Combination of two anti-inflammatories can save nerves

Reick C, Ellrichmann G, Thöne J, Scannevin RH, Saft C, Linker RA, Gold R Neuroprotective dimethyl fumarate synergizes with immunomodulatory interferon beta to provide enhanced axon protection in autoimmune neuroinflammation. Exp Neurol. 2014 Apr pii: S0014-4886(14)00098-3.

Despite recent advances in development of treatments for multiple sclerosis, there is still an unmet need for more effective and also safe therapies. Based on the modes of action of interferon-beta (IFN-β) and dimethyl fumarate (DMF), we hypothesized that anti-inflammatory and neuroprotective effects may synergize in experimental autoimmune encephalomyelitis (EAE).
METHODS:EAE was induced in C57BL/6 mice by immunization with MOG35-55-peptide. Mouse IFN-β was injected s.c. every other day at 10.000IU, and DMF was provided at 15mg/kg by oral gavage twice daily. Control mice received PBS injections and were treated by oral gavage with the vehicle methylcellulose. Mice were scored daily by blinded observers and histological, FACS and cytokine studies were performed to further elucidate the underlying mechanism of action.
RESULTS:Combination therapy significantly ameliorated EAE disease course in comparison to controls and monotherapy with IFN-β. Histological analyses showed a significant effect on axon preservation with almost twice as much axons present in inflamed lesions as compared to control. Remarkably, the effect on axonal preservation was more pronounced under combination therapy than with both monotherapies. Neither monotherapy nor combination therapy demonstrated modulation of cytokines and frequency of antigen presenting cells.
DISCUSSION: Combination of IFN-β and DMF resulted in greater beneficial effects with improved tissue protection as compared to the respective monotherapies. Further combination studies of these safe therapies in human disease are warranted.

In this study they used a dose of interferon beta and a dose of a BG-12 (Tecfidera) homologue which were not totally effective in controlling EAE and then put them together. They got a better effect on clinical disease and unsurprisingly they did not get much nerve loss.

So Biogen Idec can rub its hands together and test two expensive drugs in MS, one anti-inflammatory and the other anti-inflammatory (with suspected neuroprotective effects-but does it get in the brain?).

This could be used to justify a trial using optimised doses of BG-12 and beta interferon, neither of which yet to robust actions on brain atrophy, unlike some other DMT.

So is this result unexpected?. It says that the drugs are working either on different mechanisms or they add together to give more punch against a disease mechanism.

Teva has done exactly the same experiment (check out their patents) with laquinimod and all other chemical DMT. The two together work better than either sub-optimal drug individually….Justification of patent and trial.

As the inflammatory response causes nerve loss, get rid of the inflammatory response and you get more neuroprotection…what would you see with a fully optimised single treatment…No disease and no nerve loss? So it could save nerves even if the drug does not get into the brain.

In this study they claim synergism of the two drugs. Synergism is a thing that we often hear. However is the effect an additive effect of two drugs or real synergism, where the sum of the two parts are greater than simple addition.

So we have an additive effects where 1 (bad effect) + 1 (bad effect) = 2 (good effect) where synergistic effect is 1 + 1 = 4 (great effect).

However, the problem with EAE scoring is that the EAE scale is probably not linear so the pathological difference between a score 0 and a score 1 may not be the same as the difference between a score 3 and a score 4. So we can have (a + a = c) or is it (a + a = m). So it is difficult to say if there is true synergism. What do you think in this case?

It makes some sense to combine lower doses of drugs as it may reduce the side-effects of both, however adding one immune suppressive drug to another may actually increase the chances of side effects, those of each drug plus the combined effect because they may be a greater immunosuppressive agent and so increase the risks of serious adverse events.

If you put the effects of the two drugs against an effective dose of one DMT would it really be better?…In MS maybe, in acute EAE?

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  • Interestingly, safety results of a small 6 months clinical study of add on therapy BG-12 plus IFNB (EXPLORE study) will be presented tomorrow at the AAN 2014

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