Use of factor B inhibitors for the treatment of age-related macular degeneration - Patents.com

Abstract

Described herein are methods for treating early or intermediate age-related macular degeneration with the factor B inhibitor iptacopan, or a pharma- ceutically acceptable salt thereof, such as iptacopan hydrochloride.

Description

[Technical field]

[0001] The present disclosure relates to methods of treating complement-driven diseases, and in particular age-related macular degeneration, with the factor B inhibitor iptacopan or a pharma- ceutically acceptable salt thereof, such as iptacopan hydrochloride. [Background technology]

[0002] Age-related macular degeneration (AMD) is the leading cause of visual impairment in the elderly population in developed countries, with approximately 11 million people affected by AMD in the United States overall, and a global prevalence of 170 million (Pennington and DeAngelis Eye Vis (Lond), 34, 2016), which is expected to increase with the aging population.

[0003] Early and intermediate AMD (e / iAMD) are characterized by the formation of drusen (lipid deposits containing complement proteins) and pigmentary changes in the macula, with mild to moderate loss of visual function, especially under low light conditions (Schneck et al, Optom Vis Sci; 64-72, 2021). Early AMD is defined as drusen sizes ≥ 63 μm and ≤ 125 μm, and intermediate AMD is defined by drusen > 125 microns and / or pigmentary changes. High-risk intermediate AMD patients have a 50% risk of conversion to late-onset wet (n) AMD or geographic atrophy (GA) over a 5-year period (Ferris et al, Arch Ophthalmol; 1570-4, 2005). Patients with GA have significant visual impairment and continue to progress until visual acuity deteriorates and they become legally blind (Chakravarthy et al, Ophthalmology; 842-849, 2018). Attempts to delay GA have been of limited effectiveness, highlighting the need for earlier treatment of the disease process (Guymer, Ophthalmol Retina; 515-517, 2018). Anti-VEGF injections can reduce the retinal fluid blindness observed in nAMD, but do not prevent the underlying disease progression and development of atrophy. Anti-VEGF reduces visual morbidity from nAMD, but 98% of patients treated with IVT anti-VEGF therapy will continue to develop atrophy by 7 years of follow-up (Rofagha et al, Ophthalmology; 2292-9, 2013). The lack of treatment for GA and the progression of nAMD to GA highlight the need for earlier treatment of the disease.

[0004] Spectral-domain optical coherence tomography (SD-OCT) has made it possible to identify high-risk features that are highly predictive of progression to late AMD. These features include intraretinal hyperintense lesions (thought to represent migration of retinal pigment epithelial cells (RPE) into the retina), hypointense lesions within drusen (corresponding to calcific nodules), subretinal drusen-like deposits, and high central drusen volume. Recently, researchers (Lei et al, Arch Clin Exp Ophthalmol; 1551-1558, 2017) proposed a system using OCT images to combine these factors into a simple score that can reflect a given patient's risk of conversion to late AMD. This system was later validated by Nassisi et al (Ophthalmology; 1667-1674 2019) in a post-hoc analysis of fellow eyes without late AMD from subjects enrolled in the HARBOR study. Fellow eyes without late AMD at baseline (including intermediate, early, or normal aging) who had one or more high-risk OCT features showed a 2-year conversion rate to advanced AMD of 33.1% to 84.4%.

[0005] Inflammatory and immune-mediated events involving complement proteins have been linked to the biogenesis of drusen. Overactivity of the alternative complement pathway is strongly associated with AMD pathology (Fritsche et al, Nat Genet; 433-9, 439e1-2, 2013). The RPE-choroid has been considered as a key site of complement dysregulation in AMD. Inhibition of the alternative RPE-choroid pathway (AP) can slow or halt choroidal shedding, thereby promoting blood flow to the RPE and allowing better nutrient transfer to the retina as well as improved retina / RPE waste clearance. Furthermore, inhibition of AP activation within drusen and at the Bruch's membrane / RPE interface may improve the health and function of RPE cells and associated photoreceptors, thereby reducing disease activity in nAMD (Kauppien et al, Cell Mol Life Sci; 1765-86, 2016). Oral factor B inhibitors can reduce RPE-choroidal complement activation, preventing the progression of e / iAMD to atrophy and reducing nAMD disease activity.

[0006] LNP023, also known as iptacopan, is a novel, orally administered, low molecular weight, first-in-class selective protease inhibitor that binds to the Bb domain of factor B (FB). FB is a key protease of the alternative pathway (AP), and the Bb domain is the active portion of the C3 and C5 convertases of AP. Inhibiting FB with oral iptacopan or its pharma- ceutically acceptable salts, such as iptacopan hydrochloride, may prevent or reduce the formation of drusen, thus reducing the conversion of e / iAMD and providing a therapeutic benefit beyond the current standard of care (SoC). In addition, the oral route of administration offers advantages to patients compared to the current intraocular route of administration of SoC. Summary of the Invention

[0007] The present disclosure relates to a method for treating complement-driven diseases and in particular early or intermediate age-related macular degeneration with iptacopan or its pharma- ceutically acceptable salt, such as iptacopan hydrochloride. Iptacopane belongs to the class of factor B inhibitors of the complement pathway, and acts independently of the initial mechanism of activation by inhibiting or suppressing the amplification of the complement system caused by the activation of C3. Iptacopane hydrochloride is currently in clinical development for treating paroxysmal nocturnal hemoglobinuria (PNH). Iptacopane hydrochloride is chemically referred to 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: [ka]

[0008] Iptacopane hydrochloride and methods for preparing it are disclosed in WO 2015 / 009616, which is incorporated by reference in its entirety (see Example 26d).

[0009] In one aspect, the disclosure provides a method of treating age-related macular degeneration (AMD) in an eye of a subject in need thereof, comprising orally administering iptacopan or a pharma- ceutically acceptable salt thereof to the subject at a total dose of about 400 mg per day (dosage refers to the anhydrous free base of iptacopan). In some embodiments, the administration treats a subject, e.g., a patient.

[0010] In another aspect, the disclosure provides a method for reducing the incidence of progression of early or intermediate age-related macular degeneration (AMD) in a patient in need thereof, comprising orally administering iptacopan or a pharma- ceutically acceptable salt thereof to a subject at a dose of about 400 mg per day (dosage refers to the anhydrous free base of iptacopan).

[0011] In another aspect, the disclosure provides a method for preventing the progression of early or intermediate age-related macular degeneration (AMD) in a patient in need thereof, comprising orally administering iptacopan or a pharma- ceutically acceptable salt thereof to a subject at a dose of about 400 mg per day (dosage refers to the anhydrous free base of iptacopan).

[0012] In another aspect, the disclosure provides a method of reducing the occurrence of atrophic lesions in a patient in need thereof, comprising orally administering iptacopan or a pharma- ceutically acceptable salt thereof to a subject at a dose of about 400 mg per day (dosage refers to the anhydrous free base of iptacopan).

[0013] The treatment methods described herein may additionally include various evaluation steps before and / or after treatment with iptacopan or a pharmaceutically acceptable salt thereof, such as iptacopan hydrochloride. In one embodiment, before and / or after administration of iptacopan or a pharmaceutically acceptable salt thereof, such as iptacopan hydrochloride, the method further includes a step of evaluating PK and PD parameters (e.g., plasma concentration of iptacopan or a pharmaceutically acceptable salt thereof, such as iptacopan hydrochloride, C3, fragment Bb, or sC5B). Evaluation may be achieved, for example, by mass spectroscopy, such as LC-MS, by sample analysis of body fluids, such as blood or plasma. [Brief description of the drawings]

[0014] [Figure 1] A schematic diagram of the study design is shown. [Diagram 2] Table 1 shows the sub-study design of ambulatory MCVM. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Described herein is a Phase 2 clinical study to determine the safety and efficacy of iptacopan or its pharmaceutically acceptable salt, such as iptacopan hydrochloride, in patients with early and intermediate age-related macular degeneration (e / iAMD).Therefore, described herein is a method of treating e / iAMD in a patient in need thereof, comprising orally administering to the patient two doses of iptacopan or its pharmaceutically acceptable salt, such as iptacopan hydrochloride, daily, for example, about every 12 hours, in tablet or capsule form (dosage refers to the anhydrous free base of iptacopan hydrochloride).Described herein is also a method of selecting a target patient population, a method of monitoring the treatment of the target patient population, and a method of evaluating the safety and efficacy of the treatment of the target patient population.

[0016] Details of the present disclosure are set forth in the attached specification below. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present disclosure, exemplary methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the specification and claims. In the specification and the appended claims, the singular forms include the plural, unless otherwise clearly indicated. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety.

[0017] definition Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis and chemical analysis. Certain such techniques and procedures may be found, for example, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 21st edition, 2005, which is incorporated herein by reference for all purposes. Where permitted, all patent applications, published applications, and other publications and other data cited throughout this disclosure are incorporated herein by reference in their entirety.

[0018] Unless otherwise stated, the following terms have the following meanings: As used herein, "about" means within ±10% of the value.

[0019] "Administering" or "administration" as used herein means providing a pharmaceutical agent to an individual, including, but not limited to, administration by a medical professional and self-administration. Administration of a pharmaceutical agent to an individual can be continuous, chronic, brief or intermittent.

[0020] The term "obtain" or "obtaining" as used herein refers to taking possession of a physical entity (e.g., a sample, e.g., a blood sample or plasma sample) or a value, e.g., a numerical value, by "directly obtaining" or "indirectly obtaining" a physical entity or value. "Directly obtaining" means performing a process (e.g., an analytical method) to obtain the physical entity or value. "Indirectly obtaining" refers to receiving the physical entity or value from another party or source (e.g., a third party lab that directly obtains the physical entity or value). Directly obtaining a value includes performing a process that involves a physical change of a sample or another substance, e.g., performing an analytical process that involves a physical change of a substance, e.g., a sample, performing an analytical method, e.g., a method described herein, e.g., by analysis of a sample of a body fluid, e.g., blood, e.g., by mass spectroscopy, e.g., LC-MS, e.g., LC-MS / MS methods.

[0021] As used herein, "dose" refers to a specified amount of a pharmaceutical agent provided in a single administration or within a specified time period. In certain embodiments, a dose may be administered in a capsule. As used herein, dosage refers to the anhydrous free base of iptacopane hydrochloride.

[0022] As used herein, "individual," "patient," "participant," or "subject" means a human selected for treatment or therapy.

[0023] As used herein, "pharmaceutical acceptable salt" refers to a physiologically and pharmaceutical acceptable salt of iptacopan, i.e., a salt that retains the desired biological activity of iptacopan and does not impart undesired toxic effects. The term "pharmaceutical acceptable salt" or "salt" includes salts prepared from pharmaceutical acceptable non-toxic acids or bases, including inorganic or organic acids and inorganic or organic bases. "Pharmaceutical acceptable salts" of iptacopan can be prepared by methods well known in the art. For a review of pharmaceutical acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002). Iptacopane hydrochloride and its preparation method are disclosed in WO 2015 / 009616 (see Example 26d), which are incorporated herein by reference in their entirety.

[0024] As used herein, the term "treat" means to slow, inhibit, attenuate, reduce, arrest or stabilize the onset or progression of a disorder or disease, such as e / iAMD.

[0025] Unless otherwise specified, conventional definitions of controlling terms and conventional stable atom valences are presumed to be achieved in all formulas and groups.

[0026] The articles "a" and "an" are used in this disclosure to refer to one or to more than one (e.g., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0027] How to use In some embodiments, provided herein is a method of treating age-related macular degeneration (AMD) in an eye of a subject in need thereof, comprising orally administering iptacopan or a pharma- ceutically acceptable salt thereof to the subject at a total dose of about 400 mg per day (dosage refers to the anhydrous free base of iptacopan). In some embodiments, the administration treats a subject, e.g., a patient.

[0028] In one embodiment, the AMD is early AMD.

[0029] In one embodiment, the AMD is intermediate AMD.

[0030] In one embodiment, iptacopan is administered twice daily.

[0031] In one embodiment, iptacopan is administered at a dose of 200 mg twice daily.

[0032] In one embodiment, iptacopan is administered at a dose of 100 mg four times daily.

[0033] In one embodiment, iptacopan is administered for at least one month.

[0034] In one embodiment, iptacopan is administered for at least six months.

[0035] In one embodiment, iptacopan is administered for at least one year.

[0036] In one embodiment, iptacopan is administered for about two years.

[0037] In one embodiment, administration of iptacopan results in a reduction in ocular vision loss compared to administration of a placebo.

[0038] In one embodiment, blindness is diagnosed by the following tests: Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA); ETDRS low light visual acuity (LLVA), Contrast Sensitivity (CS), or Low Luminance Contrast Sensitivity (LLCS) It is measured by one or more of the following:

[0039] Best corrected visual acuity (BCVA) may be measured using the ETDRS eye chart at 4 meters, or at 1 meter for participants unable to read the 4 meter eye chart. In some embodiments, the subject's ETDRS score on either the BCVA or LLVA assessment is at least 1 row (5 letters), 2 rows (10 letters), or 3 rows (15 letters) higher compared to administration of placebo.

[0040] In one embodiment, administration of iptacopan reduces the formation of drusen in the eye compared to placebo. In some embodiments, administration of iptacopan reduces the formation of drusen by about 10%, about 20%, about 30%, about 40%, or about 50% compared to placebo. In some embodiments, administration of iptacopan reduces the formation of drusen by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to placebo.

[0041] In one embodiment, administration of iptacopan reduces the occurrence of atrophic lesions in the subject's eye. In some embodiments, administration of iptacopan reduces the occurrence of atrophic lesions by about 10%, about 20%, about 30%, about 40%, or about 50% compared to placebo. In some embodiments, administration of iptacopan reduces the occurrence of atrophic lesions by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to placebo.

[0042] In one embodiment, administration of iptacopan reduces the occurrence and / or magnitude of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) in the eye compared to administration of a placebo. In some embodiments, administration of iptacopan reduces expression of iRORA by about 10%, about 20%, about 30%, about 40%, or about 50% compared to a placebo. In some embodiments, administration of iptacopan reduces expression of iRORA by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to a placebo.

[0043] In one embodiment, the subject, e.g., patient, has been diagnosed with early or intermediate AMD.

[0044] In one embodiment, the subject, e.g., patient, is vaccinated prior to treatment with iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride.

[0045] In one embodiment, the subject, e.g., patient, is vaccinated against Neisseria meningitidis (types A, C, Y and W-135) prior to treatment.

[0046] In some embodiments, provided herein is a method for reducing the incidence of progression of early or intermediate age-related macular degeneration (AMD) in an eye of a patient in need thereof, the method comprising orally administering iptacopan or a pharma- ceutically acceptable salt thereof to a subject at a dose of about 400 mg per day (dosage refers to the anhydrous free base of iptacopan).

[0047] In one embodiment, iptacopan is administered twice daily.

[0048] In one embodiment, iptacopan is administered at a dose of 200 mg twice daily.

[0049] In one embodiment, iptacopan is administered at a dose of 100 mg four times daily.

[0050] In one embodiment, iptacopan is administered for at least one month.

[0051] In one embodiment, iptacopan is administered for at least six months.

[0052] In one embodiment, iptacopan is administered for at least one year.

[0053] In one embodiment, iptacopan is administered for about two years.

[0054] In one embodiment, administration of iptacopan results in a reduction in ocular vision loss compared to administration of a placebo.

[0055] In one embodiment, blindness is diagnosed by the following tests: Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA); ETDRS low light visual acuity (LLVA), Contrast Sensitivity (CS), or Low Luminance Contrast Sensitivity (LLCS) It is measured by one or more of the following:

[0056] Best corrected visual acuity (BCVA) may be measured using the ETDRS eye chart at 4 meters, or at 1 meter for participants unable to read the 4 meter eye chart. In some embodiments, the subject's ETDRS score on either the BCVA or LLVA assessment is at least 1 row (5 letters), 2 rows (10 letters), or 3 rows (15 letters) higher compared to administration of placebo.

[0057] In one embodiment, administration of iptacopan reduces the formation of drusen in the eye compared to placebo. In some embodiments, administration of iptacopan reduces the formation of drusen by about 10%, about 20%, about 30%, about 40%, or about 50% compared to placebo. In some embodiments, administration of iptacopan reduces the formation of drusen by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to placebo.

[0058] In one embodiment, administration of iptacopan reduces the occurrence of atrophic lesions in the subject's eye. In some embodiments, administration of iptacopan reduces the occurrence of atrophic lesions by about 10%, about 20%, about 30%, about 40%, or about 50% compared to placebo. In some embodiments, administration of iptacopan reduces the occurrence of atrophic lesions by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to placebo.

[0059] In one embodiment, administration of iptacopan reduces the occurrence and / or magnitude of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) in the eye compared to administration of a placebo. In some embodiments, administration of iptacopan reduces expression of iRORA by about 10%, about 20%, about 30%, about 40%, or about 50% compared to a placebo. In some embodiments, administration of iptacopan reduces expression of iRORA by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to a placebo.

[0060] In one embodiment, the subject, e.g., patient, is vaccinated prior to treatment with iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride.

[0061] In one embodiment, the subject, e.g., patient, is vaccinated against Neisseria meningitidis (types A, C, Y and W-135) prior to treatment.

[0062] In some embodiments, provided herein is a method for preventing the progression of early or intermediate age-related macular degeneration (AMD) in the eye of a patient in need thereof, the method comprising orally administering iptacopan or a pharma- ceutically acceptable salt thereof to a subject at a dose of about 400 mg per day (dosage refers to the anhydrous free base of iptacopan).

[0063] In one embodiment, iptacopan is administered twice daily.

[0064] In one embodiment, iptacopan is administered at a dose of 200 mg twice daily.

[0065] In one embodiment, iptacopan is administered at a dose of 100 mg four times daily.

[0066] In one embodiment, iptacopan is administered for at least one month.

[0067] In one embodiment, iptacopan is administered for at least six months.

[0068] In one embodiment, iptacopan is administered for at least one year.

[0069] In one embodiment, iptacopan is administered for about two years.

[0070] In one embodiment, administration of iptacopan results in a reduction in ocular vision loss compared to administration of a placebo.

[0071] In one embodiment, blindness is diagnosed by the following tests: Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA); ETDRS low light visual acuity (LLVA), Contrast Sensitivity (CS), or Low Luminance Contrast Sensitivity (LLCS) It is measured by one or more of the following:

[0072] Best corrected visual acuity (BCVA) may be measured using the ETDRS eye chart at 4 meters, or at 1 meter for participants unable to read the 4 meter eye chart. In some embodiments, the subject's ETDRS score on either the BCVA or LLVA assessment is at least 1 row (5 letters), 2 rows (10 letters), or 3 rows (15 letters) higher compared to administration of placebo.

[0073] In one embodiment, administration of iptacopan reduces the formation of drusen in the eye compared to placebo. In some embodiments, administration of iptacopan reduces the formation of drusen by about 10%, about 20%, about 30%, about 40%, or about 50% compared to placebo. In some embodiments, administration of iptacopan reduces the formation of drusen by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to placebo.

[0074] In one embodiment, administration of iptacopan reduces the occurrence of atrophic lesions in the subject's eye. In some embodiments, administration of iptacopan reduces the occurrence of atrophic lesions by about 10%, about 20%, about 30%, about 40%, or about 50% compared to placebo. In some embodiments, administration of iptacopan reduces the occurrence of atrophic lesions by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to placebo.

[0075] In one embodiment, administration of iptacopan reduces the occurrence and / or magnitude of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) in the eye compared to administration of a placebo. In some embodiments, administration of iptacopan reduces expression of iRORA by about 10%, about 20%, about 30%, about 40%, or about 50% compared to a placebo. In some embodiments, administration of iptacopan reduces expression of iRORA by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to a placebo.

[0076] In one embodiment, the subject, e.g., patient, is vaccinated prior to treatment with iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride.

[0077] In some embodiments, provided herein is a method of reducing the occurrence of atrophic lesions in the eye of a patient in need thereof, comprising orally administering iptacopan or a pharma- ceutically acceptable salt thereof to a subject at a dose of about 400 mg per day (dosage refers to the anhydrous free base of iptacopan). In some embodiments, provided herein is a method of preventing atrophic lesions in the eye of a patient in need thereof, comprising orally administering iptacopan or a pharma- ceutically acceptable salt thereof to a subject at a dose of about 400 mg per day (dosage refers to the anhydrous free base of iptacopan).

[0078] In one embodiment, iptacopan is administered twice daily.

[0079] In one embodiment, iptacopan is administered at a dose of 200 mg twice daily.

[0080] In one embodiment, iptacopan is administered at a dose of 100 mg four times daily.

[0081] In one embodiment, iptacopan is administered for at least one month.

[0082] In one embodiment, iptacopan is administered for at least six months.

[0083] In one embodiment, iptacopan is administered for at least one year.

[0084] In one embodiment, iptacopan is administered for about two years.

[0085] In one embodiment, administration of iptacopan results in a reduction in ocular vision loss compared to administration of a placebo.

[0086] In one embodiment, blindness is diagnosed by the following tests: Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA); ETDRS low light visual acuity (LLVA), Contrast Sensitivity (CS), or Low Luminance Contrast Sensitivity (LLCS) It is measured by one or more of the following:

[0087] Best corrected visual acuity (BCVA) may be measured using the ETDRS eye chart at 4 meters, or at 1 meter for participants unable to read the 4 meter eye chart. In some embodiments, the subject's ETDRS score on either the BCVA or LLVA assessment is at least 1 row (5 letters), 2 rows (10 letters), or 3 rows (15 letters) higher compared to administration of placebo.

[0088] In one embodiment, administration of iptacopan reduces the formation of drusen in the eye compared to placebo. In some embodiments, administration of iptacopan reduces the formation of drusen by about 10%, about 20%, about 30%, about 40%, or about 50% compared to placebo. In some embodiments, administration of iptacopan reduces the formation of drusen by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to placebo.

[0089] In some embodiments, administration of iptacopan reduces the incidence of atrophic lesions in the eye by about 10%, about 20%, about 30%, about 40%, or about 50% compared to placebo. In some embodiments, administration of iptacopan reduces the incidence of atrophic lesions by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to placebo.

[0090] In one embodiment, administration of iptacopan reduces the occurrence and / or magnitude of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) in the eye compared to administration of a placebo. In some embodiments, administration of iptacopan reduces expression of iRORA by about 10%, about 20%, about 30%, about 40%, or about 50% compared to a placebo. In some embodiments, administration of iptacopan reduces expression of iRORA by at least 10%, at least 20%, at least 30%, at least 40%, or at least 50% compared to a placebo.

[0091] In one embodiment, the subject, e.g., patient, is vaccinated prior to treatment with iptacopan or a pharma- ceutically acceptable salt thereof, e.g., iptacopan hydrochloride.

[0092] In any of the embodiments described herein, the subject may be vaccinated against Neisseria meningitidis (types A, C, Y, and W-135) prior to administration of iptacopan or a pharmaceutically acceptable salt thereof. EXAMPLES

[0093] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the present disclosure in scope or spirit of the specific procedures described herein. It should be understood that the examples are provided to illustrate specific embodiments and are not intended to limit the scope of the present disclosure. In addition, it should be understood that various other embodiments, modifications and their equivalents that may suggest themselves to those skilled in the art can be used without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0094] [Table 1]

[0095] [Table 2]

[0096] [Table 3]

[0097] [Table 4]

[0098] [Table 5]

[0099] [Table 6]

[0100] [Table 7]

[0101] [Table 8]

[0102] [Table 9]

[0103] Example 1. A Randomized, Participant- and Investigator-Blinded, Placebo-Controlled, Multicenter, Proof-of-Concept Study Evaluating the Safety and Efficacy of Iptacopane in Patients with Early and Intermediate Age-Related Macular Degeneration the purpose The aim of this study was to evaluate the efficacy of iptacopan in preventing eyes with early or intermediate AMD from transforming into new incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) or late AMD.

[0104] [Table 10]

[0105] [Table 11]

[0106] [Table 12]

[0107] research design The study design is a 29-month multicenter, randomized participant- and investigator-blinded, placebo-controlled, proof-of-concept study evaluating the safety and efficacy of iptacopan in patients with early-to-intermediate age-related macular degeneration (e / iAMD) in one eye and wet age-related macular degeneration (nAMD) in the other eye. All enrolled participants were required to have e / iAMD with at least one high-risk OCT feature in one eye (study eye) and nAMD in the other eye (fellow eye).

[0108] Consented participants will undergo a screening evaluation to assess eligibility based on the inclusion and exclusion criteria. Participants who meet all eligibility criteria will be randomized in a 1:1 ratio to one of two treatment arms at the Baseline / Day 1 visit: Iptakopan 200 mg orally twice daily Placebo, twice daily, orally

[0109] Participants will be stratified between the two arms according to the presence of hyperintense lesions as confirmed by optical coherence tomography (OCT) by a central reading center.

[0110] For both arms of the study, the fellow eye (the eye with nAMD) will be treated with anti-VEGF therapy according to the current local standard of care.

[0111] Approximately 146 participants (73 per arm) will be treated worldwide. The maximum study duration per participant will be approximately 880 days, including screening and post-treatment follow-up.

[0112] There are three periods in this study (see Figure 1): Screening period: Day -90 to Day -1 Treatment period: Baseline / Day 1 to Day 730 Follow-up period: (EOS): Post-study safety contact at 760 days / 25 months and 30 days after the EOS visit (approximately 60 days after the final procedure)

[0113] Screening period: Day -90 to Day -1 Eligibility will be assessed over a screening period of up to 90 days.

[0114] At the screening visit following administration of the informed consent form, assessments to determine eligibility will be performed including demographics, medical history, vital signs, height and weight, physical examination, ECG, pregnancy assessment, multiple imaging and visual tests, and blood samples to assess the participant's overall health and compliance with inclusion / exclusion criteria. During the screening period, biological samples and imaging evaluations will be performed to assess eligibility.

[0115] Once all eligibility requirements are met, if the participant has not been vaccinated against N. meningitidis, S. pneumoniae, and H. influenzae (or requires a booster vaccination), arrangements will be made for these vaccinations at least 2 weeks prior to the Baseline / Day 1 visit. Vaccination logistics will be managed by the study site. Sponsor may provide assistance if needed.

[0116] Rescreening of participants is permitted. As advised by the central reading center, in case of interpretation difficulties, image evaluation may be repeated to improve quality.

[0117] Retest assessments may be repeated within the screening window up to 89 days after the original screening visit. There is no need to repeat other screening assessments that were initially passed. If rescreening occurs outside the screening window more than 89 days after the original screening visit date, all screening procedures must be repeated.

[0118] Investigator / Participant Blinded Treatment Period: Baseline / Day 1 to Month 24 / Day 730 Eligible participants will be randomized in a 1 / 1 ratio to one of the following treatment arms: iptacopan or placebo treatment at the Baseline / Day 1 visit. At the time of randomization, a study visit schedule will be established for all participants. With the exception of the Baseline / Day 1 visit, assessments may be performed on two separate days, provided that both days are within the visit window and are within 3 days of each other. On Baseline / Day 1, the first dose of study treatment will be administered on-site before the participant leaves the clinic. After the first dose, participants will self-administer the study treatment (morning and evening) for the 24-month treatment period and will be seen at 11 follow-up visits.

[0119] On the day of the clinic visit, participants must complete a complete medical questionnaire, and have vital signs, an ECG, and all blood samples taken prior to dosing. Eye exams, imaging evaluations, ETDRS visual acuity, and contrast sensitivity measurements do not need to be completed prior to dosing.

[0120] At treatment visits, some or all of the following assessments will be performed to evaluate the safety and effectiveness of treatment: vital signs, height and weight, physical examination, ECG, pregnancy test, multiple imaging and visual tests including questionnaires, and blood samples will be taken to assess the participant's overall health and compliance with treatment. In addition, participants will be asked about their general health and the occurrence of any adverse events. At all study visits during the treatment period, participants will return study medication, including any bottles used on-site, any unused medication, and a participant diary to allow for drug quantity control. Participants will be resupplied with study medication at designated visits.

[0121] The final self-administration of study drug will occur the evening prior to the Month 24 (Day 30) visit (end of treatment).

[0122] End of study (EOS) visit: Month 25 / Day 760 All participants will be seen at Month 25 / Day 760 for an EOS visit, at which time all study assessments will be completed, including study completion information.

[0123] Follow-up period: (Post-study safety contact) Month 26 / Day 790 A post-procedure safety call will be conducted approximately 30 days after the EOS (month 25 / day 760) visit.

[0124] Mobile MCVM Inspection Participants at the selected sites who meet all screening requirements and are eligible to proceed to baseline / day 1 randomization will be asked to participate in a separate 2-month substudy designed to compare the mobile MCVM with a fixed MCVM device used in a clinic. The study population for the mobile MCVM test will consist of approximately 50 participants of both sexes who consent to this substudy.

[0125] Bilateral contrast sensitivity assessment studies will be performed using the mobile MCVM in the clinic at three visits including screening, baseline / day 1, and month 2. Duplicate testing will be performed at the baseline / day 1 and month 2 visits for reproducibility.

[0126] In addition to the clinic assessments, participants will also use the mobile MCVM at home to measure the test eye 5-10 minutes apart twice weekly (same time and location recommended) during the screening visit and the Month 2 visit. During weeks when a clinic visit is scheduled, it is recommended that the mobile MCVM home test be performed on the same day as the clinic visit. The substudy workflow is shown in Figure 2.

[0127] Study design rationale The study design was to evaluate the efficacy and safety objectives of oral iptacopan 200 mg twice daily for treating e / iAMD.

[0128] The study will be participant and investigator blinded and will remain sponsor unblinded (allowing for emergency unblinding in case of adverse events requiring knowledge of the treatment arm).

[0129] The primary endpoint of conversion to new iRORA or late AMD will be based on objective assessment by a central reading center blinded to treatment allocation. Intraretinal hyperintense lesions as seen on OCT are the most predictive risk factor for conversion, therefore participants with this risk factor will be randomized equally between the iptacopan arm and the placebo arm. The 2-year study treatment period will be based on publications on conversion to late AMD in patients with high-risk factors (Lei et al, Graefes Arch Clin Exp Ophthalmol; 1551-1558, 2017, Nassisi et al, Graefes Arch Clin Exp Ophthalmol; 2079-2085, 2019).

[0130] Randomization of treatment between active and placebo arms allows for objective assessment of safety and efficacy characteristics. All study participants undergo identical study evaluations and receive the assigned study treatment under the same dosing and visit intervals. Both treatment arms proceed in parallel with each other.

[0131] Rationale for dose / regimen and duration of treatment Because e / iAMD is a slowly progressive disease, long-term treatment and observation will be necessary to detect potential clinical benefits of iptacopan. A 24-month study was chosen to allow sufficient time to observe the time to conversion of e / iAMD eyes treated with iptacopan compared to e / iAMD eyes treated with placebo.

[0132] Iptacopane 200 mg twice daily was selected for this study based on the overall safety and efficacy data from studies in healthy volunteers and an interim analysis of part 1 of the Phase 2 study. In addition, this dose has been demonstrated to have a favorable benefit-risk ratio in Phase 2 studies in patients with C3G and PNH, including reduction in proteinuria to maintain hemoglobin (Hb) levels.

[0133] In a first-in-human study, iptacopan was administered to 102 healthy volunteers at single ascending doses (SAD, 10-400 mg) and multiple ascending doses (MAD, 10-200 mg twice daily for 2 weeks). Results showed that iptacopan was highly soluble, well permeable, rapidly absorbed, and well tolerated. No deaths, SAEs, or AEs leading to discontinuation of study drug were observed. In the MAD study, dose-dependent inhibition of AP activity was achieved as measured by the Wieslab AP assay, sustaining approximately 80% or greater inhibition over 14 days at doses of 100 mg and 200 mg twice daily, while Bb levels showed a 30-40% decrease from baseline in all iptacopan cohorts.

[0134] Phase 2 data showed that the 200 mg twice daily dosing regimen produced the highest response rates in all tested indications (PNH, IgAN, C3G) without any safety concerns. This was supported by the target occupancy data collected in these studies as well as PKPD modeling. Therefore, 200 mg twice daily was selected for this study, which served to explore efficacy and PK properties in a new participant population.

[0135] In addition, preclinical studies supported an acceptable safety margin for human exposure following dosing of 200 mg twice daily.

[0136] Participants' unbound systemic exposure (based on AUC) at 200 mg twice daily remained less than 17.3-fold the lowest exposure at which off-target testicular effects were observed in a 39-week dog study (LOAEL).

[0137] A margin of safety based on unbound systemic exposure results in a ratio (NOAEL) of 2.2 (based on AUC and Cmax) calculated for the most sensitive species and sex, male dogs, in a 39-week toxicity study.

[0138] The safety and tolerability of iptacopan at a dose of 200 mg twice daily is supported by a part 1 study in IgAN and other clinical studies in PNH and C3G in which some participants received iptacopan at 200 mg twice daily for more than 12 months. Part 1 of this study showed that iptacopan at a dose of 200 mg twice daily reduced proteinuria over 90 days, supporting iptacopan at 200 mg twice daily.

[0139] Rationale for the choice of comparator (comparator / placebo) or combination drug Because there are no approved products for the treatment of e / iAMD, the current study did not include an active comparator. The control for this study was a placebo treatment, which is a common and established method of control for studies of oral therapies where no approved treatments exist.

[0140] Study population The study population in the investigation consisted of male and female participants aged ≥50 years who were diagnosed with e / iAMD in the study eye and nAMD in the fellow eye. In addition to having at least early AMD, study eyes were required to have at least one high-risk feature on OCT (intraretinal hyperintense lesions, subretinal drusen-like deposits, hypointense lesions within drusen, or ≥0.03 mm within a central 3 mm circle). 3Participants must have a history of nAMD and be undergoing standard-of-care intravitreal anti-VEGF treatment (or be receiving it by baseline / day 1). Approximately 292 participants will be screened worldwide, and 146 participants will be randomized in a 1:1 ratio (n=73 in each study arm).

[0141] The investigator will ensure that all participants considered for the study meet the eligibility criteria. No additional criteria should be applied by the investigator to ensure that the study population is representative of all eligible participants.

[0142] Inclusion criteria Participants eligible for inclusion in the study must meet all of the following criteria prior to Baseline / Day 1: 1. Written informed consent must be obtained prior to any evaluation. 2. Male or female participants aged ≥ 50 years. 3. The study eye is diagnosed with early or intermediate AMD when measured by the investigator during fundus examination (if color fundus photographs are used, confirmation by a central reading center is not required). 4. The study eye (e / iAMD eye) must have at least one of the following OCT features: intraretinal hyperintense lesions, subretinal drusen-like deposits, hypointense lesions within drusen, or ≥ 0.03 mm within a central 3 mm circle on OCT as measured by a central reading center. 3 of drusen. 5. Diagnosis of nAMD in the fellow eye as determined by the investigator: Eyes with nAMD must have a history of exudative MNV (type 1, 2, or 3) and have been treated with an intravitreal anti-VEGF injection. Newly diagnosed nAMD who received their first anti-VEGF treatment at the Baseline / Day 1 visit are eligible. 6. Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections is required before starting treatment with iptacopan. If the participant has not been previously vaccinated or requires a booster vaccination, vaccination must be offered in accordance with local regulations at least 2 weeks prior to the first dose of iptacopan. 7. If not previously received, vaccination against Haemophilus influenzae infection should be offered, where feasible, and in accordance with local regulations. Vaccination should be offered at least 2 weeks prior to the first dose of iptacopan. 8. Able to communicate well with the investigator to understand and comply with the requirements of the study.

[0143] Exclusion criteria Participants who meet any of the following criteria are not eligible for inclusion in the study: 1. Has any concomitant medical or ophthalmic condition at Screening or Baseline / Day 1 that, in the investigator's opinion, may interfere with response to study treatment, confound interpretation of study results, impair vision, require planned medical or surgical intervention during the study (e.g., cataract surgery), or interfere with scheduled study visits, completion of the study, or safe administration of the investigational product. 2. Intraocular surgery, including cataract surgery and vitreoretinal surgery, in the study eye within 3 months prior to Baseline / Day 1. 3. Presence of significant medial ocular opacification, impaired ocular motility (nystagmus), severe ptosis, limited extraocular movements, or head tremor that, in the investigator's opinion, prevents adequate fundus visualization or interferes with the quality of the retinal image data. 4. Any active intraocular or periorbital infection or active intraocular inflammation (e.g., infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) in either eye at Screening or Baseline / Day 1. 5. Has active or suspected non-ocular infection (bacterial, viral, fungal or parasitic) at the Baseline / Day 1 visit (based on investigator judgment) or a history of severe recurrent bacterial infection. 6. Uncontrolled glaucoma in the study eye defined as an intraocular pressure (IOP) >25mmHG on medical treatment at screening. Controlled, stable glaucoma with IOP ≤25mmHG is acceptable if mild or moderate (optic nerve abnormalities consistent with glaucoma and glaucomatous visual field defects in one hemifield, no fixation within 5 degrees). 7. Presence of diabetic macular edema or history / presence of severe non-proliferative or proliferative diabetic retinopathy. 8. Vital signs at Screening or Baseline / Day 1 visit including: Body temperature <35.0 or >37.5°C Systolic blood pressure <90 or >180mm Hg Diastolic blood pressure <50 or >110mm Hg Resulting pulse rate <50 or >100 bpm. A pulse rate <50 bpm is acceptable in the absence of other clinically significant ECG abnormalities as determined by the investigator. Participants with a heart rate <50 bpm must provide evidence that they have no medical history of a) moderate or severe valvular disease; b) history of coronary artery disease, myocardial infarction, hypertension, or diabetes mellitus; c) history of cardiomyopathy, congenital heart defect, open heart surgery, or ongoing arrhythmia; d) family history of sudden death in first-degree relatives. Note: If the blood pressure measurement is elevated, the investigator may obtain up to two additional readings, resulting in a total of three consecutive measurements with the participant sitting quietly for at least five minutes before repeating each measurement. At a minimum, the final reading must be within range for the participant to be eligible. 9. History of clinically significant ECG abnormalities or any of the following ECG abnormalities at the Screening or Baseline / Day 1 visit: QTcF >450 ms (males). QTcF >460 ms (females). Have a personal history of familial long QT syndrome or a known family history of torsades de pointes. 10. History of stroke or myocardial infarction during the 6 month period prior to Baseline / Day 1, any current clinically significant arrhythmia or any progressive cardiac hypertension or severe pulmonary hypertension. 11. History of renal failure, including end-stage renal failure requiring dialysis or kidney transplant. 12. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or cervical intraepithelial neoplasia), treated or untreated, within 5 years prior to Baseline / Day 1, with or without evidence of local recurrence or metastasis. 13. History of solid organ transplant or bone marrow transplant. 14. History of recurrent meningitis or meningococcal disease despite vaccination. 15. Has a history of immunodeficiency disease, including a positive HIV test result at screening. 16. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). Participants with a positive serological test for HBV surface antigen (HBsAg) or, in accordance with standard local practice, a positive HBV core antigen test will be excluded. Participants with a positive serological test for HBV core antibody (HBcAb) will be excluded unless they meet the following three criteria: a) HBV DNA test is negative. b) Prophylactic treatment with lamivudine or entecavir initiated no later than day 1 of treatment and continued until 6 months after the last treatment. c) Hepatitis B surveillance is in place: HBsAg and HBV DNA are tested every 4 weeks for the first 6 months, then every 12 weeks until prophylaxis is completed. Participants with a positive HCV antibody test should have their HCV RNA levels measured. Participants with positive (detectable) HCV RNA should be excluded. 17. Has a history of hypersensitivity to any of the study treatments or excipients or drugs of a similar chemical class, or clinically relevant hypersensitivity to fluorescein dye, as assessed by the investigator. 18. Known or suspected hereditary or acquired complement deficiency. 19. History of any porphyric metabolic disorder. 20. Received any live vaccination within 4 weeks prior to Baseline / Day 1. 21. Participant previously treated with immunosuppressants or other immunomodulatory agents, including but not limited to, cyclophosphamide, rituximab, infliximab, eculizumab, canakinumab, mycophenolate mofetil (MMF) or mycophenolate sodium (MPS), cyclosporine, tacrolimus, sirolimus, everolimus, or systemic corticosteroid exposure (>7.5 mg / d prednisone / prednisolone equivalent) within 90 days (or 180 days for rituximab) prior to the first dose of study drug. 22. Participants at risk for tuberculosis (TB), especially those who: Participants with current clinical, radiographic or laboratory evidence of active or latent TB: Evidence of TB infection (active or latent) confirmed by a positive QuantiFERON (QFT) test or a positive Purified Protein Derivative (PPD) test (≥ 5mm induration) at screening or within 2 months prior to screening, according to national guidelines. Participants with a positive or indeterminate QFT test may enter the study if they have completed a full TB workup (according to local practice / guidelines) within 12 weeks prior to randomization and have conclusively established that the participant has no evidence of active or latent TB. If the presence of latent TB infection is established, treatment for TB according to national guidelines must have been initiated or completed prior to Baseline / Day 1. In the absence of national guidelines, the following has been demonstrated: TB has been adequately treated with antibiotics and can be demonstrated to be cured, and risk factors resulting in TB exposure and acquisition have been eliminated. -Have a history of active TB: Within 2 years of screening (even if treated) More than 2 years prior to screening, unless there is documentation of appropriate treatment in accordance with locally accepted guidelines. There is a risk of TB reactivation that, in the investigator's opinion and based on appropriate evaluation, precludes the use of conventional immunosuppressants. 23. Use of other investigational medications within 30 days (e.g., small molecules) or within 5 half-lives of screening or until expected pharmacodynamic effect returns to baseline / Day 1 (e.g., biologics), whichever is longer; or longer if required by local regulations. 24. Prior treatment with strong CYP2C8 inhibitors such as gemfibrozil or clopidogrel within 7 days prior to Baseline / Day 1. 25. Any surgical or medical condition that may significantly alter drug absorption, distribution, metabolism or excretion or that may put the participant at risk if entering the study at Screening or Baseline / Day 1. The investigator should make this determination considering the participant's medical history and / or clinical or laboratory evidence of any of the following: History of invasive infection caused by encapsulated organisms, e.g., meningococcus or pneumococcus Splenectomy Severe gastrointestinal disorders, including inflammatory bowel disease, peptic ulcers, and rectal bleeding Major gastrointestinal surgery such as gastrectomy, gastroenterectomy or bowel resection Pancreatic injury or pancreatitis Liver disease or injury as indicated by any single parameter, ALT (SGPT), AST (SGOT), γ-GT, alkaline phosphatase, or serum bilirubin, greater than twice the upper limit of normal (ULN). Urinary obstruction or difficulty urinating, or evidence of any urinary disorder, including hematuria Serious concurrent comorbidities, such as advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension (WHO class IV) or other conditions as determined by the investigator. 26. Abnormal coagulation panel results at screening suggestive of disseminated intravascular coagulation (DIC). 27. Blood donation or blood loss of ≥ 400 mL within the 8 weeks prior to Baseline / Day 1 or beyond if required by local regulations. Plasma donation (> 200 mL) within 30 days prior to Baseline / Day 1. 28. Pregnant or nursing (lactating) females, where pregnancy is defined as the female's status from conception through the completion of pregnancy as confirmed by a positive human chorionic gonadotropin (hCG) pregnancy test at Screening or Baseline / Day 1. 29. Females of childbearing potential, defined as any female who is physiologically capable of becoming pregnant (unless they are using an acceptable method of contraception while receiving the study drug). Complete abstinence from heterosexual intercourse (if this is consistent with the participant's preferred usual lifestyle). Periodic abstinence (e.g., calendar, ovulation, symptomatic-thermal, postovulatory methods) and withdrawal are not acceptable methods of contraception. Female sterilization (having had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior to taking the study drug. In the case of oophorectomy alone, only if the female's reproductive status has been confirmed by follow-up hormone level evaluation. Male sterilization (at least 6 months prior to screening). For female participants in this study, the vasectomized male partner must be the participant's only partner. · Barrier contraception: condoms or occlusive caps (diaphragms or cervical / fornix caps). For the UK: spermicidal foam / gel / film / cream / vaginal suppository. Use of oral (estrogen and progesterone), injectable or implantable hormonal contraception or other forms of hormonal contraception with comparable effectiveness (failure rate <1%), such as hormonal vaginal ring or transdermal hormonal contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS). If using oral contraception, women must be stable on the same pill for a minimum of 3 months prior to taking study drug.

[0144] If local regulations deviate from the contraceptive methods listed above and more extensive measures to prevent pregnancy are required, the local regulations will apply and will be noted on the Informed Consent Form (ICF).

[0145] Women are considered postmenopausal and of no childbearing potential if they have had 12 months of spontaneous amenorrhea with an appropriate clinical profile (e.g., appropriate age, history of vasomotor symptoms) or have undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior. In cases of oophorectomy alone, women are considered of no childbearing potential only if their reproductive status has been confirmed by follow-up hormone level evaluation.

[0146] Equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments specifically described herein which equivalents are intended to be encompassed within the scope of the following claims.

Claims

1. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt thereof for use in treating age-related macular degeneration (AMD) in the eye of a subject in need thereof, wherein the pharmaceutical composition is for oral administration to the subject at a total dose of about 400 mg per day, the dose administered referring to the amount of anhydrous free base of iptacopan.

2. The pharmaceutical composition of claim 1, wherein the AMD is early AMD.

3. The pharmaceutical composition of claim 1, wherein the AMD is intermediate AMD.

4. 10. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered twice daily.

5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered twice daily at a dose of 200 mg.

6. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is administered for at least one month, or for at least six months, or for at least one year, or for two years.

7. The pharmaceutical composition of claim 1, wherein administration of the pharmaceutical composition reduces blindness in the eye compared to administration of a placebo.

8. The blindness is determined by the following test: Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA); ETDRS low luminance visual acuity (LLVA), Contrast Sensitivity (CS), or Low Luminance Contrast Sensitivity (LLCS) The pharmaceutical composition of claim 7, wherein the amount of ATP is measured by one or more of the following:

9. The pharmaceutical composition of claim 1, wherein administration of the pharmaceutical composition reduces the formation of drusen compared to a placebo.

10. The pharmaceutical composition of claim 1, wherein administration of the pharmaceutical composition reduces the occurrence of atrophic lesions in the eye of the subject.

11. The pharmaceutical composition of claim 1, wherein administration of the pharmaceutical composition reduces the occurrence and / or magnitude of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) in the eye compared to administration of a placebo.

12. The pharmaceutical composition of claim 1, wherein the subject has been vaccinated against Neisseria meningitidis (types A, C, Y, and W-135) prior to administration of the pharmaceutical composition.

13. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

14. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt thereof for use in reducing the incidence of progression of early or intermediate age-related macular degeneration (AMD) in the eye of a patient in need thereof, wherein the pharmaceutical composition is for oral administration to the subject at a dose of about 400 mg per day, the dose administered referring to the amount of anhydrous free base of iptacopan.

15. 15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is administered twice daily.

16. The pharmaceutical composition described in claim 14, wherein the pharmaceutical composition is administered twice daily at a dose of 200 mg.

17. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is administered for at least one month, or for at least six months, or for at least one year, or for two years.

18. The pharmaceutical composition of claim 14, wherein administration of the pharmaceutical composition reduces blindness in the eye compared to administration of a placebo.

19. The blindness can be determined by the following tests: Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA); ETDRS low luminance visual acuity (LLVA), Contrast Sensitivity (CS), or Low Luminance Contrast Sensitivity (LLCS) The pharmaceutical composition of claim 18, wherein the composition is measured by one or more of the following:

20. The pharmaceutical composition of claim 14, wherein administration of the pharmaceutical composition reduces the formation of drusen in the eye compared to a placebo.

21. The pharmaceutical composition described in claim 14, wherein administration of the pharmaceutical composition reduces the occurrence of atrophic lesions in the eye of the subject.

22. The pharmaceutical composition of claim 14, wherein administration of the pharmaceutical composition reduces the occurrence and / or magnitude of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) in the eye compared to administration of a placebo.

23. The pharmaceutical composition of claim 14, wherein the subject has been vaccinated against Neisseria meningitidis (types A, C, Y and W-135) prior to administration of the pharmaceutical composition.

24. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

25. 1. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt thereof for use in reducing the occurrence of atrophic lesions in the eye of a patient in need thereof, wherein the pharmaceutical composition is for oral administration to the subject at a dose of about 400 mg per day, the dose administered referring to the amount of anhydrous free base of iptacopan.

26. 26. The pharmaceutical composition of claim 25, wherein the patient is suffering from early or intermediate age-related macular degeneration (AMD).

27. 26. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition is administered twice daily.

28. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition is administered twice daily at a dose of 200 mg.

29. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition is administered for at least one month, or for at least six months, or for at least one year, or for two years.

30. The pharmaceutical composition of claim 25, wherein administration of the pharmaceutical composition reduces blindness in the eye compared to administration of a placebo.

31. The pharmaceutical composition described in claim 25, wherein administration of the pharmaceutical composition reduces the formation of drusen compared to a placebo.

32. The blindness can be determined by the following tests: Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA); ETDRS low luminance visual acuity (LLVA), Contrast Sensitivity (CS), or Low Luminance Contrast Sensitivity (LLCS) 31. The pharmaceutical composition of claim 30, wherein the composition is measured by one or more of the following:

33. The pharmaceutical composition described in claim 25, wherein administration of the pharmaceutical composition reduces the formation of atrophic lesions in the eye of the subject.

34. The pharmaceutical composition of claim 25, wherein administration of the pharmaceutical composition reduces the occurrence and / or magnitude of incomplete retinal pigment epithelium and outer retinal atrophy (iRORA) in the eye compared to administration of a placebo.

35. 26. The pharmaceutical composition of claim 25, wherein the subject has been vaccinated against Neisseria meningitidis (types A, C, Y, and W-135) prior to administration of the pharmaceutical composition.

36. The pharmaceutical composition of claim 25, wherein the pharmaceutically acceptable salt of iptacopan is iptacopan hydrochloride.

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