Rare Disease Report
Patients & Caregivers

Trial of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease Is Underway

DECEMBER 17, 2014
Christin Melton

A year after the US Food and Drug Administration (FDA) declined to approve tolvaptan (Samsca) for autosomal dominant polycystic kidney disease (ADPKD), Otsuka Pharmaceutical began recruiting patients for a randomized, placebo-controlled phase 3b trial (NCT02160145) that the company hopes will convince the FDA of tolvaptan's effectiveness. The trial will enroll 1300 men and women with ADPKD-related chronic kidney disease (late stage 2 to early stage 4).

Tolvaptan is an oral drug that targets the vasopressin 2 receptor (V2R) found on the kidney collecting tubules. Binding of tolvaptan to the V2R inhibits downstream synthesis of intracellular cyclic AMP, or cAMP, a molecule that promotes cyst formation and growth in the kidneys of patients with ADPKD. The cysts cause progressive kidney enlargement and destroy kidney structure and function, ultimately leading to end-stage renal disease. The FDA approved tolvaptan in 2009 to treat clinically significant hyponatremia and granted tolvaptan orphan drug status in 2012 for evaluation in ADPKD.

In December 2012, investigators published 3-year findings from a multicenter, randomized, placebo-controlled, double-blind, phase 3 trial of tolvaptan in the New England Journal of Medicine. The trial enrolled 1445 patients aged 18 to 50 years with early to mid-stage ADPKD (NCT00428948). Eligibility requirements included total kidney volume >750 mL and an estimated creatinine clearance rate >60 mL/min. Over 3 weeks, the tolvaptan dosage was titrated from 60 mg/day to 120/mg per day, with dose reductions permitted during the study's 3-year maintenance phase. The study's primary endpoint was yearly growth in kidney volume.

Final data associated tolvaptan with a significantly slower mean annual increase in kidney volume than placebo (2.8% vs 5.5%, respectively; P<.0001). Kidney function also deteriorated more slowly in patients taking tolvaptan than in those given placebo (P<.0001), and the tolvaptan arm reported fewer ADPKD-related events (P=.01). However, tolvaptan failed to demonstrate a benefit in ADPKD-related hypertension and albuminuria.

Although the adverse event rates were approximately 97% in both arms, patients taking tolvaptan had more than double the rate of aquaresis events (eg, thirst, polyuria, and nocturia). Tolvaptan was also associated with quadruple the rate of liver-related adverse events, although the risk for liver injury was much higher during the first year of treatment. Some patients in the tolvaptan arm developed serum alanine aminotransferase levels 3 times the upper limit of normal and total bilirubin levels more than twice the upper limit of normal. Patients in the tolvaptan arm were more likely than patients in the placebo arm to drop out of the study (23% vs 14%, respectively), primarily due to adverse events. 
After reviewing the trial data, an FDA Cardiovascular and Renal Drugs Advisory Committee voted 9 to 6 against recommending an ADPKD indication for tolvaptan. Some committee members said the study included too few patients with advanced kidney disease and worried that treatment-related liver damage might progress with longer use, causing liver failure in an estimated 1 of every 3000 patients. Committee members also disagreed about the extent to which slower growth in kidney volume was clinically meaningful.

In a complete response letter rejecting Otsuka's application, the FDA expressed concern about the quantity of data missing from the efficacy analysis due to the high dropout rate in the tolvaptan arm. The FDA gave examples of how adjusting the way missing data were accounted for could change the P value for some secondary endpoints from significant to nonsignificant. The agency requested more data and worked with Otsuka’s researchers to come up with an acceptable design for the phase 3b trial now underway.

The trial is being conducted at 220 sites, several of which are in the United States. In addition to having chronic kidney disease (late stage 2 to early stage 4) due to ADPKD, eligible participants must be aged 18 to 55 years with an estimated glomerular filtration rate (eGFR) between 25 and 65 mL/min/1.73 m2 or aged 25 to 44 with an eGFR between 25 and 44 mL/min/1.73 m2. Exclusion criteria include hepatic impairment or liver function abnormalities not typical for patients with ADPKD, advanced diabetes, and certain kidney conditions. Patients will receive 45 to 120 mg/day of tolvaptan for 13.5 months. The primary endpoint is change in eGFR from baseline. Other efficacy endpoints and hepatic safety relative to placebo will also be assessed.

ADPKD – Rare Disease Quick Facts

  • The prevalence of ADPKD in the United States is 1:2000
  • A kidney in someone with ADPKD may contain thousands of cysts
  • In ADPKD, a cyst-filled kidney can weigh 20 to 30 pounds
  • ADPKD causes approximately 5% of cases of end-stage renal disease
  • 85% of ADPKD cases are caused by PKD1 mutations, and 15% are caused by PKD2 mutations
  • Cysts may grow for some time without impairing function, which delays diagnosis
Image showing gross pathology of polycystic kidneys courtesy CDC.gov

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