Otsuka Pharmaceutical Co., Ltd.

August 30, 2013

Otsuka Receives Complete Response Letter From U.S. Food And Drug Administration For Tolvaptan For Use In Patients With Autosomal Dominant Polycystic Kidney Disease

Tokyo, Japan - August 30, 2013 - Otsuka Pharmaceutical Co., Ltd announced today the company has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) regarding the new drug application (NDA) for tolvaptan for the treatment of adult patients with rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). The FDA issues CRLs to convey that their initial review of an application is complete; however, they cannot approve the application in its present form and request additional information.

In its letter to Otsuka, the FDA requested Otsuka provide additional data to further evaluate the efficacy and safety of tolvaptan in patients with ADPKD.

"Otsuka is evaluating the content of the FDA's response and will work closely with the Agency to determine if there are viable paths forward to address its outstanding questions," said Robert McQuade, Ph.D., Executive Vice President and Chief Strategic Officer, Otsuka Pharmaceutical Development & Commercialization, Inc. "Otsuka remains committed to patients with ADPKD and their healthcare providers."

About Tolvaptan

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

Tolvaptan is believed to inhibit cyst formation, proliferation and growth.*1 Cyst formation is dependent on the binding of a hormone called arginine vasopressin to the V2 receptor.*1,2 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.*1,2 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.*1


ADPKD is a genetic disease that is diagnosed in approximately 1 in 2,000 (120,000) adults in the U.S. and has been designated by the FDA to be an orphan condition.*3 It is the most common type of inherited genetic kidney disorders called polycystic kidney disease (PKD).*4,5 PKD is a progressive disease characterized predominantly by the development of numerous cysts in both kidneys.*5 The disease is caused by mutations in genes that regulate kidney function.*4 Two types of genetic mutations can cause ADPKD, the PKD1 mutation and the PKD2 mutation.4 People with the PKD1 mutation generally have kidney disease that progresses more rapidly than people with the PKD2 mutation.*4 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.*5

ADPKD is a life-threatening disease that causes significant kidney damage and dysfunction.*5,6 It is the fourth leading cause of end-stage renal disease (ESRD).*6 The average age at which ADPKD patients enter ESRD is 56.*7 Kidneys affected by PKD become significantly enlarged, due to the formation and growth of multiple cysts which proliferate through healthy kidney tissue.*5

  • References:
  • *1 Torres, VE et al. "Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease." The New England Journal of Medicine, 2012: 367 (25): 2407-2418
  • *2 Patel V, et al. "Advances in the Pathogenesis and Treatment of Polycystic Kidney Disease" University of Texas, Department of Pediatrics 2009
  • *3 Data on File. TOLV-002. Otsuka America Pharmaceuticals, Inc.
  • *4 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
  • *5 Polycystic Kidney Disease. National Kidney and Urologic Diseases Information Clearinghouse. (Sept., 2010). Retrieved June 17, 2013, from:
  • *6 Elhassan E, et al. "Progress on Autosomal Dominant Polycystic Kidney Disease." The Arab Journal of Nephrology and Transplantation 2009; 2(2): 27-44
  • *7 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