This is a repeat trial but this time in seondary progressive MS. This repeats what was found in relapsing remitting disease.
This is a drug made for asthma, which has been repurposed for use in MS.
This has not occurred with Ibudilast…Why?
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.
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?
As to commitees…it is having a voice that is heard:-(
Yep 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.
Its parked:-(
"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…
I'll have a watch when I am able
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.
Take that as feeding not freeding from the pharma hand…..
If you haven't seen the documentary "Living Proof," with Matt and Ashton Embry, you might be interested. George Ebers is the featured expert and asserts existing drugs do not stop progression.https://www.seelivingproof.com/digital
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)
"existing drugs do not stop progression". We are talking interferons:-(
"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.
Take your pick…Anti-Oxidant is a common one roled out.
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?
Not every one:-(
This press report from the Cleveland clinic redescribes the result for ibudilast as 48% reduction in brain atrophy. https://health.clevelandclinic.org/new-drug-shows-unprecedented-slowing-in-progressive-multiple-sclerosis/?utm_campaign=cc%20posts&utm_medium=social&utm_source=twitter&utm_content=083118%20ms&cvosrc=social%20network.twitter.cc%20posts&cvo_creative=083118%20ms
This news report states that the lipoic acid study showed a "68% rate of improvement in slowing the rate of brain atrophy over a placebo" and noted that for Ocrevus, it showed only a "18% rate of improvement" over a placebo.
https://www.sciencedaily.com/releases/2017/06/170630105055.htm
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
Glad to hear this…Best wishes
These guys are legends. Stop being so blinkered about cladribine and do something else about the disease.
How to answer this commnet…I best not try.
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.