Tolvaptan slows renal damage in advanced autosomal dominant polycystic kidney disease

Last Updated: 2017-11-06

By Gene Emery

NEW YORK (Reuters Health) - Tolvaptan's ability to slow renal damage in people with early autosomal dominant polycystic kidney disease appears to extend to those with later-stage disease, according to a one-year randomized trial involving 1,370 patients.

About 65% of the participants had stage 3b or stage 4 disease.

After taking the drug for a year, volunteers in the tolvaptan group saw their estimated glomerular filtration rate drop by 2.34 mL/min/1.73m2 of body-surface area, compared to a significantly larger decline of 3.61 mL/min/1.73m2 in the placebo group.

The research team estimated that if the drug's yearly advantage over placebo of 1.27 mL/min/1.73m2 continued, tolvaptan users would take 9.0 years to reach stage 5 chronic kidney disease rather than 6.2 years.

The cost of the treatment: more a $1 million per year, according to dosages cited in the study and discounted prices for the drug on the website GoodRx.com.

Japan's Otsuka Pharmaceuticals, which sells tolvaptan under the brand names Jinarc or Samsca, supported the study. The results were published online November 4 by the New England Journal of Medicine and reported at the American Society of Nephrology's Kidney Week meeting in New Orleans.

Tolvaptan is approved for polycystic kidney disease in the European Union, Japan, Canada and other countries - but not the United States.

"Those taking tolvaptan enjoyed a small but clinically important slowing of their decline in kidney function," said Dr. Julie Ingelfinger, an NEJM editor. "Further studies will be needed to show whether these results can translate into meaningful delays in the need for renal-replacement therapy and whether the adverse events observed presage more substantial issues over time."

Chief author Dr. Vicente Torres of the division of nephrology and hypertension at the Mayo Clinic in Rochester, Minnesota, told Reuters Health in a telephone interview that the results of earlier tolvaptan trials known as TEMPO 3:4 and TEMPO 4:4, where participants have been followed for several years, show progressive benefit of the drug.

"These results make one feel hopeful the benefit is going to be maintained," he said. And the hope is that, "provided the benefit is maintained, the earlier you start, the longer the benefit."

The inherited genetic disease produces cysts in the kidneys, and about half the patients have end-stage disease by age 60.

The earlier studies showed that tolvaptan helped people with less-severe disease but that the side effects caused nearly 1 in 4 volunteers to discontinue the medication. A few developed liver damage that was probably attributable to the drug. The U.S. Food and Drug Administration also has warned about potential hepatotoxicity.

In the new study, known as REPRISE, 9.5% of tolvaptan recipients and 2.2% of placebo recipients discontinued the drug because of side effects. But the researchers spent five weeks per person weeding out 6.8% of the volunteers who were clearly sensitive to the drug's adverse effects before the blinded portion of the trial started.

"Presumably, this (9.5%) rate would have been substantially higher if randomization had not been limited to patients who initially had not had treatment-limiting side effects from tolvaptan," said Dr. Ingelfinger.

She also called the higher hepatic enzyme levels in the tolvaptan recipients "a worrisome signal."

Volunteers who received the drug instead of matching placebo got either 90 mg or 120 mg per day, with 30 mg given in the afternoon and the rest in the morning. If side effects persisted, doctors could cut the total dose to as low as 45 mg.

The benefit was statistically significant among whites and people younger than 56. Nonwhites and older patients were under-represented: The mean age of all trial participants was 47, and 92% were white.

The rate of serious liver-related adverse events was 4.6% with tolvaptan versus 0.6% with placebo. Alanine aminotransferase levels rose to more than three times the upper limit of normal among 5.6% of the tolvaptan group versus 1.2% of the placebo group.

Dr. Torres said the risk of liver damage seems to level off after 18 months. "There appears to be a window of susceptibility, mostly in the first 12 months," he said.

The rates of polyuria, nocturia, thirst, polydipsia, dry mouth, and diarrhea were twice as high with tolvaptan than with placebo.

Dr. Torres said in countries where tolvaptan's use in polycystic kidney disease has been approved, it is generally recommended for patients whose disease is in stage 1 to 3a. "These recommendations are likely to change because the REPRISE trial shows it's equally effective in stage 3b or even stage 4."

SOURCE: http://bit.ly/2j157mM

N Engl J Med 2017.