The first human trial of bexarotene, the skin cancer drug shown to clear beta-amyloid brain plaques in mice with Alzheimer’s-like pathology, will commence sometime in September.

The phase Ib trial will randomize 12 healthy subjects to placebo or bexarotene (Targretin), Gary E. Landreth, Ph.D., said in an interview.

Dr. Gary E. Landreth

Researchers will obtain hourly samples of cerebrospinal fluid and blood for 36 hours after administration of the drug, looking for signs that bexarotene increases natural clearance of the beta-amyloid protein, said Dr. Landreth of Case Western Reserve University, Cleveland.

“If our hypothesis is correct, the drug should accelerate the synthesis and steady-state levels of apolipoprotein E,” a protein that helps break down soluble beta-amyloid, he said. Hungry microglia are bexarotene’s second punch; in mice, the drug activated these cells to scavenge beta-amyloid plaques.

If these two events also occur in humans, Dr. Landreth said, “we will have a reason to go forward” into phase II trials.

Media stories about Dr. Landreth’s research sparked a firestorm of dialogue on Alzheimer’s Internet forums and message boards this spring. Families discussed traveling to Canada for bexarotene, and begging their family doctors for a prescription.

Two opinion pieces in the Aug. 9 issue of the New England Journal of Medicine tackled the thorny problem physicians may face when desperate families come looking for answers.

“Writing an off-label prescription is completely permissible and would fulfill family members’ desire to try anything to help their loved ones,” wrote Dr. Steven D. Pearson of Massachusetts General Hospital’s Institute for Technology Assessment, Boston, and his colleagues. But in the case of bexarotene, they asked, “is it the right thing to do?”

In the second editorial, Frank M. LaFerla, Ph.D., of the University of California, Irvine, warned against overenthusiasm: “Only a well-designed and carefully executed clinical trial will reveal whether this class of drug lives up to its promise. Until such trials are performed, it would be a mistake to offer this treatment to Alzheimer’s patients.”

Dr. Landreth agrees. Although relatively benign, bexarotene can cause hypothyroidism and dyslipidemia in cancer patients. Although volunteers in the upcoming trial will almost certainly experience neither of these, “there is no guarantee at all that it would be safe in an Alzheimer’s population,” he said. “I have absolutely no idea what could happen when this drug interacts with a diseased brain. If you remove the plaque, then what happens? Do you end up with holes in the brain? This is the question that keeps me up at night.”

Dr. Landreth and his colleague, Paige Cramer, hold a U.S. provisional patent application for bexarotene as a potential therapy for Alzheimer’s disease and have founded ReXceptor Inc., which has licensing options from the university to use bexarotene to treat Alzheimer’s disease.