Alzheimer's Cured by Methylene Blue Celebration Thread!

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J11
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

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Full Press Release.

https://taurx.com/news-insights/taurx-a ... ubmissions



PRESS RELEASE

TauRx Announces Results from Phase 3 Alzheimer’s Disease Study, LUCIDITY, Assuring Path for Regulatory Submissions

• For people with early Alzheimer’s (MCI), HMTM treatment resulted in sustained improvement in cognition over pre-treatment baseline, and normalisation of brain atrophy to a rate similar to healthy individuals

• For people with mild to moderate Alzheimer’s, HMTM stabilised cognition and function and reduced rate of brain atrophy compared to historical matched individuals with AD

• HMTM is an oral drug with a strong safety profile, having no risk of amyloid related imaging abnormalities

• TauRx will present the Phase 3 findings at the Clinical Trials in Alzheimer’s Disease (CTAD) conference on Wednesday, 30th November 2022, in San Francisco

Aberdeen, UK and Singapore, October 6, 2022
TauRx Pharmaceuticals Ltd is a global leader in tau-based research in Alzheimer’s disease (AD). Pathological aggregation of Tau correlates with clinical disease severity and brain atrophy. It is a hallmark of the disease now generally recognised as an important potential target for treating AD.

Hydromethylthionine mesylate (HMTM) is a potent inhibitor of Tau aggregation pathology which is taken orally. The Phase 3 LUCIDITY study compared HMTM 16 mg/day with methylthioninium chloride (MTC) given at a dose of 4 mg twice weekly, the minimum required to prevent bias arising from potential urinary discolouration. The study was conducted in 598 patients with AD severity ranging from Mild Cognitive Impairment (MCI) through to the moderate stage of disease.

TauRx has now completed the first 12-month double-blind phase of the trial. The second 12-month open label period is ongoing, during which all participants receive HMTM 16 mg/day. All participants were required to have a positive amyloid-PET scan and not to be taking standard symptomatic treatments for AD.

Of those receiving MTC 4 mg twice weekly, the majority were unexpectedly found to have blood levels of active drug above the threshold needed to produce a clinical effect. In the absence of a true placebo, the trial as designed could not determine outcomes on primary clinical endpoints relative to a therapeutically inactive placebo as prespecified. In light of the evidence now available, TauRx does not believe that a valid blinded placebo-controlled trial of HMTM with clinical endpoints is technically feasible. TauRx has therefore analysed the data in terms of the relationship between blood concentration of drug and treatment effect, change from pre-treatment baseline, and comparisons against historical controls available from closely matched data from the Alzheimer’s Neuroimaging Initiative (ADNI).
The overall baseline MMSE score was 21 for the study population spanning MCI through to moderate disease. There was minimal decline over the first 12 months in participants receiving the 16 mg/day dose on both coprimary cognitive and functional endpoints (1.3 ADAS-cog11 units and -1.0
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www.taurx.com

ADCS-ADL23 units). The expected decline over 12 months in an untreated population would be approximately 5 units on both scales.

In the 105 participants with MCI (baseline MMSE score 23) receiving the 16 mg/day dose, there was statistically significant cognitive improvement of 2 units over the pre-treatment baseline at 6 months (p=0.0002), 12 months (p=0.0391) and 18 months (p=0.0473) on the ADAS-cog13 scale. The mean change on the instrumental activities of daily living subscale of ADCS-ADL also remained above the pre-treatment baseline at 6, 12 and 18 months.

In the 147 participants with mild to moderate AD (baseline MMSE 20) receiving 16 mg/day, there was a 2.5 unit cognitive decline in the first 9 months and no further decline over the following 9 months. The functional decline on the ADCS-ADL scale was -2 units at 12 months and -3 units at 18 months representing a reduction in decline of about 75% relative to a published meta-analysis of publicly available placebo decline data from historical trials in mild to moderate AD.

Statistically significant reductions in disease progression as measured by change in cognitive function (p=0.0008) and brain atrophy (p<0.0001) were confirmed by comparisons of participants receiving the 16 mg/day dose against ADNI subjects who were closest to the study population by age and clinical severity. The differences remained statistically significant in both MCI and AD subgroups. As expected, LUCIDITY trial participants with MCI entered the study with more brain atrophy than ADNI healthy aging subjects and consistent with ADNI MCI subjects. Those treated with HMTM 16 mg/day had a rate of progression of brain atrophy that was significantly less than in ADNI MCI subjects (p<0.0001) and comparable to that seen in ADNI healthy aging subjects.

Recent trials that have tested treatments targeting amyloid have been conducted in comparable or milder populations than the MCI group in the LUCIDITY trial. When HMTM is compared to publicly available placebo decline data from these studies as a benchmark, the treatment effects on cognitive and functional decline are about three-fold larger over 18 months. The benefit seen with HMTM is clinically meaningful for people with Alzheimer’s.
The safety profile seen in LUCIDITY remains strong and consistent with earlier published HMTM trial data. There were no treatment-related serious adverse events or evidence of amyloid related imaging abnormalities (ARIA).
On the outcome of the current data analysis, Professor Claude Wischik, Executive Chairman and co-founder of TauRx, explains, “This is the first time any treatment has produced evidence of sustained improvement over the individual’s own pre-treatment baseline lasting 18 months at an early clinically detectable stage of AD, and stabilization of disease progression at more severe stages. The results in AD confirm published findings from two earlier HMTM Phase 3 trials. The availability of an accessible oral treatment which does not require expensive monitoring over routine clinical care opens up an opportunity to intervene before the onset of the cognitive and functional decline that lead to loss of independence.

“Tau pathology of the disease is now recognized as an important target for treatment, and it is encouraging that cognitive improvement is seen at such an early stage of the disease with a drug targeting Tau. The field has focused mainly on amyloid as a target for early intervention. Our data are consistent with the evidence that Tau pathology begins at least 20 years before clinical symptoms appear and is a viable first-line target for treatment.”
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www.taurx.com

To assist with next stages, TauRx has appointed strategic regulatory advisors in the UK, US and Canada, alongside naming Dr Richard Stefanacci, an established global key opinion leader in Alzheimer’s, as Chief Medical Officer. Dr Stefanacci is a US-based Internist and fellowship trained Geriatrician who is an active physician caring for people with Alzheimer’s daily.

Dr Stefanacci commented: “These data support our ability to pursue regulatory submissions. We look forward to making a significant difference addressing this global unmet need with a medication that is affordable, easy to administer, and safe. I’m very pleased to be joining the team and supporting the work we’re undertaking to achieve our mission of bringing treatments to people affected by neurodegenerative diseases caused through protein aggregation – Alzheimer’s is just the beginning.”

On the appointment of Dr Stefanacci, Professor Claude Wischik said, “This is an exciting time for TauRx, and we are very pleased to welcome Dr Stefanacci as our Chief Medical Officer. His joining the dedicated team at TauRx is testament to our science and prospects for the future success of the company in helping to transform the lives of people with Alzheimer’s and other neurodegenerative conditions, as well as the caregivers supporting them.”
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

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Phase 2 a.PNG
Cognitive 3.PNG
Dosing 5.png
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

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Here are some of the details. As we see in the figure above, there was a 3.7 benefit on ADAS-cog 11 at week 52 on the total population. The historical control suggests that this decline should be 5 points. This represents a 74% slowing of decline on treatment. Also see above is that for the MCI patients there was actually a 2 point improvement on treatment at the difference time points. MCI patients got better on LMTM?

The problem with the results though is that it appears on the as specified statistical plan LMTM did not report out positive. The company explains this is due to the placebo not being a placebo! Apparently even 4 mg twice a week (the placebo dose) also had a therapeutic effect. This could be another migraine inducing type think through. The company
is working around the miss on the topline by thinking in terms of slowing of decline of patients versus historical placebo. There will be another 600 patient years of treatment results as of January so that will be helpful.

This was reported last week, so I am somewhat late in noting these important results. It takes no great imagination to realize that combining a mab with LMTM would probably be an extremely powerful treatment combination. Notably, the press release mentioned that LMTM treatment was devoid of serious side effects and instances of ARIA.
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

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FrankT
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Post by FrankT »

New to this website. Where can one purchase the methylene blue that's shown promise? THx, FrankT
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

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FrankT wrote: Thu Oct 27, 2022 12:55 pm New to this website. Where can one purchase the methylene blue that's shown promise? THx, FrankT
Welcome to the ApoE4 Forum, FrankT. I'm not sure where you can purchase this particular form of methylene blue as referenced in the posts by j11. I suspect it may still be in clinical trials. You may want use the search engine on our site, PubMed, and the internet at large to find a reputable source..

As this is your first post on the forum, I'd like to welcome you and make sure you are aware of the various resources available. The Primer was written by Stavia, a member, physician and carrier of two copies of the APOE-ε4 allele. This page provides accessible science background and prioritized sensible preventative measures.

Another good resource is the WIKI. I did a preliminary search for methylene blue and didn't find anything, but there is a lot of useful information there, nonetheless.

One of the strengths of this forum is the community of members. Check out Our Stories to learn about the experiences of other members. If you so choose, please feel free to share your story there, as well. I am certain the support and sense of community you will find there will be very helpful. From a community standpoint, if you're a Facebook user, there is also an ApoE4 Info Facebook page. Here you will also find summaries of new research.

As a welcome intern, I hope I have given you a good place to begin searching for an answer to your question. If you're anything like me, the more you search and read, the more questions you will have. Please feel free to post your subsequent questions. I look forward to hearing from you in the future.

Best,
Kathleen
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

Post by J11 »

FrankT, thank you for posting.

I am glad to see that you are paying attention; yes methylene blue -- leuco-methylene blue has clearly posted exceptionally strong results. There was the phase 2 trial with MB that had very strong results. Then there were 2 AD phase 3 results with leuco-MB that were also exceptionally strong (one of these trials had a reworked statistical plan gleaned from the nature of the blocking of response by traditional AD medications-- this trial reported strong prospective statistical significance) ... now there is another strong result with Lucidity using low dose leuco-MB. All of these results have demonstrated similar treatment effects. A phase 3 in China is expected to begin soon.

Of course, it is highly impressive that treatment appears to have effect across a very wide range of AD cognitive impairment. I will be very interested to see how this could be combined with the anti-amyloid mabs. What one could see is that combined with leuco-MB mabs could be trialed at all stages of AD dementia, though likely with much less aggressive dosing. The idea could be that the MB would act to strongly control the cognitive symptoms and the mabs would be there to act directly on the disease progression.

MB offers the startling potential to possibly reverse even very severe dementia. If tau is dissolved by MB, then one clearly does start to wonder whether a "reawakening" from severe AD might even be possible. That would truly be an unforgettable moment in the history of AD clinical science. My hope is that leuco-MB will be cleared through the regulatory process and that trials for end stage AD could then begin.

Problem of course is that there was another murky readout in the latest trial. The pure science types will not be happy that the primary topline as described by the statistical plan has not been reported but has been post facto changed to historical controls. Yep, I am seeing another ADCOM; better put out some help wanted ads-- could be interesting. I don't know if I can take another ADCOM, I am thinking perhaps I should retire from the thread before that point.

In terms of access, the press release talks of this going to various regulators next year. There are already brands of MB that have been medically approved and perhaps could then be used off label (might want to chemically modify it to the leuco form). There is also the online purchase route, though now the fish tank brand is perhaps best avoided.
taurx has sent out signals that they envision this to be an accessible medicine, so given the choice I would go with their product. They have put a great deal of effort into formulating it etc. and I would feel better knowing that I was dosing with a highly researched product. It is still somewhat surprising to me that they have not tried to do some fancy nanoformulations. For those skilled in the art there would seem to be many such approaches that could give exceptionally power results possibly down to nM. Considering all of the blue pee placebo problems that they have had it is surprising that they haven't already done this -- with properly formulated nanomolar dosing there might no longer even be blue pee to worry about in the treatment arm.
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

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Thanks for the excellent information on MB. We have and use MB for different purposes - it provides a fascinating broad range of benefits - and it was interesting to see the posts on MB for AD. We use the BioPharm MB USP, 1% formulation purchased via AMazon. This company - https://www.macsenlab.com/blog/methylen ... lzheimers/ - offers an MB product, but very expensive - $410 for 50 grams of MB powder. Their webpage on MB and Alzheimer's is interesting.

In a few days I'll post some info about transcranial photobiomodulation (tPBM) using either the Dermalume or Weber Medical infrared helmets or the Vielight head-mounted red light device. I recall Dr. Bredesen mentioning the Vielight device briefly in his latest book as an example of this kind of technology.

My wife and I use the Weber Medical helmet, 30 minutes, 3 times weekly, along with oral EGCG taken that day. Apparently, EGCG is the best photoactive substance to be activated at the 810 nm range level, which is what the Weber helmet produces.

MB is also a photoactive substance, but is activated - and don't take this to the bank - I'll have to check somewhere in my various notes - but believe it's activated in the 600-something nm range ... which won't penetrate the dura mater.

Weber and other source data advocates 810 nm as the most effective range to penetrate the dura mater and produce results. If there is a way to attach a users manual, I will attach the Weber Users manual that describes the various protocols suggested for Improving Cognitive Function, Depression, Anxiety, Alzheimer's and Dementia, Parkinson's, Addiction, TBI, and PTSD.
Regards, Frank T
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Re: Alzheimer's Cured by Methylene Blue Celebration Thread!

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While methylene blue came to our attention via several articles and papers, my wife and I have found Mark Sloan’s book to be a handy quick reference: “The Ultimate Guide to Methylene Blue: Remarkable Hope for Depression, COVID, AIDS & other Viruses, Alzheimer’s, Autism, Cancer, Heart Disease, Cognitive Enhancement & The Great Transition to Metabolic Medicine,” May 14, 2021.

Our initial interest in MB was because of its’ antiviral and pain relief properties and we’ve been pleased to see how broad its’ value is. And to think this product started life over 100 years ago as a dye for textiles.

Among other studies and references related to using MB for Alzheimer’s and Dementia, he writes about the patented form of MB called LMTX by the TauRX Pharmaceuticals (page 72).

Here’s the book’s Table of Contents:

Part I: Nitric Oxide & The Origins of Disease
Nitric Oxide: Miracle Molecule or Aging Accelerant?
Gene Therapy Failure & The Future of Medicine

Part II: Methylene Blue – The Great Nitric Oxide Inhibitor
Meet Methylene Blue
Top 10 Benefits of Methylene Blue
1. An Antidote for Chemical Poisoning and Overdose
2. The Greatest Anti-Malarial Drug Ever Discovered?
3. Methylene Blue: The Virus Warrior
4. Forget Dementia: MB vs Alzheimer’s and Parkinson’s (page 67)
5. Cognitive Enhancement: A Brain-Boosting Powerhouse (page 76)
6. Depression No More
7. Hope for Autism
8. The Great Pain Reliever
9. A Healthier Heart
10. Methylene Blue vs Cancer
The Methylene Blue Battery
Methylene Blue for Dogs, Cats, Cows, Fish and Horses
Safety, Dose, & Where to Get Methylene Blue?
Conclusion

General Safety Guidelines (page 126):
• Methylene Blue should not be taken with SSRI medication
• Methylene Blue should not be given to babies
• Do not use methylene blue if you’re pregnant or breastfeeding

Another major caution: there are three grades of MB – Industrial (dye fabrics); Chemical (lab experiments, stain slides, etc); and Pharmaceutical Grade. Pharmaceutical grade is identified by the USP designation. Only use the pharmaceutical grade for human purposes, whether you’re using it topically or internally. (page 120)

Pay attention to dosing. As Paracelsus said 500 years ago “The dose makes the poison.” As Sloan states “MB exhibits very different effects at low doses than it does at high doses. They call this a ‘hormetic drug response,’ where the effects of a low dose are the opposite than a high dose.” (page 119)

Dosing suggestions start on page 123.

Sources/Options for MB
We have been using the BioPharm MB USP, 1% formulation ($145 for 250 ML) and we’re switching to the brand that Sloan recommends, made by Compass Labs ($145 for 237 ML). We’re willing to pay a little more for the glass bottle versus plastic of the BioPharm product. We order through Amazon for convenience although there are several other ordering options.

A third alternative is the USP Grade Methylene Blue Powder - 1 gm of the powder for $30. You mix the 1 gram in 100 ML of water and shake well, which produces 100 ML of a 1% solution. So that’s about $75 for 250 ML.
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