Vonafexor, a Selective FXR Agonist, as a Novel Therapeutic Strategy in CKD

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Background: Chronic kidney disease (CKD) is characterized by progressive loss of renal function, with limited therapies available to slow its progression. FXR (NR1H4), a druggable nuclear receptor, has emerged as a promising therapeutic target. This study investigated the efficacy of Vonafexor, a selective FXR agonist, in experimental CKD models. Methods: Two murine models were used: subtotal nephrectomy (Nx) and Col4a3-/- mice (Alport syndrome). Vonafexor was administered orally from weeks 5–8 post-surgery (Nx) or post-birth (Alport). FXR and its downstream targets were assessed by qRT-PCR, western blot, and immunohistochemistry. Renal injury, inflammation, fibrosis, and podocyte loss were quantified. Comparisons were made with Losartan and other FXR agonists. Nrh1h4-/- mice were also studied. RNA-seq (NovaSeq6000) was performed to assess transcriptomic changes. Human kidney biopsies complemented the mouse studies. Results: FXR and its targets were significantly downregulated in Nx kidneys. FXR localized predominantly in proximal tubules. At week 5, renal lesions were present in both models. Vonafexor halted CKD progression and reversed fibrosis, outperforming Losartan and other FXR agonists. It significantly reduced lymphocyte/macrophage infiltration, myofibroblast activation, and podocyte loss. In Col4a3-/- mice, Vonafexor also extended lifespan. Transcriptomic analysis revealed that Wnt-β-catenin pathway was one of the most downregulated pathways in Vonafexor-treated Nx mice. We confirmed that Wnt-β-catenin signaling was aberrantly activated in both CKD models and suppressed by Vonafexor. Notably, active β-catenin accumulation in Nrh1h4-/- mice supported a mechanistic link between FXR loss and Wnt pathway activation. In human CKD biopsies, FXR expression was significantly reduced across multiple kidney diseases, highlighting translational relevance. Conclusion: Together, our results demonstrate that Vonafexor significantly attenuates CKD progression in experimental models by modulating the Wnt–β-catenin signaling pathway, surpassing the efficacy of current treatments. These preclinical findings, combined with clinical data from the LIVIFY phase 2 trial showing improved eGFR in NASH patients with CKD, underscore the therapeutic potential of Vonafexor as a novel therapeutic strategy for CKD. Funding: Other NIH Support - INSERM, CNRS, Universite Paris Cité, Government Support – Non-U.S.

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