Ravulizumab cut protein leakage in IgA nephropathy by targeting a different pathway

Ravulizumab, a long-acting antibody that shuts down part of the immune system's complement cascade, reduced protein leakage from the kidneys in people with IgA nephropathy in the interim analysis of the phase 3 I CAN trial [s1]. It is the latest in a run of positive trials in this disease, but it stands apart from the others: where the rest target the B cells and antibodies that start the disease, ravulizumab blocks the inflammatory machinery further downstream [s1].

IgA nephropathy begins when the body makes a faulty form of the antibody immunoglobulin A. Immune complexes built around that antibody settle in the kidney's filtering units and trigger inflammation, leaking protein into the urine and eroding kidney function over years. One of the ways those complexes inflame the kidney is by switching on complement — a cascade of blood proteins that amplifies immune attack. Ravulizumab blocks the complement protein C5, the same target it already hits in rarer blood and neuromuscular disorders, now redirected at the most common primary disease of the kidney's filters [s1]. Repurposing an established drug in this way carries a practical advantage: its safety profile and long-acting, eight-weekly dosing are already well mapped from years of use in those other conditions, so the chief unknown in IgA nephropathy is efficacy rather than tolerability [s1].

What the trial did

I CAN is a randomised, double-blind, placebo-controlled phase 3 trial [s1][s2]. Adults with biopsy-confirmed IgA nephropathy were assigned 1:1 to intravenous ravulizumab or placebo every eight weeks on top of standard care [s1]. In total 485 patients were randomised — 240 to ravulizumab and 245 to placebo — and this prespecified interim analysis covered the first 352 of them, 176 in each group, followed to week 34 [s1]. The primary endpoint was the change in the 24-hour urinary protein-to-creatinine ratio (UPCR), the standard surrogate for disease activity [s1].

What it found

Protein leakage fell on the drug and barely moved on placebo. The geometric mean UPCR on ravulizumab dropped from 1.56 at baseline to 0.83 at week 34 — a reduction of 46.6% — while on placebo it went from 1.60 to 1.48, a fall of just 5.6% [s1]. After statistical adjustment, the ratio was 43.4% lower with ravulizumab than with placebo (99% confidence interval 30.1 to 54.2; P<0.001), a difference comfortably clear of chance [s1].

Safety was reassuring, including on the specific hazard that comes with blocking complement. Adverse events occurred in 69.5% of the ravulizumab group versus 75.8% on placebo, and serious adverse events were less frequent on the drug, at 4.6% versus 9.0% [s1]. Crucially, no meningococcal infections occurred — the signature risk of C5 inhibitors, because complement is central to defence against that bacterium — and there were no deaths [s1].

How to read it

The headline caveat is familiar from the rest of this field: a roughly 43% reduction in proteinuria is a surrogate result, not proof that ravulizumab preserves kidney function. This interim analysis stops at week 34 and covers 352 of the trial's 485 patients, so the measure that matters most — the eGFR slope over the longer haul — is not yet in [s1]. Two other drugs reported exactly that confirmatory eGFR evidence the same week (atacicept and sibeprenlimab); ravulizumab has not reached that stage [s1].

What makes the result interesting despite that is its mechanism. The newest IgA nephropathy drugs cluster around B-cell signalling — APRIL, BAFF, or both, as with povetacicept. Complement inhibition attacks a different link in the chain, which raises the prospect that it could one day be layered on top of a B-cell-directed drug rather than competing with it — two drugs hitting two separate steps of the same disease, in principle additively [s1]. The absence of meningococcal infections in the trial is encouraging, though the eight-weekly intravenous dosing is a heavier commitment than the subcutaneous injections used by several rivals [s1].

What to watch

The full I CAN trial is built to deliver the eGFR data this interim cannot, and that read-out will decide where ravulizumab fits [s1]. The larger strategic question its mechanism poses is whether complement inhibition works best alone or in combination with the B-cell-targeting drugs now crowding the field — a question that will need trials designed specifically to test drugs against and alongside one another [s1]. For now, ravulizumab's contribution is a proof of principle: that quieting the complement cascade, not only the antibody that sets it off, can measurably calm the disease [s1].

This article describes research and is not medical advice. Treatment of IgA nephropathy is a decision for treating clinicians.