Kidney Week

Abstract: SA-PO926

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

Session Information

• Glomerular Diseases: Therapeutics
  November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1402 Glomerular Diseases: Clinical, Outcomes, and Trials

Authors

• Barbour, Sean, University of British Columbia, Vancouver, British Columbia, Canada

Sean Barbour,

• Makris, Angela, Liverpool Hospital, Liverpool, New South Wales, Australia

Angela Makris,

• Hladunewich, Michelle A., Sunnybrook Research Institute, Toronto, Ontario, Canada

Michelle A. Hladunewich,

• Tan, Sven-Jean, The Royal Melbourne Hospital, Melbourne, Victoria, Australia

Sven-Jean Tan,

• Wong, Muh Geot, University of Sydney, Sydney, New South Wales, Australia

Muh Geot Wong,

• Choo Chon Jun, Jason, Singapore General Hospital, Singapore, Singapore

Jason Choo Chon Jun,

• Frazer-Abel, Ashley, Exsera Labs, Denver, Colorado, United States

Ashley Frazer-Abel,

• Yin, Lixuan, Ionis Pharmaceuticals Inc, Carlsbad, California, United States

Lixuan Yin,

• Yang, Qingqing, Ionis Pharmaceuticals Inc, Carlsbad, California, United States

Qingqing Yang,

• Ruckle, Jon Leslie, Ionis Pharmaceuticals Inc, Carlsbad, California, United States

Jon Leslie Ruckle,

• Geary, Richard, Ionis Pharmaceuticals Inc, Carlsbad, California, United States

Richard Geary,

• Schneider, Eugene, Ionis Pharmaceuticals Inc, Carlsbad, California, United States

Eugene Schneider,

• Mccaleb, Michael, Ionis Pharmaceuticals Inc, Carlsbad, California, United States

Michael Mccaleb,

• Brice, Gary Todd, Ionis Pharmaceuticals Inc, Carlsbad, California, United States

Gary Todd Brice,

Background

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-L_Rx (ISIS696844, RO7434656) targets FB mRNA in the liver. IONIS-FB-L_Rx treatment led to inhibition of AP and reduction in proteinuria in IgAN patients (2022 ASN Abstract#SA-PO714).

Methods

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-L_Rx 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 (last dose Wk17) to initiate SGLT-2 inhibitors. 24-hr urine samples collected 3 weeks after the last dose of IONIS-FB-L_Rx, but prior to use of SGLT-2 inhibitors (Wk27), demonstrated a 41% reduction in proteinuria. IONIS-FB-L_Rx 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.

Conclusion

This Ph2 open-label study provides continuing clinical evidence that IONIS-FB-L_Rx, reduces complement levels and proteinuria in patients with IgAN, supporting Ph3 development (NCT05797610) to determine the potential of IONIS-FB-L_Rx to reduce the progression of IgAN.

Funding

• Commercial Support – Ionis Pharmaceuticals