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Interim phase III analyses presented at the American Society of Nephrology Kidney Week meeting found significant reductions in proteinuria with povetacicept, ravulizumab and sefaxersen compared with placebo. The findings are early efficacy results based on a surrogate measure; longer-term eGFR data are still needed to show whether the drugs slow kidney-function decline.
Interim analyses from three phase III IgA nephropathy trials found that povetacicept, ravulizumab and sefaxersen reduced proteinuria more than placebo, according to results presented at the American Society of Nephrology’s Kidney Week meeting. The results add evidence about treatments for the kidney disease, but the studies have not yet established whether the reductions will translate into slower long-term loss of kidney function.
In the RAINIER trial, the geometric mean 24-hour urinary protein-to-creatinine ratio (UPCR) fell 52.0% with povetacicept by week 36, compared with 4.3% with placebo. The adjusted difference was 49.8 percentage points (95% confidence interval 39.2 to 58.6 percentage points in favor of treatment; P<0.001). The interim efficacy analysis covered the first 199 randomized participants in the trial’s main cohort. The overall cohort includes 557 adults receiving stable supportive care.
In I CAN, ravulizumab reduced geometric mean UPCR by 46.6% at week 34, compared with 5.6% with placebo. The adjusted geometric mean UPCR was 43.4% lower with ravulizumab (99% confidence interval 30.1% to 54.2%; P<0.001). The analysis included 352 participants who had reached, or would have reached, week 34. Ravulizumab has already received FDA accelerated approval to reduce proteinuria in adults with primary IgA nephropathy at risk of rapid progression.
In IMAgINATION, sefaxersen lowered UPCR by 46.9% at week 37, versus a 6.6% reduction with placebo. The reported relative reduction compared with placebo was 43.1% (95% confidence interval 32.5% to 52.0%; P<0.0001). The primary cohort randomized 408 participants to sefaxersen or placebo on top of standard care. The supplied trial report does not provide further details about the drug’s mechanism or safety findings.
Proteinuria Falls, Kidney Outcomes Pending
Proteinuria is excess protein in the urine and is used as a measure of kidney damage. The trial investigators described its reduction as a commonly used, validated surrogate endpoint for assessing IgA nephropathy treatments. That makes these interim results relevant to patients and clinicians weighing options for a disease that can progressively damage the kidneys.
But a change in this marker is not the same as proof that treatment preserves kidney function over time. The trials are still expected to provide eGFR slope data, which track changes in the kidneys’ filtering capacity. For ravulizumab, continued approval may depend on evidence that it slows kidney-function decline. The results therefore offer encouraging interim efficacy signals, not a final account of long-term benefit.
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Three Different Treatment Approaches
The studies examined drugs with different targets and schedules. Povetacicept is an investigational fusion protein designed to inhibit BAFF and APRIL, two signaling proteins involved in B-cell activity. In RAINIER, participants received a subcutaneous dose every four weeks; 97% were taking renin-angiotensin system inhibitors and 66% were taking SGLT2 inhibitors as background care.
Ravulizumab blocks terminal complement protein C5 and was given by intravenous infusion every eight weeks in I CAN. The report also described changes in hematuria and urinary biomarkers in that trial. Sefaxersen was tested by subcutaneous injection in IMAgINATION among people with biopsy-confirmed disease, persistent proteinuria and an eGFR of at least 20 mL/min/1.73 m².
RAINIER’s interim analysis also reported that 42% of povetacicept recipients, compared with 6% on placebo, reached UPCR below 0.5 g/g. Hematuria resolved in 85% versus 23%, respectively. In the overall safety population, adverse events occurred in 75% with povetacicept and 78% with placebo; serious adverse events occurred in 3% and 4%. Injection-site reactions were reported in 15% and 2%, nearly all mild, and there were no deaths.
“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
Long-Term Kidney Benefit Still Uncertain
The interim analyses report proteinuria changes, not completed evidence that any of the treatments slows kidney-function decline. The trials’ longer-term eGFR results are still pending, and the available report does not give the full set of safety and efficacy findings for sefaxersen. Interim data also cannot answer every question about how effects may hold up over time or apply across the wider population of people with IgA nephropathy.
For povetacicept, the report says the FDA is reviewing an application for accelerated approval, with a target action date of November 30. The year is not specified for that date in the supplied material. Ravulizumab’s accelerated approval is in place, but the report says continued approval may depend on confirmation of slowed kidney-function decline. No corresponding regulatory status for sefaxersen is provided.
Follow-Up Results and FDA Review
RAINIER will continue toward its primary week-104 endpoint, which measures total eGFR slope. I CAN is also expected to generate two-year data on annualized eGFR slope to test whether ravulizumab’s proteinuria reduction accompanies sustained clinical benefit. Those longer-term results will help clarify whether the interim signal predicts preservation of kidney function.
The next developments to watch are the completion and reporting of those follow-up analyses, along with the FDA’s decision on povetacicept. For ravulizumab, the confirmatory evidence will matter to the status of its accelerated approval. The source material does not give a timeline for the next IMAgINATION results, so the timing of additional sefaxersen data remains unclear.
Key Questions
What did the three interim analyses find?
Each reported a greater reduction in urinary protein-to-creatinine ratio with the study drug than with placebo: povetacicept at week 36, ravulizumab at week 34 and sefaxersen at week 37.
Do the results prove the drugs slow kidney disease?
No. The reported findings concern proteinuria, a surrogate measure. Longer-term eGFR results are still needed to establish whether treatment slows loss of kidney function.
Which drug already has FDA accelerated approval?
Ravulizumab has accelerated approval to reduce proteinuria in adults with primary IgA nephropathy who are at risk of rapid progression. Povetacicept is under FDA review, while the supplied report does not state sefaxersen’s regulatory status.
When will longer-term results be available?
The report says RAINIER is continuing toward its week-104 eGFR endpoint and I CAN will assess two-year eGFR slope, but it gives no publication dates for those findings. It also does not specify a timeline for further IMAgINATION results.
Source: rss
