Otsuka Pharmaceutical Co., Ltd.

November 5, 2012

Otsuka’s Investigational Compound for Autosomal Dominant Polycystic Kidney Disease (ADPKD), Tolvaptan, Meets Primary Endpoint in a Phase III Clinical Trial

• Results were presented at the American Society of Nephrology 2012 annual “Kidney Week” meeting and published online in the New England Journal of Medicine (NEJM). The results are intended to form the basis of regulatory filings in multiple countries seeking a new drug approval in ADPKD
• Investigational Phase III trial met its primary efficacy endpoint, demonstrating reductions of change in total kidney volume for subjects receiving tolvaptan compared to placebo
• ADPKD is the most common inherited cause of kidney failure, accounting for about 5 percent of end-stage renal disease in the U.S. The diagnosed prevalence is estimated to be between 1:1000 and 1:4000 globally

(Tokyo, Japan, Nov 4, 2012) – Otsuka Pharmaceutical Co., Ltd. today announced that the clinical trial results for tolvaptan, an investigational drug for the treatment of ADPKD, were presented for the first time at the American Society of Nephrology annual meeting and simultaneously published online in the New England Journal of Medicine (available online at www.NEJM.org). Autosomal dominant polycystic kidney disease (ADPKD) is a genetic illness characterized by the development of multiple cysts in the kidneys. Tolvaptan met its primary endpoint of demonstrating a statistically significant (p<0.001) reduction (nearly 50% reduction) in the rate of increase in Total Kidney Volume (TKV) over the 3-year study period as compared to placebo among patients with ADPKD. These findings are from the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3:4 Study, a Phase III, multi-center, randomized, double-blind, placebo-controlled, parallel-arm trial involving more than 1,400 patients. Tolvaptan is a selective V2 vasopressin receptor antagonist, which had been hypothesized to slow the progression of ADPKD by reducing the development and growth of kidney cysts, which are characteristic of the disease and often associated with pain, hypertension and kidney failure. ADPKD is the leading cause of inherited kidney disease, affecting an estimated 1:1,000-1:4,000 diagnosed patientsi.

Trial results were presented by Vicente E. Torres, M.D., Ph.D, Professor of Medicine, Division of Nephrology and Hypertension, Mayo Clinic during the "High Impact Clinical Studies" session at the American Society of Nephrology's (ASN) 2012 annual “Kidney Week,” the world's premier nephrology meeting. The study assessed the efficacy and safety of tolvaptan in treating ADPKD and the complications it causes those patients affected by the disease.

“ADPKD is the most common inherited and the fourth most common overall cause of kidney failure worldwide,” said Dr. Torres. “In most patients with this disease, relentless cyst growth within the kidneys destroys the tissue, causes hypertension and painful complications, and negatively impacts the quality of life. The results of this study reveal a potential treatment that blunts kidney growth, lessens associated symptoms and slows kidney function decline when given over three years.”

“The data from this study are compelling and provide a strong basis for global regulatory filings,” said William H. Carson, M.D., President & CEO, Otsuka Pharmaceutical Development & Commercialization, Inc. “Tolvaptan was discovered by Otsuka in Japan, and if approved by regulatory agencies, could become the first pharmaceutical therapy for patients who suffer from ADPKD. Our research philosophy is to take untraveled paths to discoveries that only Otsuka can reach.”

Study Design and Findings

This phase III randomized, double-blind, placebo-controlled 3-year trial enrolled adult patients (men and women between 18-50 years of age) with ADPKD at 129 study sites worldwide. The study was designed to assess the efficacy and safety of tolvaptan, an investigational drug, for the treatment of ADPKD. Patients were randomized 2:1 to receive either a morning/afternoon split dose regimen of tolvaptan (45/15, 60/30 or 90/30 mg daily as tolerated) or placebo. In this study, 1,445 patients were randomized into the study with 961 assigned to receive tolvaptan and 484 to receive placebo.

The primary efficacy endpoint was annual rate of change in TKV (a measurement of kidney cyst growth) of tolvaptan compared with placebo. The key secondary endpoint was a composite of events of ADPKD progression including worsening kidney function, incidence of significant kidney pain, worsening of hypertension and worsening albuminuria (or protein in urine) and a measure of kidney function (change in slope of the reciprocal of serum creatinine levels).

Tolvaptan demonstrated a statistically significant reduction in the rate of increase in TKV over the 3-year study period compared to placebo (2.80% per year versus 5.51% per year, respectively, p<0.001).

For the key secondary endpoint, tolvaptan showed a statistically significant reduction in the risk of multiple events of worsening kidney function, kidney pain, hypertension or albuminuria (hazard ratio = 0.87, 95% CI: 0.78-0.97, p=0.0095). The effect on this endpoint was driven by a 61% reduction in the risk of an event of worsening kidney function (hazard ratio = 0.39, CI: 0.26-0.57, p<0.001) and a 36% reduction in the risk of an event of worsening kidney pain (hazard ratio = 0.64, CI: 0.47-0.89, p=0.007). Further, tolvaptan was shown to reduce the slope (i.e. rate) of decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 versus -3.81 (mg/mL)-1 per year, p <0.001).

Overall, 1,157 (80.1%) patients completed the three-year trial (77.0% and 86.2% for tolvaptan and placebo treated patients, respectively). More patients treated with tolvaptan discontinued treatment for adverse events than those treated with placebo (15.4% vs. 5.0%, respectively). The most common adverse events (≥10% and nominally significantly more than placebo) associated with tolvaptan treatment were related to its aquaretic mode of action: thirst (55.3% vs. 20.5%), polyuria (38.3% vs. 17.2%), nocturia (29.1% vs. 13.0%), pollakiuria (23.2% vs. 5.4%), and polydipsia (10.4% vs. 3.5%). Common adverse events more frequent in placebo (≥10% and nominally significantly more than tolvaptan) included renal pain, haematuria and urinary tract infection. Laboratory abnormalities more common in tolvaptan treated patients included increased sodium (4.0% vs 1.4%), uric acid (6.2% vs 1.7%), and significant ALT or AST elevations (4.7% vs 1.7%).

About ADPKD

Polycystic kidney disease (PKD) is characterized by the development of multiple, non-malignant cystic structures arising in the kidneys due to inherited or acquired genetic mutation(s).^ⅰ,ⅱ There are two main inherited forms of PKD. Autosomal Dominant (ADPKD) is the most common form of PKD, with a diagnosed prevalence of 1:1,000-1:4,000 people.^ⅰ Cyst development and growth in both kidneys leads to slow deterioration of kidney function, and in ~50% of patients, to end-stage renal disease (ESRD) and renal failure.^ⅲ ADPKD typically results in symptom manifestations in adulthood.^ⅱ

• *ⅰ：Torres, VE, Harris, PC, and Pirson, Y. Autosomal Dominant Polycystic Kidney Disease Lancet. 2007;369:1287-1301.
• *ⅱ：Patel V, Chowhury R, and Igarashi P. Advances in the pathogenesis and treatment of polycystic kidney disease. Curr Opin Nephrol Hypertens. 2009;18:99-106.
• *ⅲ：Tan Y, Blumenfeld J, and Rennert H. Autosomal dominant polycystic kidney disease: genetics, mutations and microRNAs. Biochimica Biophysica Acta. 2011;1812:1202-1212.