Roche's sefaxersen meets primary endpoint in Phase 3 IMAgINATION trial in IgA nephropathy
核心洞察
Roche's investigational antisense oligonucleotide sefaxersen met the primary endpoint of the Phase 3 IMAgINATION study in adults with primary IgA nephropathy (搜索) at 37 weeks.
The prespecified interim analysis showed statistically significant and clinically meaningful reductions in 24-hour urine protein-to-creatinine ratio versus placebo, with no new safety signals.
Roche did not disclose the magnitude of the proteinuria reduction, limiting cross-trial comparison with approved and investigational IgAN therapies.
Roche reported positive prespecified interim results from the ongoing Phase 3 IMAgINATION study of investigational sefaxersen in adults with primary IgA nephropathy (搜索) (IgAN). The trial met its primary endpoint, with sefaxersen producing statistically significant and clinically meaningful reductions in proteinuria versus placebo at 37 weeks, as measured by 24-hour urine protein-to-creatinine ratio (UPCR).
Proteinuria is a key indicator of kidney damage, and a reduction in UPCR is strongly associated with preservation of long-term kidney function. The safety and tolerability profile of sefaxersen was consistent with previously reported data, and no new safety signals were identified.
"These interim phase III results show the clinical potential of sefaxersen to modify a key surrogate endpoint of kidney function in people with IgA nephropathy (搜索)," said Levi Garraway, MD, PhD, Roche's Chief Medical Officer and Head of Global Product Development. "Sefaxersen may therefore offer a new treatment option to help slow disease progression and potentially reduce the long-term need for dialysis or kidney transplantation."
Mechanism and dosing
Sefaxersen is a highly specific, liver-directed antisense oligonucleotide that inhibits production of complement factor B (搜索), blocking a key driver of IgAN-related kidney damage. Roche describes it as the first mRNA-targeted therapy for IgAN. Serum complement factor B levels are elevated in people with IgAN, and reducing these levels in turn reduces urinary protein, a key indicator of improved kidney function.
The agent is designed to provide sustained control of the alternative complement pathway, enabling once-monthly subcutaneous dosing intended for self-administration. In Phase 1 and Phase 2 trials, sefaxersen was generally well tolerated in healthy volunteers and in people with IgAN at high risk of progression, and reduced proteinuria and plasma complement factor B (搜索). Roche licensed sefaxersen from Ionis for the treatment of complement-mediated diseases.
Trial design
IMAgINATION (NCT05797610) is a Phase 3, multicentre, randomised, double-blind, placebo-controlled study evaluating subcutaneous sefaxersen in patients with primary IgAN at high risk of progression. The study enrolled 459 people randomised 1:1 to receive sefaxersen or placebo for 105 weeks. Participants may switch to open-label treatment after week 105 at the investigator's discretion or after the common-close timepoint, whichever occurs first. The primary endpoint is change from baseline in the urine protein-to-creatinine ratio at 37 weeks.
The study will continue as a blinded study to evaluate change in kidney function over two years, measured by estimated glomerular filtration rate (eGFR) at week 105. Interim analysis data will be presented at an upcoming medical congress and shared with health authorities.
Undisclosed effect size in a crowded field
Roche did not disclose the magnitude of the proteinuria reduction in the interim announcement, which precludes cross-trial comparisons at this stage. The company said the data show best-in-class potential.
The efficacy bar in IgAN has risen quickly. Otsuka (搜索)'s APRIL inhibitor sibeprenlimab reduced UPCR by 51.2% versus placebo at nine months in Phase 3, while Vertex's BAFF/APRIL inhibitor povetacicept achieved a 49.8% placebo-adjusted reduction at week 36. Vera Therapeutics' atacicept delivered a 41.8% between-group reduction at week 36. Iptacopan (Fabhalta) received FDA accelerated approval for IgAN in August 2024 on the basis of a 44% proteinuria reduction; Novartis' complement factor B (搜索) inhibitor reduced proteinuria by 38.3% versus placebo at nine months and has since shown significantly slower loss of kidney function over two years.
Sefaxersen silences complement factor B (搜索) at the mRNA level, suppressing the alternative complement pathway upstream of where most approved agents intervene. Whether upstream silencing translates into deeper or more durable proteinuria suppression than existing options is a question the full IMAgINATION dataset will need to answer.
Disease burden and unmet need
IgAN, also known as Berger's disease, is a chronic and progressive autoimmune kidney disease. It is typically diagnosed before the age of 40 and affects at least 25 adults per million worldwide each year. It is the most common form of primary glomerulonephritis and a major cause of chronic kidney disease and kidney failure, with up to 50% of patients progressing to end-stage kidney disease within 20 years of diagnosis, requiring dialysis or transplantation.
In IgAN, immune complexes deposit in the kidneys, activating the complement system's alternative pathway, which leads to inflammation and subsequent kidney damage. Many current therapies aim to reduce urinary protein levels and control blood pressure to slow disease progression.
"For patients and families navigating IgAN, the prospect of kidney failure, dialysis, or transplantation creates overwhelming uncertainty," said Bonnie Schneider, Director and Co-Founder of the IgA Nephropathy (搜索) Foundation. "As someone who has advocated for this community for over two decades, positive results from the IMAgINATION study give us hope that emerging therapies could help preserve kidney function and transform the treatment landscape."
Updated KDIGO 2025 guidelines highlight the need to address both the underlying immune-mediated causes of IgAN and the downstream consequences of kidney damage. While new therapies have expanded treatment options, Roche states that important unmet needs remain, including improved long-term preservation of kidney function and more targeted approaches that address key drivers of disease progression.
The interim read is not the final word on safety or long-term kidney function outcomes. The eventual eGFR trajectory data will matter as much as the proteinuria result for any label claim that goes beyond the accelerated pathway.