Sefaxersen
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| Other names | RO7434656, RG6299 , IONIS-FB-LRx, ISIS-696844 |
| Drug class | Antisense oligonucleotide |
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| Formula | C296H445N77O148P20S19 |
| Molar mass | 8678.82 g·mol−1 |
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Sefaxersen (also known as RO7434656, RG6299, ISIS-696844 and IONIS-FB-LRx) is an investigational antisense oligonucleotide (ASO) drug developed by Roche Holding AG in partnership with Ionis Pharmaceuticals. It targets complement factor B (CFB) to treat complement system-mediated diseases, primarily IgA nephropathy (IgAN) and geographic atrophy (GA) secondary to age-related macular degeneration.[1][2][3] By inhibiting CFB expression, Sefaxersen reduces harmful inflammation driven by the alternative complement pathway.[4]
As of 2025, it is in Phase 2/3 trials for IgAN and Phase 2 trials for GA.[5][6][7][8]
Mechanism of action
Sefaxersen is an antisense oligonucleotide that binds to the messenger RNA (mRNA) of the complement factor B (CFB) gene, preventing CFB protein production.[3][9] CFB is a key component of the alternative pathway of complement activation, which can drive inflammation and tissue damage in diseases like IgAN and GA.[3] By reducing CFB levels, Sefaxersen dampens this pathway, aiming to slow disease progression.[4] This RNA-targeted approach offers precision compared to traditional drugs, making it suitable for complex conditions.[1][3]
Development
Sefaxersen was developed by Ionis Pharmaceuticals, a pioneer in RNA-targeted therapeutics, in partnership with Roche for late-stage clinical development and potential commercialization.[2][4] Ionis’ expertise in antisense technology complements Roche’s focus on neurology, rare diseases, and ophthalmology.[4] Early clinical trials demonstrated that Sefaxersen effectively reduced complement factor B (CFB) levels, supporting its advancement into Phase 2/3 trials for IgA nephropathy (IgAN) and Phase 2 trials for geographic atrophy (GA).[1][3][10]
Sefaxersen is currently being evaluated in clinical trials for its safety and efficacy in treating the following complement-mediated diseases.[10]
IgA Nephropathy (IgAN)
Sefaxersen is in Phase 2/3 trials for primary IgA nephropathy (IgAN), a kidney disorder characterized by the deposition of IgA immune complexes in the glomeruli, leading to inflammation and progressive kidney damage.[1][10][11] Results from Phase 2 trials showed a significant reduction in proteinuria and stabilization of kidney function in treated patients, supporting the continuation of development.[12] The ongoing Phase 3 trial is focused on evaluating efficacy, safety, and pharmacokinetics in patients at high risk of disease progression.[11][7]
Geographic Atrophy (GA)
Overactivation of the alternative complement pathway plays a key role in the progression of GA.[3] In Phase 1 studies involving healthy volunteers, Sefaxersen was shown to reduce systemic CFB levels and overall complement activity, supporting its potential use in GA treatment.[9][13] Sefaxersen entered Phase 2 trials (NCT03815825) for geographic atrophy (GA), an advanced form of age-related macular degeneration that leads to irreversible vision loss.[1][10][9] However, further development of Sefaxersen for GA has been discontinued by Ionis Pharmaceuticals.[14]
References
- ^ a b c d e McCaleb ML, Hughes SG, Grossman TR, Frazer-Abel A, Jung B, Yin L, et al. (2025-03-01). "Inhibiting the alternative pathway of complement by reducing systemic complement factor B: Randomized, double-blind, placebo-controlled phase 1 studies with Sefaxersen". Immunobiology. 230 (2) 152876. doi:10.1016/j.imbio.2025.152876. ISSN 1878-3279. PMID 39893955.
- ^ a b "Sefaxersen". NCATS Inxight Drugs. National Center for Advancing Translational Sciences. Retrieved June 16, 2025.
- ^ a b c d e f "Sefaxersen - Drug Targets, Indications, Patents". Synapse. PatSnap. Retrieved June 16, 2025.
- ^ a b c d "Delving into the Latest Updates on Sefaxersen with Synapse". Synapse. PatSnap. Retrieved June 16, 2025.
- ^ Ionis Pharmaceuticals, Inc. (2025-01-17). An Open-Label Phase 2a Clinical Study to Evaluate the Effectiveness and Safety of IONIS-FB-LRx, an Antisense Inhibitor of Complement Factor B, in Adult Subjects With Primary IgA Nephropathy (Report). clinicaltrials.gov.
- ^ Ionis Pharmaceuticals, Inc. (2025-03-05). A Phase 2, Randomized Placebo-Controlled, Double-Masked Study to Assess Safety and Efficacy of Multiple Doses of IONIS-FB-LRx, an Antisense Inhibitor of Complement Factor B, in Patients With Geographic Atrophy Secondary to Age-Related Macular Degeneration (AMD) (Report). clinicaltrials.gov.
- ^ a b Hoffmann-La Roche (2025-06-03). A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of RO7434656, an Antisense Inhibitor of Complement Factor B, in Patients With Primary IgA Nephropathy at High Risk of Progression (Report). clinicaltrials.gov.
- ^ "IONIS FB LRx - AdisInsight". adisinsight.springer.com. Retrieved 2025-06-16.
- ^ a b c Yin L, Henry SP, Monia BP, Geary R, Grossman TR, Schneider E, et al. (2025-03-01). "Inhibiting the alternative pathway of complement by reducing systemic complement factor B: Randomized, double-blind, placebo-controlled phase 1 studies with Sefaxersen". Immunobiology. 230 (2) 152876. doi:10.1016/j.imbio.2025.152876. ISSN 0171-2985. PMID 39893955.
- ^ a b c d "Product Development Portfolio". Roche. Retrieved June 16, 2025.
- ^ a b "A Study to Evaluate the Efficacy and Safety of Sefaxersen (RO7434656) in Participants With Primary Immunoglobulin A (IgA) Nephropathy at High Risk of Progression". CenterWatch. Retrieved June 16, 2025.
- ^ "Ionis presents positive Phase 2 data in patients with IgA Nephropathy at American Society of Nephrology's Kidney Week 2022". Ionis Pharmaceuticals. Retrieved June 16, 2025.
- ^ Ionis Pharmaceuticals, Inc. (2025-03-05). A Phase 2, Randomized Placebo-Controlled, Double-Masked Study to Assess Safety and Efficacy of Multiple Doses of IONIS-FB-LRx, an Antisense Inhibitor of Complement Factor B, in Patients With Geographic Atrophy Secondary to Age-Related Macular Degeneration (AMD) (Report). clinicaltrials.gov.
- ^ Taylor NP (2024-08-01). "Ionis axes eye disease from targets of Roche-partnered prospect after data disappoint | Fierce Biotech". www.fiercebiotech.com. Retrieved 2025-06-16.