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Kidney Drug Tolvaptan Meets Primary Endpoint in Phase III Trial

Increase in kidney volume reduced in patients with polycystic disease (Nov. 4)

Clinical trial results for tolvaptan (Otsuka Pharmaceutical Co., Ltd.) — an investigational drug for the treatment of autosomal dominant polycystic kidney disease (ADPKD) — have been published online in the New England Journal of Medicine.

In the study, tolvaptan met its primary endpoint of demonstrating a statistically significant (P < 0.001) reduction of nearly 50% in the rate of increase in total kidney volume (TKV) over the 3-year study period compared with placebo in 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, multicenter, randomized, double-blind, placebo-controlled, parallel-arm trial involving more than 1,400 adult patients (aged 18 to 50 years).

Tolvaptan is a selective V2 vasopressin receptor antagonist that is believed to slow the progression of ADPKD by reducing the development and growth of kidney cysts, which are characteristic of the disease and are often associated with pain, hypertension, and kidney failure. ADPKD is the leading cause of inherited kidney disease, affecting an estimated 1 in 1,000 to 1 in 4,000 diagnosed patients.

The TEMPO study was designed to assess the efficacy and safety of tolvaptan for the treatment of ADPKD. Patients were randomly assigned to receive either a morning/afternoon split-dose regimen of tolvaptan (45/15, 60/30, or 90/30 mg daily, as tolerated; n = 961) or placebo (n = 484). The primary efficacy endpoint was the annual rate of change in TKV (a measurement of kidney cyst growth) with tolvaptan compared with placebo. The key secondary endpoint was a composite of events of ADPKD progression, including worsening kidney function, the incidence of significant kidney pain, worsening of hypertension, and worsening albuminuria.

Tolvaptan achieved a statistically significant reduction in the rate of increase in TKV over the 3-year study period compared with 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 [HR] = 0.87; P = 0.0095). The effect on this endpoint was driven by a 61% reduction in the risk of an event of worsening kidney function (HR = 0.39; P < 0.001) and a 36% reduction in the risk of an event of worsening kidney pain (HR = 0.64; P = 0.007).

The most common adverse events associated with tolvaptan therapy were related to the drug’s aquaretic mode of action: thirst (55.3% for tolvaptan vs. 20.5% for placebo), 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%).

Polycystic kidney disease (PKD) is characterized by the development of multiple, nonmalignant cystic structures arising in the kidneys due to inherited or acquired genetic mutation. ADPKD is the most common form of inherited PKD. Cyst development and growth in both kidneys leads to slow deterioration of kidney function, and to end-stage renal disease (ESRD) and renal failure in more than 50% of patients. The symptoms of ADPKD typically manifest during adulthood.

Source: Otsuka Pharmaceutical Co., Ltd.; November 4, 2012.

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