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Antibiotic resistance. May be of interest.
2018 Dec 11;9(6). pii: e02391-18. doi: 10.1128/mBio.02391-18.
Chemical Synergy between Ionophore PBT2 and Zinc Reverses Antibiotic Resistance.
1, 1, 2, 3, 4, 1, 1, 4, 1, 1, 1, 5, 6, 7, 1, 4, 1, #2, #3, #8.
Abstract
The World Health Organization reports that antibiotic-resistant pathogens represent an imminent global health disaster for the 21st century. Gram-positive superbugs threaten to breach last-line antibiotic treatment, and the pharmaceutical industry antibiotic development pipeline is waning. Here we report the synergy between ionophore-induced physiological stress in Gram-positive bacteria and antibiotic treatment. PBT2 is a safe-for-human-use zinc ionophore that has progressed to phase 2 clinical trials for Alzheimer's and Huntington's disease treatment. In combination with zinc, PBT2 exhibits antibacterial activity and disrupts cellular homeostasis in erythromycin-resistant group A Streptococcus (GAS), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococcus (VRE). We were unable to select for mutants resistant to PBT2-zinc treatment. While ineffective alone against resistant bacteria, several clinically relevant antibiotics act synergistically with PBT2-zinc to enhance killing of these Gram-positive pathogens. These data represent a new paradigm whereby disruption of bacterial metal homeostasis reverses antibiotic-resistant phenotypes in a number of priority human bacterial pathogens.IMPORTANCE The rise of bacterial antibiotic resistance coupled with a reduction in new antibiotic development has placed significant burdens on global health care. Resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus are leading causes of community- and hospital-acquired infection and present a significant clinical challenge. These pathogens have acquired resistance to broad classes of antimicrobials. Furthermore, Streptococcus pyogenes, a significant disease agent among Indigenous Australians, has now acquired resistance to several antibiotic classes. With a rise in antibiotic resistance and reduction in new antibiotic discovery, it is imperative to investigate alternative therapeutic regimens that complement the use of current antibiotic treatment strategies. As stated by the WHO Director-General, "On current trends, common diseases may become untreatable. Doctors facing patients will have to say, Sorry, there is nothing I can do for you."
https://www.medicalnewsbulletin.com/drug-alzheimers-disease-antibiotic-resistance/
http://www.uq.edu.au/research/impact/stories/so-long-superbugs-crowdsourcing-is-here/
PRAN. If anybody is interested they just submitted their safety data package and Huntington's phase3 trial design to the FDA to hopefully lift the partial clinical hold, which is preventing use of the therapeutic level dose of 250mg. A comment from a world leading movement disorder doc on Prana's board on HD results to date.
.[Prana director and movement disorders expert Professor Ira Shoulson welcomed the analysis findings.These analyses are reassuring, and the findings provide clinical meaningfulness to the objective and statistically significant improvement we saw in Trailmaking B testing of cognitive performance from the trial,"]
Here is what he is talking about.
• Within positive, negative, and no change TMT-B performance groups, 90% of improvement in CSTP occurred among PBT2- treated subjects.
•HD-PROP may capture the subjects’ own experience of meaningful improvement in cognition, observed in the REACH2HD trial on formal testing.
•All positive CSTP reported zero W26 cognitive complaints, indicating absence of bothersome thinking problems.
•The higher dose of PBT2 (250mg) may be more effective in treatment of subjects’ cognitive complaints.
http://pranabio.com/wp-content/uploads/2016/06/Abstract-from-Movement-Disorders-Conference-2016-.pdf
They are also ready to commence the clinical program for the Parkinsons drug PBT434.
[We are in communication with the FDA regarding PBT434’s development plans, having submitted a pre-IND dossier for their review in respect of the suitability of the above non-clinical package and manufacturing of PBT434 drug product to support our proposed Phase 1 studies.]
http://pranabio.com/wp-content/uploads/2016/10/Prana-AR-2016.pdf
Hi RKF, the trial has identified plaque reduction. A statement they made on page 3 of the report was interesting, indicating no changes in measurements between 1yr and 2 yr.
http://pranabio.com/wp-content/uploads/2015/08/150826_Prana-Annual-Report-and-4E.pdf
That would be brilliant if the patients were more advanced, but the differences over one year in these earlier stage patients would possibly have been tiny. I would take from that data that PBT2 may have stopped or slowed AD in the second year but the trial is too small to be able to reach that conclusion. Still, no changes over one year is a good sign.
When Prana started the Reach2HD and IMAGINE trials it was always the plan that Reach2HD would lead PBT2 to market and IMAGINE was run to try to attract a pharma partner for the AD program with a demonstration of target engagement.
They are still on track with HD for phase3, and like you I don't think they will have a problem getting the partial hold lifted when the safety analysis and HD trial design are complete.
Interim look, did anybody see the charts? I can't get into the site. Was there some separation of the lines that may indicate it could be close to significant.
The answer to why some people get Alzheimer's and some don't probably lies elsewhere.
Exactly. The plaque removal endpoint was chosen because they thought it was a safe target.PBT2's effects lie elsewhere.
Iandy, that was the first imaging trial for PBT2. It solved the mystery of why PBT2 reduces AB42 while the MABs saw an increase in AB42.
Lindquist identified the main action from MPACs was inside the neurons.
There should be no change in the plan ahead for HD disease, which was always the fastest way to market. The Reach2HD trial clearly identified very early HD disease as the patient group to go after.
I think maybe the IMAGINE dose was way too low. I stuck to it because I believed they were and still are on the right track. That little trial disproved nothing.They didn't choose that design, it chose them as it was all the funds they could raise. Results from the AIBL made it possible to prove the biomarker so they went for it.
Meanwhile the Parkinson's-Movement disorder drug PBT434 moves closer to the clinic.
Results from this study could generate some interest. The Florey is collaborating with the University of Leeds on it. UOL I don't know much about, but the Florey is a research powerhouse with several hundred neuroscience scientists and staff working from there, including Prana co founders Masters and Bush.
http://www.marketwatch.com/story/parkinsons-uk-awards-gbp-150000-to-study-pranas-pbt434-2013-09-04
Previous work in the model with a similar drug were impressive.
"'Treating a tau KO mouse with an iron chelator was not an experiment you would have predicted to be obvious from the existing literature,' says Bush. 'We were quite stunned by how profoundly clioquinol rescued the tau KO mice.' A further experiment revealed that a lack of tau impairs the trafficking of
a protein involved in neuronal iron export. "
http://www.rsc.org/chemistryworld/News/2012/January/alzheimers-parkinsons-neurodegeneration-linked-iron.asp
Iandy, obviously I did not find it entertaining at all. Safety and tolerability are important considering they have a phase 3 HD trial planned and the IMAGINE extension still running.
That was always biomarker trial and to miss the plaque reduction end point was a shocker. Masters et el have been running a biomarker study(AIBL) in 1000 patients for 8 years or so and they know amyloid does not decrease. The Imagine trial was designed around AIBL findings.
Dr Shoulson's independence I think gives his opinions more credibility, but looking at his record I think that is a given. He founded the volunteer HSG and PSG. From memory he has been principal investigator in 25 clinical trials. He is there looking for an HD drug.
The trial was too small to say for sure there are no cognition effects. They needed some biomarkers. So far they know PBT2 reduces AB42 in the CSF, which was not tested in this trial. Now a trend in reduced atrophy at this dose. Lets see what comes out of the full data analysis.
PRAN, I have no idea of the right dose. I just know that the results they have are dose dependent. Looking at the differences between the 100mg and 250mg I guess 350 or 400mg.
The Whitehead study identified maximum efficacy just before toxicity in the Lindquist yeast model.
I think Prana have been playing it safe, and with 20 times the ability to pass the BBB than clioquinol, nobody knows what the safe level is.
The dose finding trial went to 800mg per day with good clearance from the body, but that was just a week or so from memory, and it did not find a dose limiting toxicity.
As for Prana, this is breaking new ground and they now have some more info.
PBT2 reduces brain atrophy and reduces AB42 levels in the CSF.
Dew, $10. I think the HD results were good, considering nothing else has helped in cognition, the result is a replication in TMTB and the earlier stage patients were identified as a much stronger effect. Reach2HD has identified the ideal trial population for a phase 3.
HD was always going to be the fastest route to market and nothing has changed there
$10
The AD trial identified brain atrophy in a trial that was not powered to pick up much, that is 42 patients versus combining 2 thousand patient trials to show efficacy in Sola.
Plaque reduction as an end point is past.
So far PBT2 has now identified effect in AB42 in the CSF and reduction in brain atrophy. The IMAGINE extension is still running and my guess is that brain atrophy in the placebo will slow to the same pace as the drug arm but not make up the lost ground. That would be disease modification, by the last FDA guidance,not?
MLG may not have been impressed with the HD results, but the top trial doctor in the field, with 25 trials as lead investigator was. Sorry MLG, but you don't know much compared to Shoulson.
It only took 6 patients to identify the brain atrophy in HD which was replicated in IMAGINE.
All that stuff about growing spines and neurons etc, just maybe the atrophy effect is the first evidence of that in humans. I think they will go to a higher dose as the HD phase 3 progresses.
No change in time to approval.
So right now I think there are some very cheap stock out there.
Dew, so far from their phase 2 program in AD they know PBT2 reduces AB42 in the CSF now it reduced atrophy in the hippocampus, as they also saw in the small Reach2HD sample. The extension trial is still running.It is not dead. I think they have to go for a higher dose. A home run in a 42 patient trial was never going to happen in cognition results regardless of the outcome. Plaque reduction in the placebo confounded their primary end point. I guess something like that is always possible with such a small placebo.It was said on this board when the IMAGINE trial started that no cognition result from this trial could be regarded as proof of efficacy because of the small sample size. On the conference call Prof Shoulson indicated that cuts both ways. That is fact, not spin.
Considering the reduction in brain atrophy at this small 250mg dose(dose study went to 800mg with no problems), there may be some value there to AD with a higher dose. Do you know of any other drugs that have reduced atrophy?
I would like to see the HD phase3 design. That snapshot of atrophy reduction from the HD trial was probably correct looking at the IMAGINE top line results.
All I can say is I think it is worth more than current levels.
Yes and Elan lost 10B on the failure of the phase 2. I get the feeling Dimebon soured the water somewhat for small development AD companies. Having JNJ and PFE on board didn't hurt Elan. I guess Selkoe was just a very good salesman as well as a brilliant scientist.
Everything I have seen so far, including the HD results and even mouse tests indicate PBT2 will be at its most effective in very early stage. Being able to provide a measurable cognition improvement even before plaques appear will make it sought after. I think you will be OK, my family has cardomyopathy running through the past generations and there is not too much for that yet.
MLG, I don't read anything into it at all. This is a phase 2 trial and it will be used to develop a phase 3 trial. They need to know every trend in every subgroup. Even the biomarkers could be complex relationships with the cognition responses and every little thing will be examined in fine detail I am sure. As you have previously pointed out this trial is only powered to prove biomarkers, but with a phase 3 in mind everything will need to be looked at. I think there is still doubt over the roles of many biomarkers, as alluded to by the FDA in their guidance document. These guys have been running the AIBL biomarker study for best part of a decade now and don't you think they will be working this to death to correlate effect with biomarkers. This will be the first opportunity they have had to look at a disease modifying drug effect against the the biomarkers they have been studying so long in that longitudinal study. AD has defeated some very big players and now if Prana with some very limited resources wants to take time to be thorough in this landmark trial, I am not at all concerned.
Iandy, I guess I formed my opinion of Bapi chances because I started researching AD research through an interest in Prana. Both prana co founders are in the top 10 JAD rankings for articles cited and Masters is in the top 10 for number of publications. Neither is inferior to Selkoe or Sperling. They have even published some papers together.
Nature magazine cited the work done by Masters and Beyreuther in the early 80's as doing more than any to found the Amyloid Hypothesis. They called AB A4 at the time. Masters has been working on Amyloid since then and was instrumental is starting the CSIRO AIBL study, whose findings were used to design the IMAGINE biomarker trial. Tanzi discovered APP and several related genes. Both Masters and Tanzi have powerful research institutions behind them.
From a perspective of Prana scientists, amyloid has many uses in the brain and to mount an all out attack on amyloid cannot work. I think this is pretty much an accepted fact now, but going back a few years Selkoe et el had done a much better job of selling the all out amyloid attack to KOLs. Contrary opinions were not tolerated very well. I found Prana's argument much more logical. You say they knew the MOA. They didn't know how removing amyloid plaques would stop AD. They didn't know the MOA and could not verify effect in long trials.
Tanzi and Moir supplied pretty good evidence here all out amyloid attack was no good.
http://www.rsc.org/chemistryworld/News/2010/March/23031003.asp
Prana had demonstrated in a model that removing amyloid from around synapses could free up iron clearance mechanisms, and I thought Bapi may see some improvement from that.
The MOA of PBT2 has many facets, Removing the metals from plaques breaks up the plaques, but PBT2 does not attack the amyloid system. It is logical that preventing dishomeostasis in metals that are essential to the brain has to be a good thing.Copper and zinc are used in several functions within the neuron from neutralizing ROS, growing spines and protecting tau from hyper-phosphorylation. Too much to go into here with the time I have, but there are probably other effects to be discovered, but a lot is known about the MOA of PBT2.
I agree it could be used in combination. For prevention trials, if PBT2 can improve cognition in prodromal patients I doubt there will be anything to compare with it.
Prana's theories were around since 2000, but nobody listened. Not the KOLs.
I think it has a 90% chance of success. This is a biomarker trial. No time right now. Will be back on MOA.
Pfizer had no clue of Dimebon MOA because it didn't have one.
Tanzi discovered APP. PRESEN2 and contributed to many other discoveries. Both Selkoe and Sperling thought Bapi would work. I heard Tanzi mutter once it didn't even come close to PBT2. We are about to see the superior scientist, if his discoveries are not enough.
"I finally did something great with PRAN. Dimebon and bapineuzumab had more credibility IMHO"
Even though bapi failed its phase2 after starting its phase3 and dimebon had nothing at all. I guess you made money by going against your better judgement
FWIW, I think the two of them had zero credibility from the start. I did think Bapi may show a little efficacy, and being a antihistamine, Dimebon perhaps demonstrated some efficacy in the younger trial population in Russia by improving sleep.I am sitting on a ten bagger already, and it has been so obvious from years back. When you get so called KOLs ignoring the opinions of the likes of Tanzi and Masters it has got to be a money making opportunity if they have a drug, and they did.
Pran, "How can it be said that the delay is for the purpose of date mining? Wouldn't that violate disclosure laws?"
ASX continuous disclosure laws state once information is final disclosure must be made immediately. A company is allowed a maximum 2 day trading halt.
http://www.asx.com.au/documents/rules/abridged-continuous-disclosure-guide-clean-copy.pdf
PRAN, Thanks for that. Interesting the A4 has opened a center in Melbourne. I know Reisa Sperling is interested in recruiting from the AIBL study patients there. They are patients with 6 year biomarker records. Could they be considering using PBT2 depending on these results? Now that would be a positive coming out of left field.
I also think it will come down to combination trials. The Lindquist paper identified synergies between different MPACs in the yeast model.
"8-OHQs synergize to rescue proteotoxicity - Our
results thus far support distinct activities for each
8-OHQ."
"Taken together these data indicate that
each compound has a unique mode of action.
Furthermore, the non-additive interactions (both
synergistic and antagonistic) observed with
otherwise inactive compounds indicates they
provide distinct activities that, on their own, do not
affect growth"
http://www.jbc.org/content/early/2011/12/06/jbc.M111.308668.full.pdf+html
It is not hard to imagine the movement disorder MPAC PBT434 which is almost ready for the clinic, being used with PBT2 in both HD and PD.
PRAN, MLG, data wasn't even unblinded last I heard a few weeks back. If you remember the last AD trial missed some efficacy and I doubt they will leave any stone unturned. Prana always said March.IF they announce in March, it is exactly what they predicted.
I don't know who is evaluating the scans, but there is some serious expertise in Melbourne associated with the AIBL study, which has been running almost 8 years. Both Colin Masters and Ashley Bush have been very quiet of late. Maybe they are involved.
Pran Iandy, Congrats on the trade. I expect good results and a phase3 to follow. I guess there will be a storm over interpretation again. Now that they can measure subtle changes to executive function just pre onset of HD symptoms I expect the HD trial to move first unless the AIBL grabs PBT2 to try on its 1000 patient longitudinal study. They have previously stated they are looking for a disease modifying drug. The I&B in AIBL stands for imaging and biomarker, which is what IMAGINE is.
The tiny MRI snapshot from the Reach2HD trial was encouraging, suggesting a reduction in brain atrophy.
I think it will be next weekend. With PBT just gaining a position on the ASX300 about now, I am guessing they will unblind the results after some funds get set, but I am not sure how much control they have over that.
That was interesting Fidelity picking up 1m ADRs. The Nasdaq site does not register it yet, but it is here.
http://investors.morningstar.com/ownership/shareholders-concentrated.html?t=PRAN®ion=usa&culture=en-US&ownerCountry=USA
Out of my mind, I hope not
The API study is in a patient population with a rare presenilin mutation, which brings on early onset AD. From what I have read it has an end effect on the AB40 and AB42 ratio. I am not sure I have seen anything in the MOA to address that. They have not completed a phase 2 on normal AD yet and by next month Prana will be in front if Genentech don't come clean. Prana have a much smaller patient population and I expect the TMTB to be replicated again, along with success in some biomarkers.
They should be years ahead of Prana but they are not. Next stop for PBT2 in AD will be phase 3.
"I do believe in amyloid removal as a target, and I also believe Genentech's program with crenezumab has the best chance for success"
Lets look at crenezumab. I am sure you know phase 2 trial results were expected late last year and didn't appear. http://clinicaltrials.gov/ct2/show/NCT01343966?term=genentech+ABE4869g&rank=1
http://clinicaltrials.gov/show/NCT01397578
Note the extension study commenced in late 2012, about when we could have expected results.
http://clinicaltrials.gov/show/NCT01723826
Roche bought in crenezumab in 2006, and despite their immense resources have done very little with it and are no further ahead than Prana who started their phase2 in 2006 then had to sit out the GFC.
Roche have now selected crenezumab for a very large prevention trial, sopping up about 31m in charity funds in the process, BEFORE the phase2 trial was even due to finish. It hasn't finished yet, and we all know what that means. I was expecting the failure of that phase2 to demonstrate any efficacy would boost PRAN a little and it didn't come.
http://www.alzforum.org/news/conference-coverage/nih-director-announces-100m-prevention-trial-genentech-antibody
I do not hope they fail, I just think they will, and not reporting that phase2 on time does not fill me with confidence.
If you apply the same stringent standards expected of Prana I think several of the big pharma efforts will come up wanting.
Dew, to me it stands to reason that ability would be lost at the outer edge of difficulty, rather than a measurement at an easier point.
Prana, In support of the importance of the Trial Making test part B in other neurodegenerative conditions, including normal aging, which is going to be another story.
To write off TMTB gains is a big mistake and in other forms of neurodegeneration including AD in my view.
This was posted on YMB
"Participants who performed best on the trail making test B were more than twice as likely to be alive at 8 year follow up"
" Executive function was measured using the Trail-Making Test Part B (TMT B), and subjects were divided into four subgroups from lowest to highest TMT B score."
The thing is that executive function improves quality of life and is perhaps why it extends life as seen in this study.
http://www.ncbi.nlm.nih.gov/pubmed/24479144
Another
Performance on the TMT is a strong, independent predictor of mobility impairment, accelerated decline in lower extremity function, and death in older adults living in the community.
http://www.researchgate.net/publication/43180791_Trail_Making_Test_predicts_physical_impairment_and_mortality_in_older_persons
Maybe bodes well for the almost there IMAGINE trial results in AD.
Dew, I thought Tanzi's comments on the same article were relevant considering he is closer to the data.
" Given the evidence from an earlier trial (2008), which showed that PBT2 improved executive function in Alzheimer’s disease patients, the Reach2HD trial included a plan to assess the effects of PBT2 on an Executive Function Composite z-score. There was a statistically significant improvement in this z-score (p=0.038), but only in a pre-specified analysis of Reach2HD participants with early stage Huntington disease, as measured by their Total Functioning Capacity score. Across all study participants, who comprised both early and mid-stage HD patients, there was a trend to improvement (p=0.069)."
This is Huntington's disease we a talking about in this trial. It is their first trial. It is going to be enough for a phase 3 trial in only early stage patients where they did get a strong signal over the Executive Function Composite Z-score.
Dr Dorsey commenting on the effect in the early stage group.
"In addition, the results indicated a significant benefit on cognition that is consistent with the previous trial in Alzheimer's disease and is accompanied by an encouraging finding in functional capacity"
Dr Ira Shoulson's comments
Dr. Ira Shoulson, Professor of Neurology at Georgetown University and Chair of the Huntington Study Group, who was not involved in the trial and acts as an advisor to Prana, added: "In the Reach2HD trial, the improvement in executive function performance was also accompanied by a favourable signal of a slowing of functional decline, as measured by the Total Functional Capacity score. This is the first time we have observed dose-related slowing in functional decline over a six month period of treatment – which taken together with the safety reassurance – will provide genuine optimism for the Huntington disease community to support a larger confirmatory trial of PBT2 in Huntington disease."
To ignore the success in TMT, given its importance in early stage HD, which I have posted here, is wrong, especially considering the fact it has been replicated from the AD trial,and that efficacy, predictably seems stronger in early stage patients . Prana have indicated they are going to phase3. Moving it to earlier stage patients would give a very good chance of success. Perhaps it will not be such a large trial, but they are going to phase 3 in HD.
"Regarding image studies for pb2, Amarin also did studies in Huntingtons and had excellent image studies with their omega 3 drug"
I recall a fairly recent study from the Mayo indicating Omega 3 also reduced risk in AD.
I do MLG. "You do realize the market cap of Pran would be $10B + if institutions thought this would be successful in phase 3"
As I realize that erbitux was given up for dead, Pruisner(Nobel) was doubted even after he proved prions, Provenge would never make it to market, Herbert Boyer could not get funding for his crazy idea(Genentech)and gastric ulcers were not caused by bacteria. Bapi was going to be a winner, Dimebon was more than just an antihistamine and secretase inhibitors would not make patients worse.
I could go on but you know institutions, pharma's and academia academia often get it wrong.
I look at Tanzi, Masters, Bush, Rogers, Lindquist, Massa, and all the independent scientific evidence piling in to support the metals theory from around the world.
Does this mean you think a $10b market cap is possible if the institutions are convinced?
iandy, PBT2 will be approved in Huntington's disease, Alzheimer's disease and several other diseases if nothing better comes along. Posters on this board pointed out the scores of possibilities, and yet PBT2 showed a significant result on the trial making test and it was not data mined. It was a replication of of the AD result in trial making. Considering EF was the pre specified secondary endpoint due to the previous result, how is that a bad thing.
There were other positive trends, and if you want to data mine a little those trends were stat sig in the data mined earliest stage patients.
Now that fits in perfectly with the facts emerging from HD longitudinal studies that the earliest signs of HD can be detected by the trial making tests. I think that is a very important fact that seems to have been missed, along with the fact the effect has now been replicated across two diseases.
As for general disregard for the Amyloid theory in academic circles, how many independent studies supporting the metals theory from academia would you like me to post.
It is not academic circles, it is the street and maybe vested interests in academia. Researchers are in love with the idea of the RNA drugs for HD and would perhaps love not to have to face a very safe and effective competing treatment. Add to that, if PBT2 is approved in HD, and it has shown efficacy in early AD, then it could lead to huge off label AD use.
Some academia is against it but it was one of the foremost HD experts who suggested to Prana they should trial in HD because they may be able to replicate the exec function gains seen in the AD trial, and they did. Why would you not call it a success. That was Ira Shoulson, the man who founded the HSG, which ran the 84 patient trial which led to the approval of tetrabenazine. He is now on Prana's advisory board. I am pretty sure he knows a sight more about HD than anybody who posts here. He was fielding questions on the CC everyone here didn't like.
PBT2 is not an amyloid directed drug. Removal of Amyloid is a side effect of metals homeostasis and is nothing like any Amyloid targeting drugs before it. PBT2 targets metals only.
That little sample of effect on brain volumes, remember the IMAGINE trial is full on imaging with results due in a few weeks. Brain volumes is one of the measures, as are trial making tests.
I think this could affect the thinking on HD as well.
Prana, relevance of recent clinical results. The significant result in executive function measure of trial making looks good when you take into account that this 7 year longitudinal study below found TMT deterioration preceeded symptoms.
http://currents.plos.org/hd/article/seven-year-clinical-follow-up-of-premanifest-carriers-of-huntingtons-disease-2/
" Rate of Change (RoC) analysis was performed to measure longitudinal differences between carriers and non-carriers. Carriers performed consistently worse on executive function (Symbol Digit Modalities Test (SDMT), Stroop, Trail Making Test (TMT) and WAIS-R arithmetic)."
"This longitudinal study with a follow-up of seven years demonstrated a significant decline in motor functioning, memory, and concentration in premanifest carriers of the HD gene mutation. Cognitive changes over time could be primarily ascribed to carriers who converted to manifest HD.
Cross-sectional results at baseline were comparable to previous studies demonstrating abnormalities in carriers in executive function, specifically attention, cognitive flexibility, psychomotor speed, and inhibitory processes, as assessed with WAIS-R arithmetic, SDMT, TMT and Stroop [5][6][34]. Without the carriers who converted to manifest HD during the study, cognitive abnormalities at baseline could still be demonstrated. This indicates that subtle cognitive deviations, especially on executive functions, are present, even long before the onset of HD motor signs and may be related to early deficits in the basal-ganglia circuitry [15][35]. After seven years additional cross-sectional differences emerged, with carriers showing more motor abnormalities on the UHDRS motor section and worse performance on memory and concentration tasks from the WMS, compared to non-carriers"
This TMT gain has been replicated through both the PBT2 Alzheimer's 2a trial and now in the Reach2HD trial. No one here will agree, but as there is nothing available to save converting HD patients I would suggest PBT2 should be made available the people in danger of converting now. There will be more evidence of the TMT effect in the AD imaging trial results next month.
MLG, the HSG docs on the call thought it was very good news. The Huntingtons Study Group is the croup who ran the P3 trial of tetrabenazine in 84 patients for approval.
This improvement they saw in HD executive function reinforces the improvement in the same measure they saw in the Alzheimer's trial.
The idea they should not mention that improvement and include it in the total score and call the trial a failure is ridiculous.
There has never been any improvement in cognition from any HD clinical trial. Now we have seen a significant one. Prana now have the founder of the HSG on the advisory board. If he decides PBT2 is ready for phase3 I guess it is. Your understanding of HD is nowhere near the level of the Huntington's Study Group docs.
If he says it is ready for phase 3 I will go with his opinion.
Ira Shoulson founded the HSG in the early 90's. They developed the Unified Huntington's Disease Rating Scale (UHDRS). Ira Shoulson is now advising Prana on the way forward.
http://www.huntington-study-group.org/AboutUs/tabid/54/Default.aspx
Iandy, FYI
"Encouraging signs of cognitive improvement, as measured by the Neuropsychological Test Battery (NTB), were also observed. Statistically significant improvement was evident in two of the four Executive Function NTB tests: the Category Fluency Test (p=0.028) and the Trail Making Test part B (p=0.005), both after 12 weeks of treatment at the 250mg dose compared to placebo."
http://www.sec.gov/Archives/edgar/data/1131343/000114420408011783/v105046_ex99-1.htm
Well John, dont hold back. Just explain to me why you would doubt executive function gain, which has now been replicated through two different neuro diseases. I hate to have to keep repeating myself ,but considering the number of possibilities, the odds of the same test result in executive function being significant in both neurodegenerative diseases by chance are slim. What will you say if the same result is seen in the IMAGINE trial next month.
Executive function was the secondary end point where they most expected gains.
Some think the other positive trends in cognition seen should not even be reported. I dont share that view and neither it seems do senior HSG doctors.
This is an investment forum I thought, and I would like to know about any positive trends that impressed the HSG docs. You wait for the publication. FYI I am an investor who has followed Pran for about 4 years now and hold stock. I am well aware of what they expected, and from what I have seen so far it is what they got.
I am concerned that negative reaction against these results is extreme and one sided. I am putting the opposing case. Sorry if you don't like it.
If you don't know enough about PPHM or PRAN, then considering your stand, why bring it up. I for one am not very interested in your vibes.
FYI it was the HSG Docs fielding trial questions on the conference call, not Prana.
PBT2, how long to market? AS stated on the conference call the data is still fresh and all possibilities are being looked at.
We know the opinion of the Huntington's Study Group. We don't know the reaction from the FDA yet but the chorea drug tetrabenazine was approved from an 84 patient 12 week trial run by the HSG.
PBT2 is a very different situation to tetrabenazine, which is symtomatic only.
PBT2 is a disease modifying drug possibly capable of postponing or preventing onset of the disease. HD first manifests as EF in most cases and that is the area PBT2 targets. Considering there may never be a cure for late stage disease, there are serious implications for patients close to converting into HD right now. Lets wait for how the FDA interpret the data before getting too specific.
Pran. Are you sure you are not the one who is delusional.
"But, there is no evidence this works." from you
"There was a statistically significant improvement in performance on the Trail Making Test Part B (as illustrated in the graph), in the PBT2 250mg group compared to placebo at both 12 (p<0.001) and 26 weeks (p=0.042)." From the trial report.
From Ira Shoulson, another great man perhaps you should attack next to support your short position.
"Dr Ira Shoulson, Professor of Neurology at Georgetown University and Chair of the Huntington Study Group, who was not involved in the trial and acts as an advisor to Prana, added: “In the Reach2HD trial, the improvement in executive function performance was also accompanied by a favourable signal of a slowing of functional decline, as measured by the Total Functional Capacity score. This is the first time we have observed dose-related slowing in functional decline over a six month period of treatment – which taken together with the safety reassurance – will provide genuine optimism for the Huntington disease community to support a larger confirmatory trial of PBT2 in Huntington disease.”
From Rudy Tanzi. Having replicated the same EF gain over two diseases, I think Rudy is on strong ground.
Dr Rudy Tanzi, Professor of Neurology at Harvard Medical School and Prana’s Chief Scientific Advisor, commented that “the observation of significant improvement in executive function with PBT2 in this clinical trial for Huntington disease and the previously reported Alzheimer’s trial, suggests a common mechanism for neurodegeneration in these diseases based on metal interactions. In my opinion, these findings significantly elevate the potential for PBT2 as an effective therapy for both Huntington disease and Alzheimer’s disease."
Yes Dew, that is the correct interpretation. I do not doubt the replicated EF result and as nothing else can produce that gain, why would it not be approved? The safety profile is about the same as placebo, even though the FDA have demonstrated they will tolerate some risk as seen with the chorea drug.
I think the IMAGINE trial will again replicate gains in the same measure next month. OK it is not powered to show significance, but it will be powerful evidence.
I think PBT2 will be going to market fairly quickly.
Tanzi has always said what he thinks. That is something I like about him. On his tweet from what I hear he always said he was hopeful, nothing more. I believe the statement you are taking issue with was probably after results.
"If pbt2 goes to phase 3, I think it has < 5% chance for approval"
It is safe and for sure can improve executive function. The IMAGINE results will replicate that again next month.
I think it has a 90% chance of approval once HD advocates realize PBT2 can modify executive function.
PBT434 in the clinic this year will save the dopamine producing cells. Stay tuned.
If you can guarantee me the same results, sure thing
"The Bapi phase 2 results were better looking across multiple endpoints. They were not great, but more promising than this " No they were not. They were data mined and as we both know, there was an inverse dose dependency. PBT2 is showing a dose dependency in the right direction over both AD and HD trials. This is not chance PBT2 modifies Executive Function.
"FWIW, my answers to PRAN survey are b, b, b, c, c. I would have answered c, b, c, c, c if 100mg were a little bit better than placebo."
But the 100 mg was a little better than placebo. That was also replicated across both HD and AD trials. I thought replication of results is important.