Polycystic Kidney Disease

  • PKD affects ~600,000 Americans, for whom only Tolvaptan has been approved by the FDA
  • NovaTarg has discovered a series of disease-modifying drugs that treat the underlying cause of PKD
    1. Kidney epithelial cell proliferation
    2. Fluid secretion that drives cyst development

Disease-Modifying AMPK Activators for PKD

Polycystic kidney disease (PKD) is a family of hereditary disorders involving the appearance of fluid-filled cysts in the kidneys, leading to kidney failure and end-stage renal disease (ESRD).

PKD affects >600,000 people in the US and over 12 million worldwide. Most suffer from the autosomal dominant type (ADPKD), which is the fourth leading cause of kidney failure (~10% of all ESRD). In ADPKD, the kidneys become grossly enlarged to 4–8 times normal size, the cysts are benign but progress to chronic renal failure by age 60 and require dialysis or kidney transplant.

Renal cyst development and expansion in PKD involves both fluid secretion and abnormal proliferation of cyst-lining epithelial cells. Both processes are regulated by AMPK, so biguanides that are transported by organic cation transporter 2 (OCT2) and activate AMPK, have the potential to be disease-modifying drugs to treat PKD.

NovaTarg lead compounds, particularly NT1021, activate AMPK in human ADPKD cells, inhibit cell growth and block fluid secretion. Importantly, they also inhibit cyst formation in a PKD model system in mice.

Graphic of kidneys from mice with Polycystic Kidney Disease from embryonic stage 15.5 to day 4. Two sets are imaged: one in a culture with just cAMP, and another with cAMP and NT1021. The kidney cultured in cAMP continuously grows cysts, whereas the kidney cultured with NT1021 displays no such tumor activity.
Kidneys from PKD mice, when harvested from late-stage embryos develop cysts in culture. This process is completely blocked by an early lead compound (NT1021).

No drugs are available for treatment of PKD in the US, yet the need for a therapy that would prevent cyst formation and progression to renal failure is urgent.

NovaTarg is at late-stage lead optimization with the expectation that a drug candidate will be identified by 4Q17.

This will be the first drug designed for PKD and the first drug that will address the two key processes underlying PKD development.