goutah, In fact we got the 1y Imagine results only in July 2014, when Masters presented them in his talk in Copenhagen. In the end of March 2014 there was not enough information at all to inform us investors IMO. I am equally eager to get the extension study results as soon as possible, but not kind of partial results we got in the end of March 2014. We need to get all of the results like Masters presented them in the July meeting. We have here only a "pilot study" how to measure by imaging the effect of PBT2 and because of the small numbers of patients we can only get hints of these possible methods, or hints of efficacy of PBT2 in various types of AD cases (apoe4 etc), So these results need to be presented in that kind of light. Unfortunately we do not get highly significant p values in this kind of small patient population but we will most likely get good hints about these important Imaging modalities and also about efficacy.
Because it is very difficult to get highly significant results in a study population of 40 individuals, I personally have regarded p less than 0.09 significant when evaluating the 1y effect of PBT2 on hippocampus atrophy rate in spite it is not perfectly correct to do so. I also regarded 2.5% reduction of SUVR as significant because that does not happen in historical controls in spite the difference was not statistically significant when compared with placebo. But when we have a very small population and so many unknown factors have influence to these measurements, this kind of hints are important.
Today Prana knows even more factors which most likely will have some influence on the measurements. It is very likely that it has taken much more time to try to control all these possible factors and this is why there is this delay what we inverstors do not like. I do not like revision of the results, better to get them right when they are published.
I2M, IMO PET scan is not a quantitative measure of amyloid, it is only some kind of relative measure. At high SUVR readings an amyloid plaque could be quite thick and then I do not think that PET scan can find all amyloid moleculaes in the plaque to stain them. Unfortunately I did not find anything to back up my thoughts. IMO it works the worse the thicker the plaque gets.
Within the same individual ( before and after intervention) it could be a possibility to see differences just like we can see hippocampus atrophy speed differences with MRI in spite we do not have "normal" values of hippocampus to classify it to be NC, MCI or AD hippocampus. But I do not know enough how accurate the method is. In any case there has been some reason to image glucose consumption in the Imagine study. Regeneration of neural tissues in the animal studies would be a good reason IMO at least now in 2y extension study.
ITM, I think this is important. Thanks ! In the original paper in 2014: "There were no significant changes in CSF levels of tau or phospho-tau in the solanezumab group or placebo group in either study. Hippocampal volumes decreased as expected during the 80 weeks in the solanezumab group and the placebo group in both studies, but there were no significant treatment-related differences in either study. Whole-brain volume decreased slightly in the solanezumab group and the placebo group in both studies, and the between-group comparisons were not significant".
If you have taken Sola some 1.5y you ADAS score gets worse a bit slower than that of placebos but the delay is only some 35-40 weeks. When they get all data collected the difference may be a bit bigger. Is this enough ?? With this present data I would not be convinced. I am a bit suprised that the deterioration seems to continue after 100 weeks on treatment even quicker than during the first weeks. So it looks like Sola does not kill all toxic oligomers ???
Yes, ITM, the placebo problem will be also in the extension study. They should have now some info to explain the placebos, but let us see.
My thinking above is too linear. Most likely PBT2 blocks toxic oligomers gradually, not so slowly as the SUVR measures indicated but not so immediately as it happens in animal models with much smaller brain and much bigger dosage of PBT2. So I think that perhaps most of "oligomer killing" by PBT2 has been done after 1st year and so the 2nd year atrophy rate slowering could be much lower than during the 1st year (not only 35%). If it would be the same 35% we would get to 1.7% level what is very close the atrophy rate of "normals". In this way you could think that also regeneration could happen during this extension study, at least in some cases. But this is too optimistic thinking without any other facts than the animal study results. 1.7% atrophy rate during the 2nd year would be wonderful and for sure desease modifying, 58% reduction from the placebos 1st year atrophy rate and 64% from historical controls. In any case I expect that what has started during the first year will continue during the next year. So if this is too optimistic we need to wait still few more days, max 10 trading days.
So this paper supports the hypothesis that Sola is a disease modifying drug but as they tell in this paper " EXPEDITION-EXT is still ongoing and future analyses will demonstrate whether the effect persists beyond 28 weeks".
In the Imagine extension study the numbers are very small but just by looking the 1y results IMO, it is very well possible to demonstrate corresponding disease modifying effect. If the second year on PBT2 will reduce the hippocampus atrophy speed an other 35%, that speed would be as low as 1.7 %/y and that of the earlier placebo 2.6%/y. To get hippocampus atrophy rate as low as 1.7% is enough to confirm that PBT2 is a disease modifier but it could be that even with small numbers the difference of 0.9% could be statistically significant.
My guess is that in the SUVRs difference becomes also significant particularly because the 1st year effect was only 2.5% and it happened only during the second 6 months.
But this is only guess work and the most important measurement is cognition score and we have no info what was the effect during the 1st year. We need to wait the results still perhaps 2 weeks, only the results will end all speculations.
This paper below with it's figures demonstrates how the delayed-start analysis demontrates disease modification. It gives as an example the Sola study and I do hope the same method will be used in the Imagine extension study. It is a free paper so you can google it.
PLoS One. 2015 Mar 17;10(3):e0119632. doi: 10.1371/journal.pone.0119632. eCollection 2015.
A novel approach to delayed-start analyses for demonstrating disease-modifying effects in Alzheimer's disease.
Liu-Seifert H1, Andersen SW1, Lipkovich I1, Holdridge KC1, Siemers E1.
ITM, in spite of the first sentence we can see that there is some hope and that hope made LLY to re-extend their study and offer the placebos Sola. I think these results did not only convince Masters but also Tanzi, who is now telling that amyloid targeting drugs need to be taken early, before any AD symptoms. I cannot figure asymptomatic persons to take profylactic i.v. injections every month for many years to avoid AD. It could be easier with oral PBT2.
PBT2 is very different in comparison to Sola according the 2 clinical studies: In euro study cognition improved when in this Sola study it deteriorated, in the Imagine study PET-scan SUVRs went down 2.5% but there was no change in this Sola study and then the hippocampus atrophy speed went down 35 % in the Imagine study ( p=0.09) and there was no change in this published Sola study. Total amyloids in CSF went up with Sola ( however free abeta 40 went down) but down with PBT2 ( Euro study).
I think that Masters and Tanzi are happy with this Sola study because it demonstrates that some amyloid oligomers are bad and this supports their amyloid hypothesis but IMO both of these scientists think that PBT2 works ( Masters's July presentation and now Tanzi last week in his interview).
IMO there is much more to support for PBT2 than Sola, which was behind the rumors adding several billions to the market cap of LLY. But at this phase we have no rumors about PBT2, only a lot of science.
The 80 weeks on sola was published in NEJM and if you have not seen it, it could be good to look at it.
"Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease"
The differences were small and only in the mild AD group. Totally almost 650 patients in this group (compare 40 in the Imagine study). But I would say that it is a step forward. At this level of info I do not think it could get any clinical usage, too expensive and only minimal help.
Now the placebos are taking also Sola and in the July meeting we will know if the speed of deterioration is any slower than earlier. Spinal fluid amyloid analyses in this NEJM paper would indicate that.
We had Biogen jumping from $350 level to $480, then AXON almost without anything ( one possible drug candidate) getting up to 3B market capital and now LLY adding it's market capital also by billions by some Solanezumab rumors.
As Kad told Sola and PBT2 have some similarities, they target toxic oligomers but they are very different drugs. Now even the extension studies are kind of similar: in the extension phase the placebos are taking the real drug. If the placebos will not catch the earlier drug group in the measurements it will be a sign of effecacy.
Prana's extension study will end to this 2y follow-up study but Lilly's study will be going on (IMO, see Clinical trials) . The results in the AAIC will be only interim results, data collection continues until Oct 2016.
I just wonder why LLY does not publish these interim results if they are positive. IMO Prana will give the results in the next 2.5 weeks and they may still have some kind of presentation in the AAIC meeting. I hope that if prana's results are positive as I expect the market reaction will be similar as it has been during the few last weeks.
We have not had any results about glucose metabolism in the Imagine study but it was also measured by PET scan. I hope we will get some results also about that because it could be important as demonstrated on this paper bellow
PLoS One. 2015 Jun 10;10(6):e0129250. doi: 10.1371/journal.pone.0129250.
Multimodal Discrimination of Alzheimer's Disease Based on Regional Cortical Atrophy and Hypometabolism.
Yun HJ1, Kwak K1, Lee JM1; Alzheimer’s Disease Neuroimaging Initiative.
Structural MR image (MRI) and 18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) have been widely employed in diagnosis of both Alzheimer's disease (AD) and mild cognitive impairment (MCI) pathology, which has led to the development of methods to distinguish AD and MCI from normal controls (NC). Synaptic dysfunction leads to a reduction in the rate of metabolism of glucose in the brain and is thought to represent AD progression. FDG-PET has the unique ability to estimate glucose metabolism, providing information on the distribution of hypometabolism. In addition, patients with AD exhibit significant neuronal loss in cerebral regions, and previous AD research has shown that structural MRI can be used to sensitively measure cortical atrophy. In this paper, we introduced a new method to discriminate AD from NC based on complementary information obtained by FDG and MRI. For accurate classification, surface-based features were employed and 12 predefined regions were selected from previous studies based on both MRI and FDG-PET. Partial least square linear discriminant analysis was employed for making diagnoses. We obtained 93.6% classification accuracy, 90.1% sensitivity, and 96.5% specificity in discriminating AD from NC. The classification scheme had an accuracy of 76.5% and sensitivity and specificity of 46.5% and 89.6%, respectively, for discriminating MCI from AD. Our method exhibited a superior classification performance compared with single mod