ALZ-801, tramiprosate, Ptau-181

[Cvd]

Hello,
I have been following Alzheon's ALZ-801 drug trials as I have a loved one who is e4/e4 and in their phase 3 trial.
They have just released an update saying there is a Ptau reduction of ~29% in 6 months and that potentially the drug can stop progression AD completely.

Does anyone have an idea/opinion/guess on how viable this claim is? The drug works by preventing oligomer formation. Has anyone or their LO taken tramiprosate consistently over years and what was your experience?

Also, if anyone is going to the "16th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (AD/PD conference) to be held on March 15-20, 2022, in Barcelona, Spain, and the 10th Annual Neurodegenerative Drug Development Summit (NDDS conference) to be held on March 28-30, 2022, in Boston, MA, USA," Alzheon will be presenting there and I would love to know of their updates.

My first post, so apologies if this is in the wrong area/forum or this topic has been discussed elsewhere. Would love to hear of anyone's opinion peoples' thoughts on the recent Phase 2 data and any relevant experiences with tramiprosate.

https://www.biospace.com/article/releas ... s-disease/

https://www.businesswire.com/news/home/ ... onferences

[NF52]

Hello,
I have been following Alzheon's ALZ-801 drug trials as I have a loved one who is e4/e4 and in their phase 3 trial.
They have just released an update saying there is a Ptau reduction of ~29% in 6 months and that potentially the drug can stop progression AD completely.

Does anyone have an idea/opinion/guess on how viable this claim is? The drug works by preventing oligomer formation. Has anyone or their LO taken tramiprosate consistently over years and what was your experience?

Also, if anyone is going to the "16th International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders (AD/PD conference) to be held on March 15-20, 2022, in Barcelona, Spain, and the 10th Annual Neurodegenerative Drug Development Summit (NDDS conference) to be held on March 28-30, 2022, in Boston, MA, USA," Alzheon will be presenting there and I would love to know of their updates.

My first post, so apologies if this is in the wrong area/forum or this topic has been discussed elsewhere. Would love to hear of anyone's opinion peoples' thoughts on the recent Phase 2 data and any relevant experiences with tramiprosate.

Welcome, cyd!

Like you, I have been following the progress of ALZ-801 in clinical trials for a few years, as have others on this forum. I also have two copies of ApoE4, like your loved one, and know that our participation in clinical trials makes a hug difference in the speed and accuracy of clear data on both safety and clinical effectiveness. So thank you both for your participation, assuming that you may be a study partner.

For the benefit of others reading this, I'll quote the four key bullet points from the ALZHEON news release you linked in the businesswire piece.

• 29% Reduction in Plasma P-tau181, Core Biomarker of Alzheimer’s Pathology, Observed after 6 Months Treatment in Carriers of One or Two Copies of APOE4 Gene who Represent Two Thirds of Patients with Disease

• Several-Fold Greater Reduction on P-tau181 Compared to Anti-Amyloid Antibodies Validates Superior Clinical Benefit from Prior Studies in Alzheimer’s Patients

• Significant Improvement on Memory Tests Consistent with P-tau181 Biomarker Effects to be Further Confirmed in Ongoing APOLLOE4 Phase 3 Trial

• Safety Profile in ALZ-801 Studies Remains Favorable and Consistent with Prior Safety Data in 2,000 Patients with No Evidence of Vasogenic Brain Edema

https://www.biospace.com/article/releas ... s-disease/

Here's what makes observers cautiously optimistic about ALZ-801, compared to some other anti-amyloid treatments:
*. It's a pill, not an IV infusion, and has a different mechanism than drugs such as Aduhelm, lecanemab (BAN2401) and donanemab, so it does not cause brain edema (ARIA-E). ARIA was a key reason why members of the FDA advisory panel were concerned about safety with aducanumab.
* Pills are easier to take at home than a biweekly or monthly infusion, and thus could be more accessible to people who live in rural areas or those without access to research hospitals or centers.
*. All anti-amyloid drugs appear to significantly reduce toxic beta-amyloid plaques. The newer ones, including lecanemab and donanemab and ALZ-801 also appear to greatly reduce or eliminate amyloid beta oligomers, recently seen as the most potent and dangerous form of beta amyloid.
*. Donanemab and ALZ-801 appear to also greatly reduce tau, which accumulates later than amyloid and appears to have a direct role in the death of neurons and interruptions in the brain's ability to think, remembers, learn and plan, among other skills. Several different forms of phosphorylated tau (called P-tau) exist, and scientists are still working on learning which is the most important to reduce or control. But P-tau 181 appears a strong candidate, so a 29% reduction in p-tau 181 is good news, especially since it seems to happen within 6-12 months, while other drugs may require longer periods of time.
* It appears that unlike Aduhelm, which had inconsistent and somewhat limited effect on cognitive skills, that ALZ-801 may show slowing in the rate of decline compared to people on placebo across most or all of many different cognitive tests, including ones of language learning, visual-spatial skills, focus and attention, short and long-term memory as well as daily living skills that are important to people.
* The clinical trials have received funding support from the National Institute on Aging, part of the NIH, and is building on previous studies with smaller numbers of people. They are starting a new trial for people with Mild Cognitive Impairment of mild Alzheimers's dementia. Here's the full descriptions and study location from Clinical Trials.gov: APOLLOE4

So while no one can predict exactly whether any one person will benefit from a trial, and 50% of those in this trial will be on the placebo, my own personal opinion is that this is a safe trial and one that will within a few years have important results. And I hope to see articles in the coming weeks on both the AD/PD and other conference.

Best wishes to your loved one and you in the new journey. I have been on a clinical trial for people with ApoE 4/4 and normal cognition and feel it was one of the best experiences I could have chosen for myself--along with all the other healthy habits we support and encourage!

[Theresa.J]

I have been following Alzheon's ALZ-801 drug trials as I have a loved one who is e4/e4 and in their phase 3 trial.
They have just released an update saying there is a Ptau reduction of ~29% in 6 months and that potentially the drug can stop progression AD completely.

Does anyone have an idea/opinion/guess on how viable this claim is? The drug works by preventing oligomer formation. Has anyone or their LO taken tramiprosate consistently over years and what was your experience?

Hello, Cvd -

As an Intern on the Support Team, I would like to welcome you the ApoE4.info website. The results from Alzheon's ALZ-801 studies are sure to generate some conversation here and in the media. Others, like NF52, who have been following the drug trials will likely respond to your post with their thoughts on this latest news.

In the meantime, I'd like to take this opportunity to share several tools/resources to help you get the most out of your experience on the ApoE4.info site:

First, the Primer is a detailed and informative resource written by a practicing M.D. with ApoE4/4. It includes information about the biochemistry of the ApoE4 gene and offers a variety of research-based prevention strategies.

In addition, the How to Guide offers tips on how to navigate forums and respond to posts, including how to quote members (use the quotation icon in the upper right of any post to initiate a reply) so they get an email notification of your reply. It also demonstrates how to use the Search function for topics, and how to subscribe to topics of interest in the forums.

Finally, if you would like to learn more about other community members' experiences, you can link to Our Stories.

I hope you find these tools useful as you navigate the site. Your loved one is lucky to have you by their side as they participate in the ALZ-801 Phase 3 trial, as it takes significant time and energy on your part as well. Your commitment and bravery in sharing this journey with them is admirable!

Take care and be well. Don't hesitate to reach out if you need any assistance related to navigating the site.

Warmly,
Theresa

[Cvd]

Thank you, NF52 and Theresa.
There is a wealth of information on this site! I am very relieved I found it.

Yes, I am my mom's study partner in this trial, and from what she says and what I have observed as well, the trial and some other interventions like diet and 40 Hz audio entrainment seem to be really helpful. It has only been a few months, though, so we will see, but I am hopeful.
I've been reading through some journal articles and it seems that with the first study (around 2007) with tramiprosate, CSF AB-42 was observed to decrease with increased tramiprosate dosage. But current research says that higher levels of CSF AB-42 are better, as the lower levels observed in AD patients are due to the amyloid sticking to plaques. So there are a few things that don't quite make sense to me, but trying to work through it : )

[antimatter37]

Thanks all for these updates. I believe that tramiprosate is simply homotaurine (is this correct?) Homotaurine is the amino acid taurine with an additional carbon atom attached. You can purchase it inexpensively on the web:

https://us.supersmart.com/en/shop/brain ... ement-0661

I have been using it myself with no negative effects as far as I cal tell. Has anyone else tried this supplement?

[NF52]

Thanks all for these updates. I believe that tramiprosate is simply homotaurine (is this correct?)...

Hi antimatter37,

You are correct that tramiprosate is the same as homotaurine, but ALZ-801 (valiltramiprosate) is not the same as the first two. As the drug used in the APOLLOE4 study mentioned above, it is considered a "prodrug" built upon an earlier promising drug. That's why it has to go through rigorous clinical trials with placebo arms and reach predetermined targets for both safety and efficacy, in reducing toxic amyloid beta and in "clinically meaningful benefit" in cognition and/or daily living skills.
FYI, I have no financial interest in Alzheon or ALZ-801, but am intrigued by a drug that specifically is focused on disease progression in the "preclinical" phase (i.e. normal cognition with positive amyloid PET scan) for people with Apoe4/4.

Here's an excerpt from a few sections of the company's website https://alzheon.com/clinical-data/
, https://alzheon.com/pipeline/alz-801-development/ and https://alzheon.com/amyloid-oligomers/, with emphasis added by me:

From 2004 to 2008, tramiprosate was evaluated in more than 2,000 patients with Alzheimer’s in two Phase 3 clinical trials by Bellus Health Inc.: a North American trial and a European trial. The objectives of the trials were to evaluate the efficacy and safety of tramiprosate in patients with mild to moderate Alzheimer’s over a 78-week treatment period.

The analysis of all subjects in the North American study did not show a statistically significant difference between the treatment and placebo groups for the primary efficacy endpoints. The European trial was terminated early after the results of the North American study became known.

Most commonly observed adverse events in these trials were nausea, vomiting and weight loss. Blood levels of tramiprosate in these patients showed high variability.

In 2013, Alzheon licensed ALZ-801, preclinical and clinical data for tramiprosate from Bellus.

Alzheon completed post hoc analyses of Bellus’ Phase 3 North American trial results based on APOE4 status, a pre-defined variable in Bellus’ statistical plan.

A systematic analysis of the dataset revealed a promising efficacy signal in a subgroup of patients who were APOE4 carriers. This signal was strongest in mild AD patients who carried 2 copies of the APOE4 allele (APOE4/4).

ALZ-801, is a patented, orally administered prodrug of tramiprosate that is designed to inhibit amyloid oligomer formation, a key driver of Alzheimer’s disease.
ALZ-801 was developed to improve gastrointestinal tolerability and the pharmacokinetic profile of tramiprosate by allowing ALZ-801 to be absorbed through the gut wall and be metabolized into active tramiprosate after absorption into the bloodstream. The data from our oral ALZ-801 Phase 1 clinical program showed improved gastrointestinal tolerability and more consistent plasma levels.

• ALZ-801 more consistent and better tolerated than tramiprosate

• High, sustained brain levels ~40%*

• Lower inter-patient variability ~25%

• Improved GI tolerability vs. tramiprosate

• 265 mg tablet, twice daily fully inhibits Aβ oligomer formation

And here's their explanation for why amyloid oligomers are more important than amyloid plaques (aducanumab focuses more on clearing plaques):

• Neurotoxic soluble amyloid oligomers present early in AD

• Amyloid oligomers damage neurons and trigger disease

• Oligomer levels in brain increase & drive clinical progression

• APOE4/4 homozygotes form more oligomers leading to an earlier disease onset

• Value of targeting oligomers in APOE4 patients supported by clinical evidence from aducanumab & lecanemab[BAN1401] programs

With all that, if you can avoid the GI problems seen in the earlier studies, I would hope you'd enjoy some benefit from tramiprosate!

[Tincup]

I have been using it myself with no negative effects as far as I cal tell. Has anyone else tried this supplement?

Yes, I've been taking one 100 mg Homotaurine tablet (Ismart brand) once a week for about 18 months. For those new to the topic, here is a post from about 18 months ago:

Hi All,

I am a 60 year old male apoe 3/4 Hetero-zygote with family history of Alzheimer's (Mother's Brother did not know where he was or who anybody was at 70). I am 6'3 200 lbs, in excellent shape, vegetarian, run hard once a week. B- blood. 99% European descent.

This summer (2020) I progressed to the point that I would lose my thought in mid sentence. I could "see" my subject / thought fading down a hole and then it was gone no matter how hard I tried to retrieve / recall it. All the subject changing in the world could not save me at that point.

I had read about apoe4 being one of the markers for a worse outcome with covid-19 which spurred my memory of my personal apoe 3/4 from 23&me raw data. Research led me to the current Phase 3 trial.

I ordered Homo-taurine online and began a 150ml dose immediately on way home from PO ( the dose in original 2003 Phase 3). Normally I tolerate supplements well. Here within an hour I puked my empty guts out. The next day I took one 50 ml tablet after brunch and another after dinner. Repeated the next day. Can feel some upset stomach and nausea that passes quickly.

By the third day I was "High" and agitated but clear headed. Every thought that I had forgotten suddenly raced back all at once. I found myself racing around other cars on the freeway and generally acting like a 16 year old. Beyond the above, I was madly pacing the floor and hyperactive. I could feel the waves of energy surging through me and childhood memories flooded my thoughts throughout the day.

By the fourth day I recognized the feeling of caffeine overdose where you are jittery and could jump out of your skin at the slightest provocation. I began bickering with business associates and was generally out of control (again like I was 16). I did not take the second dose on forth day and did not take another dose for 1 week. By the third deprived day, the foregoing side effects had begun to subside. But I was 'High' like effervescent Champagne makes me feel for 6 days.

I ran hard on the sixth day and seem to be free of all side effects. I took on 50ml yesterday (7th day) and had no side effects. I will stay on a once a week 50ml for immediate future. I am not nauseated but have absolutely no interest in food. I am force feeding myself, eating twice daily and trimming fat.

My memory is back, if I lose a thought I can find it. I have had entire days where I did not lose one thought. My mental function seems to be at the highest level in years. I can feel the difference in my body and brain chemistry. Lifelong Inflammation in my colon has improved incrementally to the point of almost no symptoms.

I have rare, low percentage genes all across the promethease DNA application with many at 1% or less of Caucasian of European descent. I will do all I can to help any interested parties.

Sincerely D

Link to original thread.

[antimatter37]

Thanks all. I will also continue my 2 per week 100 mg of homotaurine.

[mike]

*. All anti-amyloid drugs appear to significantly reduce toxic beta-amyloid plaques. The newer ones, including lecanemab and donanemab and ALZ-801 also appear to greatly reduce or eliminate amyloid beta oligomers, recently seen as the most potent and dangerous form of beta amyloid.

NF52, in this paper, they say specifically that ALZ-801 does not remove the AB plaques (which they say are not toxic) and instead specifically targets the formation of AB oligomers.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231952/

The oral agent ALZ-801 specifically and completely blocks aggregation of Aβ monomers into oligomers at the clinical dose without interacting with amyloid plaque

[mike]

Yes, I am my mom's study partner in this trial, and from what she says and what I have observed as well, the trial and some other interventions like diet and 40 Hz audio entrainment seem to be really helpful. It has only been a few months, though, so we will see, but I am hopeful.

I've been reading through some journal articles and it seems that with the first study (around 2007) with tramiprosate, CSF AB-42 was observed to decrease with increased tramiprosate dosage. But current research says that higher levels of CSF AB-42 are better, as the lower levels observed in AD patients are due to the amyloid sticking to plaques. So there are a few things that don't quite make sense to me, but trying to work through it : )

Cvd, Does the study that your LO is on include the 40 Hz audio as well as ALZ-801? Seems strange they would combine two different interventions at once...

For the AB-42, higher levels are good, because normally AB-42 likes to become plaques and no longer show on the test. The higher ratio of AB-42 to AB-40 means that it is not clumping. Not something that I fully understand. It would be better if the AB-42 was not created in the first place and just produce AB-40 which doesn't clump much.

IMHO AB-42 more likely to fold and clump the more glucose is metabolized in the brain. Glucose needs more oxygen than ketones to produce a given amount of ATP (energy) and this changes brain chemistry - more oxidative. This leads to AB-42 folding and then clumping. ApoE4 is less good at taking out these clumps. I'm hoping by keeping to a VERY low carb diet, I can keep the AB-42 from folding in the first place, so I get fewer plaques.

Failing that, ALZ-801 seems like it could be that AD magic pill for E4s. It prevents AB from becoming toxic. And since it stops an intermediary stage, it would seem likely that it will stop AB plaques from increasing as well.