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Alternative complement pathway inhibition with iptacopan in IgA nephropathy

| Matt Graham-Brown

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IgA nephropathy is the commonest glomerulonephritis in the Western world. Nephrologists know this, but it is a sentence that has been drilled into my consciousness because I trained and work in Leicester (UK), an international centre of excellence where the breakthrough finding that patients with IgA nephropathy exhibited aberrant O-glycosylation in the hinge region of the IgA molecule was made some 25 years ago.1 (I had nothing to do with this breakthrough!) It struck me as a trainee that, whilst it was great to work in a centre so renowned for its research into IgA nephropathy, it was somewhat depressing that, for most of the last 20 years, the mainstay of treatment had been blood pressure control with drugs that target the renin–angiotensin system – principally ACE inhibitors and angiotensin receptor blockers (ARBs). 

 

The last two decades have seen an increased appreciation and understanding of the pathogenesis of IgA nephropathy.2 The current understanding is multi-factorial, and stems from increased levels of the aberrantly glycosylated circulating IgA1 molecule (probably from the mucosal immune system) generating immune complexes that deposit in the glomeruli, triggering inflammation, complement activation and kidney damage. This increased understanding has provided new targets for treatments. One is the alternative complement pathway, which is thought to play a key role in mediating inflammation and kidney damage. Iptacopan specifically binds to factor B (a single-chain polypeptide in the alternative pathway), ultimately blocking formation of the membrane attack complex. Iptacopan is an oral agent and was shown in a phase 2 study to reduce proteinuria, a key surrogate of important long-term outcomes in IgA nephropathy.3

 

The present study by Perkovic and colleagues4 is a phase 3, multicentre, international, double-blind, placebo-controlled, randomised controlled trial assessing the effects of iptacopan on proteinuria in individuals with IgA nephropathy at risk of progression. To take part in the trial, participants needed to have biopsy-proven IgA nephropathy with <50% tubulointerstitial fibrosis with proteinuria at baseline despite optimal best supportive care. Key to note, participants were required to be vaccinated against Neisseria meningitidis, Streptococcus pneumoniae and (where possible) Haemophilus influenzae, owing to the nature of iptacopan as an inhibitor of the complement pathway. 

 

443 participants were randomised 1:1 to oral iptacopan (200 mg) twice a day or placebo (all in addition to optimised supportive care). The primary end point was change in proteinuria from baseline to 9 months, and the study presents this taken from the interim efficacy analysis, which was built in after the first 250 patients were randomised. Groups were well matched at baseline, 99% were on ACE/ARB therapy and 12.8% were taking an SGLT2 inhibitor. The primary analysis was positive, with iptacopan reducing proteinuria by 38.3% compared to the control group, a finding that was remarkably consistent across subgroups (including age, sex, baseline proteinuria/eGFR, SGLT2 inhibitor use and histological classification). Importantly there were no adverse safety signals. No data were presented on change in kidney function or eGFR slope, but these are expected in subsequent trials.

 

IgA nephropathy must be the disease area in nephrology with the most rapid increase in therapeutic options. In recent years, enteric-coated oral budesonide (Nefecon)5 and a combined endothelin–angiotensin receptor antagonist (Sparsentan)6 have both proved to be effective therapies, targeting different parts of the disease pathway in IgA nephropathy. Now add iptacopan and we really do have multiple options to slow the progression of disease and prevent kidney failure for many. The explosion in therapeutics illustrates the importance of working to define mechanisms of disease to develop targeted interventions. I am so pleased the efforts of so many are finally paying off.

 

A digest of the study can be ready here.

 

References

  1. Allen AC, Bailey EM, Barratt J et al (1999) Analysis of IgA1 O-glycans in IgA nephropathy by fluorophore-assisted carbohydrate electrophoresis. J Am Soc Nephrol 10: 1763–71
  2. Cheung CK, Alexander S, Reich HN et al (2024) The pathogenesis of IgA nephropathy and implications for treatment. Nat Rev Nephrol 4 Sep [Epub ahead of print]
  3. Zhang H, Rizk DV, Perkovic V et al (2024) Results of a randomized double-blind placebo-controlled Phase 2 study propose iptacopan as an alternative complement pathway inhibitor for IgA nephropathy. Kidney Int 105: 189–99
  4. Perkovic V, Barratt J, Rovin B et al (2024) Alternative complement pathway inhibition with iptacopan in IgA nephropathy. N Engl J Med 25 Oct [Epub ahead of print]
  5. Lafayette R, Kristensen J, Stone A et al; NefIgArd trial investigators (2023) Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. Lancet 402: 859–70. Erratum in: Lancet (2023) 402: 850
  6. Heerspink HJL, Radhakrishnan J, Alpers CE et al; PROTECT Investigators (2023) Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial. Lancet 401: 1584–94
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