Thursday, 22 October 2015

Statin plus interferons fail to stop brain atrophy.


No evidence for an effect on brain atrophy rate of atorvastatin add-on to interferon β1a therapy in relapsing-remitting multiple sclerosis (the ARIANNA study).Lanzillo R, Quarantelli M, Pozzilli C, Trojano M, Amato MP, Marrosu MG, Francia A, Florio C, Orefice G, Tedeschi G, Bellantonio P, Annunziata P, Grimaldi LM, Comerci M, Brunetti A, Bonavita V, Alfano B, Marini S, Brescia Morra V; ARIANNA study group.Mult Scler. 2015 Oct 14. pii: 1352458515611222. [Epub ahead of print]

BACKGROUND:A previous phase 2 trial has suggested that statins might delay brain atrophy in secondary progressive multiple sclerosis.
OBJECTIVES:The objective of this study was to evaluate the effect of atorvastatin add-on therapy on cerebral atrophy in relapsing-remittingmultiple sclerosis.
METHODS:This randomised, placebo-controlled study compared atorvastatin 40 mg or placebo add-on therapy to interferon β1b for 24 months. Brain magnetic resonance imaging, multiple sclerosis functional composite score, Rao neuropsychological battery and expanded disability status scale were evaluated over 24 months.
RESULTS:A total of 154 patients were randomly assigned, 75 in the atorvastatin and 79 in the placebo arms, with a comparable drop-out rate (overall 23.4%). Brain atrophy over 2 years was not different in the two arms (-0.38% and -0.32% for the atorvastatin and placebo groups, respectively). Relapse rate, expanded disability status scale, multiple sclerosis functional composite score or cognitive changes were not different in the two arms. Patients withdrawing from the study had a higher number of relapses in the previous 2 years (P=0.04) and a greater probability of relapsing within 12 months.
CONCLUSIONS:Our results suggest that the combination of atorvastatin and interferon β1b is not justified in early relapsing-remitting multiple sclerosis and adds to the body of evidence indicating an absence of significant radiological and clinical benefit of statins in relapsing-remitting multiple sclerosis.

The simvastatin trial is held out as an example of a drug that can limit brain atophy in progressive MS based on phase II data. 


Statins are statins are statins you may think, in their cholesterol reducing ability they may have common effects but they each have different proterties and so no, they are not the same. 

Some statins do not get in the brain and so maybe one should do Simvastatin (CNS penetrant) versus Pravastatin (CNS excluded) study to work out is it an effect on atrophy or a systemic co-morbidity. 

However should we do a phase III trial of simvastatin to see if it protects against brain atrophy..or should that be two phase III trials because this is what the regulators make pharma do.. However this is going to take (<£5)millions of pounds to do, for a £2 a week drug.. 

So what happens when the study is repeated in this study they look at atrovastatin as an add-on to interferon and there is no effect. 

This means we are going to need to repeat the simvastatin study at a minimum to convince any body that it is worthwhile. The trial design here was different because the demographic of MSers on beta interferon and atorvostatin is going to be different from SPMSers on simvastatin. 

The dose of simvastatin was very high in teh SPMS trials and so surely a dose response is needed if the trials are to go anywhere. But should they do a phase II again to work out the dose response before committing people to a trial? This will waste another 3 years

Is this a good candidate for a repurposed drug as it will take about 3-4years before trials are done to really know if it works and for a phase III trial it will be 6-7years...there is no quick fix.  

It could argue against the therapeutic pyramid of a neuroprotective on top of a DMT but beta interferon is a weak DMT and is statin really a neuroprotectant? A rational mechanism to why it should be a neuroportective has not been presented.

However, we now know we have to re-baseline scans after pseudo atrophy has occurred in a hope to see any therapeutic effect.. 

4 comments:

  1. Having been on the active drug in the trial, it was disappointing not to be able to continue with a cheap, commonly prescribed drug at a lower dose - would you please comment on why a lower dose was not trialled at the same time? Is it because any (beneficial) effect would be shown by the higher dose then it could be replicated with lower doses (with the additional costs and time taken, as you mention)/ Thank you

    ReplyDelete
    Replies
    1. Simply put money.... To do an extra arm would have cost more money and academicc trials are always a cut price version of how proper trials by pharma are done.

      For a trial in academia you get up to 2 million, pharma spend about100,000

      Delete
    2. Pharma would also keep you on drug after a positive trial in academia they dont follow this rule

      Delete
  2. The choice of interferon with brain atrophy is wrong as interferon has some positive effect on atrophy and to prove an added benefit on top would be difficult. I don't think the statin hypothesis should be abandoned on this study.

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.