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Abstract: SA-PO714

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

Session Information

Category: Glomerular Diseases

  • 1303 Glomerular Diseases: Clinical‚ Outcomes‚ and Trials


  • Barbour, Sean, The University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada
  • Hladunewich, Michelle A., University of Toronto, Sunnybrook, Ontario, Canada
  • Irvine, John, CDHB, Christchurch, New Zealand
  • Makris, Angela, Liverpool Hosp Renal Clinic, Liverpool, New South Wales, Australia
  • Robson, Richard Austin, Christchurch Clinical Studies Trust Ltd, Christchurch, Canterbury, New Zealand
  • Tan, Sven-Jean, The Royal Melbourne Hospital, Parkville, Victoria, Australia
  • Wong, Muh Geot, Royal North Shore Hospital, St Leonards, New South Wales, Australia
  • Frazer-Abel, Ashley, Exsera Biolabs, Denver, Colorado, United States
  • Yang, Qingqing, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Yin, Lixuan, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Barrett, Terry, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Ruckle, Jon Leslie, Pacific Pharma Grp, Tacoma, Washington, United States
  • Schneider, Eugene, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Geary, Richard, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
  • Canducci, Filippo, Roche, Basel, Switzerland
  • Mccaleb, Michael, Ionis Pharmaceuticals Inc, Carlsbad, California, United States

Pathogenesis of IgA nephropathy (IgAN) is known to be dependent upon multiple factors, one being the complement system. Overactivity of the complement Alternative Pathway (AP) has been proposed to be responsible in part for the renal deposition of complement C3 activation-products and subsequent renal sequalae. We sought to test the hypothesis that a reduction of systemic AP would improve proteinuria. This was accomplished by lowering the production of complement factor B (FB), a required component of the AP, using an investigational antisense oligonucleotide that targets FB mRNA in the liver.


An exploratory, single arm, open label Ph 2 study recruited patients with biopsy-confirmed IgAN within 12 months (C3 deposition, ≤50% IFTA, ≤50% crescents), proteinuria>1.5g/d, eGFR>45, hematuria, despite maximum ACEi/ARB for at least 60 d. Patients received monthly SC administration of IONIS-FB-LRx. Primary outcome was change in 24-hr proteinuria at Wk29 (4 wk after last dose) compared to baseline (BL). Secondary outcome measures included: safety, complement levels and eGFR. (NCT04014335)


Study enrolled 10 subjects, 25-59 yr, 40% Female, 6 Asian, and 4 White. There was a selective reduction of plasma complement FB protein levels, serum AP activity and urinary Ba from BL to end of treatment (mean % change of -69%, -39% and -88%, respectively). Median proteinuria (24 hr urine collection) at BL was 2.06 g/d (IQR 1.43, 3.51 g/d). At Wk 29, the change in proteinuria was -1.09 g/d (IQR -1.68, -0.79 g/d), corresponding to a 44% reduction. There was no change in eGFR at Wk 29 compared to BL (mean±SD; BL 68±26; Wk29 69±21 mL/min/1.73m2). The drug demonstrated an acceptable safety profile with no Treatment Emergent SAE and the only clinically meaningful safety signal (moderate TEAE) was a reversible elevation of ALT without changes in bilirubin in one subject. All subjects completed the study (wk 29).


This Ph 2 open label study provides initial clinical evidence that IONIS-FB- LRx, reduces complement and proteinuria in patients with IgAN, supporting further development to determine the potential of IONIS-FB-LRx to reduce the progression of IgA nephropathy.


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