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

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

Post by J11 »

I have read online comments that have questioned the claims of efficacy for LMTM. How could the LMTM results as published not be as how they appear? As highlighted in the below quote from the Mild-Moderate phase 3 clinical trial for LMTM, there were very very large clinical benefits for those on treatment versus those on placebo. While the patients were randomized, it is true that they were not randomized for the particular analysis that was eventually conducted; this adds some level of uncertainty to the results. Yet, the size of the benefits for those treated is extremely large. It is also notable that the 4 mg bid treatment arm was not receiving what is now considered the most effective dose of 8 mg bid which was the dose used in Lucidity.

"Clinical efficacy outcomes

The treatment comparisons for the co-primary outcomes
as defined in the Statistical Analysis Plan
finalized prior to database lock were significant at
the threshold of 0.025 for 100 mg twice a day as
monotherapy compared with all patients receiving
4 mg twice a day as randomly assigned (ADAS-cog
effect size –3.14, 95% CI –5.32 to –0.97, p = 0.0047;
ADCS-ADL effect size 3·49, 95% CI 0.66 to 6.30,
p = 0.0157 [Comparison A, Table 2a, Fig. 2]). The
treatment comparisons for the co-primary outcomes
were also significant at the threshold of 0.025 for
4 mg twice a day as monotherapy compared with
4 mg twice a day as add-on to approved AD treatments
(ADAS-cog effect size –4·22, 95% CI –6.19 to
–2.24, p < 0.0001; ADCS-ADL effect size 4.85, 95%
CI 2.31 to 7.40, p = 0.0002 [Comparison B, Table 2a,
Fig. 2]). A similar comparison between 100 mg twice
a day as monotherapy and as add-on therapy produced
similar results (ADAS-cog effect size –4·08, 95% CI
–6.07 to –2.08, p = 0.0001; ADCS-ADL effect size
5.27, 95% CI 2.70 to 7.81, p = 0.0001 [Comparison
C, Table 2b, Fig. 2]). There was no difference between
4 mg and 100 mg twice a day as monotherapy in the
corresponding monotherapy versus add-on therapy
treatment comparisons."



Potential of Low Dose Leuco-Methylthioninium Bis(Hydromethanesulphonate) (LMTM) Monotherapy for Treatment of Mild Alzheimer’s Disease: Cohort Analysis as Modified Primary Outcome in a Phase III Clinical Trial
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Re: AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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The first countdown came and went; let's try for a second time.
This one would seem to be more of a certainty for the results to be released.

https://www.timeanddate.com/countdown/l ... t=sanserif
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Re: AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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taurx intends to begin enrolling a phase 3 trial for LMTM in China in the 4th quarter of 2022. There are expected to be 400 patients with presumably 200 assigned to placebo and 200 to 8 mg bid. When you run these numbers through the online stats calculator with 75% patient retention at 52 weeks, the p-value is impressive even when the ADAS-cog benefit is only 2.5 points.

Lucidity seemed to somewhat overenroll patients at 598; the 400 patients in the upcoming phase 3 seems about right. It would be of interest to have more details of the trial. Will the patients receive 8 mg bid as was true in Lucidity? There could be value in exploring the dosing range from ~ 10 mg bid to ~ 20 mg bid. It is not obvious how much evidence taurx had when they determined that 16 mg was the optimal dose. All that we can see in the figures is this vast gap from ~ 10 mg daily dosing up to 100 mg daily dosing. It isn't clear whether 16 mg daily dosing truly is the optimal dose. In the upcoming phase 3 trial perhaps they could dose 3:1 in treatment and then explore to find the optimal dose.

A very effective trick that taurx has used before was to learn from one trial to the next. With the trial taurx could have a smallish lead in study that gathered some dose ranging research so that they would have some idea beforehand what they might find.
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Re: AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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I am not making that much progress in figuring out when exactly taurx might present its findings at AAIC 2022.
None of the plenary speakers seem to be devoted to LMTM; also not that easy to see where it would fit in with the scientific sessions. I think AAIC has late breaking sessions for releasing results like the Lucidity phase 3 which perhaps is where the results will be announced. We might have to wait to get closer to the conference to have a better idea about this.

Notably taurx is not actually a sponsor for AAIC 2022. The big sponsors have anti-amyloid mabs etc.; no LMTM.
taurx should do the right thing and sign up to be a bronze sponsor, throw them some money, get a bag of stale cheesies in the green room and report essentially a cure for Alzheimer's. I think it would otherwise be somewhat cheesy to just crash the party and not at least pay up; it would be a deductable so most of the bill would be paid by government anyways. Being a prominent sponsor at such a monumental meeting would seem to make a great deal of sense.

https://aaic.alz.org/about/future-scien ... etings.asp
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Re: AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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Other aspect of taurx that I now find interesting is how exactly the Chinese phase 3 will be conducted. I think this phase 3 could be a great opportunity to add in some innovation to the clinical trial process. Lucidity will essentially definitively answer the question about efficacy. It is always important with clinical trials to move the ball at least somewhat further upfield with every additional trial.

With the Chinese phase 3 one new aspect could be helping to clarify specifically how an Asian patient population would respond to LMTM. The initial results suggest that Asians are above average responders to anti-amyloids. This may or may not be true with LMTM. Amyloid and tau are different neuropathological features of Alzheimer's that might have differential racial responses.

Other features of the Chinese phase 3 that I am interested in having clarified include how dose ranging treatment might be incorporated; how the design might allow for a rolling finish type trial; how a lead in placebo registry phase might be attempted; how an adaptive treatment might be added etc.. There are a range of exciting potential tweaks that could be added to the standard vanilla trial design. Typically such variances are not tried because the risk for a negative or non-conclusive result or other irregularity are thought unjustified. Yet, after the Lucidity results are reported, there will largely be no uncertainty. This provides a near unique opportunity to take a free shot on goal and try something interesting. For example, probing the region somewhat above 16 mg daily dose of LMTM could find an even more effective dosage. Extending randomized dosing for those who started the trial earlier on would allow for treatment results past 1 year; those patients on placebo could be randomized to various which would maintain the blind and also give more insight into dose response.

One additional aspect of LMTM that I have thought as being of interest is how it is able treat tau pathology which is central to other neurodegenerative illnesses. It has also been noted that Alzheimer's itself should likely not be considered a truly separate illnesses from these other related diseases. From this perspective treating "AD" with LMTM makes more sense than does treating with a highly specific AD treatment such as anti-amyloid mabs because even in diagnosed AD patients there are other pathologies involved that might be driving tau dysfunction. HMTM as a pan neurodegenerative agent is able to counter the complexity that can arise with these mixed pathology patients. Even if the patients in the clinical trials do not have canonical AD, they could still be helped by HMTM!
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Re: AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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I noticed that there is a company in the Genting family that is listed on NASDAQ (Genting Malaysia Berhad (GMALF)) . This has me wondering: Could Genting take over this listing, put its shares of taurx into the shell listing and then reissue shares?

What would this achieve? It would then have its taurx shares into a pure play and it would allow a clear valuation of the worth of LMTM and other assets in its shares of taurx. This also makes me wonder whether taurx itself could then agree to sell parts of itself through the listing. Genting might purchase the shares etc. and then just sell them into the market when opportunities arose. I am unclear whether security laws would allow this happen. An advantage in this approach is that taurx would then be able to average into the market instead of selling most of the company at the IPO price. As the value of taurx becomes more established through time, taurx would then capture more of this benefit for themselves.
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Re: AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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taurx Graphical Abstract 2.png
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Re: AD cured? taurx reports positive Lucidity results !!!!!!!!!!

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Earlier on thread I grumpily complained about not being able to understand the graphical abstract above. Must have been fairly tired at the time. Usually the graphical abstract is a great way to understand an article without even reading it, though I had trouble on the first time through. The initial presentation was confusing to me. It was not clear to me how riva fit into the picture with LMT; the abstract did not use the usual red blocking notation to express the intended meaning. For me the intended meaning was then highly opaque.

I have now added these two red blocker lines in the figure above and it is clear to me. Rivastigmine (riva) blocks the SNAP 25 pathway and the OXPHOS ETC IV pathway as seen above. Yeah J11! Here to make things clear for the people (and for me).

Now that I have this understanding it is of interest to note that the figure shows how we can separate out the different effects with this knowledge of the riva blocking effect. So, even with riva blocking SNAP and OXPHOS IV, LMTM still inhibits formation of tau aggregates and still works through Nrf2. The tau and Nrf2 benefits still occurred with the LMTM add-on patients and they constituted about 50% of the full benefit (as judged by the full benefit as measured with monotherapy) . Such quantifications for the tau aggregation and Nrf2 (and SNAP 25 and OXPHOS IV) components are helpful and somewhat surprisingly large for OXPHOS IV and SNAP 25.
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