Unmet medical need
Diabetic nephropathy is a chronic debilitating complication of diabetes that results in kidney failure with patients progressing to end stage renal disease requiring either kidney dialysis or kidney transplant. The morbidity and societal cost associated with this disease is significant. Over 9 million patients in the United States have diabetic nephropathy and the cost of these patients to our heath care system is over 100 billion dollars per year.
Developing new treatment options that delay or prevent the progression of disease represents a significant unmet need and is now a national priority.
See Health and Human Services website announcing the “Advancing American Kidney Health” initiative at link below:
Role of Tie2 and VE-PTP
Vascular stabilization by activation of Tie2 pathway is of high interest in diabetic nephropathy. Aerpio is a leader in Tie2 activation and is developing first in class treatments for vascular diseases based on novel therapeutics targeting vascular endothelial-protein tyrosine phosphatase (VE-PTP), a key negative regulator of the Tie2 pathway in vascular endothelial cells.
There are significant preclinical data implicating Tie2 activation as a potential mechanism for restoring renal function in diabetics. There are multiple studies that support VE-PTP inhibition as a mechanism to protect kidney function as outlined below:
- VE-PTP is upregulated by hypoxia, hyperglycemia and hypertension
- VE-PTP is markedly upregulated in Akita and db/db diabetic mice and in RenAAV hypertensive mice
- Normal mice with conditional VE-PTP knockout have enhanced Tie2 and eNOS activation, decreased blood pressure, higher glomerular filtration rates, and normal glomeruli
- AAV renin/Akita model has increased VE-PTP, decreased Tie2 activation, glomerular scarring and proteinuria
- When crossed with conditional VE-PTP knockout mouse, glomerular scarring, fibrosis and proteinuria were all decreased with no effects on glucose levels
These preclinical studies support the development of AKB-9778 for the treatment of diabetic nephropathy.
Our two completed Phase 2 clinical studies in diabetics also support further developing AKB-9778. In [analysis from prespecified secondary endpoints from] the 3-month TIME-2 trial and the 48 week TIME-2b trial we observed approximately a 20% reduction (improvement) in urine albumin-creatinine ration (UACR) with a suggestion of a dose response in once daily (QD) and twice daily (BID) dose groups in the TIME-2b study. The TIME-2b data from the subjects with baseline Albuminuria greater than 30 mg/g are shown below.