Otsuka Pharmaceutical Co., Ltd.

August 6, 2013

U.S. Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee Recommends Against Approval of Otsuka Pharmaceutical's Tolvaptan for Use in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Tokyo, Japan - August 6, 2013 - Otsuka Pharmaceutical Co., Ltd. announced today the U.S. Food and Drug Administration's (FDA) Cardiovascular and Renal Drugs Advisory Committee voted against approval of tolvaptan for the treatment of ADPKD. The Advisory Committee voted 9 to 6 not to approve tolvaptan for ADPKD. The FDA is not bound by the Committee's guidance but takes its advice into consideration.

"While we are disappointed in the Committee's recommendation, we remain committed to providing patients and physicians with a novel treatment for ADPKD, a rare genetic disease. We are looking forward to continuing discussions with the FDA to address the panel's concerns," said Robert McQuade, Ph.D., Executive Vice President and Chief Strategic Officer, Otsuka Pharmaceutical Development & Commercialization Inc.

ADPKD is characterized predominantly by the formation of cysts in both kidneys that cause progressive kidney enlargement, and it is associated with pain, hypertension, decreased kidney function and ultimately, kidney failure.*1 The average age at which ADPKD patients enter end-stage renal disease (ESRD) is 56.*2 Today, there are no treatment options specifically indicated for ADPKD and physicians have had limited resources to manage the disease, relying on symptom management, dialysis and transplantation as treatments of last resort when ADPKD progresses.*1,3

The FDA accepted Otsuka's new drug application (NDA) for tolvaptan earlier this year, granting the drug a priority review status and assigning a Prescription Drug User Fee Act (PDUFA) goal date of September 1, 2013.

About Tolvaptan

Tolvaptan is currently under review as a treatment to slow the progression of kidney disease for patients at risk of rapidly progressing ADPKD. Tolvaptan was studied in patients with enlarged kidneys who were in chronic kidney disease (CKD) stages 1-3 at initiation of treatment. Results were published in the New England Journal of Medicine in December 2012.

Tolvaptan is believed to inhibit cyst formation, proliferation and growth.*4 Cyst formation is dependent on the binding of a hormone called arginine vasopressin to the V2 receptor.*4,5 Vasopressin acts as an agonist of the V2 receptor, accelerating cyst proliferation, fluid secretion into the cystic structures and cyst growth, ultimately leading to enlarged, dysfunctional kidneys.*4,5 Tolvaptan is a selective V2 receptor antagonist that blocks the vasopressin-mediated activation of the cyclic AMP pathway that leads to cell proliferation and fluid secretion.*4


ADPKD is the most common type of inherited genetic kidney disorders called polycystic kidney disease (PKD).*6 PKD is a progressive disease characterized predominantly by the development of numerous cysts in both kidneys.*1 The disease is caused by mutations in genes that regulate kidney function.*6 Two types of genetic mutations can cause ADPKD, the PKD1 mutation and the PKD2 mutation.*6 People with the PKD1 mutation generally have kidney disease that progresses more rapidly than people with the PKD2 mutation.*6 The genetic mutation that causes ADPKD is a dominant trait, which means that if a person has the disorder, there is a 50 percent chance that each of their children or siblings will also be at risk of developing the disease.*1

ADPKD is a life-threatening disease that causes significant kidney damage and dysfunction.*1,7 It is the fourth leading cause of ESRD.*7 The average age at which ADPKD patients enter ESRD is 56.2 Kidneys affected by PKD become significantly enlarged, due to the formation and growth of multiple cysts which proliferate through healthy kidney tissue.*1

  • *1 Polycystic Kidney Disease. National Kidney and Urologic Diseases Information Clearinghouse. (Sept., 2010). Retrieved June 17, 2013, from:
  • *2 Ahsan A & Perrone R. "End-stage renal disease in polycystic kidney disease." Polycystic Kidney Disease: from Bench to Bedside 2013; 164-174 doi:10.2217/9781780841748
  • *3 Wüthrich, P and Changlin M. "Aquaretic Treatment in Polycystic Kidney Disease." The New England Journal of Medicine; 2012, 367 (25): 2440-2441
  • *4 Torres, VE et al. "Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease." The New England Journal of Medicine, 2012: 367 (25): 2407-2418
  • *5 Patel V, et al. "Advances in the Pathogenesis and Treatment of Polycystic Kidney Disease" University of Texas, Department of Pediatrics 2009
  • *6 Ahrabi, A, et al. "PKD1 Haploinsufficiency Causes a Syndrome of Inappropriate Antidiuresis in Mice" Journal of the American Society of Nephrology 2007; 18: 1740-1753
  • *7 Elhassan E, et al. "Progress on Autosomal Dominant Polycystic Kidney Disease." The Arab Journal of Nephrology and Transplantation 2009; 2(2): 27-44