• REPRISE trial presented as a late breaking abstract at American Society of Nephrology (ASN) Kidney Week 2017
  • Tolvaptan reduced the rate of decline of kidney function by 35 percent over a 12-month period, compared to placebo, in patients with ADPKD
  • ADPKD, the most common type of polycystic kidney disease, is a progressive disease leading to kidney failure, diagnosed in 100,000 to 150,000 people in the U.S.[i]

TOKYO, JAPAN – November 4, 2017 Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced detailed results from the Phase 3 REPRISE trial of tolvaptan, which is under investigation in the United States in patients with autosomal dominant polycystic kidney disease (ADPKD).
According to trial results, tolvaptan showed greater reduction on the primary endpoint, the rate of change in estimated glomerular filtration rate (eGFR) compared to placebo. Estimated GFR, the primary endpoint of the trial, is a key measure of kidney function. Change in estimated eGFR from pre-treatment baseline to post-treatment follow-up, adjusted by the duration of the trial for each patient and expressed per year was ‑2.34 mL/min/1.73 m2-year with tolvaptan versus ‑3.61 mL/min/1.73 m2-year with placebo, representing a 35% reduction of 1.27 mL/min/1.73 m2-year (95% CI 0.86 to 1.68; P<0.001). These data were presented today as a late breaking oral abstract at the American Society of Nephrology (ASN) 2017 Kidney Week in New Orleans,[ii] and were simultaneously published online in the New England Journal of Medicine (available online at NEJM.org).
Polycystic kidney disease (PKD) is a progressive genetic disorder affecting the kidneys, in which fluid-filled cysts develop in the kidneys over time, enlarging these organs and inhibiting their ability to function normally, leading to kidney failure in most patients.[iii] Autosomal dominant PKD, known as ADPKD, is the most common type,[iii] and is the fourth leading cause of kidney failure.[iv] By age 57, more than half of people with ADPKD will need dialysis or a kidney transplant.[v]
Vicente Torres, MD, PhD, Director of the Mayo Clinic Translational Polycystic Kidney Disease Center, and lead investigator on the REPRISE trial, commented, “Tolvaptan slowed the rate of kidney function decline in this trial. These data represent a significant milestone in the investigation of this condition, for which there are currently no approved treatments in the U.S.”
“It is gratifying to see the significance of findings from the REPRISE trial, which further support the utility of tolvaptan in patients with ADPKD,” said Robert McQuade, Ph.D., Executive Vice President and Chief Strategic Officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “These robust findings provide evidence that tolvaptan, if approved in the U.S., may be an important new treatment option with the potential to help patients with this debilitating disease, and we look forward to discussing these data with regulatory agencies.”
Along with results from previous pivotal studies, findings from the REPRISE trial have formed the basis of a response to the Complete Response Letter (CRL) that FDA issued in August 2013, which Otsuka has submitted to the U.S. Food and Drug Administration (FDA) for tolvaptan as a treatment for patients with ADPKD.
Otsuka Pharmaceutical will host a telebriefing for investor and media on the REPRISE clinical trial results on November 4th at 7:00 pm U.S. Central Standard time. To register, please visit http://event.on24.com/wcc/r/1534382-1/77E66445B009CE3491DBB035504DCF69.
About the Phase 3 REPRISE Trial
REPRISE was a Phase 3, multi-center, randomized withdrawal, placebo-controlled, double-blind trial in adult patients with late-stage 2 to early-stage 4 chronic kidney disease due to ADPKD. After an 8-week pre-randomization period including sequential placebo and tolvaptan treatments, 1,370 ADPKD patients were randomized 1:1 to tolvaptan (90 or 120 mg per day) or placebo and treated for 12 months. The primary endpoint measured change in estimated GFR from pre-treatment baseline to post-treatment follow-up adjusted by the duration of the trial for each patient. The key secondary endpoint was the estimated GFR slope derived from the individual slopes in each patient adjusted for the duration of the observations and expressed per year. This analysis used all serum creatinine values from placebo run-in, tolvaptan run-in (not including tolvaptan titration), 12-month double-blind treatment, and posttreatment follow-up measurements. In the trial, tolvaptan patients had a significantly smaller decline, of 3.16mL/min/1.73m2/year compared with 4.17 mL/min/1.73m2/year for placebo treated patients (p<0.0001).
Key safety findings (collected monthly) were generally consistent with previous pivotal data with the majority of events across the study. Following randomization, patients who received tolvaptan experienced more frequent polyuria, nocturia, thirst, polydipsia, dry mouth, fatigue and diarrhea, whereas those who received placebo experienced more frequent peripheral edema, renal pain, and urinary tract infection; most treatment-emergent adverse events (TEAEs) were mild or moderate in severity. In the double-blind treatment period, 5.6 percent of patients taking tolvaptan had significantly abnormal liver blood tests (greater than 3 times the upper limit of normal), compared with 1.2 percent of those taking placebo. Transaminase elevations were reversible after stopping tolvaptan and no patients showed concomitant bilirubin elevations greater than 2 times the upper limit of normal. In the study, risk minimization measures consisting of monthly monitoring of liver parameters helped minimize the risk of serious liver toxicity.
Otsuka collaborated on the development of the protocol for this clinical trial with the FDA through the special protocol assessment process in order to address a CRL issued by the agency for a New Drug Application (NDA) for tolvaptan in ADPKD in 2013. In the coming weeks the FDA will acknowledge whether the company’s response is complete and whether their regulatory review can proceed.
About Tolvaptan
Tolvaptan is a selective vasopressin V2-receptor antagonist. By selectively blocking vasopressin at the V2-receptor, tolvaptan has been shown in preclinical trials to decrease cyst-cell proliferation and fluid secretion, ultimately reducing cyst growth.[vi] In a prior Phase 3 trial, tolvaptan demonstrated a reduction in kidney growth and a slower decline in kidney function compared with placebo.[vii] 
Tolvaptan is approved for the treatment of adult patients with ADPKD in Japan, the EU, Canada, South Korea, Switzerland, Hong Kong and Australia (see local prescribing information for specific indications in each country).

About Otsuka
Otsuka Pharmaceutical Company is a global healthcare company with the corporate philosophy: “Otsuka-people creating new products for better health worldwide.” Otsuka researches, develops, manufactures and markets innovative products, with a focus on pharmaceutical products to meet unmet medical needs and nutraceutical products for the maintenance of everyday health.
In pharmaceuticals, Otsuka is a leader in the challenging area of mental health and also has research programs on several under-addressed diseases including tuberculosis, a significant global public health issue. These commitments illustrate how Otsuka is a “big venture” company at heart, applying a youthful spirit of creativity in everything it does.
Otsuka Pharmaceutical Company is a subsidiary of Otsuka Holdings Co., Ltd. headquartered in Tokyo, Japan. The Otsuka group of companies employed 45,000 people worldwide and had consolidated sales of approximately USD 11 billion (€ 9.9 billion) in 2016.
All Otsuka stories start by taking the road less travelled. Learn more about Otsuka Pharmaceutical Company on its global website at https://www.otsuka.co.jp/en. Learn more about Otsuka in the U.S. at www.otsuka-us.com and connect with us on Twitter at @OtsukaUS.