Methods of using factor b inhibitors

Abstract

To provide a pharmaceutical composition for use in the treatment of paroxysmal nocturnal hemoglobinuria (PNH).SOLUTION: A pharmaceutical composition comprises the Factor B inhibitor LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to a factor B inhibitor, LNP023, or its derivatives, such as, for example, LNP023 hydrochloride. The pharmaceutically acceptable salts of the compound of formula (I) are useful in the treatment of complement disorders, particularly paroxysmal nocturnal hemoglobinuria (PNH). The present invention relates to a method for treating a driving disorder. [Background technology]

[0002] Paroxysmal nocturnal hemoglobinuria (PNH) is a condition characterized by complement-mediated intravascular hemolysis, bone marrow failure (B MF), and Risita, a rare acquired hemolytic disorder characterized by a severe thrombophilia. no AM(2012).Paroxysmal nocturnal hemoglo binuria and other complement-mediated he matological disorders.Immunology;217:108 0-1087). It is a phosphatidylinositol N-acetylglucosaminyltransferase. Clonal expansion of hematopoietic stem cells that have acquired somatic mutations in the PIGA gene. Starting with (Brodsky RA (2014) Paroxysmal nocturna l hemoglobinuria.Blood;124:2804-2811). As a result, PNH blood cells express glycosylphosphatidylinositol (GPI) anchors. They lack the protein and the membrane-bound complement inhibitory proteins CD55 and CD59. As a result, PNH-infected red blood cells (RBCs) are attacked by complement, leading to complement-mediated lysis. .

[0003] The clinical spectrum of PNH is diverse, with signs and symptoms including anemia, thrombosis, and smooth muscle Clinical symptoms include dystonia, fatigue, hemoglobinuria, chronic kidney disease, and pulmonary hypertension. The clinical manifestations are driven by uncontrolled complement activation on CD55- and CD59-deficient PNH RBCs. This leads to hemolysis and release of free hemoglobin, and platelet activation (Hill A, e t 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 N Inhibition of O synthesis, resulting in vasoconstriction and tissue ischemia, can lead to abdominal pain, dysphagia, erectile dysfunction, It causes platelet activation and a prothrombotic state (Hill et al. 2013, B Thromboembolism is a major cause of morbidity and mortality in patients with PNH. It can occur anywhere; venous is more common (80-85%), but arterial Sometimes (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 (derived from eculizumab with extended dosing intervals) (C5) is the only approved anti-C5 antibody therapy for treating PNH and is the current standard available. It is semi-therapeutic (SoC). Summary of the Invention [Problem to be solved by the invention]

[0005] Anti-C5 antibody therapy is generally effective in treating intravascular hemolysis (IVH), but its efficacy in treating PNH is unclear. There remains a high unmet medical need for eculizumab. Heterogeneous hematologic responses and a significant proportion of patients had normal or near-normal hemoglobin levels reported that the level was not achieved (Risitano AM, et al (2009) C omplement fraction 3 binding on erythroc ytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria p patients 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 extravasculum 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;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). The heterogeneous response to eculizumab or other anti-C5 antibody therapies may be due to the progression of the complement cascade. This can be explained in part by its mechanism of action, which inhibits only the end portion of CD5. Deposition of C3 fragments on the cell surface of PNH-type erythrocytes lacking 5 was unaffected, and Extracellular hemolysis is the main cause of hemolysis in patients treated with eculizumab. This may be an important mechanism (Risitano et al. 2009), and C3-mediated extravascular lysis Blood represents an unmet medical need.

[0006] LNP023 is a novel oral small molecule compound that inhibits factor B (FB) and is a potential treatment for PNH. Factor B (FB) is a key component of the alternative complement pathway (AP). Oral LNP023 or its pharmaceutical forms, such as LNP023 hydrochloride, Inhibition of FB by acceptable salts may prevent both intravascular and extravascular hemolysis. Therefore, it offers therapeutic benefits beyond the current standard of care (SoC). This administration route offers advantages to patients compared to the current intravenous administration route of SoC. [Means for solving the problem]

[0007] The present disclosure provides a method for the preparation of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. These salts are used to treat complement-driven disorders, particularly paroxysmal nocturnal hemoglobinuria (PNH). LNP023 belongs to the class of factor B inhibitors of the complement pathway, and acts as a primary inhibitor of activation. Regardless of the mechanism of action, it inhibits or suppresses the amplification of the complement system caused by C3 activation. LNP023 hydrochloride acts by inhibiting paroxysmal nocturnal hemoglobinuria (P LNP023 hydrochloride is chemically a 4- ((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indo It is called (methyl-4-yl)methyl)piperidin-2-yl)benzoic acid hydrochloride and has the following chemical formula: It can be represented by the following grammatical structure: [ka]

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

[0009] In one aspect, the present disclosure provides a method for treating paroxysmal nocturnal syndrome in a subject, e.g., a patient in need thereof. The present invention provides a method for treating parahemoglobinuria (PNH), the method comprising administering a dose of 100 mg of parahemoglobin to a subject, for example, about every 12 hours. LNP023 or, e.g., LNP023, at a dose of approximately 200 mg twice daily (bid), A pharmaceutically acceptable salt thereof, such as the hydrochloride salt, is orally administered to a subject, such as a patient. thereby treating a subject, e.g., a patient (wherein the dosage is NP023 hydrochloride anhydrous free base), so that a subject, e.g., a patient, can be 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 for treating hemolysis, the method comprising administering an oral dose twice daily (bi), such as about every 12 hours. d.) at a dose of about 200 mg of LNP023 or its derivatives, such as 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 water free base), thereby treating a subject, e.g., a patient.

[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 intravenous hemolysis (IVH) and / or extravascular hemolysis (EVH), the method comprising, for example, For example, LNP023 is administered at a dose of approximately 200 mg twice daily (bid), such as approximately every 12 hours. or orally administering a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, to a subject. (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 present disclosure provides a method for reducing the incidence of PNH-associated hemolysis in a patient population. and the method comprises administering about 200 mg twice daily (bid), e.g., about every 12 hours. LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, at a dose of 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 for treating intravascular lysis in a subject, e.g., a patient in need thereof. The present invention provides a method for treating IVH, such as suppressing IVH, the method comprising, for example, administering a steroid to a subject in need of treatment for about 12 days. LNP023 or e.g., at a dose of approximately 200 mg twice daily (bid), e.g., every hour orally administering to a subject a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. (where the dosage refers to the anhydrous free base of LNP023 hydrochloride), so that, e.g. For example, a subject, such as a patient, is treated.

[0014] In another aspect, the present disclosure provides a method for treating extravascular vascular disease in a subject, e.g., a patient in need thereof. The present invention provides a method for treating EVH, such as suppressing EVH, the method comprising, for example, administering a steroid to a subject in need of treatment for about 12 hours. LNP023 or e.g., at a dose of approximately 200 mg twice daily (bid), e.g., every hour orally administering to a subject a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. (where the dosage refers to the anhydrous free base of LNP023 hydrochloride), so that, e.g. For example, a subject, such as a patient, is treated.

[0015] In another aspect, the present disclosure provides a method for treating hemoglobin in a subject, e.g., a patient in need thereof. The present invention provides a method for normalizing bin levels, the method comprising administering bin levels twice daily (b), for example, about every 12 hours. LNP023 or, for example, LNP023 hydrochloride, at a dose of about 200 mg of orally administering to a subject a pharmaceutically acceptable salt thereof, wherein the dosage is , which refers to the anhydrous free base of LNP023 hydrochloride), resulting in Hemoglobin levels are normalized.

[0016] In another aspect, the present disclosure provides a method for reducing C3 deposition in a subject in need thereof. The method provides, for example, about 200 mg twice daily (bid), such as about every 12 hours. LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose to a subject, e.g., a patient, wherein the dose is 023 hydrochloride anhydrous free base), resulting in, for example, C3 Deposition is reduced.

[0017] In another aspect, the present disclosure provides a method for treating, e.g., a pulmonary artery disease, in a subject, e.g., a patient in need thereof. and a method for increasing red blood cell (RBC) viability, such as increasing RBC lifespan. The method may involve administering, for example, at a dose of about 200 mg twice daily (bid), such as about every 12 hours. , LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. wherein the dosage is an anhydrous free base of LNP023 hydrochloride. ), resulting in increased RBC survival in a subject, e.g., a patient.

[0018] In another aspect, the present disclosure provides a method for treating a pulmonary artery disease, e.g., a pulmonary artery disease, in a subject, e.g., a patient in need thereof.

[0013] Methods for inhibiting the alternative complement pathway, such as sustained inhibition, are provided, for example, by administering a medicament containing a compound to a subject about every 12 hours. and the like, at a dose of about 200 mg twice daily (bid), LNP023 or e.g., LN orally administering to the subject a pharmaceutically acceptable salt thereof, such as P023 hydrochloride. (where the dosage refers to the anhydrous free base of LNP023 hydrochloride), resulting in, for example, The alternative complement pathway is suppressed in subjects such as those with HIV.

[0019] In another aspect, the present disclosure provides a method for detecting a fragment in a subject, e.g., a patient in need thereof. The present invention provides a method for reducing cerebrospinal fluid (CEF) levels, the method comprising administering CEF twice daily, e.g., about every 12 hours. (bid) at a dose of about 200 mg of LNP023 or, for example, LNP023 hydrochloride orally administering to a subject a pharmaceutically acceptable salt thereof, such as a pharmaceutically acceptable salt thereof, The amount refers to the anhydrous free base of LNP023 hydrochloride), so that a subject, e.g., a patient The fragment Bb in is reduced.

[0020] The methods of treatment described herein involve administering LNP023 or its derivatives, such as, for example, LNP023 hydrochloride. Various evaluation steps may be performed prior to and / or following treatment with a pharmaceutically acceptable salt of In one embodiment, LNP023 or, for example, LNP023 hydrochloride may be used. The method comprises measuring PK and PD parameters before and / or after administration of the pharmaceutically acceptable salt thereof. (e.g., LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride) The method further comprises assessing the plasma concentration of sC5B, C3, fragment Bb, or sC5B. The evaluation may be carried out by analyzing a sample of a body fluid, such as blood or plasma, for example, by mass spectroscopy, such as LC-MS. This may be achieved by analyzing a sample of the fluid. [Brief explanation of the drawings]

[0021] [Figure 1] A schematic diagram of the study design is shown. [Figure 2-1] Figure 2: Schedule of assessments during the randomized treatment period. [Figure 2-2] (As mentioned above.) [Figure 3] This is a table showing the evaluation schedule during the extension period. DETAILED DESCRIPTION OF THE INVENTION

[0022] Described herein are methods for treating patients with C5-associated leukemia who present with residual anemia despite treatment with anti-C5 therapy. , LNP023 or a pharmaceutical formulation thereof, such as LNP023 hydrochloride, in patients with PNH. This is a Phase III clinical trial to determine the safety and efficacy of commercially acceptable salts. Therefore, described herein are methods for treating PNH in a patient in need thereof. and the method includes administering LNP023 twice daily, e.g., about every 12 hours, or LNP0 A pharmaceutically acceptable salt thereof, such as the hydrochloride salt of 23, is orally administered to a patient in capsule form, for example. (wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride). Also described herein are methods for selecting a target patient population, monitoring the treatment of a target patient population, and and methods for evaluating the safety and efficacy of treatments in target patient populations.

[0023] Details of the disclosure are set forth in the accompanying description below. Although similar or equivalent methods and materials can be used in the practice or testing of this disclosure, exemplary methods and materials are described in detail below. Other features, objects, and advantages of the present disclosure are set forth in the description and claims. It will be clear from the scope of the specification and the accompanying claims that the context requires exceptions. Unless expressly stated otherwise, the singular also includes the plural. All technical and scientific terms used herein are understood by those skilled in the art to which this invention belongs. All patents and publications referred to herein have the same meaning as commonly understood by those skilled in the art. are incorporated herein by reference in their entireties.

[0024] definition Unless specific definitions are provided, analytical chemistry, synthetic organic chemistry, and pharmaceuticals described herein The nomenclature used in connection with, and the procedures and techniques used in, product chemistry are well known in the art. Standard methods were used for chemical synthesis and chemical analysis. Certain such techniques and procedures may be found, for example, in the US Pat. No. 6,499,499, incorporated herein by reference for all purposes. "Remington's Pharmaceuticals S.A.," incorporated herein by reference. sciences,” Mack Publishing Co., Easton, Pa., 21st edition, 2005. Where permitted, this All patents, applications, published applications, and other publications, and other materials cited throughout the disclosure The data are incorporated herein by reference in their entirety.

[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 agent to an individual. These include, but are not limited to, administration by a healthcare professional and self-administration. Administration of a pharmaceutical agent to an individual may be continuous, chronic, short-term, or intermittent.

[0027] As used herein, "acquire" or "take" The term "acquiring" refers to "directly obtaining" or "obtaining" a physical entity or value. By "indirectly obtaining" a physical entity (e.g., a blood sample or plasma sample) "Direct acquisition" refers to taking ownership of a data sample (e.g., a sample of data) or a value (e.g., a numerical value). "To perform" means to perform a process (e.g., an analytical method) to obtain a physical entity or value. "Indirectly acquired" means acquired through another party or source (e.g., a physical entity). This refers to receiving a physical entity or value from a third-party laboratory (or a third-party laboratory from which the value was obtained directly). Direct acquisition includes analytical processes that involve physical changes to a substance, e.g., a sample. For example, by mass spectrometry such as LC-MS, e.g., LC-MS / MS methods. By analyzing a sample of a body fluid such as blood, analytical methods such as those described herein can be performed. This includes performing a process that involves a physical change in a sample or another substance, such as performing a do.

[0028] As used herein, a "dose" refers to a dose provided in a single administration or within a specified period of time. , refers to a predetermined amount of a pharmaceutical agent. In certain embodiments, the dose may be administered in a capsule. As used herein, dosages refer to the anhydrous free base of LNP023 hydrochloride.

[0029] As used herein, an "individual," "patient," "participant," or "subject" refers to a person or entity involved in a treatment or therapy. By "therapeutic agent" is meant a human selected for therapy.

[0030] As used herein, "pharmaceutically acceptable salts" refers to salts that are compatible with the physiological and pharmaceutical properties of LNP023. and pharmaceutically acceptable salts, i.e., salts that retain the desired biological activity of LNP023 and are compatible with the desired "Pharmaceutically acceptable salt" or "salt" means a salt that does not have rare toxicological effects. The term "aliphatic acid" includes pharmaceutically acceptable non-toxic acids, including inorganic or organic acids and bases. A "pharmaceutically acceptable salt" of LNP023 includes salts prepared from acids or bases. They may be prepared by methods well known in the art. Review of Pharmaceutically Acceptable Salts For more information, see Stahl and Wermuth, Handbook of Pharmacology. 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

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

[0032] Unless otherwise specified, conventional definitions of terms are provided for all chemical formulas and groups. The future stable valence is estimated 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 element. ent) means one element or more than one element.

[0034] How to use Provided herein are methods for treating seizures 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 A pharmaceutically acceptable salt thereof, such as P023 hydrochloride, is orally administered to a subject, such as a patient. (wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride), As a result, the subject, e.g., a patient, is treated.

[0035] In one embodiment, a subject, eg, a patient, is being treated with an anti-C5 therapy.

[0036] In one embodiment, a subject, e.g., a patient, receives LNP023 or e.g., LNP023 anti-C for at least about 8 months prior to administration of a pharmaceutically acceptable salt thereof, such as the hydrochloride salt. 5 has been treated with therapy.

[0037] In one embodiment, a subject, e.g., a patient, receives LNP023 or e.g., LNP023 anti-C for at least about 6 months prior to administration of a pharmaceutically acceptable salt thereof, such as the hydrochloride salt. 5 has been treated with 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, the subject, eg, the patient, has residual anemia.

[0041] In one embodiment, a subject, e.g., a patient, receives LNP023 or e.g., LNP023 have been vaccinated prior to treatment with a pharmaceutically acceptable salt thereof, such as the hydrochloride salt.

[0042] In one embodiment, a subject, e.g., a patient, is treated with Neisseria meningitidis prior to treatment. Neisseria meningitidis (types A, C, Y and W-135) have been vaccinated against.

[0043] In one embodiment, treating PNH comprises one or more red blood cell (RBC) transfusions. In the absence of And so it happens.

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

[0045] In one embodiment, the hemoglobin level in a subject, e.g., a patient, is determined by measuring the hemoglobin level of LNP02. 3 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, do.

[0046] In one embodiment, the hemoglobin level, haptoglobin level, etc. of a subject, e.g., a patient, The blood glucose level, reticulocyte levels, and / or bilirubin levels are measured using a combination of LNP023 hydrochloride and its analogs. The pharmaceutically acceptable salt is evaluated prior to administration.

[0047] In one embodiment, the hemoglobin level of a subject, e.g., a patient, is measured using LNP023 or For example, about 12 g of LNP023 before treatment with a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. / dL, less than about 11.5g / dL, less than about 11g / dL, less than about 10.5g / 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.

[0048] In one embodiment, the hemoglobin level of a subject, e.g., a patient, is measured using LNP023 hydrochloride. It is about 10 g / dL or less before salt administration.

[0049] In one embodiment, e.g., compared to baseline, e.g., LNP023 or e.g., and hemoglobin levels before treatment with a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. Hemoglobin levels in a subject, such as a patient, compared to a control, such as a patient, are increased by administration of LNP023 or, e.g., , for example, about 1 g after treatment with a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. / dL or more, about 1.5g / dL 2g / dL, about 2.5g / dL or more, or about 3g / dL Increase by more than.

[0050] In one embodiment, e.g., compared to baseline, e.g., LNP023 or e.g., and hemoglobin levels before treatment with a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. For example, hemoglobin levels in subjects such as patients are approximately 2 g / dL or higher compared to Increased upward.

[0051] In one embodiment, treating PNH includes, for example, reducing intravascular lysis in a subject, such as a patient. Normalizing intravenous hemolysis (IVH) and / or extravascular hemolysis (EVH). In this condition, normalizing IVH and / or EVH hemolysis may be achieved, for example, by reducing hemolysis compared to baseline. For example, LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. haptoglobin, reticulocytes, or Haptoglobin levels in a subject, e.g., a patient, compared to bilirubin levels including increasing blood glucose levels, decreasing reticulocyte levels, or decreasing bilirubin levels. And so it happens.

[0052] In one embodiment, treating PNH does not include treating PNH-associated hemolysis. do.

[0053] In one embodiment, treating PNH includes, for example, reducing C3 deposition in a subject, such as a patient. In one embodiment, C3 deposition is measured by, for example, reducing the C3 deposition from baseline to In comparison, for example, LNP023 or its pharmaceutically acceptable salts, such as LNP023 hydrochloride. compared to the level of C3 deposition in a subject, e.g., a patient, prior to administration of the tolerable salt, 30%, approx. 35%, approx. 40%, approx. 45%, approx. 50%, approx. 55%, approx. 60%, approx. 65%, approx. 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or about 99% is reduced.

[0054] In one embodiment, treating PNH refers to, for example, reducing red blood cell ( RBC) survival.

[0055] In one embodiment, treating PNH includes, for example, complement replacement in a subject, such as a patient. Inhibiting a pathway.

[0056] In one embodiment, treating PNH includes, for example, reducing fragmentation in a subject, such as a patient. The method comprises reducing cerebrospinal fluid (CEF) levels.

[0057] In one embodiment, treating PNH can be, for example, reducing a patient's PNH risk by, for example, increasing a patient's PNH risk compared to baseline. , administration of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride Compared to a previous hemoglobin level in a subject, e.g., a patient, e.g., and increasing hemoglobin levels in the subject by, for example, about 2 g / dL or more. become.

[0058] In one embodiment, treating PNH comprises a sustained increase in hemoglobin levels. In one embodiment, treating PNH comprises achieving a blood glucose level of about 10 g / d More than about 10.5 g / dL, more than about 11 g / dL, more than about 11.5 g / dL greater than about 12 g / dL, greater than about 12.5 g / dL, or greater than about 13 g / dL In one embodiment, the method comprises achieving a sustained increase in hemoglobin levels. Treating PNH is characterized by a persistent hemoglobin level of about 12 g / dL or higher. achieving an increase.

[0059] In one embodiment, treating PNH is achieved by administering, to a patient, a compound, or both, e.g., LNP023 or, e.g., LNP For example, hemoglobin levels in patients prior to treatment with a pharmaceutically acceptable salt thereof, such as the hydrochloride salt. Compared with globin levels, approximately 1.5 g / dL or more and approximately 2 g / dL or more from baseline , 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 , a persistent hemoglobin level of about 4.5 g / dL or greater, or about 5 g / dL or greater achieving an increase.

[0060] In one embodiment, treating PNH is achieved by administering, to a patient, a compound, or both, e.g., LNP023 or, e.g., LNP For example, hemoglobin levels in patients prior to treatment with a pharmaceutically acceptable salt thereof, such as the hydrochloride salt. Compared with baseline hemoglobin levels, a hemoglobin level of approximately 2 g / dL or more achieving a sustained increase in

[0061] In one embodiment, the increase in hemoglobin levels is due to the administration of LNP023 or, e.g., LNP02 about 1 week, about 2 weeks, about 3 weeks after administration of a pharmaceutically acceptable salt thereof, such as the trihydrochloride salt , after about 4 weeks, after about 6 weeks, after about 8 weeks, after about 10 weeks, after about 12 weeks, after about 14 weeks, Maintained after about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, or about 24 weeks can be.

[0062] In one embodiment, the increase in hemoglobin levels is due to the administration of LNP023 or, e.g., LNP02 The effect is maintained after approximately 18 to 24 weeks of administration of a pharmaceutically acceptable salt thereof, such as the trihydrochloride salt.

[0063] In one embodiment, the increase in hemoglobin levels is due to the administration of LNP023 or, e.g., LNP02 The effect is maintained after about 18 or 24 weeks of administration of a pharmaceutically acceptable salt thereof, such as the trihydrochloride salt.

[0064] In one embodiment, the efficacy of treatment is assessed, e.g., as compared to baseline, e.g., LNP or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. For example, the hemoglobin level in a subject, such as a patient, may be compared to, for example, This is determined by measuring hemoglobin levels in the blood.

[0065] In one embodiment, hemoglobin levels are measured using, for example, LNP023 or, for example, LNP0 in a subject, e.g., a patient, prior to administration of a pharmaceutically acceptable salt thereof, such as 23 hydrochloride. Compared to hemoglobin levels: about 1.5 g / dL or more, about 2 g / dL or more, and about 2.5 g / dL or more, about 3g / dL or more, about 3.5g / dL or more, about 4g / dL or more, about 4.5g / dL or more, or an increase of about 5 g / dL or more.

[0066] In one embodiment, hemoglobin levels are measured, e.g., compared to baseline, e.g., Prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. For example, the hemoglobin level in a subject, such as a patient, increases by about 2 g / dL or more. Add.

[0067] 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 intravenous hemolysis (IVH) and / or extravascular hemolysis (EVH), the method comprising, for example, For example, patients may receive a dose of about 200 mg twice daily (bid), such as about every 12 hours. orally administering LNP023 hydrochloride to a subject, such as a subject in need thereof, refers to the anhydrous free base of NP023 hydrochloride), resulting in, e.g., IVH and / or EVH are normalized.

[0068] In one embodiment, a subject, e.g., a patient, has or is diagnosed with PNH. It has been done.

[0069] In one embodiment, normalizing IVH and / or EVH hemolysis can be achieved by, for example, baseline Compared to LNP023 or its pharmaceutical forms, such as LNP023 hydrochloride, haptoglobin, reticulitis, and the like in a subject, e.g., a patient, prior to administration of a physiologically acceptable salt. haptoglobin levels in a subject, e.g., a patient, compared to blood cell or bilirubin levels. Increases blood reticulocyte levels, decreases reticulocyte levels, or decreases bilirubin levels The present invention relates to a method for manufacturing a semiconductor device.

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

[0071] In one embodiment, the bilirubin or reticulocyte levels are increased by about 10%, about 15%, about 20%, or %, approx. 25%, approx. 30%, approx. 35%, approx. 40%, approx. 45%, approx. 50%, approx. 55%, approx. 60 %, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% reduction.

[0072] In one embodiment, the haptoglobin level, reticulocyte count, and the like in a subject, e.g., a patient, are measured. The level, or bilirubin level, is obtained by analyzing a sample of a body fluid such as blood or plasma. will be done.

[0073] 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 for treating hemolysis, the method comprising administering an oral dose twice daily (bi), such as about every 12 hours. d.) at a dose of about 200 mg of LNP023 or its derivatives, such as LNP023 hydrochloride. orally administering to a subject, e.g., a patient, a pharmaceutically acceptable salt of The dosage here refers to the anhydrous free base of LNP023 hydrochloride), so that, e.g., Which subject is being treated?

[0074] In one embodiment, PNH-associated hemolysis is a breakthrough hemolysis, e.g., as defined in Table 2. Hemolysis (BTH).

[0075] In another aspect, the present disclosure provides a method for reducing the incidence of PNH-associated hemolysis in a patient population. and the method comprises administering about 200 mg twice daily (bid), e.g., about every 12 hours. LNP023, or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, at a dose of or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, orally administering to a subject, such as a subject, an amount of LNP023 hydrochloride free, refers to the water free base), resulting in a reduced incidence.

[0076] In one embodiment, PNH-associated hemolysis is a breakthrough hemolysis, e.g., as defined in Table 2. Hemolysis (BTH).

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

[0078] 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 treating IVH, such as suppressing IVH, the method comprising, for example, administering a steroid to a subject in need of treatment for about 12 days. LNP023 or e.g., at a dose of approximately 200 mg twice daily (bid), e.g., every hour orally administering a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to a subject, such as a patient. (wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride) ), thereby treating a subject, e.g., a patient.

[0079] In one embodiment, a subject, e.g., a patient, has or is diagnosed with PNH. It has been done.

[0080] In one embodiment, treating IVH, e.g., controlling IVH, includes, e.g., Compared to baseline, e.g., LNP023 or e.g., LNP023 hydrochloride compared to the level of LDH in a subject, such as a patient, prior to administration of a pharmaceutically acceptable salt thereof. , e.g., reducing the level of lactate dehydrogenase (LDH) in a subject, e.g., a patient. It comprises:

[0081] In one embodiment, the LDH level in a subject, e.g., a patient, is measured using a serotonin receptor agonist (SLAM) in blood or plasma, e.g., It is obtained by analyzing a sample of body fluids.

[0082] In one embodiment, the LDH level in a subject, e.g., a patient, is 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 In one embodiment, the LDH level in a subject, e.g., a patient, is reduced by at least 80%. at least about 50%, at least about 55%, at least about 60%, at least about 65%, or In one embodiment, the LD in a subject, e.g., a patient, is reduced by at least about 70%. H levels are reduced by at least about 60%.

[0083] In another aspect, the present disclosure provides a method for treating extravascular vascular disease in a subject, e.g., a patient in need thereof. The present invention provides a method for treating EVH, such as suppressing EVH, the method comprising, for example, administering a steroid to a subject in need of treatment for about 12 hours. LNP023 or e.g., at a dose of approximately 200 mg twice daily (bid), e.g., every hour orally administering a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to a subject, such as a patient. (wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride) ), thereby treating a subject, e.g., a patient.

[0084] In one embodiment, a subject, e.g., a patient, has or is diagnosed with PNH. It has been done.

[0085] In one embodiment, the treatment of EVH, e.g., controlling EVH, is achieved by administering a therapeutically effective amount of EVH to a patient, e.g., by administering a therapeutically effective amount of EVH to a patient. reducing bilirubin or reticulocyte levels in a subject, or Compared to threonine, LNP023 or its pharmaceutical equivalents, such as LNP023 hydrochloride, For example, bilirubin or reticulocyte levels in a subject, such as a patient, prior to administration of an acceptable salt. The method comprises increasing the level of haptoglobin compared to normal control.

[0086] In one embodiment, the bilirubin or reticulocyte levels are increased by about 10%, about 15%, about 20%, or %, approx. 25%, approx. 30%, approx. 35%, approx. 40%, approx. 45%, approx. 50%, approx. 55%, approx. 60 %, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% reduction.

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

[0088] In one embodiment, the method comprises measuring bilirubin, reticulocytes, or haptoglobin in a subject, e.g., a patient. The value of the globin level is obtained by analysis of a sample of a body fluid such as blood or plasma. .

[0089] In another aspect, the present disclosure provides a method for treating hemoglobin in a subject, e.g., a patient in need thereof. The present invention provides a method for normalizing bin levels, the method comprising administering bin levels twice daily (b), for example, about every 12 hours. LNP023 or, for example, LNP023 hydrochloride, at a dose of about 200 mg of and administering orally to a subject, such as a patient, a pharmaceutically acceptable salt thereof. (where dosage refers to the anhydrous free base of LNP023 hydrochloride), resulting in, for example, Hemoglobin levels are normalized in a subject, such as a patient.

[0090] In one embodiment, the hemoglobin level is greater than about 10 g / dL, about 10.5 g / dL greater than about 11 g / dL, greater than about 11.5 g / dL, greater than about 12 g / dL, Normalized to above 12.5 g / dL or above about 13 g / dL.

[0091] In one embodiment, hemoglobin levels are normalized to about 12 g / dL or greater.

[0092] In one embodiment, a subject, e.g., a patient, has or is diagnosed with PNH. It has been done.

[0093] In one embodiment, normalizing hemoglobin levels occurs in the absence of red blood cell transfusions. can be.

[0094] In another aspect, the present disclosure provides a method for detecting C3 deposition in a subject, e.g., a patient in need thereof. The method includes administering the drug twice daily (bid), such as about every 12 hours. ) at a dose of about 200 mg, LNP023 or its derivatives, such as LNP023 hydrochloride orally administering a physiologically acceptable salt to a subject, e.g., a patient, Dosage refers to the anhydrous free base of LNP023 hydrochloride), resulting in patients e.g. The subject is treated.

[0095] In one embodiment, a subject, e.g., a patient, has or is diagnosed with PNH. It has been done.

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

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

[0098] In another aspect, the present disclosure provides a method for improving erythropoiesis in a subject, e.g., a patient in need thereof. The present invention provides a method for increasing survival rates, the method comprising administering the drug twice daily (bi), such as about every 12 hours. d.) at a dose of about 200 mg of LNP023 or its derivatives, such as LNP023 hydrochloride. orally administering to a subject, e.g., a patient, a pharmaceutically acceptable salt of The dosage here refers to the anhydrous free base of LNP023 hydrochloride), so that, e.g., Which subject is being treated?

[0099] In one embodiment, a subject, e.g., a patient, has or is diagnosed with PNH. It has been done.

[0100] In another aspect, the present disclosure provides a method for treating a pulmonary artery disease, e.g., a pulmonary artery disease, in a subject, e.g., a patient in need thereof.

[0010] Methods for inhibiting the alternative complement pathway, such as achieving sustained inhibition, are provided, the methods comprising, for example, administering a compound comprising: LNP023 or e.g., at a dose of approximately 200 mg twice daily (bid), e.g., every 12 hours. For example, administering a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, to a subject, such as a patient. orally administering the anhydrous free base of LNP023 hydrochloride refers to the treatment of a subject, e.g., a patient, thereby treating the subject.

[0101] In one embodiment, a subject, e.g., a patient, has or is diagnosed with PNH. It has been done.

[0102] In one embodiment, sustained inhibition of the alternative complement pathway is achieved by administering LNP023 or, e.g., LNP02 about 1 week, about 2 weeks, about 3 weeks after administration of a pharmaceutically acceptable salt thereof, such as the trihydrochloride salt , after about 4 weeks, after about 6 weeks, after about 8 weeks, after about 10 weeks, after about 12 weeks, after about 14 weeks, Achieved after about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, or about 24 weeks can be.

[0103] In one embodiment, sustained inhibition of the alternative complement pathway is achieved by administering LNP023 or, e.g., LNP02 This is achieved after approximately 18 to 24 weeks of administration of a pharmaceutically acceptable salt thereof, such as the trihydrochloride salt.

[0104] In one embodiment, sustained inhibition of the alternative complement pathway is achieved by administering LNP023 or, e.g., LNP02 This is achieved after about 18 or 24 weeks of administration of a pharmaceutically acceptable salt thereof, such as the trihydrochloride salt.

[0105] In another aspect, the present disclosure provides a method for detecting a fragment in a subject, e.g., a patient in need thereof. The present invention provides a method for reducing cerebrospinal fluid (CBP) Bb, the method comprising administering CBP twice daily (bi 100 mg / kg / day), for example, about every 12 hours. .d.) at a dose of about 200 mg, LNP023 or, for example, LNP023 hydrochloride orally administering a pharmaceutically acceptable salt thereof to a subject, such as a patient. The dosage here refers to the anhydrous free base of LNP023 hydrochloride), so that, e.g., patients The fragment Bb in the subject is reduced.

[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 pharmaceutically 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 A pharmaceutically acceptable salt thereof, such as P023 hydrochloride, is orally administered to a subject, such as a patient. (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. LN for use in the treatment of, for example, the suppression of intravenous hemolysis (IVH) and / or extravascular hemolysis (EVH). and providing P023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, to treat Treatment is typically administered at a dose of approximately 200 mg twice daily (bid), e.g., approximately every 12 hours. NP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, can be administered by, 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, a subject, e.g., a patient, has or is diagnosed with PNH. It has been done.

[0111] In another aspect, the present disclosure provides a method for treating PNH-related disorders in a subject, e.g., a patient in need thereof. LNP023 or a salt thereof, such as, for example, LNP023 hydrochloride, for use in the treatment of hemolysis. A pharmaceutically acceptable salt is provided and treatment is administered, for example, twice daily (bi), such as about every 12 hours. d.) at a dose of about 200 mg of LNP023 or its derivatives, such as LNP023 hydrochloride. orally administering to a subject, e.g., a patient, a pharmaceutically acceptable salt of The dosage here refers to the anhydrous free base of LNP023 hydrochloride), so that, e.g., Which subject is being treated?

[0112] In another aspect, the present disclosure provides a method for treating paroxysmal night sickness in a subject, e.g., a patient in need thereof. in the manufacture of a medicament for treating paroxysmal hemoglobinuria (PNH), For example, the present invention provides the use of a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, in which the treatment comprises: For example, at a dose of approximately 200 mg twice daily (bid), such as approximately every 12 hours, LNP0 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, can be administered to, for example, a patient. orally administering to a subject, (referring to the free base), thereby treating a subject, e.g., a patient.

[0113] In another aspect, the present disclosure provides a method for treating, for example, a rheumatoid arthritis in a subject, e.g., a patient in need thereof. Drugs for the treatment of intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, in the manufacture of Treatment is typically administered twice daily (bid), for example, approximately every 12 hours. ) at a dose of about 200 mg, LNP023 or its derivatives, such as LNP023 hydrochloride orally administering a physiologically acceptable salt to a subject, e.g., a patient, Dosage refers to the anhydrous free base of LNP023 hydrochloride), resulting in patients e.g. IVH and / or EVH in the subject is normalized.

[0114] In one embodiment, a subject, e.g., a patient, has or is diagnosed with PNH. It has been done.

[0115] In another aspect, the present disclosure provides a method for treating PNH-related disorders in a subject, e.g., a patient in need thereof. LNP023 or, e.g., a salt of LNP023, in the manufacture of a medicament for treating hemolysis. and the like, wherein the treatment is, for example, about every 12 hours. LNP023 or, e.g., LNP023, at a dose of approximately 200 mg twice daily (bid), A pharmaceutically acceptable salt thereof, such as the hydrochloride salt, is orally administered to a subject, such as a patient. (wherein the dosage refers to the anhydrous free base of LNP023 hydrochloride), As a result, the subject, e.g., a patient, is treated.

[0116] Patient Selection and Monitoring In a phase III study, patients treated with SoC (eculizumab or ravulizumab) experienced residual anemia, defined as hemoglobin below 10 g / dL, regardless of with or without regular red blood cell transfusions in the past 6 months, and Patients with PNH whose diagnosis was confirmed by endothelial growth factor (clone size ≥ 10%) were enrolled. PNH blood cells contain glycosylphosphatidylinositol (GPI) anchors. They lack the membrane-bound complement inhibitory proteins CD55 and CD59. The absence of these two GPI-APs, CD55 and CD59, leads to hemolysis and This leads to uncontrolled complement activation, which explains other manifestations of PNH. The rationale is that these patients have unmet medical needs despite SoC treatment. This is because it exhibits the following characteristics.

[0117] LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, may be used as a co-administrator. Thus, for example, a patient is first evaluated, e.g., determining whether the subject has GPI-AP deficient blood cells, e.g., peripheral blood cells. whereby a subject, such as a patient, receives LNP023 or, for example, LNP023 hydrochloride, A subject, such as a patient, may be selected for treatment with the pharmaceutically acceptable salt thereof. If a subject is determined to have GPI-AP deficient peripheral blood cells, the subject, e.g., a patient, may be administered L NP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is optionally It is administered selectively.

[0118] In one embodiment, sensitive flow cytometry is used to determine whether a patient has, for example, about two or more The above cell lines will be examined to determine whether they have GPI-AP-deficient peripheral blood cells.

[0119] In one embodiment, a subject, e.g., a patient, receives LNP023 or e.g., LNP023 The level of its pharmaceutically acceptable salts such as hydrochloride, the level of LDH, the level of hemoglobin By assessing specific PK / PD parameters such as PNH clone size and can be monitored.

[0120] Efficacy evaluation As used herein, at a dose of about 200 mg twice daily (bid), such as about every 12 hours, treated with LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. Also provided are methods for assessing the efficacy of a treatment in a selected patient population, the methods 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 effectiveness of the treatment; The compound may be LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. The hemoglobin levels in the patient population before administration of

[0121] In one embodiment, a sustained increase in hemoglobin levels from baseline, for example, The increases are approximately 1.5g / dL or more, approximately 2g / dL or more, approximately 2.5g / dL or more, and approximately 3g / 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, hemoglobin levels in patients prior to treatment with a pharmaceutically acceptable salt thereof, such as the hydrochloride salt. Increases, such as a sustained increase in hemoglobin levels compared with baseline levels, The average blood glucose level is approximately 2 g / dL or higher.

[0122] In one embodiment, the increase in hemoglobin levels is measured by, for example, LNP023 or For example, at least about 18 weeks after administration of a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. In one embodiment, the increase in hemoglobin level is maintained for a period of time, e.g., after LNP0 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, Both are maintained for approximately 24 weeks.

[0123] In one embodiment, the increase in hemoglobin levels is measured by administering LNP023 or, e.g., LN For at least about one month after administration of a pharmaceutically acceptable salt thereof, such as P023 hydrochloride, 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 for at least This will be maintained for at least 12 months.

[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 Approximately 99% of the compounds are LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. The hemoglobin level in the patient before treatment with the soluble salt is compared to, for example, The company has achieved increases such as sustained increases in its energy consumption levels.

[0125] In one embodiment, the patient has or has been diagnosed with PNH.

[0126] In another aspect, the present disclosure provides about 200 mg twice daily (bid), such as about every 12 hours. LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, at a dose of The present invention provides a method for assessing the efficacy of treatment in a salt-treated patient population, the method comprising, for example, For example, determine the percentage of the patient population that achieves a hemoglobin level of about 12 g / dL or greater, and and thereby assessing the effectiveness of the treatment.

[0127] In one embodiment, the patient has or has been diagnosed with PNH.

[0128] 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 Approximately 99% of the compounds are LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. The hemoglobin level in the patient before treatment with the soluble salt is compared to, for example, The company has achieved increases such as sustained increases in its energy consumption levels.

[0129] In one embodiment, the increase in hemoglobin levels is measured by, for example, LNP023 or For example, at least about 18 weeks after administration of a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. In one embodiment, the increase in hemoglobin level is maintained for a period of time, e.g., after LNP0 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, Both are maintained for approximately 24 weeks.

[0130] In one embodiment, the increase in hemoglobin levels is measured by administering LNP023 or, e.g., LN For at least about one month after administration of a pharmaceutically acceptable salt thereof, such as P023 hydrochloride, 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 for at least This will be maintained for at least 12 months. [Example]

[0131] This disclosure is not intended to be limited in scope or spirit to the specific procedures described herein. The present invention is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope of the present invention. The examples are provided to illustrate particular embodiments and thereby contribute to the scope of the present disclosure. It should be understood that no limitation is intended. Various other implementations may suggest themselves to those skilled in the art without departing from the scope of the claimed invention. It is further understood that forms, modifications and equivalents may have to be resorted to.

[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. Patients with PNH and residual anemia despite treatment with intravenous anti-C5 antibody To evaluate the efficacy and safety of LNP023 hydrochloride administered orally twice daily to adult patients A randomized, multicenter, active-controlled, open-label study to the purpose This phase I study was performed in patients with PNH who presented with residual anemia despite treatment with anti-C5 antibodies. The objective of the Phase II trial is to demonstrate the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy. To determine whether LNP023 hydrochloride is effective and safe for treating PNH. This Phase III study was a 24-week, randomized, active-controlled, open-label study. The study will have a 24-week open-label extension period and a 12-week follow-up period. Efficacy will be assessed in the absence of red blood cell transfusions. Proportion of participants achieving the following hemoglobin response criteria, as well as other hematologic response endpoints , transfusion avoidance, breakthrough hemolysis rate, and fatigue score (FACIT - fatigue, patient-reported prognosis questionnaire).

[0141] Results of analyses performed after the last participant completed the 24-week randomized treatment period showed: Form the basis of a data package for regulatory submission.

[0142] Primary Objectives and Evaluation Items The main objectives are: 1) Baseline hemoglobin level of 2 g / dL or higher in the absence of red blood cell transfusions in the proportion of participants achieving sustained gains from LN compared with anti-C5 antibody therapy Demonstrate the superiority of P023 hydrochloride, 2) Participants achieving a sustained Hb level of 12 g / dL or greater in the absence of red blood cell transfusions To demonstrate the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy in terms of the rate of progression-free survival.

[0143] Discontinuation of the study drug and occurrence of breakthrough hemolysis or major adverse vascular events (MAVEs) L at a dose of 200 mg bid in PNH patients with residual anemia regardless The efficacy of NP023 hydrochloride treatment was compared with anti-C5 antibody therapy. * An increase of 2 g / dL or more from baseline in Hb levels * Hb level of 12 g / dL or higher The endpoint is defined as a composite of the above and is assessed for the probability of becoming a responder. R, Both endpoints were assessed between days 126 and 168, and between days 14 and 168 (evaluated for not requiring red blood cell transfusions).

[0144] Secondary Objectives: Secondary objectives are: 1) Between Days 14 and 168, patients will be screened for packed red blood cells according to protocol-defined criteria. By assessing the proportion of participants who did not receive a blood transfusion, Percentage advantage of LNP023 hydrochloride compared with anti-C5 antibody therapy in avoiding blood transfusions To demonstrate; 2) Hemoglobin change from baseline to average visits between Days 126 and 168 The mean change in hemoglobin was assessed by assessing the change in anti-C5 Demonstrating the superiority of LNP023 hydrochloride compared to antibody therapy; 3) FACIT-Fatigue questionnaire was used as the average of visits between days 126 and 168. Fatigue was assessed by assessing the change from baseline in the FACIT-Fatigue score. To demonstrate the superiority of LNP023 hydrochloride compared to anti-C5 antibody therapy in improving sensitivity; 4) The mean of visits between Days 126 and 168 was the baseline reticulocyte count. Changes in (10 9 / L) in the mean change in reticulocyte count. 5 Demonstrate the superiority of LNP023 hydrochloride compared to antibody therapy; 5) Baseline LDH levels (U / L) as the average between visits 126 and 168 days Anti-C5 antibody in mean % change of LDH by assessing % change from line To demonstrate the superiority of LNP023 hydrochloride compared to chemotherapy; 6) Breakthrough hemolysis in participants with reported breakthrough hemolysis between Days 1 and 168 The rate of through-hemolysis (BTH) was significantly higher with LNP023 hydrochloride compared to anti-C5 antibody therapy. Demonstrating superiority; 7) MAVE (including thrombosis) of LNP023 hydrochloride occurring between Day 1 and Day 168 ) compared with anti-C5 antibody therapy.

[0145] Purpose of exploration The objectives of the exploration are as follows: 1) Safety, including adverse events / serious adverse events, safety test parameters, vital signs, etc. To assess the safety and tolerability of LNP023 compared to anti-C5 therapy using efficacy assessments ; 2) Anti-C5 on hematological parameters, units of RBC transfusion, and signs and symptoms of PNH To evaluate the efficacy of LNP023 compared to antibody therapy; hematological parameters (RBC, including haptoglobin), bilirubin levels, units of packed RBC transfusion, and PN H signs and symptoms were averaged across model-derived estimates for visits between days 126 and 168. Collected between days 1 and 168 by average; 3) Patient-reported overall fatigue severity and health-related quality of life were significantly improved with anti-C5 To evaluate the efficacy of LNP023 compared with antibody therapy; between days 126 and 168 Days 1–16 focused on comparing treatments on average estimates derived from the visit model. PGIS, EORTC QLQ-C30, and EQ-5D-5L collected during day 8 Changes in patient-reported outcome scores will be assessed; 4) Antibodies against C3 fragment deposition on PNH-type red blood cells and PNH clone size To evaluate the efficacy of LNP023 compared to C5 treatment; collected between days 1 and 168 The percentage of C3d-positive PNH red blood cells was determined, and PNH types II and III red blood cells were and total PNH clone size (percentage) of red blood cells collected between days 1 and 168. ; 5) To characterize the PK of LNP023 in the PNH population based on PK exposure data and 6) Medical supplies based on the occurrence of hospitalizations, readmissions, and emergency room visits between days 1 and 168 To evaluate the effect of LNP023 compared with anti-C5 therapy on resource utilization.

[0146] Study design This study was a multicenter, randomized, open-label, active-controlled, parallel-group study consisting of three periods. (See Figure 1). A screening period lasting up to 8 weeks (extending it to accommodate vaccinations required for enrollment) (unless it needs to be longer) A 24-week randomized, open-label, active-controlled, parallel-group study for primary efficacy and safety analyses Treatment duration 24-week open-label LNP023 hydrochloride treatment extension period The study included patients receiving anti-C5 antibody therapy (eculizumab or ravulizumab) for 6 months prior to randomization. defined as hemoglobin <10 g / dL despite a stable regimen of steroids (anticoagulants) Approximately 40% of participants had a residual anemia before randomization. Receiving at least one packed red blood cell transfusion in the past 6 months. A total of approximately 91 participants All participants will be informed of the study before commencing any study-related activities. Informed consent must be provided. The study design is shown in Figure 1.

[0147] Study design rationale The Phase III trial also included treatment with a stable regimen of anti-C5 antibody therapy (SoC). Hematological response parameters and fatigue incidence in PNH patients with residual anemia regardless of Comparison of 200mg b.i compared with intravenous anti-C5 antibody therapy on patient-reported outcome measures A multicenter, open-label, study to demonstrate the superiority of LNP023 hydrochloride at an oral dose of .d. It will be designed as a randomized, active-controlled, parallel-group study.

[0148] screening Patient eligibility will be determined prior to the start of the run-in period (based on assessments performed at Visit 1) Inclusion and exclusion criteria will be assessed to ensure participants are eligible to enroll in the study. The screening assessments are listed in Figure 2.

[0149] Participants must be vaccinated at the time of screening. Vaccines are available As many serotypes as possible (including meningococcal serotypes A, C, Y, W-135, and B) To minimize the burden on patients, locally available and current The use of multivalent vaccines in accordance with local guidelines and regulations is recommended (e.g., serogroup A N. meningitidis (N. meningitidis) covers 1, C, Y, and W-135. A quadrivalent vaccine for S. pneumoniae (S. pneumoniae) and 23 species of S. pneumoniae (S. pneumoniae) niae) serotypes covered by Pneumovax-23).

[0150] To meet hemoglobin eligibility criteria, participants were screened prior to randomization. Two types of samples collected during the period were tested at a central laboratory, and the average value was less than 10 g / dL. If the participant received an RBC transfusion after the initial sample collection, Eligibility is based on initial median hemoglobin level if it is less than 10 g / dL.

[0151] Participants who met the eligibility criteria at screening were asked to provide information on the type of prior anti-C5 antibody therapy (e.g., excretion, ulizumab or ravulizumab) and reported transfusion history in the 6 months prior to randomization (i.e., Approximately 100 randomized participants were randomized to receive a blood transfusion. 40% had received at least one packed red blood cell transfusion in the 6 months prior to randomization It is expected.

[0152] Randomization and randomized treatment period Participants will each receive LNP023 hydrochloride monotherapy at an oral dose of 200 mg bid. therapy (approximately 56 participants), or iv anti-C5 antibody therapy (randomized as before Approximately 35 participants will continue the same regimen during the standardized treatment period. Patients will be randomized in an 8:5 ratio to one of the treatment groups.

[0153] Treatment began on the first day of dosing (day 1) and continued for 24 weeks, with the schedule described in Figure 2. Study visits and corresponding evaluations will be conducted according to a schedule. Participants assigned to the comparison treatment group will Participants will receive the same type and regimen of anti-C5 antibody therapy as they received before randomization. Participants randomized to the LNP023 hydrochloride treatment group will continue to receive 200 mg of Patients will be initiated on LNP023 hydrochloride at a bid dose.

[0154] Some patients present with very low hemoglobin levels (e.g., less than 7 g / dL), As a result, red blood cell transfusions may be required within the first 2 weeks of the randomized treatment period. Therefore, transfusions administered within these first 2 weeks are not considered in the definition of transfusion avoidance. .

[0155] Extension period Participants randomized to the active comparator treatment group received anti-C5 (eculizumab or ravulizumab) LNP023 hydrochloride on day 168 (at the 24th week visit) after the final dose of antibody therapy The comparison treatment group did not agree to the treatment switch and entered an extended treatment period. For participants in this study, week 24 marks the end of the study visit and they will not participate in the extension period. For participants who agreed to switch to oral LNP023 hydrochloride, extended treatment was initiated at week 24. It begins the day after the examination is completed.

[0156] After switching to LNP023 hydrochloride, participants in the comparator treatment group were randomly assigned to Comply with study visits and evaluations according to the protocol.

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

[0158] Key inclusion criteria Eligible participants for this study must meet all of the following criteria: 1. Granulocytes / monocytes in RBCs and / or WBCs confirmed by high-sensitivity flow cytometry Male and female participants aged 18 years or older who were diagnosed with PNH with a globular clonality of 10% or more. 2. Anti-C5 antibody therapy (eculizumab or ravulizumab) for at least 6 months prior to randomization A stable regimen (dose and interval) of either Average hemoglobin level less than 3.10 g / dL 4. For at least 4 months prior to screening 5. Confirmed by central laboratory assessment during screening 6. Neisseria meningitidis Vaccination against infectious diseases is necessary before treatment begins. If the patient has not been previously vaccinated, If you have not received it or need a booster, the vaccine, if available, should be administered locally. According to regulations, the vaccine must be administered at least two weeks before the first dose. 7. If not previously received, if possible, obtain streptococcal vaccination in accordance with local regulations. Streptococcus pneumoniae and haemophilus For Haemophilus influenzae infection The vaccine must be administered after the first LNP023 hydrochloride dose. It must be administered at least two weeks before

[0159] Main exclusion criteria Participants who meet any of the following criteria are ineligible for this study: 1.Participants with a stable eculizumab dose but with 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 failure confirmed by laboratory tests (reticulocyte count 100 x 10 9 / L; platelets 30×10 9 / L; neutrophils 500 × 10 6 / L). 5. Active systemic bacterial, viral, or fungal infection within 14 days prior to administration of the study drug 6. Recurrent invasive infections caused by encapsulated organisms such as Neisseria meningitidis or Streptococcus pneumoniae History. 7. Any reason that, in the opinion of the investigator, would prevent the participant from participating in the study, including but not limited to: Excluded: severe renal disease (e.g., dialysis), advanced heart disease (e.g., NYHA class I V), severe lung disease (e.g., severe pulmonary hypertension (WHO class IV)), or liver disease ( Major comorbidities, including active hepatitis.

[0160] treatment Participants will receive oral LNP023 hydrochloride monotherapy (anti-C5 antibody therapy) administered bid. will be discontinued, see below for timing) or intravenous anti-C5 antibody therapy (randomized Patients were randomized in an 8:5 ratio to either 1 mg / kg or 2 mg / kg of steroids (continued at the same dose as given before the initiation of treatment) or 2 mg / kg of steroids (continued at the same dose as given before the initiation of treatment). can be.

[0161] First administration of LNP023 hydrochloride (visit on day 1) The timing of the first LNP023 hydrochloride administration is important for patients who have not received prior anti-C5 antibody therapy but who have not received LNP02 Provides seamless switchover to the LNP023 hydrochloride salt, and as LNP023 hydrochloride exposure accumulates This allows for the administration of anti-C when starting oral agents, while limiting the potential risk of breakthrough hemolysis. 5 Allowing for some overlap of exposure to antibody therapy. - Participants on a previous eculizumab regimen will receive their first LNP023 hydrochloride dose within 2 weeks This is done at the beginning of the second week of the dosing interval (i.e., preferably about 7-8 days after the last infusion). It must be done. The first LNP023 hydrochloride dose for participants on a previous ULTOMIRIS regimen was It is administered at the beginning of the 7th week of an 8-week dosing interval (preferably approximately 41-43 days after the last infusion). It must be done. Next, participants continued to receive monotherapy with 200 mg of LNP023 hydrochloride bid. Use.

[0162] First dose of anti-C5 in the study (visit on day 1) Participants assigned to the comparison treatment group continued to receive anti-C5 infusions according to a stable regimen. However, the next administration date of anti-C5 for the "start of study" coincides with the "Day 1" study day. Investigators are advised to "count backward" from the planned date of the infusion. It is recommended that

[0163] Extension period: Administration of LNP023 hydrochloride to the comparator group At the 24-week visit, participants in the comparison group received their last anti-C5 infusion and were followed up on the day of the visit ( The first dose of LNP023 hydrochloride will be administered starting the morning after (day 169).

[0164] If participants in the extension period start taking LNP023 hydrochloride from day 169, Only participants assigned to the comparator arm were included in the initial LNP023 The visit schedule will be standardized except for day 182, when patients will return 7 days after hydrochloride administration.

[0165] investigational treatment In this study, the "investigational treatment" included the investigational drug LNP023 hydrochloride and anti-C5 antibody. Active comparators (either eculizumab or ravulizumab) were included.

[0166] [Table 9]

[0167] The study drug, LNP023 hydrochloride, in 10 mg and 200 mg capsules, is available from Novartis. The study will be prepared by IS and supplied to the investigator's site in unblinded participant packs. Crizumab and ULTOMIRIS will be marketed in each participating country in accordance with local practices and local regulations. , commercially available products, or products that are not sold by Novartis or its subsidiaries or designees. s will provide it on-site.

[0168] Treatment duration 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 the patient switched to the previous anti-C5 antibody therapy If so, every effort will be made to continue study evaluations until the 24-week visit.

[0169] The extension period lasted up to 24 weeks, and the LNP023 hydrochloride treatment group was randomized during the randomized treatment period. Participants randomized to the anti-C5 treatment group continued LNP023 hydrochloride treatment. Participants will be offered to switch to LNP023 hydrochloride monotherapy.

[0170] Rationale for dose and duration of treatment The dose of 200 mg LNP023 hydrochloride bid for continuous treatment is primarily for ongoing 2 Two Phase II PNH trials (ClinicalTrials.gov Identifiers) r:NCT03439839 and NCT03896152) obtained during the interim analysis were selected for this Phase III trial based on available efficacy and safety data. This is supported by the results of the PKPD model.

[0171] CLNP02 in patients with active hemolysis despite treatment with eculizumab In the 3X2201 study, LNP023 hydrochloride was administered at a bid dose of 200 mg to 10 patients. PNH participants (Cohort 1) received LNP023 hydrochloride at a dose of 50 mg bid for 6 consecutive days. 10 participants with PNH (Cohort 2). An interim analysis (IA) was conducted in 10 participants (Cohort Horoscope 1) was the addition of 200 mg bid of LNP023 hydrochloride to eculizumab. This was done after completing at least 12 weeks of treatment.

[0172] In a Phase II study (NCT03439839) in patients naïve to anti-C5 antibody therapy, Participants received LNP023 hydrochloride monotherapy at 25 mg bid at week 4. LNP023 hydrochloride at 100 mg bid (Sequence 1) or 50 mg bid The dose was gradually increased from 0.01 to 200 mg bid of LNP023 hydrochloride (Sequence 2). The IA was performed after 8 patients were randomized and 7 patients completed the Week 8 visit evaluation. Ta.

[0173] The 200 mg bid dose was determined based on the following significant findings from two interim analyses: As a monotherapy with an appropriate safety profile, it offers optimal efficacy for PNH. Expected to provide: Administered 200 mg bid of LNP023 hydrochloride (addition to eculizumab) Participants who received the drug experienced suppression of IVH, as evidenced by a decrease in LDH, bilirubin, and reticulocytes. Suppression of EVH demonstrated by a reduction in erythrocyte transfusions and the survival of the majority of patients in the absence of red blood cell transfusions. Eculizumab has shown a number of beneficial effects, including an increase in haptoglobin, which leads to normalization of haptoglobin. No clinical benefit was achieved. LNP023 hydrochloride at 200 mg bid The hematologic response achieved by participants with additional therapy continued with LNP023 hydrochloride monotherapy. In 5 / 10 participants, L Following IA, two additional participants received NP023 hydrochloride monotherapy. Clizumab treatment was discontinued. C3 deposition was reduced by LNP02 at a dose of 200 mg bid. The PNH red blood cell survival was prolonged and completely reversed by the addition of 200 mg of 3-hydroxybenzoates. This further supports the control of EVH by LNP023 hydrochloride at a bid dose of There is 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 25 mg bid or higher dose levels. LNP023 hydrochloride demonstrated a 60% or higher LDH increase from baseline in all participants showed a reduction in hemoglobin levels and an early increase without transfusion in the majority of participants. Other hemolysis-related laboratory test results 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 this method is to suppress both the increase in the number of bins and the increase in the number of bins.

[0174] Preliminary information from Cohort 2 of the Phase II trial (NCT03439839) indicates that Optimal efficacy required for LNP023 hydrochloride monotherapy in patients receiving 50 mg bid The dose of LNP023 hydrochloride may not be sufficient. Optimal responses were observed in three participants. The dose was titrated to 200 mg bid because no improvement was observed.

[0175] LNP023 hydrochloride at a 200 mg bid dose 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 (FH) studies 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 greater than 100 mg of inhibition of the alternative pathway (Wieslab assay), approximately 200 mg of Predict the need for bid doses. Hemolysis in cases where inhibition of complement activity is insufficient. Given the risk of breakthrough and the potential for complete inhibition, modeling results suggest that PN This further supports the choice of a 200 mg bid dose for H.

[0177] Contraindicated drugs Use of the therapies listed below is not permitted during administration of LNP023 hydrochloride. Live vaccines are prohibited throughout the entire treatment period. Gemfibrozil (metabolizing enzymes CYP2C8, UGT1A, and hepatic uptake transporter) (a potent inhibitor of OATP1B1) was administered 48 hours before the first LNP023 hydrochloride dose. should be discontinued until the end of LNP023 hydrochloride treatment (and if indicated) (This may be replaced by another appropriate drug used for this purpose). If LNP023 hydrochloride is resumed during a study, prohibited medications may be used. Immediately discontinue treatment. Clopidogrel (a strong CYP2C8 inhibitor) was administered after the first dose of LNP023 hydrochloride. LNP023 hydrochloride treatment must be discontinued for 7 days prior to and until the end of treatment (and (Substitute another appropriate drug used for the indication). If LNP023 hydrochloride is resumed during a study, prohibited medications may be used. Immediately discontinue treatment.

[0178] In the event of any interruption during LNP023 hydrochloride administration, participants will continue in the study and undergo safety assessment. Tolerance must be carefully monitored.

[0179] Examination schedule and evaluation The assessment schedule (Figures 2 and 3) lists all assessments as they are performed. During the screening period, a mean hemoglobin of less than 10 g / dL was required for 2 weeks before randomization. Assessed by two hemoglobin measurements (mean <10 g / dL) ~8 weeks apart By central laboratory evaluation; or initial evaluation in patients who received pRBC transfusions after the initial evaluation This will be confirmed by a single hemoglobin measurement (<10 g / dL) from the If a packed RBC transfusion was received after the initial evaluation performed at the cleaning visit (central laboratory), If so, participants will be eligible without additional hemoglobin assessment by a central laboratory.

[0180] Effectiveness During the randomized treatment period, hematology, clinical chemistry, and C3 + R Blood samples for BC, PNH type II / III RBC, and PNH clone size is collected.

[0181] The following laboratory parameters will be evaluated: hemoglobin (and haptoglobin), reticulocyte count, Bilirubin (as a marker of extravascular hemolysis), LDH (as a marker of intravascular hemolysis), RBC, PNH clone size, PNH-type RBC, and C3 on PNH-type RBC + .

[0182] During the extension period, evaluations will be conducted according to the schedule in Figure 3.

[0183] red blood cell transfusion The need for red blood cell transfusion administration will be continuously monitored during the randomized treatment period.

[0184] To standardize dosing, transfusion criteria have been established and will be applied from day one of the study. .

[0185] Packed red blood cell transfusions will be administered to participants in the following cases: A hemoglobin level of 9 g / dL or less with serious symptoms and / or have symptoms Hemoglobin <7g / dL, regardless of the presence of clinical signs and symptoms

[0186] Breakthrough hemolysis The occurrence of breakthrough hemolysis will be continuously monitored during the randomized treatment period. If either of the floor criteria is met, the criteria for clinical breakthrough are defined in Table 2 below. A meaningful decrease in hemoglobin, as opposed to a defined clinical breakthrough Isolated findings of increased intravascular hemolysis in the absence of other clinical signs or symptoms of hemolysis Laboratory evidence (see Table 2) is defined as potential breakthrough hemolysis.

[0187] [Table 10]

[0188] During the extension period, breakthrough hemolysis will be assessed at the end of the study visit according to the same criteria and indicators as above. It will be continuously monitored until completion.

[0189] Patient-Reported Outcomes (PRO)-FACIT-Fatigue The FACIT-Fatigue measures self-reported fatigue and its impact on daily activities and function. This is a 13-item questionnaire that assesses patient-reported fatigue. The FACIT-Fatigue is a measure of health-related quality of life in the FACIT measurement system. Many different FACIT scales are part of a collection of (HRQoL) questionnaires. 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 Symptom Ma nage;13:633-74). The use of FACIT-F in patients with PNH has been reported in several publications and are sensitive to changes in disease state, statistically significant, and clinically meaningful. (Brodsky RA, et al. (2008) Multicenter phase 3 study of the complem ent inhibitor eculizumab for the treatment nt of patients with paroxysmal nocturnal 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 possible 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 receiving LNP023 hydrochloride. LNP023 hydrochloride is measured by a validated LC-MS / MS method. The expected lower limit of quantitation (LLOQ) is 1.0 ng / mL. Metabolites (if necessary) Concentrations are expressed as mass per unit of volume (ng / mL) and may be measured as appropriate. Refers to the water free base.

[0192] Cancellation and completion of the study Discontinuation of a participant's study treatment may occur if study treatment is discontinued earlier than planned by the protocol. It occurs when a clinical trial is initiated by either the participant or the investigator.

[0193] Upon discontinuation of LNP023 hydrochloride, participants should be closely monitored for signs and symptoms of hemolysis. At a minimum, elevated LDH, decreased hemoglobin levels, and P Monitor for decrease in NH clone size, increase in serum creatinine, thrombosis, and changes in mental status If severe hemolysis occurs, the investigator should take the following measures: Chronic therapy should be considered (and recorded on the appropriate CRF page): ●Blood transfusion (concentrated RBC), or if PNH RBCs exceed 50% of total RBCs by flow cytometry , exchange transfusion Corticosteroids ●Anticoagulant therapy Any other supportive care or treatment as determined by the investigator.

[0194] Even if administration of LNP023 hydrochloride must be discontinued immediately, This does not mean that administration of NP023 hydrochloride must be discontinued; In cases of termination due to a decision by the patient / guardian or confirmed pregnancy, the trial will be terminated at the discretion of the investigator. It is recommended to immediately restart anti-C5 antibody therapy. A tapering of LNP023 hydrochloride should be considered over the following period: Three 10 mg capsules of LNP023 hydrochloride taken in the evening for seven days (1 capsule per day) times) One 10 mg capsule of LNP023 hydrochloride taken in the evening for 7 days (1 capsule per day) times)

[0195] equivalent Those skilled in the art will be able to, using no more than routine experimentation, identify the specific embodiments specifically described herein. Numerous equivalents may be recognized or discerned. Such equivalents include, but are not limited to, the following: It is intended that all such modifications and variations be covered by the following claims.

Claims

1. For example, LNP0 at a dose of 200 mg twice daily (b.i.d.), such as approximately every 12 hours, 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered (previously The above dosage refers to the anhydrous free base of LNP023 hydrochloride, thereby allowing, for example, patients To treat a subject, e.g., a patient, suffering from paroxysmal nocturnal hemoglobinuria ( LNP023 or its derivatives, such as LNP023 hydrochloride, for use in the treatment of pulmonary hypertension (PNH) A pharmaceutical composition comprising a pharmaceutically acceptable salt of

2. For example, the subject, e.g., a patient, is receiving, e.g., LNP023 or, e.g., LNP023 hydrochloride. and / or a pharmaceutically acceptable salt thereof, such as a salt thereof, for at least about 8 months, e.g., LNP0 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, 10. The use of claim 1, wherein both patients have been previously treated with an anti-C5 therapy, such as for about 6 months. A pharmaceutical composition comprising:

3. 3. The use of claim 2, wherein the anti-C5 therapy is an anti-C5 monoclonal antibody therapy. A pharmaceutical composition comprising:

4. 4. The use of claim 2 or 3, wherein the anti-C5 therapy is eculizumab or ravulizumab. A pharmaceutical composition for

5. For example, the subject, such as a patient, has residual anemia. A pharmaceutical composition for the described uses.

6. For example, the hemoglobin level, haptoglobin level, reticulocyte count, LNP023 or, e.g., LNP023 HCl, 6. The method of claim 1, wherein the method is evaluated before administration of a pharmaceutically acceptable salt thereof, such as a pharmaceutically acceptable salt thereof. A pharmaceutical composition for use as described in claim 1.

7. For example, the hemoglobin level of the subject, such as a patient, is determined to be higher than that of LNP023 or, e.g., less than about 12 g / dL prior to administration of a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride; 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 7. The pharmaceutical composition for use according to claim 6, wherein the blood glucose level is less than 1000kJ / dL.

8. For example, the hemoglobin level of the subject, such as a patient, is determined to be higher than that of LNP023 or, e.g., at or below about 10 g / dL prior to administration of a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride.

7. A pharmaceutical composition for use according to claim 6.

9. Treatment of PNH, e.g., compared to baseline, e.g., with LNP023 or e.g., or to said subject, such as a patient, prior to administration of a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. the hemoglobin level in the subject, e.g., a patient, compared to the hemoglobin level in the For example, the serum erythrocyte serum level may be about 1 g / dL or more, about 1.5 g / dL or more, about 2 g / dL or more, about 2 g / dL or more, or about 2 g / dL or more. 5 g / dL or more, or about 3 g / dL or more. A pharmaceutical composition for use according to any one of claims 1 to 4.

10. Treating PNH can include, for example, reducing intravascular hemolysis (IVH) in the subject, e.g., a patient. and / or normalizing extravascular hemolysis (EVH). A pharmaceutical composition for use according to any one of claims 1 to 4.

11. Normalizing IVH and / or EVH hemolysis may be, for example, compared to baseline: For example, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. haptoglobin, reticulocytes, or virions in the subject, e.g., a patient, prior to administration of the The haptoglobin level in the subject, e.g., a patient, is compared to the level of lirubin. It may increase blood cholesterol, decrease reticulocyte levels, or decrease bilirubin levels.

11. A pharmaceutical composition for use according to claim 10 comprising:

12. 1 to 1, wherein treating PNH comprises treating PNH-associated hemolysis.

1. A pharmaceutical composition for use according to any one of claims 1 to 9.

13. Treating PNH reduces C3 deposition in the subject, e.g., a patient. A pharmaceutical composition for use according to any one of claims 1 to 12, comprising:

14. C3 deposition, e.g., compared to baseline, e.g., with LNP023 or e.g., L the subject, e.g., a patient, prior to administration of a pharmaceutically acceptable salt thereof, such as NP023 hydrochloride. Compared to the level of C3 deposition in elephants, 0%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 9 14. The method of claim 13, wherein the amount of erythrocyte proliferation is reduced by 0%, about 95%, about 98%, or about 99%. Pharmaceutical compositions.

15. Treating PNH may involve, for example, reducing red blood cell (RBC) viability in the subject, e.g., a patient. For the use according to any one of claims 1 to 14, comprising increasing the survival rate of A pharmaceutical composition comprising:

16. Treating PNH may involve inhibiting the alternative complement pathway in the subject, e.g., a patient. A pharmaceutical composition for use according to any one of claims 1 to 15, comprising:

17. Treating PNH can be achieved by, for example, increasing fragment Bb levels in the subject, e.g., a patient. The use according to any one of claims 1 to 16, comprising reducing the Pharmaceutical compositions.

18. Treating PNH can be achieved, for example, by measuring the level of serotonin in a patient receiving LNP023 or serotonin compared to baseline. For example, a patient may be administered a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, prior to administration. and comparing the hemoglobin levels in the subject, e.g., a patient. The method comprises increasing the hemoglobin level in the patient by, for example, about 2 g / dL or more.

18. A pharmaceutical composition for use according to any one of claims 1 to 17.

19. Treating PNH involves achieving a sustained increase in hemoglobin levels. A pharmaceutical composition for use according to any one of claims 1 to 18, comprising

20. Treating PNH can be achieved by increasing blood pressure by more than about 10 g / dL, more than about 10.5 g / dL, more than about 11 g / dL, greater than about 11.5 g / dL, greater than about 12 g / dL, greater than about 12.5 g / dL Achieving a sustained increase in hemoglobin levels of greater than about 10 g / dL or greater than about 13 g / dL A pharmaceutical composition for use according to any one of claims 1 to 19, comprising:

21. Treating PNH results in a sustained increase in hemoglobin levels of about 12 g / dL or greater. A pharmaceutical composition for use according to any one of claims 1 to 20, comprising achieving Finished product.

22. Treating PNH can be achieved in the absence of one or more red blood cell (RBC) transfusions, even if For example, increasing hemoglobin levels in said subject, such as a patient.

22. A pharmaceutical composition for use according to any one of claims 1 to 21.

23. For example, the subject, such as a patient, is administered LNP023 or, e.g., LNP023 hydrochloride. Approximately six months prior to administration of the pharmaceutically acceptable salt, e.g., at least one packed RBC The pharmaceutical composition for use according to any one of claims 1 to 21 in patients receiving a blood transfusion.

24. For example, the subject, such as a patient, is administered LNP023 or, e.g., LNP023 hydrochloride. Before administration of the pharmaceutically acceptable salt thereof, for example, Neisseria meningitidis (Ne Isseria meningitidis (types A, C, Y, and W-135) 24. The method of claim 1, wherein the animal has been vaccinated, such as by vaccination prior to the start of the vaccination. A pharmaceutical composition for the described uses.

25. The efficacy of treatment can be evaluated, e.g., as compared to baseline, e.g., LNP023 or e.g., , before administration of a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, e.g., to a patient The hemoglobin level in the subject, e.g., a patient, is compared to the hemoglobin level in the subject.

25. The method according to claim 1, wherein the level of ATP is determined by measuring the ATP level. A pharmaceutical composition for the described uses.

26. The hemoglobin level, e.g., compared to baseline, e.g., LNP023 or, for example, prior to administration of a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, and / or a hemoglobin level of about 1.5 g / dL or more, about 2.0 g / dL or more, compared to the hemoglobin level in the subject, such as a 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 26. The pharmaceutical composition for use according to claim 25, wherein the vasoconstriction is increased.

27. For example, LNP0 at a dose of 200 mg twice daily (b.i.d.), such as approximately every 12 hours, 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered (previously The above dosage refers to the anhydrous free base of LNP023 hydrochloride, thereby allowing, for example, patients Normalizing IVH and / or EVH in a subject, e.g., a patient in need thereof. Normalization of intravascular hemolysis (IVH) and / or extravascular hemolysis (EVH) in said subject. LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, for use. Pharmaceutical compositions comprising possible salts thereof.

28. 28. The method of claim 27, wherein the subject has or has been diagnosed with PNH. Pharmaceutical compositions for use.

29. Normalizing IVH and / or EVH hemolysis may be, for example, compared to baseline: For example, LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride. haptoglobin, reticulocytes, or virions in the subject, e.g., a patient, prior to administration of the The haptoglobin level in the subject, e.g., a patient, is compared to the level of lirubin. It may increase blood cholesterol, decrease reticulocyte levels, or decrease bilirubin levels.

29. A pharmaceutical composition for use according to claim 27 or 28, comprising:

30. For example, haptoglobin levels, reticulocyte levels, or The bilirubin level is obtained by analysis of a sample of a bodily fluid, such as blood or plasma. Item 30. A pharmaceutical composition for use according to Item 29.

31. For example, LNP0 at a dose of 200 mg twice daily (b.i.d.), such as approximately every 12 hours, 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered (previously The above dosage refers to the anhydrous free base of LNP023 hydrochloride, thereby allowing, for example, patients and treating a subject, e.g., a patient in need thereof, with PNH-associated inflammatory disease. LNP023 or a drug thereof, such as LNP023 hydrochloride, for use in the treatment of hematologic malignancies. A pharmaceutical composition comprising a physiologically acceptable salt.

32. The PNH-associated hemolysis may be, for example, breakthrough hemolysis (BTH) as defined in Table 2.

32. The pharmaceutical composition for use according to claim 31, wherein

33. For example, LNP0 at a dose of 200 mg twice daily (b.i.d.), such as approximately every 12 hours, 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered (previously The above dosage refers to the anhydrous free base of LNP023 hydrochloride, thereby allowing, for example, patients To treat a subject, e.g., a patient in need thereof, e.g., to treat a blood LNP023 or e.g., a compound selected from the group consisting of LNP023 and LNP023-containing compounds, for use in the treatment of intravascular hemolysis (IVH), such as the inhibition of IVH. A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride.

34. For example, the subject, such as a patient, has or has been diagnosed with PNH.

34. A pharmaceutical composition for use according to claim 33.

35. For example, treatment of IVH, such as suppression of IVH, may result in, for example, a significant improvement in For example, administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. For example, the level of lactate dehydrogenase (LDH) in the subject before and after administration is compared to the level of lactate dehydrogenase (LDH) in the subject before and after administration. 33 or 34, comprising reducing the level of LDH in the subject, such as a human.

34. A pharmaceutical composition for use as described in 34.

36. For example, the LDH level in the subject, such as a patient, can be determined by measuring the LDH level in a body fluid, such as blood or plasma.

36. A pharmaceutical composition for use according to claim 35, obtained by sample analysis.

37. For example, the LDH level in the subject, such as a patient, is at least about 40% lower. at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least 35. The method of claim 35, wherein the level of ATP is reduced by at least about 85%, at least about 90%, or at least about 95%. Or a pharmaceutical composition for use as described in 36.

38. The LDH level is at least about 40%, at least about 45%, or at least about 50% , at least about 55%, at least about 60%, at least about 65%, or at least about 7 38. The pharmaceutical composition for use according to any one of claims 35 to 37, wherein the amount of erythrocyte colony-stimulating factor (B1) is reduced by 0%.

39. For example, the LDH level in the subject, such as a patient, is reduced by at least about 60%. The pharmaceutical composition for use according to any one of claims 35 to 38.

40. For example, LNP0 at a dose of 200 mg twice daily (b.i.d.), such as approximately every 12 hours, 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered (previously The above dosage refers to the anhydrous free base of LNP023 hydrochloride, thereby allowing, for example, patients To treat a subject, e.g., a patient in need thereof, e.g., to treat a blood LNP023 or e.g., a compound selected from the group consisting of LNP023 and LNP023-containing compounds for use in the treatment of extravascular hemolysis (EVH), such as the inhibition of EVH. A pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride.

41. For example, the subject, such as a patient, has or has been diagnosed with PNH.

41. A pharmaceutical composition for use according to claim 40.

42. For example, treatment of EVH, such as suppression of EVH, may result in, for example, a reduction in For example, administration of LNP023 or a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. bilirubin, reticulocytes, or haptoglobin in the subject, e.g., a patient, prior to administration. and comparing the bilirubin or reticulocyte levels in the subject, e.g., a patient. and / or increasing haptoglobin levels.

42. A pharmaceutical composition for use according to claim 40 or 41.

43. For example, the level of bilirubin, reticulocytes, or haptoglobin in the subject, such as a patient.

43. The level value is obtained by analysis of a sample of a bodily fluid such as blood or plasma. A pharmaceutical composition for use as described in claim 1.

44. Bilirubin or reticulocyte levels are 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% reduction in the IL-1 receptor agonist activity. A pharmaceutical composition for the described uses.

45. Haptoglobin levels are 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 Any one of claims 42 to 44, wherein the increase is 75%, about 80%, about 85%, or about 90%. A pharmaceutical composition for use as described in claim 1.

46. For example, LNP0 at a dose of 200 mg twice daily (b.i.d.), such as approximately every 12 hours, 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered (previously The above dosage refers to the anhydrous free base of LNP023 hydrochloride, thereby allowing, for example, patients Normalizing hemoglobin levels in a subject in need thereof LNP023 or, e.g., LNP023 Hydrochloride for use in normalizing leukocyte globin levels and a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, such as a salt thereof.

47. Hemoglobin levels greater than about 10 g / dL, greater than about 10.5 g / dL, greater than about 11 g / dL, greater than about 11.5 g / dL, greater than about 12 g / dL, and about 12.5 g / dL or greater than about 13 g / dL, e.g., normalized to about 12 g / dL or greater. Item 47. A pharmaceutical composition for use according to Item 46.

48. For example, the subject, such as a patient, has or has been diagnosed with PNH.

48. A pharmaceutical composition for use according to claim 46 or 47.

49. 49. The method of claim 46, wherein the normalization of hemoglobin levels occurs in the absence of red blood cell transfusions. A pharmaceutical composition for use according to any one of claims 1 to 4.

50. For example, LNP0 at a dose of 200 mg twice daily (b.i.d.), such as approximately every 12 hours, 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered (previously The above dosages refer to the anhydrous free base of LNP023 hydrochloride, thereby, for example, reducing C3 deposition in said subject, e.g., a patient in need thereof; LNP023 or a salt thereof, such as, for example, LNP023 hydrochloride, for use in reducing deposition A pharmaceutical composition comprising a pharmaceutically acceptable salt.

51. For example, the subject, such as a patient, has or has been diagnosed with PNH.

51. A pharmaceutical composition for use according to claim 50.

52. C3 deposition 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%, about 90%, about 95%, about 98% 52. The pharmaceutical composition for use according to claim 50 or 51, wherein the amount of IL-16 in the blood is reduced by 99%, or by about 99%.

53. C3 deposition is completely reversed, e.g., C3 deposition occurs as C3 fragment deposition on red blood cells.

53. The method according to any one of claims 50 to 52, wherein the method is quantified by flow cytometry. A pharmaceutical composition for use in

54. For example, LNP0 at a dose of 200 mg twice daily (b.i.d.), such as approximately every 12 hours, 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered (previously The above dosage refers to the anhydrous free base of LNP023 hydrochloride, thereby allowing, for example, patients increasing RBC survival in a subject, such as a patient in need thereof. LNP023 or for use in increasing red blood cell (RBC) survival in elephants For example, a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride.

55. 55. The method of claim 54, wherein the subject has or has been diagnosed with PNH. Pharmaceutical compositions for use.

56. For example, LNP0 at a dose of 200 mg twice daily (b.i.d.), such as approximately every 12 hours, 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered (previously The above dosage refers to the anhydrous free base of LNP023 hydrochloride, thereby allowing, for example, patients to treat a subject, e.g., to maintain inhibition in said subject, e.g., a patient in need thereof LNP023 or e.g., LNP023 for use in inhibiting the alternative complement pathway, such as by inhibiting the complement pathway. 023 and its pharmaceutically acceptable salts, such as the hydrochloride salt.

57. For example, the subject, such as a patient, has or has been diagnosed with PNH.

57. A pharmaceutical composition for use according to claim 56.

58. Administration of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride About 1 week later, about 2 weeks later, about 3 weeks later, about 4 weeks later, about 6 weeks later, about 8 weeks later, about 10 weeks later After about 12 weeks, after about 14 weeks, after about 16 weeks, after about 18 weeks, after about 20 weeks, 5. Sustained inhibition of the alternative complement pathway is achieved after 22 weeks or about 24 weeks. 6 or 57. A pharmaceutical composition for use according to claim 6 or 57.

59. Administration of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride 56-5, wherein sustained inhibition of the alternative complement pathway is achieved after about 18-24 weeks of administration.

9. A pharmaceutical composition for use according to any one of claims 8.

60. Administration of LNP023 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride 56-59, wherein sustained inhibition of the alternative complement pathway is achieved after about 18 or 24 weeks of administration.

60. A pharmaceutical composition for use according to any one of claims 59.

61. For example, LNP0 at a dose of 200 mg twice daily (b.i.d.), such as approximately every 12 hours, 23 or a pharmaceutically acceptable salt thereof, such as, for example, LNP023 hydrochloride, is orally administered (previously The above dosage refers to the anhydrous free base of LNP023 hydrochloride, thereby allowing, for example, patients and reducing fragment Bb levels in a subject, e.g., a patient in need thereof. and (c) administering to said subject a compound selected from the group consisting of LNP023 and LNP023-containing compounds for use in reducing fragment Bb levels in said subject. For example, a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride. 。

62. For example, the subject, such as a patient, has or has been diagnosed with PNH.

62. A pharmaceutical composition for use according to claim 61.

63. Fragment Bb levels, e.g., compared to baseline, e.g., LNP023 or, for example, prior to administration of a pharmaceutically acceptable salt thereof, such as LNP023 hydrochloride, e.g., about 30%, about 35% compared to the level of fragment Bb in said subject, such as a patient , about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% 63. The method of claim 61 or 62, wherein the amount of erythrocyte proliferation is reduced by about 80%, about 85%, or about 90%. A pharmaceutical composition for the treatment of

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