Abstract: TH-PO1214
Vonafexor in Progressive Alport Syndrome: Early Evidence of Kidney Function Benefit from the ALPESTRIA-1 Trial
Session Information
- Late-Breaking Research Posters
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Knebelmann, Bertrand, Université Paris Cité, AP-HP, Paris, Île-de-France, France
- Martinez Jimenez, Víctor, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
- Silva, Arnold L., Boise Kidney, Boise, Idaho, United States
- Mehta, Ankit, Baylor University Medical Center, Dallas, Texas, United States
- Wallace, Eric L., The University of Alabama at Birmingham, Birmingham, Alabama, United States
- Simon, James F., Cleveland Clinic, Cleveland, Ohio, United States
- Rastogi, Anjay, University of California Los Angeles, Los Angeles, California, United States
- Pérez Gómez, María Vanessa, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
- Torra, Roser, Fundacio Puigvert, Barcelona, CT, Spain
- Udani, Suneel M., Nephrology Associates, Oak Park, Illinois, United States
- Rigothier, Claire, Universite de Bordeaux, Bordeaux, Nouvelle-Aquitaine, France
- Le Quintrec, Moglie, Hopital Lapeyronie, Montpellier, Occitanie, France
- Wolf, Myles, Weill Cornell Medicine, New York, New York, United States
- Vonderscher, Jacky, ENYO Pharma SA, Lyon, Auvergne-Rhône-Alpes , France
- Girma, Hugo, ENYO Pharma SA, Lyon, Auvergne-Rhône-Alpes , France
- Scalfaro, Pietro, ENYO Pharma SA, Lyon, Auvergne-Rhône-Alpes , France
Background
Alport syndrome (AS), the second most common genetic kidney disease, is marked by proteinuria and progressive kidney function loss, with no approved disease-modifying therapy. Standard of care (SOC) only modestly slows eGFR decline. Vonafexor, a selective farnesoid X receptor (FXR) agonist, modulates bile/lipid metabolism and has shown antifibrotic and anti-inflammatory effects in AS and CKD mouse models
Methods
This 24-week, single-arm, open-label phase 2 study evaluated vonafexor’s efficacy and safety in progressive AS (UACR >300 mg/g; eGFR 30–90 mL/min/1.73m2). It was given on top of stable SOC as daily fixed escalating doses: 25 mg (4 wks), 50 mg (4 wks), 100 mg (16 wks), followed by 12 wks off-treatment. Patients had 13 scheduled assessments; data were analyzed using a Mixed Model for Repeated Measures. We report preliminary on-treatment results.
Results
Of 36 screened, 26 patients with X-linked, autosomal, or digenic AS (14F/12M; age 22–53 yr) were enrolled at 12 US/EU sites. Baseline UACR was 859 ± 548 mg/g (mean ± SD) and eGFR 54.7 ± 18.7 mL/min/1.73m2. Early GGT reductions confirmed FXR engagement. Added to stable SOC (88% RAS blockade; 81% SGLT2i), vonafexor improved kidney function: the historical pre-baseline eGFR slope over 3 yr was –5.6 mL/min/1.73m2/yr (95% CI –8.5 to –2.8), whereas the on-treatment annualized slope to wk 24 was +7.0 (95% CI –0.6 to 14.5; p = 0.0008). UACR remained stable, with mean values [95%CI] of 659 mg/g [421;897] at wk 4, 941 [715;1169] at wk 8, and 790 [602;978] at wk 24 (p > 0.05 from baseline). Safety was consistent with prior trials: 20 patients (77%) reported 57 related AEs, mainly skin (11; 42%), GI (9; 35%), or lab abnormalities (7; 27%); most were mild (67%) or moderate (28%), 3 severe (5%). Five discontinued early: 2 hepatitis (adjudication ongoing), 2 pruritus, 1 epistaxis.
Conclusion
Vonafexor remarkably reversed the eGFR decline noted in AS patients despite stable SoC. This improvement occurred without a concomitant rise in UACR. The dissociation of eGFR recovery from proteinuria argues against a purely hemodynamic effect and supports a potential disease-modifying effect. A phase 3 trial is in preparation.
Funding
- Commercial Support – ENYOPharma SA