Tuesday, 31 December 2013

Laquinimod does everything in EAE or does it?

Moore S, Khalaj AJ, Yoon J, Patel R, Hannsun G, Yoo T, Sasidhar M, Martinez-Torres L, Hayardeny L, Tiwari-Woodruff SK. Therapeutic laquinimod treatment decreases inflammation, initiates axon remyelination, and improves motor deficit in a mouse model of multiple sclerosis. Brain Behav. 2013;3(6):664-82. doi: 10.1002/brb3.174

BACKGROUND:Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future treatment of multiple sclerosis (MS), as well as other diseases. Laquinimod (LQ) is an orally administered, central nervous system (CNS)-active immunomodulator with demonstrated efficacy in MS clinical trials and a favorable safety and tolerability profile.
AIMS: We aimed to explore the pathological, functional, and behavioral consequences of prophylactic and therapeutic (after presentation of peak clinical disease) LQ treatment in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS.
MATERIALS AND METHODS:Active EAE-induced 8-week-old C57BL/6 mice were treated with 5 or 25 mg/kg/day LQ via oral gavage beginning on EAE post-immunization day 0, 8, or 21. Clinical scores and rotorod motor performance were assessed throughout the disease course. Immune analysis of autoantigen-stimulated splenocytes, electrophysiological conduction of callosal axons, and immunohistochemistry of white matter-rich corpus callosum and spinal cord were performed.
RESULTS:Prophylactic and therapeutic treatment with LQ significantly decreased mean clinical disease scores, inhibited Th1 cytokine production, and decreased the CNS inflammatory response. LQ-induced improvement in axon myelination and integrity during EAE was functional, as evidenced by significant recovery of callosal axon conduction and axon refractoriness and pronounced improvement in rotorod motor performance. These improvements correlate with LQ-induced attenuation of EAE-induced demyelination and axon damage, and improved myelinated axon numbers.
DISCUSSION:Even when initiated at peak disease, LQ treatment has beneficial effects within the chronic EAE mouse model. In addition to its immunomodulatory effects, the positive effects of LQ treatment on oligodendrocyte numbers and myelin density are indicative of significant, functional neuroprotective and neurorestorative effects.
CONCLUSIONS: Our results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression.

Lacquinimod is not a very good DMT based on the doses used in MS and was worse than the interferons at stopping relapses in MS, yet in EAE it could stop CNS autoimmunity and not surprisingly this was associated with inhibition in the development of autoimmunity in the CNS and so this will inhibit the downstream consequences of this like CNS infiltration and the damage that this causes like axonal damage and myelin damage. 

In this study it is claimed that there is neurorestorative function which sounds promising. However, was this “improvement” and “recovery” in nerve function or more likely “slowing of the loss of function” so if the drug has a peripheral immunosuppressive action the downstream consequences will not occur. This is very different from having function shown to be lost and then actually recovering the lost function. In one scenario there is recovery from something in the other the something never happens. Based on the data it can be largely explained by immunosuppression.

Have a read it is open access. 

CoI. It was supported by Teva

6 comments:

  1. I accept the brain atrophy data looks better than accepted.
    To be clear when i say not a good dmt relates to relapse modificstion on which the trials were designed.

    Wil i be good foe progression i hope so but the studoes need to be done.

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  2. Isn't it enough to conclude that Laquinimod is already the best DMT with regards to brain atrophy, EDSS progression and QoL in RRMS ( at least if benefit to risk is considered )? Existing Laquinimod data in RRMS is in my view sufficient to reach that conclusion = no more studies are needed to "prove" the neuroprotective capabilities of LAQ with regards to RRMS.. The ongoing CONCERTO with a higher dose of 1,2mg will hopefully show even better effect on neuroprotection.. at least if a read-over can be made from animal models to clinic.

    Regarding PMS ( PPMS / SPMS ) I agree clinical studies are needed and to my knowledge studies in PMS will start soon. Since LAQ have a direct neuroprotective effect in the CNS I would find it surprising if LAQ will not work in PMS. I believe so because the neurodestructive process of the MS disease seems to be the same whatever MS "style" there is ( PPMS, RRMS or SPMS ). What would be the logical reason for LAQ not to be active in PMS? ( other DMT's, with at best an indirect effect in the CNS, failures in PMS have in my view nothing to do with the probabilty of LAQ to provide neuroprotection in PMS. Neuroprotection is already proven in RRMS and I see no reason for it to be otherwise in PMS ).

    The main question to debate among MSers and neurologists/KOL's should be what sense does it make to use DMT's targeting relapses ( ARR ), if they have no effect at all or less prominent effect with regards to the driver of long term disability and cognition, i.e brain atrophy, than DMT's with effect with regards to these areas of importance to MSers and society.

    Finally.. For the average MSer ( RRMS'er )... the absolute difference (=change in number of relapses during the whole RRMS period) with regards to choice of DMT must be of less significance that the impression one gets from reading all these percentage numbers on different DMT's claimed effect on ARR? In "modern" registration studies the ARR seems to have been between 0.3-0.4 per year. The maths is quite simple and for the average MSer I doubt the difference during the RRMS period will be more than maybe plus/minus 2 relapses during the RRMS period. Am I wrong?

    I understand MSers with frequent relapses need DMT's such as Gilenya or Tysabri, but I doubt such drugs are for the greater good of the average MSer considering the risks. I believe the focus on ARR-percentage change depending on what DMT you chose blur the picture, because of the reasons stated, and that brain atrophy is about to be the new biomarker of importance in RRMS as well as SPMS going forward..

    My logical conclusion is ( if I don't miss something material ) that KOL's has started to change their view and now realize brain atrophy is key ( not relapses ). Other neurologist and MSers will over time adapt to this thinking and demand for DMT's with effect on brain atrophy (long term disability progression ) will change the demand supply equation of existing and coming DMT's.

    Appreciate comments and criticism

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    Replies
    1. I see your enthusiasm I;ll leave it for ProfG toaddto.He has enthusiasm but hey what is he not enthusiastic too.

      The FDA clearly wanted more otherwise it would be available by now.

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    2. As we are all aware of FDA has a very formal attitute compared to the more pragmatic view of the EMA. I guess most of you guys have that opinion with regards to Lemtrada developments? There are actually some simularities between the previous Lemtrada and Laquinimod interactions with FDA, provided that it's true the FDA agreed to the Lemtrada trial design & now don´t agree anymore.

      With regards to the second Laquinimod Bravo phase 3 there was an agreement ( verbal ) in place stating that possible baseline inbalances would be corrected before analyzing the outcome. With baseline correction Bravo as well as Allegro had p<0.05 with regards to ARR. Without baseline correction p was 0.07 and since FDA "didn't keep their part of the agreement" Laquinimod according to FDA's formal view didn't show two spearate phase 3 studies with a p<0.05 on ARR and was not approvable. But... The FDA obviously liked what they did see with regards to brain atrophy and EDSS progression and therefore agreed to an SPA, which the ongoing CONCERTO phase 3 is running under, where primary endpoint in EDSS and secondary is Brain atrophy.

      The EMA first of all don't demand two separate clinical phase 3 studies with p<0.05 on ARR to be able to approve a new DMT. The EMA base their evaluation on benefit to risk. In other words a new drug that has benign safety and some clinical relevance will be approved by the EMA. Even without neuroprotective properties. What would be the reason not to approve a DMT with the most benign safety profile? I guess no reason at all ( from a regulatory standpoint ). Another question in such case would be that most would believe such DMT would be a marginal DMT for multi-sick persons and persons with very low lymphocyte count.

      The EMA has accepted to evaluate the pooled data from Allegro and Bravo ( published in NEjM ), the EMA hosted a workshop in October on new guidelines with regards to development of new MS drugs. Not a single word on relapses ( at least more or less... ). Only EDSS, QoL and biomarkers/MRI... So I guess the EMA is about to change their guidelines and from now on be willing to approve labels with neuroprotection on them.... Who will want DMT's that only offer some effect on ARR past such change?

      If I don't miss something material, maybe I just see the obvious since I have not been involved in this area for too long.

      Appreciate feedback on this subject, because I believe it is of huge interest to all stakeholders in the MS space.

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    3. Yep the goal posts are being moved as indicated at the MHRA recently theyxwant a disability outcome so making newcomers show what the existing ms drugs may not have been shown.

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  3. I miss Professor G's view on this. Since he has pushing brain atrophy and neuroprotection it would be nice to hear his thoughts about Laquinimod in RRMS with regards to brain atrophy and neuroprotection. ... I guess, since most data indicate the different forms of MS are basically the same, the mode of action of Laquinimod should be the most relevant mode of action for the average RRMS'er as well?

    The Laquinimosd data and science is difficult to argue against (with regards to EDSS, Brain atrophy and neuroprotection). So even if we all want Laquinimod studies in PMS. What would be the reason not to endorse Laquiimod in RRMS with regards to "proven" data in the relevant areas for most RRMS'ers?

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