Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents

Definitions

• the disclosure relates to methods of treating complement driven diseases, and in particular, paroxysmal nocturnal hemoglobinuria (PNH) with the Factor B inhibitor LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.
• PNH paroxysmal nocturnal hemoglobinuria
• Paroxysmal nocturnal hemoglobinuria is a rare acquired hemolytic disorder characterized by complement-mediated intravascular hemolysis, bone marrow failure (BMF) and severe thrombophilia (Risitano AM (2012). Paroxysmal nocturnal hemoglobinuria and other complement-mediated hematological disorders. Immunology; 217:1080-1087). It begins with the clonal expansion of a hematopoietic stem cell that has acquired a somatic mutation in the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) gene (Brodsky RA (2014) Paroxysmal nocturnal hemoglobinuria.
• PIGA phosphatidylinositol N-acetylglucosaminyltransferase subunit A
• PNH blood cells lack the glycophosphatidylinositol (GPI) anchor protein and are deficient in the membrane-bound complement inhibitory proteins CD55 and CD59.
• GPI glycophosphatidylinositol
• the clinical spectrum of PNH varies, and signs and symptoms include anemia, thrombosis, smooth muscle dystonia, fatigue, hemoglobinuria, chronic kidney disease and pulmonary hypertension.
• the clinical presentation is driven by uncontrolled complement activation on CD55 and CD59 deficient PNH type RBCs culminating with hemolysis and the release of free hemoglobin, and platelet activation (Hill A, et al. (2013). Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood; 121:4985-4996). Hemolysis results in release of intracellular hemoglobin and lactate hydrogenase (LDH) into the circulation.
• LDH lactate hydrogenase
• thromboembolism is the leading cause of morbidity and mortality in patients with PNH and can occur at any site; although venous is more common (80-85%), it can also be arterial (15-20%) (Hillmen P, et al. (2007). Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria.
• Eculizumab and ravulizumab are approved anti-C5 antibody therapies for the treatment of PNH and the current standard of care (SoC) where available.
• SoC the current standard of care
• the anti-C5 antibody therapy is generally effective in treating intravascular hemolysis (IVH), there remains a high-unmet medical need for PNH.
• LNP023 is a novel, oral, small molecule compound that inhibits factor B (FB) and is in clinical development for the treatment of PNH.
• Factor B (FB) is a key protease of the complement alternative pathway (AP).
• Inhibition of FB with oral LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride has the potential to prevent both intra- and extravascular hemolysis, and therefore, offer therapeutic benefits over and above the current standard of care (SoC). Additionally, the oral route of administration offers patients an advantage compared to the intravenous route of administration of current SoCs.
• SoC current standard of care
• the disclosure relates to methods of treating complement driven diseases, and in particular, paroxysmal nocturnal hemoglobinuria (PNH) with LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.
• LNP023 belongs to the class of Factor B inhibitors of the complement pathway and acts by inhibiting or suppressing the amplification of the complement system caused by C3 activation irrespective of the initial mechanism of activation.
• LNP023 hydrochloride is currently in clinical development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH).
• LNP023 hydrochloride is chemically designated as 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl))benzoic acid hydrochloride and can be represented by the following chemical structure:
• LNP023 hydrochloride and methods for its preparation are disclosed in WO2015/009616 (see Example 26d), which is incorporated herein by reference in its entirety.
• the disclosure provides a method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject, e.g, a patient, in need thereof, the method comprising orally administering to the subject, e.g, patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g, about every 12 hours, to thereby treat the subject, e.g., patient (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g, a patient.
• PNH paroxysmal nocturnal hemoglobinuria
• the disclosure provides a method of treating PNH associated hemolysis in a subject, e.g, a patient, in need thereof, the method comprising orally administering to the subject, e.g, patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g, about every 12 hours, to thereby treat the subject, e.g., patient (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., a patient.
• the dosing amount refers to the anhydrous free base of LNP023 hydrochloride
• the disclosure provides a method of normalizing intravascular hemolysis (IVH) and/or extravascular hemolysis (EVH) in a subject, e.g., a patient, in need thereof, the method comprising orally administering to the subject LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby normalize IVH and/or EVH the subject, e.g., a patient.
• IVH intravascular hemolysis
• EVH extravascular hemolysis
• the disclosure provides a method of reducing the rate of occurrence of PNH associated hemolysis in a patient population, the method comprising orally administering to the patients LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby reduce the rate of occurrence.
• LNP023 or a pharmaceutically acceptable salt thereof e.g. LNP023 hydrochloride
• the disclosure provides a method of treating intravascular hemolysis (IVH), e.g., controlling IVH, in a subject, e.g., a patient, in need thereof, the method comprising orally administering to the subject LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., a patient.
• IVH intravascular hemolysis
• the disclosure provides a method of treating extravascular hemolysis (EVH), e.g., controlling EVH, in a subject, e.g., a patient, in need thereof, the method comprising orally administering to the subject LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., a patient.
• EVH extravascular hemolysis
• the disclosure provides a method of normalizing hemoglobin levels in a subject, e.g., a patient, in need thereof, the method comprising orally administering to the subject LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby normalize hemoglobin levels in the subject, e.g., a patient.
• LNP023 or a pharmaceutically acceptable salt thereof e.g. LNP023 hydrochloride
• the disclosure provides a method of reducing C3 deposition in a subject in need thereof, the method comprising orally administering to the subject, e.g., a patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby reduce C3 deposition in the subject, e.g., a patient.
• the dosing amount refers to the anhydrous free base of LNP023 hydrochloride
• the disclosure provides a method of increasing red blood cell (RBC) survival, e.g., increasing the lifetime of RBCs, in a subject, e.g., a patient, in need thereof, the method comprising orally administering to the subject LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby increase RBC survival in the subject, e.g., a patient.
• RBC red blood cell
• the disclosure provides a method of inhibiting the complement alternative pathway, e.g., sustaining inhibition, in a subject, e.g., a patient, in need thereof, the method comprising orally administering to the subject LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby inhibit the complement alternative pathway in the subject, e.g., a patient.
• LNP023 or a pharmaceutically acceptable salt thereof e.g. LNP023 hydrochloride
• the disclosure provides a method of reducing Fragment Bb levels in a subject, e.g., a patient, in need thereof, the method comprising orally administering to the subject LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby reduce Fragment Bb in the subject, e.g., a patient.
• Treatment methods described herein can additionally comprise various evaluation steps prior to and/or following treatment with LNP023 or a pharmaceutically acceptable salt thereof, e.g.
• the methods prior to and/or after administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, the methods further comprise the step of evaluating PK and PD parameters (e.g., plasma concentration of LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, C3, Fragment Bb, or sC5B). Evaluation may be achieved by sample analysis of bodily fluid, such as blood or plasma by e.g., mass spectroscopy, e.g. LC-MS.
• PK and PD parameters e.g., plasma concentration of LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride, C3, Fragment Bb, or sC5B. Evaluation may be achieved by sample analysis of bodily fluid, such as blood or plasma by e.g., mass spectroscopy, e.g. LC-MS.
• FIG. 1 depicts a schematic of the study design.
• FIG. 2 is a table of the assessment schedule during the randomized treatment period.
• FIG. 3 is a table of the assessment schedule during the extension period.
• Described herein is the Phase 3 clinical study to determine safety and efficacy of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, in patients with PNH presenting with residual anemia despite treatment with anti-C5 therapy. Accordingly, described herein are methods of treating PNH in a patient in need thereof, the method comprising orally administering, e.g., in capsule form, to the patient a twice daily dose, e.g., about every 12 hours, of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride). Also described herein are methods of selecting the target patient population, methods of monitoring treatment of the target patient population, and methods of assessing safety and efficacy of treatment of the target patient population.
• administering means providing a pharmaceutical agent to an individual, and includes, but is not limited to, administering by a medical professional and self-administering.
• Administration of a pharmaceutical agent to an individual can be continuous, chronic, short or intermittent.
• the term "acquire” or “acquiring” as the terms are used herein, refer to obtaining possession of a physical entity (e.g ., a sample, e.g., a blood sample or a blood plasma sample), or a value, e.g., a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value.
• a physical entity e.g ., a sample, e.g., a blood sample or a blood plasma sample
• a value e.g., a numerical value
• Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, e.g., performing an analytical process which includes a physical change in a substance, e.g., a sample, performing an analytical method, e.g., a method as described herein, e.g., by sample analysis of bodily fluid, such as blood by, e.g., mass spectroscopy, e.g. LC-MS, e.g., LC-MS/MS methods.
• an analytical method e.g., a method as described herein, e.g., by sample analysis of bodily fluid, such as blood by, e.g., mass spectroscopy, e.g. LC-MS, e.g., LC-MS/MS methods.
• dose means a specified quantity of a pharmaceutical agent provided in a single administration, or in a specified time period. In certain embodiments, a dose can be administered in capsules. As used herein, the dosing amount refers to the anhydrous free base of LNP023 hydrochloride.
• “individual”, “patient”, “participant”, or “subject” means a human selected for treatment or therapy.
• pharmaceutically acceptable salts means physiologically and pharmaceutically acceptable salts of LNP023, i.e., salts that retain the desired biological activity of LNP023 and do not impart undesired toxicological effects thereto.
• pharmaceutically acceptable salt or “salt” includes a salt prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and bases.
• “Pharmaceutically acceptable salts” of LNP023 may be prepared by methods well-known in the art. For a review of pharmaceutically acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002). LNP023 hydrochloride and methods for its preparation are disclosed in WO2015/009616 (see Example 26d), which is incorporated herein by reference in its entirety.
• treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disorder or disease, e.g., PNH.
• an element means one element or more than one element.
• a method of treating paroxysmal nocturnal hemoglobinuria (PNH) in a subject comprising orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., patient.
• PNH paroxysmal nocturnal hemoglobinuria
• the subject e.g., patient
• the subject e.g., patient
• the subject e.g., patient
• the anti-C5 therapy is an anti-C5 monoclonal antibody therapy.
• the anti-C5 therapy is eculizumab or ravulizumab.
• the subject e.g., patient, has residual anemia.
• the subject e.g., patient
• the subject e.g., patient
• treating PNH comprises increasing hemoglobin levels in the subject, e.g., patient, in the absence of receiving one or more red blood cell (RBC) transfusion(s).
• RBC red blood cell
• the subject e.g., patient
• RBC transfusions e.g., at least 1 packed-RBC transfusion(s), e.g., about 6 months prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.
• hemoglobin levels in the subject are evaluated prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g, LNP023 hydrochloride.
• hemoglobin levels, haptoglobin levels, reticulocyte levels, and/or bilirubin levels of the subject, e.g, patient are evaluated prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.
• hemoglobin levels in the subject are less than about 12 g/dL, less than about 11.5 g/dL, less than about 11 g/dL, less than about 10.5 g/dL, less than about 10 g/dL, less than about 9.5 g/dL, less than about 9 g/dL, less than about 8.5 g/dL, or less than about 8 g/dL, prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• the hemoglobin levels of the subject are less than or equal to about 10 g/dL, prior to administration of LNP023 hydrochloride.
• hemoglobin levels in the subject, e.g., patient are increased, e.g, by about 1 g/dL or more, about 1.5 g/dL 2 g/dL, about 2.5 g/dL or more, or about 3 g/dL or more, after treatment with LNP023 or a pharmaceutically acceptable salt thereof, e.g.
• LNP023 hydrochloride e.g., as compared to baseline, e.g., as compared to hemoglobin levels prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• hemoglobin levels in the subject are increased by about 2 g/dL or more, e.g., as compared to baseline, e.g., as compared to hemoglobin levels prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• treating PNH comprises normalizing intravascular hemolysis (IVH) and/or extravascular hemolysis (EVH) in the subject, e.g., patient.
• IVH and/or EVH hemolysis comprises increasing the haptoglobin level, decreasing reticulocytes level, or decreasing bilirubin level, in the subject, e.g., patient, e.g., as compared to baseline, e.g., as compared to the level of haptoglobin, reticulocytes, or bilirubin in the subject, e.g., patient, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.
• treating PNH comprises treating PNH associated hemolysis.
• treating PNH comprises reducing C3 deposition in the subject, e.g., patient.
• C3 deposition is reduced by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or about 99%, e.g., as compared to baseline, e.g., as compared to the level of C3 deposition in the subject, e.g., patient, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.
• treating PNH comprises increasing red blood cell (RBC) survival in the subject, e.g., patient.
• RBC red blood cell
• treating PNH comprises inhibiting the complement alternative pathway in the subject, e.g., patient.
• treating PNH comprises reducing Fragment Bb levels in the subject, e.g., patient.
• treating PNH comprises increasing hemoglobin levels in the subject, e.g., patient, e.g., by about 2 g/dL or more, e.g., as compared to baseline, e.g, as compared to hemoglobin levels in the subject, e.g, patient, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.
• treating PNH comprises achieving a sustained increase in hemoglobin levels. In an embodiment, treating PNH comprises achieving a sustained increase in hemoglobin levels to 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, greater than about 12.5 g/dL, or greater than about 13 g/dL. In an embodiment, treating PNH comprises achieving a sustained increase in hemoglobin levels to greater than or equal to about 12 g/dL.
• treating PNH comprises achieving a sustained increase in hemoglobin levels from baseline is about 1.5 g/dL or more, about 2 g/dL or more, about 2.5 g/dL or more, about 3 g/dL or more, about 3.5 g/dL or more, about 4 g/dL or more, about 4.5 g/dL or more, or about 5 g/dL or more, e.g, as compared to the hemoglobin levels in the patient prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.
• treating PNH comprises achieving a sustained increase in hemoglobein levels from baseline is about 2 g/dL or more, e.g, as compared to the hemoglobin levels in the patient prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof, e.g. LNP023 hydrochloride.
• the increase in hemoglobin levels is sustained after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 6 weeks, after about 8 weeks, after about 10 weeks, after about 12 weeks, after about 14 weeks, after about 16 weeks, after about 18 weeks, after about 20 weeks, after about 22 weeks, or after about 24 weeks of administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g. , LNP023 hydrochloride.
• the increase in hemoglobin levels is sustained after about 18 to 24 weeks of administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• the increase in hemoglobin levels is sustained after about 18 or 24 weeks of administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• efficacy of treatment is determined by measuring the hemoglobin levels in the subject, e.g., patient, e.g., as compared to baseline, e.g, as compared to hemoglobin levels in the subject, e.g., patient, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• hemoglobin levels are increased by about 1.5 g/dL or more, about 2 g/dL or more, about 2.5 g/dL or more, about 3 g/dL or more, about 3.5 g/dL or more, about 4 g/dL or more, about 4.5 g/dL or more, or about 5 g/dL or more, e.g., as compared to hemoglobin levels in the subject, e.g., patient, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• hemoglobin levels are increased by about 2 g/dL or more, as compared to baseline, e.g., as compared to hemoglobin levels in the subject, e.g., patient, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• the disclosure provides a method of normalizing intravascular hemolysis (IVH) and/or extravascular hemolysis (EVH) in a subject, e.g., patient, in need thereof, the method comprising orally administering to the subject, e.g., patient, LNP023 hydrochloride at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby normalize IVH and/or EVH, in the subject, e.g., patient.
• IVH intravascular hemolysis
• EVH extravascular hemolysis
• the subject e.g., patient
• normalizing IVH and/or EVH hemolysis comprises increasing the haptoglobin level, decreasing reticulocytes level, or decreasing bilirubin level, in the subject, e.g., patient, e.g., as compared to baseline, e.g., as compared to the level of haptoglobin, reticulocytes, or bilirubin in the subject, e.g., patient, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• the level of haptoglobin is increased by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about
• the level of bilirubin or reticulocytes is reduced by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about
• the haptoglobin level, reticulocytes level, or bilirubin level in the subject is acquired by sample analysis of a bodily fluid, such as blood or plasma.
• the disclosure provides a method of treating PNH associated hemolysis in a subject, e.g., patient, in need thereof, the method comprising orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., patient.
• LNP023 or a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• the PNH associated hemolysis is breakthrough hemolysis (BTH), e.g., as defined in Table 2.
• the disclosure provides a method of reducing the rate of occurrence of PNH associated hemolysis in a patient population, the method comprising orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby reduce the rate of occurrence.
• the subject e.g., patient
• LNP023 or a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• the PNH associated hemolysis is breakthrough hemolysis (BTH), e.g., as defined in Table 2.
• the rate of occurrence is reduced by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95%.
• the disclosure provides a method of treating intravascular hemolysis (IVH), e.g., controlling IVH, in a subject, e.g., patient, in need thereof, the method comprising orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., patient.
• IVH intravascular hemolysis
• treating IVH comprises reducing the level of lactate hydrogenase (LDH) in the subject, e.g., patient, e.g., as compared to baseline, e.g., as compared to the level of LDH in the subject, e.g., patient, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• LDH lactate hydrogenase
• the LDH level in the subject is acquired by sample analysis of a bodily fluid, such as blood or plasma.
• the LDH level in the subject is reduced by at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%. In an embodiment, the LDH level in the subject, e.g., patient, is reduced by at least about 50%, at least about 55%, at least about 60%, at least about 65%, or at least about 70%. In an embodiment, the LDH level in the subject, e.g., patient, is reduced by at least about 60%.
• the disclosure provides a method of treating extravascular hemolysis (EVH), e.g., controlling EVH, in a subject, e.g., patient, in need thereof, the method comprising orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., patient.
• EVH extravascular hemolysis
• the subject e.g., patient
• treating EVH comprises reducing the level of bilirubin or reticulocytes in the subject, e.g., patient, or increasing the level of haptoglobin, e.g., as compared to baseline, e.g., as compared to the level of bilirubin or reticulocytes in the subject, e.g., patient, prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• the level of bilirubin or reticulocytes is reduced by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.
• the level of haptoglobin is increased by about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.
• the value for the level of bilirubin, reticulocytes, or haptoglobin in the subject, e.g., patient is acquired by sample analysis of a bodily fluid, such as blood or plasma.
• the disclosure provides a method of normalizing hemoglobin levels in a subject, e.g., patient, in need thereof, the method comprising orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby normalize hemoglobin levels in the subject, e.g., patient.
• LNP023 or a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• hemoglobin levels are normalized, to greater than about 10 g/dL, to greater than about 10.5 g/dL, to greater than about 11 g/dL, to greater than about 11.5 g/dL, to greater than about 12 g/dL, to greater than about 12.5 g/dL, or to greater than about 13 g/dL.
• hemoglobin levels are normalized, to greater than or equal to about 12 g/dL.
• the subject e.g., patient
• normalizing hemoglobin levels occurs in the absence of a red blood cell transfusion.
• the disclosure provides a method of reducing C3 deposition in a subject, e.g., patient, in need thereof, the method comprising orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., patient.
• LNP023 or a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• the subject e.g., patient
• C3 deposition is reduced by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 98%, or about 99%.
• C3 deposition is fully reversed. In an embodiment, C3 deposition is quantified by flow cytometry as C3 -fragment deposition on erythrocytes.
• the disclosure provides a method of increasing red blood cell survival in a subject, e.g., patient, in need thereof, the method comprising orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., patient.
• LNP023 or a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• the subject e.g., patient
• the disclosure provides a method of inhibiting the complement alternative pathway, e.g., to achieve sustained inhibition, in a subject, e.g., patient, in need thereof, the method comprising orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., patient.
• LNP023 or a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• the subject e.g., patient
• sustained inhibition of the complement alternative pathway is achieved after about 1 week, after about 2 weeks, after about 3 weeks, after about 4 weeks, after about 6 weeks, after about 8 weeks, after about 10 weeks, after about 12 weeks, after about 14 weeks, after about 16 weeks, after about 18 weeks, after about 20 weeks, after about 22 weeks, or after about 24 weeks of administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g. , LNP023 hydrochloride.
• sustained inhibition of the complement alternative pathway is achieved after about 18 to 24 weeks of administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• sustained inhibition of the complement alternative pathway is achieved after about 18 or 24 weeks of administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• the disclosure provides a method of reducing Fragment Bb in a subject, e.g., patient, in need thereof, the method comprising orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby reduce Fragment Bb in the subject, e.g., patient.
• the subject e.g., patient, has or is diagnosed as having PNH.
• Fragment Bb is reduced by about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.
• the disclosure provides LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, for use in the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in a subject, e.g., a patient, in need thereof, wherein the treatment comprises orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., patient.
• PNH paroxysmal nocturnal hemoglobinuria
• the disclosure provides LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, for use in the treatment of, e.g., the control of, intravascular hemolysis (IVH) and/or extravascular hemolysis (EVH) in a subject, e.g., patient, in need thereof, wherein the treatment comprises orally administering to the subject, e.g., patient,
• LNP023 or a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• the subject e.g., patient
• the disclosure provides LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, for use in the treatment of PNH associated hemolysis in a subject, e.g., patient, in need thereof, wherein the treatment comprises orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., patient.
• the treatment comprises orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12
• the disclosure provides use of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, in the manufacture of a medicament for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in a subject, e.g., a patient, in need thereof, wherein the treatment comprises orally administering to the subject, e.g., patient,
• PNH paroxysmal nocturnal hemoglobinuria
• LNP023 or a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• the disclosure provides use of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, in the manufacture of a medicament for the treatment of, e.g., the control of, intravascular hemolysis (IVH) and/or extravascular hemolysis (EVH) in a subject, e.g., patient, in need thereof, wherein the treatment comprises orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby normalize IVH and/or EVH, in the subject, e.g., patient.
• IVH intravascular hemolysis
• EVH extravascular hemolysis
• the subject e.g., patient
• the disclosure provides use of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, in the manufacture of a medicament for the treatment of PNH associated hemolysis in a subject, e.g., patient, in need thereof, wherein the treatment comprises orally administering to the subject, e.g., patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous free base of LNP023 hydrochloride), to thereby treat the subject, e.g., patient.
• LNP023 or a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• the Phase 3 study will enroll PNH patients with diagnosis confirmed by high-sensitivity flow cytometry (clone size of >10%) who despite being treated with SoC (eculizumab or ravulizumab) experience residual anemia defined as hemoglobin ⁇ 10 g/dL, with or without regular red blood cell transfusions in the past 6 months.
• PNH blood cells lack the glycophosphatidylinositol (GPI) anchor protein (GPI-AP) and are deficient in the membrane- bound complement inhibitory proteins CD55 and CD59.
• GPI-AP glycophosphatidylinositol
• LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride can inhibit complement activation.
• a subject e.g, a patient
• LNP023 or a pharmaceutically acceptable salt thereof, e.g, LNP023 hydrochloride can inhibit complement activation.
• a subject e.g, a patient
• LNP023 hydrochloride by first evaluating the patient to determine whether the subject, e.g., patient, has GPI-AP deficient blood cells, e.g, peripheral blood cells, and if the subject, e.g., patient, is determined to have GPI-AP deficient peripheral blood cells, then optionally administering to the subject, e.g, patient, LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• high-sensitivity flow cytometry is used to determine whether the patient has GPI-AP deficient peripheral blood cells, e.g., in about 2 or more cell lineages.
• the subject e.g, patient
• PK/PD parameters such as the level of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, the level of LDH, the level of hemoglobin, and PNH clone size.
• Also provided herein is a method of assessing the efficacy of treatment in a patient population treated with LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g, about every 12 hours, the method comprising determining the percentage of the patient population achieving an increase, e.g., a sustained increase, in hemoglobin levels as compared to baseline, to thereby assess efficacy of treatment, wherein baseline is the level of hemoglobin in a patient population prior to administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g, LNP023 hydrochloride.
• the increase, e.g., sustained increase, in hemoglobin levels from baseline is about 1.5 g/dL or more, about 2 g/dL or more, about 2.5 g/dL or more, about 3 g/dL or more, about 3.5 g/dL or more, about 4 g/dL or more, about 4.5 g/dL or more, or about 5 g/dL or more.
• the increase, e.g, sustained increase, in hemoglobein levels from baseline is about 2 g/dL or more, e.g, as compared to the hemoglobin levels in the patient prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• the increase in hemoglobin levels is sustained for at least about 18 weeks after administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride. In an embodiment, the increase in hemoglobin levels is sustained for at least about 24 weeks after administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g, LNP023 hydrochloride.
• the increase in hemoglobin levels is sustained for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, or at least about 12 months after administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• At least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% of the patient population has achieved an increase, e.g., a sustained increase, in hemoglobin levels, e.g., as compared to the hemoglobin levels in the patient prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• the patients have or are diagnosed as having PNH.
• the disclosure provides a method of assessing efficacy of treatment in a population of patients treated with LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride, at a dose of about 200 mg twice daily (b.i.d.), e.g., about every 12 hours, the method comprising determining the percentage of the population of patients achieving hemoglobin levels of, e.g., about 12 g/dL or more, to thereby assess efficacy of treatment.
• LNP023 or a pharmaceutically acceptable salt thereof e.g., LNP023 hydrochloride
• the patients have or are diagnosed as having PNH.
• At least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 99% of the patient population has achieved an increase, e.g., a sustained increase, in hemoglobin levels, e.g., as compared to the hemoglobin levels in the patient prior to treatment with LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• the increase in hemoglobin levels is sustained for at least about 18 weeks after administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride. In an embodiment, the increase in hemoglobin levels is sustained for at least about 24 weeks after administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g, LNP023 hydrochloride.
• the increase in hemoglobin levels is sustained for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, or at least about 12 months after administration of LNP023 or a pharmaceutically acceptable salt thereof, e.g., LNP023 hydrochloride.
• Example 1 A randomized, multicenter, active-comparator controlled, open label trial to evaluate efficacy and safety of LNP023 hydrochloride, administered oral, twice daily in adult patients with PNH and residual anemia, despite treatment with an intravenous anti- C5 antibody
• This Phase 3 study is to determine whether LNP023 hydrochloride is efficacious and safe for the treatment of PNH through demonstration of superiority of LNP023 hydrochloride compared to anti-C5 antibody treatment.
• This Phase 3 study has a 24-week randomized, active comparator controlled, open-label study period and a 24-week open-label extension period. Efficacy will be evaluated by the proportion of participants achieving the primary hemoglobin response criteria in the absence of red blood cell transfusions, as well as other hematological response endpoints, transfusion avoidance, breakthrough hemolysis rates and fatigue scores (FACIT-Fatigue, a patient reported outcome questionnaire).
• the primary objectives are to:
• the secondary objectives are to:
• the exploratory objectives are to: 1) assess safety and tolerability of LNP023 compared to anti-C5 treatment with safety evaluations including, adverse events/serious adverse events, safety laboratory parameters, vital signs etc. ;
• This study is a multi-center, randomized, open-label, active comparator-controlled, parallel group study, which is comprised of three periods (see FIG. 1):
• the study will enroll PNH patients with residual anemia, defined as hemoglobin ⁇ 10 g/dL, despite stable regimen of anti-C5 antibody treatment (eculizumab or ravulizumab) in the last 6 months before Randomization, with approximately 40% of participants having received at least 1 packed-RBC transfusions in the 6 months prior to randomization. A total of approximately 91 participants will be randomized in the trial. All participants must provide written informed consent prior to start of any study-related activities.
• the study design is shown in FIG. 1.
• Phase 3 study is designed as a multicenter, open-label, randomized, active- comparator controlled, parallel group study for demonstration of superiority of LNP023 hydrochloride at a dose of 200 mg b.i.d. orally compared to intravenous anti-C5 antibody treatment on hematological response parameters and patient reported outcome measures for fatigue, in patients with PNH that present with residual anemia despite treatment with a stable regimen of anti-C5 antibody treatment (SoC).
• SoC stable regimen of anti-C5 antibody treatment
• Patient eligibility will be determined before the start of the run-in period (based on the assessments performed at Visit 1). Inclusion and exclusion criteria will be assessed to verify participants' eligibility for enrollment into the study.
• the screening assessments are listed in FIG. 2
• Vaccines should cover as many serotypes as possible (including meningococcal serotypes A, C, Y, W-135 and B). To minimise patient burden, the use of multivalent vaccines is recommended as locally available and per local guidelines and regulations (e.g. quadrivalent vaccine for N. meningitidis which covers serotypes A, C, Y and W-135 and Pneumovax-23 which covers 23 S. pneumoniae serotypes).
• participant will have two different samples collected during the screening period and tested by the central laboratory with the mean ⁇ -10 g/dL, prior to Randomization.
• the patient is eligible based on the initial central hemoglobin value if ⁇ 10 g/dL.
• Participants who meet the eligibility criteria at screening will be stratified based on the type of prior anti-C5 antibody treatment (eculizumab or ravulizumab) and based on the transfusion history as reported during the last 6 months prior to Randomization (i.e. transfusion received/not received). It is assumed that approximately 40% of randomized participants having received at least one packed red blood cell (pRBC) transfusion in the 6 months prior to randomization.
• pRBC packed red blood cell
• Randomization and Randomized Treatment Period Participants will be randomized to one of the two treatment arms in a 8:5 ratio to either LNP023 hydrochloride monotherapy at a dose of 200 mg orally b.i.d. (approximately 56 participants), or i.v. anti-C5 antibody treatment (approximately 35 participants continuing with the same regimen during the Randomized treatment period as they were on prior to randomization), respectively.
• Treatment will start on the first day of dosing (Day 1) and continue for 24 weeks with study visits and corresponding assessments according to schedule described in fig. 2. Participants assigned to the comparator arm will continue receiving the same type, and regimen of anti-C5 antibody treatment as received prior to randomization, while those randomized to the LNP023 hydrochloride treatment arm will start taking LNP023 hydrochloride at dose of 200 mg b.i.d.
• the participants randomized to the active comparator arm will be offered to switch to LNP023 hydrochloride on Day 168 (Week 24 visit) and enter the Extension treatment period, after receiving a last dose of anti-C5 (eculizumab or ravulizumab) antibody treatment.
• Week 24 will be the End of Study visit for the trial and there will be no participation in the Extension period.
• the Extension treatment will start on the day after completion of the Week 24 visit.
• Stable regimen dose and intervals of anti-C5 antibody treatment (either eculizumab or ravulizumab) for at least 6 months prior to Randomization
• Vaccination against Neisseria meningitidis infection is required prior to the start of treatment. If the patient has not been previously vaccinated, or if a booster is required, vaccine should be given, as available and according to local regulations, at least 2 weeks prior to first dosing.
• a history of recurrent invasive infections caused by encapsulated organisms e.g. meningococcus or pneumococcus.
• Major concurrent comorbidities including but not limited to severe kidney disease (e.g., dialysis), advanced cardiac disease (e.g., NYHA class IV), severe pulmonary disease (e.g., severe pulmonary hypertension (WHO class IV)), or hepatic disease (e.g., active hepatitis) that in the opinion of the investigator precludes participant's participation in the study.
• severe kidney disease e.g., dialysis
• advanced cardiac disease e.g., NYHA class IV
• severe pulmonary disease e.g., severe pulmonary hypertension (WHO class IV)
• hepatic disease e.g., active hepatitis
• Participants will be randomized in an 8:5 ratio to either LNP023 hydrochloride monotherapy given orally b.i.d. (where the anti-C5 antibody treatment will be stopped - See below for timing), or intravenous anti-C5 antibody treatment (continuing with the same dose as that received prior to Randomization).
• the timing of the first LNP023 hydrochloride administration will provide a seamless switch from prior anti-C5 antibody treatment to LNP023 hydrochloride, allowing for some overlap of exposure to anti-C5 antibody treatment when starting the oral agent while limiting the potential risk of breakthrough hemolysis, as the LNP023 hydrochloride exposure builds-up.
• First LNP023 hydrochloride dose administration of participants on prior eculizumab regimen should occur at the start of the 2nd week of the 2- week dosing interval (i.e, preferably around days 7-to-8 after last infusion)
• First LNP023 hydrochloride dose administration for participants on prior ravulizumab regimen should occur at the beginning of the 7 th week of the 8-week dosing interval (preferably around days 41-to-43 after the last infusion)
• the "study treatment” includes the investigational drug, LNP023 hydrochloride, and the active comparators of anti-C5 antibodies (either eculizumab or ravulizumab).
• the duration of the Randomized Treatment period is 24 weeks. If a participant’s treatment with LNP023 hydrochloride is discontinued (e.g. due to lack of efficacy) and patient is switched back to the prior anti-C5 antibody treatment, every effort will be made to continue with the study assessments up to the Week 24 visit.
• the Extension period will last up to 24 weeks, where participants randomized to LNP023 hydrochloride arm during the Randomized treatment period will continue with LNP023 hydrochloride treatment, and participants randomized to anti-C5 arm will be offered to switch to LNP023 hydrochloride monotherapy.
• Dose and Duration of Treatment Rationale The dose of 200 mg LNP023 hydrochloride b.i.d. as continuous treatment has been selected for this Phase 3 study primarily based on the available efficacy and safety data obtained at the time of interim analyses from the two ongoing Phase 2 PNH studies (ClinicalTrials.gov Identifier: NCT03439839 and NCT03896152) and is supported by PKPD modeling results.
• LNP023 hydrochloride at a dose of 200 mg b.i.d. was administered to 10 PNH participants (cohort 1) and at a dose of 50 mg b.i.d. to 6 PNH participants (cohort 2).
• An interim analysis (IA) was conducted after 10 participants (cohort 1) completed at least 12 weeks of treatment with LNP023 hydrochloride 200 mg b.i.d. add-on treatment to eculizumab.
• the dose of 200 mg b.i.d. is expected to provide optimal efficacy required for PNH as monotherapy with an adequate safety profile based on the following key findings of the two interim analyses:
• add-on therapy was maintained with LNP023 hydrochloride monotherapy during the extension period (at the time of the IA) when eculizumab treatment was discontinued in 5/10 participants who continued with LNP023 hydrochloride monotherapy. Following the I A, two additional participants discontinued eculizumab treatment. C3 deposition was fully reversed by addition of LNP023 hydrochloride at a dose of 200 mg b.i.d. and survival of PNH red blood cells prolonged further supporting control of EVH by LNP023 hydrochloride at a dose of 200 mg b.i.d. There was sustained inhibition of the complement alternative pathway and profound and sustained reduction of Fragment Bb demonstrating target engagement.
• LNP023 hydrochloride monotherapy Participants receiving LNP023 hydrochloride monotherapy showed that LNP023 hydrochloride at dose levels ⁇ 25 mg b.i.d. had LDH reduction of more than 60% from baseline in all participants and early transfusion-free hemoglobin increase in the majority of participants. Other hemolysis relevant laboratory values indicated that LNP023 hydrochloride administered as monotherapy controls both, intra (LDH reduction) and extravascular hemolysis (decrease of reticulocytes and bilirubin, increase in haptoglobin).
• LNP023 hydrochloride at a dose of 200 mg b.i.d. was safe and well tolerated by participants in both studies in PNH, as well as at the same dose in patients with IgA nephropathy (study CLNP023X2203) and C3 glomerulopathy (CLNP023X2202), supporting its use in this Phase 3 study.
• Gemfibrozil (a potent inhibitor of metabolizing enzymes CYP2C8, UGT1A and liver uptake transporter OATP1B1) must be interrupted 48 hours before first LNP023 hydrochloride dose until end of LNP023 hydrochloride treatment (and replaced with another appropriate medication used for that indication).
• the assessment schedule (FIGs. 2 and 3) lists all of the assessments when they are performed.
• mean hemoglobin ⁇ 10 g/dL will be confirmed by central laboratory assessment prior to Randomization evaluated by two hemoglobin measurements, (mean ⁇ 10 g/dL), two up to eight weeks apart; or by one hemoglobin measurement ( ⁇ 10 g/dL) from the first assessment for patients receiving a pRBC transfusion after the first assessment. If a participant receives a packed-RBC transfusion following the first assessment carried out for the Screening visit (central laboratory), he/she will be eligible without an additional hemoglobin assessment by the central laboratory.
• Blood samples for hematology, clinical chemistry and C3 + RBCs, PNH type II/III RBCs and PNH clone size will be collected according to the schedule in FIG. 2 for the Randomized Treatment period.
• Hemoglobin and also haptoglobin
• reticulocyte count and bilirubin as makers for extravascular hemolysis
• LDH as a marker for intravascular hemolysis
• RBCs PNH clone size, PNH type RBCs as well as C3 + on PNH type RBCs.
• LDH lactate dehydrogenase
• UNN Upper Limit of Normal
• FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. It will be used to assess patient-reported fatigue.
• FACIT-Fatigue is one of many different FACIT scales part of a collection of Health-Related Quality of Life (HRQoL) questionnaires referred to as the FACIT Measurement System (Webster K, Celia D, and Yost K. (2003).
• HRQoL Health-Related Quality of Life
• FACIT Measurement System Webster K, Celia D, and Yost K. (2003).
• the functional assessment of chronic illness therapy (FACIT) measurement system properties, applications, and interpretation. Health Qual Life Outcomes; 16:1-79; Yellen SB, et al. (1997).
• FACT cancer therapy
• PK samples will be collected at the visits defined in the assessment schedule (FIGs. 2 and 3). Pharmacokinetic (PK) samples will be obtained and evaluated in all participants taking LNP023 hydrochloride. LNP023 hydrochloride will be determined by a validated LC-MS/MS method; the anticipated Lower Limit of Quantification (LLOQ) is 1.0 ng/mL. Metabolites (as needed) may be determined as appropriate. Concentrations will be expressed in mass per volume units (ng/mL) and will refer to the anhydrous free base.
• Discontinuation of study treatment for a participant occurs when study treatment is stopped earlier than the protocol planned duration and can be initiated by either the participant or the investigator.
• LNP023 hydrochloride If treatment with LNP023 hydrochloride has to be discontinued prematurely but it is not warranted to immediately discontinue LNP023 hydrochloride treatment, i.e. discontinuation due to participant/guardian decision or confirmed pregnancy, it is recommended to promptly re initiate the anti-C5 antibody treatment, as judged by the investigator. In addition, it should be considered to taper down LNP023 hydrochloride over a period of 14 days, as follows:

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