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NIH backs another repurposed drug trial
Keep It 100
Posted: Friday, December 1, 2017 3:18 PM
Joined: 2/26/2017
Posts: 581


http://www.agenebio.com/agenebio-announces-publication-of-phase-2-clinical-trial-results-for-new-approach-to-delaying-the-onset-of-alzheimers-dementia/
Larrytherunner
Posted: Sunday, December 3, 2017 11:46 AM
Joined: 2/26/2016
Posts: 225


I am glad to hear that a repurposed drug is being put into a clinical trial. The great benefit is that repurposed drugs have already gone through trials for safety and they are available now. The NIH is not paying for this trial but they are conducting it. I wish the NIH were paying for clinical trials for repurposed drugs in some cases, because there are some good candidates for Alzheimer's and dementia treatments, but there is not much interest among pharmaceutical companies in investing in these off patent drugs.

The pharmaceutical company AgeneBio is paying for the trials, and they are also getting help from the Alzheimer's Drug Discovery Foundation. (Ilee08032 mentioned this in "Younger Onset AD" under the topic "New drug study"). AgeneBio has their own low dose proprietary version of the generic drug Levetiracetam, which is approved for the treatment of epilepsy.

When a drug is already available in the generic form, companies usually don't want to invest in repurposing because the physician can prescribe the generic for a new use. However in AgeneBio's case, the dose for Alzheimer's is one fifteenth of the Levetiracetam dose for epilepsy. A physician could not prescribe 500 mg Levetiracetam tablets for someone who is supposed to take one fifteenth that amount. Therefore the physician would have to prescribe the AgeneBio brand.

Most repurposing clinical trials don't happen because companies can not be assured of exclusive rights should the drug be approved. It would be better if the NIH paid for the trials in those cases. Then it is likely that many drugs available now could be trialed for Alzheimer's and dementia and possibly some could be found to be effective


Keep It 100
Posted: Monday, December 4, 2017 5:15 AM
Joined: 2/26/2017
Posts: 581


Interesting. That makes sense.... My husband is 6 mos in to a 1 year trial for a repurposed drug, nilotinib, which is a leukemia drug, still under patent, that costs $10k/month.
Serenoa
Posted: Tuesday, December 5, 2017 5:11 AM
Joined: 4/24/2012
Posts: 484


AGB101 is AgeneBio's name for Levetiracetam (also known as Keppra) a epilepsy drug. There is some good evidence that this drug given at low dose regulates hippocampal overactivation. Hippocampal overactivation is associated with the flow of ions like Ca2+, K+, Na+ across cell membranes of hippocampal neurons. This is called membrane potential. When a neuron fires it depolarizes to pass along a signal, then it repolarizes to reach its resting state. So, as I understand it, in MCI the neurons remain in more of a depolarized state and thus are overactivated. This overactivation is the result of some defect in the transfer of ions across the membrane which involves receptors and ion channels in the membrane. This is my laymen's understanding of this hippocampal overactivation hypothesis and how AGB101 might be working. 

Here is some of the science behind it:

Reduction of Hippocampal Hyperactivity Improves Cognition in Amnestic Mild Cognitive Impairment

"Elevated hippocampal activation is observed in conditions that confer risk for Alzheimer's disease, including amnestic mild cognitive impairment (aMCI). Studies in relevant animal models have indicated that overactivity in selective hippocampal circuits contributes to cognitive impairment...Contrary to the view that greater hippocampal activation might serve a beneficial function, these results support the view that increased hippocampal activation in aMCI is a dysfunctional condition and that targeting excess hippocampal activity has therapeutic potential."

http://www.sciencedirect.com/science/article/pii/S089662731200325X 

A receptor called Insulin-like Growth Factor-1 (IGF-1) may be involved

Increased Risk of Alzheimer’s Disease Appears to Be Linked to Certain Brain Receptor

"A study from Tel Aviv University found that the IGF-1 receptor, associated with an increased lifespan in mice, is mediating hyperactivity in the hippocampus of the brain. Hippocampal hyperactivity is linked to conditions that increase the risk for Alzheimer’s disease (AD), and the findings may pave the way for new AD treatments for early stages of the disease...People who are at risk for AD show hyperactivity of the hippocampus, and our results suggest that IGF-1R activity may be an important contributor to this abnormality."

 

https://alzheimersnewstoday.com/2016/02/04/the-igf-1-receptor-mediates-hippocampal-hyperactivity-an-ad-risk-factor/

Good point Larry about the ability to market a low dose as a new drug. I think this drug may have promise. I'll keep digging.




Lane Simonian
Posted: Tuesday, December 5, 2017 9:34 AM
Joined: 12/12/2011
Posts: 4854


Levetiracetam inhibits glutamate release which limits hippocampal hyperactivity and excitotoxicity.  It thus potentially may not only help treat epilepsy but also Alzheimer's disease.

G protein-coupled receptors and receptor tyrosine kinases (including insulin growth factor receptor-1) initiate hippocampal hyperactivity and excitotoxicity in Alzheimer's disease.  Thus drugs that inhibit this activation (such as Montelukast and nilotonib) may help to slow down the initial progression of the disease.


Serenoa
Posted: Wednesday, December 6, 2017 5:11 AM
Joined: 4/24/2012
Posts: 484


What I have found so far is that Levetiracetam's exact mechanism of action is unclear. However, one study points to an inhibition of Ca2+ channels (which could be glutamate related), and would reduce excitotoxicity. Another study points to its binding to a "synaptic vesicle protein" SV2A which I am not familiar with. Lane, maybe you have seen something else that defines Levetiracetam's exact mechanism of action.

The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca2+Channels through an Intracellular Pathway

"We investigated inhibition of voltage-dependent Ca2+ (CaV) channels as a potential mechanism through which LEV exerts effects on neuronal activity...These results identify a stereospecific intracellular pathway through which LEV inhibits presynaptic CaV channels (calcium channels); resultant reductions in neuronal excitability are proposed to contribute to the anticonvulsant effects of LEV." 

http://molpharm.aspetjournals.org/content/82/2/199

The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam

 http://www.pnas.org/content/101/26/9861


Lane Simonian
Posted: Wednesday, December 6, 2017 10:53 AM
Joined: 12/12/2011
Posts: 4854


I had not found the exact mechanism by which levetiracetam inhibits excitotoxicity nor had I heard of synpatic vessicle proteins before.  Just an initial search produced something that may be relevant.  Glutamate transporters place glutamate into synaptic vessicles for disposal but glutamate transporters are damaged in Alzheimer's disease.  

I wonder if under certain circumstances levetiracetam increases the removal and disposal of glutamate.  I am not sure if Alzheimer's disease would be one of those circumstances.