Ionis and Roche Report Phase 3 Sefaxersen Data Showing Significant Proteinuria Reduction in IgA Nephropathy
Ionis Pharmaceuticals, Inc. and its partner Roche have announced positive late-breaking results from the ongoing Phase 3 IMAgINATION study evaluating investigational sefaxersen in adults with primary immunoglobulin A nephropathy (IgAN). The findings demonstrated a statistically significant and clinically meaningful reduction in proteinuria compared with placebo in patients receiving optimized standard of care, highlighting the potential of sefaxersen as a new treatment option for this chronic and progressive kidney disease.
The results were presented in a late-breaking oral presentation at the American Society of Nephrology (ASN) Kidney Week 2026. At Week 37, sefaxersen achieved a 43.1% reduction in proteinuria relative to placebo, as measured by the 24-hour urine protein-to-creatinine ratio (UPCR). The treatment effect was statistically significant, with a 95% confidence interval (CI) of 32.5% to 52.0% and a p-value of less than 0.0001.
Proteinuria, or the presence of excessive protein in the urine, is an important indicator of kidney damage in people with IgAN. Persistent protein leakage can indicate that the kidneys’ filtering structures are being damaged, potentially contributing to progressive loss of kidney function. Reducing proteinuria is therefore an important therapeutic objective, as improvements in UPCR are strongly associated with the preservation of long-term kidney function.
The findings reinforce the potential of sefaxersen to address a key measure of disease activity in IgAN. In addition to the primary proteinuria endpoint, the study also found that a greater proportion of patients with blood in their urine at baseline achieved resolution of hematuria at Week 37 with sefaxersen compared with placebo.
Significant Reduction in Proteinuria Observed at Week 37
The primary endpoint results from the IMAgINATION study showed that sefaxersen delivered a substantial reduction in proteinuria compared with placebo in adults with primary IgAN who were already receiving optimized standard-of-care treatment.
The 43.1% reduction relative to placebo at Week 37 represents a clinically meaningful improvement in a key marker used to assess kidney damage and monitor disease progression. The statistical significance of the result, reflected in the p-value of less than 0.0001, supports the strength of the observed treatment effect.
The 95% confidence interval, ranging from 32.5% to 52.0%, provides an estimate of the precision of the treatment effect. Together, these findings support further evaluation of sefaxersen as a potential therapy for people whose disease continues to pose a risk to long-term kidney health despite existing treatment.
The results are particularly relevant because IgAN can progress over many years, often leading to irreversible kidney damage. Although current treatment strategies aim to control disease activity and reduce proteinuria, many patients remain at risk of declining kidney function and may eventually require dialysis or kidney transplantation.
By demonstrating a significant reduction in proteinuria on top of optimized standard of care, sefaxersen could potentially contribute to improved disease management. However, whether this improvement translates into sustained preservation of kidney function will require further assessment through the ongoing study.
The IMAgINATION trial is continuing to evaluate longer-term kidney outcomes, allowing investigators to determine whether the observed reduction in proteinuria is accompanied by a meaningful effect on kidney function over time.
Hematuria Findings Provide Additional Evidence of Treatment Activity
Alongside the primary endpoint, the Phase 3 findings included encouraging results for hematuria, another clinical feature associated with IgAN.
Hematuria refers to the presence of blood in the urine and can occur when inflammation or injury affects the kidney’s filtering structures. In people with IgAN, hematuria may be detected through laboratory testing even when blood is not visibly apparent.
Among participants who had hematuria at baseline, a greater proportion of patients receiving sefaxersen achieved resolution of this condition at Week 37 compared with those receiving placebo.
Although the announcement did not provide specific percentages for hematuria resolution, the direction of the findings offers additional evidence of potential clinical activity beyond the primary proteinuria endpoint.
Proteinuria and hematuria are both important features of kidney involvement, although they measure different aspects of the disease. The reduction in proteinuria demonstrated in the primary endpoint, together with the reported improvement in hematuria, supports continued investigation of sefaxersen’s potential role in treating IgAN.
The study results also indicated that the treatment effect across all prespecified subgroups was consistent with the clinically meaningful proteinuria reductions observed in the primary endpoint analysis. This consistency suggests that the benefit was not limited to a single predefined patient subgroup.
Further analyses and longer-term follow-up will help clarify the durability of the treatment effect and the extent to which patients with different baseline characteristics may benefit from treatment.
Ionis Highlights Sefaxersen’s Potential for People Living With IgAN
Brett P. Monia, Ph.D., chief executive officer of Ionis Pharmaceuticals, emphasized the importance of the Phase 3 findings and the potential for sefaxersen to address the needs of people living with IgAN.
According to Monia, the results support the company’s view that sefaxersen could become an important treatment option by delivering significant and clinically meaningful reductions in proteinuria.
He also highlighted the possibility that effective treatment could help reduce the long-term burden of advanced kidney disease, including the potential need for dialysis or kidney transplantation.
Monia described sefaxersen as an example of the broader impact of Ionis’ scientific platform and its approach to developing innovative medicines for serious diseases.
The results represent an important development for Ionis and Roche as they continue evaluating the investigational therapy in a large Phase 3 clinical program. While the Week 37 findings provide encouraging evidence, the companies will need to establish whether the observed benefits translate into sustained improvements in kidney function and long-term clinical outcomes.
For patients, the potential availability of an additional treatment option could be significant, particularly given the progressive nature of IgAN and the risk of kidney failure associated with the condition.
Sefaxersen Designed for Once-Monthly Administration
Sefaxersen is an investigational therapy administered as a once-monthly subcutaneous injection. The treatment is designed to allow self-administration, potentially offering patients a convenient approach to managing a chronic condition that may require long-term treatment and monitoring.
Subcutaneous administration involves injecting a medicine beneath the skin. A once-monthly schedule could reduce the frequency of treatment administration compared with regimens requiring more frequent dosing, although the practical advantages for patients will depend on the final treatment instructions and any applicable regulatory requirements.
The companies have not yet announced a marketing authorization for sefaxersen based on the results described in the announcement. Its safety, efficacy, and long-term clinical benefits remain subject to ongoing evaluation and regulatory review.
The Phase 3 results follow earlier clinical development, including a previously reported Phase 2 study. According to the latest announcement, sefaxersen was well tolerated in the IMAgINATION study, with a safety profile consistent with the earlier Phase 2 findings.
Importantly, the study identified no new safety signals in the reported analysis. This provides additional information about the treatment’s tolerability as development advances.
Nevertheless, continued monitoring will be important to characterize the therapy’s safety profile over longer treatment periods and across a broader patient population. The ongoing blinded study will provide further evidence as patients continue to be followed.
Ongoing Study to Assess Kidney Function Over Two Years
Although the Week 37 results focused on proteinuria and additional findings related to hematuria, the IMAgINATION study is continuing to evaluate the longer-term effect of sefaxersen on kidney function.
The study will remain blinded while investigators assess changes in estimated glomerular filtration rate (eGFR) through Week 105, approximately two years after the relevant baseline assessment.
eGFR is a widely used measure of kidney function that estimates how effectively the kidneys filter waste products from the blood. A sustained decline in eGFR can indicate progressive kidney damage, while maintaining kidney function is a central objective in the management of chronic kidney disease.
The Week 105 assessment is therefore important for determining whether sefaxersen’s reduction in proteinuria is accompanied by a beneficial effect on kidney function over an extended period.
Because proteinuria is a marker rather than a direct measurement of kidney filtration capacity, longer-term data are necessary to establish the extent to which the observed improvement may translate into clinically meaningful benefits.
Roche plans to share the available data with health authorities as the companies work toward potentially bringing sefaxersen to patients as soon as possible. Future regulatory decisions will depend on the complete clinical evidence, the benefit-risk assessment, and the requirements of the relevant authorities.
The continued follow-up may also help provide a clearer understanding of the durability of treatment effects and the potential role of sefaxersen alongside existing approaches to IgAN management.
IgA Nephropathy Remains a Significant Cause of Chronic Kidney Disease
IgA nephropathy, also known as Berger’s disease, is a chronic autoimmune kidney disease characterized by the accumulation of immunoglobulin A (IgA) in the glomeruli, the tiny filtering structures within the kidneys.
These deposits can trigger inflammation and damage the glomeruli, allowing blood and protein to pass into the urine. Over time, persistent inflammation and structural injury can impair the kidneys’ ability to filter waste and maintain normal fluid and electrolyte balance.
The condition is typically diagnosed before the age of 40 and affects at least 25 adults per million worldwide each year, according to the companies’ announcement.
IgAN is the most common form of primary glomerulonephritis and represents a major cause of chronic kidney disease and kidney failure. Its clinical course varies considerably, with some patients experiencing relatively stable disease while others develop progressive loss of kidney function.
The disease can remain undetected for extended periods because symptoms may be mild or absent during its early stages. In other cases, patients may develop blood in the urine, proteinuria, high blood pressure, or signs of declining kidney function.
The announcement notes that IgAN can progress to end-stage kidney disease in up to 50% of patients within 20 years of diagnosis. For those who develop advanced kidney failure, treatment may ultimately involve dialysis or kidney transplantation.
Management generally focuses on controlling blood pressure, reducing proteinuria, slowing kidney function decline, and addressing the underlying disease process. Despite available treatment approaches, a substantial need remains for therapies that can improve disease control and reduce the risk of long-term complications.
The Phase 3 IMAgINATION results place sefaxersen among investigational therapies being evaluated to address this unmet need.
Ionis and Roche Collaboration Supports Further Development
Roche licensed sefaxersen from Ionis for the treatment of complement-mediated diseases. Under the terms of their agreement, Ionis received an upfront payment, a license fee, and development milestone payments.
Ionis is also eligible to receive additional payments tied to regulatory and commercial milestones, together with tiered royalties on net sales of sefaxersen.
The arrangement provides Ionis with the opportunity to benefit from the therapy’s potential future commercialization while Roche advances its development and regulatory strategy.
The latest Phase 3 findings represent an important milestone in the collaboration, providing evidence of a significant effect on proteinuria in adults with primary IgAN receiving optimized standard of care.
As the study progresses toward its Week 105 kidney-function assessment, longer-term results will be critical in establishing the potential clinical value of sefaxersen.
For now, the 43.1% reduction in proteinuria relative to placebo, the additional hematuria findings, and the reported safety profile provide encouraging evidence for the investigational therapy. The next phase of evaluation will determine whether these improvements can be sustained and whether they translate into better long-term outcomes for people living with IgA nephropathy.
About sefaxersen
Sefaxersen, an investigational, highly specific liver-directed antisense oligonucleotide that inhibits factor B production, is the first RNA-targeted therapy for IgA nephropathy (IgAN). Serum complement factor B levels are elevated in people with IgAN. Sefaxersen is designed to provide sustained control of the alternative complement pathway, an important pathway in IgAN, enabling once-monthly subcutaneous dosing and is intended for self-administration in people with IgAN.
About the IMAgINATION Study
IMAgINATION (NCT05797610) is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of subcutaneous sefaxersen, an investigational antisense inhibitor of complement factor B, in patients with primary IgA nephropathy at high risk of progression. The study enrolled 459 people, who are randomized 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 of the study is the change from baseline in the urine protein-to-creatinine ratio at 37 weeks.
About IgA Nephropathy (IgAN)
IgAN, also known as Berger’s disease, is a serious, chronic and progressive autoimmune kidney disease affecting at least 25 adults per million worldwide each year and is typically diagnosed before the age of 40 years. In IgAN, immune complexes deposit in the kidneys, which activates the complement system’s alternative pathway, leading to inflammation and subsequent kidney damage.
It is the most common form of primary glomerulonephritis (inflammation of kidney glomeruli) and remains a leading cause of kidney failure, with up to 50% of patients experiencing end-stage kidney disease within 20 years of diagnosis. Many current therapies aim to reduce protein levels in the urine and control blood pressure to slow progression of the disease.
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, important unmet needs remain, including improved long-term preservation of kidney function and more targeted approaches that address key drivers of disease progression.
About Ionis Pharmaceuticals, Inc.
For more than three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has marketed medicines and a leading pipeline in neurology, cardiometabolic disease and select areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit Ionis.com and follow us on X (Twitter), LinkedIn and Instagram.