Nephrogenic diabetes insipidus (NDI) is a disease characterized by the production of very large quantities of dilute urine from an inability of the kidney to respond to vasopressin. NDI can be either congenital or acquired. Acquired NDI is a common side effect of lithium therapy. Lithium-induced NDI patients produce over 3 L/d of dilute urine. Lithium is the first-line treatment for bipolar disorder but causes NDI in up to 70% of patients. Lithium-induced NDI can appear as early as 2-4 months after starting therapy, its severity increases with duration, and it causes significant morbidity and may even be lethal. Currently there is no effective therapy for any form of NDI. Extensive research by NephroDI Therapeutics co-founders identified a novel series of AMPK activators as a potential therapy for NDI. We have ample data showing that one of these AMPK activators, NDI-5033, has excellent efficacy in multiple models of X-linked congenital NDI. Importantly, NDI-5033 does not cause hypoglycemia in rat safety studies, which distinguishes it from many other AMPK activators. NephroDI is aggressively pursuing development of NDI-5033 for treatment of X-linked NDI. The major goal of this phase-I STTR application is to validate the utility of AMPK activators in lithium- induced NDI, and to identify a lead molecule from our proprietary chemical series of AMPK activators. The unmet medical need in lithium-induced NDI is enormous, as millions of patients are prescribed lithium, the most widely used and best studied treatment for bipolar disorder. Not only is there no effective treatment for NDI once it develops, the NDI often persists after stopping lithium. Based on the data generated from this grant, we aim to advance one of our AMPK activators for treatment of lithium-induced NDI. Our preliminary data show that NDI-5033 can reverse lithium-induced NDI in rats. NephroDI has the business infrastructure and domain expertise to establish human proof of concept of investigational drugs for NDI. We have a very strong IP position. NephroDI has licensed broad US patents from Emory University for methods of treating NDI, both X-linked (US Patent 9,827,222) and lithium-induced (US Patent 10,596,144), with AMPK activators. NephroDI has acquired the composition of matter patent (US Patent 8,623,897) protecting NDI-5033 and the chemical series.
Specific Aim 1. NephroDI will scale up five select AMPK activators for evaluation in efficacy studies. We will study the rat PK profile of these compounds to ensure good oral availability to support the planned efficacy studies.
Specific Aim 2. Emory will determine the efficacy of AMPK activators in our rat model of lithium-induced NDI and identify compounds that are able to reverse lithium-induced ND. The compound demonstrating the best profile will be selected as the lead molecule.
Specific Aim 3. NephroDI will assess the safety of the lead compound in rats. The lead molecule will be evaluated in a 2-week repeat oral dosing study in rats to establish a therapeutic window of >10-fold.
The goal of the project is to identify a therapy for a currently untreatable disease, nephrogenic diabetes insipidus (NDI), which causes patients to produce a very large volume of urine and can lead to severe dehydration. NDI can be present from birth because of a genetic defect or emerge as a side-effect of lithium, which is the most widely used and best studied treatment for Bipolar Disorder. We will develop a novel drug treatment for patients suffering from lithium-induced NDI.