Experts Urge Caution on Use of Bexarotene in Alzheimer's

Pauline Anderson

August 24, 2012

August 24, 2012 — Experts are calling for caution in the wake of promising research showing that a drug already approved for treating cutaneous T-cell lymphoma (CTCL) significantly and swiftly reduces the amount of beta amyloid (Aß) in mouse models of Alzheimer's disease (AD).

The study, published in the March issue of Science, showed that the drug, bexarotene (Targretin), reduced areas of plaque by more than 50% within 72 hours, and by as much as 75% in 14 days, in mice genetically engineered to exhibit symptoms of AD. The agent also reversed neural, cognitive, and social deficits, although the effects lessened as the mice aged.

The speed with which the drug removed Aß was "astonishing," Frank M. LaFerla, PhD, from the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, writes in a comment published in the August 9 issue of New England Journal of Medicine.

Weighing in on this topic in the same issue, Justin Lowenthal, BS, from the Department of Bioethics at the Clinical Center at the National Institutes of Health (NIH), Bethesda, Maryland, and colleagues say that the study is an example of "being on the cusp of a potential medical breakthrough."

Coauthors of this Perspective article are Sandra Chandros Hull, PhD, also from the Department of Bioethics at NIH and the Office of the Clinical Director, National Human Genome Research Institute, and Steven D. Pearson, MD, from the Department of Bioethics at NIH and the Institute for Clinical and Economic Review, Massachusetts General Hospital Institute for Technology Assessment, in Boston.

However, despite the encouraging results, the researchers maintain that it is too early to provide bexarotene to patients with AD, who along with their families may be clamoring to get it.

Bexarotene, which for CTCL is prescribed orally, appears to clear excess amyloid by activating retinoid receptors on brain cells that increase production of apolipoprotein E. In contrast, monoclonal antibodies, which in intravenous form have also been investigated in AD, bind directly to amyloid and then remove it.

Numerous Failures

Dr. LaFerla noted that "the field has been down this road before," with numerous therapies and interventions for AD showing success in preclinical models but ultimately failing when evaluated in human clinical trials. One explanation for this, he said, is that these compounds are evaluated in models that lack critical pathologic features other than amyloid, for example, neurofibrillary tangles.

He echoed the sentiments of Lowenthal and colleagues, saying that "only a well-designed and carefully executed clinical trial will reveal whether this class of drug lives up to its promise." Until then, he writes, it would be "a mistake" to offer this treatment to patients with AD.

Lowenthal and coauthors write that the evidence is too preliminary — a single mouse model in one laboratory — and needs confirmation before AD investigators even consider launching clinical trials in humans. Although it is "extremely premature" to believe that an effective treatment for AD in humans has been found, it is not premature to plan for such a possibility, they write.

Because the drug has already been approved by the Food and Drug Administration (FDA), physicians can legally prescribe it for off-label indications, which may present an ethical dilemma, Lowenthal and colleagues point out. They advise against prescribing bexarotene to patients with AD, given the current lack of guidance as to appropriate doses for AD, and also the drug's known risks, at least in CTCL, which can include lipid abnormalities, effects on insulin action, increased risks for acute pancreatitis, elevated liver function values, and hypothyroidism.

In the hypothetical scenario in which early testing of the drug in humans does show promising results, there would be "sudden overwhelming demand" for this approved drug to be prescribed off-label, but there would be continued uncertainty regarding the balance of risks and benefits for individual patients, they write.

To address the demand for the drug, Lowenthal and associates stressed the need for procedures analogous to the approach adopted by the FDA for HIV that allowed open-label therapeutic protocols to be run in parallel with standard clinical trials. Such models became key precursors to current regulatory mechanisms, which specify the conditions under which patients can gain "expanded access" to drugs before regulatory approval.

Unequivocal Recommendation

"We believe that all relevant stakeholders — patients, advocacy organizations, physician societies, investigators, the manufacturer, insurers, and FDA policymakers — should convene to produce guidance on how to address the potential demand for bexarotene," the commentators write.

"Recommendations for the situation today should be clear and unequivocal: bexarotene should not be prescribed before any human tests have been completed."

Lowenthal and coauthors emphasize that physician societies should not try by themselves to develop guidance for standardized eligibility criteria for off-label prescribing of bexarotene. It’s "crucial" to engage with a broad spectrum of patient advocates and others to produce guidance with true legitimacy, they conclude.

Science. 2012;335:1503-1506. Abstract

N Engl J Med. 2012;367:570-572, 488-490. Abstract Abstract

Complete disclosure details are available at the Journal Web sites.

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