Study shows Synapse Loss Reversible AZD-103!!
The results of this Alzheimers study are Huge. Correlates the Mechanism of Action with the Cognitive Improvements shown. With Elan jumping out of ongoing blinded monoclonal antibodys Phasell's to proceed with Phaselll's with the FDA and EMEA's blessing just substantiates this study. I would suggest you all read it.
But first......
From Elans Q3/07 Earnings Call.......helps to understand how they have the Phaselll proceeding whilst the Blinded Phasell is ongoing. Recall Dr. Cruz said that it would take Signs of Efficacy during one of these 'Interim Peeks' to enable Transition to do this as well.
....Operator...."Your next question comes from the line of William Tanner with Leerink Swann"
.....William Tanner Leerink Swann....."Thanks for taking my questions. Lars a couple of questions for you on Bapineuzumab, I think you did mention that the FDA had looked at the Phase 2 data, and it seems I guess or rather that they would have but I don't know if you can provide any details that you are focused on or just the whole data in general?"
.......Lars Ekman......."I cannot provide any details on that. As you know, the trial is ongoing and giving you details on that would sort of un-blind the trial. They have seen all the data relating to safety of the drug, related to the efficacy of the drug, so we have shared all the data from this trial and for the Phase 1 trial and based on the totality of that and our experience we have defined the trial and we have agreed with the trial design with the FDA."
With Elan moving forward with a Phaselll we have to assume they saw Signs of Efficacy. When looked at from the perpective of the Study by Shankar, Bloodgood, Townsend ,Walsh,Selkoe & Sabatini /2007 we can start to assume that AZD-103 will be Efficacious as well. This study showed that Natural Oligomers of the Alzheimer Amyloid-B Protein Induce Synapse Loss by Modulating and NMDA Type Glutamate Receptor (NMDAR) Dependant Signalling Pathway by affecting the Excitatory Synapses and Dendritic Spines.......They showed that AmyloidB Oligomers, Dimers & Trimers, has a detrimental effect on the Spines but that the AB Monomers (nonaggregated Amyloid) DID NOT!! .
From the Study........"Alzheimer's disease (AD) is characterized by decreased synapse density in hippocampus and neocortex, and synapse loss is the strongest anatomical correlate of the degree of clinical impairment. We demonstrate that physiological concentrations of naturally secreted Aß dimers and trimers, but not monomers, induce progressive loss of hippocampal synapses. Mechanistically, Aß-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDAR-mediated calcium influx into active spines was reduced by Aß oligomers. Our approach provides a quantitative cellular model for elucidating the molecular basis of Aß-induced neuronal dysfunction." ------
Not only did this Study show that AmyloidB Oligomers and not Monomers induce Synapse Loss .....It showed that IT IS REVERSIBLE!! They have shown that a monoclonal antibody prevents the effects of soluble oligomers on dendritic spines . The same antibody prevented the effects of acute Aß oligomer exposure on hippocampal LTP (long term potentiation) in vivo (Klyubin et al., 2005 ), suggesting that passive immunotherapy could slow the progressive perturbation of synapse structure and function in patients with mild AD and its precursor, mild cognitive impairment (MCI). This Study shows also that.......(Horns---Bells & Whistles) Similarly, they found that Scyllo-inositol (AZD-103) prevents the effects of natural Aß oligomers on dendritic spines.......... "Performance in a spatial learning task also improved, consistent with our finding that scyllo-inositol prevents oligomer-induced synaptic perturbations in the hippocampus. We recently found that scyllo-inositol binds natural Aß trimers without depolymerizing them and apparently prevents their actions on neuronal targets (Townsend et al., 2006b ), consistent with the reported binding and stabilization of small oligomers of synthetic Aß by the compound AZD-103 (McLaurin et al., 2000) Recall McLaurin is the Inventor of AZD-103.
When looked at from the supporting Studys and in particular Shankar et al 2007 as shown above we can see that AZD-103 can be correlated to immunotherapy like Elans when looking for Signs of Efficacy in relation to Synapse Loss and that AZD-103 should show Efficacy as well.
......"Our findings support the hypothesis that diffusible, low-n oligomers of human Aß can induce synaptic dysfunction and loss that is regarded as the strongest correlate of the degree of clinical impairment in AD patients. Decreasing the formation or neutralizing these soluble aggregates are promising therapeutic options for the treatment, and ultimately the prevention, of MCI and mild AD."
....."Therapeutic strategies for AD include the development of small molecules that inhibit the aggregation of Aß. One such agent is scyllo-inositol (AZD-103), a myo-inositol stereoisomer that binds to synthetic Aß42, stabilizing it as a non-neurotoxic small oligomer and blocking its propensity toward fibrillogenesis (McLaurin et al., 2000). We examined the ability of scyllo-inositol and its inactive chiro stereoisomer to prevent the effects of Aß oligomers on synapse structure. Application of scyllo-inositol (5 µM) simultaneously with the SEC-isolated Aß oligomers prevented the decrease in dendritic spine density (whereas application of chiro-inositol (5 µM) had no effect Neither 6E10 nor the myo-inositol stereoisomers affected the length of dendritic spines (thats a good thing)."
Shankar et al 2007 is entitled "Natural Oligomers of the Alzheimer Amyloid-ß Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway " and has 52 Citations Supporting it .
Pretty Compelling Supporting Studys guys and gals.
LINK.......https://www.jneurosci.org/cgi/content/full/27/11/2866#B44
GPP All. Merry Christmas.......