We are developing medicines for orphan diseases of the kidney. Our initial focus is on Polycystic Kidney Disease (PKD), a disease for which there are limited available treatment options despite high morbidity and mortality.
Our first product is lixivaptan, a selective vasopressin V2 receptor antagonist. Lixivaptan had been in development for the treatment of water retention disorders, specifically hyponatremia associated with CHF (congestive heart failure) and SIADH (syndrome of inappropriate antidiuretic hormone). The prior clinical development program for the treatment of hyponatremia included 36 completed clinical studies and dosed more than 1,600 subjects with lixivaptan. We plan to leverage this extensive data package, and the learnings from recent regulatory actions for other ADPKD treatments, to develop lixivaptan as a safe and effective drug that could potentially be used by a broad group of PKD patients.
There is pre-clinical and clinical data to support the use of vasopressin V2 receptor antagonists for the treatment of PKD. Vasopressin is a hormone produced by the brain that functions primarily to retain water in the body and, at higher concentrations, to constrict blood vessels. It regulates water retention by increasing water reabsorption in the kidney’s collecting ducts to signal the kidneys to conserve water. In cells lining renal collecting tubules, activation of vasopressin V2 receptors by circulating vasopressin contributes to the production of an intracellular signaling molecule, cAMP. It is believed that elevated intracellular cAMP, through the activation of cAMP-dependent genes, promotes fluid secretion into developing renal cysts and increases cell proliferation. The suppression of vasopressin signaling, by genetic elimination of vasopressin or vasopressin V2 receptor blockage, has been shown to normalize cAMP levels, reduce cyst burden and protect kidney function in animal models of PKD. This suggests that therapeutic interventions aimed at inhibiting vasopressin V2 receptor signaling could be effective for the treatment of PKD. Consistent with this hypothesis, the vasopressin antagonist tolvaptan showed clinical efficacy in pivotal studies and is currently approved in many countries for the treatment of ADPKD despite of concerns about its potential to cause liver injury. Early therapy initiation with a vasopressin antagonist could delay or possibly eliminate the need for dialysis in many ADPKD patients, as illustrated in the diagram below.
Palladio Biosciences recognized the need for a drug with a similar mechanism of action to tolvaptan but without its liver toxicity issues.
Lixivaptan is an orally-active, non-peptide, competitive and selective antagonist for the vasopressin V2 receptor. It is not currently approved for human use anywhere in the world, however it has an extensive data package that includes a full pre-clinical characterization and data from 36 clinical studies. No development or approval issues for other indications were noted in previous FDA discussions. Lixivaptan is functionally equivalent to tolvaptan and has shown similar efficacy in patients with hyponatremia on key measures important for ADPKD. Importantly, lixivaptan has shown no evidence of liver toxicity in the clinical studies conducted so far.
Key Development Milestones
- Results from a state-of-the-art, predictive modeling tool based on in vitro inputs, physiologically based pharmacokinetic modeling and in silico simulations suggested that lixivaptan may have a differentiated safety profile compared to tolvaptan with respect to the potential to cause liver injury. Among other key findings, this investigation indicated that lixivaptan may have lower liver exposure than tolvaptan; that lixivaptan does not affect bile acid homeostasis and mitochondrial function, two key mechanisms of liver injury that may contribute to tolvaptan liver toxicity; and that lixivaptan, unlike tolvaptan, may not cause ALT elevations. These findings need to be confirmed in the clinics.
- The U.S. FDA Office of Orphan Drug Products designated lixivaptan as an orphan drug for treating ADPKD. The orphan drug designation is granted to support the development of drugs and biologics intended for the safe and effective treatment, diagnosis or prevention of diseases or disorders that affect fewer than 200,000 people in the U.S., or that affect more than 200,000 people but are not expected to recover the costs of drug development and marketing. Orphan drug designation provides eligibility for certain benefits, including seven years of market exclusivity following receipt of regulatory approval, tax credits for qualified clinical trials, and exemption from FDA application fees. It is an important milestone in the lixivaptan development program.
- In April 2018, the FDA granted IND (investigational new drug) clearance for the ELISA Study (Evaluation of Lixivaptan In Subjects with ADPKD), a Phase 2 clinical trial that will evaluate the safety, pharmacokinetics and pharmacodynamics of multiple doses of lixivaptan in patients with ADPKD with relatively preserved kidney function (chronic kidney disease stages CKD1 and CKD2) and moderately impaired renal function (CKD3). The study is expected to enroll 32 patients beginning the end of June 2018.