The Role of Complement Blockade in the Management of IgA Nephropathy

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There has recently been a significant increase in available therapeutics and ongoing clinical trials that directly target the pathogenic mechanisms implicated in immunoglobulin A nephropathy (IgAN). Although systemic immunosuppression can be considered for patients at high risk of disease progression, it is associated with a wide degree of toxicities (1). Similar concerns remain present with the use of targeted-release enteric budesonide, although to a lesser extent (2). A growing body of evidence suggests that activation of the complement pathway plays an important role in IgAN pathogenesis, and numerous therapies targeting specific steps in the complement cascade are under development (3).

Galactose-deficient IgA1 deposition in tissues triggers local complement activation, and the alternative pathway is the primary cascade in IgAN. Activation of this cascade results in glomerular complement component 3 (C3) deposition, which has been observed in a significant majority of patients and correlates with disease progression. More intense complement deposition correlates with a worse prognosis and underscores the need for targeted complement inhibition in IgAN (4).

One such therapy is cemdisiran, a subcutaneously administered RNA interference therapeutic. Cemdisiran is designed to reduce hepatic production of C5 and thereby reduce formation of the membrane attack complex and anaphylatoxin C5a, which drive kidney injury. In a recent phase 2 study by Barratt et al. (5), adults with biopsy-proven IgAN were randomized in a 2:1 ratio to receive either cemdisiran (600 mg subcutaneously) or placebo every 4 weeks for 36 weeks.

All participants were on maximally tolerated renin-angiotensin system blockade for at least 3 months and had >1 g/day of proteinuria. The primary endpoint of the study was the percentage change from baseline of the urine protein-to-creatinine ratio (UPCR) at week 32. Patients with other significant concurrent kidney diseases and an estimated glomerular filtration rate 730 mL/min/1.73 m² and those who had received systemic immunosuppression within the past 6 months were excluded (5).

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Reprinted with permission from CJASN. See Barratt et al. (5).

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The 24-hour mean UPCR decreased from 1.55 to 1.27 g/g at week 32 for patients treated with cemdisiran with a placebo-adjusted geometric mean change from baseline in a 24-hour UPCR of −37.4%. Mean serum C5 levels were also noted to decrease for patients treated with cemdisiran compared with placebo. The most common adverse effect was injection-site reactions in the cemdisiran group; one death occurred in the therapy group due to post-operative complications of elective cardiac surgery that was considered unrelated to the study drug. No other patients discontinued the study drug (5).

Although the results will need to be confirmed in a larger phase 3 trial, this study supports the hypothesis that targeting the complement pathway is another useful method to treat patients with IgAN at high risk of disease progression. However, as the authors acknowledge, the trial was conducted prior to the widespread adoption of sodium-glucose cotransporter-2 inhibitors, which have been shown to have a beneficial role in proteinuria reduction for patients with IgAN (6). Regardless, having another potential therapeutic for IgAN is a welcome development for both nephrologists and patients alike.