sefaxersen (RG6299) / Ionis, Roche - LARVOL DELTA

PHARMACOKINETICS, PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF SEFAXERSEN IN CHINESE HEALTHY PARTICIPANTS: A RANDOMIZED, OPEN-LABEL, PARALLEL-GROUP, PHASE 1 STUDY (ISN-WCN 2026) - "A single dose of sefaxersen 40 mg or 70 mg reduced plasma FB level for up to 90 days, with the 70 mg dose resulting in a greater degree of reduction in plasma FB level. Sefaxersen was found to be generally safe and well tolerated by the study participants.Download: Download high-res image (164KB)Download: Download full-size imageDownload: Download high-res image (131KB)Download: Download full-size imageDownload: Download high-res image (172KB)Download: Download full-size imageI have potential conflict of interest to disclose.Employee of Roche Products Limited, UKI did not use generative AI and AI-assisted technologies in the writing process."

Clinical • P1 data • PK/PD data • Glomerulonephritis • IgA Nephropathy • CFB

POPULATION PK/PD MODELING TO ASSESS ETHNIC SENSITIVITY IN THE CLINICAL DEVELOPMENT OF SEFAXERSEN (ISN-WCN 2026) - P3 | "These findings indicate that ethnicity had no clinically meaningful impact on the PK or PD of sefaxersen, supporting consistent exposure–response relationships across populations.Conclusion Sefaxersen had comparable PK and PD profiles in Asian and non-Asian participants. These results confirm the global applicability of the 70 mg regimen (Days 1, 15, and 29, then every 4 weeks) currently being evaluated in the Phase 3 'IMAgINATION' study in IgAN (NCT05797610).I have potential conflict of interest to disclose.Employee of Roche Products LimitedI did not use generative AI and AI-assisted technologies in the writing process."

Clinical • PK/PD data • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Glomerulonephritis • IgA Nephropathy

EVALUATION OF PATHOPHYSIOLOGY BIOMARKERS IN KIDNEY BIOPSIES COLLECTED IN IMAGINATION, A PHASE 3 STUDY OF SEFAXERSEN IN PATIENTS WITH IGA NEPHROPATHY (ISN-WCN 2026) - P2, P3 | "In addition to blood and urine biomarkers, optional kidney biopsy samples will be collected at baseline, Week 37, and Week 105 for histopathology assessments including MEST-C score, complement and immune complex deposition, and exploratory biomarkers of inflammation and fibrosis.Results Characterization of baseline and post-treatment kidney tissue biomarkers and their concordance with blood/urine biomarkers and disease progression are expected upon study completion.Conclusion The assessment of blood, urine and tissue pathophysiology biomarkers in the placebo-controlled IMAgINATION study of sefaxersen may uniquely support the understanding of systemic and in situ drug mechanism of action, disease modification, and association with disease progression in patients with IgAN.This abstract was also submitted for the ASN Kidney Week 2025 congress. By submitting the abstract to WCN 2026, abstract authors declare that re-submitting the abstract is permitted by the..."

Biomarker • Biopsy • Clinical • P3 data • Fibrosis • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammation • Renal Disease

The expanding role of complement inhibitors in the treatment of IgA nephropathy. (PubMed, Kidney Int) - "reported promising phase 2 results of sefaxersen, an antisense inhibitor of Factor B, showing reduced proteinuria, improved hematuria, and sustained alternative-pathway inhibition. Nonetheless, as the therapeutic landscape expands, advancing precision medicine in IgA nephropathy will require defining appropriate patient profiles and predictors of therapeutic response to guide individualized treatment."

Journal • Glomerulonephritis • IgA Nephropathy • Renal Disease

A single-arm phase 2 trial of an investigational RNA therapeutic to complement factor B sefaxersen for treatment of IgA nephropathy. (PubMed, Kidney Int) - P2 | "Sefaxersen inhibited complement alternative pathway activity in patients with IgAN and reduced proteinuria with stable eGFR. Our findings support further evaluation of sefaxersen as a new therapy for IgAN in the Phase 3 IMAGINATION trial."

Journal • P2 data • Glomerulonephritis • IgA Nephropathy • Inflammation • Renal Disease • CFB

Evaluation of Pathophysiology Biomarkers in Kidney Biopsies Collected in IMAgINATION, A Phase 3 Study of Sefaxersen in Patients with IgAN (KIDNEY WEEK 2025) - P2, P3 | "The assessment of blood, urine and tissue pathophysiology biomarkers in the placebo-controlled IMAgINATION study of sefaxersen may uniquely support the understanding of systemic and in situ drug mechanism of action, disease modification, and association with disease progression in patients with IgAN."

Biomarker • Biopsy • Clinical • P3 data • Fibrosis • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammation • Renal Disease

Pharmacokinetic/Pharmacodynamic Modeling to Support 70 mg Sefaxersen Dose Selection for Phase 3 (IMAgINATION) in IgAN (KIDNEY WEEK 2025) - P3 | "Conclusion These results support the 70 mg regimen (Days 1, 15, and 29, then every 4 weeks) for Phase 3 IMAgINATION in IgAN. This study has been initiated with this regimen."

P3 data • PK/PD data • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Glomerulonephritis • IgA Nephropathy • Renal Disease

Inhibition of the Complement Alternative Pathway Attenuates Hemolysis and Preserves Renal Function in a Mouse Model of Sickle Cell Disease (ASH 2024) - "Notably, ASO factor B (alone or in combination) markedly decreased RBC opsonization by C3/C3b (p<0.001)...Improvement in renal function is particularly significant, as renal impairment is a common and severe complication in SCD, impacting patient morbidity and mortality. These findings support further exploration of complement-targeted therapies to ameliorate hemolysis and preserve organ function in SCD patients."

Preclinical • Genetic Disorders • Hematological Disorders • Renal Disease • Sickle Cell Disease • CD55 • CD59 • KIM1 • LCN2

Complement Inhibition in IgA Nephropathy (KSN 2025) - "In a phase 3 trial, iptacopan achieved a ~38% greater reduction in proteinuria versus placebo at 9 months on top of standard care, leading to its accelerated approval as the first complement inhibitor for IgAN. An antisense oligonucleotide targeting factor B (IONIS-FB-LRx) similarly reduced proteinuria by ~44% in a phase 2 study, and a phase 3 trial is ongoing. In contrast, the lectin pathway inhibitor narsoplimab (anti-MASP-2) did not meet its primary endpoint in a phase 3 trial, despite promising early-phase results. We will also discuss other investigational approaches, including proximal complement blockade at C3 (pegcetacoplan) and terminal pathway inhibition (e.g., C5 monoclonal antibodies and C5a receptor antagonists). While terminal complement inhibitors like eculizumab have shown anecdotal benefits in severe IgAN, robust trial data in primary IgAN are awaited...While targeting the alternative pathway has shown the most consistent benefit to date, additional..."

Fibrosis • Glomerulonephritis • IgA Nephropathy • Immunology • Inflammation • Lupus Nephritis • Renal Disease

Suppression of complement alternative pathway by monthly dosing of sefaxersen, a novel antisense oligonucleotide therapy in development for IgAN (ERA 2025) - P2, P3 | "Sefaxersen, a novel complement Factor B mRNA-targeting therapy, demonstrates a PK profile supporting Q4W subcutaneous administration and provides durable reduction in AP complement components in both blood and urine. Substantial reduction in AP functional activity was achieved while complement classical pathway activity was maintained, potentially maintaining host defense against pathogens. Taken together, sefaxersen is a convenient therapeutic approach for the treatment of IgAN, providing durable control of the alternative complement pathway that may translate into improvements in proteinuria."

Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Glomerulonephritis • IgA Nephropathy • Macular Degeneration • Ophthalmology • Retinal Disorders • CFB

IMAGINATION: A Study to Evaluate the Efficacy and Safety of Sefaxersen (RO7434656) in Participants With Primary Immunoglobulin A (IgA) Nephropathy at High Risk of Progression (clinicaltrials.gov) - P3 | N=428 | Recruiting | Sponsor: Hoffmann-La Roche | Trial completion date: Sep 2030 ➔ Mar 2029

Trial completion date • Glomerulonephritis • IgA Nephropathy • Renal Disease

Inhibiting the alternative pathway of complement by reducing systemic complement factor B: Randomized, double-blind, placebo-controlled phase 1 studies with Sefaxersen. (PubMed, Immunobiology) - "The long duration of lowering of FB levels following the last dose supports monthly dosing in future clinical trials. These clinical results support the ongoing Phase 2 development for geographic atrophy secondary to age-related macular degeneration and Ph 2/3 development for IgA nephropathy."

Clinical • Journal • P1 data • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Glomerulonephritis • Hematological Disorders • IgA Nephropathy • Macular Degeneration • Ophthalmology • Renal Disease • Retinal Disorders • CFB

Phase II Results of an Investigational RNA Therapeutic to Complement Factor B, IONIS-FB-LRx, for Treatment of IgA Nephropathy (KIDNEY WEEK 2024) - P2, P3 | "IONIS-FB-LRx met primary endpoints in patients with biopsy-confirmed IgAN. This Ph2 open-label study provides consistent clinical evidence supporting ongoing Ph3 study of IONIS-FB-LRx /RO7434656 to reduce the progression of IgAN (NCT05797610)."

Late-breaking abstract • P2 data • Glomerulonephritis • IgA Nephropathy • Renal Disease • CFB

GOLDEN STUDY: A Study to Assess Safety and Efficacy of Multiple Doses of IONIS-FB-LRx in Participants With Geographic Atrophy Secondary to Age-Related Macular Degeneration (AMD) (clinicaltrials.gov) - P2 | N=332 | Completed | Sponsor: Ionis Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders

IONIS-FB-LRx, An Antisense Oligonucleotide to Complement Factor B for Treatment of IgA Nephropathy. (ERA-EDTA 2024) - P2, P3 | "This Ph2 open-label study provides continuing clinical evidence that IONIS-FB-L Rx reduces complement levels and proteinuria in patients with IgAN, supporting Ph3 development (NCT05797610) to determine the potential of IONIS-FB-L Rx to reduce the progression of IgAN."

Glomerulonephritis • IgA Nephropathy • Renal Disease • CFB

A Study to Evaluate the Effectiveness and Safety of IONIS-FB-LRx, an Antisense Inhibitor of Complement Factor B, in Adult Participants With Primary IgA Nephropathy (clinicaltrials.gov) - P2 | N=23 | Completed | Sponsor: Ionis Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Glomerulonephritis • IgA Nephropathy • Renal Disease

IMAGINATION: A GLOBAL PHASE 3 TRIAL OF RO7434656, AN ANTISENSE OLIGONUCLEOTIDE INHIBITOR OF COMPLEMENT FACTOR B, IN IGA NEPHROPATHY (ISN-WCN 2024) - P2, P3 | "The unique antisense modality and long tissue half-life of RO7434656 enables Q4W SC administration to inhibit the alternative complement pathway. IMAGINATION aims to evaluate the efficacy and safety of RO7434656 in adults with IgAN using a broad range of assessments over 105 weeks. This abstract was also submitted and accepted for presentation at ASN Kidney Week 2023."

Clinical • P3 data • Glomerulonephritis • IgA Nephropathy • Renal Disease • CFB

A Study to Evaluate the Effectiveness and Safety of IONIS-FB-LRx, an Antisense Inhibitor of Complement Factor B, in Adult Participants With Primary IgA Nephropathy (clinicaltrials.gov) - P2 | N=23 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Phase classification: P2a ➔ P2 | Trial completion date: Dec 2023 ➔ Apr 2024 | Trial primary completion date: Dec 2023 ➔ Apr 2024

Phase classification • Trial completion date • Trial primary completion date • Glomerulonephritis • IgA Nephropathy • Renal Disease

GOLDEN STUDY: A Study to Assess Safety and Efficacy of Multiple Doses of IONIS-FB-LRx in Participants With Geographic Atrophy Secondary to Age-Related Macular Degeneration (AMD) (clinicaltrials.gov) - P2 | N=332 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc.

Trial completion date • Trial primary completion date • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders

An Exploratory Trial of an Investigational RNA Therapeutic, IONIS-FB-LRx, for Treatment of IgA Nephropathy: New Interim Results (KIDNEY WEEK 2023) - P2a, P3 | "This Ph2 open-label study provides continuing clinical evidence that IONIS-FB-LRx, reduces complement levels and proteinuria in patients with IgAN, supporting Ph3 development (NCT05797610) to determine the potential of IONIS-FB-LRx to reduce the progression of IgAN."

Glomerulonephritis • IgA Nephropathy • Renal Disease • CFB

IMAGINATION: A Global Phase 3 Trial of RO7434656, an Antisense Oligonucleotide Inhibitor of Complement Factor B, in IgA Nephropathy (KIDNEY WEEK 2023) - P2a, P3 | "The unique antisense modality and long tissue half-life of RO7434656 enables Q4W SC administration to inhibit the alternative complement pathway. IMAGINATION aims to evaluate the efficacy and safety of RO7434656 in adults with IgAN using a broad range of assessments over 105 weeks."

Clinical • P3 data • Glomerulonephritis • IgA Nephropathy • Renal Disease • CFB

A Study to Evaluate the Effectiveness and Safety of IONIS-FB-LRx, an Antisense Inhibitor of Complement Factor B, in Adult Participants With Primary IgA Nephropathy (clinicaltrials.gov) - P2a | N=23 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Glomerulonephritis • IgA Nephropathy • Renal Disease

IMAGINATION: A Study to Evaluate the Efficacy and Safety of RO7434656 in Participants With Primary Immunoglobulin A (IgA) Nephropathy at High Risk of Progression (clinicaltrials.gov) - P3 | N=428 | Recruiting | Sponsor: Hoffmann-La Roche | Not yet recruiting ➔ Recruiting

Enrollment open • Glomerulonephritis • IgA Nephropathy • Renal Disease

IMAGINATION: A Study to Evaluate the Efficacy and Safety of RO7434656 in Participants With Primary Immunoglobulin A (IgA) Nephropathy at High Risk of Progression (clinicaltrials.gov) - P3 | N=428 | Not yet recruiting | Sponsor: Hoffmann-La Roche

New P3 trial • Glomerulonephritis • IgA Nephropathy • Renal Disease

GOLDEN STUDY: A Study to Assess Safety and Efficacy of Multiple Doses of IONIS-FB-LRx in Participants With Geographic Atrophy Secondary to Age-Related Macular Degeneration (AMD) (clinicaltrials.gov) - P2 | N=330 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2024 ➔ Jul 2024 | Trial primary completion date: Jan 2024 ➔ Apr 2024

Enrollment closed • Trial completion date • Trial primary completion date • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Macular Degeneration • Ophthalmology • Retinal Disorders