Friday, 26 February 2016

ResearchSpeak: reply to an email from an expert PPMSer

Why shouldn't MSers engage with drug development for progressive MS? #ResearchSpeak #MSBlog

"The following is a personal email I received from a reader on the blog that I thought I should respond to via the blog as it has relevance to many people with PPMS."


Problem with sleeping, due to anxiety, so I thought I just drop you a line, that hopefully you can air about in your blog.

I wonder if you can bring up in your blog, the statement you made earlier on in your blog about an experimental agent called laquinimod (LAQ). It was written some time ago, namely 10 sept 2013 and also I managed to google an abstract where you were one of the authors connected to Ectrims 2014.

The title of the blog that you wrote is: "Is laquinimod the new wonder drug that progressive MSers need?". The statement you made in this blog , was that laquinimod is the first drug that has shown in phase III Clinical trials to have an impact on disability INDEPENDENT of RELAPSES and MRI activity. And to my understanding the HR was 0.61, in essence a 39% risk reduction in relapse free patients to have CDP (confirmed disability progression) in favour for laquinimod.

QUESTION 1: so since I have progressive MS myself, I of course wonder if that statement sticks, to your best knowledge; I mean that laquinimod is the first drug able to halt disability in non-relapsing MS patients in the Phase III studies, even if it was in RRMS patients? If your statements sticks, it sounds inspiring and that I as a patient could be cautiously optimistic about the ongoing PPMS trial with this laquinimod. Who knows, maybe this agent will have a fair chance for success in PPMS. We have now Ocrelizumab, but I was a little disappointed by the results. But the hype was too big, so there were bound to be some disappointments.


REPLY: "Yes, I stick by my statement that laquinimod has a striking impact on disability, and for that matter progressive brain volume loss, or brain atrophy, independently of relapses. It is not necessarily the only drug, when we do so called post-hoc analyses of subjects in other studies of high efficacy drugs we also see an effect when we compare these to placebo-treated subjects who were relapse-free in the studies. However, are these patients really relapse-free? In other words they may have had subclinical relapses (MRI activity) that was driving disease progression. But laquinimod is a DMT that only has a modest effect on relapses and focal MRI activity and yet has a much larger impact on disability progression and brain atrophy. This observation is not unique to laquinimod and has been observed with another drug called ibudilast, which is also in phase 2 clinical trials in progressive MS. It is clear that these drugs are working downstream of focal inflammatory MS lesions and may be targeting the so called hot-microglia that we think are responsible for driving some of the nerve and axonal loss in progressive MS."

REPLY"I don't think you should be disappointed by the results of the ocrelizumab results. They were clearly positive in an early population of people with PPMS. Ocrelizumab may become the platform treatment onto which we add neuroprotective drugs like laquinimod. Who knows the combination of ocrelizumab and laquinimod may be so much more effective than either agent alone."

QUESTION 2: Furthermore, I also found an abstract, where you contributed, with the title "Ambulation benefit with laquinimod in patients with worsening MS (EDSS over 3) is consistent with reduction in confirmed disability progression". It was published at Ectrims in October 2014 (see abstract below). Now my second and last last question would be, that apart from that this poster and abstract showed some positive result for the subgroup EDSS over 3, in that the laquinimod subgroup showed a 59% treatment effect on the MSFC measure T25FW, you also made a remark or conclusion, that "an interaction between LAQ treatment effect on T25FW and CDP (I quote abstract) was found: pts on PBO in the EDSS > 3, who also showed CDP declined with 8.6 seconds more than equivalent LAQ treated patients". This should also work in favour for having some hopes for laquinimod in PPMS. So this measure also works in favour, or points, in a direction that laquinimod could serve a treatment purpose in PPMS in the future, given that ongoing trials will hopefully show positive results. So my question is then: does this abstract, "Ambulation benefit with laquinimod in patients with worsening MS (EDSS over 3) is consistent with reduction in confirmed disability progression ", provide a reasonable rational to perform a PPMS study with laquinimod - especially combined with the positive results on CDP in non-relapsing patients - a penny for your thoughts on the matter Prof Gavin? 

REPLY"Yes, these observations and the effect of laquinimod on brain volume loss is precisely the reason why we are doing a study of laquinimod in PPMS. Teva the sponsor of this study would not be spending large amounts of money unless there was a compelling case for testing laquinimod in PPMS. I should add that there is also a large unmet need in this group as well."

To be noted: I am aware of that Teva have had to terminate the highest dose, 1.5 mg in PPMS. But the dose 0.6 mg continues, and the above results is, to my best understanding, based on the 0.6 mg dose, which were used in both previously performed phase III studies with laquinimod. To my best understanding, this dose 0.6 had no arising safety problems, as the case were with the dose 1.5 mg.

REPLY"Yes, you are correct the safety signal that has been noted with with the higher doses of laquinimod. There was a press release earlier this year that stated that non-fatal cardiovascular events occurred in 8 people on the higher doses (1.2mg or 1.5mg)."

Remark, for the record: According to abstract there were no significance different between PASAT and 9HPT z scores. But the MSFC measure T25FW results seem solid enough - yes encouraging; which, to my opinion was rather impressive, if it would stick in the PPMS study Arpeggio with laquinimod. 

REPLY"Yes, I agree with you and that is why we are continue to recruit and follow-up all the patients in the ARPEGGIO, or PPMS laquinimod, study. I am the principal investigator on this study and am very supportive of it continuing, for the reasons you highlight above."  

I have some problems with upper limbs, which negatively affect my ability to write, so please excuse me for all spelling errors and also it is very late into the night. Most obliged if you could give an comment on this agents prospects in PPMS, based on your "claims" or statement before, as aired above.

REPLY"I remain very optimistic about laquinimod as a potential treatment for PPMS. I still standby my previous posts that I think laquinimod, or a laquinimod-like drugs, will be best used as add-on neuroprotective therapies. According to our treatment pyramid below they will need to be added onto a platform anti-inflammatory therapy. However, to do combination therapy trials you have to have one of the drugs licensed. So the big debate in our heads is which agent should you add laquinimod on to? My preference would be to add on  top of an induction therapy."

Now time to go to bed. And in fact a little less anxiety about my MS disease after this writing. Sometimes it helps just to write on the matter, especially if you see some hope out there.

REPLY"Thank you for taking the time to read our blog and to make quite sophisticated arguments about how we need to treat PPMS. I actually thrilled to see someone with PPMS have such a clear understanding what we are trying to achieve and more importantly has hope. Hope is such a positive thing; a world without hope would be a very dark place."

"Don't worry about your writing, I took the liberty of make a few minor grammatical and typographical corrections to make it easier for the readers. Sleep well."



Background: In pooled data from the Phase III ALLEGRO and BRAVO studies of oral laquinimod (LAQ) 0.6mg once-daily (QD) vs. placebo (PBO) in RRMS, a 46% reduction in 6-month confirmed disability progression (CDP) was not accompanied by a significant treatment (Tx) effect on the Multiple Sclerosis Functional Composite (MSFC). However, for a subgroup of LAQ-treated patients (pts) with worsening MS (EDSS >3 at baseline [BL]), a 53% reduction in 6month CDP was accompanied by a significant MSFC effect vs. PBO.

Objectives: To investigate LAQ 0.6mg QD Tx effects on individual MSFC components in the pooled ALLEGRO and BRAVO pt subgroup with BL EDSS score >3, and to determine the association between MSFC component scores and improvements in CDP. 

Methods: Pooled data from ALLEGRO and BRAVO (N=1990) were used for this post hoc analysis of LAQ vs. PBO Tx effects on change in MSFC subscores at 24 months for the Paced Auditory Serial Addition Test (PASAT), 9-Hole Peg Test (9HPT), and Timed 25-Foot Walk (T25FW), in pts with EDSS >3 at BL. Adjusted mean z-score differences and 95%CIs were evaluated by ANCOVA. CDP was defined as an increase of 1 point if BL EDSS was ≤5.0, or of >0.5 point if BL EDSS was 5.5.

Results: Overall, 655 pts (33%) had a BL EDSS score >3 (LAQ n=328, PBO n=327), with a mean (SD) BL EDSS score of 4.1 (0.7). At BL, pts in the EDSS >3 subgroup were older than pts with BL EDSS ≤3 (mean age 41 vs. 37 years, respectively), had longer disease duration (5.2 vs. 3.7 years), and less brain volume (1547 vs. 1601 cm3). Mean (SD) T25FW time at BL was 8.29 (6.8) seconds (5.40 [5.3] seconds in the EDSS ≤3 subgroup). A 59% LAQ Tx effect on mean [SE] T25FW time (-2.79 [0.96] seconds, 95%CI -4.66, -0.92; p=.0035) appeared to drive the overall MSFC benefit in the EDSS >3 subgroup. There was no significant difference between LAQ and PBO for change in PASAT or 9HPT z-scores, though change directions favored LAQ. Further, an interaction between LAQ Tx effect on T25FW and CDP was found: pts on PBO in the EDSS >3 subgroup who also showed CDP declined by 8.6 seconds more than equivalent LAQ-treated pts.

Conclusions: In pts with worsening MS and EDSS >3 at BL, LAQ was associated with a substantial benefit on ambulatory function as measured by the T25FW, consistent with LAQ CDP benefit in these pts.

CoI: multiple, I am the principal investigator on the PPMS laquinimod trial

21 comments:

  1. It was good of you to do this response, Prof G. it provides this blog with a connectible and human angle. This is a good approach and one hopes to see more of it. Well done.

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  2. All those drugs? No. Not for me. Sorry if that's an unsophisticated outlook.

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    Replies
    1. That's a choice Not one I aspire too I am afraid

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    2. As a person with "PPMS" - yes, it is my informed and considered choice.

      You have to run with the hares and hunt with hounds on this blog. One day - no wrecking balls required. Next day - out with the blunt instruments again.

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  3. Prof G,

    The treatment pyramid has been around for a while, but we are stll stuck on first base. Are we ever going to see any other treatments beyond anti-inflammatories? Repair seems as far away as ever.

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    Replies
    1. Why say that, there are repairs studies with results to report so until they crash I am not so gloomy.

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    2. Do you guys mind doing a post summarizing various repair trials?

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    3. The problem is accessing data. if you asked about experimental promise we could be here all week. But of stuff near the clinic frankly I don't know it is not my thing so I am not close enough to the pulse
      to know precise details. I know of things planned but until the results materialise it is impossible to say

      STEM TRIALS ongoing.Alot of hope and alot of hype.
      Mesenchymal stem cells. Targeted as a DMT if that is all they do then they will have to go head to head with current DMT and probably loose based on animal data.
      There is not much evidence to support repair.Less see if TRIALS do better.

      NEURAL STEM cells...I would say same based on animal data. Cells do not last long. Some centres claiming success...Is this to support funding for the centre or real success. Let's see the data.
      Before commenting on.

      GSK trial with their anti histamine drug. it must have finished...all is very quiet so maybe assume the worse.

      Clemastine trial presumably finished we will have to wait to see the data.

      Biogen anti lingo trial finished results are out modest impact. Progressive trial results not yet presented. However as antibody is 99.9% excluded from CNS this is hardly useful and one can ask is the trial property controlled would high amounts of antibody without lingo activity have benefit.

      Human IgM. I've been waiting so long for this to arrive I've gone grey in the mean time.

      The plus point care these studies are ongoing and the key will be to work out how to detect success. With one in the bag many will follow as the number of candidates expand by the day

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    4. Thank you for answering this.

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  4. ProfG, I don't think we will conquer the pyramid in our lifetimes.

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    Replies
    1. The spire is rather science fiction today but can you remember life before computers smartphones, it only takes one bright invention and things can change dramatically. Yes the drug development will take time but hopefully not a life time

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    2. This "spire" is really the vision of the future for "PPMS"?

      I give up.

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    3. Be optimistic. The acceleration of advances in genetic engineering and regenerative medicine will lead the way to the top of the mountain. Keep the faith.
      But then again...
      " ..the best laid schemes of mice and men
      Often go askew
      And leave us nothing but grief and pain
      For promised joy!" ;-)

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  5. Thank you for posting this - extremely helpful. I wish that your expert PPMS'er correspondent would help in the creation of a patient advocacy group for PPMS. I think a high profile group with some expertise would help "shake some trees." (Jason Dasilva, Wheelchair Kamikaze, Dr. Giovanni's correspondent). Wouldn't that be something? Look at what TAG did as part of ACT UP....

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    Replies
    1. Yes, us PPMSers need an active movement. Jason Dailva is a young PPMSer too, which is a shocking reality.

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  6. Very nice to read this post. Keep up the good work Prof G.

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  7. If the base of the triangle is antiinflammatories, please remind me why these are not prescribed/licensed for people with SP or PPMS? Thanks, I'd appreciate it

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    Replies
    1. These drugs were evaluated in flawed trials. The scientific establishment believes that the results based on a two year trial is gospel and the truth.

      They are just now starting to realize how to evaluate progression but since all previous trials for progressive disease failed, no insurance company is going to flip the bill.

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  8. I would not be so pessimistic about solving the problem of MS. In the last 50 years we have discovered and learnt moŕe about the incredible universe we are part of, solving the deepest mysteries of humanity. We've built machines that were just a century ago the stuff of science fiction. I truly believe with the amount of research I'm reading, due in no small part to the exponential growth of knowledge and technology, that we will have this disease figured out very soon and with that a cure. Especially when we have people like team G on the case. Hope will soon turn to reality.

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  9. I have a question about Brain Atrophy and atrophy in NABT (Normal appearing Brain Tissue):


    BACKGROUND:
    I read the following article about laquinimod and neurodegeneration:

    "Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage."


    Source:
    http://www.ncbi.nlm.nih.gov/pubmed/24029546

    I also read som other articles on the subject connected to this agent laquinimod, which also support laquinimods ability to prevent neurodegeneration.

    QUESTION to MD or PROFESSOR Gavin, as a follow up on your nice post about laquinimod above.

    So, I was obvioulsy positively triggered by the above post about laquinimod and reflections from Professor Gavin about this agents prospects in Brain Atrophy / neuroprotection.

    So given that, I tried to learn a little bit more about published results about laquinimod in neuroprotection and its ability to prevent brain atrophy and neurodegeneration

    Now, according to the article that I refer to above, this experimental agent laquinimod was able to significantly inhibit the number of permanent black holes (PBH= irreversible neuro damage)compare to placebo. That is very good.

    BUT ... there is one thing which I need a´better insight to - i.e. I don´t fully understand the meaning or purpose about one specific MRI measure, which puzzels me.

    It is about that laquinimods prevents neurodegeneration in NABT (normal-appearing Brain Tissue) from baseline to month 24 (p-value 0.015). In fact the NABT tissue seem to significantly increase in laquinimod patients, as oposed to placebo, where the NABT tissue in fact decreased.

    SO HERE IS MY QUESTION:
    But NABT is tissue without lesions, in essence the tissue is not damaged. I interpret NABT as healthy tissues. And here I am lost.

    What is the use / purpose (sorry if I don´t understand) that laquinimod seem to increase the NABT tissue, while at the the same time drecreased in placebo Group, since this tissue is healthy and not damaged by lesions ?

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    Replies
    1. Normal appearing means normal appearing on MRI and so may not be normal at all but the point is that laquinimod slows the rate of loss of Normal appearing tissue, so not an increase but less of a loss.

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