Suspended Resveratrol Clinical Trial: More Details Emerge
Published: May 6, 2010 11:37 pm
Representatives from Sirtris Pharmaceuticals, developer of a proprietary formulation of resveratrol called SRT501, confirmed yesterday that a clinical trial of the drug in multiple myeloma patients was suspended because several patients developed kidney failure. The Myeloma Beacon reported the trial's suspension in an article earlier this week.
Sirtris representatives also have told the Beacon that all patients who experienced kidney failure during the trial were being treated with only SRT501 when their kidney problems developed.
However, it is still uncertain whether the kidney failures were simply a manifestation of the underlying myeloma, or if they were related to the resveratrol treatment.
“We still are investigating. We do not know all the details, and we have a lot of data to review,” said Dr. Eric Jacobson, Chief Medical Officer of Sirtris, in an interview with The Beacon. “But we think it likely that the drug itself is not directly toxic to the kidneys.”
“This was most likely a manifestation of the underlying myeloma.” Dr. Jacobson noted that SRT501 has not caused a single case of kidney failure in any of the previous trials of the drug, which involved some 340 healthy persons, colon cancer patients, and diabetes patients. “We have never seen another case of [kidney] failure except in this myeloma study.”
Sirtris is a subsidiary of the pharmaceutical company GlaxoSmithKline.
SRT501 is a formulation of resveratrol, a molecule found in small quantities in the skin of red grapes and in red wine. Resveratrol is thought to be the source of red wine’s reported health benefits.
According to Sirtris representatives, the resveratrol in SRT501 is from a plant-based source and is micronized, or milled into very small uniform particles, to maximize uptake into the body.
Previous studies have indicated that resveratrol may be effective at killing cancer cells, including multiple myeloma cells. Research has also shown that it may make other chemotherapy drugs, like Velcade (bortezomib) and thalidomide (Thalomid), more effective.
Scientific evidence for these claims has been controversial and confined mostly to the laboratory. The SRT501 trial was the first attempt to determine the effectiveness of resveratrol in treating multiple myeloma patients.
Participants in the SRT501 trial received five grams of the drug once per day on 20 days of a 21-day cycle. Testing for disease progression was scheduled after every two cycles.
Patients with stable results after two cycles continued with the SRT501 treatment alone, while those who experienced disease progression received supplemental treatment with Velcade.
The study was suspended before recruitment was complete due to safety concerns. More specifically, five of the 24 patients (21 percent) developed cast nephropathy, or “myeloma kidney.” In all cases, the cast nephropathy developed while the patients were only receiving SRT501.
According to Dr. Nelson Leung, a kidney specialist at the Mayo Clinic in Rochester, Minnesota, cast nephropathy is a common complication of multiple myeloma. It occurs when excess protein blocks the kidney, resulting in kidney failure, and it affects 15 to 30 percent of myeloma patients.
The exact cause of cast nepropathy is not known, but free light chains -- molecules in the blood overproduced by people with myeloma -- are thought to play a key role. "Dehydration and high calcium levels have also been associated with cast nephropathy," said Dr. Leung.
Patients in the SRT501 trial were required to have normal kidney function prior to the trial in order to participate in it. Due to the relatively high dose of SRT501 used in the study, however, some participants experienced nausea and vomiting, which could have led to dehydration. Sirtris believes this may have been a factor in the kidney failure seen in the clinical trial.
“In a patient who was prone to the renal failure from their high light chains, ” said Dr. Jacobson, “dehydration could have tipped the balance. That could have been an indirect precipitating cause of the kidney problems.”
Dr. Jacobson also noted that all of the patients in the trial had experienced at least one treatment failure for multiple myeloma, and the majority of participants had failed several treatments.
Nonetheless, there is some concern that the dose of resveratrol used in the study could have contributed to the safety issues. Dr. Bharat Aggarwal, Professor of Cancer Research at the University of Texas M. D. Anderson Cancer Center, expressed surprise at the amount of SRT501 given to the patients.
“I am not surprised that they had toxicity. It is too high a dose,” said Prof. Aggarwal, who has studied resveratrol in myeloma cells but is not involved in the SRT501 study.
“Phase 1 clinical trials with resveratrol showed that even when tested in high doses, it was safe,” Prof. Aggarwal added. “Whether SRT501 has a different profile of toxicity, is not clear.”
Sirtris, however, believes that the high dose is necessary. “We are using an extraordinary amount of resveratrol because of what we know about the amounts that are probably required to show a biological effect,” said George Vlasuk, CEO of Sirtris, in an interview yesterday with The Beacon. The daily five gram dose of SRT501 used in the suspended trial also was a common dose used in other SRT501 trials.
Representatives from Sirtris emphasized in their discussions with the Beacon that the SRT501 myeloma trial has not been stopped. Although new participants are not being recruited at this time, evaluation of SRT501 and its efficacy will continue.
“The trial was not stopped. The trial remains active,” said Vlasuk. “We are simply, out of an abundance of caution, trying to understand if SRT501 is actually providing a benefit to these patients.”
“If we determine that’s the case, or at least that it doesn’t have an adverse safety finding, we will continue with this trial.”
Company representatives also emphasized that, despite news reports to the contrary, Sirtris has not made a decision to halt overall development of SRT501.
It is not clear what implications, if any, the safety issues during the SRT501 trial may have for the use of dietary supplements containing resveratrol. SRT501 is a very pure form of the compound, and the five gram dosage is higher than the amounts contained in most supplements.
When Dr. Aggarwal was asked whether he would recommend that certain myeloma patients take resveratrol supplements, he said, “We have no data in patients to suggest that resveratrol helps.”
Update (November 30, 2010) - GlaxoSmithKline has decided to halt all further development of SRT501. See the related Myeloma Beacon news story.
- Resveratrol Trial In Multiple Myeloma Suspended Due To Safety Concerns
- GlaxoSmithKline Halts All Further Development Of Resveratrol Drug SRT501
- Red Wine, Resveratrol, And Multiple Myeloma: The Evidence Is Promising, But Needs Further Study
- Novel Therapeutic Agents May Reduce Kidney Impairment In Newly Diagnosed Myeloma Patients (ASH 2009)
- Beacon NewsFlashes - April 16, 2012