Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

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J11
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Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

Post by J11 »

Cheer up everyone!
The winter has been cold and dark, but there could be good times ahead for the AD community.

The Phase 2 clinical Trial for Methylene Blue has finally been published (8 years after the end of the trial!!).
The results are very impressive. AD progression was essentially halted in both mild and moderate AD patients over a
period of up to a year (though the trial ran for a first period of 24 weeks and then was extended out).
There was some confusion about the higher dose not being as effective as a lower dose. After extensive study it was determined that the higher dose, strangely, had less effective dosage than the lower dose (see article for the explanation).

The trial did have some problems. For example, a small group of patients continued on with the study after 50 weeks. This introduces the
problem of selection effects. Many other AD trials with positive sub-group analysis wound up disappointing in phase 3. The explanation for the problems with the high dose group is post facto. Despite these potential drawbacks the results give reason for optimism. It will not be too long before we know the results of trials that we have waited almost ten years for.



http://iospress.metapress.com/content/x ... lltext.pdf
(open access article)

http://www.ncbi.nlm.nih.gov/pubmed/25320049

Large phase 3s in mild and mild to moderate AD will end this year and next with a new formulation (LMTX) abd a higher equivalent dose
than used in the published phase 2 study. LMTX is thought to be a more effective formulation for the drug. There is reason to expect if the original findings can be verified in the phase 3s that results could be very impressive. It might be possible that disease stabilizations (or even reversals) over the course of a 65 week treatment period will be reported when the trials read out.

Such results could (and should) invite the bandwagon of special interests to step forward and offer support. AD costs the world economy at least 1 billion dollars (approaching 2 billion dollars) per day. It is projected that America is approaching a 1 trillion dollar per year AD treatment cost (which would not be economically supportable). Positive LMTX results would hopefully encourage deep pockets to advance a wave of research. (For example, the results seem positive even for moderate AD, a study that tested into advanced AD would be extremely welcomed by those coping with that level of severity).

It would be very helpful for funders to recognize that such a result would extend beyond the scope of a single biotech advancing a product to market. It would be in the self-interest of the world community to offer collective material assistance to advance such a product to address all stages of dementing illness.
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Re: Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

Post by sarahb12 »

That's pretty interesting. I wonder if it would be tolerated ok in people with teh COMT variation or low MAOA variation. In the case of COMT and overmethylating, I wonder if there could be a countermeasure such as niacin to use up extra methyl donors.

In any case, it sounds promising. I also wondered if the methyl blue works just as well as the pharmaceutical formula and the formula is just a way to extract money from patents.

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Re: Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

Post by J11 »

I am not sure about the COMT genotype tolerance. The phase 2 article did note that there was some trouble with side effects, though these might be less of a problem with the new formulation. It is exciting that this is the first drug ever tested against tau in AD and it appears to have had a large effect. Dr. Alzheimer noted two hallmarks of Alzheimer's disease over 100 years ago: amyloid and tau. It is disappointing that amyloid occupied so much of the research effort while repeatedly disappointing in clinical trials, while tau seemed to be constantly ignored. It had been understood for years that amyloid did not track well with cognitive decline while tau did.

The patent issue does lurk with methylene blue. Methylene blue is apparently one of the oldest of all modern medicines. It predates the FDA! It is used for a variety of applications and seems unlikely to be patentable for AD. However, it is not entirely clear that LMTX would be a much better patent candidate. Internet reports suggest that converting methylene blue to LMTX would be simple.
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Re: Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

Post by Kim »

Could someone explain what Methylene Blue is, or link an article please? I am unfamiliar with it.

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Re: Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

Post by rep »

J11 - You say
The patent issue does lurk with methylene blue.
but then what you go on to say makes it seem that it would NOT be patentable. I don't understand. Would you clarify? It seems to me that methylene blue might actually be affordable if proven to work since it would NOT be patentable. So why do you say "The patent issues does lurk?"
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Re: Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

Post by J11 »

Here's a link to a methylene blue discussion.

http://www.longecity.org/forum/topic/51 ... -products/

The site notes that the new form of methylene blue used for the AD trial is leucomethylene blue which is the reduced form of MB.
This form can be made by adding Vitamin C to methylene blue until it turns clear. (This is described in detail on the above url [near the end of the thread].)

The patentability of MB seems murky for use in AD. MB has been used in other indications (for example, malaria) and as fish tank additive.
The above url notes that many of the users were sourcing MB from pet stores. MB is also widely used in chemistry labs. One question that arises is how could such a widely used substance have an enforceable patent. Patents might be granted, though it appears that distribution can work around the patent.

This topic deserves to be fully considered and discussed on this forum. Halting the progression of mild and moderate AD is a very important achievement. If the phase 3 trial confirms the phase 2 result the lives of many on this forum will be transformed. It is quite possible that giving MB before overt dementia onset would entirely prevent progression to dementia.
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Re: Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

Post by Julie G »

I'm really intrigued, J11. Thank you for bringing this to our attention. I've been able to learn that this works by enhancing mitochondrial function- Hello!!! :D No wonder it's been helpful. However, I'm fairly clueless as to the mechanism behind HOW it works. I'd love to have someone help me understand that. Initially, I wondered if it was a form of ketone ester...but it appears not to be.

I wish the full-text study you had linked would have separated the subjects by APOE status. Regardless, the results were pretty impressive for a specific subset at a specific dose- important clues there. Seeing as how it wasn't as helpful for mild cognitive impairment with a smaller dose, it makes me think the tau clearance may be a bigger factor than mitochondrial enhancement. But, who knows at this point? I want to learn more!
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Re: Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

Post by J11 »

Yes, separation by APOE4 genotype would have been welcome to members of this forum. I am not sure why that was not done (it seems the obvious thing to do). It would not be unexpected that such a separation would have found even more compelling results, as they have found in many of these trials that up to 30-40% of Alzheimer patients in Alzheimer trials do not have Alzheimer's disease!

Such non-patients add noise to the results and dilute any treatment effect. This might be especially true in the mild patients as a firm diagnosis might be difficult for them. Long term non-progressors in an AD trial especially for the moderate ADs might contribute to the statistical analysis to a lesser extent than progressors. APOE4s are a more homogenous group with a more defined decline trajectory.

The phase 3 trials have measured APOE genotype. It would be also very interesting if they were to do full genome scans for the people in the trial. The current full genome price of $1000 would seem to be justified in such a trial. Much of the genetics of AD is now known. Being able to remove any noise from the dataset would be very helpful.

I am glad, though, that APOE was not included in the phase 2 report. So many phase 2 trials included such ad hoc results that were later shown to be inaccurate. They often did this when they did not hit the top line number and so they went data fishing. Doing enough such post facto comparisons would certainly yield something erroneously positive.


The article notes that the placebo group of mild patients did not deteriorate at 24 weeks, so the treatment groups could not show a relative improvement. However, at 50 weeks the mild patients had achieved a substantial relative benefit versus placebo that was more statistically significant than that achieved by the moderate group (even though the moderate group achieved a larger absolute gain over placebo).

The moderate AD trial actually includes mild to moderates with MMSEs of 14-26. It would probably make considerable sense in such a trial to make it adaptive. Finding the right group of AD patients to treat with the drug might save a large headache later.

The mild to moderate trial is now already past week 24 after full enrollment so the trial result (as per the phase 2 result) should already be statistically significant. If so, it would be amazing if they were to call an early end to the trial. All the patients could then be switched to active treatment. Perhaps an open access program could start up.
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Re: Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

Post by J11 »

I just had to bump up this thread. It is too important to let it just move to the second page.


The Taurx website has some provocative quotes about tau.

"In the neocortex, for example, there is evidence of Tau protein aggregation and loss of neuronal function from Braak stage 2 onwards, but tangle-mediated cell death is not seen in the neocortex until Braak stage 6." [It is noted below that 100% of the population will attain Braak Stage 2 or higher by age 90.]

http://taurx.com/alzheimers-potential-f ... ntion.html


Consider:

Page 6, "... attempted to devise a staging system based on the beta amyloid pathology of AD but showed that this was not possible because it appears to be a general feature of the aging brain and does not appear to follow any clear pattern of progression or spread."


Page 6, "... the time interval between Braak stages 2 and 4 is about 20 years. There is therefore a long pre-tangle preclinical and early clinical period during which therapeutic intervention..." (This research dates to the early 1990s!)

page 8 of the pdf .... Figure 11.4 A shows MCI starting at Braak Stage 2-3.3, Mild AD at 3.3-4.5 , Moderate 4.5-5.2, and Severe at 5.2-6.

page 9.. Here is an especially interesting quote "This indicates that, ... the entire process is clearly embedded within the blueprint of the general aging human population and regardless of specific genetic factors that may accelerate the process in some. "


page 10.. Figure 11.6 shows the probability of attaining a given Braak Stage as a function of age. At Age 90, 100% were Stage 2 or higher.


Why haven't human prevention studies already started? It will take years, perhaps a decade, to work through prevention clinical trials. There might not be any clinical knowledge of dosing etc for such prevention.

http://taurx.com/uploads/RSC_Chapter-hd%5B1%5D.pdf


Also,
http://taurx.com/scientific-publications.html
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Re: Methylene Blue Phase 2 Results Published Finally- Halts Progression of AD

Post by LanceS »

Juliegee wrote:I'm really intrigued, J11. Thank you for bringing this to our attention. I've been able to learn that this works by enhancing mitochondrial function- Hello!!! :D
Has also had some success with certain cancers. Metabolic theory of cancer is controversial I understand. But this would be consistent with mb enhancing mitochondrial function. I didn' t look too much into it but if you can stabilize or reduce tumor size you can go from chemo to cure. Lots of interesting activity on the cancer front. Not much of it in the cure department.
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