Daniel M. Keller, PhD

November 09, 2012

SAN DIEGO, California — Treatment with tolvaptan, a currently marketed drug, can slow the progression of autosomal dominant polycystic kidney disease (ADPKD). Although not currently approved for this indication, tolvaptan slowed the increase in kidney volume and decline in kidney function over a 3-year period, Vicente Torres, MD, PhD, professor of medicine and chairman of the Division of Nephrology and Hypertension at Mayo Clinic in Rochester, Minnesota, told delegates here at Kidney Week 2012.

The trial was published online November 3 in the New England Journal of Medicine to coincide with its presentation here.

In the trial, the Tolvaptan Efficacy and Safety in Management of Polycystic Kidney Disease and Its Outcomes (TEMPO 3:4), aquaresis caused some patients to discontinue the drug, and increases in liver enzyme levels among some participants indicate that close monitoring during therapy is advisable.

ADPKD is the most common genetic cause of end-stage renal disease (ESRD), and it is the fourth most common cause of ESRD overall. Prevalence is estimated at 1 in 400 to 1 in 1000 if one considers all the undiagnosed cases.

ADPKD causes cysts to form in the kidneys, and their relentless progression destroys the kidneys, leads to hypertension, bleeding in the kidney, stone formation, pain, and diminished quality of life.

Tolvaptan is a vasopressin receptor antagonist, and vasopressin is thought to promote the growth of cysts. Therefore, investigators are testing tolvaptan in animals and in human trials to slow the progression of cysts.

TEMPO 3:4 was a phase 3, multinational, randomized, placebo-controlled, parallel-group trial of tolvaptan in ADPKD. Patients (N = 1445; mean age, 39 years) were randomly assigned 2:1 to tolvaptan or to placebo between January 2007 and January 2009.

Entry criteria were age 18-50 years, a total (bilateral) kidney volume of 750 mL or greater, and an estimated creatinine clearance of 60 mL/min/1.73m2. Normal kidney volume is about 300 mL, and these patients had rapidly progressive disease. But because they were relatively young and still had fairly good kidney function, the idea was that treatment may help preserve it.

Study drug was started at 45 mg in the morning and 15 mg in the afternoon and was up-titrated weekly to 60/30 mg and to 90/30 mg if tolerated. The maximally tolerated dose was maintained for 3 years, and patients had renal chemistries done every 4 months, as well as yearly renal magnetic resonance imaging. Patients were instructed to drink enough water not to feel thirsty.

At the end of the study, patients had 2 follow-up visits at least 1 week apart at 1 to 6 weeks after stopping treatment. Patients who did not tolerate even the lowest dose were still followed by telephone every 4 months throughout the study period. The primary endpoint was the annual percent change in kidney volume, which would reflect development and enlargement of the cysts.

Tolvaptan Slowed Disease Progression

"Tolvaptan reduced the rate of increasing kidney volume from 5.5% [per year over 3 years] in the placebo [group] to 2.8%," Dr. Torres reported in a news conference (P < .001).

The researchers also did a mixed model for repeated measures sensitivity analysis to assess the effect year-to-year. "We saw that the greatest effect of tolvaptan was from baseline to year 1 but that this effect was also significant from year 1 to year 2 and from year 2 to year 3," he said.

There was an increasing separation of the kidney volumes between the tolvaptan and placebo groups over the course of the trial (P < .001 at years 1, 2, and 3).

For the secondary endpoint of the change in kidney function, tolvaptan reduced the slope of kidney function decline (reciprocal of the serum creatinine). The rate of decline was -3.81 (mg/mL)-1/year with placebo and -2.61(mg/mL)-1/year with tolvaptan, an absolute difference in decline of 1.2 (mg/mL)-1/year (P < .001).

Similarly, for the time to the secondary endpoint of multiple progression events (including kidney function decline, severe kidney pain, and development or progression of hypertension or albuminuria), tolvaptan was superior to placebo (hazard ratio [HR] = 0.87; 95% confidence interval [CI] 0.78 - 0.97; P = .0095). This finding was driven by a 61% reduction in the worsening of kidney function with tolvaptan (HR = 0.39; 95% CI 0.26 - 0.57; P < .001) and by a 36% lower risk for kidney pain events requiring intervention (HR = 0.64; 95% CI 0.47 - 0.89; P = .007) with tolvaptan.

"This effect on kidney pain occurred immediately and throughout the duration of the trial, whereas the effect on worsening kidney function became evident later," Dr. Torres said. There was no treatment effect with regard to hypertension or albuminuria events.

Adverse effects related to the aquaretic consequences of tolvaptan, as expected, were more common in the tolvaptan group vs placebo — thirst (55.3% vs 20.5%, respectively), polyuria (38.3% vs 17.2%), nocturia (29.1% vs 13.0%), and pollakiuria (23.2% vs 5.4%). Conversely, renal pain, hematuria, and urinary tract infections were less common with tolvaptan.

Elevated laboratory values with clinical significance at any visit were more common in the tolvaptan group, including increases in serum sodium (4.0% vs 1.4%), uric acid (6.2% vs 1.7%), and liver enzyme levels greater than 3 times the upper limit of normal (4.7% vs 1.7%).

Dr. Torres concluded that "tolvaptan given over 3 years slowed the increase in kidney volume and the decline in kidney function and lowered the frequency of ADPKD-related events." He also said that aquaresis related to tolvaptan led to drug discontinuation by 8.3% of the participants, and clinically significant increases in liver enzymes were seen in 4.7% of participants so will require close monitoring in the future.

In response to a question from Medscape Medical News, Dr. Torres said that one can estimate through calculations that for patients such as the ones in this trial the need for renal replacement therapy could be delayed from 12.5 years following a natural course to 25 years with tolvaptan. "So you double from 12.5 to 25 [years]," he said. "Now that doesn't mean it's going to be delayed by 25 years because that's just based on 3 years," but that is the best estimate from the trial results so far.

Session cochair Julie Ingelfinger, MD, senior consultant in pediatric nephrology at Massachusetts General Hospital, professor of pediatrics at Harvard Medical School in Boston, Massachusetts, and deputy editor of the New England Journal of Medicine, in commenting to Medscape Medical News, cautioned that this study, like many studies with "vaptan" drugs, is rather short term.

"If a person has ADPKD it's going to be a long trajectory to ESRD. This group of patients [in this study] had relatively well preserved glomerular filtration rate, so they are a good population. And yet even in the length of this trial...there were discontinuations because of the side effects," she said. "On this kind of drug a person is thirsty, needs to drink a lot, may have liver enzyme issues. This gives one pause, and yet this study is positive but modestly so."

She said that for patients with polycystic kidney disease who may go many years before needing dialysis, "maybe for some of those people it holds out the hope for maybe the first time that this might really change their trajectory...so it's an encouraging signal. It's not an obvious home run."

In an accompanying editorial, Rudolf Wũthrich, MD, from the Division of Nephrology at University Hospital in Zurich, Switzerland, and Changlin Mei, MD, from the Kidney Institute at Changzheng Hospital in Shanghai, China, write that tolvaptan slowed the rate of kidney volume increase and reduced the decline in glomerular filtration rate. Although patients on tolvaptan experienced more adverse events, they had fewer adverse events related to ADPKD, including kidney and back pain, hematuria, and urinary tract infections.

The editorial writers noted that the rate of increase in kidney volume was lower for the patients in TEMPO 3:4 than is usually seen in ADPKD. All patients with ADPKD are recommended to increase their water intake to suppress vasopressin-mediated increases in cyclic adenosine monophosphate (cAMP), which leads to cyst growth.

"The fact that participating patients followed this prescription could explain the reduced growth of kidney volume observed in this study," the editorialists write. "Nevertheless, tolvaptan, by driving fluid intake, slowed the expansion of cyst volume significantly more than placebo did."

Dr. Wũthrich and Dr. Mei add that the study did not examine in a systematic manner tolvaptan's effect on pain, and therefore the pain data need to be confirmed. There was also no explanation for the fact that tolvaptan had no effect on the worsening trajectories of hypertension and albuminuria. "Assuming that tolvaptan causes structural rather than functional improvements, one would have expected beneficial effects on urinary protein excretion and blood pressure," the editorial writers propose.

Despite some criticisms, these authors called the TEMPO 3:4 study "a major advancement in the quest for a cure for ADPKD." In light of the benefits, risks, and adverse effects related to aquaresis, they said it will be necessary to develop criteria for tolvaptan treatment and patient selection "if tolvaptan is to be a successful therapy for patients with ADPKD."

The trial was supported by Otsuka Pharmaceuticals Co, Ltd, Tokyo, Japan, and Otsuka Pharmaceutical Development & Commercialization, Inc, Rockville, Maryland. Dr. Torres has received grant and travel support to his institution from Otsuka. He is a consultant to Ipsen Innovation and Primrose Therapeutics and has received payment for lectures for Amgen. He has been paid as a contributor to UpToDate. Boehringer Ingelheim and Merck have contributed study drug for an NIH-funded trial. Dr. Wũthrich is a consultant to Novartis and has been a consultant to Wyeth (now Pfizer). He has grant support from Otsuka. Dr. Mei has disclosed no relevant financial relationships. Dr. Ingelfinger was not involved in the study and had no relevant financial relationships to disclose other than to say that she is a deputy editor of the journal in which the study is published.

Kidney Week 2012: Abstract HI-OR02. Presented November 3, 2012.