Palladio is actively investigating the efficacy of lixivaptan as well as its potential to deliver a differentiated safety profile in terms of drug induced liver toxicity for patients with Polycystic Kidney Disease (PKD).
Lixivaptan is a new 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 causing cysts to grow. In animal models of disease, vasopressin V2 suppression has been proven to inhibit that cyst growth and decrease fluid secretion into cysts, thus decreasing cyst burden. Extensive clinical trials have proven that vasopressin V2 antagonists like lixivaptan can effectively treat ADPKD.
The development program for lixivaptan is expected 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 diagram below.
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 will be conducted 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 development program with lixivaptan for the treatment of hyponatremia, a water retention disorder. This work included an extensive pre-clinical characterization and results from 36 completed clinical studies in which more than 1,600 subjects were dosed with lixivaptan. These data confirm lixivaptan’s activity for key measures important for ADPKD.
Key development milestones achieved to date include:
DILIsym Evaluation of Potential for Liver Toxicity
Prior to administering lixivaptan to ADPKD patients, Palladio studied the potential for liver safety in a state-of-the art, predictive toxicology modeling tool. Full details of this study have been published in a peer-reviewed journal. Briefly, results suggest that lixivaptan may have a better safety profile in terms of potential to cause liver injury compared to the currently approved therapy. Possible reasons include lower liver exposure and lack of negative effects on bile acid homeostasis and mitochondrial function, two key mechanisms associated with liver injury. The study suggested that lixivaptan may not cause ALT elevations, an indication of liver toxicity.
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 (Evaluation of Lixivaptan in Subjects with ADPKD) Clinical Trial
ELiSA was a Phase 2 clinical trial to evaluate the safety, pharmacokinetics, and pharmacodynamics of multiple doses of lixivaptan in patients with ADPKD and relatively preserved kidney function (chronic kidney disease stages CKD 1 and CDK 2) and moderately impaired renal function (CKD 3). Results confirmed lixivaptan’s activity as a potent vasopressin V2 receptor antagonist in ADPKD patients and defined the dose range for further clinical trials. Lixivaptan demonstrated good safety and tolerability. Adverse events were consistent with previous studies with other vaptans.
Lixivaptan in a Single Subject with Intractable Pain Due to Polycystic Kidney Disease
This study investigated the use of lixivaptan in a patient who cannot tolerate a related vasopressin antagonist. Results of more than 12 months of lixivaptan treatment will be presented during the 2020 Kidney Week.
Current Clinical Trials
The ALERT Study--Safety of Lixivaptan in Subjects Previously Treated with Tolvaptan for ADPKD
Palladio is currently enrolling ADPKD patients into The ALERT Study (PA-ADPKD-303), the company’s first Phase 3 clinical trial for lixivaptan. In this study, ADPKD patients between the ages of 18-65, who had been permanently discontinued from tolvaptan therapy due to liver chemistry abnormalities or other signs of liver toxicity, will be treated with lixivaptan for up to 58 weeks. The primary objective of the study is to determine the liver safety of lixivaptan in these patients.
More detailed information for Lixivaptan’s clinical development program can be found here.
Palladio is exploring a development program for Autosomal Recessive Polycystic Kidney Disease.