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Interim phase III analyses reported statistically significant reductions in proteinuria with povetacicept, ravulizumab and sefaxersen compared with placebo. The results do not yet establish whether the drugs slow long-term kidney-function decline; eGFR follow-up is ongoing.
Interim phase III analyses of three IgA nephropathy drugs found significantly greater reductions in proteinuria than placebo, according to results presented at the American Society of Nephrology Kidney Week meeting. The findings cover investigational povetacicept and sefaxersen, and ravulizumab, which has received FDA accelerated approval; longer-term data are still needed to show whether treatment slows loss of kidney function.
In the RAINIER trial, povetacicept reduced geometric mean 24-hour urine protein-to-creatinine ratio (UPCR) by 52.0% at week 36, compared with 4.3% with placebo. The adjusted difference was 49.8 percentage points in favor of the drug (95% CI 39.2 to 58.6; P<0.001). The prespecified interim efficacy analysis included the first 199 randomized participants; the main trial cohort included 557 adults.
In I CAN, ravulizumab reduced geometric mean UPCR by 46.6% at week 34, while placebo was associated with a 5.6% reduction. The adjusted geometric mean UPCR was 43.4% lower with ravulizumab than placebo (99% CI 30.1 to 54.2; P<0.001). The primary analysis included 352 of the 485 randomized adults who had reached, or would have reached, week 34.
In IMAgINATION, sefaxersen reduced 24-hour UPCR by 46.9% at week 37, compared with 6.6% with placebo. The reported relative reduction versus placebo was 43.1% (95% CI 32.5 to 52.0; P<0.0001). The primary cohort randomized 408 participants. The supplied report does not include further details of sefaxersen’s mechanism or its safety results.
Proteinuria Results Need Longer Follow-Up
Proteinuria is a measure of protein leaking into urine and is used as a surrogate endpoint in IgA nephropathy studies. The results offer evidence that all three treatments affect this disease marker over the reported interim periods. They do not, by themselves, establish that patients will retain kidney function longer or avoid kidney failure.
That distinction matters because a reduction in a surrogate measure is not the same as proof of sustained clinical benefit. The trials are continuing to collect eGFR data, which track kidney filtration over time. Those results are expected to provide evidence about whether the early proteinuria changes correspond to slower kidney-function decline.
The findings also differ in regulatory status. Ravulizumab has FDA accelerated approval to reduce proteinuria in adults with primary IgA nephropathy at risk of rapid progression. Povetacicept remains under FDA review, while the supplied report identifies sefaxersen as an investigational treatment. Interim trial findings should not be read as proof that either investigational drug is approved or that the three treatments have been compared directly.
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Three Trials, Different Treatment Approaches
The studies were presented at the same Kidney Week meeting and each compared a drug with placebo in adults with IgA nephropathy receiving standard or supportive care. They were separate trials, with different participants, treatment schedules and analysis time points. Their reported percentage reductions therefore do not establish which drug works best.
In RAINIER, participants received subcutaneous povetacicept or placebo every four weeks; most were also taking renin-angiotensin system inhibitors, and about two-thirds were taking SGLT2 inhibitors. Povetacicept is described by the study investigators as an investigational fusion protein that inhibits BAFF and APRIL, signaling proteins involved in B-cell activity. Among the interim cohort, 42% of those receiving the drug reached UPCR below 0.5 g/g, compared with 6% on placebo. The trial also reported reductions in galactose-deficient IgA1 and resolution of hematuria in 85% versus 23%.
I CAN tested intravenous ravulizumab, a terminal complement C5 inhibitor, every eight weeks. The report also described changes in hematuria and urinary biomarkers, but these are additional measures and do not replace the pending kidney-function outcomes. The separate IMAgINATION trial tested subcutaneous sefaxersen in people with biopsy-confirmed disease, persistent proteinuria and baseline eGFR of at least 20 mL/min/1.73 m².
“Povetacicept is an investigational TACI fusion protein designed to inhibit both BAFF and APRIL, two cytokines involved in B-cell activation, differentiation, and survival.”
— Richard Lafayette, MD, speaking to MedPage Today
Kidney Function Outcomes Still Pending
The interim findings report proteinuria outcomes, not final evidence that any treatment slows kidney-function decline. RAINIER is continuing toward its primary week-104 endpoint, total eGFR slope. I CAN also requires longer follow-up, with two-year data intended to assess annualized eGFR slope and sustained benefit. The supplied report does not state the corresponding long-term endpoint or timeline for IMAgINATION.
Safety observations are also limited to the periods and participants reported so far. In RAINIER’s overall safety population, adverse events occurred in 75% of povetacicept recipients and 78% of placebo recipients; serious adverse events occurred in 3% and 4%, respectively. Injection-site reactions were reported in 15% versus 2%, and no deaths occurred. In I CAN, adverse events were reported in 69.5% versus 75.8%, and serious events in 4.6% versus 9.0%; no meningococcal infections or treatment-related deaths were reported. These interim figures do not settle longer-term safety.
It is also not clear from the supplied material how sefaxersen performed on safety measures, what its mechanism is, or when its longer-term kidney-function results are expected. The studies were not head-to-head comparisons, and the reported interim percentages should not be used to rank the drugs.
FDA Review and Trial Follow-Up
The next major evidence milestone is the completion of longer follow-up for eGFR slope, the measure used to assess change in kidney filtration over time. RAINIER continues toward its week-104 primary endpoint, while I CAN is expected to report two-year data on annualized eGFR slope. Those outcomes can help determine whether the proteinuria reductions are accompanied by slower decline in kidney function.
The FDA is reviewing povetacicept for accelerated approval, with a target action date of November 30, according to the report. For ravulizumab, the report says continued approval may depend on evidence that it slows kidney-function decline. No regulatory decision or further data release for sefaxersen is specified in the supplied material.
Key Questions
What did the interim analyses find?
Each trial reported a larger reduction in proteinuria with its study drug than with placebo: povetacicept at week 36, ravulizumab at week 34, and sefaxersen at week 37. The trials were separate and cannot be used as direct comparisons between the drugs.
Do the results show that the drugs prevent kidney failure?
No. The reported findings concern proteinuria, a surrogate endpoint. Longer-term eGFR results are still needed to determine whether treatment slows kidney-function decline; the interim analyses do not prove prevention of kidney failure.
Which of the three drugs is approved?
According to the report, ravulizumab has FDA accelerated approval to reduce proteinuria in adults with primary IgA nephropathy at risk of rapid progression. Povetacicept is under FDA review, and sefaxersen is described as investigational.
When will longer-term results be available?
RAINIER is continuing toward its week-104 eGFR endpoint, and I CAN plans to assess two-year kidney-function data. The supplied report does not give a release date for those results or a timeline for IMAgINATION’s longer-term outcomes.
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