Discovery (APL2-201): Phase 2 Clinical Trial of APL-2 Therapy in Patients with IgAN, LN, Primary MN, and C3G

A phase 2 study to evaluate the safety and biologic activity of APL-2 in patients with IgA nephropathy (IgAN), lupus nephritis (LN), primary membranous nephropathy (Primary MN), or C3 glomerulopathy (C3 glomerulonephritis or dense deposit disease)

Disease Overview

Complement-Mediated Glomerulopathies

The kidney is a location that may be susceptible to the effects of uncontrolled hyperactivation of the complement cascade, which is part of the innate immune system. This hyperactivation of the complement system can happen through any of the 3 pathways of complement activation: the classical pathway, the alternative pathway, or the lectin pathway. Each of these pathways leads to the activation of complement C3, which is the central protein of the complement cascade. C3 serves as the master switch, controlling the subsequent effects that cause the destruction of healthy cells.

Four types of glomerulopathy have been linked to overactivation of C3. They include IgA nephropathy (IgAN), lupus nephritis (LN), primary membranous nephropathy (primary MN), and C3 glomerulopathy (C3G). The resulting inflammatory response causes damage to the filtration system of the kidney: the glomerulus. Each kidney contains about a million of these tiny filters.1 The glomeruli are supposed to hold the protein and blood cells in the blood, while allowing waste products to pass into the urine.1 If not controlled, this damage can ultimately lead to kidney injury, and even to end-stage renal disease.

In patients with these conditions, decreased levels of circulating C3 and deposition of C3 fragments in kidney tissue have been independently associated with poor renal outcomes. Studies of genetic mutations involved in the regulation of the complement cascade also suggest that the alternative pathway plays an important role in one of these diseases: C3 glomerulopathy. All of these findings suggest that inhibition of the activation of C3 could play an important role in altering the course of these diseases.

IgA Nephropathy (IgAN)

IgA nephropathy (also known as Berger’s disease) is the most common form of primary glomerulopathy. It is a chronic kidney disease that usually first appears during adolescence or young adulthood (age, 15 to 35 years). It is most common in people of Asian or European ancestry.2 Its prevalence is about 25 to 50 cases per 100,000 people.2 It occurs 2 to 3 times more often in males than in females. Many cases are mild and self-limited; however, roughly 25% of cases may ultimately progress to kidney failure.3

IgAN usually appears after a viral infection of the upper respiratory or gastrointestinal tract. The initial sign is often the passing of blood in the urine (hematuria).3,4 The condition is associated with deposits of IgA immune complexes and C3 fragments in the glomeruli. The glomeruli are the tiny filters within the kidney. The glomeruli are supposed to allow waste to pass from the blood to the urine, while keeping the protein and blood cells in the bloodstream. IgAN is considered to be an autoimmune disease, but the mechanisms leading to the deposition of immune complexes in the glomeruli are unclear.3 Approximately 20% to 25% of patients develop end-stage renal disease within 20-years after their IgAN is diagnosed.5

Lupus Nephritis (LN)

Systemic lupus erythematosus (SLE) is an autoimmune disease that often affects the kidneys. When SLE involves the kidneys, the condition is called lupus nephritis (LN). SLE is more common in females than in males.6 The female:male ratio is 4:3 among children before puberty, rising to 15:1 among people of reproductive age.6 Estimates of the prevalence of SLE in the United States range from 4.8 to 78.5 cases per 100,000 people.6 The signs and symptoms of lupus may include fatigue, joint pain and stiffness, headaches, hair loss, anemia, and a “butterfly rash” across the cheeks and nose.7 The cause of lupus is unknown. However, about 98% of lupus patients have antibodies to the nuclei (DNA and RNA) of their own cells.8

Approximately 50% of SLE patients already have evidence of kidney disease by the time their lupus is diagnosed. Ultimately, 75% of SLE patients will end up with some degree of kidney damage from their SLE. Lupus nephritis seems to be more common and more aggressive in black patients than in white patients.6

Lupus nephritis can cause a decrease in kidney function. This can be seen as an increase in serum creatinine level and the presence of protein and blood in the urine. A kidney biopsy in a case of lupus nephritis often reveals deposits of immune complexes (containing IgG, IgA, and IgM antibodies to double-stranded DNA), along with the complement proteins C3 and C1q, in the glomeruli.9 These immune complexes activate the complement system via the classical complement pathway, resulting in the overproduction of C3a and C5a, which cause an influx of immune cells—neutrophils and mononuclear cells.10 A low serum C3 or C4 correlates with disease activity in some patients, and anti-C1q antibodies are associated with lupus nephritis.11 The products of C5 metabolism may also contribute directly to glomerular injury.12

Primary Membranous Nephropathy (Primary MN)

Membranous nephropathy (MN) is a kidney disease that can be primary (ie, occurring by itself) or secondary to other disease. MN is the most common cause of nephrotic syndrome in adults. Nephrotic syndrome is a set of problems that results from the loss of protein through the kidneys (protein in the urine, shortage of protein in the blood, and swelling [edema] in the feet). The worldwide incidence of primary membranous nephropathy is about 1.2 cases per 100,000 people per year.13 The mean age of the patients is between 50 and 60 years. The condition is more common in men than in women. It is most common among white patients, followed by Asians, Hispanics, and then blacks.

Primary MN occurs when IgG and IgM antibodies slip through the filtering membrane of the glomerulus and bind to antigens on podocytes, which are cells that wrap around the capillaries within the glomerulus. In approximately 70% of primary membranous nephropathy cases, the phospholipase A2 receptor (PLA2R) on the surface of epithelial cells in the glomerulus is the target of the autoantibodies.14 These resulting immune complexes lead to activation of the complement system, via the classical pathway. The classical pathway leads to cleavage of C3 into C3a and C3b. C3b can lead to the activation of C5, which then leads to the activation of the terminal complement components C5b, C6, C7, C8 and C9 forming C5b-C9 or the membrane attack complex (MAC). These injure the podocytes, but usually without killing them. The injured podocytes then release material that causes thickening of the basement membrane.

When kidney biopsy specimens are examined with a microscope, uniform granular deposits of IgG and C3 can be seen in the capillary walls.10 The IgG activates the alternative or even the lectin pathway.11,12 Between 25% and 40% of patients with MN eventually develop chronic renal failure, usually in association with persistent proteinuria in the nephrotic range.5

C3 Glomerulopathy (C3G)

There are two major forms of C3 glomerulopathy (C3G): dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Although both cause similar kidney problems, the features of DDD tend to appear earlier than those of C3 glomerulonephritis, usually in adolescence.15 The prevalence of C3G is estimated at 1 to 2 cases per 1,000,000 people worldwide.16

C3 glomerulopathy may cause high levels of protein in the urine (proteinuria), blood in the urine (hematuria), reduced amounts of urine, high blood pressure, low levels of protein in the blood, and swelling in many areas of the body.15 People with this condition may have particularly low levels of a protein called complement component 3 (or C3) in the blood,15 and/or high levels of C5b-9 as a result of C3 activation.

C3G may also be associated with changes in genes that regulate the complement system.15 The loss of regulation leads to an overactive complement system that damages the glomeruli, which are the filter-like structures in the kidney. The glomeruli are supposed to allow waste to pass from the blood to the urine, while keeping protein and blood cells in the bloodstream. C3 glomerulopathy can also result from the presence of autoantibodies (C3 nephritic factor or C3 Nefs). These autoantibodies cause the condition by increasing the activity of proteins involved in the complement system.15

In C3G, deposits of abundant C3 and other proteins that belong to the complement system are deposited in the glomerular basement membrane (GBM), resulting in progressive damage to the glomeruli. The kidney problems associated with C3 glomerulopathy (C3G) tend to worsen over time. About half of affected individuals develop end-stage renal disease (ESRD) within 10 years of their diagnosis.15

Learn More About the Complement System

Role of Complement in Glomerulopathies

The underlying mechanisms that trigger complement activation vary from disease to disease; but in general, they involve an imbalance between the activators and regulators of the complement system.12,17 Immune complexes containing IgG and IgM activate the classical complement pathway and trigger neutrophil infiltration and injury. Activation of the classical pathway causes co-deposition of C3 and C4 fragments in the kidney.18

Activation of the lectin pathway contributes to glomerular injury in several types of glomerular disease, including lupus nephritis (LN) and IgA nephropathy (IgAN). Activation of this pathway is associated with increased severity of disease.18

Spontaneous activation followed by amplification via the alternative pathway is associated with IgA and some bacterial proteins being deposited in the glomeruli. The resulting tissue inflammation is caused by the inadequate local regulation of complement. The alternative pathway is also responsible for C3 glomerulopathy and is involved in LN and IgAN. C3b generated by activation of the classical or lectin pathways can secondarily activate the alternative pathway, amplifying the extent of complement activity within tissues.18

Complement activation generates multiple different pro-inflammatory mediators, such as C3a, C3b, C5a, and C5b-9 (ie, the membrane attack complex, MAC). A MAC forms a pore in the outer membrane of cells. If there are enough MACs making holes in the cell’s outer membrane, the cell is destroyed (cell lysis). C3a and C5a bind to renal cells and several immune cells, eliciting a wide range of local and systemic responses. These include direct injury, vasoactive changes, attraction of inflammatory cells and modulation of the immune response to antigens. C3b attaches to the surface of cells. There, the C3b results in further activation of complement.18

Learn More About the Complement System

The Complement System

The complement system is an integral part of our immune defense system. In healthy people, complement orchestrates the destruction and clearance of pathogens of our own cells that need to be replaced. It also has proinflammatory capabilities.19

The complement system consists of a cascade of proteins, each of which activates the next protein in the cascade by cleavage (splitting.)19 Complement C3 is the central protein of the cascade, positioned at the point where all complement activation pathways come together. Activation of C3 then leads to the activation of the terminal pathway, which includes C5, in turn leading to the activation of membrane attack complexes (MACs).19

Complement may be activated by different pathways.19 The classical complement pathway is activated when an antibody recognizes a foreign pathogen (non-self target) that invaded the body and needs to be destroyed.19 The alternative complement pathway can be initiated by spontaneously activated complement.19 There is also a lectin pathway, which is activated by mannose-binding lectin.19

The complement system is normally regulated to avoid its overactivation and to protect the host against immune attack.19 When the complement system is overactivated, it can cause or worsen illness.

Disease Overview

Complement-Mediated Glomerulopathies

The kidney is a location that may be susceptible to the effects of uncontrolled hyperactivation of the complement cascade, which is part of the innate immune system. This hyperactivation of the complement system can happen through any of the 3 pathways of complement activation: the classical pathway, the alternative pathway, or the lectin pathway. Each of these pathways leads to the activation of complement C3, which is the central protein of the complement cascade. C3 serves as the master switch, controlling the subsequent effects that cause the destruction of healthy cells.

Four types of glomerulopathy have been linked to overactivation of C3. They include IgA nephropathy (IgAN), lupus nephritis (LN), primary membranous nephropathy (primary MN), and C3 glomerulopathy (C3G). The resulting inflammatory response causes damage to the filtration system of the kidney: the glomerulus. Each kidney contains about a million of these tiny filters.1 The glomeruli are supposed to hold the protein and blood cells in the blood, while allowing waste products to pass into the urine.1 If not controlled, this damage can ultimately lead to kidney injury, and even to end-stage renal disease.

In patients with these conditions, decreased levels of circulating C3 and deposition of C3 fragments in kidney tissue have been independently associated with poor renal outcomes. Studies of genetic mutations involved in the regulation of the complement cascade also suggest that the alternative pathway plays an important role in one of these diseases: C3 glomerulopathy. All of these findings suggest that inhibition of the activation of C3 could play an important role in altering the course of these diseases.

IgA Nephropathy (IgAN)

IgA nephropathy (also known as Berger’s disease) is the most common form of primary glomerulopathy. It is a chronic kidney disease that usually first appears during adolescence or young adulthood (age, 15 to 35 years). It is most common in people of Asian or European ancestry.2 Its prevalence is about 25 to 50 cases per 100,000 people.2 It occurs 2 to 3 times more often in males than in females. Many cases are mild and self-limited; however, roughly 25% of cases may ultimately progress to kidney failure.3

IgAN usually appears after a viral infection of the upper respiratory or gastrointestinal tract. The initial sign is often the passing of blood in the urine (hematuria).3,4 The condition is associated with deposits of IgA immune complexes and C3 fragments in the glomeruli. The glomeruli are the tiny filters within the kidney. The glomeruli are supposed to allow waste to pass from the blood to the urine, while keeping the protein and blood cells in the bloodstream. IgAN is considered to be an autoimmune disease, but the mechanisms leading to the deposition of immune complexes in the glomeruli are unclear.3 Approximately 20% to 25% of patients develop end-stage renal disease within 20-years after their IgAN is diagnosed.5

Lupus Nephritis (LN)

Systemic lupus erythematosus (SLE) is an autoimmune disease that often affects the kidneys. When SLE involves the kidneys, the condition is called lupus nephritis (LN). SLE is more common in females than in males.6 The female:male ratio is 4:3 among children before puberty, rising to 15:1 among people of reproductive age.6 Estimates of the prevalence of SLE in the United States range from 4.8 to 78.5 cases per 100,000 people.6 The signs and symptoms of lupus may include fatigue, joint pain and stiffness, headaches, hair loss, anemia, and a “butterfly rash” across the cheeks and nose.7 The cause of lupus is unknown. However, about 98% of lupus patients have antibodies to the nuclei (DNA and RNA) of their own cells.8

Approximately 50% of SLE patients already have evidence of kidney disease by the time their lupus is diagnosed. Ultimately, 75% of SLE patients will end up with some degree of kidney damage from their SLE. Lupus nephritis seems to be more common and more aggressive in black patients than in white patients.6

Lupus nephritis can cause a decrease in kidney function. This can be seen as an increase in serum creatinine level and the presence of protein and blood in the urine. A kidney biopsy in a case of lupus nephritis often reveals deposits of immune complexes (containing IgG, IgA, and IgM antibodies to double-stranded DNA), along with the complement proteins C3 and C1q, in the glomeruli.9 These immune complexes activate the complement system via the classical complement pathway, resulting in the overproduction of C3a and C5a, which cause an influx of immune cells—neutrophils and mononuclear cells.10 A low serum C3 or C4 correlates with disease activity in some patients, and anti-C1q antibodies are associated with lupus nephritis.11 The products of C5 metabolism may also contribute directly to glomerular injury.12

Primary Membranous Nephropathy (Primary MN)

Membranous nephropathy (MN) is a kidney disease that can be primary (ie, occurring by itself) or secondary to other disease. MN is the most common cause of nephrotic syndrome in adults. Nephrotic syndrome is a set of problems that results from the loss of protein through the kidneys (protein in the urine, shortage of protein in the blood, and swelling [edema] in the feet). The worldwide incidence of primary membranous nephropathy is about 1.2 cases per 100,000 people per year.13 The mean age of the patients is between 50 and 60 years. The condition is more common in men than in women. It is most common among white patients, followed by Asians, Hispanics, and then blacks.

Primary MN occurs when IgG and IgM antibodies slip through the filtering membrane of the glomerulus and bind to antigens on podocytes, which are cells that wrap around the capillaries within the glomerulus. In approximately 70% of primary membranous nephropathy cases, the phospholipase A2 receptor (PLA2R) on the surface of epithelial cells in the glomerulus is the target of the autoantibodies.14 These resulting immune complexes lead to activation of the complement system, via the classical pathway. The classical pathway leads to cleavage of C3 into C3a and C3b. C3b can lead to the activation of C5, which then leads to the activation of the terminal complement components C5b, C6, C7, C8 and C9 forming C5b-C9 or the membrane attack complex (MAC). These injure the podocytes, but usually without killing them. The injured podocytes then release material that causes thickening of the basement membrane.

When kidney biopsy specimens are examined with a microscope, uniform granular deposits of IgG and C3 can be seen in the capillary walls.10 The IgG activates the alternative or even the lectin pathway.11,12 Between 25% and 40% of patients with MN eventually develop chronic renal failure, usually in association with persistent proteinuria in the nephrotic range.5

C3 Glomerulopathy (C3G)

There are two major forms of C3 glomerulopathy (C3G): dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Although both cause similar kidney problems, the features of DDD tend to appear earlier than those of C3 glomerulonephritis, usually in adolescence.15 The prevalence of C3G is estimated at 1 to 2 cases per 1,000,000 people worldwide.16

C3 glomerulopathy may cause high levels of protein in the urine (proteinuria), blood in the urine (hematuria), reduced amounts of urine, high blood pressure, low levels of protein in the blood, and swelling in many areas of the body.15 People with this condition may have particularly low levels of a protein called complement component 3 (or C3) in the blood,15 and/or high levels of C5b-9 as a result of C3 activation.

C3G may also be associated with changes in genes that regulate the complement system.15 The loss of regulation leads to an overactive complement system that damages the glomeruli, which are the filter-like structures in the kidney. The glomeruli are supposed to allow waste to pass from the blood to the urine, while keeping protein and blood cells in the bloodstream. C3 glomerulopathy can also result from the presence of autoantibodies (C3 nephritic factor or C3 Nefs). These autoantibodies cause the condition by increasing the activity of proteins involved in the complement system.15

In C3G, deposits of abundant C3 and other proteins that belong to the complement system are deposited in the glomerular basement membrane (GBM), resulting in progressive damage to the glomeruli. The kidney problems associated with C3 glomerulopathy (C3G) tend to worsen over time. About half of affected individuals develop end-stage renal disease (ESRD) within 10 years of their diagnosis.15

Learn More About the Complement System

Role of Complement in Glomerulopathies

The underlying mechanisms that trigger complement activation vary from disease to disease; but in general, they involve an imbalance between the activators and regulators of the complement system.12,17 Immune complexes containing IgG and IgM activate the classical complement pathway and trigger neutrophil infiltration and injury. Activation of the classical pathway causes co-deposition of C3 and C4 fragments in the kidney.18

Activation of the lectin pathway contributes to glomerular injury in several types of glomerular disease, including lupus nephritis (LN) and IgA nephropathy (IgAN). Activation of this pathway is associated with increased severity of disease.18

Spontaneous activation followed by amplification via the alternative pathway is associated with IgA and some bacterial proteins being deposited in the glomeruli. The resulting tissue inflammation is caused by the inadequate local regulation of complement. The alternative pathway is also responsible for C3 glomerulopathy and is involved in LN and IgAN. C3b generated by activation of the classical or lectin pathways can secondarily activate the alternative pathway, amplifying the extent of complement activity within tissues.18

Complement activation generates multiple different pro-inflammatory mediators, such as C3a, C3b, C5a, and C5b-9 (ie, the membrane attack complex, MAC). A MAC forms a pore in the outer membrane of cells. If there are enough MACs making holes in the cell’s outer membrane, the cell is destroyed (cell lysis). C3a and C5a bind to renal cells and several immune cells, eliciting a wide range of local and systemic responses. These include direct injury, vasoactive changes, attraction of inflammatory cells and modulation of the immune response to antigens. C3b attaches to the surface of cells. There, the C3b results in further activation of complement.18

Learn More About the Complement System

The Complement System

The complement system is an integral part of our immune defense system. In healthy people, complement orchestrates the destruction and clearance of pathogens of our own cells that need to be replaced. It also has proinflammatory capabilities.19

The complement system consists of a cascade of proteins, each of which activates the next protein in the cascade by cleavage (splitting.)19 Complement C3 is the central protein of the cascade, positioned at the point where all complement activation pathways come together. Activation of C3 then leads to the activation of the terminal pathway, which includes C5, in turn leading to the activation of membrane attack complexes (MACs).19

Complement may be activated by different pathways.19 The classical complement pathway is activated when an antibody recognizes a foreign pathogen (non-self target) that invaded the body and needs to be destroyed.19 The alternative complement pathway can be initiated by spontaneously activated complement.19 There is also a lectin pathway, which is activated by mannose-binding lectin.19

The complement system is normally regulated to avoid its overactivation and to protect the host against immune attack.19 When the complement system is overactivated, it can cause or worsen illness.

About APL-2

What is APL-2?

APL-2 is a PEGylated cyclic peptide inhibitor of complement C3. PEGylation helps keep APL-2 in the body longer, reducing dosing frequency. The peptide portion of APL-2 binds to C3, exerting broad inhibition of the complement cascade and helping to prevent excessive complement activity.20

Through this broad inhibition of C3, APL-2 helps the body regain control of the complement system, protecting it from further complement-mediated immune attack.20

Why Evaluate APL-2 in Complement-Mediated Glomerulopathies?

All 4 of the known complement-mediated glomerulopathies (IgA nephropathy [IgAN], lupus nephritis [LN], primary membranous nephropathy [primary MN], and C3 glomerulopathy [C3G]) have a shared pathogenesis: activation of the complement C3, the central protein in the complement cascade. Furthermore, these diseases involve activation of at least 1, if not all 3, of the pathways that lead to C3 activation (classical, lectin, and alternative complement pathway). All of the complement activation pathways run through C3, which controls all downstream effects of the complement cascade, including the possible damage to kidney cells. The 4 types of glomerulopathy that have been linked to overactivation of C3 (IgAN, lupus nephritis, primary membranous nephropathy, and C3 glomerulopathy) result in inflammatory responses that cause damage to the filtration system of the kidney: the glomerulus. If not controlled, this damage can ultimately lead to kidney failure, and even to end-stage renal disease.

APL-2 inhibits the activation of C3. By targeting the point where all 3 complement activation pathways meet, APL-2 has the potential to block activation from any pathway AND to prevent and control the C3-mediated inflammatory response and the downstream inflammatory events in these diseases. Thus, APL-2 may be useful in preventing the renal injury that results from these diseases. To date, no safety signals that would preclude further development have emerged from ongoing studies of APL-2. Thus, the aim of this proposed phase 2 study is to explore treatment efficacy and safety of APL-2 for the treatment of IgAN, LN, primary MN, and C3G.

About APL-2

What is APL-2?

APL-2 is a PEGylated cyclic peptide inhibitor of complement C3. PEGylation helps keep APL-2 in the body longer, reducing dosing frequency. The peptide portion of APL-2 binds to C3, exerting broad inhibition of the complement cascade and helping to prevent excessive complement activity.20

Through this broad inhibition of C3, APL-2 helps the body regain control of the complement system, protecting it from further complement-mediated immune attack.20

Why Evaluate APL-2 in Complement-Dependent Glomerulopathies?

All 4 of the known complement-dependent glomerulopathies (IgA nephropathy [IgAN], lupus nephritis [LN], primary membranous nephropathy [primary MN], and C3 glomerulopathy [C3G]) have a shared pathogenesis: activation of the complement C3, the central protein in the complement cascade. Furthermore, these diseases involve activation of at least 1, if not all 3, of the pathways that lead to C3 activation (classical, lectin, and alternative complement pathway). All of the complement activation pathways run through C3, which controls all downstream effects of the complement cascade, including the possible damage to kidney cells. The 4 types of glomerulopathy that have been linked to overactivation of C3 (IgAN, lupus nephritis, primary membranous nephropathy, and C3 glomerulopathy) result in inflammatory responses that cause damage to the filtration system of the kidney: the glomerulus. If not controlled, this damage can ultimately lead to kidney failure, and even to end-stage renal disease.

APL-2 inhibits the activation of C3. By targeting the point where all 3 complement activation pathways meet, APL-2 has the potential to block activation from any pathway AND to prevent and control the C3-mediated inflammatory response and the downstream inflammatory events in these diseases. Thus, APL-2 may be useful in preventing the renal injury that results from these diseases. To date, no safety signals that would preclude further development have emerged from ongoing studies of APL-2. Thus, the aim of this proposed phase 2 study is to explore treatment efficacy and safety of APL-2 for the treatment of IgAN, LN, primary MN, and C3G.

Phase 2 Study Design

Objectives

This is a prospective, phase 2 open-label study, consisting of a single cohort with a total of approximately 48 subjects with a diagnosis of 1 of the 4 complement-mediated nephropathies: IgAN, LN, primary MN, or C3G (~12 subjects per disease).

The planned length of participation in the study for each subject is up to 52 weeks, including a screening period, a 16-week treatment period, and a 24-week follow-up period.

Primary Objective

The primary objectives of this study are to establish preliminary efficacy and safety of the investigational drug APL-2 in patients with IgAN, LN, primary MN, and C3G.

Key Inclusion Criteria
1. Patients ≥18 years of age
2. Diagnosis of IgAN, LN, primary MN, or C3G confirmed by renal biopsy and required measurements performed prior to study participation
3. Proteinuria (urine protein:creatinine ratio >750 mg/g) during the first screening visit
4. If on immunosuppressive treatment, patients have been on a stable dose for at least 2 months prior to screening visit
5. Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 calculated by CKD-EPI creatinine equation at screening visit
6. Systolic blood pressure of <140mm Hg and a diastolic blood pressure of <90mm Hg at rest; patients taking blood pressure medications may be eligible if they are receiving stable, optimized treatment
Key Exclusion Criteria

Subjects will be excluded from the study if there is evidence of any of the following criteria at specified screening and/or treatment visits, as appropriate.

1. Hemoglobin <9.0 g/dL at screening visits
2. Platelet count <100,000/mm3 at screening visits
3. Absolute neutrophil count <1000 cells/mm3 at screening visits
4. ALT or AST >3.0x the upper limit of normal at screening visits
5. Use of belimumab, eculizumab, or rituximab within 6 months prior to screening visit
6. Diagnosis of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection, or positive serology at screening visits
Dosing

Subcutaneous (SC) once-daily at-home infusions of 360 mg APL-2 for 16 weeks

Key Endpoints
Primary Efficacy Endpoints
  • All indications: Proteinuria reduction by 50%, calculated by the change in urinary protein to creatinine ratio from baseline to week 16
Secondary Efficacy Endpoints
  • Changes of disease-specific biomarkers:
    • Serum C3 levels
    • AH50 and C3a concentrations
  • All indications: Complete clinical remission, defined as urine protein:creatinine ratio <200 mg/g from baseline to week 16
  • All indications: Stabilization or improvement in eGFR from baseline to week 16
  • LN: Complete renal response, defined as urine protein:creatinine ratio <200 mg/g and stabilization or improvement in eGFR from baseline to week 16
Safety Endpoints
  • Physical examination; incidence and severity of adverse events (AE)
  • Changes from baseline in laboratory parameters
  • Changes from baseline in electrocardiography parameters

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.

  • Stanford, CA
  • Washington, DC
  • Coral Gables, FL
  • Takoma Park, MD
  • Kansas City, MO
  • Valhalla, NY
  • Atlanta, GA
  • Bronx, NY
  • Wilmington, NC
  • Alexandria, VA
  • Chesapeake, VA
  • Wauwatosa, WI
  • Cincinnati, OH

Common Questions About Discovery and APL-2

Four types of glomerulopathy have been linked to overactivation of C3, a central protein of the complement system within the immune system. They include IgA nephropathy (IgAN), lupus nephritis (LN), primary membranous nephropathy (primary MN), and C3 glomerulopathy (C3G). Activation of either the classical or the alternative pathway of the complement cascade can cause complement-mediated damage in the kidney. The classical pathway is activated by the action of antibodies. When an antibody binds to its antigen, it forms an immune complex. Immune complexes that are being carried by the bloodstream can be deposited in the glomerulus, which is the filtration system of the kidney. It is also possible for some antibodies to bind to antigens in the glomerulus. In the glomerulus, the immune complexes can activate C3. The activation of C3 then causes inflammation that can cause damage in the kidney. C3 can also be activated by the alternative pathway, which does not involve antibodies or immune complexes.

Activation of C3 through any pathway (classical, alternative, or lectin) can cause inflammation in the kidney, which can damage the glomerulus. The body does have ways to regulate the action of the complement cascade. However, a complement-mediated glomerulopathy can result from any problem that interferes with the body’s ability to regulate the complement cascade or that leads to excessive activation of complement.4

IgA nephropathy (IgAN, also known as Berger’s disease) is the result of the buildup of immunoglobulin A (IgA) antibodies in the glomerulus (filtering system) of the kidney. This condition often follows a viral infection of the upper respiratory or gastrointestinal tract. However, it can occur along with other systemic diseases, such as liver failure, celiac disease, and several autoimmune diseases (including various forms of inflammatory arthritis). IgAN is 3 times as common in males as in females, and it usually arises in people between the ages of 15 and 35.3

The classic sign is the passing of blood in the urine (hematuria). In some cases, the hematuria recurs every few months. The patient may also feel pain in the groin. In some cases, the hematuria is detectable only through laboratory testing of the urine. Although many cases of IgAN are benign and resolve on their own, up to 25% of cases can lead to end-stage renal disease within 20 years after onset. The cause of the IgA deposition is unknown. IgAN is suspected to be an autoimmune disorder.3

Systemic lupus erythematosus (SLE) is an autoimmune disease that can cause inflammation throughout the body. In up to 75% of cases, the SLE eventually affects the kidneys. That problem is called lupus nephritis. To evaluate lupus patients for lupus nephritis, physicians measure the amount of creatinine in the blood and the amount of protein and blood in the urine. Kidney biopsy reveals that the glomeruli contain deposits of immune complexes (containing IgA, IgG, and IgM antibodies to double-stranded DNA), along with C3 and C1q. The immune complexes activate the classical complement pathway, which generates C3a and C5a, causing an influx of damaging immune cells.10 The products of C5 metabolism may also contribute directly to glomerular injury.12

Membranous nephropathy (MN) is a kidney disease associated with thickening of the basement membrane of the glomerulus. The basement membrane forms part of the filtering system within the kidney. The condition begins when antibodies pass through the basement membrane and bind to antigens on the podocytes, which are cells that wrap around the capillaries within the glomerulus. This antigen-antibody interaction leads to activation of complement via the classical complement pathway. This leads to the formation of MACs, which damage the podocytes. The damaged podocytes then secrete material that causes the thickening of the basement membrane.10 The lectin pathway of complement activation probably also plays a role in membranous nephropathy, because the IgG autoantibodies can bind to mannose-binding lectin.10-12 About 25% to 40% of patients with membranous nephropathy eventually develop chronic renal failure.5

In cases of C3 glomerulopathy, deposits of C3 and other complement system proteins are lodged in the glomerular basement membrane. These deposits result in progressive damage to the glomeruli. Within 10 years, cumulative damage leads to kidney failure in about half of all people with C3 glomerulopathy. These patients will require dialysis or kidney transplantation.16 The signs and symptoms include blood in the urine (hematuria); dark foamy urine due to the presence of protein (proteinuria); cloudy urine due to presence of white blood cells; edema (swelling), initially of the legs, although any part of the body can be affected; high blood pressure; decreased urine output; and decreased alertness.16

The average age at diagnosis varies with the type of glomerulopathy. For example, lupus nephritis is often diagnosed in people around 30 years of age, while membranous nephropathy is often diagnosed in people who are about 50 years old.5

The underlying mechanisms that trigger complement activation vary from disease to disease; but in general, the problem involves an imbalance between the activators and regulators of the complement cascade.12,17 Immune complexes (ICs) containing IgG and IgM activate the classical pathway, causing co-deposition of C3 and C4 fragments within the kidney.18

Activation of the lectin pathway contributes to glomerular injury in multiple types of glomerular disease, including lupus nephritis and IgA nephropathy.18 C3b generated by activation of either the classical pathway or the lectin pathway can secondarily activate the alternative pathway, which amplifies the extent of complement activation within tissues.18

Complement-mediated glomerulopathies are largely regarded as autoimmune diseases. Often, a person will have more than one autoimmune disease. Thus, the complement-mediated glomerulopathies are more common among people who have other autoimmune diseases, or who have close relatives who have an autoimmune disease. However, these disorders can occur in people who have no close relatives with any autoimmune disease.

Doctors may suspect glomerulopathy if a patient has abnormal results from urine and blood tests. However, the diagnosis of a glomerulopathy can be confirmed only by kidney biopsy. A needle is used to take a tiny sample of the kidney tissue, which is then examined under a microscope. Special stains can be used to reveal whether the complement system is playing an important role in the kidney disease. The information from the kidney biopsy is important because traditional anti-inflammatory drugs often do little good for patients with a C3 glomerulopathy. Thus, the results of the kidney biopsy will help the doctor choose the proper treatment and predict the course of the disease.21

At present, patients with complement-mediated glomerulopathies are generally given medications to control their blood pressure (eg, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) and nonspecific anti-inflammatory or immunosuppressive agents (eg, steroids, cyclophosphamide, mycophenolate mofetil, or rituximab). No drugs that affect the complement system are approved for use in complement-mediated glomerulopathies. The C5 inhibitor eculizumab has reportedly been used off-label in cases of C3G, with variable results.22-25 (Eculizumab is approved for treatment of an autoimmune hemolytic disease.)

The complement system is an integral part of our immune defense system. In healthy people, complement orchestrates the destruction and clearance of foreign pathogens or of the body’s own cells that need to be replaced. It can also promote inflammation.19

The complement system consists of a cascade of more than 40 proteins, each of which activates the next protein in the cascade by cleavage.19 Complement C3 is the central protein of the cascade, positioned at the point of where all complement activation pathways come together, upstream of all effectors.19

Complement may be activated by different pathways.19 The classical complement pathway is activated when an antibody recognizes a non-self (foreign) target that invaded the body and needs to be destroyed.19 The alternative complement pathway can be initiated by spontaneously activated complement.19 There is also a lectin pathway, which is activated by the binding of mannose-binding lectin to bacteria or to dying cells or cell debris.19

Complement activation in healthy people is regulated to avoid its overactivation and to protect the body against inappropriate immune attack.19 When the complement system gets out of balance, it can cause or worsen some illnesses.19

Learn More About the Complement System

Some kidney disorders involve activation of the classical pathway of complement activation. Others involve the alternative pathway or even the lectin pathway.

The classical pathway is triggered when an antibody binds to an antigen. The antigen is usually a foreign protein; but in some kidney diseases, autoantibodies are formed inappropriately by the body.6 These autoantibodies can bind to the body’s own proteins by mistake. The unit formed by an antibody bound to an antigen is called an immune complex. These immune complexes can be deposited in the glomerulus, which is the filtering system of the kidney. Immune complexes can also form when autoantibodies bind to a protein within the glomerulus. In the glomerulus, the immune complex can trigger the classical pathway of the complement cascade.4

The alternative pathway does not involve antigen-antibody triggering of the complement system. Instead, the alternative pathway has a low level of activity all the time; and when regulation of the complement system is not maintained, it can continue to feed the loop of activation and cause inflammation and cell damage.19 In some kidney diseases, like C3G, autoantibodies are formed inappropriately by the body, causing increased complement activation and additional damage where complement system components have been deposited in the kidney.

Both the classical and the alternative pathway lead to the cleavage of C3, into C3a and C3b. Both C3a and C3b can promote inflammation. C3b can also lead to the activation of C5.19 The inflammation that results from overactivation of the complement cascade can harm or destroy healthy cells in the kidney.4

Overactivation of the complement system seems to play an important role in many kidney diseases. A monoclonal antibody called eculizumab is already being used to treat a blood disease called atypical hemolytic uremic syndrome.12 Eculizumab works by blocking the activation of C5. However, it may be better to target C3, which is upstream of C5 in the complement cascade, due to the type of damage involved in glomerular nephropathy.19

The kidney injury due to glomerular nephropathy seems to be partly due to C3b, which is produced by cleavage of C3.12 Thus, an agent that inhibits the cleavage of C3 might be more useful than a C5 inhibitor in the management of glomerulopathies.

APL-2 is a small (13–amino-acid) cyclic peptide coupled via a linker to each end of a linear 40 kDa PEG chain.20 APL-2 binds to primate complement C3 and exerts broad inhibition of the complement cascade. The complement cascade is a biological process that is part of innate immunity and is involved in multiple inflammatory processes.20 PEGylation allows the APL-2 to remain longer in the body.20

APL-2 targets C3, which is the central point where the 3 main pathways of complement activation come together. This point is upstream of the activation of C5. By targeting C3, APL-2 can inhibit all 3 of the major complement activation pathways. Thus, APL-2 may be more effective in a broad patient population than partial inhibitors of the complement system would be.

This phase 2 study will evaluate the safety and efficacy of APL-2 in patients with IgA nephropathy, lupus nephritis, primary membranous nephropathy, or C3 glomerulopathy (C3 glomerulonephritis and dense deposit disease [DDD]).26

C3 is the point where all 3 pathways of the complement cascade meet. By inhibiting the activation of C3, APL-2 can prevent the inflammation that would result from activation of any or all of those pathways. For this reason, APL-2 may prevent many forms of inflammation in the kidney.20 In the studies that have been done so far, APL-2 has been well tolerated.20

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References

  1. Glomerular diseases. National Institute of Diabetes and Digestive and Kidney Diseases Web site https://www.niddk.nih.gov/health-information/kidney-disease/glomerular-diseases.
  2. Ilyas M. Pediatric IgA nephropathy. Medscape. 2017. https://emedicine.medscape.com/article/981516-overview.
  3. IgA nephropathy. National Organization for Rare Disorders Web site https://rarediseases.org/rare-diseases/iga-nephropathy/. Accessed May 18, 2018.
  4. Caliskan Y. Complement pathway asssociated glomerulopathies. Eur Med J. 2016;1(1):30-38.
  5. Cohen AH, Glassock RJ. The primary glomerulopathies. In: Schrier's Diseases of the Kidney. Philadelphia, PA: Lippincott Williams & WIlkins; 2013?
  6. Almaani S, Meara A, Rovin BH. Update on lupus nephritis. Clin J Am Soc Nephrol.
  7. Lupus. NHS Choices Web site https://www.nhs.uk/conditions/lupus/. Accessed May 31, 2018.
  8. Lupus blood tests. Johns Hopkins Lupus Center Web site https://www.hopkinslupus.org/lupus-tests/lupus-blood-tests/. Accessed May 31, 2018.
  9. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241-250.
  10. Bomback AS, Markowitz GS, Appel GB. Complement-mediated glomerular diseases: a tale of 3 pathways. Kidney Int Rep. 2016;1(3):148-155.
  11. Popat RJ, Robson MG. Complement and glomerular diseases. Nephron Clin Pract. 2014;128(3-4):238-242.
  12. Salvadori M, Rosso G, Bertoni E. Complement involvement in kidney diseases: From physiopathology to therapeutical targeting. World J Nephrol. 2015;4(2):169-184.
  13. McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011;26(2):414-430.
  14. Couser WG. Primary membranous nephropathy. Clin J Am Soc Nephrol. 2017;12(6):983-997.
  15. C3 glomerulopathy Genetics Home Reference 2015; https://ghr.nlm.nih.gov/condition/c3-glomerulopathy. Accessed May 18, 2018.
  16. Smith RJH. C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis. National Organization for Rare Disorders Web site https://rarediseases.org/rare-diseases/c3-glomerulopathy-dense-deposit-disease-and-c3-glomerulonephritis/. Accessed May 18, 2018.
  17. Noris M, Remuzzi G. Glomerular diseases dependent on complement activation, including atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and C3 glomerulopathy: core curriculum 2015. Am J Kidney Dis. 2015;66(2):359-375.
  18. Thurman JM. Many drugs for many targets: novel treatments for complement-mediated glomerular disease. Nephrol Dial Transplant. 2017;32(suppl_1):i57-i64.
  19. Murphy K, Weaver C. Innate immunity: the first lines of defense. In: Janeway's Immunobiology. 9th ed. London, UK: Garland Science; 2016.
  20. Data on file, Apellis Pharmaceuticals.
  21. Nester CM, Smith RJ. Diagnosis and treatment of C3 glomerulopathy. Clin Nephrol. 2013;80(6):395-403.
  22. Gurkan S, Fyfe B, Weiss L, et al. Eculizumab and recurrent C3 glomerulonephritis. Pediatr Nephrol. 2013;28(10):1975-1981.
  23. Vivarelli M, Emma F. Treatment of C3 glomerulopathy with complement blockers. Semin Thromb Hemost. 2014;40(4):472-477.
  24. Le Quintrec M, Lapeyraque AL, Lionet A, et al. Patterns of clinical response to eculizumab in patients with C3 glomerulopathy. Am J Kidney Dis. 2018.
  25. Le Quintrec M, Lionet A, Kandel C, et al. Eculizumab for treatment of rapidly progressive C3 glomerulopathy. Am J Kidney Dis. 2015;65(3):484-489.
  26. Apellis Pharmaceuticals. Phase II study assessing safety and efficacy of APL-2 in glomerulopathies. ClinicalTrials.gov Web sites 2018; https://clinicaltrials.gov/ct2/show/NCT03453619. Accessed May 18, 2018.

References

  1. Glomerular diseases. National Institute of Diabetes and Digestive and Kidney Diseases Web site https://www.niddk.nih.gov/health-information/kidney-disease/glomerular-diseases.
  2. Ilyas M. Pediatric IgA nephropathy. Medscape. 2017. https://emedicine.medscape.com/article/981516-overview.
  3. IgA nephropathy. National Organization for Rare Disorders Web site https://rarediseases.org/rare-diseases/iga-nephropathy/. Accessed May 18, 2018.
  4. Caliskan Y. Complement pathway asssociated glomerulopathies. Eur Med J. 2016;1(1):30-38.
  5. Cohen AH, Glassock RJ. The primary glomerulopathies. In: Schrier's Diseases of the Kidney. Philadelphia, PA: Lippincott Williams & WIlkins; 2013?
  6. Almaani S, Meara A, Rovin BH. Update on lupus nephritis. Clin J Am Soc Nephrol.
  7. Lupus. NHS Choices Web site https://www.nhs.uk/conditions/lupus/. Accessed May 31, 2018.
  8. Lupus blood tests. Johns Hopkins Lupus Center Web site https://www.hopkinslupus.org/lupus-tests/lupus-blood-tests/. Accessed May 31, 2018.
  9. Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241-250.
  10. Bomback AS, Markowitz GS, Appel GB. Complement-mediated glomerular diseases: a tale of 3 pathways. Kidney Int Rep. 2016;1(3):148-155.
  11. Popat RJ, Robson MG. Complement and glomerular diseases. Nephron Clin Pract. 2014;128(3-4):238-242.
  12. Salvadori M, Rosso G, Bertoni E. Complement involvement in kidney diseases: From physiopathology to therapeutical targeting. World J Nephrol. 2015;4(2):169-184.
  13. McGrogan A, Franssen CF, de Vries CS. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol Dial Transplant. 2011;26(2):414-430.
  14. Couser WG. Primary membranous nephropathy. Clin J Am Soc Nephrol. 2017;12(6):983-997.
  15. C3 glomerulopathy Genetics Home Reference 2015; https://ghr.nlm.nih.gov/condition/c3-glomerulopathy. Accessed May 18, 2018.
  16. Smith RJH. C3 Glomerulopathy: Dense Deposit Disease and C3 Glomerulonephritis. National Organization for Rare Disorders Web site https://rarediseases.org/rare-diseases/c3-glomerulopathy-dense-deposit-disease-and-c3-glomerulonephritis/. Accessed May 18, 2018.
  17. Noris M, Remuzzi G. Glomerular diseases dependent on complement activation, including atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis, and C3 glomerulopathy: core curriculum 2015. Am J Kidney Dis. 2015;66(2):359-375.
  18. Thurman JM. Many drugs for many targets: novel treatments for complement-mediated glomerular disease. Nephrol Dial Transplant. 2017;32(suppl_1):i57-i64.
  19. Murphy K, Weaver C. Innate immunity: the first lines of defense. In: Janeway's Immunobiology. 9th ed. London, UK: Garland Science; 2016.
  20. Data on file, Apellis Pharmaceuticals.
  21. Nester CM, Smith RJ. Diagnosis and treatment of C3 glomerulopathy. Clin Nephrol. 2013;80(6):395-403.
  22. Gurkan S, Fyfe B, Weiss L, et al. Eculizumab and recurrent C3 glomerulonephritis. Pediatr Nephrol. 2013;28(10):1975-1981.
  23. Vivarelli M, Emma F. Treatment of C3 glomerulopathy with complement blockers. Semin Thromb Hemost. 2014;40(4):472-477.
  24. Le Quintrec M, Lapeyraque AL, Lionet A, et al. Patterns of clinical response to eculizumab in patients with C3 glomerulopathy. Am J Kidney Dis. 2018.
  25. Le Quintrec M, Lionet A, Kandel C, et al. Eculizumab for treatment of rapidly progressive C3 glomerulopathy. Am J Kidney Dis. 2015;65(3):484-489.
  26. Apellis Pharmaceuticals. Phase II study assessing safety and efficacy of APL-2 in glomerulopathies. ClinicalTrials.gov Web sites 2018; https://clinicaltrials.gov/ct2/show/NCT03453619. Accessed May 18, 2018.