Tuesday, 10 September 2013

Is laquinimod the new wonder drug that progressive MSers need?

Laquinimod needs to be tested in progressive MS ASAP. #MSBlog #MSResearch

"Why all the talk about laquinimod (LAQ)? It is the first drug that has been shown in phase 3 clinical trials to have an impact on MS disability and brain atrophy independent of relapses and MRI activity. It appears to be working downstream of events that trigger focal inflammation and relapses. In other words it appears to be truly neuroprotective, rather than anti-inflammatory."

"The following study shows that it is working via the master regulator called NF-κB to exert its effects. Interestingly, BG12 also impacts on this factor and supports it also being neuroprotective."

"Combining LAQ with a potent anti-inflammatory drug should target both upstream and downstream events; an would be an ideal strategy for progressive MS. Hence my enthusiasm for combing LAQ with an induction agent."


"This dual strategy would fit in with my proposed treatment pyramid. I wonder if it is worth lobbying Teva and Genzyme to consider partnering on combination treatment trial? 


Brück et al. Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination. Acta Neuropathol. 2012 Sep;124(3):411-24. 

Background: Laquinimod (LAQ) is a new oral immunomodulatory compound that reduces relapse rate, brain atrophy and disability progression in MS. LAQ has well-documented effects on inflammation in the periphery, but little is known about its direct activity within the central nervous system (CNS). 


Objective: To elucidate the impact of LAQ on CNS-intrinsic inflammation, we investigated the effects of LAQ on cuprizone-induced demyelination in mice in vivo and on primary CNS cells in vitro. Demyelination, inflammation, axonal damage and glial pathology were evaluated in LAQ-treated wild type and Rag-1-deficient mice after cuprizone challenge. Using primary cells we tested for effects of LAQ on oligodendroglial survival as well as on cytokine secretion and NF-κB activation in astrocytes and microglia. 

Results: LAQ prevented cuprizone-induced demyelination, microglial activation, axonal transections, reactive gliosis and oligodendroglial apoptoses in wild type and Rag-1-deficient mice. LAQ significantly decreased pro-inflammatory factors in stimulated astrocytes, but not in microglia. Oligodendroglial survival was not affected by LAQ in vitro. Astrocytic, but not microglial, NF-κB activation was markedly reduced by LAQ as evidenced by NF-κB reporter assay. LAQ also significantly decreased astrocytic NF-κB activation in cuprizone-treated mice. 

Conclusions: Our data indicate that LAQ prevents cuprizone-induced demyelination by attenuating astrocytic NF-κB activation. These effects are CNS-intrinsic and not mediated by peripheral immune cells. Therefore, LAQ downregulation of the astrocytic pro-inflammatory response may be an important mechanism underlying its protective effects on myelin, oligodendrocytes and axons. Modulation of astrocyte activation may be an attractive therapeutic target to prevent tissue damage in MS.

CoI: multiple

9 comments:

  1. I hope the MS campaigning organisations are or will be made aware of this and put the case. Do you happen to know? Stupid question really as I'm sure you put the case for it at every opportunity.

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  2. I suppose probability for Laquinimod EMA approval closes in on ONE. When can we expect Laquinimod to be available in Denmark?

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  3. ProfG
    It needs to be a wonder drug at something as it looked pretty rubbish as a DMT.

    Why shouldn't they try it with glaterimer acetate?

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    1. A compound doesn't need to be an effective DMT to be an effective neuroprotectant.
      Glatiramer acetate is a fairly poor DMT in comparison to the newer DMTs such as Alemtuzumab so would be a poor choice in my opinion. That's not to say that Teva might be considering this though!

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  4. Interesting that laquinomod acts on astrocyte but not microglial Nf-kB. Reduction of T-cell egress in corpus callosum and down regulation of pro-inflammatory factors in astrocytes. Given the importance of astrocytes in maintenance of BBB maybe there is increased integrity of BBB using laquinomod.

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    1. I think this unlikely because it is not very good at stopping relapses which is a product of loss of BBB intergrity

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  5. Prof G,

    Please could you explain what you mean by downstream and upstream. Upstream (I'm assuming the first event) could be inflammation and downstream could then be neurodegeneration. Or upstream could be neurodegeneration and downstream is inflammation ( a response to neurodegeneration).

    I haven't seen you his excited since SA won he rugby World Cup. This is either good news or Teva have promised you a Ferrari Dino.

    How will Laquinimod compare with amilioride etc. in terms of neuro protection?

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    1. The upstream downstream analogy refers to inflammation; I could have used base of the pyramid or top of the pyramid analogy as well.

      The current dogma is that everything in MS can be explained by inflammation or the inflammatory cascade. Therefore if you stop the cascade you stop downstream events such as neurodegeneration. Therefore if your drug is too powerful and switches off inflammation you can't really assess whether or not it is neuroprotective. What is interesting about laquinimod is that it is not that effective at switching off inflammation (relapses and MRI activity), but appears to be effective downstream at delaying or slowing neurodegeneration.

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  6. I think laquinimod is before NICE at the moment to consider its clinical efficacy in RRMS. As they are looking at its effect on relapse rates as well as disability, are they likely to refuse it as its not very good at preventing relapses? Presumably they can't consider its neuroprotective qualities as that wasn't the basis of Teva's application? Would the application to NICE have to start all over again on the basis of its neuroprotective appeal rather than anti-inflammatory? There's a lot of people in the RRMS community who are now on good anti inflammatories and looking for the next step- and not wanting to wait years for the beaurocracy to catch up.
    Also, I believe laquinimod has a good safety profile, but in the submission to NICE its stated that the mechanism of action 'directly modulates the CNS resident parenchymal cells which may reduce infiltration of leukocytes into the CNS'. Doesn't this raise the ugly head of PML?

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