Complement-Mediated Glomerulopathies

Age ≥16 years for patients with C3G

With a clinical diagnosis of 1 of 4 complement-mediated glomerulopathies confirmed by renal biopsy (and required measurements performed prior to study participation) but who are not in kidney failure.

Immunoglobulin A nephropathy (IgAN)

Lupus nephropathy (LN)

Primary membranous nephropathy (primary MN)

C3G glomerulopathy (C3G)

Designed for Patients

New Phase II Clinical TrialEnrolling Now

The kidney is prone to uncontrolled hyperactivation of the complement cascade. This hyperactivation happens through activation of one or more of the 3 complement pathways: the classical pathway, the alternative pathway, and the lectin pathway. Each of these pathways leads to the activation of the C3 protein, which is the central component in the complement cascade.

Four types of glomerulopathies have been linked to overactivation of C3. They include IgA nephropathy (IgAN), lupus nephritis (LN), primary membranous nephropathy (primary MN), and C3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The resulting inflammatory response can damage the filtering apparatus of the kidney: the glomerulus. This damage can ultimately lead to kidney failure, and even to end-stage renal disease. In patients with these conditions, deposition of C3 fragments in kidney tissue have been independently associated with poor renal outcomes. These findings suggest that blocking or stopping the activation of C3 could play an important role in altering the course of these diseases.

Complement-Mediated Glomerulopathies

Role of Complement in IgA Nephropathy (IgAN)

IgA nephropathy 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 2 to 3 times more common in males than females.¹ Approximately 20% to 25% of patients develop end-stage renal disease over the 20-year period after onset.² IgAN usually appears after a viral infection of the upper respiratory or gastrointestinal tract. The major symptom is the passing of blood in the urine (hematuria).1,3 The condition is considered to be an autoimmune disease associated with depositions of IgA immune complexes and C3 fragments in the glomeruli.¹

Mucosal infections, genetic predisposition, food antigens result in production of galactose-deficient IgA antibody that abnormally exposes a sugar motif

Production of autoantibodies to sugar motif on galactose-deficient IgA

Alternative pathwayactivated by dimers of IgA

Lectin pathwayactivated by exposed sugar motif

Formation of circulating immune complexes (IC) that deposit in the kidney

Kidney inflammation& interstitial fibrosis

Renal injury, loss of integrityand function (proteinuria)

Phagocytosis

Cell lysis

Renalinjury

C3b

C3a C3b

C5a C5b MAC

75%25% Amplification loop

C3b

C3b

Kidney cell

C5b

C5b

C5b

C5b C5b

C3 C3 co

nvertase

C5 C5 co

nvertase

Role of Complement in Lupus Nephritis (LN)

Systemic lupus erythematosus (SLE) is an autoimmune disease that often affects the kidneys. When SLE attacks the kidneys, the problem is called lupus nephritis (LN). About 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 kidney damage from their condition. LN typically leads to several nonspecific changes in kidney function, such as an increase in serum creatinine level and the presence of protein and blood in the urine. These changes are a result of deposits of immune complexes, along with C3 and C1q, in the glomeruli. The immune complexes trigger the activation of the complement system through the classical complement pathway. The resulting complement activation generates two potent chemoattractants (C3a and C5a), which cause chronic inflammation in the kidney⁴ contributing directly to glomerular injury.5,6

Increase of cell death and decrease of clearance, which leads to release of DNA

Anti-C3 autoantibody, correlates with disease severity

Anti-C1q autoantibody correlates with disease severity

Classical pathway Lectin pathway Alternative pathwayActivation not well understood in LNVery strong activation

Chronic kidney inflammation, fibrosis &

vein thrombosis

Podocytes and endothelial cell injury: loss of integrity and renal function (proteinuria, hematuria)

Accumulation of C3b induces phagocytosis (destruction of cells)

Renalinjury

(b) Mutations

C3b

C3a C3b

C5a C5b MAC

Amplification loop

C3b

C3b

1

About 70% of patients with LN develop anti-C1q antibodies that form more immune complexes with C1q in the kidney and amplify the activation of the classical pathway

(a) About 30% of patients with LN develop antibodies to C3 that result in lack of regulation by complement regulator

(b) Mutations in complement factor H (FH), factor I (FI) and properdin (P)

Both (a) and (b) induce more efficient alternative pathway C3 convertase and an over-activation of C3 in the kidney.

4

Production of autoantibodies against released DNA

2

Immune complexes (antibody + DNA) deposit in the kidney

3

FH

P FI

Cell death

Clearance

C1q

C1q

HH

H

Hs

r H

HH

H

Hs

r HHH

H

Hs

r H

H

C3 C3 co

nvertase

C5 C5 co

nvertase

Cell lysis

Kidney cell

C5b

C5b

C5b

C5b C5b

Role of Complement in Primary Membranous Nephropathy (Primary MN)

Membranous nephropathy (MN) is a kidney disease that can be primary (ie, occurring by itself) or can be secondary to another disease. Membranous nephropathy is the most common cause of nephrotic syndrome in adults. In 75% of cases, the antigen(s) of the immune complexes cannot be identified.² MN occurs when antibodies slip through the filtering apparatus of the kidney and bind to antigens on podocytes, which are cells that wrap around the capillaries within the glomerulus. These resulting immune complexes lead to activation of the complement system, through the classical pathway, which promotes the formation of membrane attack complexes (MACs) that attack the podocytes but do not usually kill them. The injured podocytes release material that causes thickening of the basement membrane. When the kidney biopsy specimens are examined with a microscope, uniform granular deposits of IgG antibodies and C3 can be seen in the capillary walls.⁴ The predominant IgG subclass can also activate the alternative and even the lectin pathway.5,6 Between 25% and 40% of patients with MN eventually develop chronic renal failure, usually in association with persistent proteinuria in the nephrotic range.2

Production of Ig4-Go autoantibodies that bind to PLA2R antigens on cells, called podocytes, that maintain structural integrity and function of the kidney. These autoantibodies expose a motif (N-acetylglucosamine, or GlcNac) that activates the lectin pathway.

An increase of an enzyme - called heparanase - leads to the destruction of anchors of proteins, including regulatory complement factor H (FH), at the GBM. The lack of regulation triggers the alternative pathway as a second hit.

Podocyte injury and death result in loss of barrier integrity and renal function (proteinuria, some degree of hematuria)

Lectin pathway

Anti-PLA2R antibodies

Alternative pathway

1 2

C3b C3a

C5a C5b MAC

Amplification loop

Kidney cell

Blood

Urine

Endothelialcell

Epithelial cell

Antibody

Antigen

Basement membrane

Glomerular basement membrane(GBM)

Immunecomplexes

Phagocytosis

C3b

C3b

Recruit and/or activate inflammatory and

immune cells

Renalinflammation

and injury

C3 C3 co

nvertase

C5 C5 co

nvertase

Cell lysis

C5b

C5b

C5b

C5b C5b

Role of Complement in C3 Glomerulopathy (C3G)

The prevalence of C3G is estimated at 2-3 per 1,000,000 people worldwide.⁷ There are two major forms of C3 glomerulopathy (C3G): dense deposit disease [DDD] and C3 glomerulonephritis. Although both cause similar kidney problems, the features of DDD tend to appear earlier than those of C3 glomerulonephritis (C3GN), usually during adolescence.⁸

C3G is associated with changes in genes that regulate the complement system.8,9 Abundant C3 and other complement proteins are deposited in the glomerular basement membrane (GBM), which causes progressive damage to the glomeruli, which are small blood vessels in the kidney that filter waste products from the blood. C3 glomerulopathy can also result from the presence of autoantibodies (self-directed) called C3 nephritic factors or C3Nefs that disrupt normal regulation of the complement system, resulting in hyperactivation of the alternative complement pathway.7,8 As a result, the filtering mechanism of the kidney is impaired, which permits proteins and red and white blood cells to pass into the urine-containing space.⁷ The cumulative effects (or impact) on the kidney in cases of with C3 glomerulopathy tend to worsen over time. Nearly half of affected individuals ultimately develop end-stage renal disease (ESRD) within 10 years after their diagnosis.⁸ 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.⁷ These patients will require dialysis or kidney transplantation.⁷

Alternative pathway Classical pathway

C3 and C4 nephritic factors (C3Nef and C4Nef) are antibodies that stabilize C3 convertase of the alternative and classical pathways, respectively

Both (1) and (2) lead to sustained activation of C3

Deposition of C3 and its fragments along the

glomerular basement membrane

Impairment of glomerular filtration

barrier leads to progressive renal injury

Cell lysis and tissue damage in the glomerular capillaries,

leading to renal injury

C3b C3b

C3b

C3b

Recruit inflammatory cells to the site

C3a

Recruit inflammatory cells to the site

C5a

C5b MAC

C5Nef stabilizes C5 convertase and sustains C5 activation

Dense Deposit Disease (DDD)

C3 Glomerulonephritis(C3GN)

1

Mutations of complement regulators or antibodies directed against these regulators (complement factor H or factor I and membrane cofactor protein [MCP]) impair their regulationof C3 activation

2

FH

MCP FI

C3 C3 co

nvertase

C5 C5 co

nvertase

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.6,9

Immune complexes (ICs) containing the antibodies IgG and IgM activate the classical complement pathway and trigger neutrophil infiltration and injury. Classical pathway activation also causes co-deposition of C3 and C4 fragments in lupus nephritis.10

Activation of the lectin pathway contributes to glomerular injury in multiple types of glomerular disease, including lupus nephritis and IgA nephropathy. Activation of this complement pathway is associated with increased severity of disease.10

Spontaneous activation of the complement system followed by amplification via the alternative pathway is a result of poor local regulation of complement. This pathway is responsible for C3 glomerulopathy and is also involved in lupus nephritis and IgA nephropathy. C3b generated by activation of the classical or lectin pathways can secondarily activate the alternative pathway, amplifying the extent of complement activation within tissues.10

Activation of the complement system generates multiple different pro-inflammatory mediators.

• C3a and C5a bind to kidney cells and several immune cells, eliciting a wide range of local and systemic responses including direct injury, vasoactive changes, attraction of inflammatory cells, and modulation of immune response to antigens.

• C5b-9 (the membrane attack complex, MAC) forms pores in the outer membrane of cells and in sufficient quantities causes cell lysis.

• C3b is fixed to the surface of cells and results in further activation of complement on the cell surface.10

Role of Complement in Glomerulopathy

Primary MNAnti-PLA2R antibody

Applies primarily to IgAN and only secondary to LupusLupus NephritisDNA−anti-DNA immune complexes

IgA NephropathyGalactose-deficient IgA1

C3 GlomerulopathyAnti-C3Bb antibody

Disease Pathway

Alternative pathway

Classical pathway

Mannose BindingLectin pathway

Glomerular immune complexes

Ligands for MBL and ficolins displayed on injured glomerular cells (?)

• Inadequate regulation

• Amplification of classical or MBL pathway

• Bacterial proteins

• IgA

Mechanism

By targeting C3 at the point of convergence of all complement activation pathways and upstream of C5, APL-2 can inhibit all 3 principal complement activation pathways.12 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.13

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.

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 restore normal complement activity.11

Primary Objective of the Discovery Clinical Trial

What is APL-2?

Why Evaluate APL-2 in Complement-mediated Glomerulopathies?

Discovery Key Endpoints11

All indications: Proteinuria reduction by 50%, calculated by the change in urinary protein to creatinine ratio from baseline to week 48

Primary 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 48

All indications: Stabilization or improvement in eGFR from baseline to week 48

Complete renal response: Defined as <200mg/g urine protein:creatinine ratio and stabilization or improvement in eGFR from baseline to week 48

Secondary Efficacy Endpoints

Physical examination; incidence and severity of adverse events (AE)

Changes from baseline in laboratory parameters

Changes from baseline in electrocardiography parameters

Safety Endpoints

Lo

1. Patients ≥18 years of age (≥16 years in cases of C3G)

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

4. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m² calculated by CKD-EPI creatinine equation at screening visit and not currently on dialysis

5. Must have stable renal disease (stable proteinuria, eGFR and blood pressure) on stable and optimized treatment (eg, immunosuppressive agents, anti-hypertensives and/or antiproteinurics) for at least 2 months prior to the first dose of APL-2

Key Inclusion Criteria

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

1. Platelet count <100,000/mm³ at screening visits

2. Absolute neutrophil count <1000 cells/mm³ at screening visits

3. ALT or AST >3.0 x the upper limit of normal at screening visits

4. Diagnosis of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection, or positive serology at screening visits. (Previous HBV or HCV diagnosis cleared by treatment is allowed.)

Key Exclusion Criteria

Subcutaneous (SC) once-daily at-home infusions of 360 mg APL-2 for 48 weeks

Dosing of APL-2

Physical examination; incidence and severity of adverse events (AE)

Changes from baseline in laboratory parameters

Changes from baseline in electrocardiography parameters

References

To Recommend a Patient for This Trial, Email

or visit

https://discoveryclinicaltrial.com

apellisclinicaltrials@cherryhcc.com

IgA nephropathy. National Organization for Rare Disorders Web site https://rarediseases.org/rare-diseases/iga-nephropathy/. Accessed May 18, 2018.

Cohen AH, Glassock RJ. The primary glomerulopathies. In Schrier RW, Coffman TM, Falk RJ, et al, eds: Schrier's Diseases of the Kidney. New York, NY: Wolters Kluwer, 2013.

Caliskan Y. Complement pathway asssociated glomerulopathies. Eur Med J. 2016;1(1):30-38.

Bomback AS, Markowitz GS, Appel GB. Complement-mediated glomerular diseases: a tale of 3 pathways. Kidney Int Rep. 2016;1(3):148-155.

Popat RJ, Robson MG. Complement and glomerular diseases. Nephron Clin Pract. 2014;128(3-4):238-242.

Salvadori M, Rosso G, Bertoni E. Complement involvement in kidney diseases: From physiopathology to therapeutical targeting. World J Nephrol. 2015;4(2):169-184.

C3 glomerulopathy. Genetics Home Reference Web site. https://ghr.nlm.nih.gov/condition/c3-glomerulopathy. Published December 2015. Accessed November 8, 2018.

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.

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.

Thurman JM. Many drugs for many targets: novel treatments for complement-mediated glomerular disease. Nephrol Dial Transplant. 2017;32(suppl 1):i57-i64.

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) secondary to age-related macular degeneration (AMD) [OAK v3.0], March 19, 2018. Apellis Pharmaceuticals.

Boyer DS, Schmidt-Erfurth U, van Lookeren Campagne M, Henry EC, Brittain C. 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.

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Discovery Study Locations

These studies are being conducted at over 100 locations throughout the United States

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