Magazine Article | January 7, 2014

"Type 3" Diabetes Back On Trial

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By Alvaro Arjona, editorial director for drug development, Thomson Reuters

The underlying relationship between insulin resistance and dementia has compelled some researchers to label Alzheimer’s disease (AD) as “diabetes of the brain.” Although this characterization isn’t widely recognized in the general public, the concept of “type 3” diabetes isn’t new — it’s been around for several years and is supported by some genetic and molecular research. Several studies have shown that people with type 2 diabetes are at a higher risk of developing AD, and plausible genetic links have been discovered. As research stones are overturned, growing potential for therapeutic development rises to the surface.

Exploring the Research
In July 2013, results were presented to the Alzheimer’s Association International Conference showing that insulin detemir (a long-acting human insulin analogue for maintaining the basal level of insulin) was associated with improved working memory. The study involved 20 people with Alzheimer’s and 38 with mild cognitive impairment, all of whom were given the intervention (Hanson, A. et al. AAIC July 13-18, Boston, 2013, Abst P3-276). In 2009, liraglutide, a commonly prescribed GLP-1 agonist for diabetics, was found to rescue memory loss and decrease the buildup of brain plaques in a mouse model of AD (McClean, P.L. et al. Neuropharmacology 2013, advanced publication). Results from the study conducted at Lancaster University suggest that liraglutide may be able to reverse some of the damage caused by AD in patients in the later stages of the condition.

There’s more. In 2013, researchers reported that the long-lasting glucose-dependent insulinotropic polypeptide (GIP) analogue D-Ala2- GIP demonstrated effects on memory and synaptic neurotransmission in mice; when further evaluated in the APP/PS1 mouse model, it was able to rescue synapse numbers and decrease beta-amyloid plaque buildup in the cortex (Faivre, E. et al. Alzheimers Res Ther 2013, 5(2): 20).

These and other recent results have prompted pharmaceutical developers to examine — or, in some cases, reexamine — the potential of approved and investigational antidiabetic drugs for treating Alzheimer’s disease.

Examining the Clinical Trials
However, is this renewed interest reflected in the clinical arena? What does the current clinical development landscape look like for this so-called “type 3” diabetes? In screening Cortellis Clinical Trials Intelligence for instances including antidiabetic agents in AD subjects, 10 active clinical trials involving more than 900 overall subjects were found. The trials are mostly Phase 2 studies initiated in the last 12 months that are recruiting subjects with probable diagnosis of AD and subjects with mild AD. The most common endpoints under assessment are: global and functional assessment of cognition, PET, and MRI findings, as well as regional cerebral glucose metabolic rates. There are several different interventions under evaluation: insulin, exenatide, bexarotene, tesofensine, DSP-8658 (a novel PPARα/γ agonist that penetrates the brain better than thiazolidinediones), and the aforementioned liraglutide. Liraglutide will be evaluated in the ELAD study, a randomized, double-blind, placebocontrolled Phase 2 trial that is about to initiate recruitment. This clinical trial is led by Dr. Paul Edison of Imperial College London and is partly funded by the U.K. (United Kingdom) Alzheimer’s Society.

As more progress is made in understanding the link between diabetes and AD, and more light shed on whether these interventions mediate their efficacy by modulating brain glucose homeostasis or via anti-inflammatory mechanisms, it will be exciting to follow the outcomes of the trials. The research community can then reassess whether there is an actual therapeutic advantage in exploiting the AD-diabetes link. Longsought disease-modifying AD therapies may come through the repositioning of some of these drug approaches or via novel therapeutics targeting repurposed pathways exposed by epidemiologic, experimental, or computational evidence.

The lessons learned from these trials could potentially be applied to other therapeutic areas, providing a wealth of new information for the pharmaceutical industry.

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