Friday, 25 March 2016

Will it be a Sprint to PPMS

It has been announced that the FDA will fast track the assessment of Ibudilast for the treatment of Progressive MS.

At present a Phase II study in MS is ongoing "Safety, Tolerability and Activity Study of Ibudilast in Subjects With Progressive Multiple Sclerosis" (NCT01982942) Estimated completion = May 2107 


It seems the trial is now recruited.

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study designed to evaluate the safety, tolerability and activity of ibudilast administered twice daily over a 96 week period in subjects with primary or secondary progressive multi
ple sclerosis who are currently untreated with long-term MS disease modifying therapy (DMT) or who are receiving either glatiramer acetate (GA) or interferon beta (IFNβ-1a [Avonex, Rebif] or IFNβ-1b [Betaseron Etavia]) treatment. Study drug will be administered as an adjunct to glatiramer or beta interferon treatment. A total of 250 male and female subjects from 21 to 65 years old, inclusive, are planned to be enrolled into two treatment groups. Randomization of subjects will be stratified by disease status (primary progressive multiple sclerosis or secondary progressive multiple sclerosis) and immunomodulating therapy status: current use of immunomodulating therapy or no current use of immunomodulating therapy.

According to the FDA, in order to be granted Fast Track designation, a drug must (1) be intended for the treatment of a serious or life-threatening disease or condition; and (2) demonstrate the potential to address unmet medical needs for the disease or condition.
A drug that receives Fast Track designation may be eligible for:

  • More frequent meetings with the FDA to discuss the drug's development plan and ensure collection of appropriate data needed to support drug approval;
  • Accelerated Approval, i.e., approval based on an effect on a surrogate, or substitute endpoint reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality;
  • Priority Review, with an FDA goal for completing review within six months of submission; and
  • Rolling Review, which means that a sponsor can submit completed sections of its New Drug Application (NDA) for review by the FDA, rather than waiting until every section of the application is completed before the entire application can be reviewed.

Is this action occurring because the company making Ibudilast has been pushing for this to happen (I suspect so)....... or is it the trial because it is sponsored by the US Government (NIH) & the NMSS.

Has there been any hint that Amilioride, Prozac or Riluzole will be fast tracked, if there is evidence it works in MS-SMART,...Not that I've heard. Is this the difference between academic studies and pharma led studies or pro-active Americans verses lazy bummed Brits.

However, based on what happened with Simvastatin. I think we can be sure of slow track for academic-led stuff:-(The phase II happened in 2010 phase III yet to be funded and by the time it will complete pharma will have found something so that it will never be licensed:-(

As for MS-SPRINT I suspect they will still need to do a phase III if this trial is positive. So access may not happen soon.




MS -SMART is a UK based trial originally intended to test Ibudilast, Amiloride and Riluzole in Secondary Progressive MS.

However, the UK missed out because they could not get a drug supply as I guess it was being funnelled into MS-SPRINT in the USA

I first heard about Ibudilast when someone who had been trawling the patent data base brought this to my attention and wanted us to do some EAE work.

I can now fess up as the trial it has now recruited that I was a little concerned with this choice. 

WHY?

Because of the mechanism of action of Ibudilast and past experience.

Ibudilast is a phosphodiesterase 4 inhibitior....not viagra which is a phosphodiesterase 5 inhibitior.

So phosphodiesterase 4 inhibitors  inhibit enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s).

I first came across these, because phosphodiesterase 4 inhibitors were reported to block tumor necrosis factor (TNF) and not surprisingly it was reported that they block EAE, because at the time tumour necrosis factor was considered to be bad for MS. However...

Does this ring any alarm bells?

You may know that in contrast to EAE when you block TNF then two MS trials in relapsing MS were stopped because of apparent worsening and it seems that anti-TNF can exacerbate MS. Therefore blocking TNF=bad

Now there a loads of different PDE4 inhibitors, another one was called rolipram.

This too could block EAE if used at high doses and was also reported to block TNF. 

However, this could make some symptoms of disease worse in mice, which we reported in 2002 and importantly 

Clinical trial in MS was stopped because it was apparently making MS worse.

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; 15:1206-14

Now you can say that this is yet another example of EAE failing, but rather than it making EAE worse, or better as was originally shown when TNF=Bad,  at doses equivalent to those used in humans, rolipram and ibudilast etc actually did nothing and had no effect on relapsing disease. Showing us that unless we read the animal data properly, we may get the wrong idea.


Thus animals in contrast, what many think actually,  predicted what was found with Ibudilast in humans ...in the first clinical trial there no effect on relapsing disease....No worsening Phew.

So maybe not all PDE 4 inhibitors are created equal. 
(Were the anti-TNF and rolipram trials flukes?.....the occurence in people with arthritis treated with anti-TNF says there is something in it and also that not everyone treated with anti-TNF gets MS so there is something selective in this.

I suspect TNF= good and TNF=bad also but it is context dependent and timing may be critical is what happens when. 

However the ibudilast trial was large and had nearly 300 hundred people in the trial and so if there was a problem you would hope it would have been seen.

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; 74:1033-40. 

However the ibudilast showed that it had no effect on relapses or lesion formation however unexpectedly there was a slowing of disability progression and less brain volume loss, indicating to me that it is neuroprotective. This is the basis for MS sprint. Hopefully there will not be any exacerbations but it there are, you heard it here first, and as people on the trials are on DMT this should be less likely.

It has also been reported that PDE4 inhibitors can promote remyelination

Now you may have missed out on MS-SPRINT, but if you live in the UK there is still time to get on MS-SMART where the trial is now looking at the effect of riluzole, amiloride or prozac. 

If you fit the criteria please consider volunteering click here to find out more

3 comments:

  1. Out of curiosity, what are the side-effects of Ibudilast at the doses that are being trialed in these two trials? It's interesting that Ibudilast is also a vasodilator. Makes me think there may be something legit in the whole CCSVI thing, even if CCSVI itself as a whole is apparently mostly rubbish.

    ReplyDelete
  2. Huuuummmm ...

    So it is there may be a relationship between VitD-EBV-TNF alpha?
    Both good and bad?

    ReplyDelete
  3. Huuuummmm ...

    So it is there may be a relationship between VitD-EBV-TNF alpha?
    Both good and bad?

    ReplyDelete

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