SAN DIEGO—Treatment with tolvaptan, a vasopressin V2-receptor antagonist, slowed the increase in total kidney volume and the decline in kidney function over three years in patients with autosomal dominant polycystic kidney disease (ADPKD).
These results come from a Phase 3, multicenter, double-blind, placebo-controlled trial presented concurrently during the High-Impact Clinical Studies session here at the American Society of Nephrology Kidney Week 2012 (Abstract #HI-OR02) and as an Online First article in the New England Journal of Medicine.
In the study, total kidney volume increased by 2.8% per year among patients in the tolvaptan group, versus 5.5% per year in the placebo group. Kidney function slopes, as assessed using the reciprocal of the serum creatinine level, were −2.61 per year and −3.81 per year, respectively.
“There's no question that polycystic kidney disease is clinically extraordinarily significant, affecting anywhere from one in 500 to one in 1,000 people, at least half of whom are going to go on to require renal replacement therapy,” said Michael J. Caplan, PhD, MD, C.N.H. Long Professor and Chair of the Department of Cellular and Molecular Physiology at Yale University School of Medicine, who was not part of the trial. “There's a tremendous amount of morbidity and mortality associated with the disease,” he noted in a phone interview.
“The significance of finding any therapeutic for this disease is huge, and especially a small-molecule therapeutic. Right now, there's no specific therapy, so if something could be developed that would slow the development of the disease, that would be incredibly important.”
Not Too Early, Not Too Late
In preclinical studies, vasopressin V2-receptor antagonists interfered with cyst growth and slowed the decline of kidney function, noted lead study author Vicente Torres, MD, PhD, Professor of Medicine at the Mayo Clinic, and colleagues. The Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes (TEMPO) 3:4 trial tested the approach in humans.
“I think it's a very nice example of going from basic science and bringing it all the way to patients and showing a benefit,” said Rudolf P. Wüthrich, MD, Professor of Nephrology and Director of the Division of Nephrology at University Hospital in Zurich, who coauthored the editorial that accompanied the publication of the findings in the New England Journal of Medicine. “We're still not there that we have a cure really for the disease; I think it's only the first step.”
Included in the study were 1,445 patients age 18 to 50 who had a diagnosis of ADPKD, a total kidney volume of 750 mL or more, and a creatinine clearance of 60 mL/min or greater, as estimated using the Cockcroft–Gault formula.
“If one starts a treatment very late in the disease when most of the kidney tissue is destroyed and the kidney function is going down rapidly, it's not likely to help, and if one starts treatment early in the disease—within the first few decades of life, when much of the kidney tissue is still preserved and kidney function is normal—many years or even decades of follow-up would be required to detect an effect on kidney function, so this study was designed to capture patients who were progressing fast but still were in a phase of the disease where the treatment was more likely to help,” Dr. Torres said.
The trial participants were enrolled at 129 sites worldwide between January 2007 and January 2009. They were randomized in a two-to-one ratio to receive tolvaptan or placebo.
The primary endpoint was the annual rate of percentage change in total kidney volume. The composite secondary endpoint was the time to investigator-assessed clinical progression, which was defined as worsening kidney function; clinically significant kidney pain necessitating medical leave, pharmacologic treatment, or invasive intervention; worsening hypertension; and worsening albuminuria. The next secondary endpoint was the change in kidney function slope, as measured by the reciprocal of the serum creatinine level.
There were 961 patients in the tolvaptan group, 77.0% of whom completed the three-year trial, and 484 patients in the placebo group, 86.2% of whom finished the three-year study. Demographic and baseline characteristics were well balanced across the two groups.
The trial was supported by Otsuka Pharmaceutical and Otsuka Pharmaceutical Development and Commercialization.
Total Kidney Volume
Tolvaptan slowed the increase in total kidney function volume across subgroups stratified by sex, age, baseline total kidney volume, baseline estimated creatinine clearance, and hypertension status.
“The change in total kidney volume with tolvaptan, as compared with placebo, was more pronounced in the first year of treatment,” Dr. Torres and colleagues wrote.
“The effect on kidney function was nominally greater among patients 35 years of age or older and among those with hypertension or total kidney volume of 1,500 mL or more at baseline—that is, among patients with more advanced disease, who were more likely to have functional decline during the relatively short duration of the trial.”
In terms of the composite secondary endpoint of time to clinical progression, there were fewer ADPKD-related events per 100 person-years in the tolvaptan group than in the placebo group—44 events and 50 events, respectively. Driving this outcome were the drug's benefit for kidney function decline, with two events per 100 person-years of follow-up in the treatment group and five in the placebo group, and for kidney pain, with five events per 100 person-years of follow-up in the treatment group and seven events in the placebo group.
“The secondary outcomes, particularly the pain that ADPKD patients can experience, were not evaluated in a very systematic fashion,” Dr. Wüthrich said.
“Also, they said that they had no effect on hypertension, which was a bit surprising. You would think that if the disease progression is less you'd also be able to demonstrate that they have maybe less hypertension or fewer patients developing new-onset hypertension.”
The rates of adverse events were similar in the tolvaptan group and the placebo group—97.9% of patients and 97.1% of patients, respectively.
However, in patients who received tolvaptan, adverse events related to increased aquaresis were more common as a result of the excretion of electrolyte-free water. These adverse events included thirst, polyuria, nocturia, and polydipsia. Patients in the placebo group had more ADPKD-related adverse events, such as kidney pain, hematuria, urinary tract infection, and back pain.
Potentially clinically important elevations of alanine aminotransferase, defined as a value that was more than 2.5 times the upper limit of the normal range at any trial visit, were seen in 4.9% of patients treated with tolvaptan compared with 1.2% of patients treated with placebo.
“This is something that we were not anticipating, and that was observed in about five percent of cases,” Dr. Torres said. “That's something that will need further evaluation or to be kept in mind in the future.”
In the tolvaptan group, 23.0% of patients permanently discontinued the trial drug, compared with 13.8% who received placebo. Adverse events were responsible for more discontinuations with tolvaptan than with the placebo—15.4% of patients versus 5.0% of patients. In the treatment group, 8.3% of patients discontinued the trial drug because of aquaresis, and 1.2% because of liver-function abnormalities.
“I think there are a number of issues with tolvaptan as a potential therapy, one of which of course is raised in the paper itself and in the editorial that accompanies it, which is that it requires a fairly significant lifestyle change among those patients who remain on the therapy,” Dr. Caplan said.
“They are very diuretic, and so it will be important to determine for how long patients are willing to be compliant.”
Not Ready for Clinical Use
It's not yet time to translate the positive findings from the trial into changes in clinical practice, Dr. Torres noted.
“In regard to clinical use, it is premature at the present time because the treatment still needs to have a very careful evaluation of benefits and risks that needs to be conducted by the FDA [Food and Drug Administration] and the sponsor of the trial.
“Although this medication has been approved to be used clinically for other indications like treatment of euvolemic hyponatremia, it should not be used for treatment of polycystic kidney disease unless approved by the FDA for this indication. At the present time, tolvaptan should not be administered to patients with ADPKD outside of a properly approved research study.”
Research is ongoing, and it is possible that different ways to administer this medication might be more effective and have fewer side effects, he added.
Future work also will identify other therapeutic agents for this patient population, noted Darren Wallace, PhD, Associate Professor of Medicine and a member of the Kidney Institute at the University of Kansas Medical Center, who was not involved in the study.
“I think that this would be a good first drug for treatment of PKD,” Dr. Wallace said in a phone interview. “It's certainly not going to be the last drug, meaning that as we learn more about the disease we can refine our tools to target pathways without causing nonspecific effects, such as water, diuresis, that occur in patients that take tolvaptan.”
Subsequently developed drugs could be added to a regimen with tolvaptan.
“I think we'll probably need a combination treatment in the future,” Dr. Wüthrich said.
Another area for further examination is the optimal timing of intervention.
“I think there's data emerging that a lot of the growth of the cyst occurs at a young age, and a question about how early can one actually begin to use a drug that is blocking the proliferation or the secretion, and we may have to start a lot earlier than adulthood,” said Robert W. Schrier, MD, Professor Emeritus at the University of Colorado, who was not a TEMPO investigator.
First for PKD
One of the limitations of the trial was that patients were asked to maintain good hydration and avoid thirst.
“Patients who are on tolvaptan are drinking an awful lot of water, and are they therefore having an effect beyond what water alone would do?” Dr. Caplan said. “That's something that I think remains, perhaps, to be resolved.
“It will also be really important to see whether the slowing of cyst growth is adequate to prevent the development of pathology.”
The relevance of the results extend beyond this trial and this treatment.
“In addition to the data that are presented in this study regarding the efficacy of tolvaptan, what this provides is the first clear demonstration that anyone can demonstrate positive clinical effects in a clinical trial for PKD,” Dr. Caplan said.
“One of the challenges in studying potential therapies for PKD is that the disease is slowly progressing, and so one has to be able to monitor things like renal function and cyst volume over time and hopefully be able to see a change in a time frame that's reasonable for a clinical trial, and this study demonstrates, I think for the first time, that that's feasible.
“That's huge, not only for the potential efficacy of tolvaptan, but for the assessment of the value of future additional or adjuvant therapies.”© 2012 Lippincott Williams & Wilkins, Inc.