The Current Status of Drug Development to Treat Polycystic Kidney Disease in the United States
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Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder in which bilateral fluid-filled cysts compress normal kidney tissue and blood vessels which results in inflammation, fibrosis, and progressive nephron loss. It affects nearly 500,000 people in the United States. Half of all ADPKD patients require dialysis or transplantation by the age of 60 years. There are currently no treatments to address the primary cause of ADPKD. However, Tolvaptan, a drug that blocks the kidney vasopressin V2 receptor, results in decreased water reabsorption and decreased cyst growth and fibrosis. Preclinical studies indicated that Vasopressin V2 receptor antagonists inhibit cyst growth and slow the decline of kidney function. Based on this, a phase 3, multicenter, double-blind, placebo-controlled, 3-year trial was conducted recently. The trial consisted of 1445 adults, 961 of whom received Tolvaptan, and 484 the placebo. All participants had ADPKD and relatively preserved renal function and they were considered at risk for rapid disease progression on the basis of a kidney size larger than 750ml. Although the study showed a significant increase in the renal function and significant decrease in the increase of total kidney volume with Tolvaptan (2.8% vs 5.5% per year) the FDA did not recommend this drug to be approved because of significant adverse effects, particularly skin induced liver injury. There were 3 cases of drug-induced liver injury in the Tolvaptan group, and none in the placebo group. Other adverse events included skin neoplasms (basal cell carcinoma and malignant melanoma), glaucoma, and hypernatremia with potentially clinically significant increased sodium levels, increased uric acid, gout, and dehydration. However, the European Commission has granted marketing authorization for Tolvaptan for the treatment of ADPKD in adults who have chronic kidney disease (CKD) stage one to three at initiation of treatment with evidence of rapidly progressing disease. Similarly Tolvaptan has been approved for ADPKD treatment in Japan and Canada also. I will present the results of my research findings as to why Tolvaptan was not approved by the United States FDA although it is approved by other countries and examine the other therapeutic targets actively pursued to treat ADPKD worldwide.