WO2024073097A2

Movatterモバイル変換

Info

Publication number: WO2024073097A2
Application number: PCT/US2023/034207
Authority: WO
Inventors: Cedric Francois; Pascal Deschatelets; Federico GROSSI
Original assignee: Apellis Pharmaceuticals, Inc.
Priority date: 2022-09-30
Filing date: 2023-09-29
Publication date: 2024-04-04
Also published as: WO2024073097A3; AU2023350820A1

Abstract

Methods and compositions for treatment of geographic atrophy are described.

Description

Page 17 of 70 11621854v1 Attorney Docket No.2008575-0693 G/V4(5f-W)/W7(5fW)/H9A+N- 36 112xmore OH H-GICV(5fW)QD(5fW)GAHRCTN-COOH [

compstatin analog has a sequence selected from sequences 9-36. In some embodiments, the compstatin analog has a sequence of SEQ ID NO: 28. As used herein, “L-amino acid” refers to any of the naturally occurring levorotatory alpha-amino acids normally present in proteins or the alkyl esters of those alpha-amino acids. The term “D-amino acid” refers to dextrorotatory alpha- amino acids. Unless specified otherwise, all amino acids referred to herein are L-amino acids. [0053] In some embodiments, one or more amino acid(s) of a compstatin analog (e.g., any of the compstatin analogs disclosed herein) can be an N-alkyl amino acid (e.g., an N-methyl amino acid). For example, and without limitation, at least one amino acid within the cyclic portion of the peptide, at least one amino acid N-terminal to the cyclic portion, and/or at least one amino acid C-terminal to the cyclic portion may be an N-alkyl amino acid, e.g., an N-methyl amino acid. In some embodiments, for example, a compstatin analog comprises an N-methyl glycine, e.g., at the position corresponding to position 8 of compstatin and/or at the position corresponding to position 13 of compstatin. In some embodiments, one or more of the compstatin analogs in Table 1 contains at least one N-methyl glycine, e.g., at the position corresponding to position 8 of compstatin and/or at the position corresponding to position 13 of compstatin. In some embodiments, one or more of the compstatin analogs in Table 1 contains at least one N-methyl isoleucine, e.g., at the position corresponding to position 13 of compstatin. For example, a Thr at or near the C-terminal end of a peptide whose sequence is listed in Table 1 or any other compstatin analog sequence may be replaced by N-methyl Ile. As will be appreciated, in some embodiments the N-methylated amino acids comprise N-methyl Gly at position 8 and N-methyl Ile at position 13. [0054] Compstatin analogs may be prepared by various synthetic methods of peptide synthesis known in the art via condensation of amino acid residues, e.g., in accordance with conventional peptide synthesis methods, may be prepared by expression in vitro or in living cells from appropriate nucleic acid sequences encoding them using methods known in the art. For example, peptides may be synthesized using standard solid-phase methodologies as described in Malik, supra, Katragadda, supra, WO2004026328, and/or WO2007062249. Potentially reactive Page 18 of 70 11621854v1 Attorney Docket No.2008575-0693 moieties such as amino and carboxyl groups, reactive functional groups, etc., may be protected and subsequently deprotected using various protecting groups and methodologies known in the art. See, e.g., "Protective Groups in Organic Synthesis", 3^rd ed. Greene, T. W. and Wuts, P. G., Eds., John Wiley & Sons, New York: 1999. Peptides may be purified using standard approaches such as reversed-phase HPLC. Separation of diasteriomeric peptides, if desired, may be performed using known methods such as reversed-phase HPLC. Preparations may be lyophilized, if desired, and subsequently dissolved in a suitable solvent, e.g., water. The pH of the resulting solution may be adjusted, e.g., to physiological pH, using a base such as NaOH. Peptide preparations may be characterized by mass spectrometry if desired, e.g., to confirm mass and/or disulfide bond formation. See, e.g., Mallik, 2005, and Katragadda, 2006. [0055] A compstatin analog can be modified by addition of a molecule such as polyethylene glycol (PEG) to stabilize the compound, reduce its immunogenicity, increase its lifetime in the body, increase or decrease its solubility, and/or increase its resistance to degradation. Methods for pegylation are well known in the art (Veronese, F.M. & Harris, Adv. Drug Deliv. Rev.54, 453-456, 2002; Davis, F.F., Adv. Drug Deliv. Rev.54, 457-458, 2002); Hinds, K.D. & Kim, S.W. Adv. Drug Deliv. Rev.54, 505-530 (2002; Roberts, M.J., Bentley, M.D. & Harris, J.M. Adv. Drug Deliv. Rev.54, 459-476; 2002); Wang, Y.S. et al. Adv. Drug Deliv. Rev.54, 547-570, 2002). A wide variety of polymers such as PEGs and modified PEGs, including derivatized PEGs to which polypeptides can conveniently be attached are described in Nektar Advanced Pegylation 2005-2006 Product Catalog, Nektar Therapeutics, San Carlos, CA, which also provides details of appropriate conjugation procedures. [0056] In some embodiments, a compstatin analog of any of SEQ ID NOs: 9-36, is extended by one or more amino acids at the N-terminus, C-terminus, or both, wherein at least one of the amino acids has a side chain that comprises a reactive functional group such as a primary or secondary amine, a sulfhydryl group, a carboxyl group (which may be present as a carboxylate group), a guanidino group, a phenol group, an indole ring, a thioether, or an imidazole ring, which facilitate conjugation with a reactive functional group to attach a PEG to the compstatin analog. In some embodiments, the compstatin analog comprises an amino acid having a side chain comprising a primary or secondary amine, e.g., a Lys residue. For example, a Lys residue, or a sequence comprising a Lys residue, is added at the N-terminus and/or C-terminus of a Page 19 of 70 11621854v1 Attorney Docket No.2008575-0693 compstatin analog described herein (e.g., a compstatin analog comprising any one of SEQ ID NOs: 9-36). [0057] In some embodiments, the Lys residue is separated from the cyclic portion of the compstatin analog by a rigid or flexible spacer. The spacer may, for example, comprise a substituted or unsubstituted, saturated or unsaturated alkyl chain, oligo(ethylene glycol) chain, and/or other moieties, e.g., as described herein with regard to linkers. The length of the chain may be, e.g., between 2 and 20 carbon atoms. In other embodiments the spacer is a peptide. The peptide spacer may be, e.g., between 1 and 20 amino acids in length, e.g., between 4 and 20 amino acids in length. Suitable spacers can comprise or consist of multiple Gly residues, Ser residues, or both, for example. Optionally, the amino acid having a side chain comprising a primary or secondary amine and/or at least one amino acid in a spacer is a D-amino acid. Any of a variety of polymeric backbones or scaffolds could be used. For example, the polymeric backbone or scaffold may be a polyamide, polysaccharide, polyanhydride, polyacrylamide, polymethacrylate, polypeptide, polyethylene oxide, or dendrimer. Suitable methods and polymeric backbones are described, e.g., in WO98/46270 (PCT/US98/07171) or WO98/47002 (PCT/US98/06963). In some embodiments, the polymeric backbone or scaffold comprises multiple reactive functional groups, such as carboxylic acids, anhydride, or succinimide groups. The polymeric backbone or scaffold is reacted with the compstatin analogs. In some embodiments, the compstatin analog comprises any of a number of different reactive functional groups, such as carboxylic acids, anhydride, or succinimide groups, which are reacted with appropriate groups on the polymeric backbone. Alternately, monomeric units that could be joined to one another to form a polymeric backbone or scaffold are first reacted with the compstatin analogs and the resulting monomers are polymerized. In some embodiments, short chains are prepolymerized, functionalized, and then a mixture of short chains of different composition are assembled into longer polymers. [0058] In some embodiments, a compstatin analog moiety is attached at each end of a linear PEG. A bifunctional PEG having a reactive functional group at each end of the chain may be used, e.g., as described herein. In some embodiments, the reactive functional groups are identical while in some embodiments different reactive functional groups are present at each end. [0059] In general and for compounds depicted herein, a polyethylene glycol moiety is drawn with the oxygen atom on the right side of the repeating unit or the left side of the repeating unit. Page 20 of 70 11621854v1 Attorney Docket No.2008575-0693 In cases where only one orientation is drawn, the present disclosure encompasses both orientations (i.e., (CH2CH2O)n and (OCH2CH2)n) of polyethylene glycol moieties for a given compound or genus, or in cases where a compound or genus contains multiple polyethylene glycol moieties, all combinations of orientations are encompasses by the present disclosure. [0060] In some embodiments a bifunctional linear PEG comprises a moiety comprising a reactive functional group at each of its ends. The reactive functional groups may be the same (homobifunctional) or different (heterobifunctional). In some embodiments the structure of a bifunctional PEG may be symmetric, wherein the same moiety is used to connect the reactive functional group to oxygen atoms at each end of the -(CH₂CH₂O)_n chain. In some embodiments different moieties are used to connect the two reactive functional groups to the PEG portion of the molecule. The structures of exemplary bifunctional PEGs are depicted below. For illustrative purposes, formulas in which the reactive functional group(s) comprise an NHS ester are depicted, but other reactive functional groups could be used. [0061] In some embodiments, a bifunctional linear PEG is of formula A: Formula A wherein each T and “Reactive functional group” is independently as defined below, and described in classes and subclasses herein, and n is as defined above and described in classes and subclasses herein. Each T is independently a covalent bond or a C1-12 straight or branched, hydrocarbon chain wherein one or more carbon units of T are optionally and independently replaced by -O-, -S-, - N(R^x)-, -C(O)-, -C(O)O-, -OC(O)-, -N(R^x)C(O)-, -C(O)N(R^x)-, -S(O)-, -S(O)2-, -N(R^x)SO2-, or -SO2N(R^x)-; and each R^x is independently hydrogen or C_1-6 aliphatic. The Reactive functional group has the structure -COO-NHS. [0062] Exemplary bifunctional PEGs of formula A include: Page 21 of 70 11621854v1 Attorney Docket No.2008575-0693

[0063] In some embodiments, a functional group (for example, an amine, hydroxyl, or thiol group) on a compstatin analog is reacted with a PEG-containing compound having a “reactive functional group” as described herein, to generate such conjugates. By way of example, Formula I can form compstatin analog conjugates having the structure:

wherein, represents the attachment point of an amine group on a compstatin analog. In certain embodiments, an amine group is a lysine side chain group. [0064] In certain embodiments, the PEG component of such conjugates has an average molecular weight of about 5 kD, about 10 kD, about 15 kD, about 20 kD, about 30 kD, or about 40 kD. In certain embodiments, the PEG component of such conjugates has an average molecular weight of about 40 kD. [0065] The term “bifunctional” or “bifunctionalized” is sometimes used herein to refer to a compound comprising two compstatin analog moieties linked to a PEG. Such compounds may be designated with the letter “BF”. In some embodiments a bifunctionalized compound is symmetrical. In some embodiments the linkages between the PEG and each of the compstatin analog moieties of a bifunctionalized compound are the same. In some embodiments, each linkage between a PEG and a compstatin analog of a bifunctionalized compound comprises a carbamate. In some embodiments, each linkage between a PEG and a compstatin analog of a bifunctionalized compound comprises a carbamate and does not comprise an ester. In some embodiments, each compstatin analog of a bifunctionalized compound is directly linked to a PEG via a carbamate. In some embodiments, each compstatin analog of a bifunctionalized compound is directly linked to a PEG via a carbamate, and the bifunctionalized compound has Page 22 of 70 11621854v1 Attorney Docket No.2008575-0693 the structure: . [0066] In some embodiments of formulae and embodiments described herein, represents point of attachment of a lysine side chain group in a structure:

wherein the symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or

formula. [0067] PEGs comprising one or more reactive functional groups may, in some embodiments, be obtained from, e.g., NOF America Corp. White Plains, NY or BOC Sciences 45-16 Ramsey Road Shirley, NY 11967, USA, among others, or may be prepared using methods known in the art. [0068] In some embodiments, a linker is used to connect a compstatin analog described herein and a PEG described herein. Suitable linkers for connecting a compstatin analog and a PEG are extensively described above and in classes and subclasses herein. In some embodiments, a linker has multiple functional groups, wherein one functional group is connected to a compstatin analog and another is connected to a PEG moiety. In some embodiments, a Page 23 of 70 11621854v1 Attorney Docket No.2008575-0693 linker is a bifunctional compound. In some embodiments, a linker has the structure of NH2(CH2CH2O)nCH2C(=O)OH, wherein n is 1 to 1000. In some embodiments, a linker is 8- amino-3,6-dioxaoctanoic acid (AEEAc). In some embodiments, a linker is activated for conjugation with a polymer moiety or a functional group of a compstatin analog. For example, in some embodiments, the carboxyl group of AEEAc is activated before conjugation with the amine group of the side chain of a lysine group. [0069] In some embodiments, a suitable functional group (for example, an amine, hydroxyl, thiol, or carboxylic acid group) on a compstatin analog is used for conjugation with a PEG moiety, either directly or via a linker. In some embodiments, a compstatin analog is conjugated through an amine group to a PEG moiety via a linker. In some embodiments, an amine group is the α-amino group of an amino acid residue. In some embodiments, an amine group is the amine group of the lysine side chain. In some embodiments, a compstatin analog is conjugated to a PEG moiety through the amino group of a lysine side chain (ε-amino group) via a linker having the structure of NH2(CH2CH2O)nCH2C(=O)OH, wherein n is 1 to 1000. In some embodiments, a compstatin analog is conjugated to the PEG moiety through the amino group of a lysine side chain via an AEEAc linker. In some embodiments, the NH₂(CH₂CH₂O)nCH₂C(=O)OH linker introduces a –NH(CH₂CH₂O)nCH₂C(=O)– moiety on a compstatin lysine side chain after conjugation. In some embodiments, the AEEAc linker introduces a – NH(CH₂CH₂O)₂CH₂C(=O)– moiety on a compstatin lysine side chain after conjugation. [0070] In some embodiments, a compstatin analog is conjugated to a PEG moiety via a linker, wherein the linker comprises an AEEAc moiety and an amino acid residue. In some embodiments, a compstatin analog is conjugated to a PEG moiety via a linker, wherein the linker comprises an AEEAc moiety and a lysine residue. In some embodiments, the C-terminus of a compstatin analog is connected to the amino group of AEEAc, and the C-terminus of AEEAc is connected to a lysine residue. In some embodiments, the C-terminus of a compstatin analog is connected to the amino group of AEEAc, and the C-terminus of AEEAc is connected to the α- amino group of a lysine residue. In some embodiments, the C-terminus of a compstatin analog is connected to the amino group of AEEAc, the C-terminus of AEEAc is connected to the α-amino group of the lysine residue, and a PEG moiety is conjugated through the ε-amino group of said lysine residue. In some embodiments, the C-terminus of the lysine residue is modified. In some embodiments, the C-terminus of the lysine residue is modified by amidation. In some Page 24 of 70 11621854v1 Attorney Docket No.2008575-0693 embodiments, the N-terminus of a compstatin analog is modified. In some embodiments, the N- terminus of a compstatin analog is acetylated. [0071] In certain embodiments a compstatin analog may be represented as M-AEEAc-Lys- B2, wherein B2 is a blocking moiety, e.g., NH2, M represents any of SEQ ID NOs: 9-36, , with the proviso that the C-terminal amino acid of any of SEQ ID NOs: 9-36 is linked via a peptide bond to AEEAc-Lys-B₂. The NHS moiety of a monofunctional or multifunctional (e.g., bifunctional) PEG reacts with the free amine of the lysine side chain to generate a monofunctionalized (one compstatin analog moiety) or multifunctionalized (multiple compstatin analog moieties) PEGylated compstatin analog. In various embodiments any amino acid comprising a side chain that comprises a reactive functional group may be used instead of Lys (or in addition to Lys). A monofunctional or multifunctional PEG comprising a suitable reactive functional group may be reacted with such side chain in a manner analogous to the reaction of NHS-ester activated PEGs with Lys. [0072] With regard to any of the above formulae and structures, it is to be understood that embodiments in which the compstatin analog component comprises any compstatin analog described herein, e.g., any compstatin analog of SEQ ID NOs; 9-36 are expressly disclosed. For example, and without limitation, a compstatin analog may comprise the amino acid sequence of SEQ ID NO: 28. An exemplary PEGylated compstatin analog in which the compstatin analog component comprises the amino acid sequence of SEQ ID NO: 28 is depicted in FIG.1. It will be understood that the PEG moiety may have a variety of different molecular weights or average molecular weights in various embodiments, as described herein. In certain embodiments, a compstatin analog is pegcetacoplan (“APL-2”), having the structure of the compound of FIG.1 with n of about 800 to about 1100 and a PEG having an average molecular weight of about 40 kD. Pegcetacoplan is also referred to as Poly(oxy-1,2-ethanediyl), α-hydro-ω-hydroxy-, 15,15’- diester with N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl-L-α- aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-[2-(2- aminoethoxy)ethoxy]acetyl-N⁶-carboxy-L-lysinamide cyclic (2-->12)-(disulfide); or O,O'- bis[(S²,S¹²-cyclo{N-acetyl-L-isoleucyl-L-cysteinyl-L-valyl-1-methyl-L-tryptophyl-L-glutaminyl- L-α-aspartyl-L-tryptophylglycyl-L-alanyl-L-histidyl-L-arginyl-L-cysteinyl-L-threonyl-2-[2-(2- aminoethoxy)ethoxy]acetyl-L-lysinamide})-N^6.15-carbonyl]polyethylene glycol (n = 800-1100). Additional compstatin analogs are described in, e.g., WO 2012/155107 and WO 2014/078731. Page 25 of 70 11621854v1 Attorney Docket No.2008575-0693 IV. Complement-Mediated Eye Disorders [0073] In some embodiments, a compstatin analog described herein is introduced into the eye of a subject for treatment of an eye disorder such as age-related macular degeneration (AMD). For example, a compstatin analog may be introduced into the vitreous cavity (e.g., by intravitreal injection), for treatment of a subject suffering from or at risk of AMD. In some embodiments the AMD is neovascular (wet or exudative) AMD. In some embodiments the AMD is dry AMD. As will be appreciated by those of ordinary skill in the art, dry AMD encompasses geographic atrophy (GA), intermediate AMD, and early AMD. In some embodiments, a subject with GA is treated in order to slow or halt progression of the disease. For example, in some embodiments, treatment of a subject with GA reduces the rate of retinal cell death. A reduction in the rate of retinal cell death may be evidenced by a reduction in the rate of GA lesion growth in patients treated with a compstatin analog as compared with control (e.g., patients given a sham injection). In some embodiments, a subject has intermediate AMD. In some embodiments, a subject has early AMD. In some embodiments, a subject with intermediate or early AMD is treated in order to slow or halt progression of the disease. For example, in some embodiments, treatment of a subject with intermediate AMD may slow or prevent progression to an advanced form of AMD (neovascular AMD or GA). In some embodiments, treatment of a subject with early AMD may slow or prevent progression to intermediate AMD. In some embodiments an eye has both GA and neovascular AMD. In some embodiments an eye has GA but not wet AMD. In some embodiments, a subject has one eye with GA and one eye without GA. In some embodiments, a subject has one eye with GA and one eye without wet AMD. In some embodiments, a subject has one eye with GA and one eye with wet AMD. In some embodiments, a subject has one eye having both GA and neovascular AMD and one eye without wet AMD. In some embodiments, a subject has one eye having both GA and neovascular AMD and one eye with wet AMD. In some embodiments, both eyes of a subject have both GA and neovascular AMD. [0074] Geographic atrophy (GA) is a late-stage disease manifestation in nonneovascular age- related macular degeneration (AMD) that progresses to severe central vision loss. Geographic atrophy has traditionally been defined on color fundus photography (CFP) as a sharply delineated circular or oval area of hypopigmentation or depigmentation in which choroidal Page 26 of 70 11621854v1 Attorney Docket No.2008575-0693 vessels are visible. The size requirement for GA varies with the different studies, ranging from one eighth to one fourth of a disc area (corresponding roughly to 175 mm and 430 mm in diameter, respectively) on CFP (see, e.g., Bird et al., Surv. Ophthalmol.39:367-374 (1995) and Schmitz-Valckenberg, Ophthalmologica 237:11-20 (2017)). Geographic atrophy was retained as a term for a late stage of AMD in the 2013 Beckman CFP classification of AMD (see Ferris et al., Ophthalmology 120:844-851 (2013)). As a clinical trial end point, the ability to slow GA expansion using a novel therapy has been approved by regulatory authorities, in which atrophy can be defined and quantified by fundus autofluorescence (FAF) (Csaky et al., Invest. Ophthalmol. Vis. Sci.58:3456-3463 (2017); Holz et al., Ophthalmology 121:1079-1091 (2014); Schmitz-Valckenberg et al., Ophthalmology 123:361-368 (2016)). Recent trials aiming to slow progression of atrophy were required to enroll eyes with established regions of GA that could be measured reliably by a reading center, usually measuring at least 0.5 to 1.0 disc areas (1.25-2.5 mm²) (Cheng et al., Ophthalmol. Retina 2:518-525 (2018); Holz et al., JAMA Ophthalmol. 136:666-677 (2018); Rosenfeld et al., Ophthalmology 125:1556-1567 (2018)). In some embodiments, GA is assessed using FAF. In some embodiments, GA is assessed using optical coherence tomography (OCT). [0075] Drusen are localized extracellular deposits of lipoproteinaceous material that accumulate between the retinal pigment epithelium (RPE) and the capillary network in the choroid (choriocapillaris), typically between the RPE and Bruch’s membrane (a multilayered extracellular matrix complex that separates the RPE from the choriocapillaris). It will be appreciated that the term “druse” is sometimes used in the art to refer to a single such deposit (i.e., as a singular referent) while “drusen” is sometimes used in the art to refer to multiple such deposits (i.e., as a plural referent). As used herein, the term “drusen” should be understood to encompass a single “druse” or multiple “drusen” in various embodiments unless indicated to the contrary or clearly evident from the context. Also, reference to “a druse” should be understood to encompass reference to a single “druse” or multiple “drusen” in various embodiments unless indicated to the contrary or clearly evident from the context. Drusen are a clinical hallmark of AMD and are typically the earliest clinical finding in AMD. The presence, location, size, and number of drusen are factors used in the art for classifying AMD into stages and monitoring its progression. However, a few small drusen are commonly observed in the eyes of people over 40 years of age, most of whom do not go on to develop AMD. Drusen can be detected, assessed, Page 27 of 70 11621854v1 Attorney Docket No.2008575-0693 and/or classified according to known methods, e.g., imaging, scanning laser ophthalmoscopy, and optical coherence tomography (OCT) (e.g., spectral domain optical coherence tomography (SD-OCT)). Additional methods are described in, e.g., WO2014/028861. [0076] In some embodiments early, intermediate, or advanced AMD are defined in accordance with the classification scheme used in the Age-Related Eye Diseases Study (AREDS) (The Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report number 8. Arch Ophthalmol 2001;119:1417-36). The classification of AMD from the AREDS is summarized as follows: [0077] No AMD (AREDS category 1) is characterized by no or few small drusen (<63 microns in diameter). [0078] Early AMD (AREDS category 2) is characterized by presence of a combination of multiple small drusen, few intermediate drusen (63 to 124 microns in diameter), or RPE abnormalities. [0079] Intermediate AMD (AREDS category 3) is characterized by presence of extensive intermediate drusen, at least one large druse (at least 125 microns in diameter), or geographic atrophy not involving the center of the macula. [0080] Advanced AMD (AREDS category 4) is characterized by geographic atrophy involving the center of the macula and/or neovascular macular degeneration. Neovascular macular degeneration is typically associated with manifestations of CNV and/or retinal or RPE detachment associated with subretinal serous fluid, exudates, and/or blood. Other manifestations of neovascular AMD may include retinal hard exudates, subretinal and sub-RPE fibrovascular proliferation, and/or disciform scar. [0081] Other classification schemes, or modified forms of the AREDS scheme, may be used, such as the ICD10 classification system. The terms “extrafoveal” and “nonsubfoveal” lesions are used interchangeably herein, and refer to lesions having a distance from the atrophy junction to the center of the fovea of greater than zero. The terms “subfoveal” and “foveal” lesions are used interchangeably herein, and refer to lesions having a distance from the atrophy junction to the center of the fovea that is not greater than zero. In some embodiments, such distance is assessed using autofluorescence. Page 28 of 70 11621854v1 Attorney Docket No.2008575-0693 [0082] In some embodiments, age-related macular degeneration can be divided into 3 main clinical stages (early, intermediate, and late) based on overall disease severity (Ferris et al., Ophthalmology.2013; 120: 844-851), with decreased quality of life and significant visual impairment occurring during the late stage. Late AMD can be subdivided into the exudative form, which is characterized by the presence of macular neovascularization (MNV), and the nonexudative form, known as geographic atrophy (GA), which is characterized by progressive loss of macular photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris (Holz et al., Ophthalmology.2014; 121: 1079-1091; Barbazetto et al., Arch Ophthalmol.2003; 121: 1253-1268). Geographic atrophy is also referred to as complete RPE and outer retinal atrophy (Holz et al., JAMA Ophthalmol.2018; 136: 666-677). The exudative form of AMD (eAMD) can be treated with intravitreal injections of vascular endothelial growth factor (VEGF) A inhibitors (Finger et al., BMC Ophthalmol.2020; 20: 294). Although anti-VEGF therapy has been shown to improve vision and reduce the risk of severe vision loss over several years in eyes with eAMD (Heier et al., Ophthalmology.2012; 119: 2537-2548; Rosenfeld et al., N Engl J Med.2006; 355: 1419-1431; Gillies et al., Ophthalmology.2015; 122: 1837-1845), the nonexudative form of AMD can continue to progress to macular atrophy, independent of the exudative process (Gune et al., Ophthalmology.2020; 127: 523-532). For most patients with late AMD, macular atrophy is the characteristic end stage of the disease process, resulting in progressive and irreversible loss of visual function as the area of macular atrophy enlarges. See also Wykoff et al., Ophthalmology 128:1325-1336, 2021. V. C5 Inhibitors [0083] In some embodiments, a subject treated with a compstatin analog described herein, e.g., pegcetacoplan, has received one or more C5 inhibitors before treatment with the compstatin analog, receives one or more C5 inhibitors in combination with at least one dose of the compstatin analog, and/or continues to receive one or more C5 inhibitors during the entire treatment with the compstatin analog. [0084] C5 inhibitors are known and/or commercially available. Non-limiting examples of C5 inhibitors include, e.g., eculizumab, ALXN1210 (ravulizumab), SKY59 (crovalimab), LFG316, REGN3918, ABP959, RA101495, Coversin, and ALNCC5 (described in, e.g., Risitano et al., Frontiers Immunology 10:1157 (2019)). Additional C5-targeting agents are described in, Page 29 of 70 11621854v1 Attorney Docket No.2008575-0693 e.g., US Pat. Nos.9,718,880 and 9,079,949; and PCT Publs. WO2004106369; WO2010015608; WO2013093762; WO/2014/160129; WO2015134894; WO2015191951; WO/2016/040589; WO/2016/044419; WO2016098356; WO2016117346; WO2016123371; WO/2016/201301; WO2017104779; WO2017105939; WO2017212375; WO2017212391; WO/2017/214518; WO2017/217524; WO2017218515; WO2018106859; WO2018143266; WO2018165062; WO2018183449; WO2019014360; WO2019023564; WO2019084438; WO2019112984; WO2019118556; and WO2020006266. [0085] In some embodiments, the C5 inhibitor is an anti-C5 antibody, e.g., an anti-C5 monoclonal antibody. In some embodiments, a C5 inhibitor is eculizumab or ravulizumab. In some embodiments, a C5 inhibitor is an antibody that binds to the same epitope as eculizumab or ravulizumab. In some embodiments, a C5 inhibitor is an antibody that competes for binding to C5 with eculizumab or ravulizumab. In some embodiments, a C5 inhibitor includes the same or substantially the same amino acid sequence as eculizumab or ravulizumab, or an antigen binding portion thereof. VI. Pharmaceutical Compositions and Administration [0086] The disclosure provides and/or utilizes a variety of compositions comprising a compstatin analog. In various embodiments, a composition can have any feature or combination of features discussed herein so long as they are not mutually exclusive. The invention provides embodiments of such compositions, and methods of use thereof, in which the compstatin analog is any compstatin analog, e.g., an analog described herein. [0087] Suitable preparations, e.g., substantially pure preparations of a compstatin analog or other active agent, may be combined with pharmaceutically acceptable carriers or vehicles, etc., to produce an appropriate pharmaceutical composition. The term “pharmaceutically acceptable carrier or vehicle” refers to a non-toxic carrier or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. One of skill in the art will understand that a carrier or vehicle is “non-toxic” if it is compatible with administration to a subject in an amount appropriate to deliver the compound without causing undue toxicity. Pharmaceutically acceptable carriers or vehicles that may be used in the compositions of this invention include, but are not limited to, water, physiological saline, Ringer’s solution, sodium acetate or potassium acetate solution, 5% dextrose, and the like. The composition may include Page 30 of 70 11621854v1 Attorney Docket No.2008575-0693 other components as appropriate for the formulation desired, e.g., as discussed herein. Supplementary active compounds, e.g., compounds independently useful for treating a subject suffering from a complement-mediated disorder, can also be incorporated into the compositions. The invention provides such pharmaceutical compositions comprising a compstatin analog and, optionally, a second active agent useful for treating a subject suffering from AMD. [0088] In some embodiments, the invention provides a pharmaceutically-acceptable composition suitable for administration to humans, packaged together with a label approved by a government agency responsible for regulating pharmaceutical agents, e.g., the U.S. Food & Drug Administration. In some embodiments, the invention provides a pharmaceutical kit or pack for use in performing an intravitreal injection of a composition, e.g., pegcetacoplan, as described herein. In some embodiments, a pharmaceutical kit comprises one or more sterile needles. In some embodiments, a pharmaceutical kit comprises: (a) a transfer needle (e.g., a filtered transfer needle) and/or (b) a needle for injection. In some embodiments, the invention provides a pharmaceutical kit or pack comprising: (a) a single use vial comprising a pharmaceutical composition comprising pegcetacoplan, as described herein, (b) a transfer needle (e.g., a filtered transfer needle), and/or (c) a needle for injection. In some embodiments, a transfer needle and/or needle for injection are sterile needles. In some embodiments, a transfer needle and/or needle for injection are for administration of a single dose. In some embodiments, a transfer needle is a sterile 5-micron filter needle. In some embodiments, a needle for injection is a 1/2 inch, 29- gauge thin-wall injection needle. In some embodiments, a needle for injection is a 1/2 inch, 29- gauge thin-wall injection needle with a Luer-lock hub. In some embodiments, a transfer needle and/or needle for injection are contained in a sealed plastic tray comprising suitably sized compartments to house the transfer needle and/or needle for injection. In some embodiments, a pharmaceutical kit or pack further comprises a syringe for administration of a composition, e.g., pegcetacoplan, as described herein. In some embodiments, a syringe is a sterile 1-ml Luer-lock syringe. In some embodiments, a sterile 1-ml Luer-lock syringe has a 0.1 ml dose mark. In some embodiments instructions for administration are provided. [0089] A pharmaceutical composition can be administered to a subject by any suitable route of administration including, but not limited to, intravitreally, intravenous, intramuscular, subcutaneously, by inhalation, by nasal delivery, intrathecally, intracranially, intraarterially, orally, rectally, transdermally, intradermally, subdermally, etc. It will be understood that Page 31 of 70 11621854v1 Attorney Docket No.2008575-0693 “administration” encompasses directly administering a compound or composition to a subject, instructing a third party to administer a compound or composition to a subject, prescribing or suggesting a compound or composition to a subject, and, as appropriate, other means of making a compound or composition available to a subject. [0090] Pharmaceutical compositions suitable for injectable use (e.g., intravitreal administration) typically include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. Sterile solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent, optionally with one or a combination of ingredients such as buffers such as acetates, citrates, lactates or phosphates; agents for the adjustment of tonicity; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid, glutathione, or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; and other suitable ingredients etc., as desired, followed by filter-based sterilization. One of skill in the art will be aware of numerous physiologically acceptable compounds that may be included in a pharmaceutical composition. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide, if desired. Preferably solutions for injection are sterile and acceptably free of endotoxin. In some embodiments, solutions for injection are substantially free of preservative (e.g., are preservative free solutions). A composition is “substantially free” of a particular substance or substances if the composition contains no more than 0.1% weight/volume (w/v) of that substance or substances, e.g., no more than 0.01% w/v, e.g., no more than 0.001% w/v, of that substance or substances. [0091] In certain embodiments a composition comprising a compstatin analog, or a composition to which a compstatin analog is to be added, comprises one or more non-reducing sugars or sugar alcohols. In certain embodiments a composition comprising a compstatin analog, or a composition to which a compstatin analog is to be added, comprises one or more reducing sugars, e.g., dextrose. One of ordinary skill in the art appreciates that a reducing sugar is a sugar that is capable of acting as a reducing agent, typically because it has a free aldehyde group or a free ketone group, e.g., when it assumes an open-chain form. [0092] In some embodiments, compositions provided by the present disclosure include a compstatin analog and do not include a reducing sugar, e.g., dextrose, as a component. In some embodiments a composition comprising a compstatin analog, or to which a compstatin analog is Page 32 of 70 11621854v1 Attorney Docket No.2008575-0693 to be added, is free or substantially free of one or more reducing sugars, e.g., dextrose. In certain embodiments a composition comprising a compstatin analog, or to which a compstatin analog is to be added, is free or substantially free of reducing sugars. [0093] In some embodiments of any of the aspects described herein, a composition described herein comprises a compstatin analog described herein and water. In some embodiments of any of the aspects described herein, a composition described herein comprises a compstatin analog described herein, water, and one or both of a tonicity adjusting agent and a buffer substance. In some embodiments of any of the aspects described herein, a composition described herein consists essentially of or consists of a compstatin analog described herein and one or more specified components, e.g., a buffer substance and/or a tonicity adjusting agent. In some embodiments, such a composition consists of such substances in water as a pharmaceutically acceptable carrier. In some embodiments of any of the aspects described herein, a composition comprising a compstatin analog described herein has a pH as described herein. [0094] In certain embodiments the composition comprises one or more excipients in an amount such that the composition is approximately isotonic with respect to normal human plasma. In some aspects, a composition is considered “isotonic with respect to normal human plasma” (also referred to simply as “isotonic”) if the concentration of solutes that cannot freely diffuse across a plasma membrane of a normal human cell, e.g., a normal human red blood cell or an epithelial cell, is between 260 mOsm/kg and 320 mOsm/kg, e.g., between 280 mOsm/kg and 300 mOsm/kg, e.g., 285 mOsm/kg and 295 mOsm/kg. In some embodiments a composition comprising a compstatin analog described herein and a pharmaceutically acceptable carrier has a pH of between 6.5 and 7.5, e.g., between 6.8 and 7.2, e.g., 7.0. In some embodiments, a composition comprising a compstatin analog and a pharmaceutically acceptable carrier has a pH of between 6.0 and 6.5, between 5.5 and 6.0, or between 5.0 and 5.5. In certain embodiments a yet lower pH, e.g., between 4.5 and 5.0 may be used. In particular embodiments, for example, a composition has a pH between 4.6 and 5.4, e.g., between 4.8 and 5.2, between 4.9 and 5.1, e.g., 5.0. In some embodiments the composition further comprises one or more pharmaceutically acceptable buffer substances appropriate to maintain the pH within a selected range (e.g., any of the afore-mentioned ranges). Suitable buffer substances are described herein (e.g., acetates, citrates, lactates or phosphates). In some embodiments the composition additionally or alternately comprises a salt, e.g., any of the pharmaceutically acceptable salts described herein. Page 33 of 70 11621854v1 Attorney Docket No.2008575-0693 In certain embodiments the buffer substance comprises sodium acetate. In certain embodiments the buffer substance, e.g., sodium acetate, is present at a concentration between 10 mM and 50 mM, e.g., 10 mM – 15 mM, 15 mM – 20 mM, 20 mM – 25 mM, 25 mM – 30 mM, 30 mM – 35 mM, 35 mM – 40 mM, 40 mM – 50 mM. In particular embodiments the buffer substance is present at a concentration of about 15 mM, about 17.5 mM, about 20 mM, about 22.5 mM, about 25 mM, about 27.5 mM, or about 30 mM. In certain embodiments the sodium acetate may be provided by including acetic acid and sodium acetate trihydrate in the solution. In certain particular embodiments, the composition comprises a phosphate. [0095] It will be appreciated that the compstatin analog and/or additional active agent(s) can be provided as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Also, pharmaceutically- acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts, if appropriate depending on the identity of the active agent. [0096] It will be understood that the pharmaceutically acceptable carriers, compounds, and preparation methods mentioned herein are exemplary and non-limiting. See, e.g., Remington: The Science and Practice of Pharmacy.21st Edition. Philadelphia, PA. Lippincott Williams & Wilkins, 2005, for additional discussion of pharmaceutically acceptable compounds and methods of preparing pharmaceutical compositions of various types. [0097] In some aspects, described herein are various doses, dosing regimens, compositions, and methods useful for treating patients by IVT injection, e.g., in a manner that is acceptable to physicians and patients in terms of the time and pressure required to deliver a given volume of the composition through a needle of a given inner diameter or gauge number. Gauge number describes the outer diameter of a hollow needle, with a higher gauge number indicating a smaller Page 34 of 70 11621854v1 Attorney Docket No.2008575-0693 outer diameter. Generally, needles having a higher gauge number may be preferred by patients and physicians as they may be associated with (or may be perceived to be associated with) less pain and/or tissue damage as compared with needles having a lower gauge number. Inner diameter depends on both outer diameter and wall thickness. For standard needles, the higher the gauge number, the smaller the inner diameter (e.g., a 27 gauge needle has a larger inner diameter than a 29 gauge needle, which in turn has a larger inner diameter than a 30 gauge needle). [0098] In some aspects, the present disclosure teaches particular utility of certain thin-walled needles for administration of a compstatin analog in accordance with the present invention. For example, in some embodiments a thin wall needle is used for intraocular (e.g., intravitreal) injection of a compstatin analog. Thin wall needles have identical outer diameters to standard needles but larger inner diameters for a given gauge. For example, a thin wall needle may have an internal diameter size that is the same as that of a standard needle of a gauge one to two numbers lower (e.g., a 29 gauge thin wall needle may have an internal diameter that is the same as that of a 27 gauge or 28 gauge standard needle but an outer diameter that is the same as that of a standard 29 gauge needle). An increase in internal diameter can result in a considerable increase in fluid flow for a given pressure and/or a considerable reduction in pressure needed to maintain a given flow. Lower pressure means that less injection force is needed to administer a composition of a given viscosity. In general, low injection force facilitates administration and is therefore typically a desirable feature. In some embodiments a thin wall needle has a given internal diameter that is uniform along the length of the needle. In some embodiments a thin wall needle has an internal diameter that varies along the length of the needle. For example, the diameter may be the same as that of a standard 29 gauge needle at one end of the needle and progress to the diameter of a standard 27 gauge needle at the other end. In some embodiments a microtapered needle may be used. In some embodiments a needle with a scalpel-like tip may be used. The length of the needle may vary. In some embodiments a short needle such as a 5 mm or 6 mm needle may be used. In some embodiments a needle having a length between 6 mm and 8 mm, or between 8 mm and 12 mm may be used. Suitable needles and syringes are available commercially, e.g., from Becton Dickinson and Company (BD), Terumo Corp., etc. [0099] In some embodiments a composition having a given viscosity and/or concentration may be administered using a thin wall needle having a gauge that is one or two numbers higher Page 35 of 70 11621854v1 Attorney Docket No.2008575-0693 than the gauge size that is preferably used when a standard needle is used to administer a composition of the same viscosity and/or concentration at a selected flow rate and/or with a selected injection force. For example, in some embodiments a composition that is preferably administered using a 25 gauge standard needle in order to attain a desired flow rate and/or injection force can be administered with such a flow rate and/or injection force using a 26 or 27 gauge thin wall needle. In some embodiments a composition that is preferably administered using a 27 gauge standard needle in order to attain a desired flow rate and/or injection force can be administered with such a flow rate and/or injection force using a 28 or 29 gauge thin wall needle. In some embodiments a composition that is preferably administered using a 29 gauge standard needle in order to attain a desired flow rate and/or injection force can be administered with such a flow rate and/or injection force using a 30 or 31 gauge thin wall needle. [00100] In some embodiments a composition is administered using a syringe with one or more design features that reduce friction and/or required injection force, such as a relatively short barrel and/or relatively large plunger size. [00101] In some embodiments, a composition, e.g., pegcetcoplan, is administered using a sterile 1-ml Luer-lock syringe. In some embodiments, a sterile 1-ml Luer-lock syringe has a 0.1 ml dose mark. In some embodiments, such a syringe is provided in a kit comprising a transfer needle (e.g., a filtered transfer needle) and/or needle for injection as described herein. [00102] In some aspects, described herein are various doses, dosing regimens, compositions and methods of use for treating a patient in need of treatment for a complement-mediated eye disorder that affects the posterior segment of the eye, e.g., the retina, by intravitreal (IVT) administration of a compstatin analog. In some embodiments, the eye disorder is AMD, e.g., advanced AMD (geographic atrophy (GA) or neovascular AMD). In some embodiments a composition, e.g., a pharmaceutical composition, comprises a compstatin analog comprising a PEG having a molecular weight of about 40 kD (e.g., pegcetacoplan) at a concentration of about 150 mg/ml. [00103] In some embodiments a dose for intravitreal injection of a compstatin analog (e.g., comprising two compstatin analog moieties and a PEG having a molecular weight of about 40 kD) is 5 mg – 20 mg. In some embodiments the dose is about 10 mg. In some embodiments the dose is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In certain particular Page 36 of 70 11621854v1 Attorney Docket No.2008575-0693 embodiments the dose is about 15 mg. In some embodiments, any of the afore-mentioned doses is administered by intravitreal injection in a volume of between about 90 and about 110 microliters, e.g., in a volume of about 100 microliters. [00104] In certain embodiments a composition, e.g., a composition that may be used for IVT administration, e.g., for treatment of AMD, comprises about 150 mg/ml compstatin analog (e.g., comprising a PEG of about 40 kD, e.g., pegcetacoplan), and one or more excipients selected from the group consisting of NaCl, trehalose, and sorbitol. In certain embodiments any of the compositions comprising about 150 mg/ml compstatin analog has a concentration between 140 mg/ml and 150 mg/ml, e.g., between 145 mg/ml and 155 mg/ml, e.g., between 148 mg/ml and 152 mg/ml, e.g., 150 mg/ml compstatin analog. In certain embodiments any of the compositions comprises about 20 mM sodium acetate. In certain embodiments any of the compositions has a pH between 4.8 and 5.2, e.g., about 5.0. [00105] In some embodiments the composition comprises about 150 mg/ml compstatin analog and between 0.45% and 0.60% w/v NaCl, e.g., between 0.45% and 0.50%, between 0.50% and 0.55%, or between 0.55% and 0.60% NaCl. In certain embodiments the composition comprises between 0.51% NaCl and 0.54% NaCl. In certain embodiments the composition comprises between 0.52% NaCl and 0.53% NaCl. In particular embodiments the composition comprises 0.500% NaCl. In particular embodiments the composition comprises 0.505% NaCl.0.510% NaCl. In particular embodiments the composition comprises 0.515% NaCl. In particular embodiments the composition comprises 0.520% NaCl. In particular embodiments the composition comprises 0.525% NaCl. In particular embodiments the composition comprises s 0.530% NaCl. In particular embodiments the composition comprises 0.535% NaCl. In particular embodiments the composition contains 0.540% NaCl. In particular embodiments the composition comprises 0.545 % NaCl. In particular embodiments the composition comprises 0.550% NaCl. [00106] In certain embodiments the composition comprises about 150 mg/ml compstatin analog and between 2.5% and 4.5% w/v sorbitol w/v, e.g., between 2.5% and 3.0%, between 3.0% and 3.5%, between 3.5% and 4.0%, or between 4.0% and 4.5% sorbitol. In particular embodiments the composition comprises 3.0% sorbitol. In particular embodiments the composition comprises 3.1% sorbitol. In particular embodiments the composition comprises 3.2% sorbitol. In particular embodiments the composition comprises 3.3 % sorbitol. In Page 37 of 70 11621854v1 Attorney Docket No.2008575-0693 particular embodiments the composition comprises 3.4% sorbitol. In particular embodiments the composition comprises 3.5% sorbitol. [00107] In certain embodiments the composition comprises about 150 mg/ml compstatin analog and between 6.0% and 8.0% w/v trehalose, e.g., between 6.0% and 6.5%, between 6.5% and 7.0%, between 7.0% and 7.5%, or between 7.5% and 8.0% trehalose. In particular embodiments the composition comprises 6.5% trehalose. In particular embodiments the composition comprises 6.6% trehalose. In particular embodiments the composition comprises 6.7% trehalose. In particular embodiments the composition comprises 6.8% trehalose. In particular embodiments the composition comprises 6.9% trehalose. In particular embodiments the composition comprises 7.0% trehalose. In some embodiments, the composition comprises about 5.0% to about 6.0% trehalose, about 5.0% to about 5.5% trehalose, about 5.5% to about 6.0% trehalose, about 5.0% to about 5.3% trehalose, or about 5.2% to about 5.5% trehalose. In particular embodiments, the composition comprises about 5.3% to about 5.4% (e.g., about 5.38%) trehalose. In certain embodiments, the trehalose may be provided by including trehalose dehydrate in the solution. [00108] In some embodiments, the osmolality of a solution comprising a compstatin analog may be measured at a dilution such that the concentration of compstatin analog is about 75 mg/ml or less. A solution comprising a compstatin analog and, optionally, an osmolality modifier, may be diluted with water by an appropriate dilution factor such that the concentration of the compstatin analog is 75 mg/ml or less, e.g., between 25 mg/ml and 40 mg/ml or between 40 mg/ml and 75 mg/ml. The osmolality of the resulting solution is measured and then multiplied by the dilution factor to correct for the dilution. For example, a solution having a compstatin analog concentration of 100 mg/ml may be diluted by a factor of 2, i.e., to a concentration of 50 mg/ml. The osmolality of the resulting solution is measured and multiplied by 2 to yield the osmolality of the original 100 mg/ml solution. As another example, a solution having a compstatin analog concentration of 150 mg/ml may be diluted by a factor of 2, i.e., to a concentration of 75 mg/ml. The osmolality of the resulting solution is measured and multiplied by 2 to yield the osmolality of the original 100 mg/ml solution. [00109] In some embodiments a composition comprising a compstatin analog may have a selected osmolality. In some embodiments a composition comprising a compstatin analog, e.g., a composition for ocular, e.g., intravitreal, administration, has an osmolality of between 150 Page 38 of 70 11621854v1 Attorney Docket No.2008575-0693 milliosmoles/kilogram (mOsm/kg) and 600 mOsm/kg, e.g., between 180 mOsm/kg and 500 mOsm/kg, e.g., between 200 mOsm/kg and 400 mOsm/kg. In certain embodiments a composition comprising a compstatin analog has an osmolality between 250 mOsm/kg and 380 mOsm/kg, e.g., between 275 mOsm/kg and 350 mOsm/kg. In certain embodiments a composition comprising a compstatin analog has an osmolality of between 275 mOsm/kg and 285 mOsm/kg, between 285 mOsm/kg and 295 mOsm/kg, between 295 mOsm/kg and 305 mOsm/kg, or between 305 mOsm/kg and 315 mOsm/kg. In particular embodiments the osmolality of the composition is 300 mOsm/kg. In some embodiments the osmolality of a composition may be measured using a vapor pressure depression osmometer. In some embodiments the osmolality of a composition may be measured using a membrane osmometer. In some embodiments the osmolality of a composition may be measured using a freezing point depression osmometer. [00110] In some embodiments a dose of a composition comprising a compstatin analog is administered by ocular administration (e.g., IVT injection) once a month (e.g., 30 days), every 6 weeks, or every 2 months (i.e., every other month, (e.g., 60 days)). In some embodiments a dose of a composition comprising a compstatin analog is administered by IVT injection every 3 months, every 4 months, every 5 months, or every 6 months, or less frequently, e.g., every 9 months, every year). Thus in some embodiments a patient may receive between 1 and 6 injections per year, typically at approximately equal intervals. In some embodiments, a patient may receive between 6 and 12 injections per year, typically at approximately equal intervals. In some embodiments a patient is initially treated with monthly injections (e.g., for the first 3 – 6 months or the first 6 – 12 months), followed by less frequent administration (e.g., every 2, 3, 4, 5, or 6 months, or less frequently, e.g., every 9 months, every year). [00111] In some embodiments, a pharmaceutical composition described herein includes pegcetacoplan at 15 mg/0.1 mL (150 mg/mL), as a sterile, aqueous, acetate-buffered trehalose solution for intravitreal administration. In some embodiments, such pharmaceutical composition is included in a single-use 2R vial containing 60 mg of pegcetacoplan in 0.4 mL solution, 75 mg of pegcetacoplan in 0.5 mL solution, 150 mg of pegcetacoplan in 1.0 mL solution, 45 mg of pegcetacoplan in 0.3 mL solution, or 30 mg of pegcetacoplan in 0.2 mL solution. In some embodiments, each vial is designed to deliver a single dose of 0.1 mL solution containing 15 mg of pegcetacoplan. Those skilled in the art, reading the present disclosure, will appreciate that, in Page 39 of 70 11621854v1 Attorney Docket No.2008575-0693 accordance with standard practice in the field, a container containing a particular volume, as described herein my include an additional volume sufficient to permit the designated particular volume (e.g., unit dose) to be withdrawn from the container for administration. [00112] In some embodiments, a pharmaceutical composition includes 15 mg/0.1 mL pegcetacoplan, 16-22 mM acetate buffer (e.g., about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, or about 22 mM acetate buffer), 5% to 6% trehalose (e.g., about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, or about 6.0% trehalose, e.g., about 5.38% trehalose), with a pH of about 4.8 to about 5.2 (e.g., about 5.0). [00113] In some embodiments, a pharmaceutical composition includes the following, in a 0.1 mL volume: 15 mg Pegcetacoplan, about 5.5 mg to about 6.5 mg trehalose dihydrate (e.g., about 5.5 mg, about 5.6 mg, about 5.7 mg, about 5.8 mg, about 5.9 mg, about 6 mg, about 6.1 mg, about 6.2 mg, about 6.3 mg, about 6.4 mg, or about 6.5 mg trehalose dihydrate (e.g., about 5.95 mg trehalose dihydrate)), about 0.085 mg to about 0.095 mg glacial acetic acid (e.g., about 0.085 mg, about 0.0855 mg, about 0.086 mg, about 0.0865 mg, about 0.087 mg, about 0.0875 mg, about 0.088 mg, about 0.0885 mg, about 0.089 mg, about 0.0895 mg, about 0.09 mg, about 0.0905 mg, about 0.091 mg, about 0.0915 mg, about 0.092 mg, about 0.0925 mg, about 0.093 mg, about 0.0935 mg, about 0.094 mg, about 0.0945 mg, or about 0.095 mg glacial acetic acid (e.g., about 0.0895 mg glacial acetic acid)), about 0.03 mg to about 0.04 mg sodium acetate trihydrate (e.g., about 0.031 mg, about 0.032 mg, about 0.033 mg, about 0.034 mg, about 0.035 mg, about 0.036 mg, about 0.037 mg, about 0.038 mg, about 0.039 mg, or about 0.04 mg sodium acetate trihydrate (e.g., about 0.0353 mg sodium acetate trihydrate)), water for injection, and optionally sodium hydroxide and/or additional glacial acetic acid in an amount sufficient to adjust the pH of the pharmaceutical composition to about 4.8 to about 5.2 (e.g., about 5.0). VII. Treatment Methods [00114] In some embodiments, a compstatin analog described herein, e.g., pegcetacoplan, is used to treat geographic atrophy (GA). In some embodiments, a compstatin analog described herein, e.g., pegcetacoplan, is administered to an eye of a subject having or suffering from GA. In some embodiments, one eye of the subject has GA, and pegcetacoplan is administered to that eye. In some embodiments, both eyes of the subject have GA, and pegcetacoplan is administered Page 40 of 70 11621854v1 Attorney Docket No.2008575-0693 to both eyes. In some embodiments, one eye of the subject has GA and one eye has wet AMD, and pegcetacoplan is administered to the eye having GA. In some embodiments, one eye of the subject has GA, and a second eye of the subject has wet AMD but not GA, and pegcetacoplan is administered to the first eye. In some embodiments, one eye of the subject has GA, and a second eye of the subject has wet AMD and has GA, and pegcetacoplan is administered to the first eye. In some embodiments, one eye of the subject has GA, and a second eye of the subject has wet AMD and has GA, and pegcetacoplan is administered to the second eye. In some embodiments, one eye of the subject has GA, and a second eye of the subject has wet AMD and has GA, and pegcetacoplan is administered to the first eye and to the second eye. [00115] In some embodiments, administration of a compstatin analog described herein, e.g., pegcetacoplan, to a subject maintains, reduces loss of, and/or improves visual function in the subject. In some embodiments, visual function is assessed by one or more of microperimetry, monocular maximum reading speed, Functional Reading Independence (FRI) Index, best- corrected visual acuity (BCVA) (e.g., normal luminance BCVA (NL-BCVA) or low luminance BCVA (LL-BCVA)). In some embodiments, administration of a compstatin analog described herein, e.g., pegcetacoplan, to a subject maintains, reduces loss of, and/or improves visual function in the subject by at least 10%, 20%, 30%, 40%.50%, or more, relative to a control (e.g., as assessed by one or more of microperimetry, monocular maximum reading speed, Functional Reading Independence (FRI) Index, best-corrected visual acuity (BCVA) (e.g., normal luminance BCVA (NL-BCVA) or low luminance BCVA (LL-BCVA)). For example, in some embodiments, visual function of the eye is assessed by microperimetry, and after administration of a compstatin analog described herein, e.g., pegcetacoplan, mean threshold sensitivity of the eye is about 0.25, about 0.5, about 0.75, or about 1 db higher, relative to a control. In some embodiments, visual function of the eye is assessed by microperimetry, and after administration of a compstatin analog described herein, e.g., pegcetacoplan, the subject exhibits fewer number of scotomatous points, relative to a control. In some embodiments, the eye of the subject has a geographic atrophy lesion, and microperimetry is assessed within an area peripheral to a lesion border, e.g., within an area within about 500 microns (e.g., within about 400 microns, within about 300 microns, within about 250 microns, within about 200 microns, within about 150 microns) of each side of the lesion border. In some embodiments, a control is level of visual function in a sham-treated subject (e.g., an untreated subject having the same level of risk and/or Page 41 of 70 11621854v1 Attorney Docket No.2008575-0693 stage or severity of GA as the treated subject) or an average level of visual function in an untreated subject population (e.g., an untreated subject population having the same level of risk and/or stage or severity of GA as the treated subject). [00116] In some embodiments, a compstatin analog described herein, e.g., pegcetacoplan, is administered, e.g., intravitreally, to the eye of the subject as a pharmaceutical composition that includes pegcetacoplan at 15 mg/0.1 mL (150 mg/mL). In some embodiments, the composition is administered to the eye of the subject once a month (e.g., 30 days), e.g., for about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 1.2 years, 1.4 years, 1.6 years, 1.8 years, 2 years, 3 years, 4 years, 5 years, or longer. In some embodiments, the composition is administered to the eye of the subject every other month (e.g., 60 days), e.g., for about 8 weeks, about 16 weeks, about 24 weeks, about 32 weeks, about 40 weeks, about 48 weeks, about 1.2 years, 1.4 years, 1.6 years, 1.8 years, 2 years, 3 years, 4 years, 5 years, or longer. In some embodiments, a specific improvement (e.g., a statistically significant or clinically significant improvement) of one or more GA symptoms or parameters is achieved in the subject, e.g., one or more target levels described herein is achieved. [00117] In some embodiments, a subject may be monitored and/or evaluated for elevated intraocular pressure (IOP) prior to administration, e.g., intravitreal injection, of a composition described herein. In some embodiments, IOP is measured using tonometry. In some embodiments, a subject may be administered ocular hypotensive medication to lower IOP. In some embodiments, prior to administration, e.g., intravitreal injection of a composition described herein, IOP is about ≤21 mmHg. In some embodiments, an eye of the subject may be softened and/or decompressed prior to administration, e.g. intravitreal injection, of a composition described herein. In some embodiments, an eye of the subject may be softened and/or decompressed using a cotton-tipped applicator. In some embodiments, a cotton-tipped applicator may be saturated with sterile topical anesthetic drops. In some embodiments, an eye of the subject may be softened and/or decompressed by pushing against the globe with the cotton- tipped applicator at the planned injection site for between about 30 to about 60 seconds. In some embodiments, softening and/or decompressing an eye of a subject prior to administration, e.g., intravitreal injection, of a composition described herein may prevent and/or minimize an increase in IOP. Page 42 of 70 11621854v1 Attorney Docket No.2008575-0693 [00118] In some embodiments, methods of the disclosure include diagnosing the subject as suffering from or at risk of geographic atrophy (GA), e.g., GA secondary to age related macular degeneration (AMD), and/or selecting the subject for treatment with pegcetacoplan. In some embodiments, diagnosing may comprise performing fundus autofluorescence (FAF) and/or optical coherence tomography (OCT). In some embodiments, the subject is determined to have foveal GA (e.g., in one or both eyes) and is selected for treatment. In some embodiments, the subject is determined to have extrafoveal GA (e.g., solely extrafoveal GA) (e.g., in one or both eyes) and is selected for treatment. In some embodiments, the subject is selected for treatment if total GA area is ≥2.5 mm² (e.g., ≥2.5 mm² and ≤17.5 mm²). [00119] In some embodiments a method of the disclosure may comprise assessing foveal light sensitivity of one or both eyes of a subject. In some embodiments such assessment may comprise performing microperimetry. In some embodiments the subject retains foveal light sensitivity in at least one eye at the time treatment with pegcetacoplan is initiated. In some embodiments the subject retains foveal light sensitivity in an eye at the time treatment of that eye with pegcetacoplan is initiated. In some embodiments the subject has reduced foveal light sensitivity in an eye relative to a control at the time treatment of that eye with pegcetacoplan is initiated. [00120] In some embodiments an eye treated with pegcetacoplan by monthly IVT injection has a risk of about 6% or less per year for developing exudation. In some embodiments an eye treated with pegcetacoplan by every other month IVT injection has a risk of less than about 4% per year for developing exudation. In some embodiments the risk of developing exudation for an eye treated with pegcetacoplan by monthly IVT injection is about 2.5 (or less) times that of a control eye not treated with pegcetacoplan, e.g., between about 2.0 and about 2.5 times that of a control eye not treated with pegcetacoplan, e.g., over a specified time period such as a year. In some embodiments the risk of developing exudation for an eye treated with pegcetacoplan by monthly IVT injection is about 1.7 (or less) times that of a control eye not treated with pegcetacoplan, e.g., between about 1.5 and about 1.7 times that of a control eye not treated with pegcetacoplan, e.g., over a specified time period such as a year. [00121] Methods described herein can include preparing and/or providing a report, such as in electronic, web-based, or paper form. The report can include one or more outputs from a method described herein, e.g., a subject’s response to a treatment described herein. In some Page 43 of 70 11621854v1 Attorney Docket No.2008575-0693 embodiments, a report is generated, such as in paper or electronic form, which identifies one or more endpoints described herein for a subject, and optionally, a recommended course of therapy. In some embodiments, the report includes an identifier for the subject. In some embodiments, the report is in web-based form. [00122] In some embodiments, additionally or alternatively, a report includes information on prognosis, resistance, or potential or suggested therapeutic options. The report can include information on the likely effectiveness of a therapeutic option, the acceptability of a therapeutic option, or the advisability of applying the therapeutic option to a subject, e.g., identified in the report. For example, the report can include information, or a recommendation, on the administration of a compstatin analog described herein, e.g., pegcetacoplan, to the subject. The report can be delivered, e.g., to an entity described herein, within 7, 14, 21, 30, or 45 days from performing a method described herein. [00123] In some embodiments, a report is generated to memorialize each time a subject is assessed using a method described herein. The subject can be reevaluated at intervals, such as every month, every two months, every six months or every year, or more or less frequently, to monitor the subject for responsiveness to compstatin analog, e.g., pegcetacoplan, and/or for an improvement in one or more GA symptoms, e.g., described herein. In some embodiments, the report can record at least the treatment history of the subject. [00124] In some embodiments, the method further includes providing a report to another party. The other party can be, for example, the subject, a caregiver, a physician, an oncologist, a hospital, clinic, third-party payor, insurance company or a government office. [00125] The disclosure encompasses administration of a compstatin analog in combination with additional therapy. Such additional therapy may include administration of any agent(s) used in the art or potentially useful for treating a subject suffering from the disease. For example, in some embodiments a compstatin analog is administered in combination with a C5 inhibitor (e.g., eculizumab or any of the other C5 inhibitors mentioned herein or known in the art) to a patient, e.g., a patient with AMD. In some embodiments a compstatin analog is administered in combination with an anti-vascular endothelial growth factor (VEGF) agent to a subject, e.g., a subject with wet AMD. Anti-VEGF agents include antibodies that bind to VEGF such as ranibizumab (Lucentis), bevacizumab (Avastin), brolucizumab (Novartis), faricimab (Roche), and polypeptides comprising a soluble portion of VEGF receptor such as aflibercept Page 44 of 70 11621854v1 Attorney Docket No.2008575-0693 (Eylea, also known as VEGF-Trap) and conbercept (Chengdu Kanghong Biotech). In particular embodiments the anti-VEGF agent is ranibizumab or aflibercept. [00126] In some embodiments a subject treated with a compstatin analog, e.g., pegcetacoplan, may develop exudation in the treated eye. In some embodiments a subject who exhibits evidence of exudation in an eye being treated with pegcetacoplan may be started on therapy with an anti- VEGF agent administered to said eye. In some embodiments a method of treatment comprises administering pegcetacoplan to an eye suffering from GA and evaluating said eye for development of exudation (e.g., related to active CNV). Evaluating may comprise performing fundus examination and/or optical coherence tomography (OCT). In some embodiments, a subject may be determined to have exudation based on detection of, e.g., subretinal fluid, intraretinal fluid, cystoid macular edema, and/or serous pigment epithelial detachment. In some embodiments evaluating for presence of exudation may comprise performing fluorescein angiography (FA) and/or optical coherence tomography angiography (OCT-A). In some embodiments a subject may be confirmed to have exudation by FA and/or OCT-A. In some embodiments an evaluation procedure may be performed when the subject is visiting a health care provider, e.g., an eye care professional, for administration of pegcetacoplan. In some embodiments, a subject may be instructed to report to a health care provider, e.g., an eye care professional, any symptoms of exudation. In some embodiments a subject determined to exhibit exudation (e.g., onset of exudation) in an eye treated with pegcetacoplan may be started on treatment of said eye with an anti-VEGF agent. In some embodiments a method of treatment comprises determining that an eye being treated with pegcetacoplan exhibits evidence of exudation and administering an anti-VEGF agent to said eye. In some embodiments a method of treatment comprises determining that an eye having wet AMD exhibits GA and administering pegcetacoplan and an anti-VEGF agent to said eye. In some embodiments a method of treatment comprises determining that an eye has wet AMD and GA and administering pegcetacoplan and an anti-VEGF agent to said eye. In some embodiments an anti-VEGF agent may be an agent that is approved for treatment of neovascular AMD and is administered according to its approved dosing regimen for treatment of neovascular AMD as described in the prescribing information for such anti-VEGF agent. In some embodiments an eye may be treated by IVT injection with pegcetacoplan and an anti-VEGF agent on the same day. In some embodiments an eye may be treated by IVT injection with pegcetacoplan and an anti-VEGF agent on different days. In Page 45 of 70 11621854v1 Attorney Docket No.2008575-0693 embodiments wherein an eye is treated with pegcetacoplan and an anti-VEGF agent on the same day, the anti-VEGF agent may be administered before administration of pegcetacoplan. In some embodiments administration of the anti-VEGF agent and pegcetacoplan are administered at least 30 minutes apart on the same day. In some embodiments, administration of the anti-VEGF agent is administered at least 30 minutes before administration of pegcetacoplan. In some embodiments, wherein an eye is treated with pegcetacoplan and an anti-VEGF agent on the same day, the anti-VEGF agent may be administered after administration of pegcetacoplan. In some embodiments, administration of the anti-VEGF agent and pegcetacoplan are administered at least 30 minutes apart on the same day. In some embodiments, administration of the anti-VEGF agent is administered at least 30 minutes after administration of pegcetacoplan. [00127] When two or more therapies (e.g., compounds or compositions) are used or administered “in combination” with each other, they may be given at the same time, within overlapping time periods, or sequentially (e.g., separated by up to 2 weeks in time, or more, e.g., separated by up to about 4, 6, 8, or 12 weeks in time), in various embodiments of the invention. They may be administered via the same route or different routes. In some embodiments, the compounds or compositions are administered within 48 hours of each other. In some embodiments, a compstatin analog can be given prior to or after administration of the additional compound(s), e.g., sufficiently close in time that the compstatin analog and additional compound(s) are present at useful levels within the body at least once. In some embodiments, the compounds or compositions are administered sufficiently close together in time such that no more than 90% of the earlier administered composition has been metabolized to inactive metabolites or eliminated, e.g., excreted, from the body, at the time the second compound or composition is administered. [00128] In some embodiments, a composition that includes both a compstatin analog and additional compound(s) is administered. [00129] All publications, patent applications, patents, and other references mentioned herein, including GenBank Accession Numbers, are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be Page 46 of 70 11621854v1 Attorney Docket No.2008575-0693 used in the practice or testing of the present invention, suitable methods and materials are described herein. [00130] The disclosure is further illustrated by the following example. The example is provided for illustrative purposes only. It is not to be construed as limiting the scope or content of the disclosure in any way. EXEMPLIFICATION EXAMPLE 1 – Phase III, Multi-Center, Randomized, Double-Masked, Sham-Controlled Studies to Compare the Efficacy and Safety of Intravitreal APL-2 Therapy with Sham Injections in Patients with Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (AMD) [00131] This Example describes results from two Phase 3 multi-center, randomized, double- masked, sham-controlled studies (“DERBY” and “OAKS”) to compare the efficacy and safety of intravitreal APL-2 (pegcetacoplan, also referred to as “Study Drug” in this Example) therapy with sham injections in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Methods Patient Selection [00132] To participate in the studies, subjects must have been diagnosed with GA of the macula secondary to AMD in the study eye. At screening, male and female subjects were required to fulfill all of the following inclusion criteria to be eligible for participation in the study. If both eyes met the inclusion criteria, the eye with the worst normal luminance visual acuity at the screening visit was designated as the study eye. If both eyes had the same visual acuity, the right eye was selected as the study eye. Ocular-specific inclusion criteria applied to the study eye only, unless otherwise specified. Inclusion Criteria 1. Age ≥60 years. Page 47 of 70 11621854v1 Attorney Docket No.2008575-0693 2. Normal Luminance best corrected visual acuity (BCVA) of 24 letters or better using Early Treatment Diabetic Retinopathy Study (ETDRS) charts (approximately 20/320 Snellen equivalent). 3. Clinical diagnosis of GA of the macula secondary to AMD as determined by the investigator and confirmed by the reading center. 4. The GA lesion must have met the following criteria as determined by the central reading center’s assessment of FAF imaging at screening: a. Total GA area must be ≥2.5 and ≤17.5 mm² (1 and 7 disk areas [DA] respectively). b. If GA was multifocal, at least 1 focal lesion must be ≥1.25 mm² (0.5 DA), with the overall aggregate area of GA as specified above in 4a. c. The entire GA lesion must be completely visualized on the macula centered image and must be able to be imaged in its entirety and not contiguous with any areas of peripapillary atrophy. d. Presence of any pattern of hyperautofluorescence in the junctional zone of GA. Absence of hyperautofluorescence (ie, pattern = none) was exclusionary. 5. Adequate clarity of ocular media, adequate pupillary dilation, and fixation to permitted the collection of good quality images as determined by the investigator. 6. Met the following criteria related to microperimetry: a. Able to detect fixation target. b. Total elapsed time to complete the 10-268-point exam was ≤30 minutes in duration. c. Fixation losses must be ≤20%. Page 48 of 70 11621854v1 Attorney Docket No.2008575-0693 d. Subject was willing and able to undertake microperimetry assessment in the opinion of the investigator. 7. Female subjects must have been: a. Women of non–childbearing potential (WONCBP), or b. Women of childbearing potential (WOCBP) with a negative serum pregnancy test at screening and agreed to use protocol defined methods of contraception for the duration of the study and refrain from breastfeeding for the duration of the study. 8. Males with female partners of childbearing potential must agree to use protocol defined methods of contraception and agree to refrain from donating sperm for the duration of the study. 9. Willing and able to give informed consent and to comply with the study procedures and assessments. [00133] Subjects were excluded from the studies based on the following exclusion criteria. Ocular specific exclusion criteria applied to the study eye only, unless otherwise specified. Exclusion Criteria 1. GA secondary to a condition other than AMD such as Stargardt disease, cone rod dystrophy, or toxic maculopathies like plaquenil maculopathy in either eye. 2. Spherical equivalent of the refractive error demonstrating > 6 diopters of myopia or an axial length >26 mm. 3. Any history or active CNV in the study eye, associated with AMD or any other cause, including any evidence of retinal pigment epithelium rips or evidence of neovascularization anywhere based on SD-OCT imaging and/or fluorescein angiography as assessed by the reading center. 4. Presence of an active ocular disease that in the opinion of the investigator compromised or confounded visual function, including but not limited to, uveitis, other macular diseases (e.g., clinically significant epiretinal membrane [ERM], full thickness macular hole) or uncontrolled Page 49 of 70 11621854v1 Attorney Docket No.2008575-0693 glaucoma/ocular hypertension). Benign conditions in the opinion of the investigator such as peripheral retina dystrophy were not exclusionary. 5. Intraocular surgery (including lens replacement surgery) within 3 months prior to randomization. 6. History of laser therapy in the macular region. 7. Aphakia or absence of the posterior capsule. Note: YAG laser posterior capsulotomy for posterior capsule opacification done at least 60 days prior to screening was not exclusionary. 8. Any ocular condition other than GA secondary to AMD that may have required surgery or medical intervention during the study period or, in the opinion of the investigator, could have compromised visual function during the study period. 9. Any contraindication to IVT injection including current ocular or periocular infection. 10. History of prior intravitreal injection. 11. Unable to perform microperimetry reliably in the opinion of the investigator. 12. Prior participation in another interventional clinical study for intravitreal therapies in either eye (including subjects receiving sham). 13. Prior participation in another interventional clinical study for geographic atrophy in either eye including investigational oral medication and placebo. 14. Participation in any systemic experimental treatment or any other systemic investigational new drug including within 6 weeks or 5 half-lives of the active ingredient (whichever was longer) prior to the start of study treatment. Note: clinical trials solely involving observation, over-the-counter vitamins, supplements, or diets were not exclusionary. 15. Medical or psychiatric conditions that, in the opinion of the investigator, would make consistent follow-up over the 24-month treatment period unlikely, or would make the subject an unsafe study candidate. Page 50 of 70 11621854v1 Attorney Docket No.2008575-0693 16. Any screening laboratory value (hematology, serum chemistry or urinalysis) that in the opinion of the investigator was clinically significant and not suitable for study participation. 17. Known hypersensitivity to fluorescein sodium for injection or hypersensitivity to pegcetacoplan or any of the excipients in pegcetacoplan solution. Study Design [00134] The design of the DERBY and OAKS studies are schematically depicted in Figure 2. Each subject was assigned a unique screening number after signing the informed consent. Subjects who completed the study screening assessments and met all the eligibility criteria entered the study and were randomized on Day 1. As part of the screening process, the reading center evaluated FAF, OCT, Digital Color Fundus Photograph (DCFP), Near Infrared Reflectance (NIR), and fluorescein angiography (FA) to provide an objective assessment of subject eligibility. Subjects were randomized 2:2:1:1 to receive treatment with Study Drug monthly (PM), Study Drug every other month (PEOM), sham injection monthly (SM) or sham injection every other month (SEOM), respectively. [00135] All randomized subjects returned every month to the clinical site for assessments and additional pegcetacoplan or sham injections according to their randomization scheme until Month 12. From Month 12 onwards, subjects return to the clinical site based on their randomized treatment schedule (monthly or EOM) and follow the treatment regimen and assessments outlined in the Visit Schedule until Month 24. Safety was assessed throughout the study by a number of evaluations including: monitoring of AEs, preinjection and postinjection monitoring, blood and urine samples collected, physical examination, vital signs, and follow-up phone calls. Blood samples were also be collected for anti-therapeutic antibodies, genotyping, and clinical repository (if the subject consented to this portion). Study Treatments [00136] The Study Drug was pegcetacoplan (also referred to as “APL-2”) (see FIG.1), which was provided for intravitreal injection at 15 mg/0.1 mL (150 mg/mL) as a sterile, isotonic solution of pegcetacoplan in acetate-buffer, pH 5.0, containing trehalose, supplied in stoppered glass vials. Page 51 of 70 11621854v1 Attorney Docket No.2008575-0693 Screening Period—Within 28 Days Prior to Randomization/ Treatment (Day –28 to –1) Visit 1—All Subjects [00137] Note: All ophthalmic procedures (including imaging) were performed on both eyes, except where specified. Demographic information, significant medical/surgical history within the previous 5 years, invasive ocular procedures within the previous 5 years, and concomitant medications used within 30 days prior to screening were collected (including vitamins and all over-the-counter as well as prescription medications). Complete smoking/ tobacco history was also collected. [00138] Subject eligibility was then be determined by reviewing the inclusion/exclusion criteria and the study eye was selected. Prior to the administration of fluorescein, blood and urine was collected for safety labs (including blood for human chorionic gonadotropin/follicle- stimulating hormone/luteinizing hormone [HCG/FSH/LH], if applicable) and vital signs along with a physical examination including weight and height was performed. [00139] A complete ophthalmic exam including slitlamp exam of the cornea, iris, anterior chamber, aqueous reaction (cells and flare), dilated fundus exam of the vitreous and retina, and intraocular pressure (IOP) measurement. Normal luminance BCVA was performed prior to dilating the eyes. Images were captured as outlined in the Visit Schedule (FAF, NIR, DCFP, FFA) and forwarded to the reading center for determination of eligibility if applicable. Mesopic microperimetry was performed on both eyes post dilation of the eyes and forwarded to the reading center. Randomization/ Initial Treatment—Day 1—Within 28 Days of Screening Visit 2—All Groups [00140] At this visit, all inclusion/exclusion criteria was reviewed prior to randomization and dosing, including the determination of eligibility by the reading center. Subjects were randomized using the Interactive Web Response (IWR) System. A complete ophthalmic exam including slitlamp exam of the cornea, iris, anterior chamber, lens, and aqueous reaction (cells Page 52 of 70 11621854v1 Attorney Docket No.2008575-0693 and flare), dilated fundus exam of the vitreous and retina, and IOP measurement were performed and imaging collected as per the Visit Schedule. [00141] All assessments were performed on the same day. All study visits were scheduled and projected based on the Day 1 visit date. [00142] Blood was drawn for anti-pegcetacoplan antibodies. [00143] Prior to dilating the eyes, all functional tests were performed (NL-BCVA, LL-BCVA, and MNREAD or Radner Reading Charts [in select sites]). Subjects at select sites were trained on how to use the home-based digital applications for visual function and reading speed if the subject decided to participate in this portion. This training occurred after completion of all functional tests (NL-BCVA, LL-BCVA). Tests completed using the digital application at select sites (optional) were completed prior to dilating the eyes but after completion of all functional tests and quality of life measures (NL-BCVA, LL-BCVA, MNREAD or Radner Reading Charts [in select sites], NEI VFQ-25, and FRI). The subject was instructed to take the electronic device home and to complete the digital application weekly on the same day each week, if possible. The quality of life measures (NEI VFQ-25 and FRI) was administered by the masked site staff. [00144] Imaging performed included FAF, SD-OCT, OCT-A (select sites), endothelial cell count (select sites) and NIR and sent to the reading center for evaluation. [00145] Study drug or sham injection was performed by the unmasked physician as described herein and the study eye was monitored post injection. Subjects received a single dose of 15 mg pegcetacoplan/0.1 mL or sham injection intravitreally. A follow-up phone call was scheduled with the subject 4 ± 2 days after randomization Day 1 to assess for any AEs. Treatment Phase—24 Months Months 1-12 Visits 3-14 (Monthly and Every-Other Month Group) [00146] During this phase, there were clinic visits every month. Dosing and assessments occurred monthly in the monthly pegcetacoplan and sham injection treatment arms. Dosing Page 53 of 70 11621854v1 Attorney Docket No.2008575-0693 occurred every other month in the EOM pegcetacoplan and sham injection treatment arms, however, the subjects returned monthly for assessments (with no dose given). [00147] A complete ophthalmic exam including slitlamp exam of the cornea, iris, anterior chamber, lens, and aqueous reaction (cells and flare), dilated fundus exam of the vitreous and retina, and IOP measurement were performed and imaging collected as per the Visit Schedule. [00148] Blood was drawn for safety labs, anti-pegcetacoplan antibodies, and genotyping (Month 2 only) prior to the administration of fluorescein as per the Visit Schedule. Samples were collected for the clinical repository for those subjects that consent to this portion. [00149] Prior to dilating the eyes, all functional tests were performed (NL-BCVA, LL-BCVA, and MNREAD or Radner Reading Charts [in select sites]). Tests completed using the digital application at select sites (optional) were completed prior to dilating the eyes but after completion of all functional tests and quality of life measures (NL-BCVA, LL-BCVA, MNREAD or Radner Reading Charts [in select sites], NEI VFQ-25, and FRI). At select sites the subject was instructed to take the electronic device home and to complete the digital application weekly on the same day each week, if possible. The subject was instructed to bring back the electronic device for the visits specified in the schedule of events. The quality of life measures (NEI VFQ-25 and FRI) was administered by the masked site staff. [00150] Mesopic microperimetry was performed on both eyes (where specified) post dilation of the eyes and forwarded to the reading center. Imaging was performed including FAF, FFA, SD-OCT, OCT-A (select sites), endothelial cell count (select sites) and NIR and sent to the reading center for evaluation per the visit schedule. Months 13-24 Visits 15-26 (Monthly Group) and 15-20 (Every-Other-Month Group) [00151] During this phase, clinic visits follow treatment designation (i.e., the monthly subjects return monthly for dosing and assessments and the EOM group returned EOM for dosing and assessments). At select sites, subjects complete the home-based digital assessments weekly during this period. Page 54 of 70 11621854v1 Attorney Docket No.2008575-0693 [00152] A complete ophthalmic exam including slitlamp exam of the cornea, iris, anterior chamber, lens, and aqueous reaction (cells and flare), dilated fundus exam of the vitreous and retina, and IOP measurement is performed and imaging is collected as per the Visit Schedule. Blood is drawn for safety labs, genotyping, and anti-pegcetacoplan antibodies prior to the administration of fluorescein as per the Visit Schedule. Samples are collected for the clinical repository for those subjects that consent to this portion. [00153] Prior to dilating the eyes, all functional tests are performed (NL-BCVA, LL-BCVA, and MNREAD or Radner Reading Charts [in select sites]). The quality of life measures (NEI VFQ-25 and FRI) is administered by the masked site staff. [00154] Mesopic microperimetry is performed on both eyes (where specified) post dilation of the eyes and forwarded to the reading center. Imaging is performed including FAF, FFA, SD- OCT, OCT-A (select sites), endothelial cell count (select sites) and NIR and sent to the reading center for evaluation per the visit schedule. [00155] The completion of the 24-month study period occurs approximately 30 days (monthly treatment group) and approximately 60 days (EOM treatment group) after the last visit at which Study Drug is administered. The period following last dose of Study Drug is sufficient to evaluate the safety of pegcetacoplan. At the end of the 24-month study period, subjects have the option to enroll in a separate open-label study. Measures of Clinical Efficacy [00156] The primary endpoint in the studies was the change from baseline to Month 12 in total area of GA lesion(s) in the study eye (in mm²) based on Fundus Autofluorescence (FAF). Key secondary endpoints included change from baseline in the mean threshold sensitivity of all points (study eye) assessed by mesopic microperimetry at Month 24; change from baseline in monocular maximum reading speed (study eye), at Month 24 as assessed by MNRead or Radner reading charts (in select sites); change from baseline in mean FRI Index score (subject-level assessment) at Month 24; and change from baseline in NL-BCVA score (study eye) at Month 24 as assessed by Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Additional secondary endpoints included change from baseline in LL-BCVA score (study eye) over time as Page 55 of 70 11621854v1 Attorney Docket No.2008575-0693 assessed by ETDRS chart; change from baseline in the total area of GA lesion(s) in the study eye (in mm²) as assessed by FAF over time other than Month 12; change from baseline in monocular critical print size (study eye), as assessed by MNRead or Radner reading charts (in select sites) over time; change from baseline in the NEI VFQ-25 distance activity subscale score (in select sites) (subject level assessment) over time; change from baseline in the number of scotomatous points assessed by mesopic microperimetry over time; and change from baseline in the mean threshold sensitivity within 500 microns outside the GA lesion, (perilesional points) assessed by mesopic microperimetry over time. [00157] Safety endpoints included incidence and severity of ocular and systemic treatment- emergent adverse events; incidence of ADA directed against pegcetacoplan peptide or PEG; incidence of new active CNV in the study eye; incidence of new onset of subclinical CNV in the study eye; incidence of subjects who lost letters based on NL-BCVA categories (≥15, ≥15 - < 30, ≥30 ETDRS letters); change/shift from baseline in clinical labs and incidence of abnormal lab values; change from baseline in vital signs and incidence of abnormal vital sign results; shift from baseline in ocular examination assessments including slit-lamp examination and indirect ophthalmoscopy; change from baseline in Intra Ocular Pressure (IOP) and incidence of IOP above specified thresholds; and change/shift from baseline in ocular imaging assessments (including specular microscopy; select sites). Statistical Analysis [00158] Two sham treatment arms (SM and SEOM) were pooled into a single control (Sham) group for analyses. [00159] The Intent-to-treat (ITT) set consisted of all randomized subjects. Subjects were analyzed in the treatment arm assigned at randomization. [00160] The modified ITT (mITT) set consisted of all randomized subjects who received at least one injection of pegcetacoplan or sham and had baseline and at least one post-baseline value of GA lesion area in the study eye as assessed by FAF. Subjects were analyzed in the treatment arm assigned at randomization. Page 56 of 70 11621854v1 Attorney Docket No.2008575-0693 [00161] The Safety set consisted of all subjects randomized who received at least one injection of pegcetacoplan or sham. Subjects were analyzed according to the actual treatment received. In the case a subject received an incorrect injection of study medication than what they were randomized to, subjects were presented under the corresponding pegcetacoplan arm if they received at least one injection of pegcetacoplan during the study and were only be presented under the corresponding sham arm if they did not receive any injections of pegcetacoplan. This population was used for all safety analyses. [00162] The Per-Protocol (PP) sets will be identified separately for Month 12 and Month 24 analysis, respectively (i.e., Month 12 PP set and Month 24 PP set). The PP sets consisted of all mITT subjects who had a valid GA lesion area assessment for either Month 10 or 12 (Month 12 PP set) or have a valid GA lesion area assessment for at least one of Month 18, 20, 22, 24 (Month 24 PP set) and who follow the protocol without any major deviation(s) that could affect the primary efficacy data. A valid GA lesion area assessment is defined as a non-missing measured GA lesion area assessment at a given timepoint where at least 75% of the expected injections over the course of participation ahead of the given timepoint have been received by the subject. For example, a valid GA lesion measurement at Month 10 in the Monthly arm would be a result available at Month 10 with no more than 2 missed injections prior to the Month 10 assessment (10 scheduled before Month 10, 2 missed = 80% compliance); a valid GA lesion measurement at Month 20 in the every other month (EOM) arm would be a result available at Month 20 with no more than 2 missing injections prior to the Month 20 assessment (10 scheduled before Month 20, 2 missed = 80% compliance). [00163] Efficacy analysis including primary, key secondary, secondary, and exploratory analysis will be performed primarily using the mITT set, with subjects grouped according to the treatment assigned at randomization. Available data from all randomized subjects regardless of adherence to the protocol will be included in the efficacy analyses; this includes data from subjects who discontinued study drug early but continued with study assessments. All efficacy data will be listed for the ITT set. [00164] Unless otherwise noted, hypothesis testing and estimation of treatment effects will be performed with a mixed effect model for repeated measure (MMRM) that includes data from all Page 57 of 70 11621854v1 Attorney Docket No.2008575-0693 three treatment arms (PM, PEOM, and Sham). The Sham arm will represent the pool of the two sham treatment groups: SM and SEOM (i.e., the two sham arms will be pooled into a single “control” group). All hypothesis tests for efficacy endpoints will be two-sided. [00165] Unless otherwise noted, analysis of efficacy endpoints (primary, key secondary, secondary, and exploratory) in the overall population will be adjusted for the following randomization stratification factors (actual status) and baseline covariates: [00166] For primary efficacy endpoint: presence of CNV in the fellow eye (yes; no); baseline GA lesion area (< 7.5 mm² or ≥ 7.5 mm²). [00167] For key secondary, and secondary endpoints: presence of CNV in the fellow eye (yes; no); baseline GA lesion area (< 7.5 mm² or ≥ 7.5 mm²); baseline value of the endpoint. [00168] Of note, the randomization stratification factors were assessed at the screening visit. In the event of a change in status in the GA lesion area between the screening visit and the baseline visit (i.e., GA lesion area< 7.5 mm² at screening to ≥ 7.5 mm²) then the baseline status will be used. Results Efficacy [00169] As shown in Figure 3, no statistically significant differences were observed across study arms on key secondary endpoints at 24 months. [00170] As shown in Figure 4, no differences in microperimetry assessment were observed at 24 months across study arms. Microperimetry was assessed using iCare MAIA Microperimeter using 25 Hz eye-tracking with confocal SLO imaging. [00171] A post hoc microperimetry perilesional analysis was performed on patients in the OAKS study to assess whether pegcetacoplan preservation of retinal tissue was reflected in preserved photoreceptor function in retina near GA lesion borders at baseline. Geographic atrophy lesion borders grow at approximately 100-150 microns per year. An assessment was performed of visual function of cells within 250 microns on either side of the lesion border, which are at the highest risk of permanently losing visual function as lesions expand. Reduction Page 58 of 70 11621854v1 Attorney Docket No.2008575-0693 of retinal sensitivity as measured by microperimetry reflects loss of function. At 24 months, positive trends in microperimetry measures were demonstrated (all p-values nominal), as discussed below. [00172] Perilesional area (area within 250 microns of each side of GA lesion border) was created on fundus autofluorescence for each patient, and microperimetry endpoints were assessed within this region (68 spots on grid). In this analysis, approximately 21-22 points (out of 68 total – about one-third) qualified as “peri-lesional” using the 500 micron zone definition (250 inside and 250 outside of GA lesion border). A representative image is depicted as Figure 5. As shown in Figure 6, the post hoc microperimetry perilesional analysis signaled functional preservation with pegcetacoplan treatment, consistent with less photoreceptor loss over time. Patients in both monthly (0.564 dB; p=0.0650) and every-other-month (EOM) (0.707 dB; p=0.0202) pegcetacoplan treatment groups lost less retinal sensitivity compared to the sham group over 24 months with increasing effects over time. Scotomatous points measure areas of the retina that have lost all light sensitivity and therefore are no longer functioning. Patients in both monthly (- 0.680 points; p=0.1444) and EOM (-1.138 points; p=0.0140) pegcetacoplan treatment groups had fewer new scotomatous points compared to sham over 24 months with increasing effects over time. [00173] Spectral-domain optical coherence tomography (OCT) allows for cross sectional visualization of the neurosensory retina, including the photoreceptor (PR) layer, as well as the retinal pigment epithelium (RPE) and other retinal structures. Furthermore, OCT imaging permits analysis of outer retinal changes such as PR loss in areas outside of geographic atrophy lesions and has demonstrated that areas of PR loss in patients with GA often exceed the area of RPE atrophy. A post-hoc analysis that assessed the ability of pegcetacoplan treatment to reduce PR and RPE loss in patients with GA was performed using SD-OCT images acquired from a subgroup of patients in the OAKS and DERBY studies, namely those for whom Spectralis SD- OCT images were available. Automated, deep learning based segmentation of RPE loss and PR thickness on SD-OCT volumes acquired at baseline and months 2, 4, 6, 8, 10, and 12 was performed according to previously published methods. The difference in the change from baseline of RPE loss area and of PR loss area (determined based on PR thickness measurements) was compared among the monthly, every other month, and pooled sham treatment arms using LS Mean MMRM modeling. Results are presented in Figures 7 and 8. A statistically significant Page 59 of 70 11621854v1 Attorney Docket No.2008575-0693 reduction in PR loss and RPE loss at 12 months was observed in the monthly and every other month pegcetacoplan treatment arms as compared with sham treatment in both DERBY and OAKS. The magnitude of the treatment effects at 12 months, as determined using LS mean MMRM modeling, are summarized below. DERBY ^ RPE loss o EM vs. Sham Pooled: -36.0% difference (p<0.0001) o Every other month vs. Sham pooled: -20.4% difference (p<0.0065) o EM vs EOM: -19.6% difference (p =0.0103) ^ PR loss o EM vs. Sham Pooled: -77.4% difference (p<0.0001) o Every other month vs. Sham pooled: -61.0% difference (p<0.0001) o EM vs EOM: -42% difference (p =0.0785) OAKS ^ RPE loss o EM vs. Sham Pooled: -19.7% difference (p=0.0070) o Every other month vs. Sham pooled: -14.8% difference (p=0.0342) o EM vs EOM: -5.7% difference (p =0.5282) o ^ PR Loss o EM vs. Sham Pooled: -74.5% difference (p<0.0001) o EOM vs. Sham pooled: -47.7% difference (p<0.0001) o EM vs EOM: -51.3% difference (p =0.0049) Safety [00174] Pegcetacoplan was well tolerated in both Phase 3 studies. Table 2 shows the patient disposition and exposure at month 24 for the patients in the OAKS and DERBY studies. Page 60 of 70 11621854v1 Attorney Docket No.2008575-0693 Table 2 – Patient disposition and exposure at Month 24

randomized patients who received at least 1 injection of pegcetacoplan or sham and had baseline and at least 1 post-baseline value of geographic atrophy lesion area in the study eye; ITT=intent- to-treat; N=number of patients; PEOM=pegcetacoplan every other month; PM=pegcetacoplan monthly; SD=standard deviation. Page 61 of 70 11621854v1 Attorney Docket No.2008575-0693 [00175] Table 3 lists the overall TEAEs observed for the OAKS and DERBY studies over 24 months: Table 3 - TEAEs observed for OAKS and DERBY over 24 months I

endophthalmitis include infectious and non-infectious endophthalmitis; sham patients did not receive injections; AE=adverse event; AMD=age-related macular degeneration; N=number of patients; PEOM=pegcetacoplan every other month; PM=pegcetacoplan monthly; TEAE=treatment-emergent AE. EXAMPLE 2 – Post-hoc Analysis of 24 Month Data [00176] This Example describes a post-hoc analysis of results from the OAKS and DERBY studies described in Example 1. Functional data by lesion distance from foveal center were assessed over 24 months. Patients were divided into two subgroups: the first subgroup had a baseline lesion distance of ≥ 250 µm from the foveal center, and the second subgroup had a baseline lesion distance of < 250 µm from the foveal center. [00177] “Foveal Occupancy” was defined as proportion of the central 3 mm foveal region occupied by a GA lesion (see Figure 9B). As shown in Figure 9A, baseline BCVA from OAKS and DERBY patients was correlated with foveal occupancy, with increasing levels of foveal occupancy showing a trend toward lower BCVA scores. Page 62 of 70 11621854v1 Attorney Docket No.2008575-0693 [00178] In the patient subgroup having lesions ≥ 250 µm away from the foveal center, pegcetacoplan slowed vision loss and improved quality of life in patients. As shown in Figure 10A, patients treated with pegcetacoplan exhibited less of a BCVA change from baseline at 24 months, relative to sham-treated patients (pegcetacoplan treated patients had a baseline BCVA of 73, and sham treated patients had a baseline BCVA of 75, and patients treated monthly or every other month were combined). As shown in Figure 10B, pegcetacoplan treated patients had better quality of life relative to sham treated patients at 24 months by over 4 points, assessed by VFQ- 25. This subgroup included patients in the mITT sample with non-missing baseline measurements of RPE central 3mm occupancy (C3O) in regions 1-5 and lesion distance from fovea center. Mean changes were calculated among patients with BCVA measurements at each timepoint and thus samples varied across outcomes shown with no imputation for missing data. Adjusted differences from bootstrapped inverse probability weighted regressions controlling for baseline C3O in regions 1-5, study and fellow eye GA characteristics, study eye visual acuity, and patient characteristics. [00179] In the patient subgroup having lesions < 250 µm from the foveal center, overall trends in BCVA (Figure 11A) and VFQ-25 (Figure 11B) changes over time were similar across pegcetacoplan and sham treated patients. This subgroup included patients in the mITT sample with non-missing baseline measurements of RPE central 3mm occupancy (C3O) in regions 1-5 and lesion distance from fovea center. Mean changes were calculated among patients with BCVA measurements at each timepoint and thus samples varied across outcomes shown with no imputation for missing data. Adjusted differences from bootstrapped inverse probability weighted regressions controlling for baseline C3O in regions 1-5, study and fellow eye GA characteristics, study eye visual acuity, and patient characteristics. EXAMPLE 3 – Pegcetacoplan Treatment Prolongs Foveal Sensitivity in Patients With Geographic Atrophy (GA) Secondary to Age-Related Macular Degeneration (AMD) [00180] This Example describes a post-hoc analysis of results from the OAKS study described in Example 1 that was performed in order to assess the effect of pegcetacoplan monthly (PM) or every other month (PEOM) vs sham treatment in delaying occurrence of foveal insensitivity measured by the 4 most centrally located stimulus points of the MAcular Integrity Assessment Page 63 of 70 11621854v1 Attorney Docket No.2008575-0693 (MAIA) grid. Absolute scotomatous points of -1 dB were considered present when a reaction was not evoked by the brightest possible light stimulus. [00181] Light insensitivity was defined as absence of response to -1 dB at the stimulus point. For the time-to-event analysis, a foveal light insensitivity event was defined as the first light insensitivity (-1 dB) occurring at all 4 central stimuli. Events were measured at the exact date of a patient visit and depicted via Kaplan-Meier plots. A Cox proportional hazards model was applied factoring treatment, choroidal neovascularisation in the fellow eye, baseline GA lesion area, and baseline number of central 4 scotomatous points (categorical). Hazard ratios (HRs) of PM and PEOM were estimated. Study eyes of patients with 4 central light insensitive points at baseline (floor effect) or who did not have a post-baseline microperimetry assessment were excluded from the analysis [00182] At baseline, 18.3% of the 637 patients (PM, n=213; PEOM, n=212; sham pooled, n=212) enrolled in OAKS with a microperimetry assessment had 4 central scotomatous points (i.e., foveal light insensitivity) with mean NL-BCVA of 47.1 letters. Of these patients, 85.6% had baseline subfoveal involvement of the GA lesion. Additionally, 34.9% of patients with baseline microperimetry assessment had 2 or 3 central scotomatous points at baseline (mean NL- BCVA = 56.8) and 46.8% had ≤1 central scotomatous point at baseline (mean NL-BCVA = 65.3). A total of 453 patients (PM, n=155; PEOM, n=152; sham pooled, n=146) who had ≤3 central scotomatous points at baseline and a post-baseline microperimetry assessment were included in this analysis. Conversion of all 4 central points to scotoma in the study eye occurred in 54 (34.8%), 59 (38.8%), and 64 (43.8%) patients in the PM, PEOM, and sham pooled arms, respectively. PM significantly delayed the occurrence of foveal light insensitivity vs sham (HR: 0.66; 95% confidence interval [CI]: 0.46, 0.96; p=0.0282). PEOM similarly delayed the occurrence of foveal light insensitivity vs sham (HR: 0.64; 95% CI: 0.45, 0.92; p=0.0164). [00183] Twenty-four-month data from the OAKS pivotal trial demonstrated a significant functional benefit of pegcetacoplan treatment in delaying onset of foveal light insensitivity in patients with GA reflected by the development of absolute scotomas at the 4 central stimulus points of the MAIA grid located closest to the foveal centre. Meaningful delays in loss of foveal light sensitivity were observed for both PM and PEOM regimens, supporting the use of pegcetacoplan treatment in maintaining foveal functionality of patients with GA lesions. Page 64 of 70 11621854v1 Attorney Docket No.2008575-0693 EQUIVALENTS [00184] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the following claims: Page 65 of 70 11621854v1

Claims

Attorney Docket No.2008575-0693 CLAIMS 1. A method of maintaining, or reducing loss of, visual function of an eye of a subject suffering from or at risk of geographic atrophy (GA), e.g., GA secondary to age related macular degeneration (AMD), the method comprising intravitreally administering to an eye of the subject a composition comprising pegcetacoplan, wherein: (a) the composition comprises about 15 mg pegcetacoplan; and (b) wherein visual function of the eye of the subject is maintained, or loss of visual function is reduced, relative to control. 2. The method of claim 1, wherein visual function of the eye is assessed by microperimetry, monocular maximum reading speed, Functional Reading Independence (FRI) Index, best- corrected visual acuity (BCVA) (e.g., normal luminance BCVA (NL-BCVA) or low luminance BCVA (LL-BCVA)). 3. The method of claim 1 or 2, wherein after the administration, level of visual function of the eye is about 5%, 10%, 20%, 30%, 40%, 50%, or 60% better relative to a control. 4. The method of any one of claims 1-3, wherein visual function of the eye is assessed by microperimetry. 5. The method of claim 4, wherein after the administration, mean threshold sensitivity of the eye is about 0.25, about 0.5, about 0.75, or about 1 db higher, relative to a control. 6. The method of claim 4 or 5, wherein the eye of the subject has a geographic atrophy lesion, and microperimetry is assessed within an area peripheral to a lesion border. 7. The method of claim 6, wherein microperimetry is assessed within an area within about 500 microns (e.g., within about 400 microns, within about 300 microns, within about 250 microns, within about 200 microns, within about 150 microns) of each side of the lesion border. Page 66 of 70 11621854v1 Attorney Docket No.2008575-0693 8. The method of any one of claims 1-4, wherein after the administration the presence of foveal light sensitivity is prolonged relative to a control. 9. The method of claim 8, wherein the subject has a subfoveal GA lesion. 10. The method of claim 8, wherein the subject has reduced foveal light sensitivity relative to a control at the time treatment is started. 11. The method of any of claims 1 – 10, wherein the composition is administered monthly. 12. The method of any of claims 1 – 10, wherein the composition is administered every other month. 13. The method of any of claims 1 – 10, wherein the composition is administered by intravitreal injection between 6 and 12 times per year. 14. The method of any of claims 1 – 13 wherein the composition is administered in a volume of about 0.1 mL. 15. A method of decreasing new scotomatous points in an eye of a subject diagnosed with geographic atrophy, the method comprising administering to the eye of the subject a composition comprising about 15 mg pegcetacoplan for at least 24 months, and wherein the number of new scotomatous points is decreased relative to control. 16. The method of claim 15, wherein the pegcetocoplan is administered intravitreally. 17. The method of claim 15 or 16, wherein visual function of the eye is maintained, or loss of visual function is reduced, relative to control. 18. The method of any of claims 15 - 17, wherein visual function of the eye is assessed by microperimetry, monocular maximum reading speed, Functional Reading Independence (FRI) Page 67 of 70 11621854v1 Attorney Docket No.2008575-0693 Index, best-corrected visual acuity (BCVA) (e.g., normal luminance BCVA (NL-BCVA) or low luminance BCVA (LL-BCVA)). 19. The method any of claims 15 - 18, wherein after the administration, level of visual function of the eye is about 5%, 10%, 20%, 30%, 40%, 50%, or 60% better relative to a control. 20. The method of any of claims 15 - 19, wherein visual function of the eye is assessed by microperimetry. 21. The method of any of claims 15 - 20, wherein the pegcetacoplan is administered in a volume of about 0.1 mL. 22. The method of any of claims 15 - 21, wherein the pegcetacoplan is administered monthly. 23. The method of any of claims 15 - 21, wherein the pegcetacoplan is administered every other month. 24. The method of any of any of claims 15 - 21, wherein the pegcetacoplan is administered between 6 and 12 times per year. 25. A method of improving the quality of life of a subject diagnosed with geographic atrophy, the method comprising administering a composition comprising about 15 mg pegcetacoplan to an eye of the subject, wherein said eye has a geographic atrophy lesion greater than or equal to 250 µm away from the foveal center, wherein the quality of life of the subject is improved relative to a control. 26. The method of claim 25, wherein the pegcetocoplan is administered intravitreally. 27. The method of claim 25 or 26, wherein visual fuction of the at least one eye is maintained, or loss of visual function is reduced, relative to control. Page 68 of 70 11621854v1 Attorney Docket No.2008575-0693 28. The method of any of claims 25 - 27, wherein visual function of the eye is assessed by microperimetry, monocular maximum reading speed, Functional Reading Independence (FRI) Index, best-corrected visual acuity (BCVA) (e.g., normal luminance BCVA (NL-BCVA) or low luminance BCVA (LL-BCVA)). 29. The method of any of claims 25 – 28, wherein after the administration, level of visual function of the eye is about 5%, 10%, 20%, 30%, 40%, 50%, or 60% better relative to a control. 30. The method of any of claims 25 - 29, wherein visual function of the eye is assessed by microperimetry. 31. The method of any of claims 25 - 30, wherein the pegcetacoplan is administered in a volume of about 0.1 mL. 32. The method of any of claims 25 - 31, wherein the pegcetacoplan is administered monthly. 33. The method of method of any of claims 25 - 31, wherein the pegcetacoplan is administered every other month. 34. The method of any of claims 25 – 31, wherein the pegcetacoplan is administered between 6 and 12 times per year. 35. The method of any of claims 25 – 31, the method comprising determining that the subject has a geographic atrophy lesion greater than or equal to 250 µm away from the foveal center of at least one eye and administering pegcetacoplan to that eye. Page 69 of 70 11621854v1