#388 IONIS-FB-LRx, an antisense oligonucleotide to complement factor B for treatment of IgA nephropathy
Bibliographic record
Abstract
Abstract Background and Aims Pathogenesis of IgA nephropathy (IgAN) is known to be dependent upon multiple factors, one being the complement system. Since overactivity of the complement Alternative Pathway (AP) has been proposed to contribute to pathogenesis of IgAN, it has been hypothesized that a reduction of AP activity would improve proteinuria. IONIS-FB-LRx, (ISIS696844, RO7434656), is an investigational antisense oligonucleotide targeting complement factor B (CFB) mRNA and reduces CFB production in the liver. We have previously demonstrated that administration of IONIS-FB-LRx lowered the production of CFB, a required component of the AP, and led to reduction of AP and reduction in proteinuria in IgAN patients (2023 ASN Abstract#SA-PO926, N = 13 patients). Current abstract provides an update to our previous report extending results to 19 patients treated with IONIS-FB-LRx. Method An exploratory, single-arm, multi-national open-label Ph2 study (NCT04014335) recruited patients with biopsy-confirmed IgAN, proteinuria >1.5 g/d, eGFR >40 mL/min/1.73 m2, and hematuria despite maximum tolerated RAAS blockade and/or stable dose of SGLT-2 inhibitor for a minimum of 6 months. Study drug was administered at Weeks 1, 3, and 5, and then every 4 weeks through Week 25 (Cohort A) and at Week 1 and then every 4 weeks through Week 25 (Cohort B). Primary outcome was change in 24-hr proteinuria at Week 29 (4 weeks after last dose) compared to baseline (BL). Results 19 patients have completed study to date (13Nov2023), 25-62 yr, 42% Female, 11 Asian, and 8 White. Median 24-hr UPCR at BL was 1.56 g/g (IQR 1.23, 2.33 g/g). At Week 29, a 45% geometric mean ratio reduction was observed. There was little change in eGFR at Week 29 compared to BL (mean ± SD; BL 72 ± 22; Week 29 74.6 ± 20 mL/min/1.73 m2). The drug demonstrated an acceptable safety profile with no Treatment Emergent SAEs; the only clinically meaningful laboratory finding was reversible and transient ALT elevation without a change in bilirubin. All patients completed the study and one patient discontinued study drug after 4 months to initiate SGLT-2 inhibitors. That patient experienced a 38% reduction in 24-hr UPCR collected 3 weeks (Week 27) after the last dose of IONIS-FB-LRx, but prior to use of SGLT-2 inhibitors. Conclusion 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.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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 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".