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MS treatment a step closer after drug shown to repair nerve coating

theguardian.com

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Re: MS treatment a step closer after drug shown to repair nerve coating

#61

Post by melling »

aplummer wrote: post #54
melling wrote: post #37

Earlier quoted context omitted.

“Just 20 years ago..." Personally, when people think we are making good progress on something, I’m reminded of these words: “Before this decade is out...” Sure, great and rapid progress might require a couple percent of US GDP, and a million people working on a problem, but advancing medical research a few decades in the next 10 years, would benefit everyone.

The thing about clinical trials, is there is a minimum time it takes to run one. You can up concurrency but it only gets you so far - you really need to know the long term impact before you can iterate much.

So, that wouldn’t be a good way to address basic medical research for some sort of Manhattan project.

To make great progress over a decade, we’d need to do something else to advance medical science.

Re: MS treatment a step closer after drug shown to repair nerve coating

#62

Post by PragmaticPulp »

wrkronmiller wrote: post #31

I'm confused about why Bexarotene can be sold as Targretin to treat "skin problems"[1], but cannot be used as a potentially life-saving treatment for MS. Is it that the dosages must be higher to treat MS? [1] https://www.webmd.com/drugs/2/drug-17979/targretin-oral/deta...

It’s not just pedestrian skin problems. Your quote stopped short of the full context:

“Bexarotene is used to treat skin problems from a certain type of cancer (cutaneous T-cell lymphoma-CTCL).”

Bexarotene is an already-approved cancer drug. Cancer drugs often have worse side effects than normal drugs because they’re taken toward end of life, or taken to delay or prevent death. The difference is that MS patients would presumably need to take this medication over the course of their lifetime, as it doesn’t address the core disease.

If Bexarotene accelerates heart disease and causes thyroid problems, a lifetime of taking this medication might actually worsen quality of life and even shorten lifespan. Unfortunately, many patients desperate to improve the symptoms they know might rush to replace them with side effects they don’t yet know.

Re: MS treatment a step closer after drug shown to repair nerve coating

#63

Post by gavinray »

TheAdamAndChe wrote: post #16
hprotagonist wrote: post #3

Burying the lede a bit: the drug can’t be used because its safety profile is unacceptable, but the possible mechanism might be targetable by other future drugs. Translation: come back in 2040.

Actually if they know the mechanism of action and receptor that it affects, they can run computer simulations of thousands of chemicals quickly. This method of simulating the 5-HT receptors was used to find 25i-NBOMe, an extremely powerful serotonin receptor agonist.

The entire 25x-NBOMe series was an unfortunate find (sociologically). Lot of people seemed to have a bad time on them.

That was David Nichols' lab at Purdue IIRC. I also believe that they had found other, even more potent derivatives, but refused to publish them for fear they would be used as chemical weapons.

The report had claimed activity at something like 1-10mcg range, which is real spooky when you consider the impact aerosolizing that could have on a room.

Re: MS treatment a step closer after drug shown to repair nerve coating

#64

Post by chime »

> While bexarotene will not go into phase 3 trials for MS, the finding that the nervous system can be stimulated to resheath damaged neurons has given scientists fresh hopes for another trial they hope to launch later this year. That trial will monitor the effects of the diabetes drug metformin along with clemastine, an antihistamine, a combination that Prof Robin Franklin at the Wellcome-MRC Cambridge Stem Cell Institute showed last year could drive remyelination in animals.

That would be an amazing find if it works in humans. My wife was on metformin for many years (not for diabetes) before being recently diagnosed with MS. Coincidentally she experienced her first MS symptoms shortly after stopping metformin. We suspect that use of prescription steroids along with metformin might have been masking the onset of her MS for years and in an indirect way even delayed it slightly.

She just got her first half-dose infusion of Ocrevus, other half scheduled for next week. Ocrevus is such an amazing disease-modifying drug. It's very expensive but our insurance covers it and after the initial dose, she only needs one 3-4 hour infusion every 6 months. No other medication needed on a daily basis! Ocrevus helps ensure no new flare-ups happen anytime soon but it leaves her immunocompromised and there is no remyelination. If metformin + antihistamine end up producing even a little bit of remyelination that would be a game changer because she's young and has enough time to regain everything if it just involves taking a couple of pills daily.

Unrelated but just putting this out there since it's fresh on my mind - if you or loved one ever gets diagnosed with MS or equivalent, you absolutely have to be your own advocate. Best thing you can do in the US is to get an online fax# (I use redfax) and the Dropbox app. Scan every single medical document you get with the Dropbox app, convert it to PDF, and then fax it over to 100 places as needed. Also sign up for every single patient portal including Quest/Labcorp. Be sure to get a DVD of every imaging test (CT/MRI) and upload them for free to postdicom.com to share with anyone or to just see it yourself if curious.

It is a LOT of work and very stressful. But if you're technically savvy, you can avoid a lot of driving back and forth between testing, doctor, hospital, medical centers. And above all reach out to anyone you trust for assistance, even if it's just to pick up groceries. People can surprise you with their generosity.

Re: MS treatment a step closer after drug shown to repair nerve coating

#65

Post by TheAdamAndChe »

gavinray wrote: post #63
TheAdamAndChe wrote: post #16

Earlier quoted context omitted.

Actually if they know the mechanism of action and receptor that it affects, they can run computer simulations of thousands of chemicals quickly. This method of simulating the 5-HT receptors was used to find 25i-NBOMe, an extremely powerful serotonin receptor agonist.

The entire 25x-NBOMe series was an unfortunate find (sociologically). Lot of people seemed to have a bad time on them. That was David Nichols' lab at Purdue IIRC. I also believe that they had found other, even more potent derivatives, but refused to publish them for fear they would be used as chemical weapons. The report had claimed activity at something like 1-10mcg range, which is real spooky when you consider the…

Well unlike LSD which is a partial agonist, 25i-NBOMe is a full, irreversible agonist that can be lethal in the event of an overdose. It really wasn't designed for use as a recreational drug.

It's history of discovery (as well as the 2C variants) was extremely interesting though.

Re: MS treatment a step closer after drug shown to repair nerve coating

#66

Post by baldfat »

chime wrote: post #64

> While bexarotene will not go into phase 3 trials for MS, the finding that the nervous system can be stimulated to resheath damaged neurons has given scientists fresh hopes for another trial they hope to launch later this year. That trial will monitor the effects of the diabetes drug metformin along with clemastine, an antihistamine, a combination that Prof Robin Franklin at the Wellcome-MRC Cambridge Stem Cell Inst…

My niece has aggressive MS and Ocrevus didn't help.

CRSPR is the true dream. No more MS.

Re: MS treatment a step closer after drug shown to repair nerve coating

#67

Post by roganartu »

derefr wrote: post #52
irjustin wrote: post #11

While it is sad that this drug cannot continue for MS directly, I love that this is science work at its best. Experimental drug, through the efforts of terminally ill, are able to discover/show/validate quite powerful benefits, but the drug is too dangerous to use itself. So we stop it. It is progress and many times, progress is not easy nor cost free. Thank you to all those who, even in their terminally ill state, h…

One thing I’ve always wondered is: how many drugs have we rejected like this, which were actually bimodal in their safety profile, the way many drugs are bimodal (or polymodal) in their effect profile. I.e., that there’s some inherent difference between the people the drug harms, and the people it doesn’t; and if you can identify that difference, and test for it, then you can safely give the drug to only the people i…

> We only seem to do it when a drug is initially declared as safe; introduced into the market; and then we find that it has side-effects that clearly correspond to some subpopulation.

This exact thing happened with another MS drug: natalizumab[0].

It was originally approved in 2004, but later withdrawn in 2005 due to some cases of Progressive multifocal leukoencephalopathy (PML), an opportunistic brain infection that is often fatal. The manufacturer later identified a specific antibody for a virus (JC Virus[1]) present in ~50% of the population which correlated highly with incidence of PML after 1-2 years on natalizumab (~1% chance of PML vs ~0.01% of the normal population). tl;dr the blood-brain barrier maintained by natalizumab also prevents the body from killing the JC Virus in your brain, causing inflammation and eventually death or serious permanent disability.

It was then reintroduced but now patients must undertake regular blood screening (every 6 months) for JCV antibodies, and regular (~12 months) MRI scans to monitor for inflammation (though this is pretty standard with MS these days to look for changes in lesions).

My wife has a rare type of MS (tumefactive MS, ~3000 people in the US have it) and has been on natalizumab since diagnosis about 3.5 years ago with no evidence of disease progression. The story would've been wildly different if we were born 20 years earlier before these treatments came about, it's honestly amazing. Without modern treatments it's very possible she would've been confined to a wheelchair within 10 years of diagnosis, but instead her symptoms are only really noticeable upon examination by a neurologist.

[0]: https://en.wikipedia.org/wiki/Natalizumab

[1]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128336/

Re: MS treatment a step closer after drug shown to repair nerve coating

#68

Post by PragmaticPulp »

Bexarotene, the drug used in this study, is already approved and available for certain types of cancer treatment. The problem is that the side effects are severe. Severe side effects can be acceptable in relatively short term cancer treatment, but untenable for lifelong treatment in Multiple Sclerosis patients.

Specifically, the thyroid effects of Bexarotene are so common and significant that one study even recommended that patients be given adjunctive thyroid medication when beginning treatment, even when low doses are used: https://pubmed.ncbi.nlm.nih.gov/30903705/

Likewise, the effects on blood lipids are significant enough that patients are frequently forced to take statins during their course of treatment: https://pubmed.ncbi.nlm.nih.gov/29805374/

Assuming an MS patient would have to take this drug for a lifetime, or at least use it frequently, suggests that these side effects could worsen quality of life or even shorten lifespan more than MS itself.

Promising drug candidate, but no one should be rushing out to find a way to get their hands on a Bexarotene prescription just yet.

Re: MS treatment a step closer after drug shown to repair nerve coating

#69

Post by PragmaticPulp »

derefr wrote: post #52
irjustin wrote: post #11

While it is sad that this drug cannot continue for MS directly, I love that this is science work at its best. Experimental drug, through the efforts of terminally ill, are able to discover/show/validate quite powerful benefits, but the drug is too dangerous to use itself. So we stop it. It is progress and many times, progress is not easy nor cost free. Thank you to all those who, even in their terminally ill state, h…

One thing I’ve always wondered is: how many drugs have we rejected like this, which were actually bimodal in their safety profile, the way many drugs are bimodal (or polymodal) in their effect profile. I.e., that there’s some inherent difference between the people the drug harms, and the people it doesn’t; and if you can identify that difference, and test for it, then you can safely give the drug to only the people i…

In this case, adverse effects from Bexarotene are virtually guaranteed, even at low doses. This study explored hypothyroidism in even low-dose Bexarotene and found 61 out of 66 patients exhibited hypothyroidism: https://pubmed.ncbi.nlm.nih.gov/30903705/

Bexarotene also significantly elevates cholesterol markers and blood lipids, which would accelerate heart disease and shorten lifespan.

The researchers aren’t simply dismissing drugs at the first sign of side effects. We have many drugs on the market with significant contraindications due to adverse side effects in specific populations, and doctors are generally well-informed about testing for these conditions and selecting only suitable drug candidates.

Re: MS treatment a step closer after drug shown to repair nerve coating

#70

Post by sterlind »

baldfat wrote: post #66
chime wrote: post #64

> While bexarotene will not go into phase 3 trials for MS, the finding that the nervous system can be stimulated to resheath damaged neurons has given scientists fresh hopes for another trial they hope to launch later this year. That trial will monitor the effects of the diabetes drug metformin along with clemastine, an antihistamine, a combination that Prof Robin Franklin at the Wellcome-MRC Cambridge Stem Cell Inst…

My niece has aggressive MS and Ocrevus didn't help. CRSPR is the true dream. No more MS.

How would CRISPR prevent MS? Autoimmune diseases seem a poor fit.
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