Exploring Treatment With Anticomplement Therapeutics

Supplements and Featured PublicationsUnderstanding the Role of the Complement System in Rare Disease Therapeutics

A Q&A With Richard J. H. Smith, MD

Richard J. H. Smith, MD

Richard J. H. Smith, MD

AJMC®: How has treatment of complement-driven diseases changed since 2007, when the first complement inhibitor, eculizumab, was approved?

SMITH: The development of eculizumab followed our understanding of a rare disease called paroxysmal nocturnal hemoglobinuria (PNH). Due to a genetic defect, the red blood cells of patients with PNH lack CD55 and CD59, 2 complement regulatory proteins. Because they lack CD55 (also called DAF), patients with PNH are susceptible to C3 convertase activity; for these patients, it's essential that the tickover of the alternative pathway is controlled to avoid full-fledged activation of complement. Lacking CD59, these patients’ erythrocytes are susceptible to membrane attack complex (MAC) lysis as well.

It turned out that eculizumab, a monoclonal antibody, was the perfect solution for these patients because it recognizes C5 and prevents the propagation of the terminal complement pathway. Treatment with eculizumab markedly decreases the erythrocyte lysis that occurs in patients with PNH. Therapy with this first-in-class complement inhibitor was approved to treat PNH in 2007 and was subsequently approved for the treatment of atypical hemolytic uremic syndrome (aHUS) in 2011.

Eculizumab has profoundly changed the lives of patients with PNH and aHUS. With aHUS, for example, prior to the use of eculizumab, up to 50% of patients were dying of the disease, and these were children. With eculizumab, they receive treatment every 2 weeks, and they're doing great; death is no longer looming at their doorstep.

These diseases were ultra-rare, but the success of eculizumab spurred interest in targeting different points on the complement cascade. Now, researchers are trying to determine whether targeting these other points will have an equally profound effect in PNH and other diseases.

AJMC®: In animal studies, disruption of the complement system is associated with a host of diseases ranging from asthma to diabetes. Is there hope that these agents might treat more prevalent diseases?

SMITH: The jury is still out. Marina Vivarelli, MD, and I recently chaired a KDIGO (Kidney Disease Improving Global Outcomes) Controversies Conference on the role of complement in kidney disease. We specifically asked whether complement plays a primary or a secondary role in certain diseases, the level of evidence, and the level of interest in pushing forward with anticomplement therapies. We looked at diabetic nephropathy as well as FSGS (focal segmental glomerulosclerosis), lupus antiphospholipid syndrome, ANCA-associated vasculitis, immune complex MPGN (membranoproliferative glomerulonephritis), C3G (C3 glomerulopathy), postinfectious glomerulonephritis, IgAN (immunoglobulin A nephropathy), IgA-associated vasculitis, and membranous nephropathy. Finally, we looked at the thrombotic microangiopathy or complement-mediated forms of HUS (eg, aHUS).

Right now, the cost of eculizumab precludes researchers from investigating its use in a lot of different diseases, including more common ones.

AJMC®: Eculizumab is a C5 inhibitor. Can you describe the clinical value of inhibiting a downstream or a terminal target within the complement system?

SMITH: With downstream inhibition, the upstream initiating pathways can remain active and the upstream activities of C3 are preserved. C3 produces C3a, which is an anaphylatoxin that induces cell activation and, potentially, an inflammatory response. C3 also produces C3b, which is essential for the formation of C3 convertase; it acts as an opsonin and participates in the solubilization and clearance of immune complexes.

Complement also has an intracellular function. In the end, downstream inhibitors preserve upstream functions in complement that are important to our immune system and immune defense. These functions are probably also important in many ways that we're not currently aware of.

AJMC®: Are there clinical limitations that come with downstream inhibition? Why is there a risk of meningococcal infection?

SMITH: When complement is inhibited—downstream or upstream—the primary role of complement, host defense, also is inhibited. The rapid elimination of invading bacteria, for instance, is inhibited. An activated complement cascade on a bacterial surface triggers a variety of responses that help kill the bacteria. The most rapid response, as I mentioned earlier, is forming MAC, which can kill Neisseria species within minutes. Patients who are receiving treatment with a complement inhibitor, whether it's an upstream blocker or downstream blocker, have about 1000 to 2000 times greater risk for meningococcal disease compared with otherwise healthy people in the United States who aren’t being treated with one.

Because of this risk, the Centers for Disease Control and Prevention recommends that all patients who are going to receive complement inhibitor therapy receive a meningococcal vaccine, including boosters. Although vaccination does not prevent all cases of meningococcal disease, it is still protective, and so it is important to ensure patients’ vaccinations are up to date. Most patients also are prescribed antibiotics, which add another layer of protection. Some patients must start complement inhibitor therapy immediately because of a medical emergency; however, for those patients for whom there is some time, we ensure their vaccinations are all up to date.

AJMC®: Are there other limitations with first-generation eculizumab that have been found in clinical practice? Are newer therapies adjusting for these limitations?

SMITH: Eculizumab is a great drug but it's not a wonder drug. The complement system is exceedingly complex. When it isn't working properly and something else is targeted to stop that perturbation, there can be unintended consequences. For example, when eculizumab is used to treat PNH, the anti-C5 therapy does not completely normalize hemoglobin values. That's due to extravascular hemolysis. The terminal pathway is blocked, but the initiating pathways may not be, and this allows the PNH erythrocytes to become C3 fragment–positive. As a result, the erythrocytes are cleared by the spleen and the liver and removed from the circulation by phagocytes. There may still be some ongoing hemolysis. Research into this pathogenesis was spearheaded by Antonio Maria Risitano, MD, PhD, and others have supported his finding.

As new complement therapeutics are approved, we will learn more about the nuances of the complement system. These nuances aren't apparent in a normal functioning situation. It’s like not having enough oil in your car, hearing the valves tapping, and realizing that you need to have a valve job. You didn't realize you needed to have a valve job until the oil was low. When there is an abnormality in the complement cascade—as in PNH, aHUS, and other complement-mediated diseases—that abnormality is treated by targeting the complement system at position X, Y, or Z. Each treatment may have a unique impact on the complement system and on the disease. Although dual therapy is too costly right now, dual therapy may better treat certain diseases.

AJMC®: Since the approval of eculizumab, C3 inhibitors, a C1 inhibitor, and a C5a inhibitor all have been approved. Can you explain how targeting upstream has the potential to change the treatment landscape?

SMITH: I think it's wonderful to have a variety of complement inhibitors because the spectrum of diseases that are caused by complement dysregulation is broad. Having a variety of inhibitors allows providers to target a patient’s specific disease. Providers can get the best outcome by prescribing an anticomplement therapy based on an understanding of the underlying pathophysiology.

For example, the C1 inhibitor sutimlimab has shown to be effective in patients with cold agglutinin disease, which is associated with autoimmune hemolytic anemia. Patients with this disease often have chronic anemia or fast fatigue and can have acute hemolytic crises. They also can develop agglutinin-mediated acrocyanosis, in which their extremities are cold and hemagglutination in the blood vessels. Cold agglutinin disease is caused by cold agglutinin, which involves IgM autoantibodies. Those IgM autoantibodies bind to erythrocytes. The classical pathway is triggered by IgM, so the C1 inhibitor is a potent therapeutic for that subset of patients.

Another example is the C5a inhibitor avacopan, which has shown to be effective in patients with ANCA-associated vasculitis. Patients who are ANCA-positive can experience life-threatening complications such as impaired kidney function as well as deterioration of health-related quality of life metrics because of organ damage. In the ADVOCATE trial (NCT02994927), avacopan therapy was shown to be equivalent to prednisone use with respect to disease remission at 26 weeks; avacopan therapy was superior to prednisone treatment with respect to sustained remission at 52 weeks. This is important because it is better to take a C5a inhibitor than to take lots of steroids.

By having several anticomplement therapeutic agents from which to choose and a good understanding of the disease process underlying complement dysregulation in patients with a variety of diseases, we can offer patients individualized therapy to ensure the best outcome.

However, because these are rare diseases, the number of patients is limited, so enrolling patients in trials and obtaining meaningful end points remains difficult. There also needs to be governance at the patient accrual level to ensure that the inhibitor matches the patient’s underlying pathophysiology.

AJMC®: Eculizumab was found to be effective in PNH and aHUS. Newer agents like iptacopan are being tested in several clinical trials looking at treating different disease states. Is there anything about targeting points along the alternative pathway that might allow for a more diverse set of patients to be treated?

SMITH: Yes, there is. The alternative pathway gives us even more options to treat patients effectively. However, what’s most important is that each provider make an informed decision based on the patient's complement biomarker profile, anticomplement autoantibodies, and genetics. Testing—including in vitro testing to see if the patient might be responsive to an agent—is a good idea, and this testing is doable.

When faced with a complement-driven rare disease, providers should reach out to laboratories and/or clinical experts in that disease to ask whether the use of anticomplement inhibitor X makes sense and, if it does, how patient outcomes should be measured. This is important because the complement system is complex. In many diseases, dysregulation of complement is the primary or secondary factor. Whether treating with an anticomplement agent offers patients any benefit can be a very nuanced question. Consequently, it is important to communicate with experts in those domains to move forward with an effective treatment plan, offer the best care, and utilize health care resources efficiently.

I hope lots of things stay on the formulary and that in vitro tests are offered to tell whether a certain anticomplement therapeutic might work in a given patient.

AJMC®: At the 64th American Society of Hematology (ASH) annual meeting in December 2022, 4 papers presented findings from studies related to alternative pathway inhibition. All studies examined patients with PNH. These included results from a study of biomarkers associated with clinically meaningful hemolysis in patients treated with danipocan monotherapy or with iptacopan after eculizumab,1 interim data from a phase 2 trial (NCT04170023) of vemircopan monotherapy,2 findings from an integrated analysis of 2 phase 2 trials (NCT03439839, NCT03896152) of iptacopan therapy,3 and primary efficacy and safety data from the phase 3 APPLY-PNH trial (NCT04558918) of iptacopan monotherapy.4 What do these recent findings suggest about the near-term future of alternative pathway inhibitor therapy?

SMITH: Danipocan and vemircopan are both orally administered factor D inhibitors while iptacopan is an orally administered factor B inhibitor. The result is that these drugs inhibit the alternative pathway of complement. The impact on patients with PNH is that alternative pathway inhibition prevents the decoration of erythrocytes with C3b, and as a consequence extravascular hemolysis is decreased. There are fewer C3 fragment–positive erythrocytes, and clearance by the spleen and liver is reduced.

These recent results published at ASH 2022 are promising and suggest that more effective treatments for PNH may be on the horizon.

Dr Smith is a professor of otolaryngology, internal medicine, pediatrics, molecular physiology and biophysics, and anatomy and cell biology; the director of the molecular otolaryngology and renal research laboratories; and the director of the Iowa Institute of Human Genetics at the Carver College of Medicine at the University of Iowa in Iowa City.


1. Marano L, Ricci P, Urciuoli E, et al. Complement biomarkers for tracking breakthrough hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) patients treated with last-generation complement inhibitors. Oral abstract presented at: 64th annual American Society of Hematology meeting; December 10, 2022; New Orleans, LA. Accessed December 12, 2022. https://ash.confex.com/ash/2022/webprogram/Paper158329.html 

2. Browett PJ, Kulasekararaj A, Notaro R, et al. Vemircopan (ALXN2050) monotherapy in paroxysmal nocturnal hemoglobinuria: interim data from a phase 2 open-label proof-of-concept study. Oral abstract presented at: 64th annual American Society of Hematology meeting; December 10, 2022; New Orleans, LA. Accessed December 12, 2022. https://ash.confex.com/ash/2022/webprogram/Paper169301.html

3. Risitano A, Peffault de Latour R, Yap ES, et al. Dose–exposure–response relationships of biomarkers and efficacy measures with iptacopan, a complement factor B inhibitor, in patients (pts) with paroxysmal nocturnal hemoglobinuria (PNH) with or without concomitant anti-C5 therapy. Poster abstract presented at: 64th annual American Society of Hematology meeting; December 11, 2022; New Orleans, LA. Accessed December 12, 2022. https://ash.confex.com/ash/2022/webprogram/Paper160114.html

4. Peffault de Latour R, Roeth A, Kulasekararaj A, et al. Oral monotherapy with iptacopan, a proximal complement inhibitor of factor B, has superior efficacy to intravenous terminal complement inhibition with standard of care eculizumab or ravulizumab and favorable safety in patients with paroxysmal nocturnal hemoglobinuria and residual anemia: results from the randomized, active-comparator-controlled, open-label, multicenter, phase III APPLY-PNH study. Abstract presented at: 64th annual American Society of Hematology meeting; December 13, 2022; New Orleans, LA. Accessed December 12, 2022. https://ash.confex.com/ash/2022/webprogram/Paper171469.html

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