Phase 3 Trial Update of Tolvaptan for Autosomal Dominant Polycystic Kidney Disease

Otsuka announced Phase 3 clinical trial results for tolvaptan, an investigational drug for the treatment of autosomal dominant polycystic kidney disease (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 3, multi-center, randomized, double-blind, placebo-controlled, parallel-arm trial involving more than 1,400 patients. This 3-year trial enrolled adult patients (men and women between 18–50 years of age) with ADPKD at 129 study sites worldwide. Patients were randomized 2:1 to receive either a morning/afternoon split dose regimen of tolvaptan (45/15mg, 60/30mg or 90/30mg 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 vs. 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 vs. 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 (ie, rate) of decline in kidney function when compared with that of placebo-treated patients by approximately 30% (reciprocal serum creatinine, -2.61 vs. -3.81 (mg/mL)^-1 per year, P<0.001).

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.

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