Monday, 4 January 2016

Bad News for 2016 is it Like father like Son as Laquinimod raises safety concerns

#MSResearch High dose of Laquinimod halted because of heart risk.

Happy New Year, however I am afraid to say it is a terrible New Year start and 2016 begins with a shocker.

I have just seen the news posted on Reuters (click) that the ARPEGGIO and CONCERTO trials of Laquinimod have hit a problem and so maybe more bad news for people with primary progressive MS.




The news has just been made that the high dose of laquinimod is being removed from the relapsing remitting and progressive MS trials (ARPEGGIO/ CONCERTO) because of "non-fatal cardiovascular events in eight people".

I suspect that this is causing alarm bells because Laquinimod was made as based on the actions of Linomide.


Linomide was tried in MS, but stopped because the drug was causing serious effects on the heart and vascular system. Linomide has effects on angiogenesis (formation of blood vessels). So it is possible that Laquinimod is acting like its parent and causing heart problems


Noseworthy JH, Wolinsky JS, Lublin FD, Whitaker JN, Linde A, Gjorstrup P, Sullivan HC. Linomide in relapsing and secondary progressive MS: part I: trial design and clinical results. North American Linomide Investigators. Neurology. 2000 May 9;54:1726-33.


This is sad indeed. Laquinimod was marginally effective at slowing down the relapse rate and the FDA wanted more trials. So because of them....you have the unbelievable situation of hundreds, yes hundreds of people on placebo for 2 years (I will get called-up on this aspect.......but which ethics committee approved this given that there are over 10 agents available for this purpose. Is it ethical to do trials in areas where people don't have access to drugs-because of costs so you can use placebo...Anyway that is another rant). 


The dose in the ARPEGGIO/ CONCERTO trials were increased from 0.6mg to 1.2mg-1.5mg, perhaps in the hope of a better effect and in doing so, the drug may have moved into toxicity. 


This is posted on the Teva site (Click) and there was one event in 191 people in the PPMS trial with 1.2mg dose. 7 in the RRMS study with the high dose. In the lower dose of 0.6mg this effect has not been seen in over 2,000 people

For the moment the trial continues but what now for the hundreds of people in the high doses group? Will they be switched to the low dose or stopped.? There is something on the Teva site to indicate that participants will be contacted to be re-consented. 
Maybe ProfG or DrK will have an answer on this one, as I think we are involved in both studies. 

However the study continues in the low dose and this dose has not been shown to cause any heart problems. 


Even if the effect on atrophy is better than its effect on relapses, which was a meagre slowing of relapse rate at or below that of the CRAB drugs, with the risk of heart problems how much will the drug be tainted so one wonders about the fate for laquinimod for relapsing MS? . 

However, based on atrophy data I had a thought that laquinimod could be a useful add-on as a neuroprotectant to other DMT, but this would need laquinimod to licenced, today's news potentially puts this a step backwards.

10 comments:

  1. Perhaps even with adverse cardiac events Laquinimod could be approved if the reduction of relapse rate and progression of MS within 02 years was greater than the CRABS. If it were higher it would certainly be approved as it happened with Fingolimod ...

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    1. Dear Alice
      I take on board all that you have written about the reasons you decided to participate in the laquinimod trial, and hope that you get positive outcomes with your MS - regardless of whether you find out that you were on placebo or the active drug. My problem with this and many/most clinical trails is that the EDSS is garbage as a measure of disability, and there are increasing numbers of us PwMS who are getting fed up with such a useless measurement tool being used - not just in clinical trials, but also in clinical practice. It does not accurately reflect the problems we have as a result of our MS, or the disabilities that MS so kindly bestows upon us.

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    2. Dear Cinara,

      Thank you for your comment.

      I hear what you say. But EDSS is the best we have for the moment, and it has been validated for so many trials - it is not perfect, I agree on that, but is the best we use now with long experience.

      What measuring Tool in general would you advocate for you PwMS´s - a penny for your thoughts :-)

      My very kind regards
      Alice

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    3. Hi Alice
      I am the Anon at 12.01pm, and I'm not Cinara so please don't blame her for my comment which is unkind to the EDSS - I just clicked the wrong Reply button!

      I believe we need PwMS to keep applying pressure to get new and better tools developed which more accurately measure the impacts of our MS. It is widely commented that one of the EDSS's biggest short-comings is a focus in the higher numbers on walking capacity whilst ignoring what can be significant problems in other aspects of functioning. Just as an example, there are many people who suffer from cognitive problems, and the EDSS does not even have a way to measure these - as acknowledged by the good people who run this blog (fortunately, my cognitive function is not a problem for me - yet...)

      Unfortunately, the EDSS is not really the "best we have for the moment" - it is all we have, and I believe that this is part of the problem with clinical trials - outcomes and approvals are too focussed on a measurement tool which may not truly reflect how effective a drug may be - and I must agree with you that there is so much focus on relapses and relapse rates that other aspects get "forgotten". (As someone who has never had identifiable relapses this is important to me)

      We need a tool which works and measures differently - along the lines of using a baseline of "normal function" as a starting point, and measuring how far from their normal an individual has moved as a result of the impacts of their MS. There also needs to be another dimension which looks at impacts on how someone lives their life. An example - I have quite a few bladder problems from my MS - urgency, frequency, and volume. Most embarrassingly, some incontinence problems can arise from these - thus my ability to go out and socialise or participate in things is restricted. I dread the prospect of being in a public place, standing in queue for the ladies' toilet, and not being able to hold on long enough to not wet myself. Maybe this is "too much information", but it is the only way I can try to illustrate what I am trying to say. The EDSS would simply record that I have some noticeable deficits in some particular part of my nervous system - it would not measure how much impact that damage has on me and my life. However, there is also a place for some elements of the EDSS where this type of information is recorded, where there may be clinically observable neurological deficits which do not yet have an impact on an individual's functioning.

      Some of the Quality of Life tools start to move into this sphere or recording impacts, but they are shallow and still suffer from being separated from the actual problems an individual has which affect their quality of life.

      Sorry if this is long and rambling, but you did ask for my thoughts, and I hope this makes some sort of sense to you.

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    4. Dear Anonymous (reply 09:00 am)
      One thing I want to say. Never ever be embarresed at this MS-forum, to bring up all sort of "shortcomings" in relation to your MS disease. In order to address issuses of the MS disease, we all have to be open minded and discuss all problems as an outcome of having MS.

      Warm regards
      Alice

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  2. Dear MouseDoctor!

    With all respect to Mr MouseDoctor,

    I think with regard to laquinimods efficacy, you missing the point with regard to efficacy and some other stuff you air in your statement above.

    BACKGROUND
    I participate in the concerto study - I have been randomized either to placebo or the 0.6 arm. I had my RRMS diagnos 4 years ago

    Now, my motivation to praticipate, is the consistent effect laquinimod seems to have with regard to halting the disbality progression (EDSS) on all time intervalls - especially the 6 months EDSS and beyond up to 12 months EDSS as to be followed:

    The risk for CDP in relation to different time intervalls - pooled efficacy data from the 2 previous pivotal studies with laquinimod: allegro+Bravo:

    3 months EDSS: reduction 34 % (*Best efficacy among oral agents**
    6 months EDSS: reduction 47% (*Best efficacy among oral agents *)
    9 months EDSS: reduction 46% (*Best efficacy among oral agents*)
    12 months EDSS: reduction 45% (*Best efficacy among oral agents*)

    Source:
    Poster (P070) presentation at Ectrims Boston sept 2014

    The difference in EDSS effect is growing with more stringent time intervalls for EDSS - 6 months and beyound up to 12 months if you compare with other oral agents results.

    With regard to 3 months EDSS, I acknowledge that laquinimod hovering around the same effeciacy as the other oral agents, just slightly better. But it is the more stringent EDSS measure, 6 months and beyond, that differ laquinimod from the other oral agents in a positive meaning; consistent effect that seems to get stronger by the time.

    Now,I did my homework before I diceded to participate in the Concerto study. And it is a fact that relaps efficacy taking laquinimod is not what motivate me to participate. No, my motivation is the their seem to be a clear efficacy on disability progression, especially on the more stringent time intervalls 6 months and beyond. Here the other oral agents (Gilenya, Tecfidera, Aubagio; yes I have compared with their pooled pivotal studies) are far behind laquinimod when it comes to longer, and more stringent measures of EDSS,i.e. 6 months EDSS and up to 12 months. That is a fact

    Also, the effect on Brain atrophy (pooled 30% reduction) which laquinimod seem to have, might explain the effect on EDSS.

    Furthermore, the relatively high number of patients recruited in this study, is, due to, to my best understanding, that there are rather few EDSS events compare to relapses among patients in these pivotal studies.

    Now, in order to capture these events and "proove" to significant efficacy result on EDSS (CDP), one have to raise the "n" to compensate for the relatively few EDSS events as oposed to relapses.

    Lastly, I agree with you on one thing that you aired: Since I don´t know if I recieved placebo or laquinimod 0.6 mg, it would be better in the future if they plan these studies with active comparing MS drug, instead of placebo.

    Nevertheless, with all my respect MD, you are missing the point rergarding why I and many other patients choiced to participate in laquinimnod Concerto study: the effext on EDDS, not relapses, is what trigger me and other to participate in the study. At least for me that was the my clar motivation. Also, laquinimod does not seem to be immunosupressive like other oral agens. It could be something totally new with regard to addressing the disability progression.

    My very best regards
    Alice


    ANd yes, I am an math 36 years young :-) teacher, so I know a little about statistics. My main worry;

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    1. Dear Alice
      I am well aware of the effect of Laquinimod on atrophy compared to its effect on relapses and appreciate that you selected this study because of the apparent effect on progression, which would have to be a selling point.

      The sample size will be based on the primary outcome and this is

      Time to Confirmed Disease Progression (CDP) in Period 1 [ Time Frame: 24 months (Period 1) ] [ Designated as safety issue: No ]
      CDP is defined as an increase in Kurtzke's Expanded Disability Status Scale (EDSS) of 1 point or more from baseline for subjects with baseline EDSS of ≤5.0, or an increase 0.5 points or more from baseline for subjects with baseline EDSS of 5.5. The EDSS rates a person's disability due to multiple sclerosis severity, ranging from 0 (normal neurological exam) to 10 (death due to MS). The higher score represents more severe disability. The outcome measure is the time recorded from Baseline until the subject meets this definition of CDP

      So I believe you are correct that it is based on EDSS. However I still maintain it is scandelous to have 600 people on placebo for two years.

      Now the back to my point is that mud sticks and the risk of a heart attack is not going to a good selling point, is it going to be a killer to the drug programme.....neuros are a conservative bunch.

      Now back to your point. I totally agree that laquinimod looks interesting and I think that it is probably a neuroprotective drug and not really a DMT. I have thought this for some time. Therefore it could be the perfect drug to be an add on to an effective DMT rather than a stand alone drug. Teva think this too and have filed patents of combinations of laquinimoid with virtually every DMT and even symptom control drugs which they have shown to have DMT protential in animals ((we can do this with water).

      So I have hopes for this drug in the progressive MS trial and it would be the closest neuroprotective drug to market and hence availability. It could be a game changer

      Will this happen it will depend on the the results first and foremost and then it will depend on the regulators.




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    2. Dear MD!

      Thank you so kindly for your prompt respons to my comment. I and the Community really appreciate this.

      Now, when I read the safety warnings for these other oral agents, Tecfidera, Aubagio and Gilenya, I see that these agents have problems, especially in the long run, with opportunistic infections, such as PML (Tecfidera, Gilenya), and Aubagio (Liver toxity, and other safety issues such as cancer issues with Gilenya). Well you can all read more about it in FDA´s prescribing info.

      My relief, is that the cardio events where all in the high dose arm 1.2 mg (incidence rate: ca 1%) - and twice the dose. 0.6 mg, that I (maybe) recieve in the Concerto Study, depending on whether I have been randomized into placebo arm or the 0.6 laquinimod arm.

      Sooner or later, when raising dose, you will open Pandoras box - this logics relates to many approved drugs; i.e. find the correct dose in relation to risk vs benifith. And probably 1.2 dose is probably to high with laquinimod.

      As long as 0.6 mg show no signs of any cardio risks adn oither safety issues, leaning on over 10 000 patient years on 0.6 mg, at least I remain calm.

      Warm kind regards
      Alice

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    3. My reasoning with myself when I view this with relapses vs progression of disability in my case.

      For me progressions of disability (CDP) is at the moment my gretest fear, the relapses have not been so frequent in my case. So for me a drug that can have reasonable efficacy on EDSS along with good safety on dose 0.6 mg is fair enough.

      Futhermore, when I sat and compare - yes, one should not compare studies, but ultimately that is what everyone does,including neuros of course, when making decision about treatment - I saw and reflected on that laquinimod in the extension study at year 6 had a low relaps rate: early starters 0.143 an late starters 0.189 (Source: Abstract 692 - Ectrims Barcelona 2015)

      Now, when I compare this with Tecfidera´s pivotal studies, and the same extension data for their patients, the early started patients had an ARR of 0.14 and late starters 0.10(!) ARR. (Source Poster: Check/google Ectrims Barcelona 2015 for this poster !)

      The Difference between early starters in laquinimod and early starters in Tecifera is 0.04 more ARR for laquinimod, if you take laquinimod, compare to Tecfidera. (0.14 - 0.10), all based on extension study year 6, to my best understanding when I interpret abstracts/posters from Ectrims Barcelona 2015.

      That means, with simplyfying maths, you will get 1 (one) more relapse during 25 years (twentifive)(!), when you make a snapshot of the ARR status at year 6, comparing ARR between laquinimod and Tecfidera, based on these extension studies.

      And the longer time I have RRMS, I will have less and less relapses along the time curve, as illustrated with my reasoning when comparing ARR at year 6 between laquinimod and tecfidera. Instead progression would be more of a clear worry.


      The difference in relapsrate - if "true" and representative ARR values in these extension studies, given the same baseline characteristics - is so Little; trade off profit or whatever we shall call it is small, it it at all exists in the longperspective; 1 more relaps in 25 year at a snapshot of "relaps-status at year 6.

      Look, we all reason different and that is good, becuase how borring life would be if we all would wear the same "uniform".

      But when all get very complicated, at least I try to simplyfy things, to get better understanding. You could criticize some of my reasons, of course, this is not ment to be a PhD examination. But just want you to know how I reason when I choiced to participate in the laquinimnod trial.

      We have to put the difference in ARR efficacy between some of the MS agents in perspective, especially after a couple of years of treatment.


      To be noted:
      according to my neuro, there where still about approximately 1475 patients still in the extension study of laquinimod, at the time when Ectrims 2015 in Barcelona took Place. That would be the mayority of all patients starting in the laquinimod studies (placebo + laquinimod).

      And with all alternatives approved out there, I Think it is worth a thought, why so many patients continues to take laquinimod (ca 1475 (60%) patients of total 2500 from previous pivotal studies allegro and bravo participate in extension ...(?) Many of them are for sure located in countries where they have several other options. So for some it seems to work probably.

      Furthermore, I compared the baseline characteristics between laquinimod and Tecfidera, and they where at large similar between these agents in their pivotal studies. I even "interigate" my neuro about this, and we had a rather animated discussion about this - of course in a good positiv spirit.


      Anyhow, here I elaborated a bit about MY REASONING when choosing to participate in laquinimod study, and how I view difference in relapse rate between different agents and put into that context, "my view" on disability progression along the time line.

      Its is very late, and it is time for me to go to bed.

      Warm kind regards

      Alice

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  3. I had a dose of 1.2 mg laquinimod. Currently the study is suspended for this dose . But I feel trapped ! I was called to a medical visit earlier this month , I have done analyzes by not receiving medicine earlier this month , I have boxes of medicines called back! Next week I was called to another visit! If I withdraw from the study I should do an MRI . The blood tests that I've done in the 2 years , I have never received any results ! I guess my only option is to stop being a serious person and so will be excluded from the study !
    But I WILL NEVER BE a mouse ! Instead of a problem , I risk getting 2!
    However , vitamin D have some very good results in my fight with MS!

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