A single-arm phase 2 trial of an investigational RNA therapeutic to complement factor B sefaxersen for treatment of IgA nephropathy
Bibliographic record
Abstract
Introduction Activation of the complement system and subsequent local inflammation in the kidney plays a key role in the pathogenesis of IgA nephropathy (IgAN). Here, we investigated the efficacy and safety of sefaxersen, an antisense oligonucleotide inhibitor of complement factor B (FB), for the treatment of IgAN in a global exploratory, single arm, open-label trial (NCT04014335). Methods Patients were included with biopsy-confirmed IgAN with kidney C3 deposits, hematuria, 24-hour proteinuria above 1.5 g/day, and eGFR under 40mL/min/1.73m 2 despite maximum tolerated renin-angiotensin-aldosterone-system blockade. Patients received sefaxersen 70 mg (RO7434656) subcutaneously monthly for 24 weeks followed by voluntary treatment extension. The primary endpoint was a change in 24-hour urinary protein excretion (UPE) at week 29 compared to baseline. Results The trial enrolled 23 patients with baseline geometric mean proteinuria of 2.5 g/day. There were selective reductions of plasma complement FB and Bb, urinary factor Ba and serum complement alternative pathway activity, without changes in classical pathway activity. At week 29, UPE was reduced by 43% to a geometric mean of 1.4 g/day, with similar reductions in UPCR and UACR. Estimated GFR at baseline was mean 70.4 ml/min/1.73m 2 , remained stable through week 29 (mean 73.2 ml/min/1.73m 2 ). Proteinuria reduction was sustained in all seven participants who opted to participate in the treatment extension, including four patients treated for over 12 months. There was one treatment emergent serious adverse event not related to study drug. Transient and reversible alanine amino transferase elevations (3-5X fold upper limit normal) without a change in bilirubin were observed in three individuals, who remained on study and completed treatment. Conclusions Sefaxersen inhibited complement alternative pathway activity in patients with IgAN and reduced proteinuria with stable eGFR. Our findings support further evaluation of sefaxersen as a new therapy for IgAN in the Phase 3 IMAGINATION trial. Trial Registration Registered at ClinicalTrials.gov with study number NCT04014335.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.007 | 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".