#3089 Suppression of complement alternative pathway by monthly dosing of sefaxersen, a novel antisense oligonucleotide therapy in development for IgAN
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".