Sunday, 10 September 2017

Hot Topic at the ECTRIMS Late Breaking News

The hot topic of the late breakers news at ECTRIMS 2017 is going to be whether Ibudilast has any efficacy in a progressive MS trial.

The trial is MS-SPRINT and it was a sprint to get access to the agent as both people in the USA and the UK wanted to do a trial...As is often the case the US sprinter won....
Hopefully they weren't on drugs:-) 

The reason there was a desire to do the trial was because of trial failure.


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; 74(13):1033-40.

In this multicenter, double-blind, phase 2 trial, patients with relapsing MS and gadolinium-enhancing lesions were randomly assigned 1:1:1 to receive 30 or 60 mg ibudilast or placebo every day for 12 months. The primary endpoint was the cumulative number of newly active lesions on bimonthly brain MRI over 12 months. Secondary endpoints included relapse rate, change in Expanded Disability Status Scale (EDSS) score, T2-hyperintense and T1-hypointense lesion volumes, and percent brain volume change (PBVC).
RESULTS:A total of 297 patients were randomized in 19 centers. During the first 12 months, the mean number of active lesions and relapse rate did not differ between treatment arms. A reduction in PBVC (p = 0.04) was found in the 60-mg group (0.8%) compared with placebo (1.2%). Post hoc analysis showed a reduction in the proportion active lesions that evolved into persistent black holes for the 60-mg (0.14; p = 0.004) and 30-mg (0.17; p = 0.036) groups compared with the placebo group (0.24). Over 2 years, there were fewer patients (p = 0.026) with confirmed progression on the EDSS. Treatment with ibudilast was generally safe and well tolerated.
CONCLUSION:Ibudilast showed no beneficial effect on the rate of newly active lesions and relapses. However, preliminary evidence suggests that ibudilast seems to act in a neuroprotective fashion as measured by 2 independent MRI outcomes, with a possible beneficial clinical effect on disability progression.

There was no effect on lesion load as the animal studies predicted (What!....They were the justification for the study I hear you say-but please read below), but surprisingly there were less markers of advancement of disease, such as black holes and less atrophy.

This is the type of profile we see with pure neuroprotectants, with no influence on relapses and lesion formation, but a better recovery.



Can a trial of only one year show effects? When all in the past has failed?.

So is ibudilast a neuroprotective?

This was the claim for laquinimod too, but look where this agent is now?

Anyway, The new trial design of Sprint has been reported

Fox RJ et al. Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis.Contemp Clin Trials. 2016 Sep;50:166-77

Background: Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials ares unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and -10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials.
METHODS:SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening.
CONCLUSION: SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.


The trial will assess the outcomes and the treatment agent.

When I first heard about the UK view of it being a candidate, I did not bat an eyelid as I was not aware how it worked.....I'm not a big one for drug names...hey I didn't know that fluoxetine was prozac:-(

But then I jogged by memory and then I felt that MS-SMART had been smart to have avoided it.

Whilst I don't want to be a party pooper, now is a good time to get my concerns off my chest.......again. The first time in public was here
       IPMSA Boston 2015. Do they Remember my concerns?...They weren't bothered at the time                 and didn't ask any questions. So all must be A OK.

Before the SPRINT trial I had heard of Ibudilast a number of years earlier. This is because some one had found it in Japan and they wanted us to do some animal experiments. I wasn't too keen.

Why?

Not that it had been reported to be an inhibitor of macrophage migration inhibitory factor, which you can add to blockade of macrophage chemotactic protein and migration inhibitory protein reported for PDE4 inhibitors and maybe it can inhibit microglia/macrophages, which is interesting.

However, the cytokine I was concerned about was tumor necrosis factor.

Ibudiblast is a phophodiesterase type IV (PDE4) inhibitor. This came to the forefront when the EAEers (including myself) were convinced that blocking TNF was a good thing.

So we had this paper

Sommer N, Löschmann PA, Northoff GH, Weller M, Steinbrecher A, Steinbach JP, Lichtenfels R, Meyermann R, Riethmüller A, Fontana A, et al. The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat Med. 1995;1:244-8.

According to the paper the reason the EAE was inhibited, was because rolipram is a good inhibitor of TNF.

So then we had the me-toos and every PDE 4 inhibitor can inhibit TNF including: rolipram, pentoxifylline and ibudilast to name but a few. 

Fujimoto T, Sakoda S, Fujimura H, Yanagihara T. Ibudilast, a phosphodiesterase inhibitor, ameliorates experimental autoimmune encephalomyelitis in Dark August rats. J Neuroimmunol. 1999 Mar 1;95:35-42.

They can all inhibit EAE, so let's do a clinical trial. 

However that was when we give the rolipram before EAE induction, what happens after EAE is established...Em the wheels start to come off and it ain't that great. I seem to remember trying it and was not that impressed. Some others found that too but, that was too late for planned clinical trials to occur the Nature Med paper prevails.

Jung S, Zielasek J, Köllner G, Donhauser T, Toyka K, Hartung HP.
Preventive but not therapeutic application of Rolipram ameliorates experimental autoimmune encephalomyelitis in Lewis rats. J Neuroimmunol. 1996;68:1-11.

However in 1999 the wheels really came off.

Not with this paper (below) which showed that PDE4 in humans blocks TNF

Pette M, Muraro PA, Pette DF, Dinter H, McFarland HF, Martin R.
Differential effects of phosphodiesterase type 4-specific inhibition on human autoreactive myelin-specific T cell clones.J Neuroimmunol. 1999; 98(2):147-56

Proinflammatory cytokines, secreted by autoreactive CD4+ T lymphocytes may contribute to the pathogenesis of several human autoimmune diseases, including multiple sclerosis (MS). Since the antigen specificities of these T cells are not known at present, therapeutic strategies aiming at common effector pathways, in particular cytokine secretion, may be more feasible in the near future. We have studied the influence of the isoenzyme-specific phosphodiesterase inhibitor rolipram on the proliferation and cytokine secretion of human myelin basic protein-specific T cell clones. The inhibition of proliferation correlated with interference with the IL-2/IL-2 receptor system, while the effects of rolipram revealed an interesting drug profile, with preferential inhibition of TNF-beta, TNF-alpha and IL-10. 



Is it a generalisable thing..sorry to say yes


Feng J, Misu T, Fujihara K, Sakoda S, Nakatsuji Y, Fukaura H, Kikuchi S, Tashiro K, Suzumura A, Ishii N, Sugamura K, Nakashima I, Itoyama Y. Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in multiple sclerosis. Mult Scler. 2004 Oct;10(5):494-8.

We investigated the immunoregulatory effects of ibudilast, a nonselective phosphodiesterase inhibitor, at a clinically applicable dose (60 mg/day p.o. for four weeks) in multiple sclerosis (MS) patients. Sensitive real-time PCR for quantifying cytokine mRNA in the blood CD4+ cells revealed that the ibudilast monotherapy significantly reduced tumour necrosis factor-alpha and interferon (IFN)-gamma mRNA and the IFN-gamma/interleukin-4 mRNA ratio, suggesting a shift in the cytokine profile from Th1 toward Th2 dominancy. In a flow cytometric analysis, natural killer T cells, which have been reported to relate to Th2 responses in MS and its animal model (experimental autoimmune encephalomyelitis), increased significantly after the therapy. None of the significant immunological changes were seen in healthy subjects or untreated MS patients. Ibudilast may be a promising therapy for MS and its clinical effects warrant further study.

They had not read many papers or could not assimilate knowledge because in contrast to the animals, therapeutic TNF was bad news for some people with MS. 


OBJECTIVE:A double-blind, placebo-controlled phase II study was conducted in 168 patients, most with relapsing-remitting MS, to evaluate whether lenercept would reduce new lesions on MRI.
BACKGROUND:Tumor necrosis factor (TNF) has been implicated in MS pathogenesis, has been identified in active MS lesions, is toxic to oligodendrocytes in vitro, and worsens the severity of experimental allergic encephalomyelitis (EAE) in animals. Lenercept, a recombinant TNF receptor p55 immunoglobulin fusion protein (sTNFR-IgG p55), protects against EAE.
METHODS:Patients received 10, 50, or 100 mg of lenercept or placebo IV every 4 weeks for up to 48 weeks. MRI scans and clinicalevaluations were performed at screening, at baseline, and then every 4 weeks (immediately before dosing) through study week 24.
RESULTS:There were no significant differences between groups on any MRI study measure, but the number of lenercept-treated patients experiencing exacerbations was significantly increased compared with patients receiving placebo (p = 0.007) and their exacerbations occurred earlier (p = 0.006). Neurologic deficits tended to be more severe in the lenercept treatment groups, although this did not affect Expanded Disability Status Scale scores. Anti-lenercept antibodies were present in a substantial number of treated patients; serum lenercept trough concentrations were detectable in only a third. Adverse events that increased in frequency in treated patients included headache, nausea, abdominal pain, and hot flushes.
CONCLUSIONS:Lenercept failed to be beneficial, but insight into the role of TNF in MS exacerbations was gained.

Anti-TNF makes memory B cells increase in some people!

But I guess the neuros had ignored earlier data

van Oosten BW, Barkhof F, Truyen L, Boringa JB, Bertelsmann FW, von Blomberg BM, Woody JN, Hartung HP, Polman CH. Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2.Neurology. 1996;47(6):1531-4

So there you have it. It looks like anti-TNF can exacerbate MS (There is plenty more evidence from arthritis studies with anti-TNF), and PD4 inhibitors block TNF, so PDE4-inhibition in MS is a good thing? It couldn't make MS worse? Could it?

Bielekova B, Richert N, Howard T, Packer AN, Blevins G, Ohayon J, McFarland HF, Stürzebecher CS, Martin R.Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood--brain barrier disruption in multiple sclerosis. Mult Scler. 2009 ;15(10):1206-14. doi: 10.1177/1352458509345903.

Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective (Is it really) in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear.

So based on selective vision of animal models,  a trial was done and it was stopped because of a sense of worsening. Rolipram really didn't work as an immunomodulator in relapsing EAE, so failed in RR, just as did Ibudilast did (see above). So don't blame the animals.

So what's going to happen when it is used progressive MS, which is not noted for its MRI activity. Hopefully no worsening but anti-TNF has been tried in SPMS

Skurkovich S, Boiko A, Beliaeva I, Buglak A, Alekseeva T, Smirnova N, Kulakova O, Tchechonin V, Gurova O, Deomina T, Favorova OO, Skurkovic B, Gusev E.Randomized study of antibodies to IFN-gamma and TNF-alpha in secondary progressive multiple sclerosis. Mult Scler. 2001;7:277-84.

Studies of cytokines in multiple sclerosis (MS) have shown that immune mechanisms connected with disturbance of the synthesis of cytokines probably play critical roles in the initiation and prolongation of MS. In a double-blind, placebo-controlled trial, 45 patients with active secondary progressive MS were randomized to three groups of 15 patients, each receiving a short course of antibodies to IFN-gamma, to tumor necrosis factor (TNF)-alpha, or a placebo. After 12 months with analysis of disability (Expanded Disability Status Scale scores), accompanied by interval determinations of lymphocyte subpopulations, cytokine production levels, MRI, and evoked potentials, it was found that only patients who received antibodies to IFN-gamma showed statistically significant improvement compared to the placebo group.


So anti-TNF in SPMS did nothing (didn't make things better)...is this the exception of the rule? We will soon find out. I really hope it is not, but.......

Myers LW, Ellison GW, Merrill JE, El Hajjar A, St Pierre B, Hijazin M, Leake BD, Bentson JR, Nuwer MR, Tourtellotte WW, Davis P, Granger D, Fahey JL. Pentoxifylline is not a promising treatment for multiple sclerosis in progression phase. Neurology. 1998; 51(5):1483-6.

Fourteen MS patients took pentoxifylline at varying doses for up to 24 months. In vitro production of tumor necrosis factor alpha was reduced in patients taking 2,400 to 3,200 mg/day of pentoxifylline for 12 weeks or more. Twelve of the 14 patients experienced worsening of the disease during the study according to clinical, MRI, or visual evoked potential criteria. These results provide no hint of efficacy for pentoxifylline as a treatment for MS in progression phase.


So two PDE inhibitors make MS worse, should a third have been tried?

Too late now, just as it probably was when I aired my concerns about this in March 2015 

But if it bad news in Paris 2017, you now know why. 
If it isn't, is it luck or Good Design?

However, I need to say now the fact that the study by Barkof et al. 2010 was not associated with worsening and is was a large trial and no worsening was reported, which is a good thing and may serve to ease my concerns

Ibudilast (AV111, MN-166) is a drug that has been used for the treatment of asthma in Japan for about 20 years and has been taken by millions of people. Maybe this needs  

It appears that the effect of blocking migration inhibition factor is not a typical product of PDE4 inhibitors and there are variants of ibudilast which lack PDE4 inhibitory activity, such as AV1013  (Coy et al.2013). 

The company supporting the trial will no doubt have to make an announcement to its shareholders before the results are announced at ECTRIMS.


Not long to wait now.

14 comments:

  1. Oh dear :( and it all sounded so promising. Sounds like (yet another) case of not bothering to rtfh (read the handbook). Thanks for talking us through all that MD although I can hear the tired despair in your voice :(

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  2. If anti-TNF could actually play a role in SPMS (does the immune system response alter on its own after a point?), could this too?

    I just read this on a evolved -not actually new- approach on depression
    http://www.telegraph.co.uk/science/2017/09/08/depression-physical-illness-could-treated-anti-inflammatory/?WT.mc_id=tmgoff_fb_tmg

    "Prof Kevin Tracey, President and CEO, of the US Feinstein Institute for Medical Research, discovered that the brain controls production of a deadly inflammatory chemical called TNF, which if released in high doses can be fatal, causing people to, literally, die of shock.

    He has recently developed a electrical device which reproduces the connection and switches off the chemical. Three quarters of patients with rheumatoid arthritis recovered following trials."

    Probably not useful for MS, but the article has some interesting points on how inflammation in the body can affect the brain, not only through the known blood-brain barrier.

    "However a link has taken so long to establish because until recently scientists believed the brain was entirely cut off from the immune system, trapped behind a ‘Berlin Wall’ known as the blood brain barrier.

    But recent studies have shown that nerve cells in the brain are linked to immune function and one can have an impact on the other."

    Is this of any importance for MS? Maybe. Maybe not.

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  3. I need to read but sounds like the vegal nerve story which I think is being trained in ms.

    With regards TNF it clearly does good things as well as bad things when it comes to MS, but you can't dissociate the two.

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  4. Isn't that Robert Fox in the front of the picture, didn't he question your comments?

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  5. Well, no one can call you a "bandwagon jumper" as you have most definitely called your negative shot on Ibudilast early. Thanks for this very informed update MD.

    I hope you are wrong as anyone in later stages of RRMS, SPMS or PPMS has not one meaningful treatment approved at this time to neuroprotect, remyelinate or neurorestore.

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  6. You all asked about what looked interesting in the program. I'm interested in the CLIMB and SUMMIT studies by Howard Weiner, and whether the mid-point results offer any insights for PPMS patients. He's speaking on gut microbes, which he is sampling as part of these studies. Since all the patients studying this blog probably, like me, tend to search for hints about when/how far they will progress, this study seems interesting and has potential for answering some of the major big unknowns in MS research/care. Are there other international studies that are comparable? (This should probably go in the September thread - sorry just thought of it reading about another company trying to search for a money maker despite little signs of efficacy.)

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  7. "You all asked about what looked interesting in the program."

    Get rid of EBV and you get rid of lessions..maybe.
    Now that's brain health.

    Abstract Title: Molecular signature of Epstein-Barr virus infection in multiple sclerosis brain lessions
    Lead Authors: May Han, M.D., and Lawrence Steinman, M.D.
    The meeting will also feature new results by Atara and its collaborating investigators at Stanford Medicine characterizing the molecular signature of EBV in MS brain lesions

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  8. "I'm interested in the CLIMB and SUMMIT studies by Howard Weiner"

    Hope they've got some results..will look for it. Cause looks like a huge costly study..counted 26 people on their staff photo.

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  9. Nice work Mouse Dr

    Did´nt the anti-tnf alpha therapy worked in rheumatoid arthritis?

    Obrigado

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    Replies
    1. Yes it did and made a few bob for Prof Marc Feldmann for the treatment of arthritis. I had the patent for MS with him, it made nothing:-(

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  10. The Atara Bio looks very interesting indeed and hopefully to the point -until proved otherwise. It might seem naive, but what I dont understand is that it still is an immune modulator mechanism instead of a regenerating one, that works well on SPMS and PPMS where all the others fail (even the most "potent DMT", HSCT). How is that possible? How come they have such a mechanism and they tried it first on PPMS and not RRMS where they would possibly have better results? I guess wait and see.

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    Replies
    1. They have a immune mechanism and tried it first in PPMS what do I think...Stupidity

      Delete

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