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Abstract: SA-PO926

An Exploratory Trial of an Investigational RNA Therapeutic, IONIS-FB-LRx, for Treatment of IgA Nephropathy: New Interim Results

Session Information

Category: Glomerular Diseases

  • 1402 Glomerular Diseases: Clinical, Outcomes, and Trials


  • Barbour, Sean, University of British Columbia, Vancouver, British Columbia, Canada
  • Makris, Angela, Liverpool Hospital, Liverpool, New South Wales, Australia
  • Hladunewich, Michelle A., Sunnybrook Research Institute, Toronto, Ontario, Canada
  • Tan, Sven-Jean, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
  • Wong, Muh Geot, University of Sydney, Sydney, New South Wales, Australia
  • Choo Chon Jun, Jason, Singapore General Hospital, Singapore, Singapore
  • Frazer-Abel, Ashley, Exsera Labs, Denver, Colorado, United States
  • Yin, Lixuan, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Yang, Qingqing, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Ruckle, Jon Leslie, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Geary, Richard, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Schneider, Eugene, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Mccaleb, Michael, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Brice, Gary Todd, Ionis Pharmaceuticals Inc, Carlsbad, California, United States

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).


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).


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.


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.


  • Commercial Support – Ionis Pharmaceuticals