MS-SMART 2. Is it coming?

M


Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis.
Cunniffe N, Vuong KA, Ainslie D, Baker D, Beveridge J, Bickley S, Camilleri P, Craner M, Fitzgerald D, de la Fuente AG, Giovannoni G, Gray E, Hazlehurst L, Kapoor R, Kaur R, Kozlowski D, Lumicisi B, Mahad D, Neumann B, Palmer A, Peruzzotti-Jametti L, Pluchino S, Robertson J, Rothaul A, Shellard L, Smith KJ, Wilkins A, Williams A, Coles A.J Neurol Neurosurg Psychiatry. 2020 Nov 12:jnnp-2020-324286

Objective To establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS).

Methods We long-listed licensed drugs with evidence of human safety, blood–brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review.

Results From a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine.

Conclusions We report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.

This was planned that to have been access but Nick (Cunniffe) has sent me the accepted version. I have put it in dropbox

https://www.dropbox.com/s/cfara6nyfjedr76/JNNP%20submission%20accepted%20for%20university%20open%20access%2012Nov2020.pdf?dl=0

The MS Society are leading the charge to try and find treatments for progressive MS and they first undertook meta analysis of different treatments

Drug repurposing: a systematic approach to evaluate candidate oral neuroprotective interventions for secondary progressive multiple sclerosis. Vesterinen HM, Connick P, Irvine CM, Sena ES, Egan KJ, Carmichael GG, Tariq A, Pavitt S, Chataway J, Macleod MR, Chandran S.PLoS One. 2015 Apr 9;10(4):e0117705.

There a set criteria was used select potential treatments and they “identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation”. Ibudilast was already taken by the Americans for SPRINT-MS so riluzole, amiloride, fluoxetine were tested in a trial call MS-SMART. Sadly these all failed to influence progression as assessed by brain atrophy.

Therefore we got egg on our faces and it seemed it was “MS not so Smart”. People may say that Ibudilast fit the bill and it showed some effect

Fox et al.Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 week

However you can say that they they already knew it could work because of the failed relapsing study.

Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R; MN166-001 Investigators. Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant? Neurology. 2010 Mar 30;74(13):1033-40

Ibudilast is a phosphodiesterase type IV inhibitor and both rolipram and pentoxyfylline had been found to be of no use or worse in relapsing MS

Now I will admit I was there, when the drugs were selected, but was not part of selecting the approach. I am not a big fan of meta-analysis if it is not interlinked with biology and proper understanding. For example meta-analysis of animal data was never going to be useful, as the way EAE is used it is a relapsing not progressive model.

Ibudilast was perhaps a reasonable candidate because it had shown positive effects on brain atrophy. Riluzole was found to inhibit motor neuron disease, but in our hands was really rather toxic in animals and pretty sedative. I thought amiloride was the best candidate at the time as it did seem to induce neuroptotection in mice, but had no experience of it. However, witinh a few months of the trial starting, other trials in MS questioned whether riluzole and fluoxetine were going to be of use.

Not deterred it is time for round two. There are alot of people involved

One group was charged with trial design. There is a desire for an adaptive design where you start off with a few drugs, if they fail you replace with other candidates. This approach was pioneered in cancer. In cancer the trial design and outcomes are easy as it is survival from cancer. In MS it is way more complicated as there are different processes occuring that influence the trial design and outcome. If it was a trial to inhibit relapsing MS I would say not problem, but for progressive MS, you are not working to a tried and tested formula for success.

I have strong opinions on clinical trials and firmly believe that it does not matter what candidates you select, if the trial design is wrong the trial fails. Whole brain atrophy can have issues as a main outcome and this was highlightd with the failed lamotrigine trial, in that it appearred to cause shrinkage. However it also highlighted that lamotrigine is a problem because the epileptic dose is too high for MS and people simple did not take the drug due to side effects. If you don’t take the drug it can’t possibly work no matter how much supportive data there is.

We have been arguing that to get protection that you need to do add-on studies with potent disease modifying treatment on the bottom. Once you do this the value of neurofilament light as an outcome measure will be an issue.

However, the other Group was a drug selection process and this paper describes that process. This was chaired by ProF Coles from Cambridge. The Chairs (Drug selection and clinical trial lead) had agreed that they would not be recipients of any grants. This time the approach was based on opinion of the some of the participants and it was decided that it would be mechanistically focused. The agreed mechanistic areas were: (1) energy, blood flow and mitochondria; (2) the neuron and axon; (3) sodium channels; (4) microglia and astroglia; (5) intrathecal B cells and plasma cells; (6) demyelination and myelin repair; and (7) antioxidants. It was also agreed that the process of drug selection should be literative.

A list was drawn up and drug characteristics were assessed.These were scored

However, it was decided that alternative appoaches would be used and other selection processes occurred and found similar options.

I was not at the final selection meeting and so cannot be credited or chastised for the choices. Some seemed obvious and others I have doubts. These doubts included thinking that they may not work. I guess top of the list was lipoic acid as there is clinical evidence that it may works and it will never be develoed by pharma. It is trial ready and you dont need to do any animal experiments. To develop some of the others you may need more work.

As you know there has been a lot of interest in metformin as a rejuvenator, so this was added to the mix. Therefore, you have a neuroprotective (lipoic acid) and a repair agent (metformin), surely it has to go on top of an effective disease modifying treatment!. But now you see that the trial design is key. Shoulf the trial design for a repair agent be the same as a neuroprotective agent?

I understand that another trial aims to examine clemastine and metformin as a repair agent.

However, I hope you can see that the UK scientists and clinicians are working together to try and bring treatments to progressive MS. The MS Society have been doing their bit co-ordinating this and fund raising.

There will be a calmor to start late to give options to people with progressive MS ….but this makes the task harder to get a positive answer . Start early to get maximum opportunity to show an effect.

What do you think?

About the author

MouseDoctor

30 comments

    • The authors would have had their chance…as there was an open call for people to make requests for agents to be looked at. I think the remylination section had the most different agents…However, this process was started 2-3 years ago so if something appeared in July 2020 it was too late. It is one of the many remylination pathways and Theophylline is used in COPD, but it should not be used outside of a controlled trial as it can cause seizures. Potential side effects was one of the reasons drugs were removed by the members with MS…including one of our candidates…ProfG probably killed it off by being too frank about one side effect…others discussed before profG spoke with way worst side effects sailed through because the side effects weren’t mentioned by the advocates.

      How to do a trial…Look at the bexarotine tiral and replicate the positve electrophysiology data

  • Lipoic acid comes out top of the list, I already buy that through Amazon or at my chemist.
    I’m not the only one who already takes it. Would we have to stop taking it if we were accepted for the trial, should it get off the ground?

    • yes the trial would be randomised to lipoic acid, metformin, lipoic acide + metformin or placebo. However you highlight why these approaches never really develop, because if one can access a treatment many people will try it on the off chance it work. Obviously there is the dose..I am not sure what the oregon group use and here you have an problem as the regulators want dose responses, where is it?

  • Thanks for the update MD.
    This time trial participants may also be taking siponimod or ocrelizumab 🙂

    Out of interest (relevant to metformin) where a dose in animal studies suggests a high dose in humans, would a lower dose also have been tried in the animals? Just wondered how these things work? Easier to try different doses in animals before embarking on human trials…?

    There’s a kinda pattern emerging with these repurposing trials, take the usual daily dose and double for good measure:

    Lamotrigine 200mg epilepsy = trial 400mg
    Simvastatin 10mg to 40mg cholesterol = trial 80mg
    Metformin 2000mg diabetes = (mouse study suggests) 3750mg…. wonder what dose will trial design go with?

    I was one of the pwMS at the meetings. Don’t remember pwMS being over sensitive about side effects, but you could be right. As you point out, no treatment likely to do much if not taken.

  • Lipoic Acid and Metformin look like an interesting choice as they seem to have a good potential risk-benefit profile. When are the trials expected to start? Just wondering, what dose they might use (fo R-LA, Metformin, R-LA + Metformin)? The Oregon Health and Science University trail uses 1200mg racemic LA (not R-Lipoic Acid). They also do a comparison study with racemic LA of 1200mg and R-LA of 600mg. As for Metformin, I know only about a double blind study of Metformin in children with multiple sclerosis. The dose they use: dose of 500 mg/m2/day po (to be rounded) given in 1 or 2 divided doses for one week and if there are no side effects increased to 1000 mg/m2/day po given in 2 divided doses up to a maximum dose of 2000 mg/day.

    • The MS Society has been running a campaign to raise £100 million pouunds…Obviously this was on schedule before COVID-19 arrived

      • Maybe someone could get in touch with J.K. Rowling. Her mother died because of MS. I can imagine she would donor if someone reaches out to her. She already donored to the MS Society.

        • Although she can do what she likes with her money….It has largely all been ploughed into Edinburgh..to build buildings:-(. ProfG has tried to contact her but she is a guarded treasure and the only way in is via Scotland and I think does not donate to stuff South of the Border.
          So please JKR…spread the love!

  • One of the think i have study a lot (not only in ms)
    Was the efect of lipoic acid in the body
    One thing to remmber is that some antioxidant like Lipoic acid can be both anti ,and prooxidant

    Be mindfull of the dose

    If you want to learn more google Ufuk cakatay

  • Why is ALA written as “r-a-lipoic acid 1200mg”? while in the referenced studies “ 1,200 mg daily oral racemic LA” is used. In the referenced studies r-a-lipoic is not even mentioned. Why was this difference made?

    • A racemic mixture has an axis for example in one variant an arm point forwards and in the other it point backwards they are designated R or S

      • Boa Mouse
        🙂

        Can i had?

        Lipoic acid is a a Chiral molecule

        In chemistry, a molecule or ion is called chiral (/kaɪˈræl/) if it cannot be superposed on its mirror image by any combination of rotations and translations. This geometric property is called chirality.[1][2][3][4] The terms are derived from Ancient Greek χείρ (cheir), meaning “hand”; which is the canonical example of an object with this property.

        https://en.wikipedia.org/wiki/Chirality_(chemistry)#/media/File:Chirality_with_hands.svg

          • MD and Luis, thank you for explaining of chiral molecules, but my real question still remains: in the trails the used the R and S forms (racemic) and in this proposal specifically the R form is mentioned?

            Is there any clinical motivation why they proposed this specific form? Do they work differently?

          • R (+) and S (-) can work dramatically differently that HU210 the R is is a highly potent cannabinoid receptor agonist and in the S form (HU211) it is an NMDA glutamate receptor modulator.

            As for lipoic acid I was not part of the selction process although R mediates the benefit, it seems S helps with the stability. If this approach is taken forward I am sure they will be informed by the manufacturers as formulation is going to be key. Likewise they would be foolish not to contact the oregon group with all the experience.

            Racemic mixture versus R-lipoic acid only
            R-lipoic acid is the isomer that is synthesized by plants and animals and functions as a cofactor for mitochondrial enzymes in its protein-bound form (see Biological Activities). Following the ingestion of R,S-lipoic acid, peak plasma concentrations of R-lipoic acid were found to be 40%-50% higher than S-lipoic acid, suggesting better absorption of R-lipoic acid. Both isomers were nonetheless rapidly metabolized and eliminated. It has been suggested that the presence of S-lipoic acid in the racemic mixture may limit the polymerization of R-lipoic acid and enhance its bioavailability.

      • Is r-a-lipoic acid the one available through most stores over the counter? I take 1200mg ALA a day, and I must say, it has done wonders when it comes to my MS symptoms.

          • Hi,

            I assume this question was meant for me?

            Since starting taking it I have;
            – lost the sunburn sensation I used to have on the right side of my neck
            – the weakness in my left arm and leg has improved
            – the cold, itchy and dry feeling on my skin is gone
            – I’m not as sensitive to poor sleep, when it comes to getting fatigued
            – I feel better in general

            Before these things were going up and down, but the feelings was always there in a way still.

            I still have some memory issues though.

            I had my first and only recognizable attack september 2018. Finished last round of oral cladribine decembwr 2019. Started taking lipoic acid august 2020. Of course, the improvements could probably be attributed to a lasting effect of the cladribine, but I feel it is a bit too much of a coincidence how I started feeling improvments gradually since 2-3 weeks after starting taking ALA. Now I am terrified about stopping taking it.

  • Thanks again MD and Luis, it becomes clear for me there is a (suspected) difference between the forms in clinical effect, bio availability and proberly riskpeofile as well. We will have to wait for the exact mixture if the study takes place.

    The following meta analysis made it understandable for me:

    http://morelife.org/supplements/RLA.html

    Conclusions

    The studies listed above have shown that:
    SLA has effects in the body which are different than RLA.
    Although SLA is an excellent antioxidant (but RLA is better) none of the other effects of SLA have been shown to be beneficial.
    Since SLA does not naturally occur in the body and consequently the body has not developed mechanisms to deal with it, the effects of non-physiological doses of SLA are more likely to be harmful than are non-physiological doses of RLA which does occur naturally in the body and for which it does have mechanisms to deal with it.
    Therefore, SLA should not be considered as mere filler in the racemic mixture of enantiomers which is widely available on the supplement market, but should be considered potentially harmful until proven otherwise. This not to say that non-physiological doses of RLA may not also be harmful, only that they are less likely to be so. In particular, RLA is likely to be less harmful and more beneficial than the racemate generally used.
    The concluding remarks from the chapter on RLA in The Handbook of Antioxidants, aptly summarize these conclusions:

    “Since, the popularity and the interest in LA as an antioxidant are rising, there is, therefore, a need for better understanding of the pharmacology of this compound. Frequently, the two enantiomers of LA the R- and the S- forms do not have the same potency and biological efficacy. Occasionally, the biological effects exerted by one enantiomer were cbontradicted by the other form. However, so far R-LA, which is the natural form of LA, was superior and with more potent pharmacological activity than S-LA in all of in vitro models and clinical experiments. The two enantiomers of LA should be looked on as two different pharmacological agents, antioxidants, or drugs.”

  • Mousedoctor, can I ask for your opinion about the application of three of the substances mentioned in this article and in the following comments? Don’t Metformin, Lipoic Acid and N-Acetyl-Glucosamine (GlcNAc) all affect blood sugar as well in one way or the other? How would that affect the use of the combination of any of them? E.g. different dose should be applied in combination than alone or any restriction for their combination, etc.?

  • Why use a slow release niacin when it causes more damage to the liver than instant release? Increasing NAD+ levels in the blood will translate to greater NAD+ levels in the brain once it crosses the BBB. Niacin is a better choice than using NMN since it has been seen to accumulate in the mouse brain which could cause axon degeneration. NAM also has been seen to give good results in mice possibly due to it’s ability to increase NAD+ levels rapidly in the brain since it can cross the BBB, however it is known to inhibit the sirtuins which could be a good thing? could it be inhibiting immune cells within the brain which NAM can bind to?

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives