Phase II Results of an Investigational RNA Therapeutic to Complement Factor B, IONIS-FB-LRx, for Treatment of IgA Nephropathy
Bibliographic record
Abstract
Background: Overactivity of the complement Alternative Pathway (AP) has been implicated in pathogenesis of primary IgA nephropathy (IgAN). An antisense oligonucleotide to complement factor B (FB), IONIS-FB-LRx (ISIS 696844, RO7434656) targets FB mRNA in the liver leading to reduction of AP activation in IgAN patients. Methods: An exploratory, single-arm, global open-label Ph2 trial (NCT04014335) recruited patients with biopsy-confirmed IgAN with renal C3 deposits, hematuria, and 24-hr protein excretion >1.5g/d, eGFR>40mL/min/1.73m2 despite maximum tolerated RAAS blockade including 6 patients on stable doses of SGLT2i. Patients received monthly subcutaneous (SC) administration of IONIS-FB-LRx for 24 weeks followed by voluntary treatment extension. Primary endpoint was change in 24-hr proteinuria at week 29 (or 4 weeks after last dose) compared to baseline (BL). Results: 23 patients were enrolled (25-62 yr of age, 40% Female, 13 Asian, 9 White, 1 other). One subject discontinued study drug at week 17 to initiate SGLT2i. Median 24-hr proteinuria at BL was 2.0 g/d (IQR 1.64, 4.78 g/d). At week 29, a 43% (95% CI: 23%, 58%) geometric mean reduction of 24-hr proteinuria was observed. Reductions in UPCR and UACR were also observed. There was no change in mean eGFR at week 29 compared to BL (mean±SD; BL 70.4 ±21.6; week 29 73.2±19.9 mL/min/1.73m2). There was sustained reduction of 24-hr proteinuria in all 7 patients who opted for treatment extension, including 4 patients treated for >12 mo. There were selective reductions of plasma complement FB and Factor Bb, serum AP activity, urinary Factor Ba and urinary sC5b-9 without changes in serum CH50. There was one treatment emergent SAE assessed as not related to study drug and transient and reversible ALT elevations (3-5X fold ULN) without a change in serum bilirubin were observed in 3 subjects, all of whom remained on study and completed treatment. Conclusion: IONIS-FB-LRx met primary endpoints in patients with biopsy-confirmed IgAN. This Ph2 open-label study provides consistent clinical evidence supporting ongoing Ph3 study of IONIS-FB-LRx /RO7434656 to reduce the progression of IgAN (NCT05797610). Funding: Commercial Support - Ionis Pharmaceuticals
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".