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