FDA OKs Tolvaptan for Rapidly Progressing Rare Kidney Disease

Megan Brooks

April 26, 2018

The US Food and Drug Administration (FDA) has approved tolvaptan (Jynarque, Otsuka) to slow decline in kidney function in adults at risk for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD), the company has announced.

ADPKD is a rare, chronic, progressive, inherited disease that causes the proliferation and growth of cysts in the kidneys, leading to an increase in kidney size. Complications include chronic and acute pain, hypertension, and kidney failure leading to dialysis or kidney transplant.

ADPKD is diagnosed in about 140,000 people in the United States and affects families across multiple generations. There is a 50% chance that a parent with ADPKD will pass the disease on to each of his or her children.

Tolvaptan, a vasopressin-2 receptor antagonist, is the first FDA-approved drug treatment to slow decline in kidney function in adults at risk for rapidly progressing ADPKD, the company said.

The FDA approval of tolvaptan is supported by data from the Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO 3:4) study and the Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) study.

In the REPRISE study, which involved 1370 patients with later-stage ADPKD, use of tolvaptan resulted in a slower decline in the estimated glomerular filtration rate (eGFR) over 1 year in comparison with than placebo.

The change in eGFR from baseline to posttreatment follow-up (the primary endpoint) was −2.3 mL/min/1.73 m2/year with tolvaptan vs −3.6 mL/min/1.73 m2/year with placebo, corresponding to a treatment effect of 1.3 mL/min/1.73 m2/year (P < .0001).

"The progressive nature of ADPKD means that kidney function gets worse over time, eventually leading to end-stage renal disease. This progression happens more rapidly for some patients than others," REPRISE investigator Michal Mrug, MD, from the University of Alabama at Birmingham, said in a company news release. Tolvaptan's approval is "great news for adults at risk of rapidly progressing ADPKD because by slowing the decline in kidney function, this therapy may give them more time before kidney transplant or dialysis," said Mrug.

The TEMPO 3:4 study included 1445 patients with rapidly progressing early ADPKD. Over 3 years, the increase in total kidney volume (primary endpoint) was significantly less with tolvaptan than placebo (2.8% vs 5.5% per year; P < .001).

Key secondary endpoints, including time to clinical progression (defined as worsening of kidney function, kidney pain, hypertension, and albuminuria) and rate of decline of kidney function, also favored tolvaptan over placebo.

The rate of discontinuation due to adverse events was higher with tolvaptan than with placebo (23% vs 14%).

Tolvaptan can cause serious and potentially fatal liver injury, and acute liver failure requiring liver transplant has been reported. Tolvaptan has been associated with elevations in liver enzyme levels.

Alanine aminotransferase, aspartate aminotransferase, and bilirubin levels should be measured before initiating treatment with tolvaptan, at 2 weeks and 4 weeks after initiation, then monthly for 18 months, then every 3 months for as long as the patient is receiving tolvaptan, the company said.

Owing to the risks of serious liver injury, tolvaptan is available only through a restricted distribution program supported by a risk evaluation and mitigation strategy program approved by the FDA. Full prescribing information is available online.

Otsuka said tolvaptan will be sold in a 28-day treatment pack at a wholesale acquisition cost of $13,041.10.

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