The IMAgINATION interim result is a necessary regulatory milestone, not a commercial verdict. Sefaxersen met its prespecified primary endpoint of statistically significant and clinically meaningful UPCR reduction versus placebo at 37 weeks in a Phase 3 RCT — the highest evidence tier available — but the announcement withholds the two figures that determine competitive positioning: the actual percentage reduction in UPCR and any eGFR trajectory data. [1] The study remains blinded for kidney function evaluation over two years, meaning the evidence package is structurally incomplete against the standards that have governed every recent IgAN approval and HTA decision. The most mechanistically confirmed peer in the available evidence is iptacopan (APPLAUSE-IgAN Phase 3 interim), which targets the same biological node — complement Factor B — and achieved a −38.3% UPCR change versus placebo at month 9 globally; iptacopan has already received accelerated FDA approval for IgAN, establishing first-mover advantage with an oral twice-daily formulation. [2][3] Sefaxersen's once-monthly subcutaneous ASO modality is a dosing differentiator but not a clinical one until head-to-head data exist. [4] On the HTA side, every comparable nephropathy assessment reviewed — including AIFA's classification of budesonide's added therapeutic value as 'moderate' on surrogate-only data, NICE's retention of 'considerable uncertainty' for sparsentan's long-term kidney outcomes, and CADTH's consistent application of price-reduction conditions — signals that a UPCR-only interim package will yield a conditional or moderate-value classification at launch. No precedent in the available evidence clears the full mechanistic-fit bar for an ASO targeting Factor B in IgAN, because no such agent has previously been approved; iptacopan is the closest mechanistic peer (same target, same indication, Phase 3 RCT) but is a small molecule, not an ASO, and is already approved. [5] The sharpest risk is that the two-year eGFR data, when unblinded, replicate sparsentan's experience — where the total eGFR slope did not reach statistical significance on the FDA-preferred criterion — leaving sefaxersen with a proteinuria surrogate label in a market where the mechanism is already validated by a first mover. [5][6]
IMAgINATION met its prespecified 37-week UPCR primary endpoint in a Phase 3 RCT, but no UPCR magnitude is disclosed and the two-year eGFR data — the endpoint that determines full approval and HTA classification — remain blinded and unavailable. [6]
| Indication | IgA nephropathy (IgAN) |
| Drug | Sefaxersen |
| Mechanism of Action | Antisense oligonucleotide, Factor B inhibitor |
| Company | Ionis Pharmaceuticals, Inc. |
| Trial Phase | Phase 3 |
| Trial Acronym | IMAgINATION |
| NCT ID | NCT05797610 |
| Category | Clinical Trial Event |
| Sub Category | Interim Analysis |
| Therapeutic Area | Nephrology & Urology |
| Partner Company | Roche |
| Primary Endpoint | Proteinuria reduction |
| Key Outcome Measure | 24-hour urine protein-to-creatinine ratio (UPCR) |
| Timepoint for Primary Endpoint | 37 weeks |
| Full Study Endpoint | Change in kidney function over two years, as measured by estimated glomerular filtration rate (eGFR) at week 105 |
| Patient Population Size | 459 people |
| Comparator | Placebo |
| Dosage Frequency | Once-monthly |
| Administration Route | Subcutaneous injection |
| Regulatory Plans | Data will be shared with health authorities |
Ionis' Sefaxersen Shows Positive Phase 3 Interim Data in IgAN
Ionis Pharmaceuticals, Inc. and partner Roche announced positive prespecified interim results from the ongoing Phase 3 IMAgINATION study evaluating investigational sefaxersen in adults with primary IgA nephropathy (IgAN). The study met its primary endpoint, demonstrating statistically significant and clinically meaningful reductions in proteinuria, measured by 24-hour urine protein-to-creatinine ratio (UPCR), compared to placebo at 37 weeks. Sefaxersen, a once-monthly subcutaneous injection, exhibited a safety and tolerability profile consistent with previously reported data. These findings suggest sefaxersen's potential to slow disease progression and potentially reduce the long-term need for dialysis or kidney transplantation in IgAN patients. The study will continue as blinded to evaluate kidney function over two years.
- The Phase 3 IMAgINATION study achieved its primary endpoint, showing sefaxersen led to statistically significant and clinically meaningful reductions in proteinuria, as measured by 24-hour urine protein-to-creatinine ratio (UPCR), compared to placebo at 37 weeks. This outcome is critical as proteinuria reduction is a key indicator of kidney damage and is strongly associated with the preservation of long-term kidney function in patients with IgA nephropathy.
- Sefaxersen is an investigational, highly specific liver-directed antisense oligonucleotide that inhibits factor B production, making it the first RNA-targeted therapy for IgA nephropathy. It is designed to provide sustained control of the alternative complement pathway, which is crucial in IgAN pathogenesis. The drug offers the convenience of once-monthly subcutaneous self-administration, potentially enhancing patient adherence and quality of life.
- IgA nephropathy (IgAN) is a serious, chronic, and progressive autoimmune kidney disease that typically affects young adults, with up to 50% of patients progressing to end-stage kidney disease within 20 years. The positive interim data for sefaxersen positions it to directly address a primary driver of IgAN-related kidney damage, offering a potential new therapeutic approach to slow disease progression and reduce the long-term need for dialysis or kidney transplantation. The study will continue to evaluate the change in kidney function (eGFR) at week 105.
Addressing Unmet Needs in IgA Nephropathy Treatment
IgA nephropathy presents a complex therapeutic landscape where established treatments carry meaningful limitations and emerging therapies require further validation. The heterogeneity of clinical outcomes makes individual risk stratification challenging, and many clinical trials have been underpowered due to the slowly progressive nature of the disease.
Corticosteroid safety concerns: Full-dose methylprednisolone was associated with a significant excess of serious adverse events in the TESTING trial, including serious infections in 8.1% of the methylprednisolone group vs. 0% in the placebo group, leading to early trial termination. While a reduced-dose regimen improved the safety profile, concerns regarding adverse events continue to limit corticosteroid use to selected high-risk patients, consistent with KDIGO 2021 guidance recommending restriction of CS therapy to those who accept the high risk of adverse events.
Uncertainty around RAS inhibition in advanced CKD: The benefit of ACEI/ARB therapy in stage 4 CKD remains debated. In patients with a baseline eGFR of 15–20 ml/min/1.73 m², all six patients in one cohort reached ESRD with a median renal survival time of 7.0 months regardless of treatment, underscoring the limited therapeutic window at this disease stage. Use of ACEI/ARB requires careful monitoring of serum creatinine and potassium levels.
Limited long-term RCT evidence for non-immunosuppressive therapies: A Cochrane review of 80 studies (4,856 participants) found that available RCTs were few, small, and of insufficient duration to determine long-term benefits on kidney and cardiovascular outcomes. While RAS inhibition probably decreases proteinuria (MD −0.71 g/24 h, 95% CI −1.04 to −0.39; moderate certainty evidence), evidence for reduction in kidney failure or complete proteinuria remission remains of low certainty.
Proteinuria remission as an underachieved target: Data from the PROTECT trial highlight that only 21% of patients achieved complete remission of proteinuria (urine protein excretion <0.3 g/day) at any point up to Week 110, despite active treatment. Non-CR patients experienced a rate of eGFR decline of −4.2 mL/min/1.73 m²/year vs. −0.7 mL/min/1.73 m²/year in CR patients, and 14% of non-CR patients reached the composite kidney endpoint vs. 1% of CR patients — underscoring the gap between current treatment efficacy and the proteinuria targets associated with kidney function preservation.
Generalisability gaps in tonsillectomy evidence: Tonsillectomy data demonstrating increased remission of proteinuria (RR 1.90, 95% CI 1.45 to 2.47) and haematuria (RR 1.93, 95% CI 1.47 to 2.53) derive exclusively from Japanese patient populations, limiting applicability to broader IgAN populations and precluding wide recommendation given the potential harms of surgery.
Emerging therapies still under investigation: Novel agents targeting B cell activation, the alternative complement cascade, and the endothelin system — including iptacopan, evaluated in the Phase 3 APPLAUSE-IgAN study — show promise but have not yet established long-term efficacy and safety profiles sufficient for standard-of-care adoption.
IMAgINATION Study: Sefaxersen's Positive Interim Data in IgAN
Several landmark trials have shaped the evidence base for IgA nephropathy management, spanning supportive care, dual receptor antagonism, and surrogate endpoint validation. The studies below represent a range of designs — from prospective interventional cohorts to randomised phase 3 trials — each contributing distinct data on proteinuria reduction, eGFR trajectory, and hard kidney outcomes.
| Study | Design | Population | Intervention(s) | Primary Endpoint | Key Secondary Endpoints |
|---|---|---|---|---|---|
| PROTECT (Phase 3) | Double-blind, randomised, active-controlled; 134 sites, 18 countries; 110 weeks | Adults ≥18 years, biopsy-proven primary IgAN, proteinuria ≥1.0 g/day despite maximised RAS inhibition ≥12 weeks | Sparsentan 400 mg oral once daily vs. irbesartan 300 mg oral once daily | Change in proteinuria between treatment groups at 36 weeks | eGFR slope (chronic and total 2-year); composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality); safety and tolerability to 110 weeks |
| APPROACH (Prospective Cohort) | Prospective observational; 6-month follow-up | Treatment-naive IgAN patients, urinary protein ≥1 g/day, eGFR ≥30 ml/min per 1.73 m² | ACEi (ramipril) or ARB (losartan) with BP target ≤130/80 mm Hg | Remission of proteinuria (CR: <0.5 g/day; PR: <1 g/day with ≥50% decline from baseline and ≤25% eGFR reduction) | Tolerability and discontinuation rates; predictors of remission failure |
| RAS Inhibition in Stage 4 CKD (Retrospective Cohort) | Retrospective; immunohistochemistry analysis; median follow-up 25.5 months | 50 IgAN patients with biopsy during stage 4 CKD (eGFR 15–30 ml/min/1.73 m²), 2010–2020 | ACEI or ARB vs. no RAS blockade | Composite of ESRD and death | Renal survival time; RAS receptor expression (AT1R, AT2R, MasR, MrgD) in stable vs. progressive groups |
| Individual-Patient Meta-analysis (RCT Pool) | Individual-patient meta-analysis; 11 randomised trials | 830 IgAN patients; baseline and ~9-month proteinuria measurements, ≥1 further year follow-up for clinical outcome | RAS blockade, fish oil, immunosuppression, steroids | 9-month change in proteinuria as surrogate for clinical outcome | Doubling of serum creatinine, ESRD, or death; proportion of treatment effect on clinical outcome explained by proteinuria change |
| J-CKD-DB-Ex (Retrospective Observational) | Retrospective; real-world database (Japan); mean observation ~2,040 days | Adult IgAN patients, baseline UPCR ≥0.5 g/gCr, eGFR ≥30 mL/min/1.73 m² | ≥30% UPCR reduction at 9–12 months vs. no such reduction | Composite of 40% eGFR decline from baseline or onset of CKD stage G5 | Annual eGFR slope; association between magnitude of UPCR reduction and eGFR trajectory |
| J-IGACS (Cohort Study) | Prospective cohort; joint modelling of longitudinal and survival data; median follow-up 6 years | 937 biopsy-confirmed IgAN patients (mean age 39 years; 51% male) | Longitudinal eGFR slope assessment | Composite kidney outcome: ≥40% eGFR decline or initiation of kidney replacement therapy | Hazard ratio per 1-SD eGFR slope decrease; sensitivity analyses in treated patients and those with ≥5 eGFR measurements |
| TCM-WINE (RCT Protocol) | Single-centre, prospective, double-blind, randomised, placebo-controlled; 48-week treatment + follow-up to 3 years | 60 participants with biopsy-proven high-risk IgAN (massive proteinuria and renal dysfunction) | Yi-Qi-Qing-Jie formula (YQF) + prednisolone (± cyclophosphamide) vs. placebo-YQF + prednisolone (± cyclophosphamide) | Composite: first occurrence of 40% eGFR decrease lasting ≥3 months, initiation of continuous renal replacement therapy, or CKD-related death over 3 years | Mean annual eGFR decline rate (eGFR slope); proteinuria remission (<0.5 g/day) at weeks 24, 36, and 48; symptom and inflammation remission rate at week 48 |
Targeting the Alternative Complement Pathway in IgAN with Sefaxersen
The genetic architecture of IgAN is polygenic and complex, with nearly 20 genome-wide significant loci of small-to-moderate effect identified to date. Key susceptibility loci include regions on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2), Chr.1q32 (CFHR3/R1), and Chr.22q12 (HORMAD2), alongside novel associations at ST6GAL1 on 3q27.3, ACCS on 11p11.2, ODF1-KLF10 on 8q22.3, ITGAX-ITGAM on 16p11.2, and multiple independent signals within the DEFA locus. A seven-SNP genetic risk score explains 4.7% of overall IgAN risk and correlates with the known East-West gradient in disease prevalence. Genetic variants in MBL2 influence mannose-binding lectin (MBL) serum levels and complement system activation, with the MBL2 "O" allele associated with reduced event-free survival and increased alternative pathway (AP) activity. A significant genetic interaction has also been identified whereby the odds ratio for the HORMAD2 protective allele is reversed in homozygotes for a CFHR3/R1 deletion.
At the molecular level, IgAN pathogenesis is anchored in the "multi-hit hypothesis," in which aberrantly glycosylated galactose-deficient IgA1 (Gd-IgA1) serves as the central autoantigen. Abnormal B-cell glycosylation pathways produce Gd-IgA1, which is recognised by autoantibodies to form immune complexes amplified in size by the soluble IgA Fc receptor CD89, leading to mesangial deposition. APRIL (a proliferation-inducing ligand) and BAFF (B-cell activating factor) are key cytokines controlling B-cell development and differentiation of antibody-secreting cells, with APRIL and IL-6 synergistically, as well as independently, enhancing Gd-IgA1 synthesis. TLR9 activation further drives this process: injection of the TLR9 ligand CpG-oligonucleotides increases production of aberrantly glycosylated IgA and IgG-IgA immune complexes, elevates serum APRIL, and exacerbates kidney injury. At the cellular level, transglutaminase 2 (TGase2) is transported from the cytosol to the membrane of human mesangial cells through a RhoA-mediated vesicle-trafficking pathway, facilitating polymeric IgA1 interaction with the mesangium. Glomerular MBL deposition, observed in a predominantly mesangial pattern, activates the lectin complement pathway and is associated with more severe proteinuria, decreased renal function, and a lower renal remission rate.
Disease progression is driven by intrarenal inflammation initiated by immune complex deposition and complement activation across four principal cell types in the nephron. In mesangial cells, Gd-IgA1 deposition triggers enhanced cellular proliferation, extracellular matrix expansion, and inflammatory cytokine production. Mesangial-endothelial crosstalk results in hyperpermeability of the endothelium, loss of endothelial barrier proteins, and recruitment of inflammatory cells. Podocyte damage, mediated through mesangial-podocyte crosstalk involving TNF-α, TGF-β, the renin-angiotensin-aldosterone system (RAAS), and micro-RNAs, drives podocyte apoptosis and disorganisation of the slit diaphragm, contributing to proteinuria; podocyte density (Nv) at biopsy significantly correlates with proteinuria progression rate, with the podocytopenic group showing a significantly higher progression rate than the normopodocytic group. Tubular epithelial cell injury is mediated by filtered proteins entering the tubulointerstitium, mesangial-tubular crosstalk, and, innovatively, retinoic acid. Complement C5b-9 activation in mesangial and subepithelial areas, inversely correlated with the number of WT-1-positive podocytes, further contributes to podocyte damage. The mucosal immune system and a proposed "gut-kidney axis," including microbiota composition and nutritional status, are also implicated in triggering and modulating these intrinsic mesangial cell pathways.
Sefaxersen's Potential to Reshape the IgA Nephropathy Landscape
The treatment landscape for IgA nephropathy has undergone a marked transformation, moving beyond traditional supportive care — blood pressure control and renin-angiotensin system (RAS) blockade — toward a growing portfolio of targeted, disease-modifying therapies. Two agents have achieved particular clinical prominence. Sparsentan, a single-molecule dual endothelin angiotensin receptor antagonist, demonstrated in the phase 3 PROTECT trial (NCT03762850) that 110 weeks of treatment produced a 40% lower proteinuria versus irbesartan (geometric least-squares mean ratio 0.60, 95% CI 0.50 to 0.72), a significantly slower chronic eGFR slope (−2.7 vs. −3.8 mL/min/1.73 m² per year; difference 1.1 mL/min/1.73 m² per year, 95% CI 0.1 to 2.1; p=0.037), and a composite kidney failure event rate of 9% versus 13% in the irbesartan arm. Nefecon (targeted-release budesonide), evaluated in the phase 3 NefIgArd trial (NCT03643965), delivered a statistically significant treatment benefit in the time-weighted average eGFR over 2 years versus placebo (difference 5.05 mL/min/1.73 m², 95% CI 3.24 to 7.38; p<0.0001), supporting its full FDA approval to reduce loss of kidney function.
Beyond these approved agents, the mechanistic frontier has expanded substantially. Atacicept, a fully humanized fusion protein that inhibits both BAFF and APRIL — key drivers of pathogenic galactose-deficient IgA1 (Gd-IgA1) production — demonstrated sustained reductions in Gd-IgA1 (−66%±2%), UPCR (−52%±5%), and hematuria (−75%; 95% CI −87 to −59) over 96 weeks in an open-label extension study (ORIGIN 3, NCT04716231), with a mean annualized eGFR slope of −0.6±0.5 mL/min/1.73 m². Complement pathway inhibitors, agents targeting B-cell and plasma cell biology (including felzartamab and narsoplimab), and SGLT2 inhibitors have also entered the investigational and real-world evidence space. Real-world data on sparsentan in combination with SGLT2 inhibitors showed a sustained relative reduction in UPCR of 61% (45–95) at 1-year follow-up, with a median chronic eGFR slope of −1.5 mL/min/1.73 m² per year, even in patients already receiving SGLT2 inhibitor therapy.
A post hoc analysis of PROTECT further reinforced the clinical importance of deep proteinuria suppression: patients achieving complete remission (urine protein excretion <0.3 g/day) at any point through Week 110 had a smaller absolute eGFR change (−4.0 vs. −8.6 mL/min/1.73 m²), a slower rate of eGFR decline (−0.7 vs. −4.2 mL/min/1.73 m²/year), and only 1% reached the composite kidney endpoint versus 14% of non-remission patients. Collectively, these data reflect a paradigm shift toward proteinuria-guided, mechanism-specific treatment strategies in IgAN, though the field continues to face challenges including the absence of head-to-head trials across novel agents, limited long-term safety data, and affordability considerations.
Sefaxersen's Positive Phase 3: A New Horizon for IgA Nephropathy
The recent announcement of positive interim Phase 3 results for sefaxersen in IgA nephropathy marks a pivotal moment for patients grappling with this progressive kidney disease. By demonstrating statistically significant and clinically meaningful reductions in proteinuria, sefaxersen, a novel antisense oligonucleotide (ASO) targeting complement factor B, reinforces the critical role of the alternative complement pathway in IgAN pathogenesis. This targeted approach offers a promising avenue for disease modification, moving beyond the current landscape of therapies that often carry significant side effects or offer more generalized nephroprotection.
The success of sefaxersen not only brings a potential new treatment closer to patients but also further validates the broader ASO platform for addressing complex chronic conditions. This could unlock future development opportunities for similar precision therapies in other complement-mediated or renal diseases. However, the journey is not without its considerations. While proteinuria reduction is a strong indicator, the full two-year study will be crucial in demonstrating sustained improvements in kidney function, as long-term eGFR stabilization is the ultimate goal for patients and a key factor for regulatory and payer acceptance.
Furthermore, the safety profile of ASOs, including observations of transient transaminase elevations with sefaxersen in earlier studies and other ASOs, will require continued vigilance. The IgAN therapeutic space is also rapidly evolving, with other complement inhibitors and established agents vying for market share. Sefaxersen's once-monthly subcutaneous administration and specific mechanism of action will need to be clearly articulated to differentiate it in this competitive environment. Ultimately, these positive results offer substantial hope, but the full clinical picture and market positioning will become clearer as the study progresses and the long-term data emerges.
Frequently Asked Questions
References
- [1] Barratt J, Kristensen J et al.. Insights on Nefecon(®), a Targeted-Release Formulation of Budesonide and Its Selective Immunomodulatory Effects in Patients with IgA Nephropathy. Drug design, development and therapy. 2024. 39100224
- [2] Cheung CK, Barratt J et al.. Targeting APRIL in the treatment of glomerular diseases. Kidney international. 2024 Nov. 39182759
- [3] Kiryluk K, Li Y et al.. Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis. PLoS genetics. 2012. 22737082
- [4] Zhao YY. Metabolomics in chronic kidney disease. Clinica chimica acta; international journal of clinical chemistry. 2013 Jun 25. 23570820
- [5] Inker LA, Mondal H et al.. Early Change in Urine Protein as a Surrogate End Point in Studies of IgA Nephropathy: An Individual-Patient Meta-analysis. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2016 Sep. 27032886
- [6] Heerspink HJL, Rovin BH et al.. Association between Complete Proteinuria Remission and Kidney Function in the Phase 3 PROTECT Trial of Sparsentan in IgA Nephropathy. Clinical journal of the American Society of Nephrology : CJASN. 2026 Apr 1. 41428405
- [7] Coppo R. Treating IgA Nephropathy: Looking at the Future Without Forgetting the Past. Journal of clinical medicine. 2025 Jun 7. 40565795
- [8] Makita Y, Suzuki H et al.. TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6-mediated pathways in IgA nephropathy. Kidney international. 2020 Feb. 31748116
- [9] Rovin BH, Barratt J et al.. Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial. Lancet (London, England). 2023 Dec 2. 37931634
- [10] Lafayette R, Kristensen J et al.. Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial. Lancet (London, England). 2023 Sep 9. 37591292
- [11] Barratt J, Barbour SJ et al.. Long-Term Results from an Open-Label Extension Study of Atacicept for the Treatment of IgA Nephropathy. Journal of the American Society of Nephrology : JASN. 2025 Apr 1. 39462308
- [12] Kim D, Wong MG. Corticosteroid Therapy in Immunoglobulin A Nephropathy: A Friend or Foe?. Kidney & blood pressure research. 2023. 36972570
- [13] Ghaddar M, Barratt J et al.. An update on corticosteroid treatment for IgA nephropathy. Current opinion in nephrology and hypertension. 2023 May 1. 36866805
- [14] Maixnerova D, Tesar V. Emerging role of monoclonal antibodies in the treatment of IgA nephropathy. Expert opinion on biological therapy. 2023 May. 37183663
- [15] Alroshodi A. Recent Advances in the Management of IgA Nephropathy: From Supportive Care to Targeted Therapies. Cureus. 2026 Jun. 42368239
- [16] Li M, Foo JN et al.. Identification of new susceptibility loci for IgA nephropathy in Han Chinese. Nature communications. 2015 Jun 1. 26028593
- [17] Zhang Y, Hu YT et al.. Corticosteroids in the treatment of IgA nephropathy: lessons from the TESTING trial. Pediatric nephrology (Berlin, Germany). 2023 Oct. 36881171
- [18] Xu L, Yang HC et al.. Podocyte number predicts progression of proteinuria in IgA nephropathy. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2010 Sep. 20495534
- [19] Zhang H, Deng Z et al.. Molecular insight in intrarenal inflammation affecting four main types of cells in nephrons in IgA nephropathy. Frontiers in medicine. 2023. 36968836
- [20] Reily C, Novak J et al.. The Roles of A Proliferation-Inducing Ligand (APRIL) and B-Cell Activating Factor (BAFF) in IgA Nephropathy. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2026 May. 41794353
Contact Us
Address
One Research Ct, Suite 450
Rockville, MD 20850
For General Inquiry
info@pienomial.com
