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doi: 10.1097/01.NT.0000410755.19813.06
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News from the Society for Neuroscience Annual Meeting: Diabetes Drug Liraglutide Set for Clinical Trials of Alzheimer Disease on Promise of Animal Studies

Hurley, Dan

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ARTICLE IN BRIEF

Researchers at the University of Aarhus, Denmark, plan to begin recruiting patients for a randomized 25-week trial of liraglutide vs. placebo in 40 patients with Alzheimer disease. The trials follow promising data in animal models.

WASHINGTON, DC—On the strength of promising animal and laboratory data, two European clinical trials of the injectable diabetes drug liraglutide are set to begin in 2012 for the treatment of Alzheimer disease (AD).

The trials, in the United Kingdom and Denmark, represent yet another test of diabetes drugs for AD, along with nasal insulin spray, pioglitazone, rosiglitazone and metformin. But with none of them yet demonstrated in phase 3 trials to slow or reverse neurological deficits, a neurologist who has been keeping close tabs of the field urged caution in interpreting the latest data.

“The fact that liraglutide does something in the animal models is encouraging,” said David S. Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, MN. “But we've learned you don't want to take this kind of data to the bank just yet. We have been repeatedly disappointed when epidemiologic and animal study results don't seem to translate into success in human trials.”

Researchers at the University of Aarhus, Denmark, plan to begin recruiting patients for a randomized 25-week trial of liraglutide vs. placebo in 40 patients with AD beginning in January. A similarly sized trial of the drug, designed to last for three years, is being funded by the Alzheimer's Society UK and will be led by Paul Edison, MRCP, PhD, of the department of medicine at Imperial College London.

DR. DAVID S. KNOPMAN...
DR. DAVID S. KNOPMAN...
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ANIMAL DATA

A quintet of positive study outcomes were reported in mice and laboratory models of AD at the Society for Neuroscience meeting here in November.

The three mouse studies, all led by Christian Hölscher, PhD, head of neuroscience at the University of Ulster, showed that liraglutide, marketed under the trade name Victoza by Novo Nordisk, reduces inflammation and plaque deposition, increases neurogenesis, and improves outcomes on tests of learning and memory in the animal models that overexpress familial AD mutant forms of amyloid precursor protein and presenilin 1.

A researcher who collaborated with Dr. Hölscher on two of the studies told Neurology Today that she is “very hopeful” about the clinical trials now being planned for the drug.

“The fact that liraglutide is already an approved drug is immensely important with respect to treatment becoming available to dementia patients if it proves to be beneficial in clinical trials,” said Paula McClean, PhD, research associate in neuroscience at the University of Ulster. “Liraglutide is a more suitable anti-diabetic medication for a normal non-diabetic population than metformin, which is associated with hypoglycemic events (even in diabetic populations).”

The researcher who coined the term “type 3 diabetes” to characterize the role of insulin resistance in AD called the results “exciting.”

DR. PAULA MCCLEAN Th...
DR. PAULA MCCLEAN Th...
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“These studies provide additional evidence that, irrespective of the initiating factors, brain insulin deficiency and resistance cause cognitive impairment and neurodegeneration, and that by treating with insulin agonists (as well as insulin sensitizers), the clinical and pathological abnormalities linked to AD can be reduced and possibly cured,” said Suzanne de la Monte, MD, MPH, professor of pathology and medicine and neurology at Brown University Medical School in Providence, RI.

The studies, she added, “represent a preclinical research advance that has direct implications for treating humans with AD.”

For now, though, Dr. Knopman was quick to warn neurologists against any off-label uses of liraglutide or other diabetic drugs. The very idea of such treatments outside of a clinical trial, he said, “sends shivers down my spine. Unfortunately, some of my colleagues who feel desperate, as do their patients, are willing to try anything when there's only the slimmest of evidence. Anyone who has been in the business long enough has been burned enough times to know better. They might well say, ‘I did this with statins and I did it with vitamin E and I did it with estrogen and ibuprofen and none of them worked.’”

William L. Klein, PhD, professor of neurobiology at Northwestern University, told Neurology Today that he had just returned from a meeting in France where researchers discussed the string of recent failures of large, costly trials of AD treatments.

“There's been a lot of mismatching between the results of animal studies and human studies,” he said. While skeptical that liraglutide alone will have clinically significant benefits in patients with established AD, he said, “The trials will come up with their data. I hope it works. I'll keep my fingers crossed.”

Dr. Klein has been among the pioneers in studies suggesting that memory failure in AD is caused by small soluble oligomers of the amyloid beta peptide, which targets and disrupts synapses.

“This is a synaptic struggle for survival,” he said. “The oligomers make brain cells insulin resistant. However, when there's robust insulin signaling in the brain, the oligomers are not capable of causing pathology. So what we have proposed is a twofold approach. It's very important to stimulate insulin signaling in the brain, as these new clinical trials are attempting to do, but we would say in tandem that you would like to use therapeutic antibodies to reduce the level of toxic oligomers while you're doing that, to achieve a one-two punch.”

Dr. Klein disclosed that he is co-founder of a biotechnology firm that is developing antibodies to target the soluble oligomers of the amyloid beta peptide. (And Dr. McClean noted that in her animal studies, liraglutide reduced amyloid beta oligomers.)

The only phase 3 trial of a diabetes drug used against AD turned out disappointingly. The study on rosiglitazone, published in 2010, found no evidence of efficacy. Likewise, a randomized pilot trial of pioglitazone published online in September found no efficacy, although the tolerability in non-diabetic subjects led the authors to conclude that the drug should be studied in earlier disease stages.

Yet another diabetes drug, metformin, is also being studied in a randomized trial that has yet to report results.

DR. SUZANNE DE LA MO...
DR. SUZANNE DE LA MO...
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REFERENCES:

Gold M, Alderton C, Zvartau-Hind M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 2010;30(2):131-46. E-pub 2010 Aug. 21.
Geldmacher DS, Fritsch T, McClendon MJ, et al. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol 2011 Jan;68(1):45-50. E-pub 2010 Sep 13.
Ferreira ST, Klein WL. The Aßoligomer hypothesis for synapse failure and memory loss in Alzheimer's disease. Neurobiol Learn Mem 2011;96(4):529-543. E-pub 2011 Sep 6.

©2012 American Academy of Neurology

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