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Published on: August 8, 2012
by John Gever for MedPage Today:
A report that an approved cancer drug dramatically reduced beta amyloid plaques in transgenic mice has left clinicians in an awkward position, researchers said.
With children of Alzheimer’s disease patients “clamoring” for the drug, bexarotene (Targretin), as the Wall Street Journal reported shortly after the study was published online in February in Science, physicians must weigh the potential risks and benefits — both of which are highly uncertain — in deciding whether to accommodate them.
The difficulty they face was addressed in two articles appearing in the Aug. 9 issue of the New England Journal of Medicine.
One, by Frank LaFerla, PhD, of the University of California Irvine, summarized the Science study with some added commentary on the implications. The other, by a group of National Institutes of Health bioethicists, offered guidance on how individual clinicians and the research establishment should respond to the study.
Led by Gary Landreth, PhD, and Paige Cramer of Case Western Reserve University in Cleveland, the Feb. 9, 2012 Science paper described a series of experiments involving bexarotene, an oral drug approved for cutaneous T-cell lymphoma, in transgenic mice that develop extensive beta amyloid protein plaques similar to those seen in human Alzheimer’s disease patients.
Bexarotene activates RXR receptors, which the researchers believed would trigger translation of the APOE gene for apolipoprotein E. That, in turn, would activate mechanisms to clear beta amyloid from the nervous system.
LaFerla wrote “this is exactly what happened in transgenic mice, although the rapidity of the clearance was astonishing, with areas of beta amyloid plaques reduced by more than 50% within 72 hours.”
Cognitive function also improved in the animals, with partial restoration of activities such as nest-building.
But, LaFerla observed, “rarely is science straightforward.” The acute effects of bexarotene may have been astonishingly dramatic, but when it was given for 3 months, plaque volumes at the end of treatment barely differed from control mice.
He also noted that other drugs have also appeared successful in animal models of Alzheimer’s disease, only to fail in clinical trials. While he did not mention the anti-amyloid monoclonal antibodybapineuzumab specifically, negative results in two clinical trials, including one reported earlier this week, led its developers to end their program.
LaFerla wrote that bexarotene also must be tested in rigorous clinical trials before clinicians should consider prescribing it off-label.
Experts contacted by MedPage Today and ABC News agreed.
“Prescription of off-label bexarotene for Alzheimer’s disease cannot even be contemplated until the mouse experiment is replicated and until extended toxicity experiments are performed in the geriatric population,” said Samuel Gandy, MD, PhD, of Mount Sinai School of Medicine in New York City, in an email.
“I cannot state strongly enough how inappropriate it would be to jump the gun here. ‘Not ready for prime time’ is an understatement,” he added.
Gregory Jicha, MD, PhD, of the University of Kentucky in Lexington, commented that because Alzheimer’s disease is a devastating and fatal illness, “the impetus to do something is quite high.” But he noted that the safety of bexarotene in the Alzheimer’s disease population is completely unknown.
“This is a medical no-brainer, you should not prescribe this until tested with appropriate safety oversight,” Jicha said.
Also in agreement were the authors of the second NEJM article, led by Justin Lowenthal of the NIH’s National Human Genome Research Institute in Bethesda, Md.
They noted that contrary to comments traded in Internet chat groups, bexarotene has a host of adverse effects, including hyperlipidemia and increased risk for acute pancreatitis, hypothyroidism, leukopenia, and liver damage.
“Given these known risks, without evidence that bexarotene will be effective against human Alzheimer’s disease, and absent any guidance as to the appropriate doses for this condition, the proper exercise of clinical judgment should certainly lead physicians to counsel patients and families that it is premature to prescribe bexarotene for this purpose,” they wrote.
“Even if patients and families are willing to take the risks for the potential benefit, the physician’s answer should be no. This stance is consistent with longstanding ethical and professional guidelines,” they said.
They also addressed a hypothetical future situation, in which an initial clinical trial has confirmed a clinical benefit.
At that point, Lowenthal’s group suggested that physicians would face “sudden overwhelming demand” for the drug. Even then, ethical considerations should go beyond the risk and benefits for individual patients.
These include “the importance of gathering reliable evidence through clinical trials to inform the care of future patients, the fairness of present and future access, and the value of stewardship of limited resources,” they wrote.
They argued that this situation would not be wholly unprecedented. Physicians also had to deal with intense pressure from patients and others when the first drugs against HIV entered clinical testing in the early 1990s.
“The clinical research community needed to balance respect for patients’ desire to try a promising therapy for a fatal disease against the need to run clinical trials, some of them placebo-controlled, in order to develop reliable evidence on the safety and true relative effectiveness of the new drugs,” Lowenthal’s group wrote.
There was also recognition that access should be equal across socioeconomic classes and that the financial burden on individuals, payers, and the overall healthcare system was an important consideration.
Eventually the FDA adopted rules for HIV drug trials after consulting with a diverse group of stakeholders, laying the groundwork for current regulations on expanded access to investigational drugs.
“Bexarotene’s case is different, since off-label prescribing is already possible, but many of the ethical issues are similar and call for analogous deliberative procedures,” Lowenthal’s group suggested.
Although bexarotene’s clinical benefit in Alzheimer’s disease remains largely speculative, “it is not premature to plan for such a possibility,” they wrote.
“Physicians, patients, and families are already confronting hints of the ethical challenges that may lie ahead; the time to discuss them formally is now.”
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