Methods of using geographic atrophy lesion characteristics

Abstract

The present disclosure encompasses methods of using geographic atrophy lesion characteristics.

Description

Attorney Docket No.2008575-0770 METHODS OF USING GEOGRAPHIC ATROPHY LESION CHARACTERISTICS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No. 63 / 588,224, filed October 5, 2023, the contents of which are hereby incorporated by reference in their entirety. FIELD OF THE DISCLOSURE

[0002] The present disclosure encompasses methods of using geographic atrophy lesion characteristics. BACKGROUND

[0003] Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), a leading cause of blindness. GA lesions affect the central portion of the retina, known as the macula, which is responsible for central vision. GA is progressive and irreversible, leading to central visual impairment and permanent loss of vision. Based on published studies, approximately one million people have GA in the United States and five million people have GA globally (Rudnicka et al., Ophthalmology 119:571-580 (2012); Wong et al., Lancet Glob Health 2:e106-116 (2014)). BRIEF DESCRIPTION OF THE DRAWINGS

[0004] Figure 1 depicts a graph illustrating the RPE loss progression in the sham pooled population by [PR-RPE] quartile in the OAKS and DERBY clinical trials. Data represents a subset of patients that underwent OCT imaging.

[0005] Figure 2 depicts a graph illustrating the PR integrity loss progression in the sham pooled population by [PR-RPE] quartile in the OAKS and DERBY clinical trials. Data represents a subset of patients that underwent OCT imaging.

[0006] Figure 3 depicts graphs illustrating the RPE change from baseline by pooled [PR-RPE] quartile in the 1stquartile (panel A), the second quartile (panel B), the 3rdquartile (panel C), and the 4thquartile (panel D) in the pooled treated population of the OAKS and DERBY clinical trials. Data represents a subset of patients that underwent OCT imaging. Page 1 of 38 12356904v1Attorney Docket No.2008575-0770

[0007] Figure 4 depicts graphs illustrating the PR change from baseline by pooled [PR-RPE] quartile in the 1stquartile (panel A), the second quartile (panel B), the 3rdquartile (panel C), and the 4thquartile (panel D) in the pooled treated population of the OAKS and DERBY clinical trials. Data represents a subset of patients that underwent OCT imaging.

[0008] Figure 5 depicts a table illustrating the RPE change from baseline by pooled [PR-RPE] quartile in the OAKS and DERBY clinical trials. Data represents a subset of patients that underwent OCT imaging.

[0009] Figure 6 depicts a table illustrating the PR change from baseline by pooled [PR-RPE] quartile in the OAKS and DERBY clinical trials. Data represents a subset of patients that underwent OCT imaging. DETAILED DESCRIPTION

[0010] The present disclosure encompasses the unexpected discovery that geographic atrophy lesion characteristics such as photoreceptor integrity loss and retinal pigment epithelium loss in a patient with at least one geographic atrophy lesion may be used in several beneficial methods, as detailed below. I. PATIENT WITH AT LEAST ONE GEOGRAPHIC ATROPHY LESION (a) Geographic Atrophy

[0011] Geographic atrophy (GA) is a late-stage disease manifestation in nonneovascular age- related macular degeneration (dry AMD) that progresses to severe central vision loss. Generally speaking, AMD 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 may encompass exudative AMD, also known as wet AMD or neovascular AMD, which is characterized by the presence of macular neovascularization (MNV). Late AMD may also encompass 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). Page 2 of 38 12356904v1Attorney Docket No.2008575-0770

[0012] Geographic atrophy has traditionally been defined as at least one lesion that appears on color fundus photography (CFP) as a sharply delineated circular or oval area of hypopigmentation or depigmentation in which choroidal vessels are visible. Lesions may also be assessed using fundus autofluorescence (FAF), or optical coherence tomography (OCT). GA lesions are characterized by retinal cell death, with photoreceptor cell death preceding retinal pigment epithelium cell death as disease progresses. In some embodiments, photoreceptor cells may lose integrity before actually dying – this loss of integrity, along with cell death, may be visualized using OCT.

[0013] Lesion size at diagnosis varies, and may range, for instance, 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)). 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) and located within the visual field of the instrument (e.g. the entire lesion can be visualized and no part is outside of the field of view) (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)). (b) Patient

[0014] As used herein, “patient” refers to a human that has at least one geographic atrophy (GA) lesion in at least one eye. In certain embodiments, a patient may have at least one geographic atrophy lesion in both eyes. In some instances, a patient may be diagnosed with geographic atrophy. In other embodiments, a patient may not yet be diagnosed, but has one or more symptoms of the disease or risk factors for the disease.

[0015] For instance, in some embodiments, a patient may have early AMD, or intermediate AMD. In some embodiments a patient may have one eye with both GA and neovascular AMD. In some embodiments an eye has GA but not neovascular AMD. In some embodiments, a patient has one eye with GA and one eye without GA. In some embodiments, a patient has one eye with GA and one eye without neovascular AMD. In some embodiments, a patient has one eye with GA and one eye with neovascular AMD. In some embodiments, a patient has one eye having both GA and neovascular AMD and one eye without neovascular AMD. In some embodiments, a Page 3 of 38 12356904v1Attorney Docket No.2008575-0770 patient has one eye having both GA and neovascular AMD and one eye with only neovascular AMD. In some embodiments, both eyes of a patient have both GA and neovascular AMD. (c) Lesions

[0016] A patient with at least one GA lesion may have a unifocal lesion. As used herein, the phrase “unifocal lesion” refers to a single RPE lesion in an eye. In some embodiments, a patient has a unifocal geographic atrophy lesion with an area of at least 2.5 mm2.

[0017] In other embodiments, a patient may have a multifocal lesion. As used herein, the phrase “multifocal lesion” refers to at least two RPE lesions in the same eye. In some embodiments, a patient has multifocal geographic atrophy lesions with at least one lesion with an area of 1.25 mm2. It is possible, over the course of disease progression, for a unifocal lesion to become multifocal, and similarly, for a multifocal lesion to become a unifocal lesion.

[0018] In certain embodiments, one or more lesions may be nonsubfoveal. In other certain embodiments, one or more lesions may be subfoveal. As used herein, the terms “extrafoveal” and “nonsubfoveal” lesions are used interchangeably, and refer to lesions having a distance from the atrophy junction to the center of the fovea of greater than zero. As used herein, the terms “subfoveal” and “foveal” lesions are used interchangeably, 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. In other embodiments, such distance is assessed using CFP. In still other embodiments, such distance is assessed using OCT. II. GEOGRAPHIC ATROPHY LESION CHARACTERISTICS (a) absolute difference between photoreceptor integrity loss and retinal pigment epithelium loss [PRIloss-RPEloss]

[0019] Each of the methods detailed herein may utilize the numeric value of the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss (“[PRIloss-RPEloss]). Used in this context, “photoreceptor integrity loss” (PRIloss) refers to the extent of area, measured in suitable units, e.g. mm2, of disorganization of the photoreceptor cell layer in a GA lesion of the human retina, or the extent of area, measured in suitable units, e.g. mm2, of photoreceptor cell death in a GA lesion of the human retina. In some embodiments, photoreceptor integrity loss may be measured using OCT. PRIloss values may range from greater than 0 mm2to 17, 18, or greater than 18 mm2, and may include every discrete value in-between. Page 4 of 38 12356904v1Attorney Docket No.2008575-0770 By way of non-limiting example, a PRIloss value may be between 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6- 7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, or 17-18 mm2, and may include every discrete value in-between.

[0020] As used herein, “retinal pigment epithelium loss” (RPEloss) refers to the extent of area, measured in suitable units, e.g. mm2, of retinal pigment epithelium cell death in a GA lesion of the human retina. In some embodiments, retinal pigment epithelium loss may be measured using FAF. In other embodiments, retinal pigment epithelium loss may be measured using OCT. RPEloss values may range from 0 mm2to 17, 18, or greater than 18 mm2, and may include every discrete value in-between. By way of non-limiting example, a RPEloss value may be 0, 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, or 17-18 mm2, and may include every discrete value in-between.

[0021] In some embodiments, a GA lesion may only comprise PRIloss, and not RPEloss, in which case, the absolute difference would be equivalent to the PRIloss. In other embodiments, a GA lesion may comprise both PRIloss and RPEloss, where [PRIloss-RPEloss] is calculated by subtracting the values. In instances of multifocal GA lesions, the PRIloss is the sum of the photoreceptor integrity loss for each individual lesion, and similarly, the RPEloss is the sum of the retinal pigment epithelium loss for each individual lesion.

[0022] In some embodiments, the [PRIloss-RPEloss] is greater than zero but less than 1.0 mm2. In other embodiments, the [PRIloss-RPEloss] loss is at least 1 mm2. For instance, [PRIloss- RPEloss] may be 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2. By way of non-limiting example, [PRIloss-RPEloss] may be any value between 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 mm2.

[0023] The [PRIloss-RPEloss] may be determined at any point in time. For instance, [PRIloss- RPEloss] may be determined at screening for a study or clinical trial, at baseline for a study or clinical trial, during a study or clinical trial, before treatment, during treatment, or after treatment, etc. (b) ratio between photoreceptor integrity loss and retinal pigment epithelium loss

[0024] Each of the methods detailed herein may utilize the numeric value of the ratio between the photoreceptor integrity loss and the retinal pigment epithelium loss (“[PRIloss / RPEloss]”). Photoreceptor integrity loss (PRIloss) is the same as detailed in section (a) above. In some embodiments, photoreceptor integrity loss may be measured using OCT. PRIloss values may range from greater than 0 mm2to 17, 18, or greater than 18 mm2, and may include every discrete Page 5 of 38 12356904v1Attorney Docket No.2008575-0770 value in-between. By way of non-limiting example, a PRIloss value may be between 0-1, 1-2, 2- 3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, or 17-18 mm2, and may include every discrete value in-between.

[0025] Similarly retinal pigment epithelium loss (RPEloss) is the same as detailed in section (a) above. In some embodiments, retinal pigment epithelium loss may be measured using FAF. In other embodiments, retinal pigment epithelium loss may be measured using OCT. RPEloss values may range from 0 mm2to 17, 18, or greater than 18 mm2, and may include every discrete value in-between. By way of non-limiting example, a RPEloss value may be 0, 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-16, 16-17, or 17-18 mm2, and may include every discrete value in-between.

[0026] In some embodiments, a GA lesion may comprise both PRIloss and RPEloss, where [PRIloss / RPEloss] is calculated by dividing the values. In instances of multifocal GA lesions, the PRIloss is the sum of the photoreceptor integrity loss for each individual lesion, and similarly, the RPEloss is the sum of the retinal pigment epithelium loss for each individual lesion.

[0027] In some embodiments, the [PRIloss / RPEloss] is greater than zero but less than 1.0 mm2. In other embodiments, the [PRIloss / RPEloss] loss is at least 1 mm2. For instance, [PRIloss / RPEloss] may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or more than 21 mm2. By way of non-limiting example, [PRIloss / RPEloss] may be any value between 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15- 16, 16-17, 17-18, 18-19, 19-20, or 20-21 mm2.

[0028] The [PRIloss / RPEloss] may be determined at any point in time after RPEloss. For instance, [PRIloss / RPEloss] may be determined at screening for a study or clinical trial, at baseline for a study or clinical trial, during a study or clinical trial, before treatment, during treatment, or after treatment, etc. (c) other RPIloss and RPEloss characteristics

[0029] In certain embodiments, other RPIloss and RPEloss characteristics may be used in a method of the present disclosure. For instance, by way of non-limiting examples, a method of the present disclosure may use the square root of RPIloss, the square root of RPEloss, the square root of [RPIloss / RPEloss], or the square root of [RPIloss-RPEloss]. Page 6 of 38 12356904v1Attorney Docket No.2008575-0770 III. METHODS OF USE

[0030] In particular embodiments, relevant methods detailed below may be embodied as computer-executable instructions stored on a non-transitory computer-readable medium. (a) Methods for selecting a patient for enrollment in a clinical trial

[0031] One aspect of the present disclosure encompasses methods for selecting a patient for enrollment in a clinical trial. As used herein, the phrase “clinical trial” refers to a research study in which one or more human subjects are prospectively or retrospectively assigned to one or more interventions (which may include placebo, sham, or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. Clinical trials may be required for a governing body to approve the use or sale of an intervention, such as a pharmaceutically active composition.

[0032] Generally speaking, a method for selecting a patient for enrollment in a clinical trial comprises calculating the ratio of the photoreceptor integrity loss and the retinal epithelium loss [RPEloss / RPEloss], or calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient diagnosed with geographic atrophy. The [RPEloss / RPEloss] or [PRIloss-RPEloss] may be determined as detailed in section II above.

[0033] In some embodiments, a method of the disclosure further comprises creating a distribution of [RPEloss / RPEloss] or [PRIloss-RPEloss] values determined from a control population. As used herein, “control population” refers to a population designed to have similar demographics to the patient, such that the control population may be used as a benchmark or a point of comparison against which other study results are measured. Methods of designing control populations are known to those of skill in the art. Similarly, a control population should encompass enough members to provide a statistically relevant sample size. In some embodiments, a control population does not receive the study intervention. In some embodiments, a control population receives a placebo or sham intervention. A distribution of [RPEloss / RPEloss] or [PRIloss-RPEloss] values may be created using statistical methods known to those of skill in the art. In some embodiments, a distribution of [RPEloss / RPEloss] or [PRIloss-RPEloss] values for a control population may be divided into percentiles. Page 7 of 38 12356904v1Attorney Docket No.2008575-0770

[0034] In particular embodiments, a patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] of the patient meets a pre-selected threshold value based on a distribution of [PRIloss-RPEloss] values determined from a control population. A pre-selected threshold value may be selected to facilitate the clinical trial design. By way of non-limiting example, the pre- selected threshold value may be the 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 2nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th, 40th, 41st, 42nd, 43rd, 44th, 45th, 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, 64th, 65th, 66th, 67th, 68th, 69th, 70th, 71st, 72nd, 73rd, 74th, 75th, 76th, 77th, 78th, 79th, 80th, 81st, 82nd, 83rd, 84th, 85th, 86th, 87th, 88th, 89th, 90th, 91st, 92nd, 93rd, 94th, 95th, 96th, 97th, 98th, or 99thpercentile value based on the distribution of [PRIloss-RPEloss] values determined for a control population. For instance, by way of non-limiting example, a patient may be selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 50th percentile value based on the distribution of [PRIloss-RPEloss] values determined for the control population. In another non- limiting example, a patient may be selected for enrollment in a clinical trial if the [PRIloss- RPEloss] calculated for the patient is greater than, equal to, or less than the 25th percentile value based on the distribution of [PRIloss-RPEloss] values determined for the control population.

[0035] In some embodiments, the distribution of [PRIloss-RPEloss] values determined for a control population may be divided into quartiles. In other embodiments, the distribution of [PRIloss-RPEloss] values determined for a control population may be divided into tertiles. For instance, by way of non-limiting example, a patient may be selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 1stquartile value based on the distribution of [PRIloss-RPEloss] values determined for the control population. In another non-limiting example, a patient may be selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 2ndquartile value based on the distribution of [PRIloss-RPEloss] values determined for the control population.

[0036] In certain embodiments, a patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] of the patient is greater than or equal to 1 mm2. In other embodiments, a patient may be selected for enrollment in a clinical trial if the [PRIloss-RPEloss] is at least 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2. Further non-limiting examples include embodiments where a Page 8 of 38 12356904v1Attorney Docket No.2008575-0770 patient may be selected for enrollment in a clinical trial if the [PRIloss-RPEloss] is a value between 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 mm2.

[0037] In additional embodiments, a patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] of the patient is less than or equal to 1 mm2. By way of non-limiting example, a patient may be selected for enrollment in a clinical trial if the [PRIloss-RPEloss] is less than or equal to 1, 2, 3, 4, 5, 6, 7, or 8 mm2.

[0038] In other embodiments, a patient is selected for enrollment in a clinical trial if the [PRIloss / RPEloss] of the patient meets a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] values determined from a control population. A pre-selected threshold value may be selected to facilitate the clinical trial design. By way of non-limiting example, the pre- selected threshold value may be the 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 2nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th, 40th, 41st, 42nd, 43rd, 44th, 45th, 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, 64th, 65th, 66th, 67th, 68th, 69th, 70th, 71st, 72nd, 73rd, 74th, 75th, 76th, 77th, 78th, 79th, 80th, 81st, 82nd, 83rd, 84th, 85th, 86th, 87th, 88th, 89th, 90th, 91st, 92nd, 93rd, 94th, 95th, 96th, 97th, 98th, or 99thpercentile value based on the distribution of [PRIloss / RPEloss] values determined for a control population. For instance, by way of non-limiting example, a patient may be selected for enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is greater than, equal to, or less than the 50th percentile value based on the distribution of [PRIloss / RPEloss] values determined for the control population. In another non- limiting example, a patient may be selected for enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is greater than, equal to, or less than the 25th percentile value based on the distribution of [PRIloss / RPEloss] values determined for the control population.

[0039] In some embodiments, the distribution of [PRIloss / RPEloss] values determined for a control population may be divided into quartiles. In other embodiments, the distribution of [PRIloss / RPEloss] values determined for a control population may be divided into tertiles. For instance, by way of non-limiting example, a patient may be selected for enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is greater than, equal to, or less than the 1stquartile value based on the distribution of [PRIloss / RPEloss] values determined for the control population. In another non-limiting example, a patient may be selected for enrollment in Page 9 of 38 12356904v1Attorney Docket No.2008575-0770 a clinical trial if the [PRIloss / RPEloss] calculated for the patient is greater than, equal to, or less than the 2ndquartile value based on the distribution of [PRIloss-RPEloss] values determined for the control population.

[0040] In certain embodiments, a patient is selected for enrollment in a clinical trial if the [PRIloss / RPEloss] of the patient is greater than or equal to 1 mm2. By way of non-limiting example, a patient may be selected for enrollment in a clinical trial if the [PRIloss / RPEloss] is at least 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2. Further non-limiting examples include embodiments where a patient may be selected for enrollment in a clinical trial if the [PRIloss / RPEloss] is a value between 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 mm2.

[0041] Each of the above embodiments may further comprise measuring the photoreceptor integrity loss and the retinal pigment epithelium loss in at least one eye of a patient diagnosed with geographic atrophy. Methods of measuring the photoreceptor integrity loss and the retinal pigment epithelium loss are known in the art. In some embodiments, such measurements are performed with the aid of OCT. In particular embodiments, such measurements may be made with the help of artificial intelligence algorithms.

[0042] In further embodiments, a patient selected for enrollment in a clinical trial may be administered an intervention comprising a complement inhibitor. Complement inhibitors are known in the art, and suitable inhibitors include those detailed in WO / 2023 / 039206, hereby incorporated by reference in its entirety. In some embodiments, the complement inhibitor is administered to the eye. In other embodiments, the complement inhibitor is administered systemically. In certain embodiments, a patient may be administered a combination of two or more complement inhibitors.

[0043] In even further embodiments, a patient selected for enrollment in a clinical trial may be administered an intervention other than a complement inhibitor.

[0044] Each of the above embodiments may be used to select all or a subset of the patients enrolled in a particular clinical trial. For instance, the above methods may be used to enroll about 10%. 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the patients enrolled in a particular clinical trial. Page 10 of 38 12356904v1Attorney Docket No.2008575-0770 (b) Methods for excluding a patient from enrollment in a clinical trial

[0045] Another aspect of the present disclosure encompasses methods for excluding a patient from enrollment in a clinical trial. Generally speaking, a method for excluding a patient from enrollment in a clinical trial comprises calculating the ratio of the photoreceptor integrity loss and the retinal epithelium loss [RPEloss / RPEloss], or calculating the calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss], in at least one eye of a patient diagnosed with geographic atrophy. The [RPEloss / RPEloss] or [PRIloss-RPEloss] may be determined as detailed in section II above.

[0046] In some embodiments, a method of the disclosure further comprises creating a distribution of [RPEloss / RPEloss] or [PRIloss-RPEloss] values determined from a control population. As used herein, “control population” refers to a population designed to have similar demographics to the patient, such that the control population may be used as a benchmark or a point of comparison against which other study results are measured. Methods of designing control populations are known to those of skill in the art. Similarly, a control population should encompass enough members to provide a statistically relevant sample size. In some embodiments, a control population does not receive the study intervention. In some embodiments, a control population receives a placebo or sham intervention. A distribution of [PRIloss-RPEloss] values may be created using statistical methods known to those of skill in the art. In some embodiments, a distribution of [PRIloss-RPEloss] values for a control population may be divided into percentiles.

[0047] In particular embodiments, a patient is excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] of the patient meets a pre-selected threshold value based on a distribution of [PRIloss-RPEloss] values determined from a control population. A pre-selected threshold value may be selected to facilitate the clinical trial design. By way of non-limiting example, the pre- selected threshold value may be the 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 2nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th, 40th, 41st, 42nd, 43rd, 44th, 45th, 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, 64th, 65th, 66th, 67th, 68th, 69th, 70th, 71st, 72nd, 73rd, 74th, 75th, 76th, 77th, 78th, 79th, 80th, 81st, 82nd, 83rd, 84th, 85th, 86th, 87th, 88th, 89th, 90th, 91st, 92nd, 93rd, 94th, 95th, 96th, 97th, 98th, or 99thpercentile value based on the distribution of [PRIloss-RPEloss] values determined for a control population. For instance, by way of non-limiting example, a Page 11 of 38 12356904v1Attorney Docket No.2008575-0770 patient may be excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] calculated for the patient is greater than or equal to the 50th percentile value based on the distribution of [PRIloss-RPEloss] values determined for the control population. Alternatively, a patient may be excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] calculated for the patient is less than the 50th percentile value based on the distribution of [PRIloss-RPEloss] values determined for the control population. In another non-limiting example, a patient may be excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] calculated for the patient is greater than or equal to the 25th percentile value based on the distribution of [PRIloss-RPEloss] values determined for the control population. Alternatively, a patient may be excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] calculated for the patient is less than the 25th percentile value based on the distribution of [PRIloss-RPEloss] values determined for the control population.

[0048] In some embodiments, the distribution of [PRIloss-RPEloss] values determined for a control population may be divided into quartiles. In other embodiments, , the distribution of [PRIloss-RPEloss] values determined for a control population may be divided into tertiles. For instance, by way of non-limiting example, a patient may be excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] calculated for the patient is greater than or equal to the 1stquartile value based on the distribution of [PRIloss-RPEloss] values determined for the control population. Alternatively, a patient may be excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] calculated for the patient is less than the 1stquartile value based on the distribution of [PRIloss-RPEloss] values determined for the control population. In another non- limiting example, a patient may be excluded from enrollment in a clinical trial if the [PRIloss- RPEloss] calculated for the patient is greater than or equal to the 2ndquartile value based on the distribution of [PRIloss-RPEloss] values determined for the control population. Alternatively, a patient may be excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] calculated for the patient is less than the 2ndquartile value based on the distribution of [PRIloss-RPEloss] values determined for the control population.

[0049] In certain embodiments, a patient is excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] of the patient is greater than or equal to 1 mm2. By way of non-limiting example, a patient may be excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] is at least 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2. Alternatively, in certain embodiments, a patient is Page 12 of 38 12356904v1Attorney Docket No.2008575-0770 excluded from enrollment in a clinical trial if the [PRIloss-RPEloss] of the patient is less than 1 mm2. For instance, a patient may be excluded from enrollment in a clinical trial if the [PRIloss- RPEloss] is less than 1, 2, 3, 4, 5, 6, 7, or 8 mm2. Further non-limiting examples include embodiments where a patient may be excluded from enrollment in a clinical trial if the [PRIloss- RPEloss] is a value between 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 mm2.

[0050] In particular embodiments, a patient is excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] of the patient meets a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] values determined from a control population. A pre-selected threshold value may be selected to facilitate the clinical trial design. By way of non-limiting example, the pre- selected threshold value may be the 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 2nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th, 40th, 41st, 42nd, 43rd, 44th, 45th, 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, 64th, 65th, 66th, 67th, 68th, 69th, 70th, 71st, 72nd, 73rd, 74th, 75th, 76th, 77th, 78th, 79th, 80th, 81st, 82nd, 83rd, 84th, 85th, 86th, 87th, 88th, 89th, 90th, 91st, 92nd, 93rd, 94th, 95th, 96th, 97th, 98th, or 99thpercentile value based on the distribution of [PRIloss / RPEloss] values determined for a control population. For instance, by way of non-limiting example, a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is greater than or equal to the 50th percentile value based on the distribution of [PRIloss / RPEloss] values determined for the control population. Alternatively, a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is less than the 50th percentile value based on the distribution of [PRIloss / RPEloss] values determined for the control population. In another non-limiting example, a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is greater than or equal to the 25th percentile value based on the distribution of [PRIloss / RPEloss] values determined for the control population. Alternatively, a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is less than the 25th percentile value based on the distribution of [PRIloss / RPEloss] values determined for the control population.

[0051] In some embodiments, the distribution of [PRIloss / RPEloss] values determined for a control population may be divided into quartiles. In other embodiments, the distribution of [PRIloss / RPEloss] values determined for a control population may be divided into tertiles. For Page 13 of 38 12356904v1Attorney Docket No.2008575-0770 instance, by way of non-limiting example, a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is greater than or equal to the 1stquartile value based on the distribution of [PRIloss / RPEloss] values determined for the control population. Alternatively, a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is less than the 1stquartile value based on the distribution of [PRIloss / RPEloss] values determined for the control population. In another non- limiting example, a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is greater than or equal to the 2ndquartile value based on the distribution of [PRIloss / RPEloss] values determined for the control population. Alternatively, a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] calculated for the patient is less than the 2ndquartile value based on the distribution of [PRIloss / RPEloss] values determined for the control population.

[0052] In certain embodiments, a patient is excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] of the patient is greater than or equal to 1 mm2. By way of non-limiting example, a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] is at least 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2. Alternatively, in certain embodiments, a patient is excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] of the patient is less than 1 mm2. For instance, a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] is less than 1, 2, 3, 4, 5, 6, 7, or 8 mm2. Further non-limiting examples include embodiments where a patient may be excluded from enrollment in a clinical trial if the [PRIloss / RPEloss] is a value between 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, or 7-8 mm2.

[0053] Each of the above embodiments may further comprise measuring the photoreceptor integrity loss and the retinal pigment epithelium loss in at least one eye of a patient diagnosed with geographic atrophy. Methods of measuring the photoreceptor integrity loss and the retinal pigment epithelium loss are known in the art. In some embodiments, such measurements are performed with the aid of OCT. In particular embodiments, such measurements may be made with the help of artificial intelligence algorithms.

[0054] In further embodiments, a patient excluded from enrollment in a clinical trial may be administered a complement inhibitor. Complement inhibitors are known in the art, and suitable inhibitors include those detailed in WO / 2023 / 039206, hereby incorporated by reference in its entirety. In some embodiments, the complement inhibitor is administered to the eye. In other Page 14 of 38 12356904v1Attorney Docket No.2008575-0770 embodiments, the complement inhibitor is administered systemically. In certain embodiments, a patient may be administered a combination of two or more complement inhibitors.

[0055] In even further embodiments, a patient excluded from enrollment in a clinical trial may be administered a treatment other than a complement inhibitor.

[0056] Each of the above embodiments may be used to exclude all or a subset of the patients excluded from a particular clinical trial. For instance, the above methods may be used to enroll about 10%. 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the patients enrolled in a particular clinical trial. (c) Methods of designing a clinical trial

[0057] In some embodiments a method described herein may be used to select all or some of the patients to be enrolled in a clinical trial. In some embodiments all or at least 95% of the patients enrolled in the trial have at least one eye that has a [PRIloss / RPEloss] or [PRIloss-RPEloss] that meets a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] or [PRIloss- RPEloss] values, respectively, determined from a control population. In some embodiments at least 50%, 60%, 70%, 80%, 90%, or more of the patients enrolled in the trial have at least one eye that has a [PRIloss / RPEloss] or [PRIloss-RPEloss] that meets a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined from a control population In some embodiments all or at least 95% of the study eyes of patients enrolled in the trial have a [PRIloss / RPEloss] or [PRIloss-RPEloss] that meets a pre- selected threshold value based on a distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined from a control population. In some embodiments at least 50%, 60%, 70%, 80%, 90%, or more of the study eyes of patients enrolled in the trial have a [PRIloss / RPEloss] or [PRIloss-RPEloss] that meets a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined from a control population.

[0058] In some embodiments all or at least 95% of the patients enrolled in the trial have at least one eye that has a [PRIloss / RPEloss] or [PRIloss-RPEloss] at least as great as a pre-selected threshold value, e.g., 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2. In some embodiments at least 50%, 60%, 70%, 80%, 90%, or more of the patients enrolled in the trial have at least one eye that has a [PRIloss / RPEloss] or [PRIloss-RPEloss] at least as great as a pre-selected threshold value, e.g., Page 15 of 38 12356904v1Attorney Docket No.2008575-0770 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2. in some embodiments all or at least 95% of the study eyes of patients enrolled in the trial have a [PRIloss / RPEloss] or [PRIloss-RPEloss] at least as great as a pre-selected threshold value, e.g., 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2. In some embodiments at least 50%, 60%, 70%, 80%, 90%, or more of the study eyes of patients enrolled in the trial have a [PRIloss / RPEloss] or [PRIloss-RPEloss] at least as great as a pre-selected threshold value, e.g., 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2.

[0059] In some aspects, the present disclosure provides improvements in clinical trial technology and / or improvements in clinical trial design that may be useful e.g., in the context of a clinical trial studying a candidate therapy for treatment of GA. For example, in some embodiments a method described herein may allow for performing a clinical trial using a smaller number of patients and / or using a shorter duration of treatment with a candidate therapeutic agent than would otherwise be the case. In some embodiments a clinical trial performed with a group of patients selected as described herein may not require as many patients to demonstrate that an endpoint of interest, e.g., an efficacy endpoint, has been met as would an otherwise comparable trial performed with a group of patients who were selected without use of a method described herein. In some embodiments a clinical trial performed with a group of patients selected as described herein may not require as long a duration of treatment to demonstrate that an endpoint of interest, e.g., an efficacy endpoint, has been met as would an otherwise comparable trial performed with a group of patients that was selected without use of a method described herein. Thus, in some embodiments, use of a method described herein may reduce the length of the trial.

[0060] In certain embodiments of particular interest patients having a [PRIloss-RPEloss] value in the 4thquartile are selected for enrollment in a clinical trial. In certain embodiments selecting patients having a [PRIloss-RPEloss] value in the 4thquartile may allow for a smaller number of patients and / or a shorter trial than if patients were not so selected.

[0061] In certain embodiments of interest patients having a [PRIloss / RPEloss] value in the 4thquartile are selected for enrollment in a clinical trial. In certain embodiments selecting patients having a [PRIloss / RPEloss] value in the 4thquartile may allow for a smaller number of patients and / or a shorter trial than if patients were not so selected.

[0062] In certain embodiments of particular interest patients having a [PRIloss-RPEloss] value in the 3rdtertile are selected for enrollment in a clinical trial. In certain embodiments selecting Page 16 of 38 12356904v1Attorney Docket No.2008575-0770 patients having a [PRIloss-RPEloss] value in the 3rdtertile may allow for a smaller number of patients and / or a shorter trial than if patients were not so selected.

[0063] In certain embodiments of interest patients having a [PRIloss / RPEloss] value in the 3rdtertile are selected for enrollment in a clinical trial. In certain embodiments selecting patients having a [PRIloss / RPEloss] value in the 3rdtertile may allow for a smaller number of patients and / or a shorter trial than if patients were not so selected.

[0064] In some embodiments an endpoint of interest is a statistically significant reduction in GA lesion growth of X% in a group of patients treated with a candidate therapeutic agent as compared to a control group, where X is a prespecified value. In some embodiments an endpoint of interest is a statistically significant reduction in PR integrity loss of X% in a group of patients treated with a candidate therapeutic agent as compared to a control group, where X is a prespecified value. In some embodiments an endpoint of interest is a statistically significant reduction in RPE loss of X% in a group of patients treated with a candidate therapeutic agent as compared to a control group, where X is a prespecified value. The value for X may be, e.g., 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more. A control group may be a group of patients not treated with the candidate therapeutic agent, e.g., a group of patients who receive no treatment, sham treatment, or a placebo.

[0065] In some embodiments a clinical trial in which patients are selected as described herein will have a greater statistical power to show a difference between groups than a clinical trial having the same number of patients where the patients are selected without use of such method. In some embodiments a clinical trial in which patients are selected as described herein can enroll a smaller number of patients than a clinical trial in which the patients are selected without use of such method, yet still have an equivalent statistical power to show a difference between groups as the larger trial.

[0066] In some embodiments a method described herein may be used to select patients for a clinical trial in which a candidate therapeutic agent is compared with a sham or placebo. In some embodiments a method described herein may be used to select patients for a clinical trial in which a candidate therapeutic agent is compared with a therapy that is approved for use to treat the indication of interest, e.g., GA. In some embodiments a method described herein may be used to select patients for a clinical trial in which a first candidate therapeutic agent is compared with a second candidate therapeutic agent. In some embodiments a method described herein Page 17 of 38 12356904v1Attorney Docket No.2008575-0770 may be used to select patients for a clinical trial in which two or more dosing regimens of a candidate therapeutic agent are compared. The dosing regimens may feature different dosages, different dosing intervals, and / or different administration routes. In some embodiments a method described herein may be used to select patients for a clinical trial in which there are 2, 3, 4, or more treatment groups. Any such trial may include a control group.

[0067] In some embodiments a candidate therapeutic agent tested in a clinical trial that utilizes a method described herein for patient selection may comprise a peptide, a protein, an antibody, a nucleic acid such as an siRNA or antisense oligonucleotide or aptamer, a small molecule, a gene therapy, or a cell therapy.

[0068] In some aspects, methods described herein, e.g., methods for selecting a patient for enrollment in a clinical trial, may be embodied as computer-executable instructions stored on a non-transitory computer-readable medium. In some aspects, methods described herein, e.g., methods for selecting a patient for enrollment in a clinical trial, may be implemented as part of a system for determining clinical trial eligibility and / or as part of a system for stratifying patients and assigning them to an arm of a study. Specifically, in some embodiments, the present disclosure encompasses methods of stratifying patients in a clinical trial between treatment or intervention arms.

[0069] In some aspects, methods described herein may be applied in a post-hoc analysis of clinical trial data for a clinical trial that enrolled patients that were not selected using a method described herein. In some embodiments methods described herein may be used to select a subset of patients for analysis, where the subset consists of patients selected as described herein.

[0070] In some aspects, a system that measures PR integrity and-RPE area may provide an output that includes a computation of [PRIloss / RPEloss] or [PRIloss-RPEloss]. In some embodiments such a system may be used in performing a method described herein. (d) Methods of treating a patient diagnosed with geographic atrophy

[0071] In another aspect, the present disclosure encompasses a method of treatment for a patient diagnosed with geographic atrophy. Generally speaking, the method comprises calculating at least one geographic atrophy lesion characteristic, such as [PRIloss / RPEloss] or [PRIloss- RPEloss], in at least one eye of a patient diagnosed with geographic atrophy. The [PRIloss / RPEloss] or [PRIloss-RPEloss] may be determined as detailed in section II above. Page 18 of 38 12356904v1Attorney Docket No.2008575-0770

[0072] In some embodiments, a method of the disclosure further comprises creating a distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values determined from a control population. As used herein, “control population” refers to a population designed to have similar demographics to the patient, such that the control population may be used as a benchmark or a point of comparison against which other study results are measured. Methods of designing control populations are known to those of skill in the art. Similarly, a control population should encompass enough members to provide a statistically relevant sample size. A distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values may be created using statistical methods known to those of skill in the art. In some embodiments, a distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values for a control population may be divided into percentiles.

[0073] In particular embodiments, a method of treatment for a patient with at least one geographic atrophy lesion in at least one eye is selected based on the [PRIloss / RPEloss] or [PRIloss-RPEloss] value of the patient. If the [PRIloss / RPEloss] or [PRIloss-RPEloss] value meets a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] or [PRIloss- RPEloss] values, respectively, determined from a control population, then the patient is administered a first treatment. A pre-selected threshold value may be selected to indicate patients that are predicted to respond to a first treatment. By way of non-limiting example, the pre- selected threshold value may be the 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 2nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th, 40th, 41st, 42nd, 43rd, 44th, 45th, 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, 64th, 65th, 66th, 67th, 68th, 69th, 70th, 71st, 72nd, 73rd, 74th, 75th, 76th, 77th, 78th, 79th, 80th, 81st, 82nd, 83rd, 84th, 85th, 86th, 87th, 88th, 89th, 90th, 91st, 92nd, 93rd, 94th, 95th, 96th, 97th, 98th, or 99thpercentile value based on the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] value determined for a control population.

[0074] For instance, by way of non-limiting example, a patient may be administered a first treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 50th percentile value based on the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined for the control population. In another non- limiting example, a patient may be administered a first treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 25th Page 19 of 38 12356904v1Attorney Docket No.2008575-0770 percentile value based on the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined for the control population.

[0075] In some embodiments, the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values determined for a control population may be divided into quartiles. In other embodiments, the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values determined for a control population may be divided into tertiles. For instance, by way of non-limiting example, a patient may be administered a first treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 1stquartile value based on the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined for the control population. In another non-limiting example, a patient may be administered a first treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 2ndquartile value based on the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values determined for the control population.

[0076] In certain embodiments, a patient is administered a first treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] of the patient is greater than or equal to 1 mm2. By way of non-limiting example, a patient may be administered a first treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] is at least 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2. Further non-limiting examples include embodiments where a patient may be administered a first treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] is a value between 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, or 7- 8 mm2.

[0077] In additional embodiments, a patient is administered a first treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] of the patient is less than or equal to 1 mm2. By way of non-limiting example, a patient may be administered a first treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] is less than or equal to 1, 2, 3, 4, 5, 6, 7, or 8 mm2.

[0078] In particular embodiments, if the [PRIloss / RPEloss] or [PRIloss-RPEloss] value meets a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined from a control population, then the patient is administered a second treatment. A pre-selected threshold value may be selected to indicate patients that are predicted to respond to a second treatment. By way of non-limiting example, the pre-selected threshold value may be the 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 2nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, Page 20 of 38 12356904v1Attorney Docket No.2008575-0770 39th, 40th, 41st, 42nd, 43rd, 44th, 45th, 46th, 47th, 48th, 49th, 50th, 51st, 52nd, 53rd, 54th, 55th, 56th, 57th, 58th, 59th, 60th, 61st, 62nd, 63rd, 64th, 65th, 66th, 67th, 68th, 69th, 70th, 71st, 72nd, 73rd, 74th, 75th, 76th, 77th, 78th, 79th, 80th, 81st, 82nd, 83rd, 84th, 85th, 86th, 87th, 88th, 89th, 90th, 91st, 92nd, 93rd, 94th, 95th, 96th, 97th, 98th, or 99thpercentile value based on the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] value determined for a control population.

[0079] For instance, by way of non-limiting example, a patient may be administered a second treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 50th percentile value based on the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined for the control population. In another non- limiting example, a patient may be administered a second treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 25th percentile value based on the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined for the control population.

[0080] In some embodiments, the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values determined for a control population may be divided into quartiles. In other embodiments, the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values determined for a control population may be divided into tertiles. For instance, by way of non-limiting example, a patient may be administered a second treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 1stquartile value based on the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined for the control population. In another non-limiting example, a patient may be administered a second treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] calculated for the patient is greater than, equal to, or less than the 2ndquartile value based on the distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values determined for the control population.

[0081] In certain embodiments, a patient is administered a second treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] of the patient is greater than or equal to 1 mm2. By way of non-limiting example, a patient may be administered a second treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] is at least 1, 2, 3, 4, 5, 6, 7, or more than 7 mm2. Further non-limiting examples include embodiments where a patient may be administered a second treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] is a value between 0-1, 1-2, 2-3, 3-4, 4- 5, 5-6, 6-7, or 7-8 mm2. Page 21 of 38 12356904v1Attorney Docket No.2008575-0770

[0082] In additional embodiments, a patient is administered a second treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] of the patient is less than or equal to 1 mm2. By way of non-limiting example, a patient may be administered a second treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] is less than or equal to 1, 2, 3, 4, 5, 6, 7, or 8 mm2.

[0083] In some embodiments, the [PRIloss / RPEloss] or [PRIloss-RPEloss] of the patient, when compared to a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, from a control population, may initially indicate administration of a first treatment, and then, subsequently, a later in time [PRIloss / RPEloss] or [PRIloss-RPEloss] of the patient, when compared to a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, from a control population, may indicate administration of a second treatment in addition to, or separate from, the first treatment (e.g. the second treatment alone, or the second treatment in combination with the first treatment).

[0084] In certain embodiments, a first treatment is a complement inhibitor. Complement inhibitors are known in the art, and suitable inhibitors include those detailed in WO / 2023 / 039206, hereby incorporated by reference in its entirety. In some embodiments, the complement inhibitor is administered to the eye. In other embodiments, the complement inhibitor is administered systemically. In certain embodiments, a patient may be administered a combination of two or more complement inhibitors.

[0085] In some embodiments a complement inhibitor is a C3 inhibitor. In some embodiments a complement inhibitor is pegcetacoplan. In some embodiments a complement inhibitor is a C5 inhibitor. In some embodiments a complement inhibitor is a complement factor B inhibitor.

[0086] In some embodiments a complement inhibitor may comprise a peptide, a protein, an antibody, a nucleic acid such as an siRNA or antisense oligonucleotide or aptamer, a small molecule, or a gene therapy that, e.g., inhibits expression or activity of a complement component such as C3, C5, or factor B.

[0087] In other embodiments, a second treatment is not a complement inhibitor. Suitable ocular treatments may be known in the art.

[0088] In a further aspect, the present disclosure encompasses a method of identifying a patient that responds to a first treatment or a second treatment. Generally speaking, the method comprises calculating the [PRIloss / RPEloss] or [PRIloss-RPEloss] in at least one eye of a patient Page 22 of 38 12356904v1Attorney Docket No.2008575-0770 diagnosed with geographic atrophy, and identifying the patient as a responder to a first treatment or a second treatment if the [PRIloss / RPEloss] or [PRIloss-RPEloss] value meets a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined from a control population.

[0089] In another further aspect, the present disclosure encompasses a method of identifying a patient that responds to a complement inhibitor. Generally speaking, the method comprises calculating the [PRIloss / RPEloss] or [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and identifying the patient as a responder to a complement inhibitor if the [PRIloss / RPEloss] or [PRIloss-RPEloss] value meets a pre-selected threshold value based on a distribution of [PRIloss / RPEloss] or [PRIloss-RPEloss] values, respectively, determined from a control population.

[0090] In each of the above embodiments, the [PRIloss / RPEloss] or [PRIloss-RPEloss] may be calculated at a visual screening that includes imaging. (e) Methods of identifying a patient at high or low risk for rapid progression of geographic atrophy

[0091] In still another aspect, the present disclosure encompasses a method of identifying a patient at high risk for progression of geographic atrophy in at least one eye. Generally speaking, the method comprises calculating [PRIloss / RPEloss] or [PRIloss-RPEloss] in at least one eye of a patient diagnosed with geographic atrophy, and identifying the patient as at risk for progression of geographic atrophy based on the [PRIloss / RPEloss] or [PRIloss-RPEloss] value at screening, baseline or any other timepoint.

[0092] In yet another aspect, the present disclosure encompasses a method of identifying a patient at low risk for progression of geographic atrophy in at least one eye. Generally speaking, the method comprises calculating [PRIloss / RPEloss] or [PRIloss-RPEloss]in at least one eye of a patient diagnosed with geographic atrophy, and identifying the patient as low risk for progression of geographic atrophy based on the [PRIloss / RPEloss] or [PRIloss-RPEloss] value at screening, baseline or any other timepoint. Page 23 of 38 12356904v1Attorney Docket No.2008575-0770 IV. DEFINITIONS

[0093] As used herein, the terms “approximately” or “about” in reference to a number are generally taken to include numbers that fall within a range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of the number unless otherwise stated or otherwise evident from the context (except where such number would be less than 0% or exceed 100% of a possible value). In some embodiments, the term “about X” includes the number “X” and numbers that fall within a range of 5%, 10%, 15%, or 20% in either direction (greater than or less than) of the number X. V. SPECIFIC EMBODIMENTS Embodiment 1. A method of selecting a patient for enrollment in a clinical trial, the method comprising a. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and b. Selecting the patient for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated in (a) meets a pre-selected threshold value based on a distribution of [PRIloss-RPEloss] values determined from a control population. Embodiment 2. A method of selecting a patient for enrollment in a clinical trial, the method comprising a. measuring the photoreceptor integrity loss and the retinal pigment epithelium loss in at least one eye of a patient with at least one geographic atrophy lesion, b. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in the at least one eye of the patient, and c. selecting the patient for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated in (b) meets a pre-selected threshold value based on a distribution of [PRIloss-RPEloss] values determined from a control population. Embodiment 3. The method of claim 1 or 2, wherein the patient is selected for enrollment in a clinical trial if the absolute difference calculated is greater than or equal to the 50thPage 24 of 38 12356904v1Attorney Docket No.2008575-0770 percentile value based on the distribution of [PRIloss-RPEloss] values in the control population. Embodiment 4. The method of claim 1 or 2, wherein the patient is selected for enrollment in a clinical trial if the absolute difference calculated in (a) is greater than or equal to the 25thpercentile value based on the distribution of [PRIloss-RPEloss] values in the control population. Embodiment 5. The method of claim 1 or 2, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated is greater than or equal to 1.0 mm2. Embodiment 6. A method of selecting a patient for enrollment in a clinical trial, the method comprising a. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and b. selecting the patient for enrollment in a clinical trial if the absolute difference calculated in (a) is greater than or equal to 1.0 mm2. Embodiment 7. A method of selecting a patient for enrollment in a clinical trial, the method comprising a. measuring the photoreceptor integrity loss and measuring the retinal pigment epithelium loss in at least one eye of a patient diagnosed with geographic atrophy, b. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in the at least one eye of the patient, and c. selecting the patient for enrollment in a clinical trial if the absolute difference calculated in (b) is greater than or equal to 1.0 mm2. Embodiment 8. The method of any of the above claims, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated is greater than or equal to 2.0 mm2. Embodiment 9. The method of any of the above claims, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated is greater than or equal to 3.0 mm2. Page 25 of 38 12356904v1Attorney Docket No.2008575-0770 Embodiment 10. The method of any of the above claims, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated is greater than or equal to 4.0 mm2. Embodiment 11. The method of any of the above claims, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated in (a) is greater than or equal to 5.0 mm2. Embodiment 12. The method of any of the above claims, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated in (a) is greater than or equal to 6.0 mm2. Embodiment 13. The method of any of the above claims, wherein in the at least one eye, the patient has a unifocal geographic atrophy lesion with an area of at least 2.5 mm2. Embodiment 14. The method of any of the above claims, wherein in the at least one eye, the patient has multifocal geographic atrophy lesions with at least one lesion with an area of 1.25 mm2. Embodiment 15. The method of any of the above claims, further comprising administering the patient selected for enrollment in a clinical trial a complement inhibitor as part of the clinical trial. Embodiment 16. The method of any of the above claims, wherein the complement inhibitor is administered to the eye. Embodiment 17. The method of any of the above claims, wherein the complement inhibitor is administered systemically. Embodiment 18. The method of any of the above claims, wherein the [PRIloss-RPEloss] is calculated before or during the start of the clinical trial. Embodiment 19. A method of treatment for a patient diagnosed with geographic atrophy, the method comprising a. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and b. administering a complement inhibitor to the patient when the [PRIloss-RPEloss] calculated in (a) is greater than or equal to the 20thpercentile value of a distribution of [PRIloss-RPEloss] values determined from a control population. Page 26 of 38 12356904v1Attorney Docket No.2008575-0770 Embodiment 20. A method of treatment for a patient diagnosed with geographic atrophy, the method comprising a. measuring the photoreceptor integrity loss and the retinal pigment epithelium loss in at least one eye of a patient with at least one geographic atrophy lesion, b. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in the at least one eye of the patient, and c. administering a complement inhibitor to the patient when the [PRIloss-RPEloss] calculated in (b) is greater than or equal to the 20thpercentile value of a distribution of [PRIloss-RPEloss] values determined from a control population. Embodiment 21. A method of treatment for a patient diagnosed with geographic atrophy, the method comprising a. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and b. administering a complement inhibitor to the patient when the absolute difference calculated in (a) is greater than or equal to 1.0 mm2. Embodiment 22. A method of treatment for a patient diagnosed with geographic atrophy, the method comprising a. measuring the photoreceptor integrity loss and the retinal pigment epithelium loss in at least one eye of a patient with at least one geographic atrophy lesion, b. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in the at least one eye of the patient, and c. administering a complement inhibitor to the patient when the absolute difference calculated in (b) is greater than or equal to 1.0 mm2. Embodiment 23. The method of any of claims 19-22, wherein in the at least one eye, the patient has a unifocal geographic atrophy lesion with an area of at least 2.5 mm2. Embodiment 24. The method of any of claims 19-22, wherein in the at least one eye, the patient has multifocal geographic atrophy lesions with at least one lesion with an area of 1.25 mm2. Page 27 of 38 12356904v1Attorney Docket No.2008575-0770 Embodiment 25. The method of any of claims 19-22, wherein the complement inhibitor is administered to the eye. Embodiment 26. The method of any of claims 19-22, wherein the complement inhibitor is administered systemically. Embodiment 27. A method of identifying whether a patient is at high or low risk for progression of geographic atrophy in at least one eye, the method comprising a. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and b. identifying the patient as high risk if the [PRIloss-RPEloss] calculated in (a) is greater than or equal to the 25thpercentile value of a distribution of [PRIloss- RPEloss] values determined from a control population, or identifying the patient as low risk if the [PRIloss-RPEloss] calculated in (a) is less than the 25thpercentile value of a distribution of [PRIloss-RPEloss] values determined from a control population. Embodiment 28. The method of claim 27, further comprising administering a patient identified as high risk a complement inhibitor. Embodiment 29. The method of claim 28, wherein the complement inhibitor is administered to the eye. Embodiment 30. The method of claim 28, wherein the complement inhibitor is administered systemically. Embodiment 31. A method of predicting a patient’s response to treatment with a complement inhibitor, the method comprising a. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and b. predicting a patient’s response to treatment with a complement inhibitor by comparing the [PRIloss-RPEloss] calculated in (a) to a pre-selected value based on a distribution of [PRIloss-RPEloss] values determined from a control population, wherein if the value calculated in (a) is higher than the pre-selected value, then the patient is predicted to respond to the complement inhibitor, and Page 28 of 38 12356904v1Attorney Docket No.2008575-0770 wherein if the value calculated in (a) is lower than the pre-selected value, the patient is predicted to not respond to the complement inhibitor. Embodiment 32. The method of claim 31, wherein the patient’s response is predicted before treatment is initiated. Embodiment 33. A method of selecting an effective dose of a complement inhibitor for a patient with at least one geographic atrophy lesion, the method comprising a. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and b. selecting an effective dose based on the [PRIloss-RPEloss] calculated in (a). Embodiment 34. A method of selecting an effective dose schedule of a complement inhibitor for a patient with at least one geographic atrophy lesion, the method comprising a. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and b. selecting an effective dose schedule based on the [PRIloss-RPEloss] calculated in (a). Embodiment 35. A method of preserving the PR layer in a patient with at least one geographic atrophy lesion, the method comprising a. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and b. treating with a complement inhibitor if the [PRIloss-RPEloss] calculated in (a) meets a pre-selected threshold value based on a distribution of [PRIloss-RPEloss] values determined from a control population. Embodiment 36. A method of treatment of a patient with at least one geographic atrophy lesion, the method comprising a. calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and Page 29 of 38 12356904v1Attorney Docket No.2008575-0770 b. administering a treatment other than a complement inhibitor if the [PRIloss- RPEloss] calculated in (a) meets a pre-selected threshold value based on a distribution of [PRIloss-RPEloss] values determined from a control population.

[0094] 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 used in the practice or testing of the present invention, suitable methods and materials are described herein.

[0095] 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. EXAMPLES Example 1:

[0096] The DERBY and OAKS studies were phase 3 clinical studies of intra-vitreal injection of pegcetacoplan for the treatment of geographic atrophy secondary to AMD. The design of the DERBY and OAKS trials have been previously disclosed, and may be found, for instance, at clinicaltrials.gov, or in WO / 2023 / 039206, hereby incorporated by reference in its entirety. Example 2:

[0097] A post-hoc analysis of the data from a subset of patients in the DERBY and OAK studies that had OCT imagining performed was undertaken. The [PRIloss / RPEloss] and [PRIloss- RPEloss] values were calculated for the sham treated patients, and the resulting values divided into quartiles as illustrated in Figure 1 and Figure 2. Using the quartile cut-off values from the sham population, the treated population was divided into quartiles, and the change in [PRIloss / RPEloss] and [PRIloss-RPEloss] values were evaluated for each quartile. See, for instance, Figures 3-6. Page 30 of 38 12356904v1

Claims

Attorney Docket No.2008575-0770 CLAIMS What is claimed is:

1. A method of selecting a patient for enrollment in a clinical trial, the method comprising (a) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and (b) selecting the patient for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated in (a) meets a pre-selected threshold value based on a distribution of [PRIloss-RPEloss] values determined from a control population.

2. A method of selecting a patient for enrollment in a clinical trial, the method comprising (a) measuring the photoreceptor integrity loss and the retinal pigment epithelium loss in at least one eye of a patient with at least one geographic atrophy lesion, (b) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in the at least one eye of the patient, and (c) selecting the patient for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated in (b) meets a pre-selected threshold value based on a distribution of [PRIloss-RPEloss] values determined from a control population.

3. The method of claim 1 or 2, wherein the patient is selected for enrollment in a clinical trial if the absolute difference calculated is greater than or equal to the 75thpercentile value based on the distribution of [PRIloss-RPEloss] values in the control population.

4. The method of claim 1 or 2, wherein the patient is selected for enrollment in a clinical trial if the absolute difference calculated in (a) is greater than or equal to the 25thpercentile value based on the distribution of [PRIloss-RPEloss] values in the control population.

5. The method of claim 1 or 2, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated is greater than or equal to 1.0 mm2. Page 31 of 38 12356904v1Attorney Docket No.2008575-0770 6. A method of selecting a patient for enrollment in a clinical trial, the method comprising (a) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and (b) selecting the patient for enrollment in a clinical trial if the absolute difference calculated in (a) is greater than or equal to 1.0 mm2.

7. A method of selecting a patient for enrollment in a clinical trial, the method comprising (a) measuring the photoreceptor integrity loss and measuring the retinal pigment epithelium loss in at least one eye of a patient diagnosed with geographic atrophy, (b) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in the at least one eye of the patient, and (c) selecting the patient for enrollment in a clinical trial if the absolute difference calculated in (b) is greater than or equal to 1.0 mm2.

8. The method of any of the above claims, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated is greater than or equal to 2.0 mm2.

9. The method of any of the above claims, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated is greater than or equal to 3.0 mm2.

10. The method of any of the above claims, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated is greater than or equal to 4.0 mm2.

11. The method of any of the above claims, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated in (a) is greater than or equal to 5.0 mm2.

12. The method of any of the above claims, wherein the patient is selected for enrollment in a clinical trial if the [PRIloss-RPEloss] calculated in (a) is greater than or equal to 6.0 mm2. Page 32 of 38 12356904v1Attorney Docket No.2008575-0770 13. The method of any of the above claims, wherein in the at least one eye, the patient has a unifocal geographic atrophy lesion with an area of at least 2.5 mm2.

14. The method of any of the above claims, wherein in the at least one eye, the patient has multifocal geographic atrophy lesions with at least one lesion with an area of 1.25 mm2.

15. The method of any of the above claims, further comprising administering the patient selected for enrollment in a clinical trial a complement inhibitor as part of the clinical trial.

16. The method of any of the above claims, wherein the complement inhibitor is administered to the eye.

17. The method of any of the above claims, wherein the complement inhibitor is administered systemically.

18. The method of any of the above claims, wherein the [PRIloss-RPEloss] is calculated before or during the start of the clinical trial.

19. A method of treatment for a patient diagnosed with geographic atrophy, the method comprising (a) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and (b) administering a complement inhibitor to the patient when the [PRIloss-RPEloss] calculated in (a) is greater than or equal to the 20thpercentile value of a distribution of [PRIloss-RPEloss] values determined from a control population.

20. A method of treatment for a patient diagnosed with geographic atrophy, the method comprising Page 33 of 38 12356904v1Attorney Docket No.2008575-0770 (a) measuring the photoreceptor integrity loss and the retinal pigment epithelium loss in at least one eye of a patient with at least one geographic atrophy lesion, (b) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in the at least one eye of the patient, and (c) administering a complement inhibitor to the patient when the [PRIloss-RPEloss] calculated in (b) is greater than or equal to the 20thpercentile value of a distribution of [PRIloss-RPEloss] values determined from a control population.

21. A method of treatment for a patient diagnosed with geographic atrophy, the method comprising (a) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and (b) administering a complement inhibitor to the patient when the absolute difference calculated in (a) is greater than or equal to 1.0 mm2.

22. A method of treatment for a patient diagnosed with geographic atrophy, the method comprising (a) measuring the photoreceptor integrity loss and the retinal pigment epithelium loss in at least one eye of a patient with at least one geographic atrophy lesion, (b) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in the at least one eye of the patient, and (c) administering a complement inhibitor to the patient when the absolute difference calculated in (b) is greater than or equal to 1.0 mm2.

23. The method of any of claims 19-22, wherein in the at least one eye, the patient has a unifocal geographic atrophy lesion with an area of at least 2.5 mm2. Page 34 of 38 12356904v1Attorney Docket No.2008575-0770 24. The method of any of claims 19-22, wherein in the at least one eye, the patient has multifocal geographic atrophy lesions with at least one lesion with an area of 1.25 mm2.

25. The method of any of claims 19-22, wherein the complement inhibitor is administered to the eye.

26. The method of any of claims 19-22, wherein the complement inhibitor is administered systemically.

27. A method of identifying whether a patient is at high or low risk for progression of geographic atrophy in at least one eye, the method comprising (a) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and (b) identifying the patient as high risk if the [PRIloss-RPEloss] calculated in (a) is greater than or equal to the 25thpercentile value of a distribution of [PRIloss-RPEloss] values determined from a control population, or identifying the patient as low risk if the [PRIloss-RPEloss] calculated in (a) is less than the 25thpercentile value of a distribution of [PRIloss-RPEloss] values determined from a control population.

28. The method of claim 27, further comprising administering a patient identified as high risk a complement inhibitor.

29. The method of claim 28, wherein the complement inhibitor is administered to the eye.

30. The method of claim 28, wherein the complement inhibitor is administered systemically.

31. A method of predicting a patient’s response to treatment with a complement inhibitor, the method comprising Page 35 of 38 12356904v1Attorney Docket No.2008575-0770 (a) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and (b) predicting a patient’s response to treatment with a complement inhibitor by comparing the [PRIloss-RPEloss] calculated in (a) to a pre-selected value based on a distribution of [PRIloss-RPEloss] values determined from a control population, wherein if the value calculated in (a) is higher than the pre-selected value, then the patient is predicted to respond to the complement inhibitor, and wherein if the value calculated in (a) is lower than the pre-selected value, the patient is predicted to not respond to the complement inhibitor.

32. The method of claim 31, wherein the patient’s response is predicted before treatment is initiated.

33. A method of selecting an effective dose of a complement inhibitor for a patient with at least one geographic atrophy lesion, the method comprising (a) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and (b) selecting an effective dose based on the [PRIloss-RPEloss] calculated in (a).

34. A method of selecting an effective dose schedule of a complement inhibitor for a patient with at least one geographic atrophy lesion, the method comprising (a) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and (b) selecting an effective dose schedule based on the [PRIloss-RPEloss] calculated in (a).

35. A method of preserving the PR layer in a patient with at least one geographic atrophy lesion, the method comprising Page 36 of 38 12356904v1Attorney Docket No.2008575-0770 (a) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and (b) treating with a complement inhibitor if the [PRIloss-RPEloss] calculated in (a) meets a pre-selected threshold value based on a distribution of [PRIloss-RPEloss] values determined from a control population.

36. A method of treatment of a patient with at least one geographic atrophy lesion, the method comprising (a) calculating the absolute difference between the photoreceptor integrity loss and the retinal pigment epithelium loss [PRIloss-RPEloss] in at least one eye of a patient with at least one geographic atrophy lesion, and (b) administering a treatment other than a complement inhibitor if the [PRIloss- RPEloss] calculated in (a) meets a pre-selected threshold value based on a distribution of [PRIloss-RPEloss] values determined from a control population. Page 37 of 38 12356904v1

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