As reported on PharmaBiz, Roche has reported positive interim findings from the phase 3 IMAgINATION trial evaluating sefaxersen in adults with primary immunoglobulin A nephropathy (IgAN) who are at high risk for disease progression.

In the prespecified analysis, sefaxersen met the study’s primary endpoint by producing a statistically significant and clinically meaningful reduction in proteinuria compared with placebo at week 37. The endpoint was assessed using 24-hour urine protein-to-creatinine ratio (UPCR), an important marker of kidney damage that is associated with longer-term renal outcomes.

The company also reported that sefaxersen’s safety and tolerability were consistent with findings from earlier clinical studies, with no new safety signals identified in the interim analysis.

The phase 3 trial remains ongoing and will assess whether treatment affects kidney function over a longer period. A key evaluation at week 105 will examine changes in estimated glomerular filtration rate (eGFR), a measure used to track kidney function.

Targeting the Complement Pathway in IgAN

Sefaxersen is an investigational antisense oligonucleotide designed to reduce production of complement factor B in the liver. Factor B is involved in the alternative complement pathway, which is believed to contribute to inflammation and kidney injury in IgAN.

Elevated serum levels of complement factor B have been observed in people with the disease. By suppressing factor B production at the messenger RNA level, sefaxersen is intended to provide sustained inhibition of the alternative complement pathway and, in turn, reduce proteinuria.

The treatment is administered by subcutaneous injection once monthly and is being developed for patient self-administration.

Earlier phase 1 and 2 research found that sefaxersen was generally well tolerated in healthy participants and in people with IgAN at elevated risk of progression. Those studies also demonstrated reductions in proteinuria and plasma complement factor B.

Roche licensed sefaxersen from Ionis for development in complement-mediated diseases.

IMAgINATION Study Enrolls 459 Participants

IMAgINATION (NCT05797610) is a multicenter, randomized, double-blind, placebo-controlled phase 3 study enrolling adults with primary IgAN who are considered at high risk for progression.

A total of 459 participants were randomized 1:1 to receive either subcutaneous sefaxersen or placebo for 105 weeks. The primary endpoint assesses change from baseline in UPCR at week 37.

Although the primary proteinuria endpoint has now been met in the interim analysis, the blinded portion of the study is continuing to investigate longer-term kidney outcomes. Change in eGFR will be assessed at week 105.

Under the study design, participants may transition to open-label treatment after week 105 at the investigator’s discretion or following the trial’s common-close time point, whichever comes first.

Roche said results from the interim analysis are expected to be presented at a medical congress and shared with regulatory authorities.

IgA Nephropathy Remains a Major Cause of Kidney Failure

IgAN, sometimes called Berger disease, is a chronic, progressive autoimmune kidney disorder in which immune complexes accumulate in the kidneys. Their deposition can activate the alternative complement pathway, triggering inflammation and kidney damage.

The disease is the most common form of primary glomerulonephritis and is an important cause of chronic kidney disease and kidney failure. According to the information supplied by Roche, up to half of patients may progress to end-stage kidney disease within 20 years of diagnosis.

IgAN is often diagnosed before age 40, meaning patients can face decades of disease management and the possibility of eventually requiring dialysis or kidney transplantation.

Reducing proteinuria is consequently an important therapeutic objective. However, longer-term preservation of renal function remains a central issue in determining the clinical impact of emerging treatments.

Updated KDIGO 2025 guidance has highlighted a treatment approach that considers both the immune processes responsible for IgAN and the subsequent consequences of kidney injury. Despite expansion of the therapeutic landscape, the need remains for treatments capable of more effectively preserving kidney function over the long term and targeting biological mechanisms that contribute to progression.

The ongoing eGFR evaluation in IMAgINATION will therefore provide important additional information about sefaxersen beyond its demonstrated effect on proteinuria.

A Potential New Treatment Approach

The interim findings support the potential of complement factor B inhibition as a therapeutic strategy in IgAN. Sefaxersen’s once-monthly administration and design for self-injection could also differentiate it from some approaches to chronic kidney disease management.

However, the current findings are interim results from an ongoing clinical trial, and sefaxersen remains investigational. Longer-term data, including the week-105 assessment of kidney function, will be important for establishing the therapy’s overall benefit-risk profile and potential role in IgAN treatment.