Complement Inhibitors as Therapeutic Agents for Autoimmune Disease

THE TREMENDOUS complexity of the immune system is, perhaps ironically, providing new avenues for treating diseases of and caused by the immune system. Many of these are rare conditions for which only palliative care was previously available. While the “complement revolution” that brought new treatments to market only began with the 2007 release of the C5 inhibitor eculizumab (Soliris),¹ the road to this point began some 130 years ago.

Growing scientific curiosity about how the human body defended itself against disease led to increased research into the immune system in the late 1800s.² Belgian physician Jules Bordet, who was studying cholera under Louis Pasteur at the time, discovered that the immune system includes a heat-sensitive component (the innate immune response) and a parallel ability to customize a response to the presence of specific bacteria (the adaptive immune system). This 1896 discovery of the duality of the immune system would eventually result in Bordet being awarded the 1919 Nobel Prize in Physiology or Medicine.³ Three years after Bordet’s 1896 discovery of the heat-sensitive bacteria-destroying substance, fellow future Nobel winner Paul Ehrlich, MD, termed this substance “complement” to emphasize what he saw as its role assisting antibodies in destroying invasive bacteria.⁴

Although our understanding of the specifics of the complement system has grown dramatically in the century since (for instance, what Dr. Bordet thought was a plasma is in fact a series of proteins), Bordet’s basic model of the first-line innate response and Dr. Ehrlich’s name for it remain. And while research continues into the immune system, we now know that when the complement system is malfunctioning, it can cause serious health complications. This can include conditions arising from an overactive complement system (atypical hemolytic uremic syndrome and C3 glomerulopathy) or an underperforming complement system (hereditary angioedema).

With dozens of complement proteins now identified, researchers have successfully developed a new class of immunosuppressive drugs known as complement inhibitors. Although those that are on the market have successfully passed clinical trials with the United States Food and Drug Administration (FDA), their use still requires close monitoring due to the dangerous, often life-threatening side effects associated with suppressing the immune system.

What Is the Complement System?

The complement system is part of the innate immune system, which also includes the skin and mucous membranes as a physical barrier; stomach acids to protect us when we eat; and phagocytes to attack bacteria in the bloodstream.

Following up on Dr. Bordet and Dr. Ehrlich’s work, in 1907 Adolfo Ferrata, MD, and Erwin Brand, MD, discovered that two separate substances were present in the complement system, and a third substance was added by the 1920s. The next four decades brought improved lab equipment that allowed researchers to discover that Dr. Bordet’s substance or serum was in fact a series of more than 40 proteins.²

Today, it is understood that the complement system has three pathways of activation: classical, alternative and lectin. They are defined by the specific protein that is first activated in response to infection. Once one of these proteins is cleaved from its zymogens precursor (which are spread throughout the body), it then causes other enzymes to cleave, and they do the same to a third class, which activates a fourth, etc. — very quickly unleashing a cascade of bacteria-fighting proteins.⁴

The proteins are designed to latch on to bacteria cell membranes, either tearing the membranes open and killing the bacteria (lysis), or by marking it for destruction by a phagocyte (opsonization). Other proteins in the complement cascade are anaphylatoxins, which initiate inflammation by attracting immune cells to the area of infection or injury.

Once an infection is waning, the complement system also helps clear the body of dead cells, is involved in the growth of new cells and helps regulate the overall immune system.⁷

How Do Complement Inhibitors Work?

There are more than a dozen complement inhibitors currently approved by FDA, and dozens more in clinical trials.⁶

One of the byproducts of an immune response is inflammation — the body’s call to arms to deal with infection or injury and to promote healing afterward. The C3a and C5a complement proteins in particular stimulate other immune cells to migrate to an area of injury or infection, a precursor to inflammation.⁷ But if acute inflammation is literally a lifesaver, when something goes wrong and chronic inflammation sets in, it often causes significant damage to the body. Specific conditions associated with complement dysregulation and chronic inflammation include rheumatoid arthritis, systemic lupus erythematosus, ANCA-associated vasculitis and autoimmune bullous dermatoses.⁷

Complement inhibitors are designed to stop chronic inflammation and its harm to the body by ending a wayward immune response. As the complement cascade process is hierarchical, the earlier up the chain the process is inhibited, the more effective at suppressing inflammation it is likely to be. But the obverse fact is that the more effective at suppressing inflammation a treatment is, the more likely it is to allow for unwanted secondary infections.⁶

Complement proteins are named roughly in the order of their activation during a cascade (although the initial order varies depending on whether the activation pathway is classical, lectin or alternative). In the classical pathway, the C1 protein is activated first; in the alternative pathway, it is the C3 protein; and in the lectin pathway, the C2 and C4 proteins. All three pathways quickly arrive at a common cascade point with the C5 protein.⁵ By targeting one of these complement proteins and effectively deactivating it, complement inhibitors can stop a complement cascade from proceeding further.

The first complement inhibitor, eculizumab (Soliris, Bkemv, Epysqli), works by binding to the C5 protein, preventing it from cleaving into C5a and C5b, thus interrupting the normal cascade after the first couple rounds of reactions.⁸ It was originally approved in 2007 to treat paroxysmal nocturnal haemoglobinuria (PNH), a genetic condition in which one of the naturally occurring proteins that normally regulates the complement cascade is missing, leading to the complement system running unchecked and destroying red blood cells and, if left untreated, the marrow as well.⁹

Eculizumab has subsequently also been approved by FDA to treat:

• Atypical hemolytic uremic syndrome (aHUS), an extremely rare genetic condition in which red blood cells are destroyed, platelet counts are low and the kidneys are unable to properly cleanse the blood.¹⁰ 
• Generalized myasthenia gravis (gMG). For patients of this rare neuromuscular disease who test positive for the antiacetylcholine receptor (AchR) antibody, eculizumab has shown to be effective11 as has a subsequent FDA-approved drug, zilucoplan (Zilbrysq), a macrocyclic peptide that targets the C5 protein.⁶
• Neuromyelitis optica spectrum disorder (NMOSD), an autoimmune disease in which the immune system attacks optical nerves, as well as the brainstem and spinal cord. Eculizumab use resulted in statistically relevant reduction in relapse episodes.¹²

What Other Conditions Can Be Treated with Complement Inhibitors?

While there are more than a dozen complement inhibitors presently approved by FDA, many target the same disease or condition, so there are fewer than a dozen diseases that can currently be treated with these drugs.

In addition to the above four conditions, others that have a complement inhibitor available include:

• Paroxysmal nocturnal haemoglobinuria (PNH). Physicians now have alternatives to eculizumab for treating PNH. These include iptacopan (Fabhalta), a small-molecule factor B inhibitor. This complement inhibitor has also shown promise in off-label treatment of C3 glomerulopathy (C3G),¹³ a complement-mediated kidney disease caused by uncontrolled activation of the alternative pathway of the complement cascade.¹⁴ Pegcetacoplan (Empaveli, Syfovre) is a C3 inhibitor now approved for treating PNH,15 as well as geographic atrophy.6 Another option, approved in 2018, is ravulizumab (Ultomiris), a monoclonal antibody that suppresses the C5 protein. It was also approved for treating aHUS and MG.⁶
• Hereditary angioedema. This is a rare genetic condition that causes swelling of various body parts due to a mutation in the SERPING1 gene, which contains instructions for building the C1 inhibitor protein. These mutations can lead to having too few C1 proteins, malformed C1 proteins or other abnormalities.¹⁶ Treatment consists of either extracted or synthesized C1 inhibitor to replace the missing or malformed proteins, and it is sold under the brand names Berinert, Cinryze, Haegarda and Ruconest.⁶
• Cold agglutinin disease. This is a disorder in which the immune system tags red blood cells as invaders, leading to their destruction. The cause is not yet understood, but sutimlimab (Enjaymo) — a monoclonal antibody that targets the C1s protein — has been shown to halt the anemia caused by the condition.¹⁷
• Geographic atrophy. This late stage of age-related macular degeneration not only responds to treatment with pegcetacoplan, but also avacincaptad pegol (Izervay), a C5 inhibitor.⁶
• CD55-deficient protein-losing enteropathy (CHAPLE disease). This ultrarate condition (fewer than 100 diagnosed cases around the world) is a genetic disease that results in an overactive complement system. It can now be treated with pozelimab-bbfg (Veopoz), a monoclonal antibody that targets the C5 protein.¹⁸
• Antineutrophil cytoplasmic antibodyassociated vasculitis (ANCA-associated vasculitis). This is a family of autoimmune conditions leading to inflammation of blood vessels. One of the more effective treatments has been rituximab (typically used in treating certain cancers), and recent studies show that including the C5aR inhibitor avacopan (Tavneos) improved patient outcomes.¹⁹

What Are the Drawbacks?

Immunosuppressants in general carry the risk of secondary infections, and complement inhibitors share that common danger.

With eculizumab, for instance, it is recommended patients be vaccinated for Neisseria meningitidis before treatment begins since patients on eculizumab are at heightened risk of infection.8 Also, since young children do not yet have fully developed adaptive immune systems, their bodies rely more heavily on innate immunity. The use of complement inhibition in children may thus involve a higher risk of infection than with adults.⁶

Every complement inhibitor will have detailed instructions, including any recommended prerequisite inoculations and warnings of certain secondary conditions that may preclude use of that specific treatment.

What Treatments Are in the Pipeline?

Complement inhibitors are an outlier in treating rare or orphan diseases because there is a substantial body of active research and clinical trials into these treatments. Admittedly, many of those trials are taking existing complement inhibitors and trying them on different autoimmune diseases to see if they are effective there as well — a relatively low-overhead endeavor.

For instance, at FDA’s clinicaltrials.gov website, there are more than 100 current or recent clinical trials into the already-approved eculizumab — applying it to different diseases and conditions, ranging from transplant patients to CD59 deficiency.

Other studies are looking at sutimlimab (approved for treating cold agglutinin disease) to see if it is effective at treating other complement-mediated disorders.²⁰

And new complement inhibitors are in the pipeline: One potential C1s inhibitor, RAY121, is under study by a Japanese pharmaceutical firm to gauge its safety.²¹ But complement inhibitors are also being looked at for conditions other than immunological disorders: One study in the Netherlands seeks to find out whether complement inhibitors can be used to reduce inflammation in patients with traumatic brain injury.²²

Looking Ahead

With research into the complement system truly still in its beginning stages, and with technology now allowing for the relatively quick (compared to previous decades) and inexpensive development of tailored drugs, there is hope other complement-related conditions such as lupus and rheumatoid arthritis will also have treatments available to provide relief to those suffering from them.