Development of a Treatment Response Prediction Strategy for Sparsentan in Glomerular Disease

Le résumé fourni par la source

Background: Sparsentan is a dual endothelin receptor A inhibitor and angiotensin blocker that demonstrated reduced proteinuria in patients with FSGS in Phase II studies (DUET). Gene expression data from Adriamycin (ADR) treated rats treated with sparsentan were used to develop a response profile. Methods: An interventional dose-response study was performed in rats challenged with Adriamycin (ADR) to induce an FSGS phenotype. UPCR randomization was performed at day 7 post-challenge, and daily dosing of sparsentan across a dose range was carried out for 35 days. Kidneys were harvested, stored in FFPE, and kidney cortex RNAseq profiles were generated. Differentially expressed gene (DEG) analysis followed by enrichment analysis was performed. A sparsentan response profile from the model was mapped onto human kidney RNAseq profiles from microdissected kidney biopsies from the NEPTUNE cohort and interrogated against demographic and clinical features of the cohort. Results: DEG profiles were generated in ADR+vehicle vs. Sham animals (4271, q<0.05) and from ADR+sparsentan relative to ADR + vehiclel. A high dose group (60mg/kg) generated the largest number of DEGs compared to ADR+vehicle (583, q<0.05); consistent with attenuation of proteinuria (p=0.053) and glomerulosclerosis (p<0.05) in this group at Day 33. Sparsentan reversed directionality 388 DEGs from the model. The 388 genes were enriched for genes in the endothelin pathway (p<0.01) and for genes consistent with active EDN1 (p<0.01). Based on gene expression profiles, activities of IL1B, IFNγ, TNF, and TLR4 were predicted to be attenuated by sparsentan. Mapping the signature onto human data revealed elevated signaling in glomerular and tubule profiles of patients with FSGS (p<0.05). The signature was negatively correlated with eGFR (p<0.01) and positively correlated with UPCR (p<0.05). Changes in intrarenal transcriptional profiles were reflected in plasma and urine. Conclusions: Sparsentan treatment attenuated gene expression and activity of disease-related networks in a rat model of FSGS. The sparsentan response signature from rats was elevated in human FSGS kidney tissue, associated with disease severity. Candidate non-invasive biomarkers were identified and are being developed for the NEPTUNE Match clinical trial (NCT04571658). Funding: NIDDK Support, Commercial Support - Travere Therapeutics

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.