Abstract: TH-PO574
Effects of a Novel Vasopressin V2 Receptor Antagonist on Cystic Disease Progression in the PCK Rat
Session Information
- Cystic Kidney Diseases - I
November 02, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Genetic Diseases of the Kidney
- 801 Cystic Kidney Diseases
Authors
- Pellegrini, Lorenzo, Palladio Biosciences, Newtown, Pennsylvania, United States
- Constans, Megan M., Mayo Clinic, Rochester, Minnesota, United States
- Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
- Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
Background
Vasopressin V2 receptor inhibition is a clinically validated mechanism of action for Autosomal Dominant Polycystic Kidney Disease (ADPKD), a progressive genetic disease characterized by the formation and enlargement of fluid-filled cysts in the kidneys. However, safe and effective disease-modifying therapies for ADPKD are still lacking. Here we report the first evidence that lixivaptan, a promising, selective vasopressin V2 antagonist, could have utility for the treatment of ADPKD.
Methods
We examined the effects of lixivaptan in PCK rats, an orthologous animal model of Autosomal Recessive PKD that develops a phenotype reminiscent of ADPKD. 4-week old PCK rats were randomly assigned to vehicle control, standard dose of lixivaptan or two alternative lixivaptan dosing protocols and subsequently treated for 8 weeks. At the end of treatment, a comprehensive panel of biochemical and histomorphometric endpoints was evaluated to assess the effect of lixivaptan on disease progression.
Results
PCK rats in the control group showed enlarged kidneys and extensive cyst formation, consistent with the development of a polycystic kidney phenotype. Compared to control animals, PCK rats treated with the standard dose of lixivaptan showed a 27% reduction in kidney weight as a percentage of body weight (p=0.006), a 23% reduction in kidney cAMP levels (p=0.014), a small but statistically significant reduction in liver weight as a percentage of body weight (6%; p=0.03) and a reduction in cyst burden. As expected, these reductions were associated with statistically significant increases in 24h urine output (179%; p<0.0001) and serum sodium (1.7%; p=0.02). Pharmacological efficacy on disease manifestations was also observed in animals treated with the two alternative dosing regimens of lixivaptan, however the difference with the control group did not reach statistical significance.
Conclusion
The beneficial effect of lixivaptan in the PCK rat model of PKD adds to the body of evidence implicating vasopressin V2 receptors in the pathology of ADPKD. These results pave the way to the potential demonstration of a disease-modifying effect of lixivaptan in upcoming clinical trials in ADPKD patients.
Funding
- Commercial Support –