We are developing medicines for orphan diseases of the kidney. Our initial focus is on Polycystic Kidney Disease (PKD) which has no approved drug treatments in the United States.
Our first product is lixivaptan, a selective vasopressin V2 receptor antagonist, which had been in development for the treatment of hyponatremia associated with CHF (congestive heart failure) and SIADH (syndrome of inappropriate antidiuretic hormone). We plan to reposition lixivaptan for the treatment of polycystic kidney disease, leveraging the extensive data package for lixivaptan and the learnings from recent regulatory actions for ADPKD treatments.
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 high 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. Vasopressin activity results in the production of cAMP by the kidneys. cAMP-dependent genes promote fluid section into developing renal cysts and increase cell proliferation. The suppression of vasopressin, by high water intake, genetic elimination of vasopressin, or vasopressin V2 receptor blockage, has been shown to reduce cyst burden and protect kidney function in animal models. Tolvaptan, a vasopressin antagonist marketed for certain hyponatremia conditions, has been approved for ADPKD ex-US (Japan, EU and Canada) based on results from TEMPO, a pivotal study in 1450 ADPKD patients. Tolvaptan was not approved for use in the United States, primarily due to concerns regarding tolvaptan’s safety profile based on reports of liver injury during the TEMPO drug trial. The FDA review, however, noted that early therapy initiation could eliminate the need for dialysis in many ADPKD patients.
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 has previously been dosed in 1673 subjects and has an extensive data package that includes a full pre-clinical package and data from 36 clinical studies. No development or approval issues for other indications were noted in previous FDA discussions. Lixivaptan is functionally identical to tolvaptan and has shown at least equivalent efficacy in patients with hyponatremia for key measures important for ADPKD. Importantly, lixivaptan has no evidence of liver toxicity.
Results from a predictive modeling tool based on in vitro inputs, physiologically based pharmacokinetic modeling and in silico simulations have confirmed the differentiated safety profile of lixivaptan compared to tolvaptan. Key findings include:
• Lixivaptan has a lower liver exposure than tolvaptan
• Lixivaptan does not affect bile acid homeostasis nor mitochondrial dysfunction to cause liver dysfunction, the mechanisms associated with tolvaptan liver toxicity
• No ALT elevations were noted, compared to 7.9% for tolvaptan
• No Hy’s Law cases were predicted vs three reported cases in tolvaptan clinical studies for ADPKD
This data, together with learnings from the previous regulatory experience, will inform the trial design for the lixivaptan development program.
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.
Immediate next steps to re-position lixivaptan for PKD include the following actions:
• Secure FDA alignment on clinical strategy
• Conduct initial clinical studies to characterize the pharmacokinetic and pharmocodynamic profile of lixivaptan in patients with ADPKD