In 2012, researchers reported that in mice, treatment with Eisai Inc.'s lymphoma drug Targretin (bexarotene) could reverse the symptoms of Alzheimer's disease. In a study published in Science, the authors reported that treating mice with the drug improved memories as well as social behaviors, and decreased levels of soluble A-beta. (See BioWorld Today, Feb. 13, 2012.)

The most spectacular finding of the paper, however, was the report that plaques – the anatomical calling card of Alzheimer's disease – declined by more than 50 percent within three days, and by more than 75 percent within two weeks.

Those eye-popping effects on plaque, at least, appear to have been too good to be true. Four separate replication attempts published in the May 24, 2013, issue of Science reported that they did not see an effect of Targretin on plaques.

What was replicated in two of those studies, however, were the results on soluble Abeta and the behavioral effects of Targretin.

While researchers mostly agreed on the findings, they were in sharp disagreement about what those findings meant for the significance of the original paper, as well as for the therapeutic implications of the work.

Sangram Sisodia, of the University of Chicago, who is the corresponding author on one of the papers reporting that Targretin does not affect plaques, told BioWorld Today that "behavior is kind of a nebulous term to me," and that the replication attempts did not use exactly the same experiments that were reported in the original paper.

"It may in fact be true," he said, "but it will take a long time to figure that out."

In the meantime, he asserted, "the crux of the paper is amyloid burden" – which was not replicated in any of the four technical comments now published in Science.

Gary Landreth, senior author of the original report, disagreed. "Memory is the primary and most important endpoint," he told BioWorld Today. "We are absolutely delighted that the central findings of our paper have been replicated and validated."

When the original paper was published in 2012, Landreth said he suspected Targretin's effectiveness stemmed mostly from its effects on soluble amyloid beta, not plaques. "I think that as we pull down Abeta levels, synaptic function improves, and that subserves the improvement in behavior," he said at that time. And in the original paper, the authors noted that plaque reduction poorly correlated with the behavioral effects.

Landreth is the co-founder of a company, ReXceptor Inc., which is in the process of doing a Phase Ib trial with Targretin. The company hopes to enroll its first patient in mid-August, and to complete the trial by December.

In the meantime, there are anecdotes of physicians prescribing Targretin to Alzheimer's disease patients. Robert Vassar, of Northwestern University Feinberg School of Medicine, who is a co-author on one of the replication attempts, was sharply critical of such off-label use. "This practice should be ended immediately, given the failure of three independent research groups to replicate the plaque-lowering effects of [Targretin]," he said.

But Rada Koldamova was more circumspect. "It's up to the clinicians what they are going to do," she told BioWorld Today. But "if I were a patient, I would be interested in improvement in memory" – an aspect of the original findings that has been replicated by several research groups.

Koldamova is part of a team at the University of Pittsburgh that published one of the technical comments – her team replicated the behavioral effects but not the plaque data. She said that her team was not particularly perturbed by their results.

"We are interested only in drugs that have an effect on memory," she said. Additionally, "in older mice, there is no effect on plaques in the original paper... We did not expect to have a big effect on plaques."

Why the plaque data cannot be replicated is still not clear.

Sisodia noted that the original study used only five animals per group, making it possible that the results were a statistical fluke. The small number of animals was "the first red flag for me," he said.

Landreth asserted that other reports, both at scientific meetings and in other journals, have replicated Targretin's effects on amyloid plaques as well, and that the replication failure reported in the technical comments may be due to the specifics of how the drug was administered.

"We used the drug exactly as it has been used in the FDA filing" for Targretin, while the drug was solubilized in the replication attempts.

Still, he acknowledged that for reasons his team does not fully understand, "the plaque phenotype was variable even in our own hands."

Landreth's bottom line, though, was that the plaque effect is the proverbial red herring: eye-catching but ultimately besides the point. And in his opinion, the research teams focusing their efforts on replicating Targretin's effect on plaques are missing the point as well. "We don't really understand why they focused on an issue that we said in the paper was functionally irrelevant."