Prana Biotechnology Ltd. Message Board

Tomorrow it is 26wks since the last patients started to take their drugs in Reach2HD study lasting 26 weeks for every patient. So most likely there will be some kind of info in the next few days. The good news could be that the number of drop outs was small and there has not been many side effects (?) . It is also good news that now the calculation of the results will start soon and the randomisation of treatment can be opened because all measurements and imaging have been done.

Sentiment: Strong Buy

Ceruloplasmin dysfunction and therapeutic potential for parkinson disease.
Ayton S, Lei P, Duce JA, Wong BX, Sedjahtera A, Adlard PA, Bush AI, Finkelstein DI.
Oxidation Biology Laboratory, Florey Institute for Neuroscience and Mental Health, Parkville, Victoria, Australia.
Abstract
Ceruloplasmin is an iron-export ferroxidase that is abundant in plasma and also expressed in glia. We found a ∼80% loss of ceruloplasmin ferroxidase activity in the substantia nigra of idiopathic Parkinson disease (PD) cases, which could contribute to the pro-oxidant iron accumulation that characterizes the pathology. Consistent with a role for ceruloplasmin in PD etiopathogenesis, ceruloplasmin knockout mice developed parkinsonism that was rescued by iron chelation. Additionally, peripheral infusion of ceruloplasmin attenuated neurodegeneration and nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model for PD. These findings show, in principle, that intravenous ceruloplasmin may have therapeutic potential in PD. Ann Neurol 2013.

so looks like I cannot get the abstract here. But free copper is a risk factor to get AD and those with ATP7B variant are more likely having AD.
"Individuals with free copper levels higher than 1.6 μmol/L (the upper value of the normal reference range) were more frequent among cases (p

Continue:
Individuals with free copper levels higher than 1.6 μmol/L (the upper value of the normal reference range) were more frequent among cases (p

Kadaicher, thanks for reminding!

frobinso1, IMO the paper is important because an independent research team demonstrates that iron metabolism is one important back ground factor in PD. Of course this has been understood by Prana scientist for years but this will sure increase the interest of other teams. For me the paper does not tell anything about PBT2 or PBT434 but may be Bush got much more about it. The other scientists Alzform asked their opinions only told that iron metabolism is a complex issue.
IMO PBT434 will keep the brain cells alive so that ceruloplasmin levels stay normal and there will not be accumulation of iron and no accumulation of alpha-synuclein into neurons. This side was not discussed in the paper at all.

This is the result of the Picher et al paper: We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%–6%; p = 0.001) per 10 µg/dl increase in serum iron.

Alzforum: Recent work seems consistent with the new findings. Analyzing postmortem brain tissue from sporadic PD patients, Bush and colleagues found that substantia nigral neurons lost ceruloplasmin activity. This enzyme removes excess iron from tissues, loading it onto the plasma iron transporter protein, transferrin (Ayton et al., 2012). They also reported that ceruloplasmin knockout mice develop PD pathology, but that injecting the enzyme intraperitoneally rescues symptoms. “Loss of ceruloplasmin activity can explain elevated nigral iron and lowered plasma iron, which fits with the findings by Pichler et al.,” Bush noted.

IMO it is not the AUD/USD, these changes are very small and just a couple of days it was the other way round. These changes do not move Prana shares over 5% as has been the case today. It could have been some internal trades between someones portfolios or perhaps shorting people have been on the market. But it may be even something else ??

Kadaicher, Add the info we got 2y ago from the mouse study "Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer's disease" by Adlard et al . With that it is even more easy to figure the results of the Image study.

pranfan, what is this meeting, is it for neurosurgeons ?? that is the only meeting I found in SF.

I do not say that anybody can be sure about the positive results, I say "sure" because the study plan only looks like the ones made it are not targeting to demonstrate slowing of the HD process but real improvement. The natural progress of HD is so slow that in 6 months there is almost no change in any of the parameters they are measuring and to find some 50% improvement in the natural progression of HD the study should last at least 1 y with this number of patients. Gambling with this study would never be "smart" neither smart but very stupid.
To start this kind of study every researcher will do some kind of power calculations and that is how Prana has ended with these patient numbers. I do not believe that any sponsor of this study would give money to the study without any power calculations after all failed studies and lost money.
But in spite all this, what I think the study plan indicates, there is always a possibility that the study fails. Side effects are one possibility but few pilot cases can also be misleading. So I am only "sure" and not sure before we have the results. We do not have any public info how PBT2 works in HD patients. We only have very promising animal studies.

Now we have coenzyme Q10 study going on with total 608 patients, follow up time many years ( 2008- 2017), only coenzyme Q10 group and placebo. A shorter follow-up with coenzyme Q10 did not demonstrate any efficacy in a smaller patient population.
In this kind of world with a lot of additional negative study results to treat HD Prana people are "knowingly" having in their 6 month treatment study 2 treatment groups (100mg and 250mg PBT2) only 34-35 patients each and comparing the result with 34-35 placebo treated. So they need to be very sure about the result we are getting soon. I cannot believe that they would be wasting all that money in vain and computing too optimistic figures. This is why I am "sure" that the effecacy results will be o.k. Side effect side can not be calculated but at present it also looks to be o.k.

Cherny in the HD mouse study paper :" PBT2 is being developed as a potentially disease modifying drug for AD and HD".
" therapeutic effects of metal chaperones likePBT2 are thought to be due to intervention in multiple pathological events resulting from metal dyshomeostasis including inhibition of metal mediated oxidative damage, intervention in the aggregation process and restoration of neuronal function".

To me it looks like the accumulation of iron (causing oxidative damage) could be reversed by PBT2 (remember the Bush paper in Cell), aggregation of mHtt (mutant Huntington protein) could also be reversed by PBT2 by reducing Cu needed to make it's monomers to toxic dimers (the paper by J Fox 2011).
Cherny tells also in this paper that " improved cognition with PBT2 in animal models has now been shown to correlate strongly with elevated markers of neuronal function and plasticity including NMDAr,TrKb, proBDNF, BDNF, CAMkII, spinophillin and synaptophysin as well as significant increases in hippocampal dendritic spine density" (paper by Adlard et al in 2011).
There was nothing like this type of information about the effect of Dimebon.
So if these facts seen in animals will be true also in humans, we will get positive results in the Reach2HD study. We will have the results perhaps in 2-3 months but latest in Oct.