Kidney Week

Abstract: FR-PO326

Lixivaptan, a Novel Vasopressin V2 Receptor Antagonist in Development for the Treatment of Autosomal Dominant Polycystic Kidney Disease

Session Information

• Cystic Kidney Diseases - II
  November 03, 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

Lorenzo Pellegrini,

• Woodhead, Jeffrey L, DILIsym Services, Inc., Research Triangle Park, North Carolina, United States

Jeffrey L Woodhead,

• Shoda, Lisl, DILIsym Services, Research Triangle Park, North Carolina, United States

Lisl Shoda,

• Siler, Scott Q, DILIsym Services, Research Triangle Park, North Carolina, United States

Scott Q Siler,

• Howell, Brett A, DILIsym Services Inc., Research Triangle Park, North Carolina, United States

Brett A Howell,

• Orlandi, Cesare, Lantheus Medical Imaging, Boston, Massachusetts, United States

Cesare Orlandi,

Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most prevalent inherited genetic diseases in humans. Recent advances established vasopressin V2 receptor inhibition as a clinically validated mechanism of action for ADPKD, however safe and effective disease-modifying therapies for ADPKD are still lacking. Here we evaluated whether lixivaptan, a potent, selective vasopressin V2 antagonist, has characteristics that suggest a favorable benefit-risk profile for ADPKD.

Methods

Using the large body of existing preclinical and clinical data on lixivaptan encompassing 36 clinical studies and 1,673 independent patient exposures, we evaluated the projected efficacy and safety profile of lixivaptan for ADPKD. To explore efficacy, we compared the effect of lixivaptan with the related vasopressin V2 antagonist tolvaptan on accepted pharmacodynamic markers of efficacy in ADPKD. To explore safety, we conducted a multiscale computational model of drug-induced liver injury, a DILIsym evaluation, to determine lixivaptan's propensity to cause hepatocellular injury compared with the known hepatotoxin tolvaptan.

Results

Potent suppression of urine osmolality (U_osm) was seen with lixivaptan in healthy individuals and patients with hyponatremia of various etiologies, suggesting the potential for disease-modifying efficacy in ADPKD. In particular, 200mg BID doses of lixivaptan for 7 days resulted in uninterrupted U_osm below 300 mOsm/kg over 24 hours in 78% of healthy volunteers in study CK-0407. In contrast to tolvaptan, lixivaptan exposure was lower in patients with impaired renal function than in healthy individuals (32% and 31% lower for AUC_0-∞ and C_max, respectively), without affecting lixivaptan's ability to attain target U_osm levels. Importantly, unlike tolvaptan, lixivaptan was not associated with hepatocellular toxicity at doses intended for ADPKD in the DILIsym evaluation.

Conclusion

Our analysis suggests that lixivaptan has the potential to become a safe and effective therapy for the treatment of ADPKD in a broad patient population, paving the way for upcoming clinical trials with lixivaptan for ADPKD.

Funding

• Commercial Support – Palladio Biosciences, Inc.