Sefaxersen

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Sefaxersen
Clinical data
Other namesRO7434656, RG6299 , IONIS-FB-LRx, ISIS-696844
Drug class Antisense oligonucleotide
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem SID
UNII

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]

Contents

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

  1. 1 2 3 4 5 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.
  2. 1 2 "Sefaxersen". NCATS Inxight Drugs. National Center for Advancing Translational Sciences. Retrieved June 16, 2025.
  3. 1 2 3 4 5 6 "Sefaxersen - Drug Targets, Indications, Patents". Synapse. PatSnap. Retrieved June 16, 2025.
  4. 1 2 3 4 "Delving into the Latest Updates on Sefaxersen with Synapse". Synapse. PatSnap. Retrieved June 16, 2025.
  5. ↑ 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.
  6. ↑ 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.
  7. 1 2 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.
  8. ↑ "IONIS FB LRx - AdisInsight". adisinsight.springer.com. Retrieved 2025-06-16.
  9. 1 2 3 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.
  10. 1 2 3 4 "Product Development Portfolio". Roche. Retrieved June 16, 2025.
  11. 1 2 "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.
  12. ↑ "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.
  13. ↑ 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.
  14. ↑ 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.
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