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Is LMTX the CURE for Alzheimer's? Results announced at ICAD2016, primary result was not positive
remembering
Posted: Wednesday, July 27, 2016 12:15 PM
Joined: 4/29/2016
Posts: 12


The official ICAD press release was somewhat non committal.

 http://www.multivu.com/players/English/7865354-aaic-alzheimers-drug-phase-3/

 

 taurx is calling it a positive result in the monotherapy subgroup. Progression of AD in this

subgroup appears to have been nearly entirely stopped (6.9 ADCS-ADL point difference in mild-moderate AD patients. That is close to completely halting progression.)

 http://taurx.com/press-releases/

Comments?

 


Lane Simonian
Posted: Wednesday, July 27, 2016 6:31 PM
Joined: 12/12/2011
Posts: 4634


Here is a very curious difference between the subgroup who seemed to have the progression of their disease nearly halted and the majority of people whose progression was not affected at all by LMTX.

In those study patients taking LMTX® as add-on therapy to current AD medications, there were no statistically significant differences in ADAS-cog, ADCS-ADL or LVV measurements between the control, 75mg b.i.d LMTX® or 125 mg b.i.d. LMTX® treatment groups.

One heretical thought is that perhaps part of the slowing in decline was due to people not taking Aricept (donepezil).

The potentiation of NMDA currents by donepezil was decreased by inhibition of PKC and abolished by modulation of G proteins but not by PKA inhibition. It was concluded that donepezil at low therapeutic concentrations (0.01-1 microM) potentiated the activity of the NMDA system and that this action together with cholinesterase inhibition would contribute to the improvement of learning, memory, and cognition in patients with Alzheimer's disease [in Alzheimer's disease activation of NMDA receptors actually leads to a decline in learning, memory, and cognition]. 

A larger issue is that by reducing tau hyperphosphorylation and nitration LMTX would improve neurotransmission but only partially reduce the nitro-oxidative stress that reduces the transport of choline, the conversion of choline into acetylcholine, and the release of acetylcholine that is needed for the recovery of short-term memory.  


remembering
Posted: Thursday, July 28, 2016 8:02 PM
Joined: 4/29/2016
Posts: 12


Thank you Lane for your reply.

I can only hope that the current standard of care does not diminish cognitive ability. However, if there were differences between the LMTX and placebo in regards to anti-psychotic usage, then I would be worried about the validity of the monotherapy result.

It is surprising to me how negative the interpretation of the results of the phase 3 LMTX trial have been.The LMTX monotherapy posted very strong results (p values of  p<.0001,p<.0001, 0.0013, 0.0007, p<0.0001, p<0.0001, p=0.0023, p=0.0014) and the monotherapy subgroup was comprised of a total of 135 patients. That is not exactly a small subgroup. When I was looking at the bapineuzumab trial some of the sub subgroups were less than 10 patients in size.

taurx clearly stated that the phase 2 trial was also a monotherapy trial and it also posted a positive result.

taurx has also said that the second phase 3 LMTX (this time in mild AD with 19% on monotherapy versus 15% in the first trial) showed a positive response in the monotherapy arm. Reports have indicated that taurx changed the statistical plan and the primary endpoint of the second phase 3 just before datalockdown. The mantra for this first trial was only the primary analysis matters. OK then, if taurx has changed the primary endpoint to the monotherapy group then I guess that this means that the second trial succeeded fair and square. They can't have it both ways.

These trials also are expected to go into an open label extension. The first trial finished 35 weeks ago. It will be very interesting to hear an update on these patients. With 2000 patients in the three phase 3 we should soon have a completely definitive answer. I would not want to be betting against this one when a clear answer could be known in the not distant future. By ICAD 2017 in London we should have a very clear answer.

 
This feels like one of those sociology experiments where you are in a room and you are asked to guess how long a line is. The stooges in the room are giving completely unreasonable answers. What these experiments have shown time and time again is that people will follow along with the stooges because they want to conform with group opinion. I am finding it hard to conform to group opinion on the LMTX results when the p values were so low, so consistently low, and more low consistent p values are on the way.

 


Lane Simonian
Posted: Friday, July 29, 2016 12:54 AM
Joined: 12/12/2011
Posts: 4634


I agree, with a few exceptions, the analyses of LMTX results has been very negative, probably unfairly so. When I read the negative analyses, I concluded the drug had failed, but when I began digger a bit deeper (with your help), I was not sure this was the case at all.  It all makes my head spin, although part of the problem may be that years ago I barely was able to pass a statistics class.

When I read conflicting analysis, I look toward mechanisms as a sort of north star. Here is some critical points for LMTX (a derivative of methylene blue).

Methylene blue inhibits the increase of inducible nitric oxide synthase activity induced by stress and lipopolysaccharide in the medial basal hypothalamus of rats.

 

Protection from Alzheimer's-like disease in the mouse by genetic ablation of inducible nitric oxide synthase.

 

Inducible nitric oxide combines with superoxide anions to form peroxynitrite which in turn results in the hyperphosphorylation and nitration of tau proteins.

Peroxynitrite induces Alzheimer-like tau modifications and accumulation in rat brain and its underlying mechanisms.

 

Donepezil (Aricept) increases NMDA receptor activation (memantine inhibits it) which would increase inducible nitric oxide synthase, but it is hard for me to believe that it would do so by so much that there would be such a stark difference among those who took Aricept and those who did not.  My guess is that Aricept somehow blocks the ability of LMTX to inhibit inducible nitric oxide synthase, but cannot find anything to support this guess.

I am still working on Anavex 2-73 which essentially stopped the progression of Alzheimer's disease at 31 weeks (phase two trial, no placebo, small number of people). Here, too, the participants taking donepezil with Anavex 2-73 did worse than those taking the drug alone but not by nearly as much as in the LMTX trial.  And here, too, most analysts likely misjudged/misinterpreted the data to come to a negative conclusion about the effectiveness of the drug.

In any case, this year's Alzheimer's conference clinical trial results were much more positive than last year's (with the amyloid antibodies) and I am confident that some researchers are finally heading in the right direction.


remembering
Posted: Friday, July 29, 2016 5:06 PM
Joined: 4/29/2016
Posts: 12


I would tend to avoid trying to answering why questions from biology because there tend to be few clear answers in biology. Often even FDA approved therapies do not have an unambiguous mechanism of action. Following the numbers is for me a much more comfortable choice.

I am encouraged that taurx has an open label extension trial has been ongoing since August of 2014 and is expected to finish in September of next year with an anticipated enrollment of 1000. The intention is for everyone to receive LMTX. It would be great if this could be randomized, though this might not be feasible. The patients in the trial when they became aware of the recent results might choose to stop their other AD medications. These patients could be used as their own controls. Having 1000 AD patients on monotherapy LMTX for a more than a year could provide overwhelming supporting evidence for its effectiveness. This would be especially true if some of the patients exhibited prolonged benefit from LMTX.



Lane Simonian
Posted: Friday, July 29, 2016 9:49 PM
Joined: 12/12/2011
Posts: 4634


I look forward to reading future results for LMTX--at this point I cannot seem to get past the noise created by the press and various scientists regarding the clinical trial results.
remembering
Posted: Saturday, July 30, 2016 10:55 AM
Joined: 4/29/2016
Posts: 12


Yes, Lane I think you are quite correct in your stance.

Let the dust settle on this one. We can play it cool and wait for a clear answer that should emerge within a year.


kwc
Posted: Sunday, July 31, 2016 9:30 PM
Joined: 5/22/2014
Posts: 37


I am on a open label trial by TauRx Pharmaceuticals 

LMTM.   I know  the article is LMTx   I have been doing this for over 2 yrs  I was in phase 3 trials then that ended an I am now in open labels my wife called  the people in Memphis  Thursday Friday they had a phone conference with the company ( in China I think)  my wife is calling Monday to find out what the word is. Kind of confusing due to there are a couple tests going 

 


kwc
Posted: Sunday, July 31, 2016 9:39 PM
Joined: 5/22/2014
Posts: 37


I am on the open label study NOW   I was in phase 3clinicals also . I go to on  the 8th to see my Dr in  Memphis I see a group that are handling all these in this area I travel 3.5 hrs each way to get there   Great people to work with I really enjoy them  hate the drive but worth it.  I will know more come Monday when my wife calls and when I go to see them on the 8th
remembering
Posted: Monday, August 1, 2016 8:48 AM
Joined: 4/29/2016
Posts: 12


kwc, welcome!

Obviously, there is a large amount of interest in the LMTX trial. 

Anything that you could add to the discussion would be very helpful.

I have a whole bunch of questions.

The Memphis clinical site was only available for the Mild AD phase 3. You were in this phase 3? 

Are you APOE epsilon 4 positive? Have you ever had an amyloid imaging scan? Do you have a known family history of Alzheimer's dementia?

Were you taking other AD medications (memantine, acetylcholinesterase inhibitor) before, during or after the phase 3 trial? Given the present findings of the phase 3 trial, would you ( if you were allowed under your clinical agreement under the open label) stop AD medications if you were taking them during the phase 3 or were taking them now?   

What is your approximate MMSE or AD staging?

What testing have they done while you have been on the open label extension? Has the cognitive testing changed on the open label extension? clinicaltrials.gov suggests that the cognitive testing stopped for those on the extension. There would be no way to learn anything from the open label without on going cognitive tests. 

You said that you have been on the phase 3/open label for over two years. Did you go onto the open label once you completed participation in the phase 3 trial?

While you were in the phase 3 trial did you (or any of your family/friends) notice any stabilization in your dementia progression?

While you have been on the extension have you or your family/friends noticed any stabilization or change in your dementia progression compared to when you were in the phase 3 or before entering the phase 3?

What did you mean by there being "a couple of tests going"? Has taurx asked you to do an amyloid scan?

Please keep us updated! There are quite a few people interested in this.

 


remembering
Posted: Monday, August 1, 2016 12:15 PM
Joined: 4/29/2016
Posts: 12


kwc, here is the MMSE test. Ask someone to ask you the questions or give it a try by yourself.

What was your score?

 http://www.mountsinai.on.ca/care/psych/on-call-resources/on-call-resources/mmse.pdf

 


kwc
Posted: Monday, August 1, 2016 12:58 PM
Joined: 5/22/2014
Posts: 37


I get that test every time I go to Memphis when I was on the blind study for two years I also have a MRI and PET scan several while On study  I went about every two months for that now I am on the open label but I still get that test along with other stuff but with both studies they take blood work also every time    They are very thorough with me plus them may ask my wife different things. She's probably telling on me  LOL I go back August 9 and in light of all this it was sit  down with my wife and my doctors just explain what all is going on but that one study  LMTM they have 15% out of a large number that had non  positive results very small number and then study was for mild to moderate Alzheimer's study that I was On LMTM not sure exactly exact details but just about the same as the other drug only this one is for  mild  ALZHEIMERS  hope this helps
remembering
Posted: Monday, August 1, 2016 2:30 PM
Joined: 4/29/2016
Posts: 12


Thank you kwc!

There is still quite a bit of uncertainty about what is going on what this study.

When you were in the phase 3 were you taking other AD drugs ( such as mematine or Aricept)?

Are you taking these drugs now on the open label?


kwc
Posted: Monday, August 1, 2016 3:32 PM
Joined: 5/22/2014
Posts: 37


aricept and I have been taking this the whole time. Since I have been on with this I have been status quo.  I am happy with the results so far
remembering
Posted: Monday, August 1, 2016 4:36 PM
Joined: 4/29/2016
Posts: 12


kwc, have you heard that the results for the first Mild-Moderate Phase 3 reported a substantial benefit in those taking only LMTX? It is not clear if this is a true treatment effect or only related to study design. The same result appears to have emerged in the second Phase 3.

The big question is: Would you stop standard of care, in order to obtain the supposed benefit of monotherapy LMTX? Have they suggested this to you yet?

(By the way there is some great news on the way with CPC-201. Quadruple strength Aricept. All the benefits of Aricept at high doses without the side effects.)     


kwc
Posted: Monday, August 1, 2016 5:55 PM
Joined: 5/22/2014
Posts: 37


I will know more about all this after my visit  there is a lot of TALK out there now 

I worked for a major drug company for 27 yrs and would expect nothing less I will do according to  what I am told by my Drs an staff. 

No I am not going off aricept   The trial I was on RESULTS HAVE NOT  BEEN RELEASED YET I do know that an can say


remembering
Posted: Monday, August 1, 2016 9:15 PM
Joined: 4/29/2016
Posts: 12


kw, sounds like you have it all together (probably a lot more so than the rest of us). Will be very very interested to hear what you have to report over the next while.
kwc
Posted: Tuesday, August 2, 2016 7:23 AM
Joined: 5/22/2014
Posts: 37


No.  I just have a very good wife of  29 yrs  and very much appreciat. she got me into this study. And I feel fortunate I have some good Drs. In Memphis.  I like everyone else take this ALZ  day to day
remembering
Posted: Thursday, August 11, 2016 10:04 AM
Joined: 4/29/2016
Posts: 12


kwc, I'd loved to hear an update from your last doctor visit for the LMTX extension trial.
kwc
Posted: Thursday, August 11, 2016 5:48 PM
Joined: 5/22/2014
Posts: 37


The study that I am on the results will not be in until about the first of the year   I am on I believe it is 005 study  for mild  az  we opted to continue knowing the results of the other one  I go back mid November,  they did up my dosage   Which they were planning on doing anyways not much new that we had not already been told

My doctor did get real technical going into the details of the workings of the bill versus the other ones and what not I forget all that stuff,  like before I even got out of the office  lol


remembering
Posted: Saturday, December 2, 2017 12:24 PM
Joined: 4/29/2016
Posts: 12


kwc, still on LMTX? This one is getting interesting.

 Amazing! This one looks like it is going back into trials.

I had thought that the original phase 3 trial design was so flawed that LMTX would be abandoned. Apparently not.

The concurrent use of AD medications is suggested to have interred with the action of LMTX. The company is also suggesting that a 4 mg is closer to optimal than dosing at 100 mg or higher. Basically the placebo was the treatment and approved treatment counteracted the benefit. Seems like drawing the target after throwing the dart, though if this all works out why quibble? 

http://taurx.com/uploads/press%20releases/JAD_005_Press%20Release_website.pdf

https://content.iospress.com/download/journal-of-alzheimers-disease/jad170560?id=journal-of-alzheimers-disease%2Fjad170560


mr.mac52
Posted: Friday, December 7, 2018 4:32 PM
Joined: 3/7/2012
Posts: 2


I would like to revisit this topic, LMTX in the Phase 3 trial.  It would appear that any chance of my receiving any further doses of LMTX has ended for me.

I was in this trial and received the placebo dosage of 4mg twice a day for 18 months.  I know this was a placebo dose as I had a weak show of blue in my urine for the 18 months.  My trial doctor during this time would ask me if I had really taken my drug or not given the pale blue color of my urine.

During the trial, on the placebo dose, my cognitive abilities continued to decline.  I have been gifted with what is commonly referred to as cognitive reserve and I was getting close to the end of this phase of my illness.  I could see the edge of the cliff and was frightenly close to falling off the edge.

After the 18 months was over, and my one-month wash-out was also over, I was promised access to the full strength LMTX.  There was one or two months of delay as I was the first one in my area to complete the full 18-month study and there was training for the local doctor’s staff on managing the open label extension.

Once that was worked out, I was started on the 100mg b.i.d. dosage, twice per day.  After I completed the first 90-day interval I was allowed to increase this to 100mg t.i.d. dosage, three per day.

I went into this open label phase expecting a light bulb to suddenly turn on given how the LMTX is supposed to work.  It did not happen like that.  I did not improve for what seemed to me, a long time, some 6 months in my case.

I went a saw one of the new Star Wars movies, the first in the new series.  Several months later I watched it again when the blue-ray media became available.  I expected to remember the story line pretty well and was shocked that I did not remember any of the story line at all.  About 3 months later I watched it again and did remember the story line, I think from watching the blue-ray version.

About the same time, I watched the blue-ray media the first time, a stunning scientific event was announced.  For the first time ever, Einstein’s Theory of Relativity concerning gravity waves was verified.  I’ve fallowed progress on proving out more of Einstein’s Theory of Relativity all my adult life and this was one of the stellar examples of his genius to be proved in my lifetime.

So, after around a year of taking the full strength LMTX dose, I was getting better, much better.  I started planning on doing things that I had given up on.  I was building a woodworking space in one of my barns and started turning projects.  We started talking about where we wanted to travel as I was clearly remembering recent things.  Life was looking up for me.  I would say that the year and a half I had access to the full strength LMTX, I gained back close to 4 years of my cognitive decline.

Then, after signing a 5-year term Informed Consent, the drug was pulled away with absolutely no notice.  The next time we reported for our 90 day check in, my unused LMTX was taken away and nothing was available to continue with.  We were read a statement from the firm that administered the trial that the use of the full strength LMTX was over and there might be in the near future access to the placebo dose. 

We’ve spent a lot of time and energy tracking access to the placebo dosage and after nearly two years, have nothing to show for it.  We keep hearing from my study doctor that access to the placebo dose is coming any day now.  We know that the study for the placebo dose is currently running but we are not any closer to getting access to the placebo dose.

You might wonder why I call the current trial a placebo dose.  The original LMTX trail used a watered-down dosage of the investigational drug for the placebo dose of 4mg b.i.d.  If you read about FDA approved drug trials, you never see any one using a watered-down version of the investigational medicine.

Furthermore, the measuring tools to track my progress in the LMTX trial was appropriate for late stage AD sufferers, not early to mid-stage in the recruitment documentation.  By not using tools to measure actual progress by members of this cohort, the data analyzed did not demonstrate any improvement.  In addition, there was no opportunity to report back to the organization what result I was seeing in the open label extension.

So, to sum it up, I feel that a strong dose of the full strength LMTX made a tremendous difference in my life and I’m very disappointed to see what I perceive as mismanagement of the LMTX trial I was involved in.

I welcome any and all comments on the above and will answer any questions posed to me about it.

John