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    Summary of the drugs that target the complement cascade in glomerular disease

  • 1.

    Rodriguez E, et al.. Should eculizumab be discontinued in patients with atypical hemolytic uremic syndrome? Clin Kidney J 2017; 10:320322. doi: 10.1093/ckj/sfx024

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Skoczynska M, et al.. Thrombotic microangiopathy in the course of catastrophic antiphospholipid syndrome successfully treated with eculizumab: Case report and systematic review of the literature. Lupus 2020; 29:631639. doi: 10.1177/0961203320917460

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Nakamura H, et al.. Atypical hemolytic uremic syndrome associated with complement factor H mutation and IgA nephropathy: A case report successfully treated with eculizumab. Nephron 2018; 138:324327. doi: 10.1159/000485194

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Palomo M, et al.. Complement activation and thrombotic microangiopathies. Clin J Am Soc Nephrol 2019; 14:17191732. doi: 10.2215/CJN.05830519

  • 5.

    Ariceta G, et al.. The long-acting C5 inhibitor, ravulizumab, is effective and safe in pediatric patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment. Kidney Int [published online ahead of print December 8, 2020]. doi: 10.1016/j.kint.2020.10.046; https://www.kidney-international.org/article/S0085-2538(20)31418-6/fulltext

    • Search Google Scholar
    • Export Citation
  • 6.

    Jayne DRW, et al.. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol 2017; 28:27562767. doi: 10.1681/ASN.2016111179

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Jayne DRW, et al.. ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021; 384:599609. doi: 10.1056/NEJMoa2023386

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Merkel PA, et al.. Evaluation of the safety and efficacy of avacopan, a C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-associated vasculitis treated concomitantly with rituximab or cyclophosphamide/azathioprine: Protocol for a randomized, double-blind, active-controlled, phase 3 trial. JMIR Res Protoc 2020; 9:e16664. doi: 10.2196/16664

    • Search Google Scholar
    • Export Citation

Complement Inhibition in Kidney Disease. What’s on the Horizon?

  • 1 Maria Jose Soler, MD, PhD, FERA, is a nephrologist, and Natalia Ramos, MD, PhD, is a nephrology attendant with the Nephrology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Research, Barcelona, Spain.
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During the last decade, several therapeutics targeting the complement cascade have begun to enter the nephrology scene (Figure 1). Examples include the following diseases:

  • Atypical hemolytic uremic syndrome (aHUS)

  • C3 glomerulopathy

  • Lupus nephritis

  • Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis

  • Immunoglobulin A (IgA) nephropathy

Figure 1.
Figure 1.

Summary of the drugs that target the complement cascade in glomerular disease

Citation: Kidney News 13, 3

IgAN, IgA nephropathy; C3GN, C3 glomerulonephritis; HUS, hemolytic uremic syndrome; SLE, systemic lupus erythematosus; AAV, anti-neutrophil cytoplasmic autoantibodies; MBL, mannose-binding lectin; MASP, mannose-binding lectin-associated serine protease; CR1, complement receptor type 1; CR2, complement receptor type 2; DAF, decay-accelerating factor; ALP2, alkaline protease 2; ACH-0144471, danicopan; LNP023, iptacopan; MAC, membrane attack complex.

The first agent to enter the stage was eculizumab, which showed impressive efficacy in patients with aHUS (1). Currently, most randomized clinical trials using complement inhibition therapy are in patients with aHUS and ANCA vasculitis. Data on use of complement inhibitors in other glomerular diseases are sparse and consist mostly of retrospective studies and case series (2, 3).

aHUS is a rare, life-threatening disease caused by complement dysregulation and characterized by thrombotic microangiopathy (TMA). Without appropriate medical treatment, mortality can be seen in up to 50% of patients with aHUS. Eculizumab is a monoclonal antibody (mAb) that binds to C5, inhibits the ability of C5 convertase to cleave C5 into C5a and C5b, and thus reduces membrane attack complex formation.

Eculizumab has been shown to be effective in children and adults with aHUS, dramatically improving patient survival and kidney prognosis. However, eculizumab needs to be administered intravenously every two weeks and is expensive. Moreover, the duration of eculizumab therapy is unclear in patients with aHUS, as only a few studies have been designed to answer this question. Thus, many questions are left unanswered about relapse rate and duration of therapy. Currently, there is an ongoing debate about whether eculizumab in aHUS is a lifelong therapy or can be safely discontinued (1). Recent studies suggest that serum from patients with aHUS may be useful to detect the risk for disease relapse. The in vitro capacity of serum from patients with aHUS to activate complement may be a future tool allowing for decisions to continue/discontinue complement inhibition therapy (4). As C3 glomerulopathy is related to complement activation, initial case series pointed out eculizumab as a therapeutic option; however, its beneficial effect has been shown to be highly heterogeneous without clear scientific evidence.

Ravulizumab is a mAb that was engineered to achieve an extended duration of complement inhibition while retaining the efficacy and safety of eculizumab. It differs from eculizumab by the substitution of 4 amino acids, which alter the pharmacokinetics and pharmacodynamics of the mAb, and resulted in a novel antibody against C5 with a terminal half-life 4 times longer than that of eculizumab. In October 2019, ravulizumab was approved by the US Food and Drug Administration (FDA) for treatment of aHUS in adults and children. The first prospective phase III, single-arm, multi-center study evaluating the efficacy and safety of ravulizumab (maintenance dosing every 4–8 weeks instead of every 2 weeks) in children with aHUS demonstrated complete and sustained terminal complement C5 inhibition, leading to hematologic remission and improvement of kidney function (5). The primary endpoint of complete TMA response (platelet count normalization, lactate dehydrogenase [LDH] normalization, and ≥25% improvement in serum creatinine at two separate assessments at least 28 days apart) was achieved in 77.8% of patients (n = 14). A clinical advantage of ravulizumab over eculizumab is the long-acting effect, allowing for fewer infusions, thus potentially leading to improved quality of life.

Avacopan is an oral C5a receptor inhibitor that has been studied in randomized clinical trials in aHUS, ANCA vasculitis, C3 glomerulopathy, and IgA nephropathy. The first study in ANCA vasculitis (CLEAR study) was promising and demonstrated an effective result in replacing high-dose glucocorticoids (6). The avacopan phase III study in the ANCA vasculitis ANCA-Associated Vasculitis (ADVOCATE) trial was first presented as an oral session during the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) Virtual Congress 2020 and was just published in the New England Journal of Medicine (7).

The study achieved both of its primary goals: disease remission at 26 weeks and sustained remission at 52 weeks, determined by changes in Birmingham vasculitis activity score (BVAS) from baseline to week 26 or 52. Seventy-two percent of patients in the avacopan group achieved remission at 26 weeks compared to 70.1% receiving standard care (control group). Sustained remission at 52 weeks occurred in 65.7% of patients in the avacopan group versus 54.9% in the control group, which was a significant improvement. However, the clear benefit of avacopan treatment at 26 weeks is the sparing of high doses of steroids and subsequently avoidance of glucocorticoid-related toxicity (8).

The exciting part of complement inhibition in glomerular diseases is ongoing, and new therapeutic strategies targeting other parts of the complement cascade, such as C3, factor B, factor D, and C1, are currently under various stages of basic and clinical development.

Dr. Soler reports personal fees from Novo Nordisk, Janssen, AstraZeneca, Fresenius, Mundipharma, Pfizer, Bayer, Vifor, Esteve, Eli Lilly, and Boehringer and grants and nonfinancial support from Boehringer, outside of the submitted work. There are no conflicts of interest with the drugs mentioned in the paper. Dr. Ramos was a paid lecturer for Alexion in 2020 on the topic of eculizumab treatment.

References

  • 1.

    Rodriguez E, et al.. Should eculizumab be discontinued in patients with atypical hemolytic uremic syndrome? Clin Kidney J 2017; 10:320322. doi: 10.1093/ckj/sfx024

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Skoczynska M, et al.. Thrombotic microangiopathy in the course of catastrophic antiphospholipid syndrome successfully treated with eculizumab: Case report and systematic review of the literature. Lupus 2020; 29:631639. doi: 10.1177/0961203320917460

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Nakamura H, et al.. Atypical hemolytic uremic syndrome associated with complement factor H mutation and IgA nephropathy: A case report successfully treated with eculizumab. Nephron 2018; 138:324327. doi: 10.1159/000485194

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Palomo M, et al.. Complement activation and thrombotic microangiopathies. Clin J Am Soc Nephrol 2019; 14:17191732. doi: 10.2215/CJN.05830519

  • 5.

    Ariceta G, et al.. The long-acting C5 inhibitor, ravulizumab, is effective and safe in pediatric patients with atypical hemolytic uremic syndrome naïve to complement inhibitor treatment. Kidney Int [published online ahead of print December 8, 2020]. doi: 10.1016/j.kint.2020.10.046; https://www.kidney-international.org/article/S0085-2538(20)31418-6/fulltext

    • Search Google Scholar
    • Export Citation
  • 6.

    Jayne DRW, et al.. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J Am Soc Nephrol 2017; 28:27562767. doi: 10.1681/ASN.2016111179

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Jayne DRW, et al.. ADVOCATE Study Group. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021; 384:599609. doi: 10.1056/NEJMoa2023386

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Merkel PA, et al.. Evaluation of the safety and efficacy of avacopan, a C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-associated vasculitis treated concomitantly with rituximab or cyclophosphamide/azathioprine: Protocol for a randomized, double-blind, active-controlled, phase 3 trial. JMIR Res Protoc 2020; 9:e16664. doi: 10.2196/16664

    • Search Google Scholar
    • Export Citation
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