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Why would anyone in their right mind make beta-amyloid an endpoint for a chelation therapy? Chelation is about metals, not about peptide plaques. We've known since at least Elan Pharmaceuticals 2002 failure that successful removal of beta-amyloid does not necessarily improve cognition, and have confirmed it several times since (Lilly, Myriad, Elan's 2nd attempt...). The whole point of PTB2 was that in a world where the beta-amyloid hypothesis had failed, PTB2 could target Alzheimer's disease in a completely different way. Are we really going to lose this unique drug candidate over a meaningless would-be biomarker metric, so close to the finish line, just before we get a chance to learn about its effects on cognition? If you discover any more info in this, please let us know here...
Some more detailed info:
PBT2 Takes a Dive in Phase 2 Alzheimer’s Trial
http://alzforum.org/...lzheimers-trial
01 Apr 2014
On March 31, the Australian company Prana Biotechnology announced negative top-line results of its only Phase 2 study of the anti-amyloid drug PBT2. Called IMAGINE, the trial had enrolled 42 people with prodromal or mild Alzheimer’s disease who had a positive brain amyloid scan.
This trial evaluated how a one-year course of a once-daily, 250 mg PTB2 capsule would affect brain amyloid deposition as measured by positron emission tomography with the amyloid imaging tracer Pittsburgh compound B (PiB). Based on draft results, the trial missed its primary endpoint, which was defined as a statistically significant reduction in plaque levels. Overall PiB retention in PBT2-treated patients did go down, but it went down in the placebo group as well. Of the 42 enrolled patients, 27 received the drug, 15 the placebo.
The market’s response was swift. Within hours, the company’s stock plummeted after it had risen temporarily in response to a February 18 announcement of top-line results of a separate Phase 2 trial in Huntington’s disease (see Feb 2014 news story).
In addition to amyloid load, the IMAGINE AD trial had five secondary outcomes. The first confirmed the results of the recent Huntington’s trial in that PBT2 was both safe and tolerable, with equivalent adverse event profiles between groups, according to Prana’s announcement. The second secondary outcome was neuronal function as measured by fluorodeoxyglucose (FDG) PET. On that measure, the company reported no benefit.
The third secondary outcome was PBT2’s effect on brain volume as measured by magnetic resonance imaging of cortical gray matter, hippocampus, and ventricles. On that, the company reported no statistical significance but a trend toward less hippocampal atrophy in the treated group. The fourth secondary outcome was cognition as measured by the neuropsychological test battery (NTB) and the mini-mental state examination (MMSE); PBT2 was negative on both. The final secondary outcome sought to quantify how patients function by way of the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL); PBT2 had no effect on this measure.
Prana scientists offered their interpretation of the results in the company press release. The company posted an audio recording of a March 31 investor call, in which company and associated scientists discussed the results and took questions.
PBT2 is a second-generation drug growing out of prior research on clioquinol. Both are so-called metal-protein interaction-attenuating compounds. MPACs are thought to reduce amyloid aggregation by interfering with the interaction of copper and zinc with beta amyloid.
For details of the IMAGINE trial design, see Australian New Zealand Clinical Trials Register. An extension study is still ongoing. The trial was partially funded by the Alzheimer’s Drug Discovery Foundation in New York City.—Gabrielle Strobel
And the company's press release:
Prana Biotechnology announces top line results of Phase 2 IMAGINE trial of PBT2 in Alzheimer’s disease
http://pranabio.com/...se#.UzqxSK1dXfY
MELBOURNE, 31st March, 2014: Prana Biotechnology (ASX:PBT/NASDAQ:PRAN) has today released the top line results of the 12-month Phase II Imaging trial in Alzheimer’s Disease (“IMAGINE” Trial), based on draft results.
Prana’s PBT2 did not meet its primary endpoint of a statistically significant reduction in the levels of beta-amyloid plaques in the brains of prodromal/mild Alzheimer’s disease patients, as measured using PiB-PET Standardized Uptake Value Ratio (SUVR). Whilst there was a reduction in the overall levels of the PiB PET signal in patients treated with PBT2, the results were confounded by an atypical reduction of levels of the PiB PET signal in the placebo group as well.
Commenting on the result, Geoffrey Kempler, CEO of Prana Biotechnology said: “This is the first time that Prana has looked at PiB-PET in a study with PBT2 to measure its effect on insoluble amyloid plaques. In our previous Alzheimer’s study (EURO)1, we looked at levels of unaggregated soluble Abeta peptides in spinal fluid, and they were significantly reduced with PBT2 treatment. So in the IMAGINE trial we looked for an impact on the insoluble plaques as well, but did not see it differ significantly from the placebo.”
“It is possible the result may point to PBT2 targeting soluble species of Abeta including toxic oligomers rather than plaques. Abeta oligomers are not visible in the PiB-PET scans which can only detect amyloid plaques. Alternatively, what we are seeing is simply the result of an inconclusive imaging readout in a small sample size with 42 participants (15 on Placebo, 27 on PBT2)”.
No improvement was observed on the secondary endpoints of brain metabolic activity, cognition and function; however there was a trend towards preserving hippocampal brain volume in the PBT2 group. Specifically, there was less atrophy in those patients treated with PBT2 relative to placebo, 2.6% and 4.0%, respectively. This is consistent with published measures of atrophy in AD patients versus healthy controls2 of 4.7% and 1.4%, respectively. The company is tracking measures of brain volume and cognition in the current 12 month extension study that will be completed at the end of the year. Further analysis of the results is ongoing.
Importantly, PBT2 was shown to be safe and very well tolerated over the 52 weeks. The adverse event profile was equivalent between placebo and treated groups. Forty of the 42 enrolled participants (95%) completed the 52 week treatment period.
Mr Kempler concluded: “Whilst not meeting all of our hopes, this result does not deter us from the future development of PBT2, a safe and well tolerated drug candidate for Alzheimer’s disease. Our scientists and those from other institutes have developed a strong body of evidence for the efficacy of PBT2 in Alzheimer’s disease. The suggestion of beneficial effect of PBT2 on brain volumes first seen in the Reach2HD Huntington disease trial and now in this Alzheimer’s disease IMAGINE trial is intriguing. We are consulting with experts in the field to further assess these results and to consider how best to progress PBT2 in Alzheimer’s disease. Indeed, the IMAGINE Extension trial is continuing, and data from this trial is likely to inform the next steps for an AD program.”
Prana is proceeding with its plans toward a confirmatory study for Huntington disease. Based on Prana’s previous discussion with the US Food and Drug Administration, the data on safety and tolerability of PBT2 in Alzheimer’s disease will support the future clinical development and, ultimately, a New Drug Application in Huntington disease.
Prana has a cash position of AU$25.4 million as at 31 March 2014.
1. Lannfelt et al. Lancet Neurology (2008) vol. 7, pp. 779-86; Lannfelt et al. Lancet Neurology (2009) vol. 8, pp. 981.
2. Barnes et al. Neurobiology of Aging (2009) 1711-1723
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Sure, one can remove beta amyloid, but this doesn't mean the brain will automatically and immediately return to a state of functioning from years ago. It has ADAPTED to the presence of "junk". Once the junk has been removed, my feeling is that it would take a bit of time, maybe many months for the brain to re-learn, re-grow, re-develop previously destroyed pathways. The removal of beta amyloid should be paired with aggressive therapy (brain training) and perhaps neuronal growth factors, in order to prove whether or not the "removal" treatment works.
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I think it is a good hypothesis, at least for testing.
In fact several hormonal/growth factor pathways have been reported to be dysregulated in brain aging/Alzheimer, e.g.: somatostatin, GH/IGF, brain derived neurotrophic factor, Wnt and Dkk1, endocannabinoids. And these are involved in the abeta processing and clearance, cell survival and the neurodegeneration and neurogenesis processes.
The beta-amyloid can cause brain damage, because for example it induces a neuroinflammatory environment that is toxic to neurons, like improper activation of microglia, which generates excessive amount of TNF, etc.
So in theory removing abeta may be helpful to stop the neurodegeneration process. And parallel with/after that, the restoration of the healthy networks and neurogenesis may give positive results.
Please listen I have Alzheimers I am beginning to make really bad cognitive mistakes but I did read a lot trying to find a cure and I found that every substance that is good at slowing the progression of the disease down is also an anti viral. The HSV1, HSV2 and cytomegalow viruses are all implicated and there may even be some more that we don't know are related as yet.
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The viruses must be irradicated but how is this to be done? Where do people start to do this? The amyloid is just the waste product left behind by the virus tell the world and get rid of this scoourge on humanity sooner. I am dying now but this is what I found just through reading on line. Time and time again every time actually the supplements that can do good are anti virals
The mentioned viruses induce the production of various cytokines in the body, e.g. TNF, interferons, which are involved in reducing virus replication, and are more or less the same as the ones that give rise to the neuroinflammation pattern in Alzheimers, and this shed light to possible problems with anti-inflammatory approaches to the treatment of the disease in the cases where these viruses are actually involved.
Mind, well, it's not just that abeta removal doesn't seem to help.
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So yes your suggestion might be viewed as an attempt to resurrect the abeta cascade hypothesis one more time. I'm not sure to what extent it's been tried. It's sometimes hard to see just what kinds of "brain training" and follow-ups doctors do on these patients after they get the drug. We do know that there isn't an improvement in late-stage patients many months after successful abeta removal either, all the way to death. It's probably best to read the original reports from those trials to get a complete view of what's known and what isn't known about that.
... whether continued abeta targeting makes sense, is something each developer needs to decide, considering the balance of the evidence....
I am not sure too, "what extent it's been tried", but in the light of the above dysregulations "continued abeta targeting" may make sense.
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Ceridwen, I hope you are successful in your battle against Alzheimer's. Each passing month brings new technology and new treatments. Take a look at some of the forum discussions here at LongeCity. You might find some helpful information.
I hope too.
And yes there is some information in the forum, but the above mentioned possible differences between the "general" and "viral" Alzheimer may have to be taken into account. In any case this needs more examination/research.
