Wednesday, 19 August 2015

Will ignoring the voice of class mates lead to bad test results

The original idea for MS-SMART was to test Ibudilast, but as a subsequent study SPRINT-MS in the USA was also planned to test Ibudilast, would it be a good use of funds to do this? 

The US team won in terms of getting access to the drug, the UK failed. 
This drug is also known by MN-166 and has a company interest in this. They are funding the development in the USA, so it is best to let them get on with it. 

If the UK trial had gone ahead, it could have helped get Ibudilast licensed as you would have had two trials within short space of each other.  

However, would it look good for the UK government to be funding commercial development of a foreign drug company.

However,this is a interesting one in relation to the post above and remember the following is just an opinion and not necessarily the right opinion:

Ibudilast is a phosphodiesterase type 4 inhibitor, commonly referred to as a PDE4 inhibitor. 

This is a drug used to block the degradative action of phosphodiesterase 4 (PDE4) on cyclic adenosine monophosphate (cAMP).The PDE4 family of enzymes are the most prevalent PDE in immune cells. They are predominantly responsible for hydrolyzing cAMP within both immune cells and cells in the central nervous system.

The clinical development of PDE4 inhibitors has been hampered by their potent emetic (nausea-causing) effects, but there are many different PDE4 inhibitors that have been used in humans. 

Ibudilast is one, rolipram is another and pentoxifylline is another. One would think that the class of all PDE4 inhibitors could do similar things, although there may be subtle different side effect issues. So when looking for the effect of ibudilast it is worth considering what has happened with other PDE4 inhibitors, notably rolipram.

I take a good old bashing for the failure of EAE to predict things in MS. This is from you the public who are not getting useful drugs, and from Neuros who are not getting positive trials. 

As you can appreciate I have been getting a bit sick of this point of view and there may be alternative views.  One view could be that pharma and neuros can get hooked on the over-inflated optimism and the take home message of a scientist and can do trials without actually reading the data.

First thing
(a) Animal data does not usually get published unless it is positive!

(b) Animal data, needs a mechanism for publication and typically this follows current dogma for its mechanism of action! Now it is Treg function, ten years ago it was Th2, thirty years ago it was T suppressor cells. I take flak for this attitude by my peers, but simply do a meta analysis and prove me wrong!

(c) The dose and time of drug delivery is optimised to show an effect in EAE! You keep going up in dose until it does something!

(d)  Animals are kept in clean environments and experiments are too short for side effects to be important and rodents can not vomit so the emetic effect of PDE4 is not an issue in mice and rats, so you can give more and more drug until it does something. 

Shrews vomit and it is not a pretty sight..... put me right off my lunch when I saw this a a meeting. MD2 can verify:-)

So what does the animal data say to me........PDE4 inhibitors will not inhibit relapsing MS and could make disease worse

What did the data in MS say..........PDE4 inhibitors do not inhibit relapsing MS and worryingly says it may just make MS worse.

What do I mean....The clinical trials were done because of the animal experiments, read the neuro-reviews!!. 

Yes I agree but, if the neuros had cared to read the data rather than the headline/abstract, would they have asked for more animal experiments before spending millions on trials and maybe wasting your time.

If we go to (b) above. When PDE4 inhibitors were first examined in EAE (Sommer et al.1995), the dogma was TNF is bad, block TNF with antibodies and it inhibits EAE, PDE4 inhibitors inhibit TNF, and PDE4 inhibitors block EAE...Bobs your uncle...Off we go clinical trial next but...

Oops block TNF in MS is not necessarily good and blocking it makes MS worse! (Trials of anti-TNF in MS are stopped), but never mind carry on regardless, So inhibit PDE4 in MS what do you get.... a block of TNF and nothing or crap maybe it can make MS worse!

Bielekova B, Richert N, Howard T, Packer AN, Blevins G, Ohayon J, McFarland HF, St├╝rzebecher 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

Abstract-"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"

Is it the animal's fault and was it really that unclear what could happen?

Was this a real worsening or just bad luck as the trial only had eight people on drug before the trial was terminated for safety reasons

But what did the animal data really show 

The human dose of PDE4 inhibitors is variable. 
Rolipram (0.1mg/kg), Ibudilast (0.5-1mg/kg), Pentoxifylline (30-40mg/kg). They all appear to inhibit TNF. 

One of the functions of TNF is to control infections and PDE4 inhibitors tend to cause infections and gastrointestinal problems. Indeed the initial development of Rolipram was halted for this reason. Now we know infections are a trigger for relapse 

Trials of anti-TNF in MS were halted because they appear to make MS worse, a trial of rolipram was also stopped because it appeared to make MS worse, and pentoxifylline did not stop progression but as it was not controlled, we could not say if it made things worse. 

The phase II trial of Ibudilast failed in RRMS (Barkhof et al. 2010), just as would have been predicted from the animal work.

If you look at animal studies you can find that some doses of PDE inhibitors can control EAE. However, in general they fail to have much of a significant effect (The lower the impact factor of the journal, the lower the effect in EAE) and only have an effect when the the doses of the PDE4 inhibitors are high or the drug is delivered early

Pentoxifylline is generally rubbish as stopping EAE even up to mega (200mg/kg) doses and has no real effect on MS. There are few studies with Ibudilast and it did not work therapeutically and only worked prophylactically (i.e. give before disease is manifest, which has no clinical correlate) at high doses(30mg/kg). Similarly rolipram tends not to work therapeutically and only works well prophylactically at doses more than 5mg/kg  (in the positive studies) and doesn't work at 1mg/kg or below,  which scaled down to the human dose is about 0.1mg/kg.  

So PDE4 inhibitors at sensible doses don't inhibit disease in animals very well. Why would they be expected to inhibit human neuroimmunological disease? Beats me, so is this not a failure of animals in the translational process or it is more of a failure of humans? 

However, you can get humans to have blood levels of ibudilast that control pain in rats (Rolan et al. 2008)

Maybe it is time that people using animal studies and importantly the reviewers and the editors read the ARRIVE guidelines that suggest some discussion of the relevance to human use. In many cases animals studies are done before people know anything about a human study or dose, but for the PDE4 inhibitors this was not the case.

In animals it is clear that TNF can have pro and anti-inflammatory effects, some studies indicate that blockage of TNF may stop nerve damage and nerve signalling. However, it was of interest that whilst Ibudilast had no effect on relapsing MS, it appeared to have a neuroprotective effect as the accumulation of disability and MRI black holes was slower. 

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; 74:1033-40T

This is why MS-SPRINT in primary and secondary progressive MS is occurring. This is similar to what appears to happening with Lacquinimod, because they must be affecting the inflammatory penumbra. 

What will happen in progressive MS? The truth is I don't know there is an indication that it could be neuroprotective. 

The trial above with Ibudilast involved nearly 300 people. Therefore, it must be said that the enhancement of gadolinium lesions seen with rolipram thankfully did not materialize.

Likewise, MS has entered a post-relapsing phase in the up and coming trial and so induced relapses may not occur and not all studies with anti-TNF showed worsening, in some notably in progressive MS it did nothing.  The reactivation of demyelinated lesions following alemtuzumab infusion has been linked to a cytokine (TNF) storm. 

Importantly one would have thought that if disease worsening would occur as seen with some of the class, it would have happened in the initial ibudilast trial involving hundreds of people. 

Our experience of rolipram is that is does nothing of any interest in early EAE, but it can make some existing (spasticity) symptoms in progressive disease transiently worse. This was published long ago before the trials in humans. 

Lets keep our fingers crossed for a positive trial. But the point is, be careful when you blame the animals for the success or failure trials as it is not always a simple matter.


  1. So this is the published grant costs from NIH for the ibudilast trial 2013-$3,102,097, 2014-$585,071. Regardless this is the reality of the cost of trials, I'm sure like building a house the costs have inflated over this period.

    1. I can see your point MD. It is amazing that the NIH paid $3.5 million a trial that failed when there was a string of failed trials with other PD4 inhibitors.

    2. The cost by NDG is for the current trial in progressive MS


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