1229 replies to this topic

[mag1]

The Bexarotene clinical study has finally been published.

Looks like it does substantially reduce amyloid in non-APOE 4 carriers.

 

 

http://www.ncbi.nlm....les/PMC4731943/

[resveratrol_guy]

The Bexarotene clinical study has finally been published.

Looks like it does substantially reduce amyloid in non-APOE 4 carriers.

 

 

http://www.ncbi.nlm....les/PMC4731943/

 

Wow the data here is very noisy, and to make matters worse, the number of participants was 4 noncarriers and 12 carriers. Sometimes, when the effect is huge and the distribution is narrow, we can get something inspiring from a study like this. But not in this case. Yes, it may well have reduced amyloid burden, but megadose Longvida probably does that as well for less money and risk. But there is no compelling evidence here that it improved cognition. If anything, there is weak evidence that the placebo group showed better improvement in MMSE.

 

Nevertheless thanks for posting this. You just saved me a ton of wasted time, money, and effort because bexarotene was on my to-try list.
 

Edited by resveratrol_guy, 07 February 2016 - 05:01 AM.

[resveratrol_guy]

Interesting, looks like Cu II(atsm) has been investigated in AD.

7 years ago?

The above quote noted that Cu II (atsm) is already used in PET scans.

Could go off lablel.

 

"glyoxalbis(N(4)methylthiosemicarbazonato)Cu^II (Cu^II (gtsm)) restored intracellular copper levels, decreased insoluble A[beta] levels and improved cognition"

http://www.ncbi.nlm..../?term=19122148

 

Only difference between Cu^II (gtsm) and Cu^II (atsm) is a double methyl substitution for the top Hydrogen.

 

They make it really hard to view the graphs. So to save time, see here, here, here, and here. (They have an annoying drag-to-zoom interface in the lower right.)

 

Anyway there are few things that stand out here. First of all, look at the P values printed on some of those bar graphs, especially in the third link, section B, showing a reduction in phosphotau (pTau) from about 100 to 65. This is critically important in halting the disease. While it's nice to see a reduction in amyloid -- and especially the trimers as opposed to the monomers -- it probably has little clinical relevance to humans. (Clearing amyloid cures mouse AD all the time, but not ours, apparently.)

 

Having said that, it sounds from your other post as though this stuff has only been sporadically used in humans for imaging purposes, rather like MRI contrast agent. If that's the case, and considering that this stuff is essentially a pharmaceutical, it lacks the longterm side effect data which we know much better for natural substances in traditional medicine. I'm also put off by the notion that getting copper into the CNS is sometimes a good thing. It seems like it comes down to oxidation state, but it might be more complicated than that. For all we know, the other end of this molecule is doing something entirely different that's resulting in the disaggregation and Y-maze improvement. It might be, for instance, that longterm use would increase toxic CNS copper, despite the short term boost that comes from some unidentified molecular domain. But my default assumption is simply the authors' hypothesis, which is that the right form of copper is as good for the brain as it is for the heart. But I'm not at all confident that we understand copper delivery well enough to try this in humans, let alone expect longterm benefits; mice don't live very long, so any nootropic effect could easily override longterm toxicity issues. I am nontheless inspired by the upcoming ALS trial. If it works half as well as nilotinib, perhaps we'll have to do a group buy.

 

It just goes to show that metal ion balance is a very sensitive science. So far, the only things I'm really sold on in this vein are (1) plasma chromium had better be lower than both nickel and cobalt and (2) avoid ingesting copper 2.

Edited by resveratrol_guy, 07 February 2016 - 05:25 AM.

[mag1]

Table 2 showed that amyloid levels in the non-epsilon 4s treated with Bexarotene separated significantly for almost

every brain region versus placebo. These were moderate AD patients, moving cognitive endpoints might be

more than could be expected. For a small study it seems encouraging. They reported 10% decreases in amyloid

levels. Going to a pre-symptomatic AD population could be very useful.   

 

Price of  Bexarotene has recently greatly increased even though it is generic. Wonder whether there is a demand explanation.

[mag1]

The Cu ATSM result for ALS is very encouraging.

There has never been any perceivable advance in ALS treatment.

This is a great start!

 

The AD extension of the Cu ATSM results are somewhat less developed. However, the ALS results in mice that have been reported are simply startling. In the recent results even when using only 5-10 mice in the different arms they were reporting p values out to e-8. I have been looking around on the ALS forums and there is quite a bit of excitement about this. It would help so much from the perspective of clarity if there were some subgroup of patients with a neurodegenerative illness such as ALS  with SOD1 variants that could show that a copper treatment such as Cu ATSM had significant treatment effect. This could help the research community focus in on copper.

 

If we could actually have a success signal this would help the entire neuroscience pharma industry. There has been such an overwhelming amount of failure in neuroscience: it is so depressing. Cu ATSM could be one success. The company behind this is considering developing this in ALs, Parkinson's, and possible AD.   

 

It has been known that with clinical AD it is more a deficiency of copper that is at play, though obviously a non-protein form of copper-2 would not be helpful. In fact with Cu-ATSM it is Cu II ATSM, yet in this form the same concerns would not arise as with inorganic Cu II.    

Edited by mag1, 07 February 2016 - 05:50 AM.

[mag1]

DHA Bexarotene combo reduced triglycericide spike and enhanced cognitive benefits

http://www.ncbi.nlm....les/PMC4469742/

 

We have already noted that an early stage Alzheimer patient appeared to benefit from long term bexarotene treatment.

In the just published study, epsilon 4s did not appear to do as well, though this patient was epsilon 34.

http://www.ncbi.nlm....pubmed/26444777

 

 

[resveratrol_guy]

DHA Bexarotene combo reduced triglycericide spike and enhanced cognitive benefits

http://www.ncbi.nlm....les/PMC4469742/

 

We have already noted that an early stage Alzheimer patient appeared to benefit from long term bexarotene treatment.

In the just published study, epsilon 4s did not appear to do as well, though this patient was epsilon 34.

http://www.ncbi.nlm....pubmed/26444777

 

Bexarotene is expensive and would require some sort of group buy to obtain without going through medical red tape. CuATSM sounds more promising with regards to cognitive remediation, although (1) it's not clear to me if it's helpful in the absence of an uncommon SOD1 mutation and (2) it appears to be very difficult to obtain, as well.

[resveratrol_guy]

Perhaps this would be more practical.

[mag1]

The ALS forums seem very excited about Cu atsm.

It is great to see any amount of excitement in the neurodegenerative community.

For too long the entire neuro community has had no sense of hope.

With ALS they have never had similar results to Cu atsm (even in mice).

 

Not only will the excitement be more broadly helpful, but so too will the focus on metals ( specifically Cu II ) in neurodegeneration.

There is also some interest in possibly moving Cu atsm into PD possibly AD.

 

Some of the sources are framing Cu atsm as an ALS cure.

[Der Springende Punkt]

Fasudil, an approved medication for people improves memory in rats and also promotes degradation of toxic tau in lab models.

[mag1]

"The liver produces the majority of circulating apoE that binds lipids and interacts with cell-surface membrane receptors to initiate cellular uptake of lipoprotein particles by the liver and other tissues"

http://www.ncbi.nlm....les/PMC3836480/

 

Brain amyloid and amyloid outside of the brain maintain a balance.

Lower amyloid outside of the brain drains brain amyloid.

 

Given this, would a liver stem cell transplant into an epsilon 44 using epsilon 22 cells possibly with other modifications be helpful 

in preventing dementia?

[resveratrol_guy]

The ALS forums seem very excited about Cu atsm.

It is great to see any amount of excitement in the neurodegenerative community.

For too long the entire neuro community has had no sense of hope.

With ALS they have never had similar results to Cu atsm (even in mice).

 

Not only will the excitement be more broadly helpful, but so too will the focus on metals ( specifically Cu II ) in neurodegeneration.

There is also some interest in possibly moving Cu atsm into PD possibly AD.

 

Some of the sources are framing Cu atsm as an ALS cure.

 

Even if I swallow all that at face value, can we even acquire CuATSM?

 

As to APOE4, we should just turn it off and forget about it. If only BioViva or someone else would do it...
 

[mag1]

Increasing APOE levels might be helpful.

It is not entirely clear yet whether APOE epsilon 4 levels should be increased or decreased.

Plasma APOE levels appears to be a strong risk factor for AD.

 

http://www.ncbi.nlm....pubmed/25469919

 

This was where the idea of liver epsilon 22 stem cells came in.

If all that is needed is to increase plasma APOE (possibly a specific epsilon type), then this seems doable.

[resveratrol_guy]

Fasudil, an approved medication for people improves memory in rats and also promotes degradation of toxic tau in lab models.

 

Thanks for sharing, but this doesn't sound very compelling. Side effects included brain bleeding. It also downregulates autophagy, which is essential for cancer prevention and other aspects of neurological health. Phosphorylated tau is probably the problem in Alzheimer's research, so any progress is good progress. But I think we can do better, perhaps with tau vaccine when it emerges from trials.

[resveratrol_guy]

Increasing APOE levels might be helpful.

It is not entirely clear yet whether APOE epsilon 4 levels should be increased or decreased.

Plasma APOE levels appears to be a strong risk factor for AD.

 

http://www.ncbi.nlm....pubmed/25469919

 

This was where the idea of liver epsilon 22 stem cells came in.

If all that is needed is to increase plasma APOE (possibly a specific epsilon type), then this seems doable.

 

Maybe I'm missing the point here, but I don't think plasma APOE4 has any significant causative relationship to AD. Rather, in the brain, it controls the efflux rate of cholesterol from neurons. Bexarotene corrects this, which is why it works in some cases (but I'm not a fan, given the study above).

 

If I'm wrong here, please explain why.

[mag1]

"Low plasma levels of apoE are associated with increased risk of future Alzheimer disease and all dementia in the general population, independent of ε2/ε3/ε4 APOE genotype."

 

http://www.ncbi.nlm....pubmed/25469919

Edited by niner, 11 February 2016 - 02:18 AM.

[resveratrol_guy]

"Low plasma levels of apoE are associated with increased risk of future Alzheimer disease and all dementia in the general population, independent of ε2/ε3/ε4 APOE genotype."

 

http://www.ncbi.nlm....pubmed/25469919

 

I have no reason to doubt that, but my point was simply I'm unaware of any evidence suggesting that correcting these plasma aberrations would ameliorate AD, any more than dying gray hair blonde would result in rejuvenation. They even state: "Hence, plasma levels of apoE may be a new, easily accessible preclinical biomarker." In other words, this is an early risk test, which is great. But I don't see a therapy here.

[aribadabar]

What do you guys make of this:

http://neurosciencen...lzheimers-3629/

[Der Springende Punkt]

 

Fasudil, an approved medication for people improves memory in rats and also promotes degradation of toxic tau in lab models.

 

Thanks for sharing, but this doesn't sound very compelling. Side effects included brain bleeding. It also downregulates autophagy, which is essential for cancer prevention and other aspects of neurological health. Phosphorylated tau is probably the problem in Alzheimer's research, so any progress is good progress. But I think we can do better, perhaps with tau vaccine when it emerges from trials.

 

 

According to the paper it upregulates autophagy and thus reduces tau, but the brain bleeding side effect may be the showstopper, right.

[niner]

The Bexarotene clinical study has finally been published.

Looks like it does substantially reduce amyloid in non-APOE 4 carriers.

 

http://www.ncbi.nlm....les/PMC4731943/

 

That's interesting.  Just this week, I found this in Science:

 

Amgen chose the three papers initially highlighted on the site not because they were particularly noteworthy, but because the company’s scientists were ready to write them up, Kamb says. In one study, Amgen was not able to confirm a 2012 report in Science that a cancer drug, bexarotene, could clear β-amyloid plaques and reverse cognitive problems associated with Alzheimer’s disease in mice. Four other groups had already questioned the findings in technical comments in Science. But Kamb says Amgen’s contribution, which uses a different tool molecule to test bexarotene’s purported mechanism, adds “another very large brick.”

 

 

This was in an article about the formation of a new journal for the purpose of publishing replication attempts, particularly if they failed to replicate.  That's a good thing, if they do it right.  Not so great if they do it wrong, fail to replicate, and everyone says "Well, that's that.  Better find something else to work on."  Depending on the quality of the work, this could have a net positive or net negative effect.  If the authors of the initial report are leaving out important details in order to throw competitors off the track, this will play into their hands, at the cost of making them look incompetent.   The proof of concept study of Bexarotene in humans looks like it's showing a signal.  Would that study have been performed if Amgen's failure to replicate had been in the record?

[mag1]

We need to reach a point where changing a biomarker alone will have a well understood meaning in terms of clinical effect, as was done with cholesterol lowering

all those years ago. After enough trials were done it could no longer be argued that lowering cholesterol was somehow unrelated to cardiovascular mortality.

AD research will greatly leap forward when it can be established that simply lowering amyloid has a well understood relationship to cognitive outcomes.

 

When Biogen moved amyloid levels down by 10%, the market rewarded them with a market cap of over $100 billion.

Bexarotene has just been shown to move down amyloid by over 10% in the APOE epsilon 3s.

 

One reason we are not witnessing the same pandemonium that occurred after the Biogen results is that there were no cognitive results reported in the Bexarotene trial.

Once the relationship is clearly established between amyloid and cognition, pandemonium can ensue without having to go through long expensive trials that need

to measure fuzzy cognitive endpoints.

 

There are amyloid lowering drugs deep into phase 3s that lower amyloid levels by over 90%. 

[mag1]

An epsilon 3,4 early stage AD patient (MMSE 26) was stabilized for 2 years while being treated with Bexarotene.

When treatment stopped the patient experienced rapid cognitive decline.

http://www.alzforum....-contradictions

 

We have referred to this patient report on this thread a few times.

However, a 2 year stabilization is a significant new development.

Other treatments have been shown to stabilize patients for 6 months without disease modification.

The fact that this patient was stable for so long is important.

Providing this treatment to patients would make considerable sense from a health economic perspective.

In other diseases, notably cancer, substantial amounts of money can be spent often with virtually no obvious benefit.

From this point of view Bexarotene offers a bargain.

 

 

This pdf from the patient care site claims no more than a $20.00 charge for commercially insured patients (for cancer?).

http://www.targretin...in Capsules.pdf

[tunt01]

 

Fifteen of twenty subjects had increases in triglyceride levels to greater than 200 mg/dl. Eleven subjects had increases in cholesterol levels to greater than 300 mg/dl.

 

 

Trig levels greater than 200 mg/dL?  No thank you.  I really wonder how they go forward w/ a Phase II trial and tell any regulatory authority that they are going to simultaneously provide bexarotene in an attempt to raise ABCA1, which will effectively provoke dyslipidemia, then give these patients a statin in attempt to lower the cholesterol (which the study authors did at week 4).  And, of course, the statin reduces ABCA1 expression.

 

Bexarotene is really interesting from a mechanism of action standpoint and they did seem to get some positive results in the non-E4 group.  But it seems like less than half an answer to a really complex problem.

 

On the other hand, lipidated curcumin should improve ABCA1 activity and is purported to lower trigs normal healthy individuals [1] (whose data I don't necessarily believe 100%, but at least they aren't spewing out trigs/cholesterol).  Co-supplementation with DHA should help keep trigs down.  Seems like Longvida curcumin / fish oil might be quite prudent.  Bexarotene seems like a gamble not worth taking.

 

 

1.  DiSilvestro RA, e. (2012). Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people. - PubMed - NCBI .Ncbi.nlm.nih.gov. Retrieved, from http://www.ncbi.nlm....pubmed/23013352

Edited by prophets, 13 February 2016 - 04:33 PM.

[mag1]

The epsilon 3,4 early stage AD patient in the encouraging recent report whose MMSE was stable for 2 years of treatment with 300 mg per day of Bexarotene was also taking 200 mg per day of fenofibrate.

Amyloid levels did not appear to move.

 

The actual mechanism of action for Bexarotene is now somewhat obscure, though at least for this patient taking fenofibrate did not counteract the net beneficial effect.

 

 

One exciting implication of this result is that very large treatment effects are at least possible in Alzheimer's. In some illnesses headline breakthroughs often result in minimal clinical benefits for patients.

The above patient was cognitively stabilized for 2 years on treatment and there is no particular reason to expect that this would not have continued had the patient not stopped treatment due to

financial considerations. A treatment that could delay dementia onset would have large financial benefits for funders.

 

"...delaying the onset of Alzheimer’s by just five years would save Medicare $345 billion in the first 10 years alone."
http://www.alz.org/n...ents_102432.asp

Edited by mag1, 13 February 2016 - 05:36 PM.

[mag1]

Trying to figure out the method of action is pretty much a roll of the roulette wheel; probably should focus in more on whether there was a cognitive benefit.

Biology has so many twists and turns, that trying to rationalize what should be happening can often give you the wrong answer.

 

http://www.eurekaler...oc-ri021016.php

[niner]

http://www.eurekaler...oc-ri021016.php

 

Bexarotene in nematodes.  The important part is that it only works if given early enough.  In this report, the authors are quoted as saying:

 

You wouldn't give statins to someone who had just had a heart attack, and we doubt that giving a neurostatin to an Alzheimer's patient who could no longer recognise a family member would be very helpful," said Dobson. "But if it reduces the risk of the initial step in the process, then it has a serious prospect of being an effective preventive treatment."

 

If people are going to use Bexarotene as a prophylactic, then the dyslipidemia needs to be dealt with.  One problem is that the people who might want a prophylactic are the ApoE4s, and that was the cohort that it didn't work well for.  OTOH, maybe that's just because they were already too far gone.   Maybe it would work for ApoE4 if you started early enough.

[mag1]

That is the confusing part. There is often this comment that the patients might be too far gone and that once cognitive symptoms are present you are already too late.

Yet, the APOE epsilon 4 patient who was stabilized with Bexarotene for 2 years was already exhibiting early Alzheimer's (MMSE 26).

His MMSE actually improved on the first readout to 28 over a treatment window of 6 months.

What is especially impressive with this patient is that the cognitive benefit persisted for the 2 years and only vanished when treatment was curtailed.

 

I am surprised that the company simply did not provide free drug to this patient, this patient represents an extraordinary research and marketing opportunity.

{It is not entirely clear to me whether that would be legal.}

If such a patient could be shown to have an essentially indefinite response to Bexarotene treatment, there would be a surge of interest in the dementia community for

Bexarotene treatment. It seems this was a huge missed opportunity.

 

It is so tragic that there are still people in this crowdfunding era who feel so alone and are unaware that there are people out there who will reach into their pockets to help out.

This is all the more true in instances such as this when the patient has provided at his expense an important data point that everyone else is now freeriding.

Perhaps there could be a mechanism whereby people would have to pay for such research results, while there was ban on reposting.

 

{This thread is great! I am have been chalking up positive ratings here: It is almost too easy!

I am almost ready to get back to the snake pit of the Robotics and Employment thread

There is so much bitterness over there about the approaching Singularity that my net ratings took a large hit.

I needed to fuel up on this more sedate thread.}  

Edited by mag1, 13 February 2016 - 11:30 PM.

[resveratrol_guy]

I've always admired your sentimental transparency, mag1!

 

Perhaps you and niner are onto something, in the sense that maybe bexarotene is working through a mechanism other than amyloid clearance. I completely agree with prophets, in that if you want to curtail amyloid, use liposomal curcumin. The side effects are basically decreased liver enzyme leakage and reduced inflammation. Personally, I've noticed some throat irritation when I binge on the stuff, but nothing too serious. In any event, it's quite clear at this point that amyloid clearance won't do much to arrest AD, although it's not at all clear, on account of a dearth of evidence, whether doing so early enough might indefinitely forestall the disease. At least, I would say it's worth using 81 mg aspirin and Longvida in an attempt to do just that. To the twenty-somethings on this forum: consider yourself lucky; you had better damn well learn fast.

 

I wonder if the triglyceride explosion somehow relates to cholesterol efflux from neurons.

 

$20 for a course of the stuff? I'm skeptical. You might need to head to India or Mexico for the help of an unscrupulous pharmacist...

 

Eventually we might do a group buy, I suppose.

 

[niner]

I didn't know what the price of Bexarotene was, so I googled it.  GoodRx.com gives prices for 200 caps, 75 mg, at all the major pharmacies.  You can save $3308.70 by getting it at Costco instead of CVS!  The Costco price is such a deal at only $49,558.10.  That's less than the price of a Tesla Model S!  So I'm wondering, why is everyone down on Martin Shkreli, when big pharma is essentially doing the same thing in a slightly less egregious way?  Bexarotene comes off patent this year, so we should expect a drop in price.  It's just a small molecule, not an antibody, so I'd expect the price to fall a lot, but that will depend on the forces of demand, supply, and greed.  

[tunt01]

 

I wonder if the triglyceride explosion somehow relates to cholesterol efflux from neurons.

 

 

The lipogenic action is in the liver.  Bexarotene is an RXR agonist, but RXR/LXR is a heterodimer  (Lalloyer 2009).  LXR activates SREBP-1c which spews trigs everywhere (Beltowski 2008).  The drug is metabolized in the liver and its action is in the liver.

 

You can see it (partially) in the ALZ forum diagram here.

 

 

This explains why Casali, et al. ran a prior study with Bexarotene and DHA.  Because as they say:

 

 

Moreover, DHA abrogates bexarotene-induced hypertriglyceridemia in vivo. Importantly, dual therapy promotes reductions in AD pathology and resultant amelioration of cognitive deficits. While monotherapy with eitherbexarotene or DHA resulted in modest effects in vitro and in vivo, combined treatment with both agents produced a significant additive benefit on associated AD-related phenotypes, suggesting that targeted combinatorial agents may be beneficial over single agents alone in treating AD.

 

 

 

 

So I come to the same conclusion we have previously.  Here they show the combination therapy (driven by DHA) downregulates the SREBP-1c action, thereby inhibiting triglyceride formation

 

 

 

 

So yea, Bexarotene + DHA probably OK.  And maybe I'm talking to myself on this issue (because I don't have Alzheimer's or any immediate family members at any stage of Alzheimer's).  So, I find liposomal curcumin + DHA to be pretty prudent, because it has a lot of the same activity as bexarotene without the lipogenic action.  And I can take a bit of fish oil to inhibit trigs (which I've been actually checking with Cardiochek PA on a fasting and post-prandial basis).

 

 

 

Casali BT, e. (2016). Omega-3 Fatty Acids Augment the Actions of Nuclear Receptor Agonists in a Mouse Model of Alzheimer's Disease. - PubMed - NCBI .Ncbi.nlm.nih.gov. Retrieved 14 February 2016, from http://www.ncbi.nlm....pubmed/26085639

 

J, B. (2016). Liver X receptors (LXR) as therapeutic targets in dyslipidemia. - PubMed - NCBI . Ncbi.nlm.nih.gov. Retrieved 14 February 2016, from http://www.ncbi.nlm....pubmed/19035881

 

Lalloyer F, e. (2009). Rexinoid bexarotene modulates triglyceride but not cholesterol metabolism via gene-specific permissivity of the RXR/LXR heterodimer in the liver. - PubMed - NCBI . Ncbi.nlm.nih.gov. Retrieved 14 February 2016, from http://www.ncbi.nlm....pubmed/19592467

Edited by prophets, 14 February 2016 - 05:01 PM.