An Exploratory Trial of an Investigational RNA Therapeutic, IONIS-FB-LRx, for Treatment of IgA Nephropathy: New Interim Results
Bibliographic record
Abstract
Background: Overactivity of the complement Alternative Pathway (AP) has been proposed to contribute to pathogenesis of IgA nephropathy (IgAN). An antisense oligonucleotide to complement factor B (FB), IONIS-FB-LRx (ISIS696844, RO7434656) targets FB mRNA in the liver. IONIS-FB-LRx treatment led to inhibition of AP and reduction in proteinuria in IgAN patients (2022 ASN Abstract#SA-PO714). Methods: An exploratory, single-arm, multi-national open-label Ph2 study (NCT04014335) recruited patients with biopsy-confirmed IgAN, proteinuria>1.5 g/d, eGFR>40mL/min/1.73m2, and hematuria despite maximum tolerated RAAS blockade. Patients received monthly SC administration of IONIS-FB-LRx for 24 weeks. Primary outcome was change in 24-hr proteinuria at Wk29 (4 weeks after last dose) compared to baseline (BL). Results: 13 subjects have completed study to date, 25-62 yr, 40% Female, 7 Asian, and 6 White. There was a selective reduction of plasma complement FB levels, serum AP activity, urinary Ba and urinary sC5b-9 (mean % change of -69%, -36%, -92%, and -26% respectively). Median 24-hr proteinuria at BL was 1.80 g/g (IQR 1.23, 2.33 g/g). At Wk29, a 47% geometric mean ratio reduction was observed. There was no change in eGFR at Wk29 compared to BL (mean±SD; BL 70±25; Wk29 72±22 mL/min/1.73m2). One subject opted to extend treatment and continued to receive treatment through Wk61, demonstrating a sustained reduction in proteinuria. One subject discontinued study drug after 4 months of treatment (last dose Wk17) to initiate SGLT-2 inhibitors. 24-hr urine samples collected 3 weeks after the last dose of IONIS-FB-LRx, but prior to use of SGLT-2 inhibitors (Wk27), demonstrated a 41% reduction in proteinuria. IONIS-FB-LRx demonstrated an acceptable safety profile with no Treatment Emergent SAE. The only clinically meaningful safety signal (moderate TEAE) was a reversible ALT elevation without a change in bilirubin in 1 subject. Conclusions: This Ph2 open-label study provides continuing clinical evidence that IONIS-FB-LRx, reduces complement levels and proteinuria in patients with IgAN, supporting Ph3 development (NCT05797610) to determine the potential of IONIS-FB-LRx to reduce the progression of IgAN. 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 | 0.002 | 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) | 0.006 | 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".