Pipeline: Lixivaptan

Palladio is actively investigating the efficacy and safety of lixivaptan as well as its potential to deliver a differentiated safety profile for patients with Polycystic Kidney Disease (PKD).

Lixivaptan is a new investigational chemical entity that works by selectively suppressing the hormone vasopressin at the V2 receptor. Vasopressin normally helps regulate water balance in the body. However, in patients with ADPKD, vasopressin also has a role in promoting cyst growth. In animal models of disease, vasopressin V2 suppression has been proven to inhibit cyst growth and decrease fluid secretion into cysts, thus decreasing cyst burden. Extensive clinical trials have proven that other vasopressin V2 antagonists can effectively treat ADPKD.

The development program for lixivaptan is designed to show that lixivaptan can slow the decline in renal function that is typically observed in ADPKD. We believe that early therapy initiation with a vasopressin V2 antagonist like lixivaptan could delay or possibly eliminate the need for dialysis or kidney transplant in many ADPKD patients, as illustrated in the Renal Function Decline graph.

Lixivaptan’s development program is designed to address other major unmet needs of ADPKD patients.It will offer another treatment option for patients who currently only have one approved drug for ADPKD.

Additional clinical trials are planned to confirm that lixivaptan is free from the serious liver toxicity caused by the current approved drug, thus expanding the number of patients who may benefit from therapy and eliminating or decreasing the need for frequent and cumbersome liver enzyme monitoring.  

Lixivaptan’s development program for ADPKD builds on a previous, extensive development program with lixivaptan for the treatment of hyponatremia, a water retention disorder. This work included 36 completed clinical studies in which more than 1,600 subjects were dosed with lixivaptan. These historical data confirm lixivaptan’s activity for key measures believed to be important for ADPKD.

Key development milestones achieved to date include:

DILIsym Liver Safety Evaluation of Lixivaptan 
Prior to administering lixivaptan to ADPKD patients, Palladio studied lixivaptan’s liver safety profile in DILIsym, a state-of-the art, predictive, quantitative systems toxicology modeling tool, and compared it to the liver safety profile of tolvaptan. Full details of this study have been published in a peer-reviewed journal. Briefly, results suggest that lixivaptan may not cause liver transaminase elevations, an indication of liver toxicity, and therefore it may have a favorable liver safety profile.

Orphan Drug Designation
The U.S. FDA, through its Office of Orphan Drug Products, designated lixivaptan as an orphan drug for treating ADPKD. This designation provides eligibility for certain benefits and confers seven years of market exclusivity following receipt of regulatory approval.

ELiSA  Clinical Trial
We completed ELiSA (Evaluation of Lixivaptan in Subjects with ADPKD), a Phase 2 clinical trial that was the first study of lixivaptan in ADPKD patients.
More information can be found here

Lixivaptan in a Single Subject with Intractable Pain Due to Polycystic Kidney Disease
Palladio completed a clinical study that investigated the use of lixivaptan in a patient who could not tolerate the vasopressin antagonist, tolvaptan, because of liver chemistry abnormalities. The patient did not experience any elevations of ALT or other chemistry tests over a year of treatment with lixivaptan.
More information can be found here

The ALERT Study- Safety of Lixivaptan in Subjects Previously Treated with Tolvaptan for ADPKD
We initiated the ALERT Study, (PA-ADPKD-303), Palladio’s first Phase 3 clinical trial for lixivaptan, designed to assess liver safety of lixivaptan therapy in patients previously discontinued from tolvaptan for liver chemistry test abnormalities.
More information can be found here