AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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J11
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AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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The end of Alzheimer's?

Prepare for the celebration everyone!
I have already consumed my supply of cashews (they are so nice and tasty), so I will now have to restock. We have until June 9th when more detailed results are expected-- Prepare!

The number setup is all different with LMTM versus Aducanumab; with LMTM it is more focused on FDG PET and less on maximal dosing. Of course, the combo LMTM and AB mab is now firmly on the table-- such a combination could be quite powerful; it could stop the upstream driver (i.e. amyloid) while also blocking the downstream effects (tau and mitochondria).


News Headline

taurx has qualitatively reported initial results for the phase 3 Lucidity: Positive!


From two previous phase 3 LMTM/MB clinical trials in Mild and Mild and Moderate AD there were massive massive treatment benefits-- approaching full clinical stasis for a year or more (see Methylene Blue Celebration Thread). When they say "substantially less" decline -- they mean it; previously we saw ~85% reduction in decline.


Press release

" Tau-targeting Alzheimer’s treatment, HMTM, moving toward regulatory submission based on initial data from TauRx’s LUCIDITY trial

• LUCIDITY data suggest that participants receiving hydromethylthionine mesylate (HMTM) decline at a rate substantially less than is typical in Alzheimer’s based on published research
• Safety profile is favourable and consistent with previous HMTM studies
• TauRx will now pursue regulatory submission and coverage for HMTM


Aberdeen, UK and Singapore, May 31, 2022 – TauRx Pharmaceuticals Ltd, the global leader in tau-based research in Alzheimer’s, today announced unblinding of initial data from completion of the randomised portion of their pivotal Phase 3 clinical trial, LUCIDITY (NCT03446001).
..."

https://taurx.com/news-insights/initial ... dity-study

Primary cognitive measures used in Lucidity were Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog11) and Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL23) for the 16 mg dose.
Last edited by J11 on Fri Jun 03, 2022 6:52 pm, edited 16 times in total.
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Re: AD cured? taurx reports positive results in Lucidity !!!!!!!!!!

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This result was from the phase 3 LMTM trial with Mild AD which reported a statistically significant result after changing the statistical analysis plan to make comparisons with the monotherapy group. (For some reason (explained in later research) concomitant treatment with other AD therapies blocked the benefit from LMTM). In below figure the monotherapy arms have n= ~80. As seen in the figures there were very large separations for the cognitive endpoints used.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734125/
P3 Mild AD.PNG


This result was from the phase 3 LMTM Mild-Moderate AD which while negative as reported, clearly the monotherapy group also had massive clinical benefit as with the phase 3 Mild trial. The A2 and B2 figures show very large benefits in those on monotherapy (i.e., not receiving standard of AD care add-ons).

https://pubmed.ncbi.nlm.nih.gov/27863809/
P3 Mild-Moderate AD.PNG

This result is for the phase 2 (?) methylene blue trial. This also showed a truly massive cognitive benefit.
(not sure of the source of this figure). As a heads up, the cognitive benefit to the AD patients in absolute ADAS-cog points at the 52 week mark (where Lucidity's primary measure is reading out) was not overly spectacular (It was 4 point decline to the placebo and 1 point decline to the MB group for a 3 point benefit at 52 weeks. This then extended out to a truly massive ~6 point benefit after 104 weeks. For taurx to report a substantial reduction in decline at 52 weeks with a smallish treatment group, suggests that the longer term followup will also report even larger benefits.

In the phase 2 80 patients were treated for 24 weeks at 138 mg/day MB. In a long term extension 49 of these patients continued on for 26 weeks of more treatment. In a second long term extension, 39 of the patients continued dosing at 138 mg per day and were treated for between 50-102 weeks total dosing. There were 16 other 138 mg per day patients treated out o 50-102 weeks though they converted from 69 mg daily dosing after 560 weeks. There were another 24 patients treated at 138 mg daily who converted from placebo after the 24 weeks of on trial treatment and then went to 152 mg per day treatment for 26 weeks and then were treated for 52 weeks at 138 mg daily. Which is all to say that the figure below has wide error bars exactly because the patient counts are so low. With Lucidity there were 598 patients treated for 52 weeks; presumably this means 299-299 split.



https://pubmed.ncbi.nlm.nih.gov/25550228/
P2 MB.PNG
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Re: AD cured? taurx reports positive results in Lucidity !!!!!!!!!!

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The phase 2 with methylene blue was confusing as the highest dose of 228 mg was not as effective as the 138 mg dose. This inconsistency was explained in later research. Notably in the phase 2 trial patients were not taking other anti-AD
medications.

https://pubmed.ncbi.nlm.nih.gov/25550228/
Phase 2 Dosing.PNG
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Re: AD cured? taurx reports positive results in Lucidity !!!!!!!!!!

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There was confusion about the dosing effect in the early MB clinical results. This figure helps to clarify dosing. Here there is an inverted u (an n?)-- too little LMTM not good; too much much LMTM not good -- just right LMTM is the best. The red vertical line shows the dosing of 16 mg per day used in the phase 3 Lucidity clinical trial. One certainly does wonder though whether increasing the dosage marginally might not be helpful -- perhaps up to 30-40 mg/day? There is that large question mark in the middle where they just seemed to assume that there would be a plateau.

The dosing results with MB/LMTM were remarkably confusing. The higher dose MB 228 was not absorbed properly so the 138 mg dose was the most effective, while with LMTM, the "placebo" 8 mg dose turned out to be an effective dose while those on add-on treatment only received 50% of the treatment effect because standard of care blocked the treatment effect of LMTM. Bayesian style adaptive trials could be so helpful in working out these confusions while clinical trials are in progress-- just let the trial supercomputer observe patient responses and adaptively learn what is best for patients. The supercomputer could see patterns that people might never think up. You could build in your priors, yet then just let the trial run and see how it goes --if the supercomputer finds that the placebo is the effective dose then just go with it.

https://pubmed.ncbi.nlm.nih.gov/31658058/

LMTX ADAS-cog Dosing Edit 1.png
The figure above was based upon the results from a large number of patients in the LMTM trials
~1300.
LMTX ADAS-cog Dosing Edit 1 Table.PNG
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Re: AD cured? taurx reports positive results in Lucidity !!!!!!!!!!

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There was also that problem that existing AD treatment (i.e., anti-acetylcholinesterase) seemed to interfere with the effect of LMTM. As seen in the figure above, the dots near the bottom are the results when patients were treated with approved AD medications.

Clearly, yes, there were a few curve balls involved.
First, there was the inverted u dosing effect. More is not better. [Unlike with Aducan and the other anti-AB mabs.]
Second, approved Alzheimer treatment greatly reduced treatment effect of LMTM. (Wonder if this also occurs with the mabs? There was some suggestion with the Aducan results that this was true, though this was unclear).

Taurx can now bank up and continue to work through these questions and perhaps also consider even better formulations for LMTM (nanoformulations?).

This is the article that explains the problem with co-treating LMTM with standard of care AD medicines.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403648/

I still want to stay away from mechanism of action because so often suggested MOAs turn out to be incorrect. It is of note nonetheless how much tau levels fell in the LMTM monotherapy treated mice.
Ache Effect 1.PNG
I generally really like these graphical abstracts as they are able to simplify long research articles. Admittedly, with this one I am not entirely sure what is going on.
Ache Effect 1 Graphical Abstract.PNG
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Re: AD cured? taurx reports positive results in Lucidity !!!!!!!!!!

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How do the taurx numbers compare to Aducanumab?

Aducanumab Emerge high dose reported (OTC n= 340) 25% and 27% (ITT n=547) slowing on ADAS-cog 13 and 46% (OTC N=340) and 40% (ITT n=547) slowing on ADSCS-ADL-MCI at 18 months.

In the previous LMTM research, ADAS-cog 11 showed 110% (88%, 122%) slowing of disease progression. Patients improved?

Clinical 3.GIF
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Re: AD cured? taurx reports positive results in Lucidity !!!!!!!!!!

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I was slightly unsure about these figures (best now that the results are in to stay away from confusions), though I was unclear whether the numbers were absolute or relative to placebo. It looks as though they are absolute.

As can be seen (the bottom panel is aligned to the top panel) LMTM produces a cognitive benefit that is off the chart in comparison to all other anti-dementing therapies.
LMTM Comparison 1.PNG
I have attached the Taurx January 2022 presentation with the figures above as the file appears to have been removed from the taurx website.
TauRx.presentation-latest-comparison-data.Jan2021.pdf
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Re: AD cured? taurx reports positive results in Lucidity !!!!!!!!!!

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This is the chemical structure for MB versus LMTM. Interesting how the sides pop up with LMTM and how the middle flexes with the extra H.
Chemical MB LMTM.png
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Re: AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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This shows the trajectory of neurodegeneration with aging. There are millions of 50 year olds that are right on the edge of clinical AD (Braak Stage ~2). With LMTM, it would seem to make a great deal of sense for them to be treated; though preventative dosing trials have not been done. (This is pdf page 15 from the above attachment)
Braak Stage 1.PNG
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Re: AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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I want to stay with a nice clean interpretation of these results as typical previous AD clinical trials have become extremely confusing. Migraine inducing, even. One concern I have from the press release is they appear to be comparing the Lucidity patients with historical controls --- " ... decline at a rate substantially less than is typical in Alzheimer’s based on published research. ..." https://taurx.com/news-insights/initial ... dity-study

That seems very odd to me. Lucidity was a placebo controlled phase 3 randomized trial. Why would they compare the reduction in decline in LMTM treated patients with historical controls? Why not just compare treated patients with placebo patients in the phase 3? This is quite confusing; I suspect it is simply a wording issue-- or perhaps in the early round of number crunching they simply wanted to focus on those on treatment as placebo treated AD patients decline at essentially a known rate.

Something else that seems odd is that the shares of Genting which has a large ownership position in taurx (Genting owns 20% of taurx) did not increase in value that much in the recent trading session. The share price increased 0.49 to RM 5.52 or 10.3%. The market capitalization of Genting is RM 20 Billion ($4.5 billion). ($450 million of increase in market capitalization on the news -- $2.25 billion for taurx as a whole (assuming Genting as a proxy for taurx valuation)). The shares trade in Malaysian ringgits (RM); the 49 sen increase is equal to ~10 US cents.

LMTM could treat ~55 million symptomatic AD patients along with ~~? 100 million pre-symptomatics. That's worth 10 cents??? LMTM is an oral medicine, with barely even minimal (if any) risk of ARIA; from what is understood there will be no great need for expensive monitoring with PET or other scans, diagnostic workup could be light and could allow for more off-label preventative dosing. How isn't that worth more?
Last edited by J11 on Sat Jun 04, 2022 9:49 am, edited 2 times in total.
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