sefaxersen (RG6299) / Ionis, Roche - LARVOL DELTA

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

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

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

Gene targeting as a therapeutic avenue in diseases mediated by the complement alternative pathway. (PubMed, Immunol Rev) - "This review explains key concepts of RNA and DNA targeting and discusses assets in clinical development for the treatment of diseases driven by the alternative pathway, including the RNA-targeting therapeutics ALN-CC5, ARO-C3, and IONIS-FB-LRX, and the gene therapies GT005 and HMR59. These therapies are but the spearhead of potential drug candidates that might revolutionize the field in coming years."

Journal • Review • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Gene Therapies • Hematological Disorders • Inflammation • Macular Degeneration • Ophthalmology • Paroxysmal Nocturnal Hemoglobinuria • Rare Diseases • Retinal Disorders

An Exploratory Trial of an Investigational RNA Therapeutic, IONIS-FB-LRx, for Treatment of IgA Nephropathy (KIDNEY WEEK 2022) - P2a | "All subjects completed the study (wk 29). Conclusion This Ph 2 open label study provides initial clinical evidence that IONIS-FB- L Rx, reduces complement and proteinuria in patients with IgAN, supporting further development to determine the potential of IONIS-FB-L Rx to reduce the progression of IgA nephropathy."

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=330 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: Oct 2022 ➔ Jan 2024 | Trial primary completion date: Oct 2022 ➔ Jan 2024

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

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=25 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | N=10 ➔ 25

Enrollment change • Glomerulonephritis • IgA Nephropathy • Renal Disease

Baseline Characteristics in the Phase 2 GOLDEN Study of IONIS-FB-LRx, an Investigational Antisense Oligonucleotide Designed to Treat AMD-Associated Geographic Atrophy (ASRS 2022) - No abstract available

P2 data • Age-related Macular Degeneration • Dry Age-related Macular Degeneration

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=10; Recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Trial completion date: Jan 2021 ➔ Dec 2023; Trial primary completion date: Jan 2021 ➔ Dec 2023

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

[VIRTUAL] Systemic Antisense Oligonucleotide Inhibition of Complement Factor B for Treatment of Geographic Atrophy: Results of a Placebo-controlled Phase 1 Dose-Escalation Study (ARVO 2021) - P2 | "IONIS-FB-LRX, is a novel antisense oligonucleotide drug, administered subcutaneously with a potential for monthly dosing. This first-in-human IONIS-FB-LRx study found the antisense drug to exhibit robust lowering of systemic FB and excellent safety profile. Based on these data, a Phase 2 double-masked, randomized placebo- controlled trial (N=330), the GOLDEN study, is currently underway to determine the potential of systemic IONIS-FB-L Rx in reducing progression of GA (NCT03815825)."

Clinical • P1 data • Age-related Macular Degeneration • Dry Age-related Macular Degeneration • Ophthalmology • Retinal Disorders • CFB

[VIRTUAL] Systemic administration of an antisense oligonucleotide, IONIS-FB-LRx for treatment of geographic atrophy (EURETINA 2020) - P2 | "IONIS-FB-LRX, is a novel antisense oligonucleotide drug, administered subcutaneously with a potential for monthly dosing. This Phase 1 study demonstrated that IONIS-FB-LRx provided a dose dependent reduction in FB and the ACP activity and was safe, supporting further development. Based on these data, a Phase 2 double-masked, randomized placebo-controlled trial (the GOLDEN study) is currently underway to determine the potential of systemic IONIS-FB-LRx in reducing progression of GA (NCT03815825)."

Age-related Macular Degeneration • Complement-mediated Rare Disorders • Dry Age-related Macular Degeneration • Hematological Disorders • Macular Degeneration • Ophthalmology • Retinal Disorders