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논문분류	춘계학술대회 초록집
제목	An Exploratory Trial of an Investigational RNA Therapeutic, IONIS-FB-LRx, for Treatment of IgA Nephropathy: New Interim Results
저자	Jason Choo
출판정보	2024; 2024(1):
키워드
초록	Objectives: 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 leading to inhibition of AP and reduction in proteinuria in IgAN patients. Methods: A single-arm, open-label Ph2 study (NCT04014335) recruited patients with biopsy-confirmed IgAN, proteinuria>1.5g/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 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. A transient and reversible ALT elevation without a change in bilirubin was observed in one subject. Conclusions: This Ph2 open-label study provides continuing evidence that IONIS-FB-LRx, reduces complement levels and proteinuria in patients with IgAN, supporting Ph3 development (NCT05797610) to determine the potential to reduce progression of IgAN.
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