Otsuka Pharmaceutical Development & Commercialization, Inc.'s Kidney Disease Drug Faces Setback

PRINCETON, N.J.--(BUSINESS WIRE)--Otsuka Pharmaceutical Development & Commercialization, Inc. 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 

About ADPKD 

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 

About Otsuka 

Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC), based in Princeton, New Jersey and Rockville, Maryland, discovers and develops new compounds that address urgent, unanswered medical needs. OPDC has numerous compounds in development to treat disorders in the neuroscience, oncologic, and cardio-renal therapeutic areas. OPDC is part of the Otsuka Group companies. For more information about OPDC, visit 

At a global level, Otsuka Pharmaceutical Co., Ltd. contributes to the advancement of human health through its leading position in the challenging field of mental health and through research programs in areas such as tuberculosis, a significant global public health issue, and in ADPKD, where Otsuka embarked on the discovery and development of tolvaptan as a potential treatment approximately a decade ago. 

The company has a long history of individualistic thinking and perseverance in the disease areas it enters into, illustrating more powerfully than words how Otsuka is a "big venture" company at heart, applying a youthful spirit of creativity in everything it does. 

Otsuka Pharmaceutical Co., Ltd. is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group that is headquartered in Tokyo, Japan. The chairman Akihiko Otsuka is the third generation of Otsuka family members to lead the business, whose origins date from 1921. The Otsuka Group has business operations in 25 countries and regions around the world, with consolidated sales of approximately USD 13 billion for fiscal year 2012 (4/1/2012-3/31/2013.) Otsuka welcomes you to visit its global website at 


Torres, VE et al. "Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease." The New England Journal of Medicine, 2012: 367 (25): 2407-2418

Patel V, et al. "Advances in the Pathogenesis and Treatment of Polycystic Kidney Disease" University of Texas, Department of Pediatrics 2009

Data on File. TOLV-002. Otsuka America Pharmaceuticals, Inc.

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

Polycystic Kidney Disease. National Kidney and Urologic Diseases Information Clearinghouse. (Sept., 2010). Retrieved June 17, 2013, from:

Elhassan E, et al. "Progress on Autosomal Dominant Polycystic Kidney Disease." The Arab Journal of Nephrology and Transplantation 2009; 2(2): 27-44

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 

August 2013 1013N-9133 



Otsuka America Pharmaceutical, Inc.

Rose Weldon

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Otsuka Pharmaceutical Co., Ltd.

Jeffrey Gilbert

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