Healthcare Industry News:  vasopressin 

Biopharmaceuticals Cardiology

 News Release - November 14, 2006

New Data on Otsuka's Investigational Product for Hyponatremia Presented at American Heart Association Annual Meeting

Results of the SALT-1 and SALT-2 Trials Show Tolvaptan Improves Serum Sodium Levels in Patients With Hyponatremia

ROCKVILLE, Md., Nov. 14 (HSMN NewsFeed) -- Results of the SALT-1 and SALT-2 trials, the two largest studies to date on hyponatremia(1), were presented earlier this week at the American Heart Association's Scientific Sessions 2006 (November 12-15) in Chicago. The studies, which evaluated the efficacy and safety of tolvaptan, an investigational product for the treatment of hyponatremia, showed that serum sodium levels can be significantly improved in patients who have hyponatremia associated with various diseases, such as heart failure, cirrhosis or syndrome of inappropriate antidiuretic hormone secretion (SIADH).(2) The studies were published in an article that appears in the November 16, 2006 issue of the New England Journal of Medicine.

Hyponatremia, characterized by low concentrations of sodium in the blood, is a known predictor of mortality in patients with serious underlying illnesses.(2) Hyponatremia has long been associated with neurological symptoms including in its worst forms seizure and coma, and in its mildest forms slowed thoughts and reflexes.(3)

Tolvaptan, developed by Otsuka Pharmaceutical Co., Ltd. (Japan) and Otsuka Maryland Research Institute, Inc., is a novel, nonpeptide, selective antagonist of the vasopressin V2 receptor.

"With mounting evidence showing that hyponatremia, commonly seen in a variety of diseases, is correlated with a poor prognosis and even death, there is a stronger need for a safe and effective medication to normalize serum sodium concentrations," said Dr. Robert W. Schrier, Professor of Medicine, Division of Renal Diseases and Hypertension at the University of Colorado Health Sciences Center in Denver, Colorado, and Chair of the Safety Oversight Committee of the SALT-1 and SALT-2 trials.

Normal serum sodium is between 135-145 mEq/L, whereas hyponatremia is defined as a serum concentration less than 135 mEq/dL(4); symptoms often arise as the serum concentration falls below 130 mEq/L.

"We are very pleased that these pivotal Phase III studies in hyponatremia have been completed," said Dr. Cesare Orlandi, Vice President, Clinical Development, Otsuka Maryland Research Institute, Inc. "The encouraging results of SALT-1 and SALT-2 suggest tolvaptan, if approved, may become a useful treatment for this potentially life-threatening condition."

About the Trials

SALT-1 and SALT-2 [Sodium Assessment With Increasing Levels of Tolvaptan in Hyponatremia] are two multicenter, randomized, double-blind, placebo- controlled studies involving 205 (SALT-1) and 243 (SALT-2) patients with hyponatremia predominantly associated with heart failure, cirrhosis or SIADH.(2) SALT-1 was conducted in the U.S. and SALT-2 was conducted in the U.S., Canada, Belgium, Germany, Spain, Italy, Poland, Czech Republic and Hungary. The studies evaluated the efficacy and safety of tolvaptan for the treatment of euvolemic hyponatremia (relative excess, but generally normal volume of total body water) and hypervolemic hyponatremia (increase in total body sodium and greater increase in total body water) of any origin. Patients were randomized to receive either placebo or tolvaptan 15 mg once-a-day. Over the first four days of treatment, doses could be titrated between 30 mg and 60 mg once-a-day, based on the observed change in serum sodium levels.

Patients received treatment for 30 days, with a follow-up visit seven days after the administration of study medication is terminated. Primary endpoints were the change in the average daily area under the curve (AUC) for the serum sodium concentration over the first four days and over 30 days of treatment.

In SALT-1, patients receiving tolvaptan had an increase in the average daily area under the curve (AUC) in serum sodium over the first four days of treatment of 3.62 plus or minus 2.68 mEq/L, compared with 0.25 plus or minus 2.08 mEq/L in the placebo group (p lesser than 0.0001). The increase in the average daily AUC in serum sodium over 30 days was 6.22 plus or minus 4.10 mEq/L in the tolvaptan group and 1.66 plus or minus 3.59 mEq/L in the placebo group (p lesser than 0.0001). Normal serum sodium is between 135-145 mEq/L (or mmol/L).

In SALT-2, patients receiving tolvaptan had an increase in the average daily AUC in serum sodium over the first four days of treatment of 4.33 plus or minus 2.87 mEq/L, compared with 0.42 plus or minus 2.56 mEq/L in the placebo group (p lesser than 0.0001). The increase in the average daily AUC in serum sodium over 30 days was 6.20 plus or minus 3.92 mEq/L in the tolvaptan group and 1.84 plus or minus 3.83 mEq/L in the placebo group (p lesser than 0.0001).

In both studies, greater changes in serum sodium at day 4 and 30 also were observed in patients with mild (greater than or equal to 130 and less than 135 mEq/L at baseline) and severe hyponatremia (lesser than 130 mEq/L at baseline) treated with tolvaptan than in those treated with placebo (p lesser than 0.0001 for all comparisons). In both studies, more patients receiving tolvaptan reached normalization (i.e. greater than 135 mEq/L) of serum sodium both at day 4 and day 30 (p lesser than 0.0001 for all comparisons). Within seven days after discontinuation of study drug, serum sodium returned to the placebo levels.

As a secondary end point, patients completed the Medical Outcomes Study 12-item Short-Form General Health Survey (SF-12), which evaluated the clinical relevance of the sodium correction. The scores from the Physical Component Summary showed no significant differences between treatments, but those for Mental Component Summary were improved for those patients receiving tolvaptan in a prespecified combined analysis vs. those receiving placebo (p equal to 0.02).

Adverse event profiles in the two study groups were similar for all intratrial and intertrial comparisons. The most common adverse events occurring during the study in the tolvaptan groups were thirst and dry mouth. Overall, there were 26 potentially study treatment-related serious adverse events in SALT-1 and SALT-2. Eleven occurred in eight patients assigned to tolvaptan (dehydration with hypotension, dehydration with dizziness, syncope, acute renal failure, ascites, increased concentrations of serum sodium and increased concentrations of serum creatinine, Escherichia sepsis with respiratory failure) and 15 occurred in ten patients assigned to placebo (acute renal failure in two patients, rash in two patients, cardiac failure aggravated twice in same patient, vomiting, hepatic encephalopathy, acute dyspnea with edema, dyspepsia, worsened anemia with decreased hemoglobin, decreased hematocrit and with increased creatinine concentration). Eight patients in the tolvaptan group withdrew because of adverse events that were potentially related to the study treatment (rash in two patients, dysgeusia, nocturia, urinary frequency, exanthema, muscle weakness, and hypernatremia in one patient each), as compared with eight patients in the placebo group (rash in two patients, acute renal failure in two patients, and increased serum creatinine concentrations, decreased serum sodium concentrations, aggravated hyponatremia, and vomiting in one patient each). Mortality in the two study groups was similar (14 deaths among 223 patients in the tolvaptan groups and 13 deaths among 220 patients in the placebo groups) and occurred within the defined observation period. In only four of the 223 patients in the tolvaptan group were desirable rates of sodium correction exceeded during the first 24 hours of the study (>0.5 mmol per liter per hour; maximum observed rate, 0.61 mmol per liter per hour). In only 4 patients (1.8%) was the predefined, potentially clinically important serum sodium concentration (>146 mmol per liter) exceeded.

The SALT-1 and SALT-2 abstract, "Results from the SALT 1 and 2 Trials. Multicenter, Randomized, Placebo-Controlled Trials in Patients with Euvolemic and Hypervolemic Hyponatremia" were presented on Tuesday, November 14, 2006, at 9:00 am [CDT] by Dr. Mihai Gheorghiade, Professor of Medicine, Division of Cardiology, Northwestern University Feinberg School of Medicine.

About Otsuka Maryland Research Institute, Inc.

Otsuka Maryland Research Institute, Inc. is involved in conducting all phases of clinical research and development of innovative healthcare products to address unmet medical needs. OMRI 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. OMRI is part of the Otsuka Pharmaceutical Group, which is comprised of 87 companies and approximately 27,000 people around the world. With 44 consolidated subsidiaries, Otsuka earned US$6.8 billion in consolidated annual revenues in fiscal 2005. For additional information, visit http://www.otsuka.com.

(1) Afdhal N, Cardenas A, Gines P, et al. Randomized, Placebo-Controlled Trial of Tolvaptan, a Novel V2-Receptor Antagonist, in Hyponatremia: Results of the SALT 2 Trial With Emphasis on Efficacy and Safety in Cirrhosis. Abstract presented at Annual Society of Nephrology meeting in November 2005.

(2) Schrier RW, Gheorghiade M, Gross P, et al. Results from the SALT 1 and 2 Trials. Multicenter, Randomized, Placebo-Controlled Trials in Patients with Euvolemic and Hypervolemic Hyponatremia. Being Presented at American Heart Association's Scientific Sessions in November 2006.

(3) Adrogue HJ, Madias NE. Hyponatremia. NEJM. 2000; 342 (21):1581-1589.

(4) Gheorghiade M, Gottlieb SS, Udelson JE, et al. vasopressin V2 Receptor Blockade With Tolvaptan Versus Fluid Restriction in the Treatment of Hyponatremia. AmJCardiol 2006; 97:1064-1067.


Source: Otsuka America Pharmaceutical

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