Introducing two new phase 3 trials in geographic atrophy (GA)

DERBY (APL2-303): A Phase 3 Clinical Study of APL-2 Therapy in Patients with GA

A phase 3, multicenter, randomized, double-masked, sham-controlled study 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)

OAKS (APL2-304): A Second Phase 3 Clinical Study of APL-2 Therapy in Patients with GA

A phase 3, multicenter, randomized, double-masked, sham-controlled study 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)

Disease Overview

Geographic Atrophy (GA)

The macula is the central section of the retina. It is responsible for providing the sharp vision that you need for reading, recognizing faces and driving.1 Age-related macular degeneration is a leading cause of sight loss in people over the age of 65 in the United States and other Western countries.2 In the United States, more than 2 million people have the advanced forms of AMD.3

The early and intermediate stages of AMD usually are asymptomatic. However, an eyecare professional can detect early and intermediate AMD by examining the back of your eye.1 In a healthy middle-aged to elderly person, this examination may reveal a few tiny yellowish dots beneath the retina of one or both eyes. These tiny dots, called drusen, are deposits of protein and fat from damaged cells. The presence of a few, tiny drusen may do no harm. However, the presence of medium-sized drusen is a sign of early AMD.1

In people with intermediate AMD, the drusen have become large, and there will be changes in the pigmentation of the retina. As the drusen grow larger, some pigmented cells beneath the retina may break down and release their pigment. This change can be seen as dark spots (hyperpigmentation). Later, this pigment may be cleared away, leaving light-colored spots (hypopigmentation). At this stage, the patient may start noticing some vision loss, especially at night.1

There are 2 types of late AMD, “dry age-related macular degeneration” and “wet age-related macular degeneration.” In dry AMD (also called geographic atrophy [GA]), there is a gradual, patchy breakdown in the light-sensitive cells of the macula, as well as of the supporting cells beneath the macula. In “wet” AMD (also called exudative or neovascular AMD), abnormal new blood vessels grow beneath the retina. These new blood vessels may leak fluid.1

Geographic atrophy (GA) is a chronic, irreversible progressive condition that causes permanent blind spots and/or blindness. While approximately 20% of all patients with GA have visual acuity of 20/200 (or worse), more than half of all patients with GA experience substantial decreases in everyday visual function,4,5which may significantly affect their quality of life. As GA progresses, it can destroy the central fovea, which is the part of the macula responsible for fine vision making it particularly hard to see in low-light conditions, to recognize faces, and to read.6,7

Macula Overview6,7

The Complement System

The complement system is an important part of the immune system. It is a set of proteins that acts (sometimes in concert with antibodies and white blood cells) to kill germs, destroy unnecessary cells that need to be removed, and to clean up the debris afterward. Through these normal processes, the complement system promotes inflammation.8 The complement system consists of more than 40 proteins, which are normally present in an inactive state. However, they can be activated by a process called cleavage, which means that a portion is split off, usually through the action of an enzyme. When one of these complement proteins becomes activated, it can act as an enzyme to activate another kind of complement protein. This chain reaction, in which one kind of complement protein sequentially activates another, is called a cascade. Complement system activation can start from any of 3 pathways, all of which trigger the cascade reaction that leads to cell destruction and removal.8

The 3 complement pathways include the classical pathway, the lectin pathway, and the alternative pathway. The classical complement pathway is activated when an antibody binds to an antigen, which is usually a foreign protein, such as a protein on a bacterium or virus. In contrast, the lectin pathway activates complement when a protein called mannose-binding lectin, which is made in the liver, binds to a foreign carbohydrate, such as those found on the outside of many bacteria, viruses, protozoa, or fungi. The alternative complement pathway can be initiated by spontaneously activated complement attaching to pathogens or cells.8

All 3 pathways (classical, lectin, and alternative) eventually lead to the cleavage of complement factor C3 into C3a and C3b. The cleavage of C3 must occur for the complement system to have its intended effects on cells. C3a promotes inflammation, while C3b opsonizes (labels) cells so that they will be cleared from the system by white blood cells. C3b also activates C5 by splitting it into C5a and C5b. C5a promotes inflammation by attracting inflammatory cells. C5b also makes up part of the membrane attack complex (MAC), which kills cells by drilling a hole in their cell membrane, resulting in their lysis (rupture).8

In a healthy person, the complement system is under tight control, to keep an immune response from damaging the body itself. Genetic and environmental risk factors can cause the body to lose control over the complement system, resulting in an overactivation (dysregulation) of the immune system. This dysregulation has been proposed as the cause of AMD.8

Role of Complement in GA7-9

There are several reasons to believe that inappropriate activation of the complement system plays a role in causing GA. Several complement activation products (including C3, C5, CFH, and activated MAC) have been found in drusen.9 Furthermore, elevated levels of complement proteins have been found in specimens of eye tissue (vitreous, Bruch’s membrane, and choroid) from advanced AMD patients who died, as compared to tissue from healthy eyes.10 In addition, a reduced amount of complement inhibitors (eg, CD59 and MCP) has been found in eyes with GA.10

People who have an unusual version of the gene for one of the complement proteins (eg, complement factor H and complement factor I) may be at higher risk for the development of wet or dry AMD.10 Also, patients with AMD and GA have been shown to have elevated plasma levels of complement breakdown products.9

Diagram of how a dysregulated complement system can lead to chronic inflammation in the macula

Complement hyperactivity leading to overactivation of the immune system and chronic inflammation in the macula is a contributing factor to GA.10 Dysregulation of the complement system is thought to play an important role in the development and progression of AMD to GA. Several potential triggers of the complement system in AMD have been described, including photo-oxidized A2E, amyloid beta, and oxidative stress.10-13

Learn more about enrolling in one of our GA trials

Disease Overview

Geographic Atrophy (GA)

The macula is the central section of the retina. It is responsible for providing the sharp vision that you need for reading, recognizing faces and driving.1 Age-related macular degeneration is a leading cause of sight loss in people over the age of 65 in the United States and other Western countries.2 In the United States, more than 2 million people have the advanced forms of AMD.3

The early and intermediate stages of AMD usually are asymptomatic. However, an eyecare professional can detect early and intermediate AMD by examining the back of your eye.1 In a healthy middle-aged to elderly person, this examination may reveal a few tiny yellowish dots beneath the retina of one or both eyes. These tiny dots, called drusen, are deposits of protein and fat from damaged cells. The presence of a few, tiny drusen may do no harm. However, the presence of medium-sized drusen is a sign of early AMD.1

In people with intermediate AMD, the drusen have become large, and there will be changes in the pigmentation of the retina. As the drusen grow larger, some pigmented cells beneath the retina may break down and release their pigment. This change can be seen as dark spots (hyperpigmentation). Later, this pigment may be cleared away, leaving light-colored spots (hypopigmentation). At this stage, the patient may start noticing some vision loss, especially at night.1

There are 2 types of late AMD, “dry age-related macular degeneration” and “wet age-related macular degeneration.” In dry AMD (also called geographic atrophy [GA]), there is a gradual, patchy breakdown in the light-sensitive cells of the macula, as well as of the supporting cells beneath the macula. In “wet” AMD (also called exudative or neovascular AMD), abnormal new blood vessels grow beneath the retina. These new blood vessels may leak fluid.1

Geographic atrophy (GA) is a chronic, irreversible progressive condition that causes permanent blind spots and/or blindness. While approximately 20% of all patients with GA have visual acuity of 20/200 (or worse), more than half of all patients with GA experience substantial decreases in everyday visual function,4,5which may significantly affect their quality of life. As GA progresses, it can destroy the central fovea, which is the part of the macula responsible for fine vision making it particularly hard to see in low-light conditions, to recognize faces, and to read.6,7

Macula Overview6,7

The Complement System

The complement system is an important part of the immune system. It is a set of proteins that acts (sometimes in concert with antibodies and white blood cells) to kill germs, destroy unnecessary cells that need to be removed, and to clean up the debris afterward. Through these normal processes, the complement system promotes inflammation.8 The complement system consists of more than 40 proteins, which are normally present in an inactive state. However, they can be activated by a process called cleavage, which means that a portion is split off, usually through the action of an enzyme. When one of these complement proteins becomes activated, it can act as an enzyme to activate another kind of complement protein. This chain reaction, in which one kind of complement protein sequentially activates another, is called a cascade. Complement system activation can start from any of 3 pathways, all of which trigger the cascade reaction that leads to cell destruction and removal.8

The 3 complement pathways include the classical pathway, the lectin pathway, and the alternative pathway. The classical complement pathway is activated when an antibody binds to an antigen, which is usually a foreign protein, such as a protein on a bacterium or virus. In contrast, the lectin pathway activates complement when a protein called mannose-binding lectin, which is made in the liver, binds to a foreign carbohydrate, such as those found on the outside of many bacteria, viruses, protozoa, or fungi. The alternative complement pathway can be initiated by spontaneously activated complement attaching to pathogens or cells.8

All 3 pathways (classical, lectin, and alternative) eventually lead to the cleavage of complement factor C3 into C3a and C3b. The cleavage of C3 must occur for the complement system to have its intended effects on cells. C3a promotes inflammation, while C3b opsonizes (labels) cells so that they will be cleared from the system by white blood cells. C3b also activates C5 by splitting it into C5a and C5b. C5a promotes inflammation by attracting inflammatory cells. C5b also makes up part of the membrane attack complex (MAC), which kills cells by drilling a hole in their cell membrane, resulting in their lysis (rupture).8

In a healthy person, the complement system is under tight control, to keep an immune response from damaging the body itself. Genetic and environmental risk factors can cause the body to lose control over the complement system, resulting in an overactivation (dysregulation) of the immune system. This dysregulation has been proposed as the cause of AMD.8

Role of Complement in GA7-9

There are several reasons to believe that inappropriate activation of the complement system plays a role in causing GA. Several complement activation products (including C3, C5, CFH, and activated MAC) have been found in drusen.9 Furthermore, elevated levels of complement proteins have been found in specimens of eye tissue (vitreous, Bruch’s membrane, and choroid) from advanced AMD patients who died, as compared to tissue from healthy eyes.10 In addition, a reduced amount of complement inhibitors (eg, CD59 and MCP) has been found in eyes with GA.10

People who have an unusual version of the gene for one of the complement proteins (eg, complement factor H and complement factor I) may be at higher risk for the development of wet or dry AMD.10 Also, patients with AMD and GA have been shown to have elevated plasma levels of complement breakdown products.9

Diagram of how a dysregulated complement system can lead to chronic inflammation in the macula

Complement hyperactivity leading to overactivation of the immune system and chronic inflammation in the macula is a contributing factor to GA.10 Dysregulation of the complement system is thought to play an important role in the development and progression of AMD to GA. Several potential triggers of the complement system in AMD have been described, including photo-oxidized A2E, amyloid beta, and oxidative stress.10-13

Learn more about enrolling in one of our GA trials

About APL-2

What is APL-2?

APL-2 is a PEGylated cyclic peptide inhibitor of complement C3. The peptide portion of APL-2 binds to C3, exerting broad inhibition of the complement cascade and helping to prevent excessive complement activity.14

Schematic of APL-2 binding to the C3 molecule to inhibit the complement cascade. Learn how dysregulation of the complement system plays a role in causing geographic atrophy.

Through this broad inhibition of C3, APL-2 helps the body regain control of the complement system, protecting it from further complement-mediated immune attacks.14

Why Evaluate APL-2 in GA?

APL-2 targets C3, which is the central protein in the complement cascade, positioned at the point where all 3 of the major complement activation pathways come together.14 C3 serves as the master switch, essentially controlling all downstream effectors.8 Thus, APL-2 could effectively inhibit activity associated with all 3 complement activation pathways.9 APL-2 may therefore be more effective in a broad patient population than an agent that inhibits only 1 or 2 of those pathways.

FILLY, an already-completed phase 2 trial of APL-2, demonstrated that intravitreal injections of APL-2 in patients with AMD were well-tolerated, and preliminary data indicate a therapeutic benefit in subjects with GA.15

In What Ophthalmic Disorders Is APL-2 Being Studied?

Two AMD clinical trials (Oaks and Derby) are being launched for the development of APL-2 for the treatment of geographic atrophy (GA) secondary to advanced age-related macular degeneration (AMD). The subject population will consist of adult male and female subjects with GA secondary to AMD.16,17

About APL-2

What is APL-2?

APL-2 is a PEGylated cyclic peptide inhibitor of complement C3. The peptide portion of APL-2 binds to C3, exerting broad inhibition of the complement cascade and helping to prevent excessive complement activity.14

Schematic of APL-2 binding to the C3 molecule to inhibit the complement cascade. Learn how dysregulation of the complement system plays a role in causing geographic atrophy.

Through this broad inhibition of C3, APL-2 helps the body regain control of the complement system, protecting it from further complement-mediated immune attacks.14

Why Evaluate APL-2 in GA?

APL-2 targets C3, which is the central protein in the complement cascade, positioned at the point where all 3 of the major complement activation pathways come together.14 C3 serves as the master switch, essentially controlling all downstream effectors.8 Thus, APL-2 could effectively inhibit activity associated with all 3 complement activation pathways.9 APL-2 may therefore be more effective in a broad patient population than an agent that inhibits only 1 or 2 of those pathways.

FILLY, an already-completed phase 2 trial of APL-2, demonstrated that intravitreal injections of APL-2 in patients with AMD were well-tolerated, and preliminary data indicate a therapeutic benefit in subjects with GA.15

In What Ophthalmic Diseases is APL-2 Being Studied?

Two AMD clinical trials (Oaks and Derby) are being launched for the development of APL-2 for the treatment of geographic atrophy (GA) secondary to advanced age-related macular degeneration (AMD). The subject population will consist of adult male and female subjects with GA secondary to AMD.16,17

About APL-2

What is APL-2?

APL-2 is a PEGylated cyclic peptide inhibitor of complement C3. The peptide portion of APL-2 binds to C3, exerting broad inhibition of the complement cascade and helping to prevent excessive complement activity.14

Schematic of APL-2 binding to the C3 molecule to inhibit the complement cascade. Learn how dysregulation of the complement system plays a role in causing geographic atrophy.

Through this broad inhibition of C3, APL-2 helps the body regain control of the complement system, protecting it from further complement-mediated immune attacks.14

In What Ophthalmic Diseases is APL-2 Being Studied?

Two AMD clinical trials (Oaks and Derby) are being launched for the development of APL-2 for the treatment of geographic atrophy (GA) secondary to advanced age-related macular degeneration (AMD). The subject population will consist of adult male and female subjects with GA secondary to AMD.16,17

Why Evaluate APL-2 in GA?

APL-2 targets C3, which is the central protein in the complement cascade, positioned at the point where all 3 of the major complement activation pathways come together.14 C3 serves as the master switch, essentially controlling all downstream effectors.8 Thus, APL-2 could effectively inhibit activity associated with all 3 complement activation pathways.9 APL-2 may therefore be more effective in a broad patient population than an agent that inhibits only 1 or 2 of those pathways.

FILLY, an already-completed phase 2 trial of APL-2, demonstrated that intravitreal injections of APL-2 in patients with AMD were well-tolerated, and preliminary data indicate a therapeutic benefit in subjects with GA.15

Phase 3 Study Design

Objectives

Primary Objective

  • To evaluate the efficacy of APL-2 compared to sham injection in patients with GA secondary to AMD assessed by change in the total area of GA lesions from baseline as measured by fundus autofluorescence (FAF)

Key Secondary Outcome Measures

  • Monocular reading speed (study eye), as assessed by Minnesota Reading or Radner Reading (MNRead) charts (in select countries)
  • Functional Reading Independence Index (FRII) composite score in the study eye
  • Normal luminance best-corrected visual acuity score (NL-BCVA) in the study eye
Key Inclusion Criteria for the Oaks and Derby Trials
1. Age ≥60 years
2. Normal Luminance Best Corrected Visual Acuity (NL-BCVA) of 24 letters or better on Early Treatment Diabetic Retinopathy Study (ETDRS) charts (~20/320 Snellen equivalent)
3. Clinical diagnosis of GA of the macula secondary to AMD
4.

Fundus autofluorescence (FAF) imaging shows:

  1. Total GA area ≥2.5 and ≤17.5 mm2 (1 and 7 disk areas [DA], respectively)
  2. If GA is multifocal, at least one focal lesion must be ≥1.25 mm2 (0.5 DA), with the overall aggregate area of GA as specified above in 4.a
  3. 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
  4. Presence of any pattern of hyper-autofluorescence in the junctional zone of GA
5. Adequate clarity of ocular media, adequate pupillary dilation, and fixation to permit the collection of good quality images
Key Inclusion Criteria for the Microperimetry Component of the Oaks Trial
1. Must be able to detect fixation target
2. Total elapsed time to complete the 10-2 68-point exam is ≤30 minutes in duration
3. Reliability test ratio must be ≤20%
4. Subject is willing and able to undertake microperimetry assessment
Key Exclusion Criteria for the Oaks and Derby Trials
1. GA secondary to a condition other than AMD
2. Spherical equivalent of the refractive error demonstrating >6 diopters of myopia or an axial length >26 mm
3. Any history or active choroidal neovascularization associated with AMD or any other cause in the study eye. Note: CNV in the fellow eye is not exclusionary
4. Presence in either eye of an active ocular disease that confounds visual function
5. Intraocular surgery within 3 months prior to randomization
6. History of laser therapy in the macular region
7. Aphakia or absence of the posterior capsule
8. Any ocular condition other than GA secondary to AMD that may require surgery or medical intervention during the study period
9. Any contraindication to intravitreal injection
10. History of prior intravitreal injection in the study eye
11. Prior participation in another interventional clinical study for intravitreal therapies in either eye (including subjects receiving sham)

Dosing

In this study, a single 15 mg/0.1 mL dose of APL-2 will be injected as an intravitreal injection once a month or once every other month for 24 months.

Key Endpoints

Primary Efficacy Endpoint
  • Change from baseline to month 12 in total area of GA lesion(s) in the study eye (in mm2) based on FAF
Key Secondary Efficacy Endpoints
  • Change from baseline in monocular reading speed (study eye), as assessed by Minnesota Reading (MNRead) or Radner Reading Charts at Month 24 (in select countries)
  • Change from baseline in Functional Reading Independence Index (FRII) composite score, at Month 24
  • Change from baseline in normal luminance best-corrected visual acuity score (NL-BCVA) at Month 24 as assessed by ETDRS chart
  • Change from baseline in low luminance best corrected visual acuity score (LL-BCVA) at Month 12 and Month 24 as assessed by ETDRS chart
  • Change from baseline in low luminance deficit (LLD) at Month 12 and Month 24
  • Change from baseline at each planned assessment in the total area of GA lesion(s) in the study eye (in mm2) as assessed by FAF (in select sites)
  • Change from baseline in monocular critical print size (study eye), as assessed by MNRead or Radner Reading Charts, at Month 12 and Month 24 (in select countries)
  • Change from baseline in the National Eye Institute Visual Functioning Questionnaire 25 Item Version (NEI VFQ-25) distance activity subscale score at Month 12 and Month 24
  • Number of scotomatous points assessed by mesopic microperimetry for the evaluation of the macular functional response (Oaks study only)
  • Change in macular sensitivity as assessed by mesopic microperimetry for the evaluation of the macular functional response
  • Systemic plasma concentration of APL-2 over time
Safety Endpoints
  • Incidence and severity of ocular and systemic treatment-emergent adverse events
  • Incidence of antitherapeutic antibodies directed against APL-2
  • Incidence of new active CNV in the study eye

Study Locations

For qualified patients who do not live near the study locations, Apellis can help to cover some or all of the costs associated with travel, if needed.

Bakersfield, CA

Encino, CA

San Diego, CA

Stanford, CA

Beverly Hills, CA

Palo Alto, CA

Sacramento, CA

New London, CT

Boston, MA

Hagerstown, MD

Cleveland, OH

Rapid City, SD

Houston, TX

The Woodlands, TX

Spokane, WA

Trial sites in the following cities are anticipated in the near future:

  • Abilene, TX
  • Asheville, NC
  • Augusta, GA
  • Austin, TX
  • Baltimore, MD
  • Bloomington, IL
  • Boston, MA
  • Boynton Beach, FL
  • Charlotte, NC
  • Charlottesville, VA
  • Chicago, IL
  • Cleveland, OH
  • Colorado Springs, CO
  • Columbus, OH
  • Dallas, TX
  • Danbury, CT
  • Detroit, MI
  • Durango, CO
  • Durham, NC
  • Edmond, OK
  • Ft. Meyers, FL
  • Grand Rapids, MI
  • Harlingen, TX
  • Hickory, NC
  • Indianapolis, IN
  • Lexington, KY
  • Los Angeles, CA
  • Madison, WI
  • Marietta, GA
  • Medford, OR
  • Miami, FL
  • Nashville, TN
  • New York, NY
  • Palm Beach Gardens, FL
  • Pensacola, FL
  • Philadelphia, PA
  • Phoenix, AZ
  • Reno, NV
  • Salt Lake City, UT
  • San Antonio, TX
  • San Diego, CA
  • San Francisco, CA
  • Santa Barbara, CA
  • Seattle, WA
  • Springfield, MA
  • Stuart, FL
  • Tampa, FL
  • Toms River, NJ
  • Traverse City, MI
  • Vancouver, WA
  • Washington, DC
  • Youngstown, OH

Study Locations

For qualified patients who do not live near the study locations, Apellis can help to cover some or all of the costs associated with travel, if needed.

Bakersfield, CA

Encino, CA

San Diego, CA

Stanford, CA

Beverly Hills, CA

Palo Alto, CA

Sacramento, CA

New London, CT

Boston, MA

Hagerstown, MD

Cleveland, OH

Rapid City, SD

Houston, TX

The Woodlands, TX

Spokane, WA

Trial sites in the following cities are anticipated in the near future:

  • Abilene, TX
  • Asheville, NC
  • Augusta, GA
  • Austin, TX
  • Baltimore, MD
  • Bloomington, IL
  • Boston, MA
  • Boynton Beach, FL
  • Charlotte, NC
  • Charlottesville, VA
  • Chicago, IL
  • Cleveland, OH
  • Colorado Springs, CO
  • Columbus, OH
  • Dallas, TX
  • Danbury, CT
  • Detroit, MI
  • Durango, CO
  • Durham, NC
  • Edmond, OK
  • Ft. Meyers, FL
  • Grand Rapids, MI
  • Harlingen, TX
  • Hickory, NC
  • Indianapolis, IN
  • Lexington, KY
  • Los Angeles, CA
  • Madison, WI
  • Marietta, GA
  • Medford, OR
  • Miami, FL
  • Nashville, TN
  • New York, NY
  • Palm Beach Gardens, FL
  • Pensacola, FL
  • Philadelphia, PA
  • Phoenix, AZ
  • Reno, NV
  • Salt Lake City, UT
  • San Antonio, TX
  • San Diego, CA
  • San Francisco, CA
  • Santa Barbara, CA
  • Seattle, WA
  • Springfield, MA
  • Stuart, FL
  • Tampa, FL
  • Toms River, NJ
  • Traverse City, MI
  • Vancouver, WA
  • Washington, DC
  • Youngstown, OH

Common Questions About Geographic Atrophy

AMD is the leading cause of severe vision loss in people over the age of 65 in the United States and other Western countries.3 It is characterized by a progressive degeneration of the central retina associated with central vision loss.2

Geographic atrophy is the “dry” form of the late stage of age-related macular degeneration (AMD).15 (You may also hear people refer to this condition as dry macular degeneration.) As the “dry” form of AMD progresses, cells in the light-sensitive portion of the macula, as well as the cells in the supporting structures (the retinal pigment epithelium and the choriocapillaris), start to die.15 This damage starts as small spots that grow into larger patches. As the light-sensitive cells in the macula die off, the person starts to lose vision in that eye. At first, the person may notice problems with reading or night vision.9 Eventually, the person will develop large, permanent blind spots (scotomata) in the center of the visual field. When the central fovea of the macula is involved, the person loses the ability to have sharp vision, such as that needed for reading and for recognizing faces.9

It’s important to note that while GA is commonly associated with people with visual acuity (VA) of 20/200 (or worse) caused by advanced AMD, more than half of all people who develop GA may experience substantial impairment of everyday visual function, which may significantly affect their quality of life.18

The early signs of AMD (drusen and pigmentary changes) are common in individuals over age 65 and precede the late stage forms.

The cause of GA is thought to be multifactorial, with numerous environmental and genetic risk factors. The dysregulation of the complement system, however, appears to play a pivotal role.5

GA is not a hereditary disease. Nevertheless, some genes do increase the risk that a person’s AMD will progress to GA.19

GA can be distinguished from other forms of dry AMD by ophthalmic exam and color fundus photography.15

Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) allow for noninvasive and rapid quantitative morphological assessment of GA in the clinical setting.15

So far, there is no approved treatment to prevent the onset and progression of GA.15 Several therapeutics are in various stages of clinical development.

The complement system is an integral part of our immune defense system. In healthy people, complement orchestrates the destruction and clearance of pathogens or of the body’s own cells that need to be removed. It also has proinflammatory capabilities.8

Complement activation is regulated to avoid its overactivation and to protect the body against inappropriate immune attack. When regulation is compromised, hyperactivation of the complement cascade can lead to inflammation and inappropriate cell destruction.8

Three pathways converge with the cleavage of complement factor C3, which induces inflammation and labels cells for phagocytosis (destruction by special white blood cells). The complement cascade continues with the cleavage of complement factor C5, which triggers cell death via phagocytosis, inflammation, and ultimately activation of the membrane attack complex (MAC) which causes damage and cell death.8

Learn More

  • Some complement activation products have been identified in drusen.9
  • Samples of vitreous, Bruch’s membrane, and choroid from patients with advanced AMD have been shown to contain elevated levels of complement proteins.9
  • Reduced levels of complement inhibitors (eg, CD59, MCP) have been found in eyes with GA.
  • Patients with AMD also have signs of systemic complement activation.9
  • Complement hyperactivity leading to overactivation of the immune system and chronic inflammation in the macula is a contributing factor to GA.10
  • Dysregulation of the complement system is thought to play an important role in the development and progression of AMD to GA.9

Learn More

Treatment with complement inhibitors may halt or reduce complement hyperactivity, thereby decreasing the overactivation of the immune system and the chronic macular inflammation that contribute to GA.9

Both could broadly be referred to as a macular degeneration study or macular degeneration trial. However, it is more accurate to call them a geographic atrophy study, because they are studying a specific form of age-related macular degeneration. In fact, these trials are specifically studying people who have been diagnosed with geographic atrophy secondary to AMD.

Common Questions About APL-2

APL-2 is a PEGylated cyclic peptide inhibitor of complement C3. The peptide portion of APL-2 binds to C3, exerting broad inhibition of the complement cascade and helping to restore normal complement activity.14

By targeting C3 at the point of convergence of all complement activation pathways, APL-2 can inhibit all 3 principal complement activation pathways.9 Thus, APL-2 may be more effective in a broad patient population than a partial inhibitor of complement would be.

Treatment with complement inhibitors may halt or reduce complement hyperactivity, thereby decreasing the overactivation of the immune system and the chronic macular inflammation that contribute to GA.5

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References

  1. Facts about age-related macular degeneration. National Eye Institute Web site. 2018; https://nei.nih.gov/health/maculardegen/armd_facts. Accessed May 6, 2018.
  2. Age-related macular degeneration. National Eye Institute Web site. 2018; https://nei.nih.gov/health/maculardegen/. Accessed May 6, 2018.
  3. Age-related macular degeneration (AMD). 2018; https://nei.nih.gov/eyedata/amd. Accessed May 7, 2018.
  4. Sunness JS, Rubin GS, Applegate CA, et al. Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. Ophthalmology. 1997;104(10):1677-1691.
  5. Chakravarthy U, Bailey CC, Johnston RL, et al. Characterizing Disease Burden and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration. Ophthalmology. 2018;125(6):842-849.
  6. Wang P, Cottrell GW. Central and peripheral vision for scene recognition: A neurocomputational modeling exploration. J Vis. 2017;17(4):9.
  7. Kolb H. Simple anatomy of the retina. Webvision Web site. 2018; https://webvision.med.utah.edu/book/part-i-foundations/simple-anatomy-of-the-retina/. Accessed July 30, 2018.
  8. Murphy K, Weaver C. Innate immunity: the first lines of defense. In: Janeway's Immunobiology. 9th ed. London, UK: Garland Science; 2016.
  9. Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, et al. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017;37(5):819-835.
  10. Ehmann DS, Regillo CD. Complement inhibition for treatment of GA. Rev Ophthalmol. 2016;23(6):69-72.
  11. Fritsche LG, Chen W, Schu M, et al. Seven new loci associated with age-related macular degeneration. Nat Genet. 2013;45(4):433-439, 439e431-432.
  12. Joseph K, Kulik L, Coughlin B, et al. Oxidative stress sensitizes retinal pigmented epithelial (RPE) cells to complement-mediated injury in a natural antibody-, lectin pathway-, and phospholipid epitope-dependent manner. J Biol Chem. 2013;288(18):12753-12765.
  13. Katschke KJ, Jr, Xi H, Cox C, et al. Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal atrophy. Sci Rep. 2018;8(1):7348.
  14. Data on file, Apellis Pharmaceuticals.
  15. Vaz F, Picoto M. Geographic atrophy. AMD Book Web site. http://amdbook.org/content/geographic-atrophy-0 Accessed May 7, 2018.
  16. Apellis protocol no. APL2-303. A phase III, multi-center, randomized, double-masked, sham-controlled study 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) [DERBY v3.0], March 19, 2018. Apellis Pharmaceuticals.
  17. Apellis protocol no. APL2-304. Phase III, multi-center, randomized, double-masked, sham-controlled study to compare the efficacy and safety of intravitreal APL-2 therapy with sham injections in patients with geographic atrophy (GA) secondaryto age-related macular degeneration (AMD) [OAK v3.0], March 19, 2018. Apellis Pharmaceuticals.
  18. Hazel CA, Petre KL, Armstrong RA, et al. Visual function and subjective quality of life compared in subjects with acquired macular disease. Invest Ophthalmol Vis Sci. 2000;41(6):1309-1315.
  19. Wang W, Gawlik K, Lopez J, et al. Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration. Signal Transduct Target Ther. 2016;1:16016.

References

  1. Facts about age-related macular degeneration. National Eye Institute Web site. 2018; https://nei.nih.gov/health/maculardegen/armd_facts. Accessed May 6, 2018.
  2. Age-related macular degeneration. National Eye Institute Web site. 2018; https://nei.nih.gov/health/maculardegen/. Accessed May 6, 2018.
  3. Age-related macular degeneration (AMD). 2018; https://nei.nih.gov/eyedata/amd. Accessed May 7, 2018.
  4. Sunness JS, Rubin GS, Applegate CA, et al. Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. Ophthalmology. 1997;104(10):1677-1691.
  5. Chakravarthy U, Bailey CC, Johnston RL, et al. Characterizing Disease Burden and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration. Ophthalmology. 2018;125(6):842-849.
  6. Wang P, Cottrell GW. Central and peripheral vision for scene recognition: A neurocomputational modeling exploration. J Vis. 2017;17(4):9.
  7. Kolb H. Simple anatomy of the retina. Webvision Web site. 2018; https://webvision.med.utah.edu/book/part-i-foundations/simple-anatomy-of-the-retina/. Accessed July 30, 2018.
  8. Murphy K, Weaver C. Innate immunity: the first lines of defense. In: Janeway's Immunobiology. 9th ed. London, UK: Garland Science; 2016.
  9. Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, et al. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017;37(5):819-835.
  10. Ehmann DS, Regillo CD. Complement inhibition for treatment of GA. Rev Ophthalmol. 2016;23(6):69-72.
  11. Fritsche LG, Chen W, Schu M, et al. Seven new loci associated with age-related macular degeneration. Nat Genet. 2013;45(4):433-439, 439e431-432.
  12. Joseph K, Kulik L, Coughlin B, et al. Oxidative stress sensitizes retinal pigmented epithelial (RPE) cells to complement-mediated injury in a natural antibody-, lectin pathway-, and phospholipid epitope-dependent manner. J Biol Chem. 2013;288(18):12753-12765.
  13. Katschke KJ, Jr, Xi H, Cox C, et al. Classical and alternative complement activation on photoreceptor outer segments drives monocyte-dependent retinal atrophy. Sci Rep. 2018;8(1):7348.
  14. Data on file, Apellis Pharmaceuticals.
  15. Vaz F, Picoto M. Geographic atrophy. AMD Book Web site. http://amdbook.org/content/geographic-atrophy-0 Accessed May 7, 2018.
  16. Apellis protocol no. APL2-303. A phase III, multi-center, randomized, double-masked, sham-controlled study 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) [DERBY v3.0], March 19, 2018. Apellis Pharmaceuticals.
  17. Apellis protocol no. APL2-304. Phase III, multi-center, randomized, double-masked, sham-controlled study to compare the efficacy and safety of intravitreal APL-2 therapy with sham injections in patients with geographic atrophy (GA) secondaryto age-related macular degeneration (AMD) [OAK v3.0], March 19, 2018. Apellis Pharmaceuticals.
  18. Hazel CA, Petre KL, Armstrong RA, et al. Visual function and subjective quality of life compared in subjects with acquired macular disease. Invest Ophthalmol Vis Sci. 2000;41(6):1309-1315.
  19. Wang W, Gawlik K, Lopez J, et al. Genetic and environmental factors strongly influence risk, severity and progression of age-related macular degeneration. Signal Transduct Target Ther. 2016;1:16016.