Tuesday, 9 June 2015

Evidence that Laquinimod is not a potent DMT

Stasiolek M, Linker RA, Hayardeny L, Bar Ilan O, Gold R. Immune parameters of patients treated with laquinimod, a novel oral therapy for the treatment ofmultiple sclerosis: results from a double-blind placebo-controlled study. Immun Inflamm Dis. 2015;3(2):45-55. doi: 10.1002/iid3.42.

Laquinimod is a novel orally administered drug for the treatment of relapsing remitting multiple sclerosis (RRMS). In this immunological substudy of the phase III Assessment of Oral Laquinimod in Preventing Progression of MS (ALLEGRO) trial, we performed an ex vivo and in vitro analysis of effects exerted by laquinimod on peripheral blood immune cell populations from RRMS patients with a special focus on monocyte phenotype and function. Approximately 100 patients were enrolled following a standardized protocol. Half of the patients received laquinimod and the other half received placebo. Peripheral blood samples were collected prior to commencement of therapy and after 1, 3, 6, 12, and 24 months of continuous therapy. Main lymphocytic and antigen presenting cell fractions were analyzed in peripheral blood mononuclear cells (PBMCs) ex vivo by flow cytometry. The proliferative response of PBMCs to mitogen or recall antigen was assessed in culture experiments. Untouched monocytes were sorted magnetically and cultured under pro-inflammatory conditions. PBMC analysis showed no significant differences of investigated lymphocytic and antigen presenting cell populations over time within each group, or between the two groups. However, the detailed in vitro analysis of monocytes demonstrated a lower level of CD86 expression on monocytes stimulated with LPS in laquinimod patients beginning from the 1st month of treatment. Upon pro-inflammatory stimulation, monocytes obtained from laquinimod treated patients tended to secrete lower levels of the proinflammatory chemokines CCL2 or CCL5. Taken together, in this prospective study, we demonstrate immune modulation but no immunosuppressive biological activity of laquinimod in a large group of MS patients.

The clinical data is there for all to see that laquinimod has pretty weak activity as a DMT (relapses) in comparison to other treatments and this is borne-out by looking in the blood....not much to report. The real question is: Is this a neuroprotector?, because it seems to have a better effect on progression.

14 comments:

  1. Thanks MD.

    But what is the potential of Laquinimod as an add-on therapy?

    Active Bio fired 47 staff last week after a failed Phase III trial and the remaining 9 guys are "solely focusing on MS".

    Does this firm have a future or is it going straight into bankruptcy?

    Tony

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  2. This is a research blog.....not a site for financial Advice

    The failed phase III your are referring to that triggered the shrinkage in staff has nothing to do with MS and relates to Phase III trial 10TASQ10 in castration-resistant prostate cancer patients

    We have heard of ALLEGRO & BRAVO laquinimod trials which gave poor results and we are waiting for CONCERTO due to finish in 2018.. where in my opinion shamefully over 600 MSers are I think on placebo...so nothing or a drug that didn't do much better based on on past history... when we have treatments that are far superior.

    228 sites... hope London 34019 isn't us...bet it is.

    Is there may be merit as an add on maybe, I suspect Teva thinks and hopes so.

    Teva obviously thinks it has As a add on

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    1. For an add-on therapy, I assume there would need to be a phase 3 trial to justify the costs they are likely to charge insurance companies. If this is the case, the patent for Laquinimod will likely run out by the time the and-on trial is finished.

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    2. Have you checked òut the patent data base to see what laquinimod has bèen added to. If these survive the lawyers no problem. Copaxone was invented inthe 1970s but the patents only stared to run out this year.

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  3. "Is there may be merit as an add on maybe, I suspect Teva thinks and hopes so."

    If it is a neuroprotector, what about laquinimod a drug for people with PPMS/SPMS???

    Would that not be quite exciting? If not, why not?

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    Replies
    1. It would be exciting if it really was neuroprotective but a lot more evidence is needed. There are better candidates in the queue IMO.

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    2. Laquinimod is currently in trial in PPMS

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    3. iT won't work in PPMS. I'm telling you.

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    4. What others are better candidates currently?

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    5. Anon 9:28..Why not? Why do you think this?
      anon 9:49....I have yet to personal experience with laquinimod so can't say..come to think of it cant say anyway

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  4. It seems like an induction with rituximab followed by maintenance with laquinimod would be a possibility and deal somewhat with the issue of costs for 2 agents

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    1. Seems like a good idea but as you have just said this and Teva appear not to have patented this combination yet, suggests that you have just disclosed this and there is now no inventive step to be had and no patent for this or ocreluzimab and laquinimod to be had...so unfortunately the chance of this happening now is probably nil

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    2. I was speaking more from a clinician perspective. Rituximab is already used off label in MS fairly extensively, there were some posters on it at AAN. I think at the Rocky Mountain MS Ctr it is part of their standard of care.

      http://www.neurology.org/content/84/14_Supplement/P3.288

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  5. Re: "The clinical data is there for all to see that laquinimod is a pretty useless DMT in comparison to other treatments..."

    This is where MD and I disagree. LQ is not as effective as other licensed DMTs when looking at relapse rates and focal MRI activity, but appears to have an effect on disability progression that is much larger than than its impact on relapses. It also has an effect on brain atrophy. This is why we are exploring LQ in progressive MS to see if it will delay disease progression and slow brain atrophy in progressive MS. It is now clear that LQ is working downstream of focal inflammatory events on glial cells and innate immunity. This sets up LQ as the ideal add-on drug; it may become the add-on drug of choice. I am still very excited about LQ's prospects and other drugs in the class.

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