An Exploratory Trial of an Investigational RNA Therapeutic, IONIS-FB-LRx, for Treatment of IgA Nephropathy
Bibliographic record
Abstract
Background: Pathogenesis of IgA nephropathy (IgAN) is known to be dependent upon multiple factors, one being the complement system. Overactivity of the complement Alternative Pathway (AP) has been proposed to be responsible in part for the renal deposition of complement C3 activation-products and subsequent renal sequalae. We sought to test the hypothesis that a reduction of systemic AP would improve proteinuria. This was accomplished by lowering the production of complement factor B (FB), a required component of the AP, using an investigational antisense oligonucleotide that targets FB mRNA in the liver. Methods: An exploratory, single arm, open label Ph 2 study recruited patients with biopsy-confirmed IgAN within 12 months (C3 deposition, ≤50% IFTA, ≤50% crescents), proteinuria>1.5g/d, eGFR>45, hematuria, despite maximum ACEi/ARB for at least 60 d. Patients received monthly SC administration of IONIS-FB-LRx. Primary outcome was change in 24-hr proteinuria at Wk29 (4 wk after last dose) compared to baseline (BL). Secondary outcome measures included: safety, complement levels and eGFR. (NCT04014335) Results: Study enrolled 10 subjects, 25-59 yr, 40% Female, 6 Asian, and 4 White. There was a selective reduction of plasma complement FB protein levels, serum AP activity and urinary Ba from BL to end of treatment (mean % change of -69%, -39% and -88%, respectively). Median proteinuria (24 hr urine collection) at BL was 2.06 g/d (IQR 1.43, 3.51 g/d). At Wk 29, the change in proteinuria was -1.09 g/d (IQR -1.68, -0.79 g/d), corresponding to a 44% reduction. There was no change in eGFR at Wk 29 compared to BL (mean±SD; BL 68±26; Wk29 69±21 mL/min/1.73m2). The drug demonstrated an acceptable safety profile with no Treatment Emergent SAE and the only clinically meaningful safety signal (moderate TEAE) was a reversible elevation of ALT without changes in bilirubin in one subject. All subjects completed the study (wk 29). Conclusions: This Ph 2 open label study provides initial clinical evidence that IONIS-FB- LRx, reduces complement and proteinuria in patients with IgAN, supporting further development to determine the potential of IONIS-FB-LRx to reduce the progression of IgA nephropathy. Funding: Commercial Support - Ionis Pharmaceuticals
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 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".