According to a press release, biopharmaceutical company Apellis Pharmaceuticals (“Apellis”) recently launched registration programs to explore pegcetacoplan for patients with C3 glomerulopathy (C3G), amyotrophic lateral sclerosis (ALS), and immune complex membranoproliferative glomerulonephritis (IC-MPGN). These conditions have little to no treatments, representing a huge unmet need. As leaders in targeted C3 drug development, Apellis is now looking to use pegcetacoplan to address new therapeutic options for patients with C3G, ALS, and IC-MPGN.

Registrational Programs

The registrational programs initiated by Apellis seek to understand pegcetacoplan as a potential treatment for these conditions. First, it is necessary to understand what pegcetacoplan is. This investigational C3 therapy works by regulating complement system activation. According to the British Society for Immunology, the complement system:

refers to a series of >20 proteins, circulating in the blood and tissue fluids. Most of the proteins are normally inactive, but in response to the recognition of molecular components of microorganisms they become sequentially activated in an enzyme cascade – the activation of one protein enzymatically cleaves and activates the next protein in the cascade.

In other words, your complement system plays a role in immune response. But when the complement system is overactive, it can lead to inflammation and disease progression. Pegcetacoplan binds to C3 and C3b to inhibit over activation and over-breakdown of C3 proteins. As of today, pegcetacoplan received Orphan Drug designation for the treatment of C3 glomerulopathy.

Nephrology Program for Patients with C3G / IC-MPGN

Both C3G and IC-MPGN are forms of rare kidney disease. Apellis notes that:

Although IC-MPGN is a distinct disease from C3G, the underlying cause and progression of the two diseases are remarkably similar. In both diseases, an important part of the immune system known as the complement cascade is overactive, which results in the excessive breakdown of a protein called C3, [which becomes] trapped in the kidney, causing inflammation and damage to the organ.

Currently, there are no approved therapies or treatments for patients with C3G or IC-MPGN. The registration program for C3G / IC-MPGN will begin with the Phase 2 NOBLE clinical trial. Through this trial, researchers will determine the safety, efficacy, and tolerability of pegcetacoplan in patients with C3G or IC-MPGN following transplantation. Ultimately, the study seeks to determine whether pegcetacoplan can reduce C3 levels and proteinuria (protein in the urine).

Overall, this trial will dose up to 12 patients following renal transplants. Apellis hopes to not only dose the first patient by the end of 2020, but start a Phase 3 clinical trial later in 2021.

Neurology Program for Patients with ALS

Initially, pegcetacoplan was looked at for conditions like C3G and IC-MPGN. However, researchers recently decided to explore the therapy as an option for patients with ALS. Patients with ALS often have high C3 levels at the neuromuscular junction, or the area where neurons and muscle cells communicate. Some hypotheses also suggest that these high C3 proteins could cause neuroinflammation.

Next, Apellis will explore pegcetacoplan for ALS through the Phase 2 MERIDIAN clinical trial. Around 200 patients with ALS will enroll. Through the MERIDIAN trial, Apellis will test pegcetacoplan’s safety, efficacy, and tolerability for patients with sporadic ALS. Ultimately, the study hopes to improve function and overall survival rate. Apellis hopes to dose the first patient by the end of 2020.

C3 Glomerulopathy (C3G)

Typically, sporadic CFHR5, C3, or CFH gene mutations (among others) cause C3 glomerulopathy (C3G), a group of progressive kidney conditions causing kidney malfunctions and damage. C3 glomerulonephritis and dense deposit disease are the two main forms of C3G, affecting 1-2 out of every 1,000,000 individuals. Currently, there are no treatments for C3G. However, this means that many patients eventually enter late-stage renal disease. Symptoms of C3G include:

• Low levels of C3 protein in the blood
• Bloody urine
• Passing less urine
• Proteinuria (high levels of protein in the urine)
• Swelling of the hands, feet, and ankles

Learn more about C3G here.

Amyotrophic Lateral Sclerosis (ALS)

While there is no distinct cause of ALS, some researchers believe it could be caused by genetics, dementia, or toxin exposure. This progressive neurological disease causes nerve cell death in the brain, brain stem, and spinal cord. Eventually, this leads to muscle weakness which can be fatal if it affects the chest. There are two forms of ALS: sporadic and familial. 90-95% of all diagnoses are sporadic ALS. Males are more affected by ALS than females. Symptoms vary, but can include:

• Slow or slurred speech
• Muscle cramping, pain, and weakness
• Poor posture
• Frequent tripping and falling
• Difficulty speaking and swallowing
• Gradual inability to move muscles
• Anxiety or depression
• Weakness in the arms, legs, and hands

Learn more about ALS here.

Immune Complex Membranoproliferative Glomerulonephritis (IC-MPGN)

In many cases, immune complex membranoproliferative glomerulonephritis (IC-MPGN) is similar to C3G. While patients with IC-MPGN also have high levels of C3 deposits in the kidneys, they also have high immunoglobulin deposits as well. C3G and IC-MPGN affect approximately 18,000 patients between the U.S. and Europe. According to the UNC Kidney Center:

Membranoproliferative glomerulonephritis (MPGN) is a disease that affects the glomeruli, or filters, of the kidneys. Most instances of MPGN are caused by other diseases or disorders, including autoimmune diseases (such as systemic lupus erythematosis), chronic infections (like hepatitis B or more commonly hepatitis C), monoclonal immunoglobulin deposition diseases, and hereditary diseases.

Some cases may be idiopathic, meaning they have no cause. Typically, idiopathic MPGN or IC-MPGN affects patients between the ages of 8 and 30. Symptoms vary but may include:

• Bloody urine
• Dark, foamy urine
• Proteinuria (high levels of protein in the urine)
• High blood pressure
• Inflammation

Around 50% of all C3G and IC-MPGN cases cause kidney failure within 5-10 years of diagnosis. Learn more about IC-MPGN here.