AN EXPLORATORY TRIAL OF AN INVESTIGATIONAL RNA THERAPEUTIC, IONIS-FB-LRx, FOR TREATMENT OF IgA NEPHROPATHY
A MAKRIS1, SJ BARBOUR3, M HLADUNEWICH4, J IRVINE5, R ROBSON6, SJ TAN7, MG WONG8, A FRAZER-ABEL9,10, Q YANG, L YIN2, TD BARRETT2, J RUCKLE2, E SCHNEIDER2, R GEARY2, M McCALEB2, GT BRICE2
1Liverpool Hospital
2Ionis Pharmaceuticals
3University of British Columbia
4Sunnybrook Research Institute
5University of Otago
6New Zealand Clinical Research
7Royal Melbourne Hospital
8University of Sydney
9Exsera Bio Labs
10University of Colorado Denver
Abstract
BACKGROUND: Overactivity of the complement Alternative Pathway (AP) has been proposed to contribute to pathogenesis of IgA nephropathy (IgAN). We hypothesized that reduction of systemic AP would improve proteinuria by lowering the production of complement factor B (FB), using an investigational antisense oligonucleotide (ISIS696844, RO7434656, IONIS-FB-LRx) targeting FB mRNA in the liver.
METHODS: An exploratory, single-arm, multi-national (incl. NZ) open-label Ph2 study recruited patients with biopsy-confirmed IgAN with hematuria, eGFR>45mL/min/1.73m2, and proteinuria >1.5g/d, despite maximally tolerated ACEi/ARB. 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). (NCT04014335)
RESULTS: Study enrolled 10 subjects in Cohort A, 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 factor B fragment Ba (mean % change of -69%, -39% and -88%, respectively). Median proteinuria (24-hr urine collection) at BL was 2.06g/d (IQR 1.43, 3.51g/d). At Wk29, the change in proteinuria was -1.09g/d (IQR -1.68, -0.79g/d), corresponding to a 44% reduction. There was no change in eGFR at Wk29 compared to BL (mean±SD; BL 68±26; Wk29 69±21 mL/min/1.73m2). All subjects completed treatment and IONIS-FB-LRx demonstrated an acceptable safety profile with no Treatment Emergent SAE and the only clinically meaningful safety signal (moderate TEAE) was a reversible ALT elevation without a change in bilirubin in one subject.
CONCLUSIONS: This Ph2 open-label study provides initial clinical evidence that IONIS-FB-LRx, reduces complement and proteinuria in patients with IgAN, supporting Ph3 development (NCT05797610) to determine the potential of IONIS-FB-LRx to reduce the progression of IgAN.
Biography
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