Novel AMPK activator for treatment of congenital X-linked nephrogenic diabetes insipidus in pediatric patients

PROJECT SUMMARY NephroDI Therapeutics (NephroDI) is advancing a first-in-class therapeutic, NDI-5001, for treatment of congenital X-linked nephrogenic diabetes insipidus (X-linked NDI). X-linked NDI is a rare pediatric orphan disease characterized by the production of very large quantities of dilute urine due to mutations in the type 2 vasopressin receptor (V2R) that prevent activation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway. Individuals with X-linked NDI produce up to 20 L/d of dilute urine, almost 1 L/h 24-7-365. If left untreated, repeated episodes of severe dehydration may occur, eventually resulting in serious complications including dehydration-induced cognitive impairment, and children are especially vulnerable. The current therapeutic option for X-linked NDI patients is to drink as much water as they urinate and severely limit dietary sodium (0.5 g/d) and solute intake. The unmet medical need in X-linked NDI is enormous. Currently, there is no effective therapy for X-linked NDI. NephroDI performed extensive efficacy, pharmacokinetic, formulation, and Investigational New Drug (IND)-enabling toxicology studies, initially during the phase 1 STTR, and subsequently with venture capital and a strategic partner. The nonclinical safety profile of NDI-5001 has been well characterized through the conduct of secondary pharmacology and pharmacodynamic studies, in vitro and in vivo genetic toxicology, in vitro and in vivo safety pharmacology, and pivotal 4-week repeat-dose toxicity and toxicokinetic (TK) studies in healthy rats and dogs. The NDI-5001 IND-enabling toxicology studies were conducted under GLP and adhered to principles set in place by the International Council on Harmonization (ICH). The NDI-5001 IND-enabling safety program is considered adequate to support a first-in-human Single Ascending Dose (SAD), Food Effects, and Multiple Ascending Dose (MAD) studies. NephroDI’s business plan is to develop NDI-5001 for the treatment of X-linked NDI. NephroDI has been granted Orphan Drug Designation (DRU-2022-9153) for NDI-5001 from the FDA. The goal of this phase 2 SBIR application is to perform the additional, well-controlled, nonclinical studies necessary to support the pivotal clinical study in pediatric subjects with X-linked NDI. NephroDI has the business infrastructure and domain expertise to establish human proof of concept for NDI-5001, an investigational new drug for X-linked NDI. We have a very strong IP position. Specific Aim 1. GLP 39-week pivotal juvenile dog (pre-weaning) toxicology studies. Specific Aim 2. GLP male-only rat fertility and early embryonic development (FEED) study. Specific Aim 3. Develop a liquid formulation suitable for pediatric populations for use in clinical trials. Completion of these Aims will enable NephroDI to proceed to the pivotal study, post-Phase 1, in pediatric NDI subjects with documented V2R mutations.