An Otsuka Kidney Drug And A Researcher's Ironic Findings
File this under ‘Life's little ironies." Last week, an FDA advisory panel voted against recommending a drug called Tolvaptan for treating ADPKD, a rare disease in which numerous cysts grow in kidneys. The reasons for rejecting the drug, which is already approved to combat low blood sodium levels, were unanswered questions about efficacy and, in particular, safety concerns over liver toxicity.
There was, however, an interesting subtext to the meeting. The lead investigator for a key clinical trial published last year, Vincent Torres, who also made a presentation (see here and here) on behalf of Otsuka Pharmaceuticals, the company that sells the drug, had previously co-authored a 2009 paper indicating that water intake may, in some cases, be a viable alternative for treating the disease.
That paper, which was published in the Clinical Journal of the American Society of Nephrology, was succinctly titled ‘A Case for Water in the Treatment of Polycystic Kidney Disease” (here is the paper). Torres is a Mayo Clinic physician who also served as principal investigator for the Tolvaptan trial published last year in The New England Journal of Medicine, called Tempo, which was dissected at the FDA meeting last week (here is the Tempo study).
“It really was a wonderful irony,” says Sid Wolfe, a senior advisor to Public Citizen Health Research Group. “Here’s a guy who’s been an enthusiast for using water intake to treat this problem – he advocated this position in a paper – but when we heard him talk (at the FDA advisory committee meeting), he wasn’t as enthusiastic about it.”
We asked Torres for comment and will update you accordingly. There were, however, caveats in his 2009 paper. For instance, the recommendations were based on preclinical data, not a randomized controlled trial. And the authors added that the value of increased water intake is uncertain because Tolvaptan and increased water intake are not equivalent.
Tolvaptan works by slowing the growth of cysts in kidneys and secretion in cysts by turning off a brain hormone called vasopressin. This hormone helps the body to retain water and, therefore, reduces urination. By inhibiting vasopressin, Tolvaptan presumably reduces the rate at which cysts will grow. But can increased water intake work as effectively?
The Tempo trial results also prompted questioning about water intake. For instance, in a letter to the editor in The New England Journal of Medicine this past March, Aaron Spital a nephrologist who worked at St. Luke’s Hospital in New York at the time, wondered why patients in both the Tolvaptan and placebo arms were not instructed to drink large amounts of water, as recommended in the 2009 paper.
“Had they done so, we would have known whether tolvaptan is superior to a high fluid intake alone,” he wrote in a letter to the editor (read here). “In view of the worrisome adverse effects of Tolvaptan seen in the trial, including elevated liver-enzyme levels, as well as the extremely high cost of Tolvaptan (the cost of daily 90-mg dose is more than $25,000 per month), a monitored high-water intake may be safer, far cheaper, and equally effective.”
In response, Torres responded that “a specifically designed clinical trial would be necessary to determine whether high water intake and Tolvaptan are equally effective treatments.” Of course, such a trial is unlikely. As he wrote in the 2009 paper: “Financial support for a trial of increased hydration in ADPDK seems unlikely, because present regulations make a trial mandatory for a drug such as Tolvaptan, but not for water, a natural product consumed in variable amounts.”
However, one of the co-authors of the Tempo trial, Jared Grantham, a nephrologist at the Kidney Institute at the University of Kansas Medical Center, co-authored another paper that was published earlier this year in Kidney International and concluded that suppressing the vasopressin hormone and reducing cyst growth can be achieved when sufficient extra water is given to increase urine volume (here is the abstract). He also co-authored the 2009 paper and is an Otsuka consultant.
As for Otsuka, the drugmaker sent us a statement saying that maintaining sufficient water intake “would be difficult, especially during sleep and difficult to maintain over a lifetime. It is important to note that in the Tempo study, all patients were encouraged to drink water ahead of thirst. The effects of Tolvaptan were observed in addition to background standard care, including increased ingestion of water.”
The Tempo trials authors noted a limitation of the study, which was that maintaining hydration in the placebo arm, which was encouraged to maintain hydration and avoid thirst, may have accounted for lower rates of kidney (cyst) growth. So would Otsuka consider a trial to further gauge water intake? The drugmaker would only say this: “Otsuka supports scientific community efforts in investigating different possibly ways to slow the progression of ADPKD.”
But as Public Citizen’s noted: “Here’s a disease for which water should be, and is effective, but no company is going to pay for a trial. It’s a shame. It’s not clear the drug works that well and it causes liver toxicity. And of course, we know that water doesn’t cause liver toxicity.”
STORY ENDS HERE
There was, however, an interesting subtext to the meeting. The lead investigator for a key clinical trial published last year, Vincent Torres, who also made a presentation (see here and here) on behalf of Otsuka Pharmaceuticals, the company that sells the drug, had previously co-authored a 2009 paper indicating that water intake may, in some cases, be a viable alternative for treating the disease.
That paper, which was published in the Clinical Journal of the American Society of Nephrology, was succinctly titled ‘A Case for Water in the Treatment of Polycystic Kidney Disease” (here is the paper). Torres is a Mayo Clinic physician who also served as principal investigator for the Tolvaptan trial published last year in The New England Journal of Medicine, called Tempo, which was dissected at the FDA meeting last week (here is the Tempo study).
“It really was a wonderful irony,” says Sid Wolfe, a senior advisor to Public Citizen Health Research Group. “Here’s a guy who’s been an enthusiast for using water intake to treat this problem – he advocated this position in a paper – but when we heard him talk (at the FDA advisory committee meeting), he wasn’t as enthusiastic about it.”
We asked Torres for comment and will update you accordingly. There were, however, caveats in his 2009 paper. For instance, the recommendations were based on preclinical data, not a randomized controlled trial. And the authors added that the value of increased water intake is uncertain because Tolvaptan and increased water intake are not equivalent.
Tolvaptan works by slowing the growth of cysts in kidneys and secretion in cysts by turning off a brain hormone called vasopressin. This hormone helps the body to retain water and, therefore, reduces urination. By inhibiting vasopressin, Tolvaptan presumably reduces the rate at which cysts will grow. But can increased water intake work as effectively?
The Tempo trial results also prompted questioning about water intake. For instance, in a letter to the editor in The New England Journal of Medicine this past March, Aaron Spital a nephrologist who worked at St. Luke’s Hospital in New York at the time, wondered why patients in both the Tolvaptan and placebo arms were not instructed to drink large amounts of water, as recommended in the 2009 paper.
“Had they done so, we would have known whether tolvaptan is superior to a high fluid intake alone,” he wrote in a letter to the editor (read here). “In view of the worrisome adverse effects of Tolvaptan seen in the trial, including elevated liver-enzyme levels, as well as the extremely high cost of Tolvaptan (the cost of daily 90-mg dose is more than $25,000 per month), a monitored high-water intake may be safer, far cheaper, and equally effective.”
In response, Torres responded that “a specifically designed clinical trial would be necessary to determine whether high water intake and Tolvaptan are equally effective treatments.” Of course, such a trial is unlikely. As he wrote in the 2009 paper: “Financial support for a trial of increased hydration in ADPDK seems unlikely, because present regulations make a trial mandatory for a drug such as Tolvaptan, but not for water, a natural product consumed in variable amounts.”
However, one of the co-authors of the Tempo trial, Jared Grantham, a nephrologist at the Kidney Institute at the University of Kansas Medical Center, co-authored another paper that was published earlier this year in Kidney International and concluded that suppressing the vasopressin hormone and reducing cyst growth can be achieved when sufficient extra water is given to increase urine volume (here is the abstract). He also co-authored the 2009 paper and is an Otsuka consultant.
As for Otsuka, the drugmaker sent us a statement saying that maintaining sufficient water intake “would be difficult, especially during sleep and difficult to maintain over a lifetime. It is important to note that in the Tempo study, all patients were encouraged to drink water ahead of thirst. The effects of Tolvaptan were observed in addition to background standard care, including increased ingestion of water.”
The Tempo trials authors noted a limitation of the study, which was that maintaining hydration in the placebo arm, which was encouraged to maintain hydration and avoid thirst, may have accounted for lower rates of kidney (cyst) growth. So would Otsuka consider a trial to further gauge water intake? The drugmaker would only say this: “Otsuka supports scientific community efforts in investigating different possibly ways to slow the progression of ADPKD.”
But as Public Citizen’s noted: “Here’s a disease for which water should be, and is effective, but no company is going to pay for a trial. It’s a shame. It’s not clear the drug works that well and it causes liver toxicity. And of course, we know that water doesn’t cause liver toxicity.”
STORY ENDS HERE
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