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Kidney Week

Abstract: TH-PO844

Effect of Lixivaptan on Pharmacokinetic (PK) and Pharmacodynamic (PD) End Points in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) in the ELiSA Study (PA-102)

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Shusterman, Neil H., Palladio Biosciences, Inc., Haverford, Pennsylvania, United States
  • Hogan, Linda C., Palladio Biosciences, Newtown, Pennsylvania, United States
  • Pellegrini, Lorenzo, Palladio Biosciences, Newtown, Pennsylvania, United States
Background

Blockade of the vasopressin V2 receptor has beneficial effects in non-clinical and clinical studies of patients with ADPKD. Lixivaptan is a novel, potent antagonist of the V2 receptor in Phase 3 development for treatment of ADPKD. We report the PK and PD results of the ELiSA study, the first clinical study with lixivaptan in ADPKD patients.

Methods

32 subjects, Chronic Kidney Disease (CKD) Stages 1, 2, and 3, were enrolled at 14 sites in the US. Subjects received lixivaptan for 7 days at 1 of 2 BID dose levels to assess PK and PD endpoints after 1 and 7 days of treatment. AM and PM doses were separated by 10 hours. Full 24 hour PK profiles were obtained on Days 1 and 7 of dosing. PD endpoints were urine osmolality (Uosm), total kidney volume measured by MRI, eGFR, serum sodium, and plasma copeptin. Adverse events were assessed. Aquaretic tolerability was assessed through a specially designed questionnaire.

Results

At the high dose, lixivaptan caused profound declines in Uosm below the iso-osmolar level (300 mOsm/kg), indicating effective V2 receptor inhibition over extended time periods. Mean Uosm declined 80% to a minimum value of 84 mOsm/kg 2 hours after the first dose of lixivaptan. Importantly, 100% of subjects in CKD Stages 2 and 3 maintained Uosm below 300 mOsm/kg over 24 hours. The high dose of lixivaptan showed a strong, reversible effect on other PD variables, including serum sodium (mean increase of 1.9% from baseline) and serum copeptin (2.5 fold increase from baseline). The effect of lixivaptan on all PD endpoints tested compares favorably with historical data for tolvaptan. Conversely, the low dose of lixivaptan tested in this study acutely reduced Uosm but did not provide continued suppression below iso-osmolar levels over an extended period of time.

Conclusion

These Phase 2 data confirm that the high dose of lixivaptan tested is a fully pharmacologically effective dose of lixivaptan for ADPKD, whereas the low dose is emerging as the starting dose of lixivaptan. These results inform the appropriate titration dose range in the upcoming pivotal Phase 3 study with lixivaptan in ADPKD patients.

Funding

  • Commercial Support