Abstract: TH-PO1205
Phase II Results of an Investigational RNA Therapeutic to Complement Factor B, IONIS-FB-LRx, for Treatment of IgA Nephropathy
Session Information
- Late-Breaking Science Posters
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics
Authors
- Barbour, Sean, The University of British Columbia, Vancouver, British Columbia, Canada
- Hladunewich, Michelle A., Sunnybrook Research Institute, Toronto, Ontario, Canada
- Makris, Angela, Liverpool Hospital Renal Clinic, Liverpool, New South Wales, Australia
- Tan, Sven-Jean, The Royal Melbourne Hospital, Melbourne, Victoria, Australia
- Robson, Richard Austin, NZCR, Auckland, Auckland, New Zealand
- Wong, Muh Geot, Royal North Shore Hospital, St Leonards, New South Wales, Australia
- Choo Chon Jun, Jason, Singapore General Hospital, Singapore, Singapore
- Frazer-Abel, Ashley, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Yin, Lixuan, Ionis Pharmaceuticals Inc, Carlsbad, California, United States
- Barrett, Terry, 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
- Ruckle, Jon Leslie, 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
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