatigue score (FACIT-Fatigue, patient-reported outcome questionnaire). The purpose of this Phase I-II trial in PNH patients with residual anemia despite treatment with anti-C5 antibody is to determine whether LNP023 hydrochloride is effective and safe for treating PNH by demonstrating its superiority compared to anti-C5 antibody therapy. This Phase III trial is a randomized, active-controlled, open-label trial with a 24-week treatment period and a 24-week open-label extension period. Efficacy is evaluated by the proportion of participants achieving the primary hemoglobin response criteria in the absence of red blood cell transfusions, as well as other hematological response assessment items, transfusion avoidance, breakthrough hemolysis rate, and fatigue score (FACIT-Fatigue, patient-reported outcome questionnaire). The purpose of this Phase I-II trial in PNH patients with residual anemia despite treatment with anti-C5 antibody is to determine whether LNP023 hydrochloride is effective and safe for treating PNH by demonstrating its superiority compared to anti-C5 antibody therapy. This Phase III trial is a randomized, active-controlled, open-label trial with a 24-week treatment period and a 24-week open-label extension period. Efficacy is evaluated by the proportion of participants achieving the primary hemoglobin response criteria in the absence of red blood cell transfusions, as well as other hematological response assessment items, transfusion avoidance, breakthrough hemolysis rate, and fatigue score (FACIT-Fatigue, patient-reported outcome questionnaire).

[0141] The results of the analysis conducted after the last participant completed the 24-week randomized treatment period form the basis of the data package for submission to the regulatory authorities.

[0142] Primary objectives and endpoints The primary objectives are as follows: 1) To demonstrate the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy in the proportion of participants achieving a sustained increase from baseline in hemoglobin levels of 2 g / dL or more in the absence of red blood cell transfusions, 2) To demonstrate the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy in the proportion of participants achieving a sustained Hb level of 12 g / dL or more in the absence of red blood cell transfusions.

[0143] Regardless of the discontinuation of the investigational drug and the occurrence of breakthrough hemolysis or major adverse vascular events (MAVEs), the efficacy of treatment with LNP023 hydrochloride at a dose of 200 mg b.i.d. in PNH patients with residual anemia, compared to anti-C5 antibody therapy, * An increase of 2 g / dL or more from baseline in Hb level * An Hb level of 12 g / dL or more is defined as a composite endpoint and is evaluated for the probability of becoming a responder, Both endpoints are evaluated between Day 126 and Day 168 and for the absence of the need for red blood cell transfusions between Day 14 and Day 168).

[0144] Secondary objectives: The secondary objectives are as follows: 1) Between Day 14 and Day 168, to determine the proportion of participants who meet the criteria defined in the protocol for concentrated red blood cells By evaluating the proportion of participants who have not received a blood transfusion, the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy in blood transfusion avoidance, as the proportion of participants who have not received a blood transfusion To demonstrate; 2) By evaluating the change (g / dL) from the baseline of hemoglobin as the average of visits between Day 126 and Day 168, to show the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy in the average change of hemoglobin 3) By evaluating the change from the baseline of the FACIT-Fatigue Score using the FACIT-Fatigue Questionnaire as the average of visits between Day 126 and Day 168, to show the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy in the improvement of fatigue 4) By evaluating the change (10 / L) from the baseline of the reticulocyte count as the average of visits between Day 126 and Day 168, to show the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy in the average change of reticulocyte count 9 5) By evaluating the % change from the baseline of the LDH level (U / L) as the average of visits between Day 126 and Day 168, to show the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy in the average % change of LDH 6) To show the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy in the proportion of breakthrough hemolysis (BTH) of participants with breakthrough hemolysis reported between Day 1 and Day 168 7) To evaluate the proportion of MAVE (including thrombosis) of LNP023 hydrochloride that occurred between Day 1 and Day 168, compared to anti-C5 antibody therapy

[0145] Exploratory Objectives ​​​​​​​​​​​​The exploration objectives are as follows: 1) To evaluate the safety and tolerability of LNP023 compared to anti-C5 treatment using safety evaluations such as adverse events / serious adverse events, safety inspection parameters, vital signs, etc.; ; 2) To evaluate the effect of LNP023 compared to anti-C5 antibody therapy on hematological parameters, units of RBC transfusion, and signs and symptoms of PNH; hematological parameters (including RBC, haptoglobin, etc.), bilirubin levels, units of concentrated RBC transfusion, and signs and symptoms of PNH are collected between day 1 and day 168 by the mean of model-derived estimates for visits between day 126 and day 168; ; 3) To evaluate the effect of LNP023 compared to anti-C5 antibody therapy on the severity of overall fatigue and health-related quality of life as reported by patients; changes in patient-reported outcome scores of PGIS, EORTC QLQ-C30, and EQ-5D-5L collected between day 1 and day 168 are evaluated, with a focus on comparing treatments by the mean of model-derived estimates from the visit model between day 126 and day 168; ; 4) To evaluate the effect of LNP023 compared to anti-C5 treatment on C3 fragment deposition on PNH erythrocytes and PNH clone size; the percentage of C3d-positive PNH erythrocytes collected between day 1 and day 168 is determined, and the total PNH clone size (percentage) of PNH type II and III erythrocytes and erythrocytes is collected between day 1 and day 168; ; ; 5) To characterize the PK of LNP023 in the PNH population based on PK exposure data; and ; and 6) Based on the occurrence of hospitalizations, readmissions, and emergency department visits between day 1 and day 168, medical resources To evaluate the effect of LNP023 compared to anti-C5 therapy in the utilization of the source.

[0146] Study design This study is a multi-center, randomized, open-label, active-controlled, parallel-group trial, consisting of three periods (see Figure 1). (See Figure 1.) ● Screening period lasting up to 8 weeks (unless it needs to be extended for the necessary vaccinations for inclusion) ● 24-week randomized, open-label, active-controlled, parallel-group treatment period for the primary efficacy and safety analysis ● 24-week open-label LNP023 hydrochloride treatment extension period In the study, despite a stable regimen of anti-C5 antibody therapy (eculizumab or ravulizumab) in the six months before randomization, PNH patients with residual anemia defined as hemoglobin less than 10 g / dL were enrolled, and approximately 40% of the participants had received at least one packed red blood cell transfusion in the six months before randomization. A total of approximately 91 participants will be randomized in the study. All participants are required to provide an informed consent form based on the notification before starting the study-related activities. The study design is shown in Figure 1.

[0147] Rationale for the study design The Phase III study is designed as a multi-center, open-label, randomized, active-controlled, parallel-group trial to demonstrate the superiority of LNP023 hydrochloride at an oral dose of 200 mg b.i.d. compared to intravenous anti-C5 antibody therapy in PNH patients with residual anemia despite treatment with a stable regimen of anti-C5 antibody therapy (SoC), in terms of hematological response parameters and patient-reported outcomes of fatigue.

[0148] Screening Patient eligibility is determined before the start of the acclimation period (based on the assessment performed at Visit 1). Inclusion and exclusion criteria are evaluated to confirm that participants are eligible to enroll in the study. The screening assessments are listed in Figure 2.

[0149] Participants must receive vaccination at the time of screening. The vaccine should cover as many serotypes as possible (including Neisseria meningitidis serotypes A, C, Y, W-135, and B). To minimize the burden on patients, the use of a locally available, multivalent vaccine that complies with local guidelines and regulations is recommended (e.g., a quadrivalent vaccine for N. meningitidis covering serotypes A, C, Y, and W-135, and Pneumovax-23 covering 23 serotypes of S. pneumoniae).

[0150] To meet the hemoglobin eligibility criteria, participants must have two samples collected during the screening period tested at a central laboratory before randomization to confirm that the mean value is less than 10 g / dL. If a participant receives an RBC transfusion after the first sample is collected, they are eligible based on the first central hemoglobin value if it is less than 10 g / dL.

[0151] Participants who meet the eligibility criteria at the time of screening are stratified based on the type of previous anti-C5 antibody therapy (eculizumab or ravulizumab) and the transfusion history reported during the six months before randomization (i.e., received / did not receive a transfusion). Approximately ​​​​​​​​​​​​It is assumed that 40% have received at least one red blood cell transfusion during the six months prior to randomization. It is assumed.

[0152] Randomization and randomized treatment period Participants will each be randomized in an 8:5 ratio to one of two treatment groups: LNP023 hydrochloride monotherapy at an oral dose of 200 mg b.i.d. (approximately 56 participants), or i.v. anti-C5 antibody therapy (approximately 35 participants who continue the same regimen during the randomized treatment period as before randomization). or i.v. anti-C5 antibody therapy (approximately 35 participants who continue the same regimen during the randomized treatment period as before randomization) one of two treatment groups, to one of two treatment groups at an 8:5 ratio.

[0153] Treatment will begin on the first day of dosing (Day 1) and continue for 24 weeks, with study visits and corresponding evaluations conducted according to the schedule described in Figure 2. Participants assigned to the comparator treatment group will continue to receive anti-C5 antibody therapy of the same type and regimen as they took prior to randomization, while participants randomized to the LNP023 hydrochloride treatment group will initiate treatment with LNP023 hydrochloride at a dose of 200 mg b.i.d. while participants randomized to the LNP023 hydrochloride treatment group will initiate treatment with LNP023 hydrochloride at a dose of 200 mg b.i.d. Participants assigned to the comparator treatment group will continue to receive anti-C5 antibody therapy of the same type and regimen as they took prior to randomization while participants randomized to the LNP023 hydrochloride treatment group will initiate treatment with LNP023 hydrochloride at a dose of 200 mg b.i.d. Participants randomized to the LNP023 hydrochloride treatment group will initiate treatment with LNP023 hydrochloride at a dose of 200 mg b.i.d.

[0154] Some patients may exhibit very low hemoglobin levels (e.g., less than 7 g / dL), and as a result, may require red blood cell transfusions within the first two weeks of the randomized treatment period. Considering this, transfusions administered within these first two weeks will not be considered in the definition of transfusion avoidance. Considering this, transfusions administered within these first two weeks will not be considered in the definition of transfusion avoidance. Considering this, transfusions administered within these first two weeks will not be considered in the definition of transfusion avoidance. .

[0155] Extension period Participants randomized to the placebo comparator treatment group will be offered a switch to LNP023 hydrochloride on Day 168 (at the Week 24 visit) after receiving the final dose of anti-C5 (eculizumab or ravulizumab) antibody therapy and enter an extended treatment period. Participants in the comparator treatment group who do not consent to the treatment switch after receiving the final dose of anti-C5 (eculizumab or ravulizumab) antibody therapy will be offered a switch to LNP023 hydrochloride on Day 168 (at the Week 24 visit) For the participants, week 24 will mark the end of the trial visits, and there will be no participation in the extension period. For participants who have consented to switch to oral LNP023 hydrochloride, the extended treatment will start on the day after the completion of the visit in week 24.

[0156] After switching to LNP023 hydrochloride, participants in the comparator treatment group will follow the schedule described in Figure 3 for trial visits and evaluations.

[0157] Trial Population Patients who are diagnosed with PNH and have been treated with a stable regimen of anti-C5 monoclonal antibody therapy (standard treatment; either eculizumab or ravulizumab) for at least 6 months before randomization but still exhibit residual anemia (i.e., Hb < 10 g / dL) will be enrolled. Approximately 40% of the participants who received at least one packed red blood cell transfusion during the 6 months before randomization are expected to be enrolled.

[0158] Major Inclusion Criteria Participants eligible for this trial must meet all of the following criteria: 1. Participants, 18 years of age or older, male or female, diagnosed with PNH by high-sensitivity flow cytometry with a clonal size of 10% or more in RBCs and / or granulocytes / monocytes of confirmed WBCs 2. A stable regimen (dose and interval) of anti-C5 antibody therapy (either eculizumab or ravulizumab) for at least 6 months before randomization 3. An average hemoglobin level < 10 g / dL 4. For at least 4 months prior to screening visit 5. Confirmed by central laboratory evaluation during screening 6. Neisseria meningitidis ​​​​​​​​Vaccination against infectious diseases is necessary before the start of treatment. If the patient has never received vaccination before, or if booster immunization is required, the vaccine, if available, must be administered at least 2 weeks before the first dose in accordance with local regulations. 7. If not previously received, and if possible, in accordance with local regulations, vaccination against Streptococcus · pneumoniae and Haemophilus · influenzae infections must be administered. The vaccine must be administered at least 2

[0159] Major exclusion criteria Participants who meet any of the following criteria are not eligible for this trial. 1. Participants with a stable dose of eculizumab but an administration interval of 11 days or less 2. Known or suspected hereditary complement deficiency at the time of screening 3. History of hematopoietic stem cell transplantation 4. Patients with bone marrow hypoplasia recognized by clinical examination (reticulocytes less than 100×10 9 / L; platelets less than 30×10 9 / L; neutrophils less than 500×10 6 / L). 5. Active systemic bacterial, viral or fungal infections within 14 days before the administration of the investigational drug 6. History of recurrent invasive infections caused by encapsulated organisms such as meningococcus or pneumococcus for example. 7. Although not limited to these, in the opinion of the responsible investigator of the clinical trial, the participant's participation in the trial is excluded, severe renal disease (e.g., dialysis), progressive heart disease (e.g., NYHA class I V), Severe lung diseases (e.g., severe pulmonary hypertension (WHO class IV)), or major co-existing diseases including liver diseases such as, for example, active hepatitis).

[0160] Treatment Participants will be randomized in an 8:5 ratio to either LNP023 hydrochloride monotherapy (anti-C5 antibody therapy is discontinued, see below for timing) administered orally b.i.d. or intravenous anti-C5 antibody therapy (continued at the same dose as administered prior to randomization). will be randomized.

[0161] First administration of LNP023 hydrochloride (clinic visit on day 1) The timing of the first administration of LNP023 hydrochloride provides a seamless switch from previous anti-C5 antibody therapy and allows for some overlap in exposure to anti-C5 antibody therapy when starting the oral agent, while limiting the potential risk of breakthrough hemolysis as LNP023 hydrochloride exposure accumulates. ● For participants on a previous eculizumab regimen, the first dose of LNP023 hydrochloride should be administered at the start of week 2 of the 2-week dosing interval (i.e., preferably approximately 7 - 8 days after the last infusion). must be done. ● For participants on a previous ravulizumab regimen, the first dose of LNP023 hydrochloride should be administered at the beginning of week 7 of the 8-week dosing interval (preferably approximately 41 - 43 days after the last infusion). must be done. Next, participants will continue to take 200 mg of LNP023 hydrochloride b.i.d.

[0162] First administration of anti-C5 in the study (clinic visit on day 1) Participants assigned to the comparator treatment group will continue to receive anti-C5 infusions according to a stable regimen ​​​​​​However, the next administration date of anti-C5 for "start of the test" must coincide with the test day of "Day 1". The principal investigator of the clinical trial is recommended to "count backwards" from the scheduled date of the planned infusion. This is recommended.

[0163] Extension period: Administration of LNP023 hydrochloride to the comparator group At the visit on Week 24, participants in the comparator treatment group receive the last infusion of the anti-C5 agent and start the first dose of LNP023 hydrochloride the morning after the visit date (Day 169).

[0164] If participants during the extension period take LNP023 hydrochloride from Day 169, the visit schedule is unified except for Day 182 when only participants assigned to the comparator treatment group return 7 days after the first administration of LNP023 hydrochloride for PK and safety evaluation.

[0165] Clinical trial treatment In this trial, "clinical trial treatment" includes the investigational drug LNP023 hydrochloride and the active drug comparison of anti-C5 antibody (either eculizumab or ravulizumab).

[0166]

Table 9

[0167] The investigational drugs, 10 mg and 200 mg capsules of LNP023 hydrochloride, are prepared by Novartis and supplied to the principal investigator's facility as an open-label participant pack. Eculizumab and ravulizumab are commercially available in each participating country and are provided by the trial conducting institution, subsidiary, or designee or by Novartis locally in accordance with local practice and local regulations.

[0168] Treatment period​​​​​​​​ The duration of the randomized treatment period is 24 weeks. Treatment of participants with LNP023 hydrochloride was discontinued (e.g., due to lack of efficacy), and patients switched to a previous anti-C5 antibody therapy In such cases, every effort is made to continue the test evaluation until the 24th week visit.

[0169] The extension period lasts for up to 24 weeks, and participants randomized to the LNP023 hydrochloride treatment group during the randomized treatment period continue with LNP023 hydrochloride treatment, and participants randomized to the anti-C5 treatment group are proposed to switch to LNP023 hydrochloride monotherapy.

[0170] Rationale for dosage and treatment duration The dose of 200 mg of LNP023 hydrochloride b.i.d. continuous treatment was mainly selected for this Phase III trial based on available efficacy and safety data obtained during the interim analysis of two ongoing Phase II PNH trials (ClinicalTrials.gov Identifier : NCT03439839 and NCT03896152), and is supported by the results of the PKPD model. r: NCT03439839 and NCT03896152) and is supported by the results of the PKPD model. Available efficacy and safety data obtained during the interim analysis of two ongoing Phase II PNH trials (ClinicalTrials.gov Identifier r: NCT03439839 and NCT03896152), and is supported by the results of the PKPD model.

[0171] In the CLNP023X2201 trial in patients with active hemolysis despite treatment with eculizumab, LNP023 hydrochloride was administered to 10 PNH participants (cohort 1) at a dose of 200 mg b.i.d. and to 6 PNH participants (cohort 2) at a dose of 50 mg b.i.d. An interim analysis (IA) was performed after at least 12 weeks of treatment of 10 participants (cohort 1) with LNP023 hydrochloride at a dose of 200 mg b.i.d. as an add-on treatment to eculizumab. In the CLNP023X2201 trial in patients with active hemolysis despite treatment with eculizumab, LNP023 hydrochloride was administered to 10 PNH participants (cohort 1) at a dose of 200 mg b.i.d. and to 6 PNH participants (cohort 2) at a dose of 50 mg b.i.d. An interim analysis (IA) was performed after at least 12 weeks of treatment of 10 participants (cohort 1) with LNP023 hydrochloride at a dose of 200 mg b.i.d. as an add-on treatment to eculizumab. In the CLNP023X2201 trial in patients with active hemolysis despite treatment with eculizumab, LNP023 hydrochloride was administered to 10 PNH participants (cohort 1) at a dose of 200 mg b.i.d. and to 6 PNH participants (cohort 2) at a dose of 50 mg b.i.d. An interim analysis (IA) was performed after at least 12 weeks of treatment of 10 participants (cohort 1) with LNP023 hydrochloride at a dose of 200 mg b.i.d. as an add-on treatment to eculizumab. In the CLNP023X2201 trial in patients with active hemolysis despite treatment with eculizumab, LNP023 hydrochloride was administered to 10 PNH participants (cohort 1) at a dose of 200 mg b.i.d. and to 6 PNH participants (cohort 2) at a dose of 50 mg b.i.d. An interim analysis (IA) was performed after at least 12 weeks of treatment of 10 participants (cohort 1) with LNP023 hydrochloride at a dose of 200 mg b.i.d. as an add-on treatment to eculizumab. In the CLNP023X2201 trial in patients with active hemolysis despite treatment with eculizumab, LNP023 hydrochloride was administered to 10 PNH participants (cohort 1) at a dose of 200 mg b.i.d. and to 6 PNH participants (cohort 2) at a dose of 50 mg b.i.d. An interim analysis (IA) was performed after at least 12 weeks of treatment of 10 participants (cohort 1) with LNP023 hydrochloride at a dose of 200 mg b.i.d. as an add-on treatment to eculizumab. In the CLNP023X2201 trial in patients with active hemolysis despite treatment with eculizumab, LNP023 hydrochloride was administered to 10 PNH participants (cohort 1) at a dose of 200 mg b.i.d. and to 6 PNH participants (cohort 2) at a dose of 50 mg b.i.d. An interim analysis (IA) was performed after at least 12 weeks of treatment of 10 participants (cohort 1) with LNP023 hydrochloride at a dose of 200 mg b.i.d. as an add-on treatment to eculizumab.

[0172] In a Phase II trial (NCT03439839) in patients with no prior history of anti-C5 antibody therapy, participants received monotherapy with LNP023 hydrochloride, starting at 25 mg b.i.d. at week 4 and escalating sequentially to 100 mg b.i.d. of LNP023 hydrochloride (sequence 1), or from 50 mg b.i.d . to 200 mg b.i.d. of LNP023 hydrochloride (sequence 2). IA was performed after randomizing 8 patients and 7 patients completed the week 8 visit assessment .

[0173] The 200 mg b.i.d. dose was based on the following key findings from two interim analyses and was expected to provide optimal efficacy for PNH as a monotherapy with an appropriate safety profile: ● Participants receiving 200 mg b.i.d. of LNP023 hydrochloride (add-on to eculizumab) had clinical benefits not achieved with eculizumab, including suppression of IVH demonstrated by a decrease in LDH, suppression of EVH demonstrated by a decrease in bilirubin and reticulocytes, and an increase in haptoglobin resulting in normalization of hemoglobin in the majority of patients in the absence of red blood cell transfusions. The hematologic responses achieved by participants with the 200 mg b.i.d. add-on therapy of LNP023 hydrochloride were maintained by LNP023 hydrochloride monotherapy in 5 / 10 participants during an extended period (at IA) when eculizumab treatment was discontinued. Following IA, an additional 2 participants discontinued eculizumab treatment. C3 deposition was completely reversed by the addition of 200 mg b.i.d. dose of LNP02 ● Participants receiving 200 mg b.i.d. of LNP023 hydrochloride (add-on to eculizumab) had clinical benefits not achieved with eculizumab, including suppression of IVH demonstrated by a decrease in LDH, suppression of EVH demonstrated by a decrease in bilirubin and reticulocytes, and an increase in haptoglobin resulting in normalization of hemoglobin in the majority of patients in the absence of red blood cell transfusions. The hematologic responses achieved by participants with the 200 mg b.i.d. add-on therapy of LNP023 hydrochloride were maintained by LNP023 hydrochloride monotherapy in 5 / 10 participants during an extended period (at IA) when eculizumab treatment was discontinued. Following IA, an additional 2 participants discontinued eculizumab treatment. C3 deposition was completely reversed by the addition of 200 mg b.i.d. dose of LNP02 ● Participants receiving 200 mg b.i.d. of LNP023 hydrochloride (add-on to eculizumab) had clinical benefits not achieved with eculizumab, including suppression of IVH demonstrated by a decrease in LDH, suppression of EVH demonstrated by a decrease in bilirubin and reticulocytes, and an increase in haptoglobin resulting in normalization of hemoglobin in the majority of patients in the absence of red blood cell transfusions. The hematologic responses achieved by participants with the 200 mg b.i.d. add-on therapy of LNP023 hydrochloride were maintained by LNP023 hydrochloride monotherapy in 5 / 10 participants during an extended period (at IA) when eculizumab treatment was discontinued. Following IA, an additional 2 participants discontinued eculizumab treatment. C3 deposition was completely reversed by the addition of 200 mg b.i.d. dose of LNP02 ● Participants receiving 200 mg b.i.d. of LNP023 hydrochloride (add-on to eculizumab) had clinical benefits not achieved with eculizumab, including suppression of IVH demonstrated by a decrease in LDH, suppression of EVH demonstrated by a decrease in bilirubin and reticulocytes, and an increase in haptoglobin resulting in normalization of hemoglobin in the majority of patients in the absence of red blood cell transfusions. The hematologic responses achieved by participants with the 200 mg b.i.d. add-on therapy of LNP023 hydrochloride were maintained by LNP023 hydrochloride monotherapy in 5 / 10 participants during an extended period (at IA) when eculizumab treatment was discontinued. Following IA, an additional 2 participants discontinued eculizumab treatment. C3 deposition was completely reversed by the addition of 200 mg b.i.d. dose of LNP02 3 hydrochloride, and the survival rate of PNH red blood cells was extended. 200 mg The hematologic responses achieved by participants with the 200 mg b.i.d. add-on therapy of LNP023 hydrochloride were maintained by LNP023 hydrochloride monotherapy in 5 / 10 participants during an extended period (at IA) when eculizumab treatment was discontinued. Following IA, an additional 2 participants discontinued eculizumab treatment. C3 deposition was completely reversed by the addition of 200 mg b.i.d. dose of LNP02 In 5 / 10 participants, during an extended period (at IA) when eculizumab treatment was discontinued, the hematologic responses achieved by participants with the 200 mg b.i.d. add-on therapy of LNP023 hydrochloride were maintained by LNP023 hydrochloride monotherapy. Following IA, an additional 2 participants discontinued eculizumab treatment. C3 deposition was completely reversed by the addition of 200 mg b.i.d. dose of LNP02 3 hydrochloride, and the survival rate of PNH red blood cells was extended. 200 mg 3 hydrochloride, and the survival rate of PNH red blood cells was extended. 200 mg This further supports the control of EVH by LNP023 hydrochloride at a bid dose of There was sustained inhibition of the alternative complement pathway and a significant and sustained reduction in fragment Bb, resulting in targeted The binding was demonstrated. Participants receiving LNP023 hydrochloride monotherapy were randomized to receive LNP023 hydrochloride increased LDH levels by 60% or more from baseline in all participants The study showed that the majority of participants had early hemoglobin increases without transfusions. Other hemolysis-related laboratory parameters were significantly higher with LNP023 hydrochloride administered as monotherapy. Intravascular hemolysis (decreased LDH) and extravascular hemolysis (decreased reticulocytes and bilirubin, haptoglobin It was shown that the effect of the α-amino acid sequence on the increase in the number of bins was suppressed.

[0174] Preliminary information from cohort 2 of the Phase II trial (NCT03439839) indicates that Optimal efficacy required for LNP023 hydrochloride monotherapy in patients with The optimal response was achieved in three participants. As no treatment was achieved, the dose was titrated to 200 mg bid.

[0175] LNP023 hydrochloride at a dose of 200 mg bid was effective in both studies in PNH. , and patients with IgA nephropathy (CLNP023X2203 study) and C3 glomerulopathy (CLNP 023X2202) at the same dose in patients, was safe and well tolerated by participants This supports its use in this Phase III trial.

[0176] First-in-human (F-Human) study using LNP023 hydrochloride in healthy volunteers The exposure-response model developed using data from the IH study demonstrated a 90% success rate in over 70% of subjects. To achieve inhibition of alternative pathways (Wieslab assay) beyond ~, a b.i.d. dose of approximately 200 mg is predicted to be required. Hemolysis and the risk of breakthrough in case of insufficient complement activity suggest that complete inhibition is desirable, and the modeling results

[0177] Contraindicated medications During administration of LNP023 hydrochloride, the use of the following therapies is not permitted. ● Live vaccines are prohibited throughout the entire treatment period. ● Gemfibrozil (a potent inhibitor of metabolic enzyme CYP2C8, UGT1A, and hepatic uptake transporter OATP1B1) must be discontinued ○ If restarted during the trial in which LNP023 hydrochloride is administered, discontinue the prohibited therapy immediately. ● Clopidogrel (a potent inhibitor of CYP2C8) must be discontinued from 7 days before the first administration of LNP023 hydrochloride until the end of LNP023 hydrochloride treatment (and replaced with ○ If restarted during the trial in which LNP023 hydrochloride is administered, discontinue the prohibited therapy immediately.

[0178] In any case of interruption during LNP023 hydrochloride administration, participants must continue the trial and safety / tolerance

[0179] Visit schedule and assessments The evaluation schedule (Figures 2 and 3) enumerates all evaluations when they are carried out. . During the screening period, an average hemoglobin of less than 10 g / dL is evaluated by two hemoglobin measurements (average less than 10 g / dL) at intervals of 2 to 8 weeks (before randomization), by central laboratory evaluation; or, for patients who received pRBC transfusions after the first evaluation, by one hemoglobin measurement (less than 10 g / dL) from the first evaluation and is confirmed. If a participant received a packed RBC transfusion after the first evaluation performed at the screening visit (central laboratory), the participant becomes eligible without additional hemoglobin evaluation by the central laboratory.

[0180] Efficacy During the randomized treatment period, blood samples are taken for hematology, clinical chemistry, and C3 + R BC, PNH type II / III RBCs, and PNH clone size according to the schedule in Figure 2.

[0181] The following test items are evaluated: hemoglobin (and haptoglobin), reticulocyte count, bilirubin (as a marker of extravascular hemolysis), LDH (as a marker of intravascular hemolysis), RBCs, PNH clone size, PNH type RBCs, and C3 on PNH type RBCs. +

[0182] During the extension period, evaluations are carried out according to the schedule in Figure 3.

[0183] Red blood cell transfusion The need for the administration of red blood cell transfusions is continuously monitored during the randomized treatment period.

[0184] To standardize the administration criteria, transfusion criteria have been established and are applied from the first day of the trial.

[0185] Packed red blood cell transfusions are administered to participants in the following situations: ● Hemoglobin level is 9 g / dL or less and there are severe signs and / or symptoms that provide a legitimate basis for transfusion ● Hemoglobin is 7 g / dL or less regardless of the presence of clinical signs

[0186] Breakthrough hemolysis The occurrence of breakthrough hemolysis is continuously monitored during the blinded treatment period. If either of two clinical criteria is met, the criteria for clinical breakthrough are defined in Table 2 below. In contrast to the defined clinical breakthrough, an isolated laboratory evidence of increased intravascular hemolysis without significant hemoglobin decrease and without other clinical signs or symptoms of hemolysis (see Table 2) is defined as potential breakthrough hemolysis. During the extension period, breakthrough hemolysis is continuously monitored until the end of the study visit according to the same criteria and indicators as above.

[0187]

Table 10

[0188]

[0189] Patient-reported outcome (PRO)-FACIT-Fatigue FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact on daily activities and function. Using this, patient-reported fatigue is evaluated. FACIT-Fatigue is part of a collection of health-related quality of life (HRQoL) questionnaires called the FACIT measurement system, and is one of many different FACIT scales. (HRQoL) questionnaires, and is one of many different FACIT scales. ​​​​​​​One (Webster K, Cella D, and Yost K. (2003 ). The functional assessment of chronic i llness therapy (FACIT) measurement system: properties, applications, and interpretati on. Health Qual Life Outcomes; 16:1 - 79; Yel len SB, et al. (1997). Measuring fatigue an d other anemia - related symptoms with fun ctional assessment of cancer therapy (FAC T) measurement system. J Pain Symmptom Ma nage; 13:633 - 74). The use of FACIT - F in PNH patients has been reported in several publications and is sensitive to changes in the disease state, allowing for the demonstration of statistically significant and clinically meaningful results (Brodsky RA, et al. (2008) Multicenter phase 3 study of the complem ent inhibitor eculizumab for the treatme nt of patients with paroxysmal nocturnal hemoglobinuria. Blood; 4:1840 - 1847; Ueda Y hemoglobinuria. Blood; 4:1840 - 1847; Ueda Y , Obara N, et al. (2018). Effects of eculizu mab treatment on quality of life in pati ents with paroxysmal nocturnal hemoglobi​ nuria in Japan.Int J Hematol;107:656-665 ;Kulasekararaj AG,et al.(2019)Ravulizuma b(ALXN1210) vs eculizumab in C5-inhibitor -experienced adult patients with PNH:the 302 study. Blood;133:540-549). All FACIT schedules The rules are scored so that higher scores indicate better outcomes. Each of the 13 items ranges from 0 to 4, so the possible score range is 0 to 52. , 0 being the worst possible score and 52 being the best score.

[0190] PNH-Associated Signs and Symptoms Signs and symptoms of PNH will be collected during the randomized treatment period according to Figure 2. The teacher (or designee) will record the presence of the following signs and symptoms: Reddish or cola-colored urine, especially in the morning, and / or hemoglobinuria Feeling weak or tired Shortness of breath / difficulty breathing Dysphagia / difficulty swallowing ●Chest pain ●Stomachache ●Erectile dysfunction / impotence

[0191] Pharmacokinetics PK samples will be collected at visits defined in the evaluation schedule (Figures 2 and 3). Pharmacokinetic (PK) samples were obtained from all participants taking LNP023 hydrochloride. , evaluated. LNP023 hydrochloride was measured by a validated LC-MS / MS method. The expected lower limit of quantification (LLOQ) is 1.0 ng / mL. Metabolites (if required) may be measured as appropriate. The concentration is expressed as mass per unit volume (ng / mL) and refers to the free base anhydride.

[0192] Termination and Completion of the Trial The termination of the investigational treatment of the participant may occur when the investigational treatment is terminated earlier than the planned period of the protocol and may be initiated by either the participant or the investigator in charge of the trial.

[0193] At the time of discontinuation of LNP023 hydrochloride, the participant must be closely monitored for signs and symptoms of hemolysis. At a minimum, it is recommended to monitor for an increase in LDH, a decrease in hemoglobin level, a decrease in the PNH clone size, an increase in serum creatinine, thrombosis, and changes in mental status. If severe hemolysis occurs, the investigator in charge of the trial should consider the following supportive therapies (and record them on the appropriate CRF page): ● Transfusion (packed RBC), ● Or, if PNH RBCs exceed 50% of total RBCs by flow cytometry, exchange transfusion ● Corticosteroids ● Anticoagulant therapy ● Any other supportive or therapeutic measures determined by the investigator in charge of the trial.

[0194] Even if the administration of LNP023 hydrochloride must be discontinued immediately, it does not necessarily mean that the administration of LNP023 hydrochloride must be stopped immediately. That is, in cases such as the decision of the participant / guardian or discontinuation due to confirmed pregnancy, it is recommended to resume anti-C5 antibody therapy immediately at the discretion of the investigator in charge of the trial. Furthermore, as follows, it must be considered to taper LNP023 hydrochloride over 14 days: ● Three 10 mg capsules of LNP023 hydrochloride taken in the evening for 7 days (once a day) ) ● One 10 mg capsule of LNP023 hydrochloride taken in the evening for 7 days (once a day) )

[0195] Equivalents One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments specifically described herein. Such equivalents are intended to be encompassed by the following claims. The present invention also includes the following aspects. <1> For example, LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, is orally administered at a dose of 200 mg twice a day (b.i.d.), such as every about 12 hours (the dose refers to the anhydrous free base of LNP023 hydrochloride), thereby treating a subject such as a patient, for example, for use in the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in a subject such as a patient. A pharmaceutical composition comprising LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. <2> For example, the subject such as a patient has been previously treated with anti-C5 therapy for at least about 8 months, for example, at least about 6 months before administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. The pharmaceutical composition for use according to 1 above. <3> The pharmaceutical composition for use according to 2 above, wherein the anti-C5 therapy is an anti-C5 monoclonal antibody therapy. <4> The pharmaceutical composition for use according to 2 or 3 above, wherein the anti-C5 therapy is eculizumab or ravulizumab. <5> For example, the subject such as a patient has residual anemia. The pharmaceutical composition for use according to any one of 1 to 4 above. <6> For example, the hemoglobin level, haptoglobin level, reticulocyte level, and / or bilirubin level of the subject such as a patient is evaluated before administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. The pharmaceutical composition for use according to any one of 1 to 5 above. <7> For example, the hemoglobin level of the subject such as a patient is less than about 12 g / dL, less than about 11.5 g / dL, less than about 11 g / dL, less than about 10.5 g / dL, less than about 10 g / dL, less than about 9.5 g / dL, less than about 9 g / dL, less than about 8.5 g / dL, or less than about 8 g / dL before administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. The pharmaceutical composition for use according to 6 above. <8> For example, the hemoglobin level of the subject such as a patient is about 10 g / dL or less before administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. The pharmaceutical composition for use according to 6 above. <9> The treatment of PNH comprises increasing the hemoglobin level in the subject, such as a patient, by, for example, about 1 g / dL or more, about 1.5 g / dL or more, about 2 g / dL or more, about 2.5 g / dL or more, or about 3 g / dL or more compared to the hemoglobin level in the subject, such as a patient, before administration of, for example, LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, compared to, for example, the baseline. A pharmaceutical composition for use according to any one of 1 to 8 above. <10> The treatment of PNH comprises normalizing intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) in the subject, such as a patient. A pharmaceutical composition for use according to any one of 1 to 9 above. <11> Normalizing IVH and / or EVH hemolysis comprises increasing the haptoglobin level, decreasing the reticulocyte level, or decreasing the bilirubin level in the subject, such as a patient, compared to the levels of haptoglobin, reticulocytes, or bilirubin in the subject, such as a patient, before administration of, for example, LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, compared to, for example, the baseline. A pharmaceutical composition for use according to 10 above. <12> The treatment of PNH comprises treating PNH-related hemolysis. A pharmaceutical composition for use according to any one of 1 to 11 above. <13> The treatment of PNH comprises reducing C3 deposition in the subject, such as a patient. A pharmaceutical composition for use according to any one of 1 to 12 above. <14> C3 deposition is reduced by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or about 99% compared to the level of C3 deposition in the subject, such as a patient, before administration of, for example, LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, compared to, for example, the baseline. A pharmaceutical composition for use according to 13 above. <15> The treatment of PNH comprises increasing the survival rate of red blood cells (RBCs) in the subject, such as a patient. A pharmaceutical composition for use according to any one of 1 to 14 above. <16> A pharmaceutical composition for use according to any one of the above 1 to 15, wherein treating PNH comprises inhibiting the alternative complement pathway in the subject, such as a patient. <17> A pharmaceutical composition for use according to any one of the above 1 to 16, wherein treating PNH comprises reducing the level of fragment Bb in the subject, such as a patient. <18> A pharmaceutical composition for use according to any one of the above 1 to 17, wherein treating PNH comprises increasing the hemoglobin level in the subject, such as a patient, by, for example, about 2 g / dL or more as compared to the hemoglobin level in the subject, such as a patient, before administration of, for example, LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, as compared to the baseline. <19> A pharmaceutical composition for use according to any one of the above 1 to 18, wherein treating PNH comprises achieving a sustained increase in hemoglobin level. <20> A pharmaceutical composition for use according to any one of the above 1 to 19, wherein treating PNH comprises achieving a sustained increase in hemoglobin level exceeding about 10 g / dL, exceeding about 10.5 g / dL, exceeding about 11 g / dL, exceeding about 11.5 g / dL, exceeding about 12 g / dL, exceeding about 12.5 g / dL, or exceeding about 13 g / dL. <21> A pharmaceutical composition for use according to any one of the above 1 to 20, wherein treating PNH comprises achieving a sustained increase in hemoglobin level of about 12 g / dL or more. <22> A pharmaceutical composition for use according to any one of the above 1 to 21, wherein treating PNH comprises increasing the hemoglobin level in the subject, such as a patient, in the absence of one or more red blood cell (RBC) transfusions. <23> A pharmaceutical composition for use according to any one of the above 1 to 21, wherein the subject, such as a patient, has received, for example, at least one concentrated RBC transfusion about 6 months before administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. <24> For example, a pharmaceutical composition for use as described in any of 1 to 23 above, wherein the subject such as a patient has been vaccinated, such as with a previous vaccination against Neisseria meningitidis (serogroups A, C, Y, and W-135), prior to administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride. <25> A pharmaceutical composition for use as described in any of 1 to 24 above, wherein the efficacy of the treatment is determined by measuring the hemoglobin level in the subject such as a patient, for example, compared to the hemoglobin level in the subject such as a patient prior to administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride, and for example, compared to the baseline. <26> A pharmaceutical composition for use as described in 25 above, wherein the hemoglobin level is increased by about 1.5 g / dL or more, about 2 g / dL or more, about 2.5 g / dL or more, about 3 g / dL or more, about 3.5 g / dL or more, about 4 g / dL or more, about 4.5 g / dL or more, or about 5 g / dL or more, for example, about 2 g / dL or more, compared to the hemoglobin level in the subject such as a patient prior to administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride, and for example, compared to the hemoglobin level in the subject such as a patient prior to administration of LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride, and for example, compared to the baseline. <27> A pharmaceutical composition comprising LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride (the dosage refers to the anhydrous free base of LNP023 hydrochloride), which is orally administered at a dose of 200 mg, for example, twice a day (b.i.d.) such as every about 12 hours, thereby normalizing IVH and / or EVH in a subject such as a patient, for example, for use in normalizing intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) in the subject such as a patient in need thereof. <28> A pharmaceutical composition for use as described in 27 above, wherein the subject has PNH or is diagnosed as having PNH. <29> Normalizing IVH and / or EVH hemolysis comprises, for example, increasing the haptoglobin level, decreasing the reticulocyte level, or decreasing the bilirubin level in the subject, such as a patient, compared to, for example, the baseline, and compared to the levels of haptoglobin, reticulocytes, or bilirubin in the subject, such as a patient, prior to administration of, for example, LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride. A pharmaceutical composition for use as described in item 27 or 28 above. <30> A pharmaceutical composition for use as described in item 29 above, wherein the haptoglobin level, reticulocyte level, or bilirubin level in the subject, such as a patient, is obtained by analysis of a sample of a body fluid such as blood or plasma. <31> For example, orally administer LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride at a dose of 200 mg twice a day (b.i.d.), such as every about 12 hours (the dose refers to the anhydrous free base of LNP023 hydrochloride), thereby treating a subject such as a patient, for example, for use in the treatment of PNH-related hemolysis in the subject such as a patient in need thereof. A pharmaceutical composition comprising LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride. <32> The pharmaceutical composition for use as described in item 31 above, wherein the PNH-related hemolysis is breakthrough hemolysis (BTH) as defined, for example, in Table 2. <33> For example, orally administer LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride at a dose of 200 mg twice a day (b.i.d.), such as every about 12 hours (the dose refers to the anhydrous free base of LNP023 hydrochloride), thereby treating a subject such as a patient, for example, for use in the treatment of IVH, such as suppression of intravascular hemolysis (IVH), in the subject such as a patient in need thereof. A pharmaceutical composition comprising LNP023 or a pharmaceutically acceptable salt thereof such as LNP023 hydrochloride. <34> The pharmaceutical composition for use as described in item 33 above, wherein the subject, such as a patient, has PNH or is diagnosed as having PNH. <35> For example, the treatment of IVH, such as the suppression of IVH, involves, for example, reducing the level of lactate dehydrogenase (LDH) in the subject before administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, compared to, for example, the baseline, compared to the level of LDH in the subject, such as a patient. A pharmaceutical composition for use as described in item 33 or 34 above, which comprises reducing the level of LDH in the subject, such as a patient. <36> For example, the pharmaceutical composition for use as described in item 35 above, wherein the LDH level in the subject, such as a patient, is obtained by analyzing a sample of a body fluid such as blood or plasma. <37> For example, the pharmaceutical composition for use as described in item 35 or 36 above, wherein the LDH level in the subject, such as a patient, is reduced by at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%. <38> The pharmaceutical composition for use as described in any one of items 35 to 37 above, wherein the LDH level is reduced by at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%. <39> For example, the pharmaceutical composition for use as described in any one of items 35 to 38 above, wherein the LDH level in the subject, such as a patient, is reduced by at least about 60%. <40> For example, LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, is orally administered at a dose of 200 mg twice a day (b.i.d.), such as every about 12 hours (the dose refers to the anhydrous free base of LNP023 hydrochloride), thereby treating a subject, such as a patient, for example, for use in the treatment of extravascular hemolysis (EVH), such as the suppression of EVH, in the subject, such as a patient in need thereof. A pharmaceutical composition comprising LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. <41> For example, the pharmaceutical composition for use as described in item 40 above, wherein the subject, such as a patient, has PNH or is diagnosed as having PNH. <42> For example, the treatment of EVH such as the suppression of EVH involves, for example, reducing the level of bilirubin, reticulocytes, or haptoglobin in the subject such as a patient compared to, for example, the baseline, or increasing the level of haptoglobin, compared to the levels of bilirubin, reticulocytes, or haptoglobin in the subject such as a patient before the administration of LNP023 or its pharmaceutically acceptable salts such as LNP023 hydrochloride. The pharmaceutical composition for use as described in item 40 or 41 above comprises this. <43> For example, the value of the level of bilirubin, reticulocytes, or haptoglobin in the subject such as a patient is obtained by analyzing a sample of body fluid such as blood or plasma. The pharmaceutical composition for use as described in item 42 above comprises this. <44> The level of bilirubin or reticulocytes decreases by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%. The pharmaceutical composition for use as described in item 42 or 43 above comprises this. <45> The level of haptoglobin increases by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%. The pharmaceutical composition for use as described in any of items 42 - 44 above comprises this. <46> For example, LNP023 or its pharmaceutically acceptable salts such as LNP023 hydrochloride is orally administered at a dose of 200 mg twice a day (b.i.d.) such as every about 12 hours (the dose refers to the anhydrous free base of LNP023 hydrochloride), thereby normalizing the hemoglobin level in the subject such as a patient. The pharmaceutical composition comprises LNP023 or its pharmaceutically acceptable salts such as LNP023 hydrochloride for use in normalizing the hemoglobin level in the subject in need thereof. <47> The hemoglobin level exceeds about 10 g / dL, exceeds about 10.5 g / dL, exceeds about 11 g / dL, exceeds about 11.5 g / dL, exceeds about 12 g / dL, exceeds about 12.5 g / dL, or exceeds about 13 g / dL, and is normalized to, for example, about 12 g / dL or more. The pharmaceutical composition for use as described in item 46 above comprises this. <48> For example, the pharmaceutical composition for use according to item 46 or 47 above, wherein the subject such as a patient has PNH or is diagnosed as having PNH. <49> The pharmaceutical composition for use according to any one of items 46 to 48 above, wherein normalization of hemoglobin level occurs in the absence of red blood cell transfusion. <50> For example, LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride is orally administered at a dose of 200 mg twice a day (b.i.d.), for example, every about 12 hours (the dose refers to the anhydrous free base of LNP023 hydrochloride), thereby reducing C3 deposition in a subject such as, for example, a patient in need thereof. A pharmaceutical composition comprising LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride for use in reducing C3 deposition in the subject such as a patient in need thereof. <51> For example, the pharmaceutical composition for use according to item 50 above, wherein the subject such as a patient has PNH or is diagnosed as having PNH. <52> The pharmaceutical composition for use according to item 50 or 51 above, wherein C3 deposition is reduced by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or about 99%. <53> The pharmaceutical composition for use according to any one of items 50 to 52 above, wherein C3 deposition is completely reversed, for example, C3 deposition is quantified by flow cytometry as C3 fragment deposition on red blood cells. <54> For example, LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride is orally administered at a dose of 200 mg twice a day (b.i.d.), for example, every about 12 hours (the dose refers to the anhydrous free base of LNP023 hydrochloride), thereby increasing RBC survival rate in a subject such as a patient. A pharmaceutical composition comprising LNP023 or a pharmaceutically acceptable salt thereof such as, for example, LNP023 hydrochloride for use in increasing the red blood cell (RBC) survival rate in the subject such as a patient in need thereof. <55> The pharmaceutical composition for use according to item 54 above, wherein the subject has PNH or is diagnosed as having PNH. <56> For example, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered at a dose of 200 mg twice a day (b.i.d.), such as every about 12 hours (the said dose refers to the anhydrous free base of LNP023 hydrochloride), thereby treating a subject, such as a patient, for example, maintaining inhibition in the said subject, such as a patient in need thereof, for use in inhibiting the alternative complement pathway. A pharmaceutical composition comprising LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. <57> A pharmaceutical composition for use as described in 56 above, wherein the said subject, such as a patient, has PNH or is diagnosed as having PNH. <58> A pharmaceutical composition for use as described in 56 or 57 above, wherein sustained inhibition of the alternative complement pathway is achieved about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, or about 24 weeks after administration of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. <59> A pharmaceutical composition for use as described in any of 56 - 58 above, wherein sustained inhibition of the alternative complement pathway is achieved about 18 - 24 weeks after administration of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. <60> A pharmaceutical composition for use as described in any of 56 - 59 above, wherein sustained inhibition of the alternative complement pathway is achieved about 18 or 24 weeks after administration of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. <61> For example, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered at a dose of 200 mg twice a day (b.i.d.), such as every about 12 hours (the said dose refers to the anhydrous free base of LNP023 hydrochloride), thereby reducing the level of fragment Bb in a subject, such as a patient, for example, for use in reducing the level of fragment Bb in the said subject, such as a patient in need thereof. A pharmaceutical composition comprising LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. <62> A pharmaceutical composition for use as described in 61 above, wherein the said subject, such as a patient, has PNH or is diagnosed as having PNH. <63> The pharmaceutical composition for use according to 61 or 62 above, wherein the fragment Bb level is reduced by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% compared to, for example, the level of fragment Bb in the subject, such as a patient, before administration of, for example, LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, compared to, for example, a baseline.

Claims

A pharmaceutical composition comprising 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof, for use in a method for normalizing intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) in a subject, wherein the pharmaceutical composition is orally administered at a dose of 200 mg of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof twice a day (b.i.d.) (provided that the dose refers to the free base anhydrous hydrochloride salt of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid), said pharmaceutical composition. The pharmaceutical composition according to claim 1, wherein normalizing intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) comprises increasing the hemoglobin level in the subject by 2 g / dL or more as compared to the hemoglobin level in the subject before administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, wherein normalizing intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) comprises increasing the haptoglobin level, decreasing the reticulocyte level, or decreasing the bilirubin level in the subject as compared to the levels of haptoglobin, reticulocytes, or bilirubin in the subject before administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 3, wherein the level of haptoglobin increases by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

5. The pharmaceutical composition according to claim 3, wherein the level of bilirubin or reticulocytes is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

6. A pharmaceutical composition comprising 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof, which is used in a method for treating intravascular hemolysis (IVH) in a subject, wherein the pharmaceutical composition is orally administered twice a day (b.i.d.) at a dose of 200 mg of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof (provided that the dose refers to the free base anhydride of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride), the treatment of intravascular hemolysis (IVH) comprising increasing the hemoglobin level in the subject by 2 g / dL or more compared to the hemoglobin level in the subject before administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof, the pharmaceutical composition.

7. The pharmaceutical composition according to claim 6, wherein the treatment of intravascular hemolysis (IVH) comprises increasing the hemoglobin level in the subject in the absence of one or more red blood cell (RBC) transfusions.

8. The pharmaceutical composition according to claim 6 or 7, wherein the treatment of intravascular hemolysis (IVH) comprises reducing the level of lactate dehydrogenase (LDH) in the subject compared to the level of LDH in the subject before administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to claim 8, wherein the LDH level in the subject is reduced by at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95%.

10. A pharmaceutical composition comprising 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof, which is used in a method for treating extravascular hemolysis (EVH) in a subject, wherein the pharmaceutical composition is orally administered at a dose of 200 mg of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof twice a day (b.i.d.) (provided that the dose refers to the free base anhydride of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride), and treating extravascular hemolysis (EVH) comprises increasing the hemoglobin level in the subject by 2 g / dL or more compared to the hemoglobin level in the subject before administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof; the pharmaceutical composition.

11. The pharmaceutical composition according to claim 10, wherein treating extravascular hemolysis (EVH) comprises increasing the hemoglobin level in the subject in the absence of one or more red blood cell (RBC) transfusions. **Claim 12**: The treatment of extravascular hemolysis (EVH) involves reducing the level of bilirubin or reticulocytes, or increasing the level of haptoglobin, in the subject compared to the levels of bilirubin, reticulocytes, or haptoglobin in the subject before administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 10 or 11. **Claim 13**: The pharmaceutical composition according to claim 12, wherein the level of bilirubin or reticulocytes is reduced by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%. **Claim 14**: The pharmaceutical composition according to any one of claims 1 to 13, wherein the subject has been previously treated with anti-C5 therapy before administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof. **Claim 15**: The pharmaceutical composition according to claim 14, wherein the anti-C5 therapy is anti-C5 monoclonal antibody therapy. **Claim 16**: The pharmaceutical composition according to any one of claims 1 to 15, wherein the subject has residual anemia. **Claim 17**: The pharmaceutical composition according to claim 1, 6, or 10, wherein the hemoglobin level, haptoglobin level, reticulocyte level, and / or bilirubin level of the subject is evaluated before administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof. **Claim 18**: The pharmaceutical composition according to claim 17, wherein the hemoglobin level of the subject is 10 g / dL or less before administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof. **Claim 19**: The pharmaceutical composition according to claim 1, 6, or 10, wherein the method includes achieving a sustained increase in hemoglobin level. The pharmaceutical composition according to claim 1, 6 or 10, wherein the method comprises achieving a sustained increase in hemoglobin level of 12 g / dL or more. The pharmaceutical composition according to claim 1, 6 or 10, wherein the method comprises increasing the hemoglobin level in the subject in the absence of one or more red blood cell (RBC) transfusions. The pharmaceutical composition according to claim 1, 6 or 10, wherein the subject has received a red blood cell (RBC) transfusion. The pharmaceutical composition according to claim 1, 6 or 10, wherein the subject has been previously vaccinated against Neisseria meningitidis (serogroups A, C, Y, and W-135) prior to administration of 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to claim 1, 6 or 10, wherein the effectiveness of the treatment is determined by measuring the hemoglobin level in the subject as compared to the baseline.

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