Yes, interestingtome, and we have much more:
- cognition improvement in Euro study
- hippocampus atrophy decline in the Imagine study ( a trend)
- cognition improvement in reach2HD
All these are much more than surv changes in the Imagine study.
So it is a big job to demonstrate that a drug does not work. It took some 3000 patient years before that was obvious enough in the 2care study. The imagine study used 41 patient years, only 1.4% of the amount what there was in the 2care study, not even close what is needed to demonstrate that a drug does not work. Unfortunately Wall Street and many investors did not understand that. You can demonstrate that a drug works in much smaller patient population ( Reach2HD) but small numbers are not enough to demonstrate that a drug does not work. With a very small numbers we have a possibility to see possible positive trends ( hippocampus atrophy rate in the Imagine study).
The study had started in 2008 and the plan was to collect data until 2017, 2 groups placebo and coenzyme 10. Over 600 cases were recruted, 300 + 300. Now the study was stopped because mortality was higher in the Q10 group ( 7% / 4% ) and the possibility to get beneficial effect was below 5%.
When comparing with Reach2HD, the positive effect with PBT2 was noticed already in 6 months in the treatment group of some 35 cases (250mg) and only 1 major side effect when PBT2 treatment was stopped.
Interestingtome, IMO the work of yours and Masters's are valuable and even more of similar data exploring has been done by Prana itself to find out possible trends and to make new hypotheses for the future studies. Until now we have not seen any data about cognition and for sure some calculations has been done also about that. The Imagine study is a very valuable study for the future big study Prana is now very "enthusiastic" about. Let us see if they can get a partner, a big Pharma, equally "enthusiasic". Nobody will solve AD problem by a study with 41 cases, not even Prana. A multi center study with hundreds of cases is needed with the most modern imaging possibilities etc. The Imagine study will help to find the weak and strong areas of the used methods. Unfortunately it will take time to get to the next phase.
interestingtome, I am sure PBT2 works. To demonstrate it to everybody and FDA a bigger study is needed. The study design needs to be randomised controlled study, not a study using historical controls. But this has been the plan of Prana: first PBT2 for HD and later for AD.
One interesting possibility could be if the hippocampus atrophy rate of the previous placebo group would go down with PBT2, et us say to 2% level (1.year 4%) and/or the 2y on PBT2 group would reduce their atrophy rate even more from 2.6 %/y. I just wonder if I Shoulson could convince FDA already with this kind of figures.
imtom, unfortunaely this is not the way to do controlled studies (original purpose of the Imagine study), the only acceptable method is randomisation. When you do randomisation in a small material there are risks as we know. Of course historical controls can be used in comparison but then you do not get an answer of a controlled randomised study and that was the purpose of the Imagine study.
I understand that Prana wants to go forward even with this disappointing result of the Imagine. The extension study does not have a control at all and when comparing the 2y treated with some other cases historical controls will be needed. Even then it perhaps is best that the comparisons are done with the same population started the study fullfilling at least the entrance criteria.
The difficulty is to find a corresponding historic control group to make the comparison valid or better than the original control. Masters made it already in his presentation and we got some explanation. It is good enough to me. However, everybody is biased when trying to find a new better control. AD is so slowly progressive disease with individual differences that IMO only way is to do randomisation as was the case in the Imagine study, what ever the results. But the number of controls was too small.
But who cares about PET scan results, they do not relate well with cognition, at least much worse than the hippocampus volumes in which a positive trend was found even in the original comparison. And we already have a positive result of amyloid in spinal fluid in the Euro study. This can be said only today when we have more understanding about amyloid and about hippocampus. As I have told earlier the Imagine study was done in such a small population that there was not any possibility to see but trends of possible valid measurements for future studies. It was a "a pilot study" and unfortunately only that. I thought that the pilot studies had been done behind the doors in few patients before the real study to make a valid plan, but that was not the case.
But Reach2HD was a real study when comparing to the Imagine. It had 109 patients, some 35 cases in each of 3 groups, but the Imagine had only 41 cases all together. So Imagine could not be anything but a pilot study. But it is very important to look all the trends seen in the Imagine study to plan the next study. IMO for HD the Reach2HD will be enough.
J Phys Chem B. 2014 Aug 12. [Epub ahead of print]
Zn2+ Effect on Structure and Residual Hydrophobicity of Amyloid β-peptide Monomers.
Shi H, Kang B, Lee JY.
Recently, Zn2+ was known to rapidly induce the Aβ peptides oligomerization under physiological conditions, indicating that Zn2+ plays an important role in promoting aggregation. The structure for Zn2+ binding to Aβ16 containing all the H6, E11, H13, and H14 residues was determined by nuclear magnetic resonance spectrum in vitro aging, but there is no information to the entire Aβ protein yet. Theoretical studies have reported structural properties of Zn2+ coordinated Aβ (Zn2+-Aβ). However, the details of hydrophobic properties in presence of Zn2+ are still unclear, which is strongly correlated with the aggregation behavior. Thus, to investigate the hydrophobic properties of each residue of the entire proteins (Aβ40 and Aβ42) under the influence of Zn2+ coordination will be helpful for understanding the aggregation behavior, hence for treating Alzheimer's disease (AD). In this work, we investigated four models (Aβ40, Zn2+-Aβ40, Aβ42, Zn2+-Aβ42) in order to get insight into the molecular mechanisms and detect the hydrophobic properties by MD simulations. Our results show that Zn2+ can strongly influence the structural properties of Aβ40 and Aβ42 by reducing helical formation and increasing turn formation to expose the hydrophobic regions. Furthermore, hydrophobicity of Zn2+-Aβ40 and Zn2+-Aβ42 was much higher than that of each monomer, since Zn2+ binding can significantly influence the hydrophilic domains of Aβ. The further analyses indicate that not only four residues (H6, E11, H13, and H14) but also R5, D7, K16, K28, and terminal residues influence hydrophobicity upon Zn2+ coordination. Importantly, R5, K16, and K28 play a crucial role to regulate solvation free energies. This work is helpful to understand the fundamental role of Zn2+ in aggregation, which could be useful for further development
J Neurosci. 2014 Aug 13;34(33):11159-11172.
Amyloid Precursor Protein Dimerization and Synaptogenic Function Depend on Copper Binding to the Growth Factor-Like Domain.
Baumkötter F1, Schmidt N1, Vargas C2, Schilling S1, Weber R1, Wagner K1, Fiedler S2, Klug W3, Radzimanowski J4, Nickolaus S5, Keller S2, Eggert S1, Wild K6, Kins S7.
Accumulating evidence suggests that the copper-binding amyloid precursor protein (APP) has an essential synaptic function. APP synaptogenic function depends on trans-directed dimerization of the extracellular E1 domain encompassing a growth factor-like domain (GFLD) and a copper-binding domain (CuBD). Here we report the 1.75 Å crystal structure of the GFLD in complex with a copper ion bound with high affinity to an extended hairpin loop at the dimerization interface. In coimmunoprecipitation assays copper binding promotes APP interaction, whereas mutations in the copper-binding sites of either the GFLD or CuBD result in a drastic reduction in APP cis-orientated dimerization. We show that copper is essential and sufficient to induce trans-directed dimerization of purified APP. Furthermore, a mixed culture assay of primary neurons with HEK293 cells expressing different APP mutants revealed that APP potently promotes synaptogenesis depending on copper binding to the GFLD. Together, these findings demonstrate that copper binding to the GFLD of APP is required for APP cis-/trans-directed dimerization and APP synaptogenic function. Thus, neuronal activity or disease-associated changes in copper homeostasis likely go along with altered APP synaptic function.
I do hope they are. If so, all Kempler needs to do is to give a pen to them and we will see the results sooner than the Annual report is due.
IMO the ones who have not demonstrated any skills of connecting the dots are the Big Pharma bosses. The evidence is there, unfortunately just a bit hidden unless you do not connect the dots. Let us see if we need to wait until the extension study results.
Yesterday up 3.5-5% with some 0.5M traded shares, now down 3.5% with 25K volume. I think this is indication of something, perhaps short manipulation.
Interestingtome, thanks once again. This is really a very important publication. The impact factor of this journal Chemical Society Reviews is 24.892 so the article is published in a very higly respected forum. Hope it will be read by neuroscientists but in any case this is a very important paper when discussing partnership with big pharma.
interestingtome, thanks again. Seems to be a good review about the metals. Hope it will be free.
Yki, Prana's board should have enough talent to see what you just told. I think that they all want to make a deal of PBT2 now when they are very close to say that PBT2 can be approved for HD by FDA ( Reach2HD results in final form + pharmacokinetics of PBT2 + Shoulson's opinion + PBT2 safety data). So the partner can get PBT2 almost immediately to pharmacy. Let us wait just few more weeks (???).
Yki, I share your concerns but I am perhaps more hopeful this time than ever before that there will be a deal within the next few months. Let us see if my instinkc is correct, unfortunately it is not very often correct.
I think that not only we investors would like to get forward with a partner but also Mr. Kempler as he has indicated this a couple of times this year. The imagine study was a big disappointment to everyone but IMO it was only a pilot study to give advice in planning the next study, it was not planned to be the study proving proof of everything seen in the mouse studies. But after this pilot study Prana has better understanding what to target in the next study. IMO it will be hippocampus atrophy and cognition which are related as has been demonstrated in human studies. Not a single drug but PBT2 and Prana is so close to demonstrate that these 2 things can be controlled by a drug. Big Pharma understand this and this is why I feel that there will be a deal in the next few months.
This deal of Bionomics / Merck has all the components what are needed also in the "future" Prana / Big Pharma deal. May be there could be also a capital injection suggested by Eso a couple of weeks ago. Kempler told earlier this year that Prana is ready for discussions but until now no news (only one weak rumor). Looks that there is now something Prana is still waiting for. IMO extension study results could trigger milestone payments (if favorable),as could FDA application for PBT2 (HD) etc. So IMO there is no clear reason to delay a deal at present. Of course everything is more complex what I can see but I cannot see things getting much better by waiting.
Prana tells in their report 3wks ago that "the company remains enthusiastic about the prospects of a large trial statistically powered to demonstrate cognitive benefit". It looks a bit like Wall Street has not been able to feel the same enthusiasm as Prana itself. The cash Prana has is not enough to get this future study done. It needs to be a multicenter study in a population of few hundred patients and needs to have also expensive imaging components included.
So most likely Prana is looking a partner to get this done. Prana seems to be also sure that a bigger better powered study could demonstrate also cognitive benefit. So the " pilot study" Imagine could have some still hidden hints that cognition effect can be demonstrated in a bigger material and not only slowing the atrophy rate of brain, almost significant in the small material of Imagine.
So I am waiting to see what is behind this "enthusiasm" Prana has but what is not felt among the investors. IMO it needs to be a deal giving financial possibilities for this study and so a Big Pharma deal is the first thing comming into my mind. And Kempler has been open to this kind of discussions already over 6 months ago.
20 M cash, over 500M milestone payments and future royalties. BNC 375 is in preclinical phase. So IMO if there would be now some kind of deal with Big Pharma and Prana the price would be something very different than Merck did with Bionomics.