Abstract: PO1545
Use of Lixivaptan in a Patient with Autosomal Dominant Polycystic Kidney Disease (ADPKD) Who Previously Experienced Liver Toxicity with Tolvaptan
Session Information
- Cystic Kidney Diseases: Mechanisms, Genetics, and Treatment
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Shusterman, Neil H., Palladio Biosciences, Horsham, Pennsylvania, United States
- Pellegrini, Lorenzo, Palladio Biosciences, Horsham, Pennsylvania, United States
- Richardson, Elaine R., Palladio Biosciences, Horsham, Pennsylvania, United States
- Hogan, Marie C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Introduction
Blockade of the vasopressin V2 receptor has beneficial effects on the renal manifestations of ADPKD, the most prevalent inherited renal cystic disease in humans. Tolvaptan, a vasopressin V2 receptor antagonist, is the only approved pharmacologic therapy for the treatment of ADPKD patients; however, it is associated with potentially serious idiosyncratic liver toxicity. Lixivaptan is a novel, potent antagonist of the V2 receptor in Phase 3 development for the treatment of ADPKD. Evidence from non-clinical and in silico studies predicts that lixivaptan will have a safer liver toxicity profile in patients with ADPKD. Here we provide the first clinical evidence of lixivaptan’s superior liver safety compared to tolvaptan.
Case Description
A female patient with ADPKD presented with severe bilateral, intractable flank and abdominal pain. The patient had been treated with tolvaptan previously in an attempt to improve her pain; however, tolvaptan therapy had to be permanently discontinued after the patient developed clinically-meaningful alanine aminotransferase (ALT) elevations on each of three sequential attempts to treat her. The patient was screened and enrolled in an open-label study of lixivaptan under a US IND expanded-access protocol (PA-103). After treatment with therapeutic doses of lixivaptan for 12 months, there have been no elevations of ALT or other liver chemistry tests. Improved pain control has allowed resumption of more normal daily activities and the cessation of use of opioid pain medications. Pharmacodynamic effects including decreases in total kidney volume and liver volume were demonstrated as well as expected changes in eGFR with a vasopressin antagonist. Treatment with lixivaptan continues.
Discussion
This is the first report of successful treatment with lixivaptan of a patient who had previously experienced liver toxicity on tolvaptan. These clinical data highlight the potential for improved liver safety with lixivaptan in a patient at high risk for developing liver toxicity. A larger study (PA-ADPKD-303: The ALERT Study) is starting up to treat ADPKD patients with lixivaptan who previously discontinued tolvaptan because of liver chemistry test elevations.