Otsuka Pharmaceutical Initiates Phase 3 Clinical Trial of Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease

  • Special Protocol Assessment for trial design and planned analysis agreed upon by the U.S. Food & Drug Administration
  • 220 worldwide sites to enroll approximately 1,300 patients with ADPKD
Princeton, N.J. – June 11 2014 – Otsuka Pharmaceutical Development & Commercialization, Inc., announced today that patient enrollment has begun for a new Phase 3b study of tolvaptan for adult patients with autosomal dominant polycystic kidney disease (ADPKD), the most common, life-threatening, inherited genetic kidney disorder.1 The company reached an agreement with the United States Food & Drug Administration (FDA) on a Special Protocol Assessment (SPA) for the design and planned analysis of this multi-center, placebo-controlled, double-blind, parallel-group trial designed to compare the efficacy and safety of tolvaptan (45 to 120 mg per day split-dose) in subjects with chronic kidney disease between late stage 2 and early stage 4 due to ADPKD. “Otsuka is pleased that the FDA has agreed to the design for this study and we are happy to report that the first patient has been enrolled into the trial,” said William H. Carson, M.D., president and CEO of Otsuka Pharmaceutical Development & Commercialization, Inc. “This study represents our ongoing commitment to patients with this rare genetic condition to provide them and their physicians with a novel treatment option.”
The trial, which will take place at approximately 220 sites worldwide, is seeking to enroll approximately 1,300 tolvaptan-naïve adult (male and female) patients with ADPKD between the ages of 18-66, depending on their estimated glomerular filtration rate (eGFR), a renal function test, at time of enrollment. Total study duration is about 15 months, and the treatment period will last for approximately 13½ months. The primary endpoint will compare the efficacy of tolvaptan treatment in reducing the change in eGFR, a renal function test, from baseline to post-treatment follow-up as compared to placebo in patients with ADPKD who tolerate tolvaptan during an initial run-in period. The trial will also compare overall safety and specifically hepatic safety and compare incidence of ADPKD complications during the trial. For more information on the trial, please visit: The FDA issued a Complete Response Letter for tolvaptan to treat ADPKD in August 2013 and requested further information to evaluate the efficacy and safety of the drug.

About Tolvaptan for ADPKD

Tolvaptan is under investigation as a treatment to slow the progression of kidney disease in patients at risk of rapidly progressing ADPKD.2 Tolvaptan was studied in patients with enlarged kidneys who were in chronic kidney disease (CKD) stages 1-3 at initiation of treatment.2 Results were published in the New England Journal of Medicine in December 2012.2 Cyst formation in the kidney has been shown to be dependent on binding of a hormone, arginine vasopressin, to the V2 receptor.2,3 Vasopressin stimulates V2 receptors and activates the cyclic AMP pathway causing acceleration of cyst proliferation and fluid secretion, leading to enlarged, dysfunctional kidneys.2,3 Tolvaptan is believed to inhibit cyst formation, proliferation, and growth as a selective V2 receptor antagonist to block the effects of vasopressin.2


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.4 It is the most common, life-threatening, inherited genetic kidney disorder.5,6 PKD is a progressive disease characterized predominantly by the development of numerous cysts in both kidneys.6 The disease is caused by mutations in genes that regulate kidney function.5 Two types of genetic mutations can cause ADPKD, the PKD1 mutation and the PKD2 mutation.5 People with the PKD1 mutation generally have kidney disease that progresses more rapidly than people with the PKD2 mutation.5 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.6
ADPKD is a life-threatening disease that causes significant kidney damage and dysfunction.6,7 It is the fourth leading cause of end-stage renal disease (ESRD).7 The average age at which ADPKD patients enter ESRD is 56.8 Kidneys affected by PKD become significantly enlarged, due to the formation and growth of multiple cysts which proliferate through healthy kidney tissue.6

About Special Protocol Assessments

A Special Protocol Assessment is a written agreement with the FDA on the details of the design and planned analysis for a clinical trial. It is intended to form the basis for a marketing application and may only be changed through a written agreement between the sponsor and the FDA, or if the FDA becomes aware of new public health concerns.

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.
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


Kevin Wiggins
Otsuka America Pharmaceutical, Inc.
+1 609 249 7292, +1 610 350-9606 (cell)

  1. 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
  2. Torres, VE et al. “Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease.” The New England Journal of Medicine 2012: 367 (25): 2407-2418
  3. Patel V, et al. “Advances in the Pathogenesis and Treatment of Polycystic Kidney Disease.” University of Texas, Department of Pediatrics 2009
  4. Data on File. TOLV-002. Otsuka America Pharmaceuticals, Inc.
  5. 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
  6. Polycystic Kidney Disease. National Kidney and Urologic Diseases Information Clearinghouse. (Sept., 2010). Retrieved June 17, 2013, from:
  7. Elhassan E, et al. “Progress on Autosomal Dominant Polycystic Kidney Disease.” The Arab Journal of Nephrology and Transplantation 2009; 2(2): 27-44
  8. 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