Public Release: 

ECLIPSE data on effects of Otsuka's investigational novel treatment, Tolvaptan

Porter Novelli

PRINCETON, N.J., Sept. 19, 2007 -- A single dose of Otsuka's investigational oral medication tolvaptan, a vasopressin receptor antagonist, resulted in favorable changes in hemodynamics associated with a significant increase in urine output in patients with advanced heart failure (ADHF) who participated in the international trial the EffeCt of ToLvaptan on HemodynamIc Parameters in Subjects with HEart failure (ECLIPSE), presented at the late breaking trials symposium of the Heart Failure Society of America's Annual Scientific Meeting (HFSA).

"These ECLIPSE data are the first to clarify the hemodynamic effects of orally dosed tolvaptan in patients with advanced heart failure due to systolic dysfunction. Such details of the mechanism of action of tolvaptan help us further understand its clinical effects," said investigator James Udelson M.D., associate chief of the Division of Cardiology at the Tufts-New England Medical Center and associate professor of medicine at Tufts University School of Medicine.

In the ECLIPSE study, 180 patients with symptomatic heart failure (New York Heart Association class III and IV) were randomized to double-blind treatment with tolvaptan at a single oral dose of 15, 30, 60 mg or placebo. All three doses of tolvaptan examined in ECLIPSE significantly changed the primary outcome variable, pulmonary capillary wedge pressure (PCWP), compared to placebo treatment (tolvaptan 15 mg -6.38 ± 0.62 mmHg, tolvaptan 30 mg- 5.67 ± 0.70 mmHg, tolvaptan 60 mg -5.71 ± 0.65 mmHg, placebo -4.16 ± 0.67 mmHg; p vs. placebo less than 0.05 for each tolvaptan group). The primary statistical analysis comparing the effects across the placebo group and two higher doses of tolvaptan approach statistical significance (p=0.0563). PCWP provides information about two aspects of lung and heart function: an estimate of the lung capillary pressure, which is the fluid pressure that plays a role in pulmonary edema, and an estimate of the filling pressures of the left side of the heart.

Compared with placebo, each dose of tolvaptan significantly increased urine volume at 3 hours after dose was given (p<0.0001). Also, during the three to eight hour interval after tolvaptan administration, mean reductions of the pressure in the pulmonary artery that carries venous blood from the right ventricle of the heart to the lungs, a secondary endpoint, were observed and were statistically greater (p<0.05) in all tolvaptan groups than in the placebo group. Over the same time period, mean reductions in pressure within the heart's right atrium were also observed, and those were statistically greater in the tolvaptan 15 mg and 30 mg groups than in the placebo group. None of the other secondary outcome measures, including cardiac output (the amount of blood the heart's left ventricle ejects into the circulation in one minute), cardiac index (cardiac output indexed to a patient's body size), systemic vascular resistance (the resistance to blood flow by all of the blood vessels, excluding those in the lungs), heart rate, and blood pressure, showed significantly different changes in the tolvaptan and placebo groups.

Overall, 77 (42.5%) subjects experienced at least one treatment-emergent adverse event during the trial. The incidence of these events was highest in the tolvaptan 60 mg group (54.3%) and lowest in the placebo group (33.3%). Most common adverse events (greater than 3% and more frequent than placebo) associated with tolvaptan were dry mouth, thirst, back pain, headache, anxiety, and haematuria. No treatment-emergent adverse event occurred in more than 10% of the patients in any of the groups. No deaths occurred during study drug administration. Two patients died during the 7-day follow-up period (originally assigned to tolvaptan 30 mg and 60 mg, respectively). Both of those patients died from complications resulting from worsening of underlying disease.

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About ECLIPSE

ECLIPSE is an international, multicenter, randomized, placebo-controlled single-dose trial conducted at 48 trials sites in United States, Romania and Bulgaria between 2005 and 2006. ECLIPSE investigators enrolled patients with heart failure (New York Heart Association Class III or IV) for at least three months duration due to left ventricular systolic dysfunction and who had a left ventricular ejection fraction (LVEF) of 40 percent or less.

Investigators assessed patients' inclusion criteria for up to two weeks prior to randomization. Suitable candidates underwent insertion of a balloon-floatation pulmonary artery catheter to assess final eligibility criteria. Final doses of cardiac concomitant medications were administered at least two hours prior to catheter insertion. Following catheter insertion, patients entered into a two- to 20-hour stabilization period. Researchers completed hemodynamic assessments periodically during this period to determine final subject eligibility. Potential participants then entered a two-hour baseline period. If a participant met all criteria during the baseline period, he or she was randomly assigned to one of four groups and received a single once-daily oral tablet of placebo or of 15, 30 or 60 milligrams (mg) tolvaptan. Investigators followed participants for up to 24 hours for assessments.

"The ECLIPSE data add to our existing knowledge about tolvaptan and its prospective uses," said Taro Iwamoto, CEO, COO and President of Otsuka Pharmaceutical Development & Commercialization, Inc. "Tolvaptan, as one of our most advanced candidate therapies, represents the successful application of Otsuka's expertise in the research and development of new medicines."

About Heart Failure

More than 14 million people in Europe and five million U.S. residents have heart failure (HF), a serious chronic condition in which the heart cannot effectively pump blood. The direct and indirect U.S. health care expenses related to HF tally about $28 billion, ACC estimates. The majority of patients hospitalized for ADHF, the worsening of chronic HF that affects 1 million US residents annually, have edema or excess body fluid.

About Otsuka Pharmaceutical Development & Commercialization, Inc.

Otsuka Pharmaceutical Development and Commercialization, Inc. is involved in conducting all phases of clinical research and development of innovative healthcare products to address unmet medical needs. OPDC is well established in the scientific community as a globally focused organization that plays a leadership role in the research and development of Otsuka's ethical healthcare products. The Company is dedicated to the improvement of the quality of human life and health of patients around the world with a strong commitment to research and development in the areas of cardiovascular, neuroscience, renal and respiratory diseases, as well as cancer and ophthalmic disorders. OPDC is part of the Otsuka Pharmaceutical Group, which is comprised of 99 companies and approximately 31,000 people around the world. With 54 consolidated subsidiaries, Otsuka earned US $7.2 billion in consolidated annual revenues in fiscal 2006. For additional information, visit www.otsuka.com.

1. SHAPE Survey Results to the General Public, Annual Congress of the European Society of Cardiology in Vienna, September 2003. 2. ACC News Release, "American College of Cardiology / American Heart Association guidelines: New heart failure guidelines stress early diagnosis and treatment," August 16, 2005. Accessed at http://www.acc.org/media/releases/highlights/2005/aug05/hf%5Fguideline%5Fupdate.htm on March 1, 2007.

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