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Yamanouchi Pharma America, Inc. Release: New Data From Two Studies Support Efficacy And Tolerability Of Vasopressin Receptor Antagonist Conivaptan Hydrochloride In Patients With Hyponatremia


10/19/2005 5:12:01 PM

ST. LOUIS, Nov. 1 /PRNewswire/ -- Yamanouchi Pharma America, Inc., a subsidiary of Yamanouchi Pharmaceutical Co., Ltd., announced that its investigational drug, conivaptan hydrochloride, produced significant increases in serum sodium levels in patients with hyponatremia, a potentially life- threatening condition that occurs when the body's sodium level falls below normal. The results of two Phase III studies were presented this weekend at the annual meeting of the American Society of Nephrology.

Conivaptan is a novel drug that blocks both V1A and V2 vasopressin receptors, increasing serum sodium and urine output without increasing sodium loss. This effect, known as aquaresis, helps to restore normal sodium levels in patients with hyponatremia.

"Hyponatremia affects nearly a million patients every year in this country alone, and available treatment options are limited and unpredictable," said Joseph Verbalis, M.D., Chair, Department of Medicine, Georgetown University Medical Center. "The results of these studies suggest that conivaptan could potentially improve our ability to manage this very common and often very serious condition."

Both Phase III studies were randomized, double-blind, placebo-controlled, multicenter trials of oral conivaptan among patients with serum sodium levels of 115 to <130 mEq/L and no clinical evidence of extracellular volume depletion. The first study was conducted in the United States, and the second was conducted in Europe. In both studies:

   -- Patients were randomly assigned to receive placebo, conivaptan
      40 mg/day or conivaptan 80 mg/day, administered orally in two divided
      doses for five days.
   -- Modest fluid restriction was maintained in all treatment groups.
   -- The primary endpoint was the change from baseline in serum sodium
      levels over the entire course of treatment (expressed as the area
      under the curve, or AUC).
   -- Secondary endpoints included change from baseline in serum sodium
      levels at day five; time to reach a >/= 4 mEq/L increase in serum
      sodium levels; number of patients who achieved a >/= 6 mEq/L increase
      in serum sodium levels or a normal serum sodium concentration (>/=
      135 mEq/L) over the course of the study; and total time from the first
      dose to end of treatment during which patients had a serum sodium
      concentration >4 mEq/L over baseline.
   -- Other endpoints included change from baseline in effective water
      clearance, urine output and urine sodium concentration.

In the U.S. study, 74 patients received either placebo (n=23), conivaptan 40 mg/day (n=24) or conivaptan 80 mg/day (n=27). The major findings of this study were the following (P values are listed where significant):

-- Both doses of conivaptan significantly increased serum sodium levels relative to placebo, with a mean change in AUC of 621.3 mEq/L*hr in the conivaptan 40 mg/day group (p=0.03 vs. placebo), 836.2 mEq/L*hr in the conivaptan 80 mg/day group (p=0.0001 vs. placebo) and 309.2 mEq/L*hr in the placebo group. -- On average, conivaptan 40 mg/day and 80 mg/day produced a >/= 4 mEq/L increase in serum sodium levels within 27.5 hours (p<0.05 vs. placebo) and 12.1 hours (p < / = 0.01 vs. placebo), respectively, compared with 71.7 hours in the placebo group. -- Patients receiving conivaptan 80 mg/day experienced >/= 4 mEq/L increases in serum sodium levels for longer periods of time compared with placebo patients (88.8 hours versus 46.5 hours, respectively; p < / = 0.001 vs. placebo). -- At study's end, the mean change in serum sodium concentration was 6.4 mEq/L in patients who received conivaptan 40 mg/day and 7.9 mEq/L in those who received conivaptan 80 mg/day (p=0.005 vs. placebo), compared with 3.9 mEq/L in patients who were given placebo. -- 70.8 percent of conivaptan 40 mg/day patients and 81.5 percent of conivaptan 80 mg/day patients (p<0.05 vs. placebo) achieved a >/= 6 mEq/L increase in serum sodium levels or a normal serum sodium concentration (>/= 135 mEq/L) over the treatment period, compared with only 47.8 percent of patients receiving placebo.

In the European study, 83 patients were randomized to receive either placebo (n=30), conivaptan 40 mg/day (n=27) or conivaptan 80 mg/day (n=26). The major findings of this study were the following (P values are listed where significant):

-- Both conivaptan doses significantly increased serum sodium levels compared to placebo, with a mean change in AUC of 634.2 mEq/L*hr in patients who received conivaptan 40 mg/day (p=0.0001 vs. placebo), 952.7 mEq/L*hr in patients who received conivaptan 80 mg/day (p=0.0001 vs. placebo) and 87.5 mEq/L*hr in patients who received placebo. -- On average, conivaptan 40 mg/day and 80 mg/day produced a >/= 4 mEq/L increase in serum sodium levels within 23.5 hours (p<0.001 vs. placebo) and 8.7 hours (p < / = 0.0001 vs. placebo), respectively. -- Patients receiving conivaptan 40 mg/day or 80 mg/day experienced >/= 4 mEq/L increases in serum sodium levels for longer periods of time compared with placebo patients (68.8 hours and 86.6 hours versus 20.3 hours, respectively; p < / = 0.0001 vs. placebo for both conivaptan groups). -- At the end of the study, the mean change in serum sodium concentration was 6.8 mEq/L in the conivaptan 40 mg/day group and 8.8 mEq/L in the conivaptan 80 mg/day group, compared with 1.0 mEq/L in the placebo group (p < / = 0.0001 vs. placebo for both conivaptan groups). -- 66.7 percent of conivaptan 40 mg/day patients (p < / = 0.001 vs. placebo) and 88.5 percent of conivaptan 80 mg/day patients (p < / = 0.0001 vs. placebo) achieved a >/= 6 mEq/L increase in serum sodium levels or a normal serum sodium concentration (>/= 135 mEq/L) over the treatment period, compared with only 20.0 percent of patients receiving placebo.

Oral conivaptan was generally well tolerated in both studies. The most common adverse events (AEs) in the U.S. study were headache, constipation and hypotension in the 40 mg/day group, and headache, constipation, hypotension and postural hypotension in the 80 mg/day group. In the European study, the most common adverse events were urinary tract infection, pyrexia and heart failure in the 40 mg/day treatment group and urinary tract infection and pyrexia in the 80 mg/day group. In the European study, the incidence of drug- related AEs was slightly higher in the conivaptan 80 mg/day group than in the placebo group. In the U.S. study, the incidence of drug-related AEs was similar across all treatment groups.

About Conivaptan

Developed by Yamanouchi, conivaptan is being reviewed by the U.S. Food and Drug Administration (FDA) as an intravenous formulation for the treatment of euvolemic and hypervolemic hyponatremia. If approved, it will be the first drug specifically indicated for this condition. Current treatments, which include fluid restriction, diuretics and hypertonic saline solution, are associated with inconsistent results. Through its unique aquaretic effect, conivaptan may help to normalize sodium levels in patients with hyponatremia.

About Hyponatremia

Hyponatremia is a common electrolyte disorder that is estimated to occur in one percent to six percent of hospitalized patients in the United States each year. Congestive heart failure, advanced renal failure, hypothyroidism and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) are frequent causes of hyponatremia. Dilutional hyponatremia, the most common form of the condition, occurs when retained water dilutes serum sodium content. While many patients with hyponatremia have no symptoms, severe cases are medical emergencies that can result in swelling of the brain, respiratory arrest and death.

About Yamanouchi Pharma America, Inc.

As the U.S. subsidiary of Yamanouchi Pharmaceutical Co., Ltd., Yamanouchi Pharma America, Inc. is dedicated to developing and delivering innovative therapeutic treatment options for unmet medical needs. Drawing upon the parent company's over 80-year heritage of research excellence and pioneering product development, Yamanouchi Pharma America has established the goal of becoming a leading pharmaceutical company in the United States.

The company has a number of exciting and innovative investigational compounds currently in clinical development, including solifenacin succinate, a muscarinic antagonist currently under review by the U.S. Food and Drug Administration for the treatment of overactive bladder.

Yamanouchi cautionary statement regarding forward-looking statements: This announcement includes forward-looking statements based on assumptions and beliefs in light of the information currently available to management and subject to significant risks and uncertainties. Actual results may differ materially depending on a number of factors including without limitation adverse economic conditions, currency exchange rate fluctuations, adverse legislative and regulatory developments, delays in the product launch, pricing and product initiatives of competitors, the inability of the company to market the product effectively, interruptions in production, infringements of the company's intellectual property rights and the adverse outcome of material litigation.

Yamanouchi Pharma America, Inc.

CONTACT: Patrice Collins, M.D. of Yamanouchi Pharma America, Inc.,+1-201-247-6578



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