Wednesday, 19 October 2016

#ResearchSpeak & #PoliticalSpeak: I am losing my marbles can you do something about it?

The issue of MS being a preventable dementia needs to be centre stage! #ResearchSpeak #PoliticalSpeak #MSResearch #MSBlog

About 3 years ago I launched a campaign to rebrand MS a 'Preventable Dementia'; I took a lot of stick for this campaign because it was considered stigmatising. However, the truth of the matter is that cognitive impairment, and progressive cognitive impairment, is what happens in MS. The study below by Ruano and colleagues, in over a 1,000 Italian MSers, confirms what we already know: 

"The overall prevalence of cognitive impairment was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP MS."

The severity of cognitive impairment was greatest in MSers with progressive disease and was related to age and level of disability. What can be done about it? The message is simple; you have to try and prevent yourself from becoming disabled, in other words early effective treatments are needed as well as a brain healthy lifestyle (please see our Brain Health challenge). There is now convincing data that cognitive impairment is strongly associated with progressive brain atrophy and disability. If your MS is getting worse you need to ask the question can anything be done about it? The answer is yes. 

Some good news in a sub-study of MS-STAT phase 2 trial showed that high-dose simvastatin signficantly slowed down progressive cognitive impairment in SPMSers. How simvastatin is doing this I can't tell, but it makes a compelling case for doing a definitive phase 3 trial of simvastatin  in progressive MS. Please watch this space we have a grant application currently being reviewed by the NIHR (research arm of the NHS) to do this; the PI on the trial is Jeremy Chataway for UCL. 

Should all progressive MSers be taking simvastatin now? No. The dose used in this trial is very high and will almost certainly cause adverse effects. The findings in this MS-STAT trial could be a type 1 error, or a false positive result. We therefore have to confirm it in a larger study and show that the benefits of high-dose simvastatin outweigh the risks of the treatment (adverse events) and for the NHS show that the treatment is cost-effective. I suspect the last point is not really an issue with simvastatin as  it is off-patent and there are very cheap generics available; I am talking a few pence per day. 

BNF price: Tablets, simvastatin 10 mg, net price 28-tab pack = 84p, 20 mg, 28-tab pack = 94p; 40 mg, 28-tab pack = £1.12; 80 mg, 28-tab pack = £2.02. 

The current price of simvastatin (7.2 p/day) raises and important point about pharmaceutical innovation; the price of pharmaceuticals eventually come down so much that they become quite insignificant in the scheme of things. I can remember when I had just finished medical school (1987), and simvastatin had just been launched, there was a major debate going on about would society afford the costs of statins and that MSD was being mercenary charging so much for the drug. Now look at the price. We have to assume that the same rule will apply to current high-cost drugs, including the biologicals. In time and with further innovation in making biosimilars cheaply, future generations will reap the benefits. What we have sort out, however, is there a better model that the current one for repurposing off-patent drugs. We need away to monetise off-patent drugs so that Pharma take-up the challenge of doing the necessary trials and regulatory work to get off-patent drugs licensed. We find ourselves in a very difficult position; academia really doesn't have the resources (money) and expertise (regulatory machinery) to license drugs. 



D Chan, S Binks, J Nicholas, A Alsanousi, N Fox… - 2016. Effect of high-dose simvastatin on cognition in secondary progressive multiple sclerosis (MS-STAT cognitive): a randomised, placebo-controlled, phase 2 trial


Background: Cognitive impairment is a major contributor to disability and reduced quality of life in secondary progressive MS (SPMS). In the 24 month MS-STAT phase 2 trial we showed that high dose simvastatin significantly reduced the rate of whole brain atrophy, as well demonstrating effects on clinician and patient observed outcome measures. We describe here results of the MS-STAT sub-study, evaluating treatment effect on cognitive and neuropsychiatric outcome measures.

Objectives: 140 patients with SPMS, with Expanded Disability Severity Scales (EDSS) scores between 4 and 6.5, were randomised to receive simvastatin (n=70) or placebo (n=70). Full cognitive and neuropsychiatric testing was undertaken at study entry, 12 and 24 months.

Methods: The following cognitive domains were tested: premorbid IQ; general intellectual functioning; verbal and nonverbal memory; semantic memory; visual perceptual function; attention, speed of information processing, and working memory (PASAT-3); frontal lobe function (frontal assessement battery, FAB). Neuropsychiatric symptoms were assessed using the Hamilton Depression Scale and the Neuropsychiatric Inventory Questionnaire. Linear mixed models were used to examine how cognitive and neuropsychiatric scores changed between baseline, 12 and 24 months and to evaluate the difference in score between the placebo and simvastatin group at 12 and 24 months.

Results: Baseline assessment revealed that nearly half of patients showed impairment on frontal lobe function (45%) and on the PASAT-3 (46%). There were also significant numbers of patients (up to 33%) with impairment on tests of verbal and nonverbal memory. Over the entire trial, the cohort as a whole declined on tests of verbal and non-verbal memory. At 24 months, there was a significant difference in FAB scores between the two treatment groups, with a 0.24 point increase in the mean FAB score observed in the simvastatin-treated group, compared with a decline of 0.92 points in the placebo group: a difference of 1.08 ( 95% CI 0.09 to 2.14). No significant treatment effect was observed on any other cognitive or neuropsychiatric measures.

Conclusion: This represents the largest SPMS published cohort to have been studied with longitudinal cognitive and neuropsychiatric assessments. Frequent cognitive impairment was observed at study entry, with decline at 24 months observed primarily in episodic memory. Although results must be interpreted carefully because of the many variables examined, we found that high dose simvastatin significantly improves frontal lobe function, adding to our previous observation of a positive treatment effect on brain atrophy rates. These results highlight the importance of including detailed cognitive outcome measures within progressive MS therapeutic trials.

Ruano et al. Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes. Mult Scler. 2016 Oct 13. pii: 1352458516674367. [Epub ahead of print]

BACKGROUND: There is limited and inconsistent information on the clinical determinants of cognitive impairment (CI) in multiple sclerosis (MS).

OBJECTIVE: The aim of this study was to compare the prevalence and profile of CI across MS disease subtypes and assess its clinical determinants.

METHODS: Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop test in consecutive patients with MS referred to six Italian centers. CI was defined as impairment in ⩾ 2 cognitive domains.

RESULTS: A total of 1040 patients were included, 167 with clinically isolated syndrome (CIS), 759 with relapsing remitting (RR), 74 with secondary progressive (SP), and 40 with primary progressive (PP) disease course. The overall prevalence of CI was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP. The severity of impairment and the number of involved domains were significantly higher in SP and primary progressive multiple sclerosis (PPMS) than in CIS and RR. In multivariable logistic regression analysis, the presence of CI was significantly associated with higher Expanded Disability Status Scale (EDSS) and older age.

CONCLUSION: CI is present in all MS subtypes since the clinical onset and its frequency is increased in the progressive forms, but these differences seem to be more associated with patient age and physical disability than to disease subtype per se.

17 comments:

  1. But major spinal lesions confound the relationship between cognitive impairment and disability in some people.

    Average doesn't necessarily hold water for the individual.

    ReplyDelete
  2. "There is now convincing data that cognitive impairment is strongly associated with progressive brain atrophy and disability. If your MS is getting worse you need to ask the question can anything be done about it? The answer is yes...."

    "Should all progressive MSers be taking simvastatin now? No."

    So, really, the quote should say If the RRMS you've had for 8 years or less from diagnosis is getting worse you need to ask the question can anything be done about it? The answer is yes...."

    ReplyDelete
    Replies
    1. We have to practice evidence-based medicine to do this we have to have a level of evidence that justifies the risks. At present we are not there yet with Simvastatin.

      Delete
  3. I'm really pleased that you stood up and said this. I have SPMS but it moves forward very slowly, phew. I am not the same person as I was a few years ago and not just because I am a bit older. Memory, decision taking and emotions have all changed as well as physical changes.

    I agree, my changes are because of MS. It is linking these changes to something else that is less agreeable is controversial.

    That is part 1 now finding something that will provide neuroprotection is the next challenge. I hope I will be around long enough with sufficient marbles for it to help me.

    ReplyDelete
  4. To Mouse Doctor (MD),

    Since "B-cells" are in fashion at the moment, I would ask the following.

    In this newly published article, published originally September 21, 2016, in the journal Neuroimmunology & Neuroinflammation, the researchers found, that an experimental agent called laquinimod, had a 94% reduction in harmful clusters of B cells called meningeal B cell aggregates in mice. The researchers claims, that in human, such clusters are found only in those with progressive MS.

    Here is my source:
    http://neurosciencenews.com/neuropharmacology-multiple-sclerosis-5104/

    Questions - your reflections
    Is these "meningeal B cells" another kind of B cells than "normal" B-cells, and how do you grade these findings ?

    My remark:
    Of course mice is mice and human is human, but nonetheless, I think these findings are slightly encouraging. Especially for us MS patients with progressive MS.

    Best wishes
    Eva

    ReplyDelete
    Replies
    1. Dear Eva
      I may review this
      If you read https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5032664/
      there is some explanation
      the main paper is here
      https://www.ncbi.nlm.nih.gov/pubmed/27704036

      Laquinimod is in trial in RRMS and PPMS because of a side effect the RRMS part was stopped because of a heart related side effect.

      In this study the drug is ace and stopped EAE completely in MS it is worse than beta interferon but it looked like ther was a much better effect on brain atrophy. Hence an interest in progressive MS.

      The models used here have so little to do with progression in my humble opinion. However there was some very interesting work presented at ectrims showing the effect of laqinimod in a progressive model.

      The space surrounding the spinal cord is the meninges and there are b cells that accumulate here in these models..are they really follicles not convincing in these pictures

      Delete
    2. TO BE OR NOT TO BE - LAQUINIMOD - PART 1 of 3
      =============================================


      To "Eva" and "MD" and all other out there ...


      Interesting comment about laquinimod, both from Eva and MD. But, with risk for being placed in "spam box", I think MD does not have a balanced view with regard to plus and minus with this experimental drug laquinimod. I am then referring to most of his blog posts, where laquinimod is the main subject.

      Hopefully this blog forum does not have to be a united choir, we can have different opinions, as long as we have some logical arguments for it. It is even refreshing to have different views, since you have to sharpen up your arguments in the matter.

      And yes, you could say that I have a clear bias (haven´t we all ...?) - see my "disclosure" at the bottom. But MD, I welcome you to challenge me on what I say down below about laquinimod:

      I will divede my comment into 2 parts, part 1 and part 2, since I suprisingly discovered that maximum ca 4000 characters are allowed in each comment.


      I will will divide my "dissertation" into three headlines,namely Disability, Relapses and lastly safety

      So here goes:


      DISABILITY
      I just checked the overall pooled result of this agent laquinimod, descended from the pivotal studies Allegro and Bravo. And with regard to disability (edss) it had a profound effect on ALL Edss intervals, 3, 6, 9 and 12 months with risk reduction 34%, 46%, 47% and 45% respectively (source: AAN 2016 abstract - link down below).

      In essence: the agent consistently shows effect on Edss, with increasingly stringent time intervals. For me, as pwMS, this is a stress test to show that this agent seem to have striking effect on disability.

      To my understanding, that is definitely robust and rather impressive results, compare to other drugs, with regard to progression. Even you, MD, could acknowledge that. And your fellow colleague, Professor Gavin Giovannoni, acknowledge several times in his blog posts, the fact that laquinimod has a striking impact on disability, and a more modest effect on relapses.

      Presentation of the Edss data AAN 2016 (copy link):
      http://www.abstractsonline.com/pp8/#!/4046/presentation/5755


      Furthermore, an abstract presented at Ectrums 2014, they showed that laquinimod had very robust ambulation benefit in patients with worsening MS (EDSS over 3). These findings are consistent with reduction in confirmed disability progression. The measure used here was the Msfc measure T25FW.

      The reduction to walk 25 foot was 59% , laquinimod vs placebo (Edss > 3 subgroup).

      Furthermore, when looking at those patients that progressed in Edss, patients in placebo declined by 8.6 seconds more than equivalent laquinimod treated patients. Now, that is a big difference, when we only talk about walking only 25 foot.

      Just a coincidence (?) No, I don´t think so, since it correlates with effect on Edss.

      To my eyes, these T25FW data support the effect of laquinimod on confirmed disease progression as an independent, relevant assessment in patients with Edss over 3.

      To be noted. Not much use, to measure T25FW in patients with Edss under 3, since disability is relatively minor in these patients.


      Presentation of the T25FW data at Ectrims 2014 (copy link):

      http://onlinelibrary.ectrims-congress.eu/ectrims/2014/ACTRIMS-ECTRIMS2014/63775/timothy.vollmer.ambulation.benefit.with.laquinimod.in.patients.with.worsening.html?f=m3


      TO CONTINUE ... PART 2: see next following separate comment


      Best wishes
      Bill

      Disclosure:
      See my disclosure at the end of PART 2

      Delete
    3. Continuation ...


      TO BE OR NOT TO BE - LAQUINIMOD - PART 2 of 3
      =============================================



      RELAPSES
      With regard to relapses, yes laquinimod has more modest effect, but the effect is in the ball park of what beta interferon beta delivered. For instance, Avonex has a 18% official reduction of relapses in the official prescribing information, was around 18% reduction (18.3%). In the Bravo study, where Avonex was used as a comparator arm, it reached 23% reduction of relapses.

      And of course this figure differs, depending on study design etc. All studies have unique features and rests on its own legs.

      But my point is, that laquinimod has efficacy in the ball park of what Avonex has performed in different studies. Not impressive efficacy in relapses, but still an effect.

      But as you have so well pointed out, MD, laquinimod is not an immunosupressive agent. Given that, I would not expect it to have an impressive effect on relapses.


      TO CONTINUE ... PART 3 OF 3 - SAFETY: see next following separate comment


      Best wishes
      Bill

      Disclosure:
      See my disclosure at the end of PART 3



      Delete
    4. Continuation ...


      TO BE OR NOT TO BE - LAQUINIMOD - PART 3 of 3
      =============================================


      ABOUT SAFETY
      The continuing dose 0.6 mg had no safety issues, to my best knowledge, supported by more than 10 000 patient years of experience - previous pivotal studies including the extension studies.

      The dose 1.2 mg (RRMS) and 1.5 mg (PPMS) that were stopped, were wild cards, since they had no previous experience of these higher doses from performed phase II study. Furthermore, the pharmacokinetics for this agent laquinimod are very narrow, more like textbook oriented pharmacokinetics, accordingly to what I have learned.

      In essence, low spreads; tight spreads with regard to plasma levels etc. That would warrant the continuation of the 0.6 dose along with the long time safety experience with this dose. Something you maybe would have missed out MD (no offence meant).


      That being said, all drugs have safety issues. The immunosuppressive drugs have more or less severe safety issues, such as risk for PML, opportunistic infections, malignancies in human, which you tend to sometimes to overlook (sorry: no offence meant) in many of your blogs.


      Yes, many of these drugs are rather efficient in halting relapses, but not so impressive with regard to halting the progression of the disease - especially with regard to be able to show efficacy on Edss with increasingly stringent time intervals - not only on 3 and 6 months confirmation.



      CONCLUSION - MY POINT:
      Don´t cunt out laquinimod just yet MD. Given my aired arguments above I think there are clear evidence for that laquinimod does have an clear impact on halting the progression without safety problems with the dose 0.6 mg.


      MD:
      You are wellcome to challenge me, disagree etc. But maybe I misinterpret you ...

      Best wishes
      Bill


      DISCLOSURE
      I participate as a patient in the first pivotal study, Allegro, and in the following extension study. This said, to explain my insight and interest in the drug. And yes, of course I am bias, being involved in the study as a patient. Before participating in the Allegro study, and its extension, I was on Avonex (interferon beta a).

      Furthermore, good to know, I am a biology and chemistry teacher and i love my work. But I work part time due to my MS. But I do my "homework" about my MS disease, and spend a lot of time reading about different agents: I read and digest all sorts of science papers that involves MS -disease. Biggest problem with my MS: So tired and exhausted ...

      Delete
    5. The laquinimod PPMS study is fully recruited. Let's wait and see what the results show.

      Delete
  5. Dear Bill

    The comments I made were about the animal data and not the MS data. The MS data show that as a DMT for relapses it is pretty poor, but on the plus side the inference that is does more on disability is why Teva continue to investigate this drug.

    I know that the work with the 0.6mg dose is ongoing and i hope it works, but as with cladribine....SH1 sticks and one wonders to what extent the side effect issues of 1.2mg dose causes the SH1 to stick, irrespective of the the number of patient years. A small person getting the 0.6mg will take on as much drug as a big person getting the 1.2mg dose.

    I agree that is is not much of an immunosuppressive in MS and 23% in my mind is simply not good enough..and I put the interferons in this class because for the majority it fails to do what other treatments can do.

    However we were excited by the benefit on the brain atrophy data and wanted to test it in our progressive MS models, but when the side-effect issue arose..interest in doing our studies were lost..not by us.

    I can make a good argumenet why it can be useful but proof is in the pudding.

    Thanks for your insight and I hope that you can find a solution for the exhaustion. I appreciate that you are one of the brave many who particupate in trials without people like you there will never be any progress.
    Best wishes


    ReplyDelete
  6. To Mouse Doctor (MD)

    Firstly I want to thank you for responding to my post about an article of progressive MS and this laquinimod

    Secondly, I am sorry, but I am not so skilled in the field as you and this Bill with some specific words in relation to the context and what you MD really was getting at or meant.


    I just want you to simply clarify for me, and others, that are not such experts in the field with terms etc. So what do you mean Mouse, when you answer Billy with the following; I quote:

    " .... but as with cladribine....SH1 sticks and one wonders to what extent the side effect issues of 1.2mg dose causes the SH1 to stick, "

    And later on you say MD, I quote:

    " ..... but when the side-effect issue arose..interest in doing our studies were lost..not by us."


    Question to you MD from me, and probably some others in the blog community:

    1.
    What is "SH1" in this context ? (Sorry if I do not fully understand this )

    2.
    What was it with this Cladribine that relates to this high dose of laquinimod - Did Cladribine also run into some problem with highest used dose or what do you mean ?
    3.
    Do I understand you correctly, that when side effects with this highest dose of laquinimod occured in a few patients, "interest in doing our studies were lost". So am I to understand that this laquinimod is not ongoing study any longer - or what you mean ?


    So MD, I and others probably did not fully understand the full meaning in your answer to this Bill. So just clarify my questions 1 --3 above.

    Kindly regards
    Eva

    ReplyDelete
    Replies
    1. 1.Sh1 = s**t = mushroom food so when you throw mud some of it will stick to the wall and so the wall is muddy. If there is bad news then this bad news is associated with the problem.

      2.In the cladribine study it was originally reported that there were six cancers in the cladribine group. It turns out that three of the issues weren't cancer so it is 3 verses 0. The odd one out is not the three because cancer is a part of life the odd one was the 0. We showed that the risk of cancer was no greater for clad than any other DMT. But ask someone about clad and they say it causes cancer so the sh1 sticks-mud sticks.

      It is not about dose but it is how back news can stick.
      Laquinimod can be tarnished as a problem heart drug.

      What will happen for ocrelizumab in PPMS there it is 0 verse 9. Is the placebo odd again. If there is a level playing field the regulators I suspect will ask for another trial. Maybe the relapsing trials will be evidence it was a fluke.

      3. When the side effect issue occurred the company had to re evaluate how it proceeds some aspects were cut some.are continuing but as a consequence the companies alter there focus and ambitions

      Delete
  7. To Mouse Doctor (MD)

    Firstly I want to thank you for responding to my post about an article of progressive MS and this laquinimod

    Secondly, I am sorry, but I am not so skilled in the field as you and this Bill with some specific words in relation to the context and what you MD really was getting at or meant.


    I just want you to simply clarify for me, and others, that are not such experts in the field with terms etc. So what do you mean Mouse, when you answer Billy with the following; I quote:

    " .... but as with cladribine....SH1 sticks and one wonders to what extent the side effect issues of 1.2mg dose causes the SH1 to stick, "

    And later on you say MD, I quote:

    " ..... but when the side-effect issue arose..interest in doing our studies were lost..not by us."


    Question to you MD from me, and probably some others in the blog community:

    1.
    What is "SH1" in this context ? (Sorry if I do not fully understand this )

    2.
    What was it with this Cladribine that relates to this high dose of laquinimod - Did Cladribine also run into some problem with highest used dose or what do you mean ?
    3.
    Do I understand you correctly, that when side effects with this highest dose of laquinimod occurred in a few patients, "interest in doing our studies were lost". So am I to understand that this laquinimod is not ongoing study any longer - or what you mean ?


    So MD, I and others probably did not fully understand the full meaning in your answer to this Bill. So just clarify my questions 1 --3 above.

    Kindly regards
    Eva

    ReplyDelete
    Replies
    1. 3 we wanted to do something they didn't any more

      Delete
    2. 1 sh1 = sh*t = mushroom it some times hits the fan but if you throw mud at a wall some of it slicks so you ways have a muddy wall. So if a drug gets a side effect it can be tarnished.

      It can be said that laquinimod has heart problems, given the weak efficacy on relapses will it be tarnished.

      2. In the cladribine trials there were six cancers verses none in the placebo group. The FDA/EMA picked up on this. In fact it turns out it was only 3 cancers v 0. But was the odd one out the cladribine. Life causes cancers and the odd one out was the plan who group. The risk of cancer with cladribine was no higher than Jan I bet ms drugs. Ask someone about cladribine and they say it causes cancer so the mud has stuck.

      What will happen with ocrelizumab in PPMS. There is is 9 to 0. It a level playing field exists then I suspect the FDA will ask for another trial. Will they be and the relapsing trial data into account or will the safety data presented be a mix of info.

      3. When the company got the news they refocused and dropped some bits and put their efforts into other bits so if you were doing stuff in the area dropped then resource to that area is removed. This is standard business practise

      Delete
  8. Hey MD,


    Thanks for your reply. Must say, that I am really most obliged for your answer MD.

    Ok, I will "step into your office"or territory, MD, and reply the following:

    Now, first of all, we need to hold our horses a bit. With regard to the high doses of this laquinimod, 1.2 mg (twice the dose of the ongoing 0,6 mg) and 1.5 mg, we have to wait and find out what the analysis will say about it.

    1)
    Could the 8 cases really be linked to HIGH dose laquinimod ?

    2)
    These 8 patients who took these high doses (1.2 mg resp 1.5 mg), could have had cardiovascular risk factors, such as obesity, hypertension, hypercholesterolemia, diabetes, smoking, family history of IHD, or evidence of IHD etc. Such confounding factors for heart problems would have to be considered when you look on these cardio events in the high doses.

    Secondly, so far the ongoing low dose 0.6 mg could be advocated as safe dose, given the safety data so far, based on these over 10 000 patients years of experience with this dose 0.6 mg (knock on wood).

    Lastly, as you brought it up MD, in extreme cases with extreme small person or extreme big person, the plasma concentration will differ extremely. In such cases I would imagine that the sponsor would have performed
    pharmacokinetics and pharmacodynamic studies in such small/big humans to adjust for extreme cases.

    As an example, my father (dead since 6 years - bless him) was a very tall person, 6 feet and 9 inches, and due to that they have to adjust the dose for him, for the different medications he took in his last years alive - to be noted: my dad did not have ms-disease.

    All said in the context of if it could be established that the high dose of laquinimod and the 8 cases of different cardio problems (non fatal) could be linked to cardiovascular risk factors, as described above.


    All of today´s modern MS agents are immunosupresssive, and these are more or less linked to "mud that really sticks", like PML opportunistic infections, malignancies in human etc etc.

    What it boils down to, drugs which are more or less efficient, they all have some safety problems. And we all have to reasons with ourselves with regard to plus and minus with a specific drug, depending on what kind of preferences we have. In that respect we have to listen more to ourselves and not so much to what the industry promote at the moment. And at the moment, B cell seem to be heavily promoted by the industy and its entourage.

    Lastly, I for sure welcome that you are entitled to have your own opinion on this blog. And quite frankly, I was surprised that my first comment was published, since I am not totally agree with all that Professor Gavin or MD air.

    But then again, this blog would be very boring and lose energy, if it would be "sculpted" united like a choir and different opinions would not be allowed.


    Best Wishes
    Bill

    Disclosure: See my previous comment above

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.