Orphan status is a firm evidence, that ph2 study (= reach2HD) could be enough (statistical 82% possibility). Only NDA can give the final "yes" or "no" and the manuscript is done very soon, it may be already in FDA or in a journal or both. Perhaps investors should know where are we today.
The exstension study results come only in "early" 2015. But it looks like Prana is checking the genetics and physical activity changes in the Imagine study population. So if these factors are confounders in the Imagine study, this will be informed earlier, IMO. I am sure some negotiations are going on with possible partners.
The short vol was yesterday 17% ( 121837 ), on Fri 12%, Thu 18% and on Wed 28%. In Australia no shorts.
A week ago Fri there was over 3M shorts (total vol 18M). So I think that there has been some pressure by shorts to get the pps down.
With this list of Jaylucks we all longs can sit calm and wait, something very positive must be comming and pritty soon.
I did not find any studies telling how accurate PET scans are in repated measurements. But I do not think that is the problem in the Imagine study but this possibility becomes bigger when the patient number is low (as was the case of the placebo group). In any case we cannot get any info of this precision before the future paper will be published one day.
It took almost 1y to get Ravicti accepted after the manuscript was ready, but for Droxidopa only 6 months. In any case it looks like 2015 is a very good possibility for PBT2 starting from March onwards if everything goes well.
interestingtome, yes it seems to be so, but "printing" may come many months after the paper has been accepted. But in the case of Droxidopa, paper was received in September 2013, accepted in April, e-published in Jun. So seems that the manuscript needs to be only ready and that can be now in any week.
During this year the first step was to get the positive results in the Reach2HD study. The step 1.5 was to get Ira Shoulson on the board. Step 2. was the Orphan status for PBT2.
What will be the step No 3 ??
- manuscript accepted ?
- marketing firm selected ???
IMO NDA can be made when the manuscript has been accepted ( or e-published). My guess is that after FDA has got the NDA it could take some 8-9 months to get it accepted. So in the best case Prana could have PBT2 in the pharmacy during 2015. But IMO Prana also needs to find a marketing company for PBT2 quite soon. I suppose that the manufacturing company will be the same as today, Dr. Reddy's.
PBT2 reduced some 3 % of the amyloid during the second 6 months in the Imagine study. So perhaps in 2years it could be recuded almost 10%. It took some 20 y to get 9.6mg into the brain (6.9 mg more than the normals) so the "reason" of AD caused every year about an extra accumulation of 0.345 mg of abeta. First PBT2 had to stop the overproduction and then start breaking down abeta.
My point is that 1) the amounts of abeta are really very small, 2) accumulation is slow and 3) breaking down by PBT2 seems to be aswell slow but quicker than accumulation 4) it is very possible (and even evident) that in 2 y time the PET scan can demonstrate a bigger difference than during the first year.
When you look at the PET-scan you would never think that some 9.6 mg of some perculiar material could be demonstrated in any scan.
Alzheimers Dement. 2014 Sep 9. pii: S1552-5260(14)02496-0. doi: 10.1016/j.jalz.2014.07.001. [Epub ahead of print]
Plasma amyloid-β and risk of Alzheimer's disease in the Framingham Heart Study.
Chouraki V1, Beiser A2, Younkin L3, Preis SR4, Weinstein G5, Hansson O6, Skoog I7, Lambert JC8, Au R5, Launer L9, Wolf PA5, Younkin S3, Seshadri S5.
Plasma amyloid-β (Aβ) peptide levels have been examined as a low-cost accessible marker for risk of incident Alzheimer's disease (AD) and dementia, but results have varied between studies. We reassessed these associations in one of the largest, prospective, community-based studies to date.
A total of 2189 dementia-free, Framingham Study participants aged 60 years (mean age, 72 ± 8 years; 56% women) had plasma Aβ1-42 and Aβ1-40 measured and were followed prospectively (mean, 7.6 ± 3.0 years) for dementia/AD.
Increased plasma Aβ1-42 levels were associated with lower risk of dementia (Aβ1-42: hazard ratio [HR] = 0.80 [0.71‒0.90], P
I do not know this, but it would be nice to know. Simple possibilities could be too low dosage of PBT2 (250mg), first targeting the soluble oligomers and only later other not so soluble abeta metabolic pools or something much more complex.
However it will be interesting to see if the extension study could demonstrate that the decrease of abeta during the second 6 months will go on and in fact the effect of the second year could be even double because the first 6 months did not change the amyloid content at all.
This could have something to do with the Imagine results. You may aswell remember that the PET scan changes were stronger on the latter half of the year. This is only a in vitro study.
Biochemistry. 2014 Sep 10. [Epub ahead of print]
The binding of apoE to oligomers and fibrils of amyloid-β alters the kinetics of amyloid aggregation.
Garai K, Verghese PB, Baban B, Holtzman DM, Frieden C.
Deposition of amyloid-β (Aβ) in Alzheimer's disease (AD) is strongly correlated with APOE genotype. However, the role of apoE on Aβ aggregation has remained unclear. Here we have used different apoE preparations, such as recombinant or protein isolated from cultured astrocytes, to examine the effect of apoE on the aggregation of both Aβ1-40 and Aβ1-42. The kinetics of aggregation, measured by loss of fluorescence of tetramethylrhodamine-labeled Aβ, is shown to be dramatically slowed by the presence of sub-stoichiometric concentrations of apoE. Using these concentrations, we conclude that apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth. At higher apoE concentrations the protein also binds to Aβ fibrils resulting in fibril stabilization and a slower rate of fibril growth. The aggregation of Aβ1-40 is apoE isoform dependent being most dramatic for apoE4 and less so for apoE3 and apoE2. Our results indicate that the detrimental role of apoE4 in AD could be related to apoE induced stabilization of the soluble but cytotoxic oligomeric and intermediates of Aβ, as well as fibril stabilization.
One side effect in the the Reach2HD study was that one individual's HD symptoms became suddenly much worse during the follow-up month when PBT2 was stopped after he had been taking it for 6 months. This is IMO a possible sign that PBT2 really works in a quite spesific way in HD. This was only a single case and needs to be verified possibly in later studies. But this single case could be a sign of the effecacy in HD.
interestingtome, just a small thing, how do you know that it is hippocampus atrophy? I would say that it is not. More likely it is caudate or putamen which do get atrophy in HD. But I have not seen Prana telling what it is. It could be general brain atrophy but IMO it is most likely basal ganglions which srink in HD before the whole brain.
Pet is only for screening, then atrophy measurements by MRI, 2 images are the minimum. The more patients the shorter the study can be. For efficacy 50-75 / study group could be enough at least in a 2 y study. IMO at least 250mg and 400mg groups are needed. To understand a wider spectrum of adverse effects some 600-900 people years are needed. But it is clear that the new study protocol will be decided only after the extension study. Another year on PBT2 could also give more changes also to amyloid content of the brain. There can be suprises also in cognition and brain atrophy.
MRI cost can be reduced from the comercial rates, perhaps to $150 level.
As you understand I do not have enough knowlede to help Prana for the next study. I do trust that they will find a very good study proposal in spite The Imagine study was a disappointment also to the who made that plan.
canadianhegemony, IMO the next study needs in the screening phase PET scans and most likely there will be at least 2 primary endpoints, a tissue related and a cognition related. The cost is important but now it is the time to get real strong evidence and when you have it in tissue imaging and in cognition nobody will argue. Imaging is important even in detecting (or not detecting) some side effects which may be observed by it. Safety is a very important issue.
In normal old age related memory loss, there is nothing known to be imaged today. Even in this study some kind of imaging could be recommended, not as a primary endpoint but as a part of initial clinical checking. As I told earlier the Imagine study is big enough as a pilot study to give numbers needed in the ph3. To me it looks that same population as in Reach2HD could be enough, but 1 year treatment time would be needed to get significant results. However genetic screening would also be needed aswell excercises controlled. 100 patients is not enough to find all possible side effects and so for that reason close to 1000 patients may be needed. Prana wil not do that kind of a study without a partner deal (IMO).