Abstract: FR-PO706
Further Insights into Iptacopan Mode of Action in IgA Nephropathy Through Protein Profiling
Session Information
- Glomerular Diseases: From Inflammation to Fibrosis - II
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: From Inflammation to Fibrosis
Authors
- Grioni, Andrea, Novartis Institutes for BioMedical Research Basel, Basel, Basel-Stadt, Switzerland
- Lysetskiy, Mykola, Novartis Institutes for BioMedical Research Inc, Cambridge, Massachusetts, United States
- Kostikova, Anna, Novartis Institutes for BioMedical Research Basel, Basel, Basel-Stadt, Switzerland
- Zub, Anastasiia, L'vivs'kij nacional'nij universitet imeni Ivana Franka, L'viv, L'vìvs'ka, Ukraine
- Ikkert, Oksana V., L'vivs'kij nacional'nij universitet imeni Ivana Franka, L'viv, L'vìvs'ka, Ukraine
- Karmash, Oleksandr I., L'vivs'kij nacional'nij universitet imeni Ivana Franka, L'viv, L'vìvs'ka, Ukraine
- Shalai, Yaryna, Novartis Institutes for BioMedical Research Basel, Basel, Basel-Stadt, Switzerland
- Schubart Wellensiek, Anna S., Novartis Institutes for BioMedical Research Basel, Basel, Basel-Stadt, Switzerland
- Harris, Claire Louise, Novartis Institutes for BioMedical Research Basel, Basel, Basel-Stadt, Switzerland
- Meier, Matthias, Novartis Institutes for BioMedical Research Basel, Basel, Basel-Stadt, Switzerland
- Valentin, Marie-Anne, Novartis Institutes for BioMedical Research Basel, Basel, Basel-Stadt, Switzerland
- Kollins, Dmitrij, Novartis Institutes for BioMedical Research Basel, Basel, Basel-Stadt, Switzerland
Background
IgA nephropathy (IgAN) can lead to progressive loss of kidney function, with ~30% of patients with proteinuria 1-2 g/day progressing to kidney failure within 10 years. Iptacopan is a proximal complement inhibitor that specifically binds factor B and inhibits the alternative complement pathway (AP). In a Phase 2 study (NCT03373461), iptacopan treatment led to a dose-dependent reduction in proteinuria and inhibition of the AP in patients with IgAN (1, 2).
Methods
SomaScan, a large proteomics platform, and statistical analysis were used to examine iptacopan’s impact on plasma proteins. Statistical threshold for biomarker definition was set to adjusted p-value < 0.05 and absolute log Fold Change > 0.1.
Results
Iptacopan resulted in a significant modulation of 81 distinct plasma proteins in IgAN patients after 90-days treatment, persisting at the 180-day timepoint. Except for four, proteins were downregulated. Approximately two-thirds of the proteins are likely originated from the kidney (Fig.1), amongst which 4 proteins were reported to have increased expression in kidney from IgAN patients (BCL2L1, HES1, LTbR, C8). These proteins are thought to be released by cellular mechanisms like necrosis, apoptotic vesicles, proteolysis, and cell activation (Fig.1). From scientific literature, the findings are implicating changes in key biological pathways like inflammation, hypercellularity, fibrosis and atrophy.This underscores the potential of iptacopan to modulate protein expression across these pivotal biological processes in the context of IgAN patients.
Conclusion
This data suggests that iptacopan may contribute to reduction of renal inflammation, hypercellularity, fibrosis and atrophy in patients with IgAN. The relevance of these encouraging early findings will necessitate confirmation in a larger data set and at tissue level.
Fig1: Mapping plasma proteins likely originated from kidney to biological functions.
Funding
- Commercial Support – Novartis Pharma AG