Monday, 16 September 2013

Laquinimod slows down the brain shredder

Can we stop the shredder? It is looking increasingly likely #MSBlog #MSResearch

"There is a lot of attention being focused on brain atrophy in MS. It is not that it is a new finding it is simply become apparent that several of the newer DMTs have a greater impact on slowing down brain atrophy compared to the so called platform or injectable first-line therapies."

"Is brain atrophy a big issue for MSers? It should be. Although brain atrophy is complex it integrates the neurodegenerative processes that occur in MS. Progressive brain atrophy is an almost universal finding in all dementias including MS. It is difficult to use brain atrophy in clinical practice as it occurs in normal people as part of the ageing process; however, brain atrophy occurs approximately 4x faster in MSers than it does in normal controls. Brain atrophy is found at all stages of MS; CIS, RRMS and progressive MS. Its presence at baseline is a poor prognostic factor in the long-term. Most of us in the field believe  that we should stop or slow down the rate of brain atrophy. Therefore it is encouraging to see new DMTs that impact on brain atrophy and other MRI measures that indicate destruction (black holes, NAA and MTR). The study below describes the MRI findings of  the new kid on the block, laquinimod. As I stated in a post last week; laquinimod is an interesting drug as it does not have a major impact on upstream inflammatory events (relapses and new T2 and Gd-enhancing MRI lesions), but has a robust effect on delaying or slowing disability progression and the associated MRI metrics that go with this. In short, laquinimod is a true neuroprotective drug, which is why I am very excited about its prospects, in particular as an add-on to current anti-inflammatory DMTs."

Epub: Filippi et al. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry. 2013 Sep 12.

OBJECTIVE: In Assessment of OraL Laquinimod in PrEventing ProGRession in Multiple SclerOsis (ALLEGRO), a phase III study in relapsing-remitting multiple sclerosis (RRMS), oral laquinimod slowed disability and brain atrophy progression, suggesting laquinimod may reduce tissue damage in MS. MRI techniques sensitive to the most destructive aspects of the disease were used to further investigate laquinimod's potential effects on inflammation and neurodegeneration.

METHODS: 1106 RRMSers were randomised 1:1 to receive once-daily oral laquinimod (0.6 mg) or placebo for 24 months. White matter (WM), grey matter (GM) and thalamic fractions were derived at months 0, 12 and 24. Also assessed were evolution of gadolinium-enhancing and/or new T2 lesions into permanent black holes (PBH); magnetisation transfer ratio (MTR) of normal-appearing brain tissue (NABT), WM, GM and T2 lesions; and N-acetylaspartate/creatine (NAA/Cr) levels in WM.

RESULTS: Compared with placebo, laquinimod-treated MSers showed lower rates of WM at months 12 and 24 (p=0.004 and p=0.035) and GM (p=0.004) atrophy at month 12 and a trend for less GM atrophy at month 24 (p=0.078). Laquinimod also slowed thalamic atrophy at month 12 (p=0.005) and month 24 (p=0.003) and reduced the number of PBH at 12 and 24 months evolving from active lesions (all p<0.05). By month 24, MTR decreased significantly in NABT (p=0.015), WM (p=0.011) and GM (p=0.034) in placebo-treated MSers, but not in laquinimod-treated MSers. WM NAA/Cr tended to increase with laquinimod and decrease with placebo at 24 months (p=0.179).

CONCLUSIONS: Oral laquinimod may reduce (at least in the initial phase of treatment) some of the more destructive pathological processes in RRMSers.

TRIAL REGISTRATION: The ALLEGRO trial identifier number with clinicaltrials.gov is NCT00509145.

"The following are MRI scans showing just how much brain atrophy can occur in MSers over an 18 month period."




"These MRIs are from two MSers I met when I did my PhD from 1993 to 1996; they were participating in a phase 2 clinical trial of a biological  therapy that targeted CD4 T-cells (anti-CD4 therapy). Unfortunately, the anti-CD4 trial was negative. This trial still questions the role that CD4 cells play in the pathogenesis of MS; well at least in my mind. Most immunologists still believe MS is driven by CD4 T cells; but that is another story."


"What the serial MRIs on these MSers show is the extraordinary amount of brain atrophy that can occur over an 18 month period - look at the black spaces in the centre of the brain, the ventricles, and see how they enlarge over 18 months. Also look at the black spaces on  the surface of the brain, the sulci, and see how they open up over 18 months. This brain atrophy is partly due to loss of axons and neurones and is unequivocally linked to disability progression and cognitive impairment. This is why there is increasing emphasis on drugs that can prevent or at least slow the rate of brain atrophy down."


"Preventing atrophy completely is unlikely to happen as brain atrophy occurs as part of normal ageing; from the age of 35 our brains shrink - mine included. The aim therefore would be shift the brain atrophy rate in MSers to that which occurs in normal ageing. Can we do this? Not yet, although several DMTs are showing promise in this area. This is why we are keen to explore attitudes to incorporating brain atrophy into clinical practice."


"The following is a re-posting of the brain atrophy survey results, which you may find interesting."



"It is clear that there is a knowledge gap, between what MSers want to know about their disease and what their neurology team is prepared to provide them. May results such as the laquinimod study will change this. Let's hope so." 


Other posts on brain atrophy:

12 Sep 2013
OBJECTIVES:Whether transcranal sonography (TCS) depicted third ventricular enlargement as a sign of brain atrophy is predictive for neuropsychological deficits in mildly affected patients with multiple sclerosis (MS).
14 Sep 2013
OBJECTIVE:To determine if progressive brain atrophy could be detected over 1- and 2-year intervals in relapsing MS, based on annual MR studies from the Multiple Sclerosis Collaborative Research Group (MSCRG) trial of ...
09 Jul 2013
Methods: These investigators used a selective reminding paradigm to determine whether deficient initial learning or delayed retrieval represents the primary memory deficit in 44 persons with MS. Brain atrophy was measured ...
28 May 2013
"It is clear that there is a knowledge gap, between what you want to know about your disease and what your neurology team are prepared to provide you, or they do not have the data to give you. The only way we are going to ...

30 Mar 2013
DESIGN: From eight MAGNIMS (MAGNetic resonance Imaging in MS) centres, we retrospectively included 261 MSers with MR imaging at baseline and after 1-2 years, and Expanded Disability Status Scale (EDSS) scoring at ...
31 Jan 2013
#MSBlog: Should we be measuring brain atrophy in routine clinical practice? "I was asked by a colleague in Porto last week whether or not I let the presence or absence of brain atrophy on MRI affect my clinical decision ...
15 Apr 2013
Objective: Through a retrospective analysis, the objective of this study was to determine whether daclizumab treatment reduces the rate of brain structure atrophy in comparison to a mixture of other disease-modifying Method: ...
05 Jul 2013
Rebranding MS a dementia (7): disease progression and brain atrophy. Progressive brain atrophy; should you accept it? #MSBlog #MSResearch. Epub: Hofstetter et al. Progression in disability and regional grey matter ...

15 Feb 2013
Methods: 136 of 181 RRMSers who participated in the Avonex-Steroids-Azathioprine study were assessed bimonthly for clinical and MRI outcomes over 2 years. MSers with disease duration (DD) at baseline of ≤24 months ...
29 Nov 2011
RESULTS: The mean (SD) annualized brain atrophy rate in MS'ers with benign MS (-0.16% [0.51%]) was lower than that in patients with early MS (-0.46% [0.72%]) (P = .02). The difference remained significant after controlling ...
10 Sep 2013
#MSBlog #MSResearch. "Why all the talk about laquinimod (LAQ)? It is the first drug that has been shown in phase 3 clinical trials to have an impact on MS disability and brain atrophy independent of relapses and MRI activity.
26 Nov 2012
"The headline result is that MSers rate a delay in disease progression the most important outcome measures in relation to DMTs." "The problem with disability progression in relatively short RRMS clinical trials is that the ...

17 Nov 2012
"Some of you who have been following this blog and my recent posts will realise that I have had a change of mind. I have been sceptical about the publications showing a very poor correlation between relapses (frequency ...
20 Mar 2012
Riccitelli et al. Mapping regional grey and white matter atrophy in relapsing-remitting multiple sclerosis.Mult Scler. 2012 Mar 15. [Epub ahead of print] Objective: We aimed to investigate the regional distribution of grey matter ...
11 Sep 2013
However, about half the patients experienced progressive disability and increasing brain atrophy, attributable on the basis of MRI spectroscopy to axonal degeneration, which correlated with the extent of cerebral inflammation ...
13 Jun 2013
Open Neurol J. 2013 May 3;7:11-6. OBJECTIVE: To estimate the quantity of multiple sclerosis (MS) patients with brain atrophy as indicated by third ventricular enlargement using transcranial colourcoded ultrasound (TCCS).

31 May 2012
METHODOLOGY/PRINCIPAL FINDINGS: Based on MRI scans of 60 MS cases and 37 healthy volunteers, we measured the volumes of white matter (WM) lesions, cortical gray matter (GM), cerebral WM, caudate nucleus, ...
18 May 2013
BACKGROUND: The impact of global and tissue-specific brain atrophy on conversion to MS after a clinically isolated syndrome (CIS) is not fully gauged. OBJECTIVES: These investigators' aimed to determine the magnitude ...
20 Oct 2012
Natalizumab may reduce cognitive changes and brain atrophy rate in relapsing-remitting multiple sclerosis: a prospective, non-randomized pilot study. Eur J Neurol. 2012 Oct 11. doi: 10.1111/j.1468-1331.2012.03882.x.
15 Jun 2013
"As you can see from the 4 studies below Alemtuzumab (aka Campath or Campath-1h) has a positive effect on brain atrophy, when compared to interferon-beta. It slows the rate of brain shrinkage. In addition it has a positive ...
01 Feb 2013
"What the serial MRIs on these MSers show is the extraordinary amount of brain atrophy that can occur over an 18 month period - look at the black spaces in the centre of the brain, the ventricles, and see how they enlarge ...
11 Sep 2013
The thalamus is a large gray matter structure deep in the brain through which the cortex (surface of the brain) communicates with structures lower down (brain stem, cerebellum and spinal cord); my anatomy teacher in medical school referred to the thalamus as the great railway junction of the brain. It is therefore not surprising that .... 05 Jul 2013. Epub: Hofstetter et al. Progression in disability and regional grey matter atrophy in relapsing-remitting multiple sclerosis.
21 Nov 2012
CONCLUSIONS: Neurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory activity is greater in patients converting to clinically definite multiple sclerosis. Six-month corpus callosum ...
09 Mar 2012
Magraner et al.The relationship between inflammatory activity and brain atrophy in natalizumab treated patients.Eur J Radiol. 2012 Mar 3. [Epub ahead of print] OBJECTIVE: To assess the evolution of brain atrophy and its ...

23 Nov 2012
BACKGROUND: Brain size, white matter hyperintensity, and the development of brain atrophy are known to be highly heritable. The decrease of brain volume starts from the very onset of MS and is 10-fold compared with ...
06 Feb 2013
We performed a prospective cross-sectional study with a statistically pre-defined endpoint to test our hypothesis that OCT measures of neuro-axonal degeneration are related to global and partial brain atrophy in early forms of ...
08 Jan 2012
In vivo scanning permitted us to evaluate brain structure volumes in individual animals over time and we observed that though brain atrophy progressed differently in each individual animal, all mice with EAE demonstrated ...
13 Jul 2013
If you have evidence of this early on in the course of your disease, as measured by brain atrophy on MRI, in particular gray matter atrophy, you need to be more active with your treatment." "Another observation is that if you are ...

18 Jun 2012
Methods: In 39 multiple sclerosis patients the area of corpus callosum in the sagittal plane, T(2) and T(1) lesion volumes, brain parenchymal fraction and brain atrophy were determined at baseline and 1 year after treatment ...
21 Aug 2013
Can that explain why relapse frequency and EDSS progression / Brain atrophy don't seem to correlate? And why some drugs seem to have good effect on reducing replases , but no effect on brain atrophy? Can Prof G please ...
15 Apr 2013
OBJECTIVE: To test the cognitive reserve (CR) hypothesis in the model of multiple sclerosis (MS) by assessing the interactions among CR, brain atrophy, and cognitive efficiency in patients with relapsing-remitting MS.

12 comments:

  1. Can I ask the question again? What are the chances of laquinimod being okayed by NICE for use in MS as I think it's before the committee now regarding RRMSers, but it has such a poor effect on relapses that I hope they don't only consider that. If it gets the go ahead, could we see it in the near future for RRMSers? Would new trials need to be done before progressive MSers could get it?

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    1. Lexie, the EMA is currently reviewing Laquinimod. Until the drug has a European license NICE won't rule on the drug. If it gets a license it will be for RRMS and not as an add-on drug for neuroprotection. In my opinion this is how the drug should be tested; as an add-on to anti-inflammatories in progressive MS.

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    3. Lexie has left a new comment on your post "Laquinimod slows down the brain shredder":

      Thanks, Prof. So does this mean that a whole new set of trials as an add on neuroprotectant will be needed, which could take years? Or Teva could only allow add on trials to Copaxone to keep a bigger share of the market.
      Also in the application to NICE it states that laquinimod'directly modulates the CNS resident parenchymal cells which may reduce the inflitration of leukocytes into the CNS'. If it was allowed as an add on to some of the stronger imunomodulatory DMTs, could PML be a problem if its restricitng leukocyte infiltration?

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    4. Lexie the PML issue is quite unique to natalizumab. I am not saying there will be no PML cases on other immunosuppressive drugs the risk will be very low, i.e. in the order of 1 in 30,000.

      Laquinmod does not appear to be immunosuppressive; i.e. it is not associated with any changes in the white cell counts or infections. Its effect on trafficking of cells into the brain is likely to be small; if it was significant it would have had a greater impact on relapses and MRI activity. Please note these comments refer to the 0.6 mg dose. With higher doses that are currently being tested things may be different.

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  2. I understand high dose Simvastatin reduced the rate of brain atrophy - what can be done to help MSers gain access to this drug?

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    1. We have one positive trial that was a phase 2 study. What we need is two large phase 3 studies. This will cost a lot of money to do; I am not sure we will be able to do this outside of Big Pharma. This is why we trying to launch the BPA (Big Pharma Alternative) to incentivise Pharma to invest in off patent drugs.

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    2. Well, good luck with the BPA, hope it comes to fruition.

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  3. According to the MS guidelines for EMA the priority is to approve drugs that can delay the progression of the disease. In the guidelines they say that DMT's that have effect on relapses but not on the progression of the disease might not be relevant from a clinical perspective. In this case LAQ is for sure relevant from a clinical perspecive since it affects the course of the disease.

    Since the EMA as well has a risk-benefit approach which, to my understanding, means that since LAQ has a very benign safety-profile is shall be approved as long as it has any clinical benefit what so ever.

    The most interesting question is if LAQ will receive a unique label saying that LAQ delays the progression of the disease ( brain-atrophy, EDSS-progression ) or not.

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  4. There was an article that fingolimod slows down atrophy as well, can you compare effectiveness of laquinimod and fingolimod?

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  5. Prof G, what are your thoughts on giving mitoxantrone to progressive MSers? There some neurologists in Britain that are known to give mitoxantrone to PPMSers, especially young PPMSers. Coonsidering the toxicity profile of mitoxantrone, do you think it's acceptable to do so, especially in light of the lack of evidence the drug impacts on progressive disability?

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  6. 1. This talks of laq's effect in early stages of the disease. Do you think it could have an effect in later stages too? Will more trials be needed to find out?
    I am thinking of MSers who got onto one of the highly effective drugs late, after considerable damage had accumulated

    2. How will anybody or any system afford an add-on drug. A single dmt is already too expensive

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