Otsuka Announces Phase III Results for Tolvaptan in Patients With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

TOKYO--(BUSINESS WIRE)-- Otsuka Pharmaceutical Co., Ltd. (Otsuka) today announced detailed results from the Phase 3 REPRISE trial of tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD).

Trial results showed that 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,² 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.³ Autosomal dominant PKD, known as ADPKD, is the most common type,³ and is the fourth leading cause of kidney failure.⁴ By age 57, more than half of people with ADPKD will need dialysis or a kidney transplant.⁵

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.”

“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, Executive Vice President and Chief Strategic Officer, Otsuka Pharmaceutical Development & Commercialization, Inc. “These robust findings provide evidence that tolvaptan, is an important new treatment option with the potential to help patients with this debilitating disease.

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 this evening at 7:00 pm Canadian Central Daylight 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 Complete Response Letter (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.⁶ In a prior Phase 3 trial, tolvaptan demonstrated a reduction in kidney growth and a slower decline in kidney function compared with placebo.⁷

Tolvaptan is approved for the treatment of adult patients with ADPKD in Canada, Japan, the EU, South Korea, Switzerland, Hong Kong and Australia (see local prescribing information for specific indications in each country).

About Otsuka

Otsuka Pharmaceutical Co., Ltd., 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 and original products, with a focus on pharmaceutical products for the treatment of diseases and nutraceutical products for the maintenance of everyday health.

Otsuka Canada Pharmaceutical Inc. (OCPI) is an innovative, fast-growing health care company that commercializes Otsuka medicines in Canada. OCPI aims to improve the quality of life and health of patients through its commitments to neuroscience, cardiovascular health, oncology and nephrology. OCPI was established in 2010, with headquarters in Saint-Laurent, Quebec.

OCPI is part of Otsuka Pharmaceutical Co., Ltd., a wholly owned subsidiary of Otsuka Holdings Co., Ltd., based in Tokyo, Japan. The Otsuka group of companies employed 45,000 people worldwide and had consolidated sales of approximately CAD 14.5 billion (USD 11 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. and about Otsuka in Canada at www.otsukacanada.com

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¹ The PKD Foundation of Canada. What is ADPKD? Accessed November 2nd 2017. http://www.endpkd.ca/learn
² Torres V et al. Tolvaptan Slows eGFR Decline in Later-Stage ADPKD. Abstract # SA-OR121. Presented on Saturday, November 4, at the American Society of Nephrology (ASN) Kidney Week 2017.
³ Polycystic Kidney Disease. Department of Health and Human Services. Accessed online at https://ghr.nlm.nih.gov/condition/polycystic-kidney-disease on October 31, 2017
⁴ Chebib F, Torres V et al. Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016. Am J Kidney Dis. May 2016; 67(5): 792-810.
⁵ Autosomal Dominant Polycystic Kidney Disease Fact Sheet. NIH Reports. Accessed online at https://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=29 on October 31, 2017.
⁶ Reif, GA, Yamaguchi, T et al. Tolvaptan inhibits ERK-dependent cell proliferation, Cl – secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am J Physiol Renal Physiol; 2011; 301:F1005-F1013
⁷ Torres V, Chapman A et al. Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease. N Engl J Med; 2012; 367:2407-2418.

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