#3089 Suppression of complement alternative pathway by monthly dosing of sefaxersen, a novel antisense oligonucleotide therapy in development for IgAN
Notice bibliographique
Résumé
Abstract Background and Aims Increased activity of the complement alternative pathway (AP) contributes to the pathogenesis of primary IgA nephropathy (IgAN). Factor B (FB), a key protein of the AP, is elevated in IgAN patients and is associated with proteinuria and poorer renal function. Approved complement inhibitors involve either IV administration or frequent dosing, presenting challenges to adherence for patients. As the complement system is important for host defense against pathogens, an unmet need remains for a convenient therapeutic approach that selectively targets the disease-associated AP in IgAN. Sefaxersen (IONIS-FB-LRx, RO7434656), an antisense oligonucleotide (ASO) against FB, is the first AP mRNA-targeting therapy in late-stage development for the treatment of IgAN. We previously reported that subcutaneous (SC) administration of sefaxersen every 4 weeks (Q4W) resulted in proteinuria reduction in IgAN patients. Here, we further describe the PK profile and mechanism of action of sefaxersen using data from Phase 2 clinical studies in patients with IgAN and geographic atrophy (GA) secondary to age-related macular degeneration. Method Sefaxersen is a second-generation GalNAc-conjugated ASO for enhanced stability and targeted delivery to the liver as the main site of FB production. Sefaxersen 40, 70, or 100 mg was administered Q4W in 223 participants with GA (NCT03815825), and 70 mg in 23 participants with IgAN (NCT04014335). An additional dose was administered 2 weeks after the first dose in the majority of participants. Complement proteins were serially measured in plasma (FB, Bb) and urine (Factor Ba, IgAN patients only). Classical pathway and alternative pathway functional activity in serum were measured by the Wieslab WCP and WAP assays, respectively. Results The plasma concentration (PK) profile of sefaxersen following SC injection shows rapid absorption, a sharp decline post-Cmax due to tissue distribution, and a slower terminal elimination phase driven by re-distribution from tissue, with apparent half-lives ranging from approximately 5 to 8 weeks. Q4W dosing with sefaxersen rapidly and durably reduced complement proteins FB and Bb in plasma, as well as Ba in urine. Near maximum suppression of FB, Bb, and Ba levels was reached by the earliest assessments of Week 5 and Week 9 and maintained over the dosing intervals in GA and IgAN patients, respectively. Plasma levels of FB and Bb were reduced by 69% and 73%, respectively, from baseline to inferred steady-state in patients with GA at the 70 mg dose. Plasma FB levels were reduced by a mean of 69%, Factor Bb by 79%, and urine Factor Ba levels by 78% from baseline to inferred steady-state in IgAN patients. The activity of the alternative pathway was reduced by 34% at inferred steady-state in patients with GA at the 70 mg dose, and reduced by 39% after 9 weeks in IgAN patients, whereas classical pathway activity was maintained. Conclusion 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. Currently, the effect of sefaxersen 70 mg on proteinuria reduction and eGFR stabilization is being evaluated in IgAN patients in a phase 3 study (IMAgINATION, NCT05797610).
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,006 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».