Treatment of Progressive MS, A new era dawns

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A comment yesterday said “Come on, give us something to help us get out of bed in the morning, something to slow down the progression to social isolation and total disability”


News for the US has surfaced that says we are on the way.

This is a repeat trial but this time in seondary progressive MS. This repeats what was found in relapsing remitting disease.

This study shows that brain shrinkage is slowed, but not halted, by ibudilast.

This is a drug made for asthma, which has been repurposed for use in MS.

Ibudilast is a phophodiesterase 4 (PDE4) inhibitor. These agents block tumor necrosis factor (TNF) and so could be anti-inflammatory, indeed that is part of their use in the lung diseases.

However, we know that TNF blockers have been shown to make MS worse or even trigger MS in people treated for arthritis with these drugs. Indeed trials with rolipram a PDE4 inhibitor was stopped because of disease worsening.

This has not occurred with Ibudilast…Why?


Simple answer is…I don’t know. I had hoped that CNS penetration may be an answer as anti-TNF has low CNS penetration, butrolipram and ibudilast get in the brain

However, it tells us that not all drugs are created equally, but what is the difference?


Ibudilast inhibits TNF but also block a macrophage migration factor (MIF) also known as glycosylation-inhibiting factor (GIF), L-dopachrome isomerase, or phenylpyruvate tautomerase.


Is this the key difference?

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis. Fox RJ, Coffey CS, Conwit R, Cudkowicz ME, Gleason T, Goodman A, Klawiter EC, Matsuda K, McGovern M, Naismith RT, Ashokkumar A, Barnes J, Ecklund D, Klingner E, Koepp M, Long JD, Natarajan S, Thornell B, Yankey J, Bermel RA, Debbins JP, Huang X, Jagodnik P, Lowe MJ, Nakamura K, Narayanan S, Sakaie KE, Thoomukuntla B, Zhou X, Krieger S, Alvarez E, Apperson M, Bashir K, Cohen BA, Coyle PK, Delgado S, Dewitt LD, Flores A, Giesser BS, Goldman MD, Jubelt B, Lava N, Lynch SG, Moses H, Ontaneda D, Perumal JS, Racke M, Repovic P, Riley CS, Severson C, Shinnar S, Suski V, Weinstock-Guttman B, Yadav V, Zabeti A; NN102/SPRINT-MS Trial Investigators. N Engl J Med. 2018 ;379(9):846-855.
Background There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.
Methods We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.
Results Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. 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 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.
Conclusions In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression.


Gastrointestinal side effects are a common problem of PDE4-inhibitors and shows some efficacy. So what next? 

Clearly a phase III will be needed to show clinical benefit. But that means a 2-3 year trial and a 5-6year wait. Is this any better that a statin. However one thing we know and thatt is that ibudilast does not inhibit relapsing disease .

To my mind we need to learn from this and rather than plough on with a sub-optimal clinical trial with a single neuroprotective compound. 

It would be sensible to add this on top of an induction treatment like rituximab/ocrelizumab, cladribine or CD52, so you remove the immune-mediated neurodegeneration element occuring in progressive MS as well.

Not to do this is simply pandering to the academic neurologists, but we need to remember that it is not their brain they are not saving, it is your brain they are not saving. 

So if you are thinking of doing a trial in advanced MS, you simply have to ask why are we not thinking this way.

Will pharma follow in the Ibudilast trail?  

If they do, what aspects of ibudilast need to be replicated as PDE4 activity alone is not enough. 

I will be off to eat my hat as I was concerned of disease worsening by this approach, but shows that sometimes you have to stop procrastinating and “bite the bullet” and do the trial

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MouseDoctor

24 comments

Leave a Reply to JoH Cancel reply

  • MD, fantastic post, thank you. I really wish MD2 and yourself were on steering and approval committees of trials.

    I 100% agree with studying neurodegenerative prevention drugs with neuroinflammatory drugs concomitantly instead of sequentially as "time is brain". Most of us do not have the luxury of time.

    Also, I thought ibudilast works mainly through inhibiting "hot" microglia?

  • So – is someone going to do the trial? C'mon, there are thousands of us out here who feel we have nothing to lose… well, actually, I do have grey matter to lose, and I'd really rather not.

  • "It would be sensible to add this on top of an induction treatment like rituximab/ocrelizumab, cladribine or CD52, so you remove the immune-mediated neurodegeneration element occuring in progressive MS as well."

    With respect, I don't buy into this constant insistance upon immunosupression, immunosupression, immunosupression. Is it actually _known_ as yet that immune system flares, i.e. relapses, will not be dampened down or made relatively inconsequential by a relatively harmless neuroprotective agent, perhaps rendering immunosuppressive DMTs essentially redundant? And is there not argument about the use of relapses as clinical outcomes being fallacious, e.g. Prof. George Ebers (https://www.youtube.com/watch?v=OqY-_K1fYJY)?

    And is it not true that immunosuppressive DMTs make pharma an awful lot of money…

    • Complusory viewing…

      As you know I am no fan of the CRAB agents and remember that NICE concluded that the efficacy did not justify the cost, so you can't make sweeping statements..but I am interested by the Content.

      We know that the CRABs have been cash cows for pharma, that is why they contniune to invest in MS.

      I have heard Prof Ebers speak many times and he has been critical, but when I asked him to do a guest post the mouse came out and nothing was said.

      Maybe in retirement he feels he can say more in public, however his comments do not fit the times and it is just as well he has retired from Neurology if he still holds these views

      In addition,there is some hypocrasy here as he was freeding from the Pharma hand and was part of the pharma advertising machine and was paid for this. I know from peronsonal experience.

    • I don't think it's fair to call Prof Ebers a mouse for not stating his views on this blog, is it? He seems to be quite outspoken elsewhere. I don't know enough and it is not my place to defend him but I think all neurologists have to work with pharma to some degree, do they not? At least he tried to get pharma to do the necessary trials to establish effect on progression? Cattiness is not becoming of you! ;o)

    • "Is it?" Why not?

      "All neurologist havve to work with pharma"…I guess so as they are supplying the tools

      Do all neurologists have to feed from the pharma hand?..Not really.
      so "Cattiness"…Not really.

  • Is it possible to compare these results with the prior studies of lipoic acid (which was found to slow brain atrophy even more dramatically I believe)? I don't think the lipoic acid news reports mentioned a mechanism of action.

    • Not sure how anti-oxidants would limit atrophy. I also take Mito-Q for michondrial "support" but also not sure exactly that limits atrophy.

      Is 48% in "reduction of brain atrophy" referring to the same thing as 68% "rate of improving the rate of atrophy." I'm a little confused that's why I posted about both press reports.

      Why is everyone so excited about ibudilast if lipoic acid (if I understand correctly) had better results? Because companies can't get a patent for lipoic acid so that will go nowhere and everyone knows that?

  • Many thanks for responding to my whinge/moan and giving us some hope.

    Lipoic acid, now that's interesting. Fampyra and lipoic acid are working wonders for me

  • How much is the reduction in brain atrophy in %age terms? Simvastatin reduced atrophy by 40% a year, I think. In the Phase II trial. I had a very depressing conversation with a medical statistician who said that effectiveness is always reduced in Phase III trials compared with Phase II.

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