Thursday, 11 June 2015

Laquinimod. Will it become a new MS DMT

Someone asked ProfG "how can you be positive about Laquinimod when MD was rather negative?

Well the answer is simple....If we look at the effect of Laquinimod
on the relapse rate, then both ProfG and MD would agree that the influence of laquinimod is rather poor compared to other DMT on relapse rates.


In the words of ProfG "Laquinimod is a drug that does not have much effect on inflammatory MS disease activity, i.e. relapses and MRI activity (Gd-enhancing and new T2 lesions"

This is in response to the trial data

Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, Filippi M; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod for multiple sclerosis.N Engl J Med. 2012;366:1000-9

Vollmer TL, Sorensen PS, Selmaj K, Zipp F, Havrdova E, Cohen JA, Sasson N, Gilgun-Sherki Y, Arnold DL; BRAVO Study Group.A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol. 2014 ;261:773-83.

In both cases the reduction of relapse rate was very modest and in support of the dim view expressed by MD, both the European and US regulator did not approve laquinimod apparently on a risk:benefit exercise. 


However, it seems that the FDA wanted more data and so CONCERTO (NCT01707992was born, which is another phase III placebo verses two doses of laquinimod with over 2,000 people in the trial. This trial is massive and has over 600 people getting nothing....well OK they are getting placebo and are on a trial so they will do better than getting nothing because of the placebo effect 

However, should we ask the question about the ethics of this, as many people will undoubtedly accumulate disability as a consequence of the relapses that they have whilst on placebo and many of the people on active drug will relapse also. 

Some people will argue that people enrolled on the trial may not have had any access to any DMT and so with a 1 in 3 chance of placebo verses active drugs...it is was worth it.  One of the MSers I spoke to had slipped through the DMT eligibility net due to NICE guidelines and this is why they volunteered. 

But should companies be able to get away with this?  Doing a trial against placebo is easier and cleaner and cheaper and suits them, but is it in the interests of people in the trial in  this day and age? 

Pharma are probably responding to the whims of the regulators, so they (FDA) are in part culpable. NICE complain about the costs, but in responding to regulators, pharma is having to spend millions of dollars in the drug develop process and Society bears the extra cost passed on.

There are currently over seven classes of drugs that have an impact on relapse rate and trial studies could be done to show they are not inferior to the other DMT. The company producing the laquinimod could have done a non-inferiority trial against their own DMT, so every one would be on a drug.

However, the risk here is that the new drug is inferior to the existing treatments and if showed this, it would probably be doomed. Hence the worry for laquinimod as it would be inferior in be terms of affect on relapses so many current DMT.

However ProfG was excited because of the apparent impact of laquinimod on the rate of brain atrophy, which suggests that it may neuroprotective capacity and slow brain shrinkage. This will be identified in CONCERTO

MD thinks this prospect would be exciting too.

ProfG said
" I am very impressed by the laquinimod phase 3 results. Why? Despite its weak anti-inflammatory effects laquinimod has an impact on disability progression, that appears to be independent of relapses and it slows the rate of brain atrophy. All this points to laquinimod having neuroprotective effects downstream of inflammation". 

MD thinks that this would be great and so agrees with ProfG. 
Then the question will arrive will you and take a drug and importantly will your neuro prescribe a drug that is beneficial in terms of slowing disability, but at the same time it is not stopping you from relapsing. Is the effect on disability better than could be 
achieved by other DMT that are more effective at stopping relapses.  However based on the published data it looks like a neuroprotective drug. In the beasties we have a lot of these now that don't inhibit relapse but do slow the accumulation of disability.

So will Laquinimod be beneficial for progressive MS.We shall see as there are currently trials in progressive MS (NCT02284568) and hope it works

We can also ask is there any merit of combining drugs? An immunomodulator and a neuroprotector. Well maybe there is some data already there 
They say that if you inject Laquinimod into EAE in mice with suboptimal dose of laquinimod and add it to a suboptimal dose of other DMT you get an better effect so this may be a way to use Laquinimod in combination with another DMT for MS. A trial will be needed 

So on its own Laquinimod may not be great at controlling relapses in MS, but it may have value in slowing the rate of progression in both relapsing MS (especially if combined with a DMT that inhibits relapsing disease) and progressive MS.

So there is no confusion. For MS you want a DMT that blocks the inflammatory response that drives relapsing MS and another to block the type of inflammation that drives progression. These may not be the same agent but they could be.

44 comments:

  1. If its action is as a neuroprotective agent, would it be better or cheaper or quicker to market than phenytoin, or all the other possible neuroprotective drugs you got so excited about after your triumph at AAN?

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    1. Quicker to market... NO the progressive trials are on going.
      Better........If we do head to head experiments we will know
      Cheaper....Phenytonin is never going to get licenced because it is too cheap unless the system changes...Go on neuros try prove me wrong. The first neuroprotective DMT to market is not going to be less than $50,000 based on current DMT pricing and may be more, unless the neuros can get a cheap one through.....which is unlikely

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  2. Is laquinimod being trialled in SPMS and PPMS?

    The simvastatin issue is still irritating. Would there ever be an incentive for someone to chemically modify simvastatin to try to get a new compund patented for MS? Too risky and long-winded? I assume the process would have to restart from phase 1?

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    1. You're right, a simvastatin analogoue would have to go through the whole process from phase 1. Although there could be patent protection if simvastatin was part of a combined pill with another neuroprotective agent. Maybe this is being explored.

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    2. it would be back to the drawing board along time before phase I to develop a new drug. The problem would still be the repricing I suspect.

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  3. Had simvastatin actually showed any succes?
    And if so what does it point to regarding the cause of orogression in PPMS spms

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    1. Yes there was some success.....How does it work it could be a number of reasons.

      Damm I have forgotten the new one that I came up with last week, when I was reading something I should have written it down hope it comes back as it was not bad idea and better than the anti-inflammatory story...ProfG has also suggested an effect may be via reducing co-morbidities

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  4. "But should companies be able to get away with this? Doing a trial against placebo is easier and cleaner and cheaper and suits them, but is it in the interests of people in the trial in this day and age?"

    There exists mountains of trial data results for MSers on placebo. It seems a surrogate placebo arm could be generated from this data so that no patient has to be on placebo.

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    1. Except, as seen with the recent CUPID trial, those on placebo did not progress as rapidly as predicted from previous published trial data.

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    2. Is that not even more reason to have an aggregate placebo arm from previous trials? Otherwise a perfectly good drug could fail because of an unusually mild course of disease in a particular control arm... Would the volumes not be greater if they pooled this from historical studies, for a better representative sample?

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    3. Yes indeed and fail it did.

      As to historical studies.

      If we look at the experience of the risk sharing schemme they based their outcomes on one historical cohort, got a rubbish result and changed it to a different cohort..

      However if we look at the historical studies the relapse rate was 3 per year in placebo and the drug effect was 0.6-1 now the placebo groups are about 0.6-1 and the drug arms are 0.1-0.2 . (I have made the figure up but you get the point that people are doing much better now that they did many years ago...some people say that the best treatment to arrive has been the development and availability of MS specialist nurses

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  5. Isn't it possible that the decrease in disability independent of relapse with laquinimod will supersede the clinical benefit of reducing 1 relapse every 5 years or whatever it is with a DMT that is more effective against relapse.

    IE placebo ARR 0.4, 50% reduction with DMT ARR becomes 0.2 so that's 1 relapse difference per 5 years. Laquinimod 25% reduction so ARR becomes 0.3....that's a difference of 1 relapse per 10 years vs. the other DMT...I know it's a bit of extrapolation but still?

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    1. This is going to be the canundrum for the neuros if this drug gets approved as a monotherapy.

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  6. we keep going round he same buoy with neuro-protective agents. Neuros / researchers conduct early trials which show promise (Simvastin, Phenytoin)... further trials to gain a licence cannot get funding... neuros / researchers conduct early trials which show promise...

    Keep repeating the same mistakes with no chance of a different outcome. My solution - academic research (MS research) to be scrapped and researchers join big pharma. At least there's a chance that ideas will reach market. At the moment all we get from academic researchers are peer reviewed papers and they are as useful as a broken wrist watch (at lease a broken wrist watch is right twice a day). Decades are passing and we are no nearer treatments for neuroprotection or repair. If we were you could tell me when (year) these will be available.

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    1. I couldn't disagree with you more. I am very grateful that researchers investigated an add-on therapy to Copaxone that results in a relapse rate better than any approved DMD. The add-on drug is a generic medication that is in widespread use so there is no hope for it being patented.

      Despite this, these researchers (some of the most respected in MS research) conducted this trial knowing that it is likely to go nowhere. But the science behind it is strong and gaining momentum and I am so indebted to these people. They are hero's in my eyes:

      http://activemsers.wssnoc.net/showthread.php?t=1811

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    2. However, if big pharma was in charge maybe you would not get the innovation.....

      Pharma are closing their R&D departments and feeding of academia that does not have the knowledge or the resource to develop drugs. If you look at UK pharma it has been decimated in recent years...

      Which bit do you want to scrap the clinical research...so you will not have MS specialists or there basic science and so not chance of finding stuff that pharma will exploit.

      We have said many times if you want to repurpose drugs for a quick fix you have to change the system.

      We are no nearer neuroprotection and repair.....what about laquinimod it is being tried in PPMS as we write.

      IT I have the phase III results to hand I still could not tell you when the drug will be available..look at laquinimod finishes its first phase IIIs and still years away....sorry

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    3. At the end of the day we are unlikely to see an real breakthroughs in our lifetimes. MS researchers are in the same boat as those studying dementia, huntingtons.... The brain and the diseases which affect it are way too complicated. Peer reviewed papers don't improve my condition. The researcher funders are going to wake up soon and realise they aren't getting any return on their investment. The worse disease get the worse treatments - just a fact of life.

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    4. Hmm not sure I agree completely with you. Yes, it may be unlikely in our lifetimes that a big breakthrough will occur, but this could be said about a lot of cancers many years ago, and that too is very complex. The major difference that I see is that the cancer lobby are very active, it has more funds and more awareness because it touches more of the population -sort of chicken and egg on that point. While MS is apparently the major cause of disability in young adults, it is still affecting a very small percentage of the overall population and because of the multitude of problems it brings people with MS, it is very hard to treat holistically or for there to be a consistent voice that breaks through into the mainstream media - to raise the awareness and get the funds needed.

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    5. Anon 7:23
      I completely disagree with you. Though MS is a neurodegenerative condition, the diference between it and dementia/motor neuron disease/parkinson's etc is that with the other conditions once you are diagnosed it is already essentially too late as you have lost too many neurons. This is not the case with MS, where diagnosis is made much earlier in the disease course. The new DMTs are much more effective at treating relapsing/remitting disease and the dawn of neuroprotective therapy is already upon us.
      I consider these real breakthroughs.

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    6. The only problem with the new DMTs is that they start to look really risky (PML) - I have no desire to get PML or cancer as a price for improving my MS - I am not sure the docs and researchers realise that the majority of MSers want safe treatments and many discontinue treatment after a time due to fear of the above mentioned (like me) or because they simply realise the long-term damage to other organs (liver for example).
      On top of that all these drugs most likely just soften MS - still no cure in sight that would at least make the risky meds worthwhile.

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    7. Seems that you are making the case that induction therapies as the way to go
      So we need to get safer ones

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    8. Dear anon 12.08pm, you say 'On top of that all these drugs most likely just soften MS - still no cure in sight that would at least make the risky meds worthwhile.' I agree that we all want a cure, preferably without major risks, but until that point I'm willing to take the risks of PML. We are all different; motivated differently, suffer differently and it will always come down to the individual. For me it was a decision of a treatment that may mitigate ("soften") the MS to some extent (despite the risks of PML, yes I'm JC positive) or do nothing and most likely get worse, which was a more serious risk or even a certainty for me.

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    9. Agree with MD2, though there needs to be rational and intelligent thinking on how to speed up progressive MS trials. How are the meetings going post phenytoin results? Any luck with getting pharma to take notice?

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    10. Once the penny drops there's even more money to be made from MS, I'm sure they'll come piling in. Mind you I'm just a lab mouse so don't get to interact with pharma that much like Prof G.

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  7. My question would be, in a disease like progressive MS, which has zero approved treatments, should we not open up therapies that have shown promise in Phase II (safe, signs of effectiveness) straight away, rather than do nothing? Especially where these drugs are licensed elsewhere.

    Would need a proper monitoring scheme, to identify after a period if the drug is less safe/effective than expected, but they manage to do this in cancer so why not MS, if the patient is willing? Why are neurologists not owning this issue like oncologists did/do?

    To say we have this approach (do nothing) that definitely won't work and will see you get much worse, and another approach that looks like it's pretty safe and stands a decent chance of working to an extent; and our advice is to sit on your hands and do nothing for 15 years (definite path to severe disability).... Just seems like terrible, soul-destroying, inhumane advice.

    It's akin to seeing someone drowning and saying "Ah - I see you're drowning! We've got this life ring which could save you, but we're not sure so rather than risk it, I hereby ban anyone from throwing it to you, and recommend you just quietly drown instead (safer option). If you're still bobbing in the water in 15 years, I'll throw it to you then instead".

    I do understand the pitfalls, and people could waste money on it. But it's the lesser of two evils for me, given this life destroying disease. Money is usually more replaceable than your brain/life.

    I wouldn't wish MS on anyone, but it'd do us all good if a few of the decision-makers/people of influence in the regulating bodies had it themselves. Might get a bit of common sense/urgency/humanity out of them then.

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    1. As a non-neuro I can't answer this question and have indeed asked my own questions.
      ......often to no avail and as it is frustrating to me, but appreciate that it is even more frustrating for you.

      The sloth and the amphioxous attitudes I wonder

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    2. p.s. Have we got stuck in a process...the do no harm and importantly where is the evidence that this works. However if you start in phase II and everyone goes on drug how do you really know if it works....OK a miraculous effect can be seen,but if the effect is subtle how do you know and once every one is on drug how are you going to get the evidence.

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  8. Can you not get access to these potential drugs on a named patient basis on the basis that there is currently unmet need?
    Especially if like simvastatin it shows promise?
    There's a lot of scepticism about ldn but doesnt it tell you everything that people are trying that because they have no choice? If they had choice they'd try others in convinced

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  9. For the likes of Simvastatin, how much would you be talking to run one phase 3 type trial? Is this all beyond the the financial power of say a group of MS charities from around the world putting money into a pot? If it isn't licenced for the indication at the end, would that really matter, if the evidence was there that taking it was a good idea? The risks of statins have been extensively studied elsewhere and would be known to all involved if being prescribed off licence.

    I presume the only people in a position to really want to take and educated gamble are the drug companies..... It's just saddening/maddening that this has to be the only way to do it.

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    1. http://app.dddmag.com/news/2015/05/researchers-discover-treatment-block-ms-progression

      Is this the breakthrough

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    2. Sad to say no. Even if the results translate to pwMS it will be a disease modifier which will have little effect on progression (which occurs independent of inflammation) as the article misleadingly states.
      interesting new target though but very preliminary also with all the current effective DMTs there is the risk there will be associated problems such as PML etc.

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    3. It's crazy to see no one knows what drives progression or at least knows how to stop it.
      Is there not a common theme in statins, biotin etc or does the fact hsct works for some with progressive disease point towards a viral implication?
      Is your charcot trial aimed at measuring orogression as Michael Penders treatment in spms was in Australia?

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    4. How much for one trial....Academic cost probably price is 2-5million and funders will cut this down....for pharma 50,000,000-100,000,000 as the staff time and the monitoring costs need to be induced and much of this is not done by academics.

      Will this get done..maybe...there is talk of phase III....We need to know is the high dose needed? Will the standard dose work?, was the phase II a fluke?....Do one trial and hope that neuros will prescribe off-label as one trial won't be good enough for a licence unless the rules are changed.....Pharma will call foul...But should we care.

      Problem may come if one of pharma drugs works and gets a licence...but should we aim to cross this bridge when it is a problem...or should we deal with it beforeit is a problem

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    5. Is this in relation to simvastatin?
      The issue is I guess for people who are interested is they are already affected by progression and anymore would be hugely detrimental
      Then there's the other possibles out there such as biotin, I know of ALOT of people who are buying bulk powders and taking 300mg per day as per phase three trial
      There are ALOT of msers willing to try anything to slow down the progression

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    6. Kris 10.46
      There are plenty of ways to target the processes that may cause progression,however to target these in MS is a slow process. You can find plenty of examples. It is possible to construct a view encompassing statins, biotin, hsct, etc. but the first problem you are making the case that they really are doing something, more meat needs to be put on these bones.

      Try think of MS as two different but interrelated problems and then it is easier not to mix the processes and treatments, the value of HSCT is really in RRMS and people with SPMS/PPMS getting benefit is possible because they are relapsing progressive.

      the charcot project idea is about cause and this probably some way distant to progressive MS.

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    7. I've done a lot of reading regarding the theories around mitochondria damage, glutamine toxicity, ccsvi, ldn, fluoxetine and they all target different issues
      Is there not a common theme in all this? The only thing I could find was the glutathione/glut ratio being implicated, but it doesn't seem to explain it all, including the male get it worse theory
      There must be a malfunctioning hormone involved in this surely?
      Is biotin not implicated in glutathione ratio too

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    8. One more thing mouse
      Your phenytoin study was that based on treatment of cerebral hypoxia? One of the neuros involved in the biotin trial States he believes that virtual hypoxia is the issue in progresive ms and that biotin works somehow by targeting this?

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  10. With simvastatin what is the issue with using this off label? From what I gather it has a good safety profile and is quite easy to purchase online

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    1. My neuro has given it to me. Been on it 6 months and am no worse.

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    2. At what dose have you been given this and what was your progression before being on them

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    3. 80mg per day. My diagnosis is neurodegeneration following a CIS. My MRI has not changed in 4 years and negative OCB LP - so no MS dx. I recovered well after the CIS but the slow onset of right leg only calf spasticity started a year later. Not much has changed over the last year and neuro thinks I have just plateaued. He was happy to give me Simvastatin as a neuroprotector. I often wonder if I just have slow going PPMS and to be honest cant relax as their is no test to completely rule it out. I just wish a negative LP would rule it out.

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  11. Hi
    Wow your situation mirrors mine except mine has been a lot quickef , what was your CIS and why haven't they diagnksed you with Ms?

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  12. My CIS was like partial transverse myelitis. Right arm and leg weakness and numbness on left arm and leg - this is known as brown-sequard pattern in 2008. Recovered then in 2010 noticed spasticity/foot drop on right side. Saw neuro in 2011 MS suspected but have had 2 megative LPs and MRI scan unchanged - last one was 6 months ago. I have one each year now just to check it is not MS. Dont satisfy McDonald criteria for MS DX - although I may be an unusual case theu cant say I dont have it either !

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