Abstract: FR-OR113
Varoglutamstat Increases Glomerular Filtration in Elderly Patients without Signs of Proteinuria and Potentially Offers a New Approach to Treat Diabetic Kidney Disease (DKD)
Session Information
- Late-Breaking Science Orals - 1
October 25, 2024 | Location: Room 6C, Convention Center
Abstract Time: 05:40 PM - 05:50 PM
Category: Diabetic Kidney Disease
- 702 Diabetic Kidney Disease: Clinical
Authors
- Weber, Frank Thomas, Vivoryon Therapeutics N.V., Halle (Saale), Germany
- Wenzkowski, Christine, Vivoryon Therapeutics N.V., Halle (Saale), Germany
- Schaeffer, Michael Karl, Vivoryon Therapeutics N.V., Halle (Saale), Germany
- Schell-Mader, Sylvia, Vivoryon Therapeutics N.V., Halle (Saale), Germany
- Meyer, Antje, Vivoryon Therapeutics N.V., Halle (Saale), Germany
- Tasler, Stefan, Vivoryon Therapeutics N.V., Halle (Saale), Germany
- Fuchs, Katharina, Vivoryon Therapeutics N.V., Halle (Saale), Germany
- Bihlet, Asger Reinstrup, NBCD A/S, Herlev, Denmark
- Carroll, Kevin, KJC Statistics Ltd, Dublin, Ireland
- Huber, Tobias B., Universitatsklinikum Hamburg-Eppendorf, Hamburg, Germany
Background
Varoglutamstat is an oral, small molecule inhibitor of glutaminyl cyclases (QPCT/L) designed to target Alzheimers disease pathology. In the phase 2b VIVIAD study, effects on kidney function as judged by a significant and clinical meaningful improvement of the estimated glomerular filtration rate (eGFR) were observed over time by slope analysis.
Methods
VIVIAD (NCT04498650) is a multicenter, randomized, placebo-controlled, double-blind, parallel group dose-finding Phase 2b study in 259 patients with Mild Cognitive Impairment (MCI) and early Alzheimers disease (AD) with a treatment duration between 48 and 96 weeks. Participants received 300 mg or 600 mg varoglutamstat, or placebo, twice-daily.
Results
A significant increase of 3.4 mL/min/1.73m2/year (p<0.001) the annualized rate of change of eGFR vs placebo was found in the overall study population. Further investigations in patients with diabetes (N=32) showed an increase of > 8 mL/min/1.73m2/year (p=0.02).
Additional effects in the diabetes subgroup included a reduction in liver transaminases (AST/ALT) of 6 units average, a mild weight loss (- 4 kg), and a reduction in mean arterial pressure (- 5 mmHg) at week 48. Semi quantitative urine dip-stick evaluation did not reveal signs of sustained proteinuria.
The safety assessment showed that varoglutamstat was safe and well-tolerated. There were no meaningful differences in adverse events observed in renal and metabolic system organ classes versus placebo or the total population.
Earlier preclinical data suggest beneficial effects for varoglutamstat on inflammation and fibrosis. However, the specific functional improvement of the kidney was unexpected and additional mechanistic studies are ongoing.
Conclusion
The significant increase in eGFR and several findings of the VIVIAD study support a further development in a new indication like diabetic kidney disease.
The precise molecular mechanism of action of varoglutamstat is under investigation. Importantly, a clinical study in a relevant population and with additional endpoints like measures of albuminuria/proteinuria (UACR/UPCR), inflammation and fibrosis-related biomarkers, in addition to eGFR slope analysis, is in planning.