Sunday, 4 May 2014

Saving Brain: early highly-effective treatment

Saving Brain: early highly-effective treatment! #MSBlog #MSResearch

Alemtuzumab 3-year brain atrophy data is simply stunning. #MSBlog #MSResearch

Will the FDA be convinced by the 3-year Alemtuzumab brain atrophy data? #MSBlog #MSResearch

"I have just returned from the AAN 2014 in Philadelphia. It was a very busy week so apologies for not posting more often. On reflection the issue that came up most at the meeting in relation to MS was that MS was a two component disease; i.e. an inflammatory (relapses and focal MRI activity) and degenerative (disease progression and brain atrophy) disease. It is clear that although many licensed DMTs are very good at suppressing inflammatory disease activity they are not that good at stopping brain atrophy. A study by Figueira and colleagues from Brazil below, showed despite many MSers being free of disease activity on platform or injectable therapies (inteferon-beta and GA) 50% of them showed a progressive brain atrophy that was comparable with those MSers who were suboptimal responders, i.e. had relapses or MRI activity."

"In comparison highly effective therapies seem to be able to suppress both inflammatory and neurodegenerative components of the disease. In a Spanish study Costa-Arpin and colleagues showed that the majority of MSers on natalizumab did not have a change in the volume of their corpus callosum and structure that is being increasinlgt used as an integrator for brain volume change in MSers. Even more impressive was the late-breaking results from the 3-year follow-up of the Alemtuzumab phase 3 studies showing that alemtuzumab has a profound impact on slowing, or even normalizing, brain volume loss in MSers. The following is the brain volume changes in the 3-years of the study. As you can see there is some pseudo-atrophy in year 1 when alemtuzumab switches-off the inflammation and then in year 2 and 3 the brain volume loss slows dramatically. You need to remember that brain atrophy is a normal phenomenon and occurs at a rate of between 0.1% and 0.4% in normal people. Therefore brain atrophy rates of 0.19% and 0.1% are well withing what is expected in normal people. 


Time PeriodCARE-MS ICARE-MS II
Year 0 to 1
−0.59%
−0.48%
Year 1 to 2
−0.25%
−0.22%
Year 2 to 3
−0.19%
−0.10%

These results are in line with what has been reported from the Canadian cohort of MSers who have been treated with bone marrow transplantation."

"After seeing and interpreting these results it is hard not to come to the conclusion that if  you want to get on top of both the inflammatory and neurodegenerative components of MS you want to be treated early with the most effective therapies. I suspect many of you will disagree with my interpretation of this data."

"'Saving Brain: early highly-effective treatment' is my new slogan!"

Arnold et al. Alemtuzumab Improves Brain MRI Outcomes in Patients With Active Relapsing-Remitting Multiple Sclerosis: Three-Year Follow-up of the CARE-MS Studies. AAN 2014; S65-008.

Addendum:

"On my Sunday run I was thinking about this data and realised it may be too good to be true (I do my best thinking when running). What may be happening is that in the subgroup of MSers who have reactivation of their disease the recurrence of inflammation may be reversing pseudo-atrophy. Therefore some of the reduction in volume loss may be rebound of disease activity. To look into this we would need to analyse brain atrophy rates in those with NEDA in year 3 vs. those without EDA (evident disease activity ) in year 3. Please note that about 1 in 5 MSers had EDA and required re-treatment with alemtuzumab in year 3." 


Normal (L) vs. MS (R): Can we save brain? 

Figueira et al. Sub-optimal Response to Therapy in Disease-free MS Patients: A Paradox? AAN 2014; P6.113 Thursday, May 1, 2014 7:30 AM

Objective: Axonal loss is an early finding in multiple sclerosis (MS) and relates to disability. So we propose its use as a marker for treatment optimization.

Background: Current MS therapies target inflammatory activity of disease, defined by clinical relapses and EDSS progression, besides with absent T1W contrast enhancing lesions as well as no new or enlarging T2W lesions on MRI, in a way to impact disability development. So, the absence of clinical and MRI activity are accepted paradigms of disease free status in treated patients. Nevertheless, axonal loss seems to be a major determinant of disability, and may occur with lacking clinical expression and sophisticated MRI requirements. In this paper, we discuss current concept of disease free applied in real world, and propose that measures of atrophy be used in daily practice as a tool for optimal therapy.


Design/Methods: Our group studied 206 consecutive non-selected patients with relapsing-remitting MS diagnosed according to 2001 McDonald criteria, on regular immunomodulatory treatment. They were submitted to serial clinical examinations and conventional MRI evaluation focus on relapses, EDSS progression and the presence of T1W Gd enhancing or T2W new/enlarging lesions. On conventional MRI sequences, we studied brain parenchymal fraction (BPF) and corpus callosum index (CCI), annually comparing results with data from a control group, composed by non-inflammatory diseases.


Results: After 5 year, 56.7% patients presented with some evidence of disease activity: all but two patients showed worsening scores in BPF and CCI. On the other hand, 43.2% fulfilled accepted criteria for free of disease status, despite 48.3% of them showed a progressive reduction on BPF and CCI, comparable with those stratified as suboptimal responders.


Conclusions: Our data demonstrates that axonal loss can be detected using corpus callosum index on routine follow up conventional MRI sequences, even among apparently stable patients. We propose axonal loss to be included as a requirement to consider a patient "disease free", during MS therapy.


Costa-Arpin et al. Evolution of Corpus Callosum Index in Patients with Relapsing Remiting Multiple Sclerosis Treated with Natalizumab. AAN 2014; P6.116 Thursday, May 1, 2014 7:30 AM

OBJECTIVE: Our main objective was analyze the evolution of cerebral atrophy in Multiple Sclerosis (MS) patients on treatment with Natalizumab.

BACKGROUND: Axonal damage has been shown in MS patients, even in early phase, conditioning cerebral atrophy and disability. An accesible form of quantify cerebral atrophy is the Corpus Callosum Index (CCI), which has been shown a low interobserver variability and a good correlation with other atrophy indices. In patients with MS, an anual average decline in CCI of 0,01+0,02 has been demonstrated.

DESIGN/METHODS: All patients on treatment with Natalizumab during one year or more were included in the study. The CCI was calculed in a basal MRI (made before treatment starting) and was compared with the CCI obtained in the last annual control MRI.

RESULTS: 22 patients were included in the study (54% women) with a middle age of 41+10 years. The median EDSS was 3,5 + 1,5. The average time between MRI was 36,9+11,15 months. The mean CCI was 0,374+0,037 on basal MRI and 0,364+0,036 in last control MRI. The annual CCI decrease was 0,006+0,01 and there were no changes in 59% (n=13).

CONCLUSIONS: More than a half of our patients with MS on treatment with Natalizumab have not been experienced changes in CCI over an average of three years. These data could reflect a possible neuroprotective effect of Natalizumab. 

CoI: multiple

19 comments:

  1. Many thanks. Any info on remyelination or repair?

    Make sure you take the bank holiday off.

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    1. MouseDoctorSunday, May 04, 2014 9:18:00 am
      I think we hope that if you start quick enough you wont need remyelination and repair, the body will do this itself...yet;s hope for the former possibility and we (MS Scientists) are working on the latter remyelinatation and repair, if the boat has been missed

      Speaking of working ...am off to work now and over the bank holiday. Yep. Mouse doctoring is a 7 day a week job. MS life straight to the lab last week. Home at 10.30pm that,why I snuck off early from Manchester.

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  2. I think your arguments are good Prof G and nobody would argue them BUT it's the safety people are concerned about.

    For me, I am thinking about switching to Tecfidera (anti-immflamatory and perhaps neuro protective as well) with a good safety record, then if it won't work I'll try Gilenya and only then I would think about Tysabri or Alem.

    I simply prefer to have MS than be dead to put it more starkly BUT I am watching the studies on Alem - if the safety profile improves I'd take it.

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    1. This study refers to Alzheimer's. Can we assume that the same applies for MS?

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    2. I don't think alem has a bad safety profile. It's not a question of being dead, you have to be vigilant. Looking at efficacy, ease of use and safety, I think it wins hands down. Good luck with trying the other agents first- I just hope you don't miss the boat on early effective treatment

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  3. Just curious, any suggestions why atrophy rate is lower in later treatment group?

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  4. Re: "any suggestions why atrophy rate is lower in later treatment group?"

    Alemtuzumab is given as a course of infusions at the beginning and at 12 months. Most MSers only needed 2 courses. According to my therapeutic lag hypothesis atrophy in the current year is due to inflammation 1 an d 2 years ago. When you switch off inflammation you need to wait at least 2 years to see the maximum impact on brain atrophy. This is why the year 3 results are so good. I am not sure if the community has registered just how good these results are and what it means for MSers and the field.

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    1. Prof G, sorry for misunderstanding, I meant, why the atrophy rate in CARE-MS-II is lower than in CARE-MS-I? It's a little bit counterintuitive. Don't the CARE-MS-II participants have a little more severe disease as they had to fail their first-line therapy first? So why their brains shrink less than in treatment naive group?
      Thanks.

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    2. Re: "... why the atrophy rate in CARE-MS-II is lower than in CARE-MS-I?"

      This could be within the error rate of the measurement or it could indicate that there is more reversal of inflammatory disease activity in the CARE-MS-II subgroup than the CARE-MS-I subgroup; i.e. reversal of pseudo-atrophy. I suspect the latter may be the most likely reason.

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  5. On my Sunday run I was thinking about this data and realised it may be too good to be true (I do my best thinking when running). What may be happening is that in the subgroup of MSers who have reactivation of their disease the recurrence of inflammation may be reversing pseudo-atrophy. Therefore some of the reduction in volume loss may be rebound of disease activity. To look into this we would need to analyse brain atrophy rates in those with NEDA in year 3 vs. those without EDA (evident disease activity ) in year 3. Please note that about 1 in 5 MSers had EDA and required re-treatment with alemtuzumab in year 3.

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    1. I don't buy your argument, Prof G. Alemtuzumab has not, to my knowledge, shown any evidence of benefitting progressive MSers, this despite the fact that alemtuzumab began its journey in MS care as an experiment on progressive sufferers. I honestly believe that MS is a two pronged attack: component one featuring inflammation and component two involving mitochondrial shutdown. The two are mutually separate and have individual driving forces.

      I do not acknowledge alemtuzumab as a cure, merely it is an inhibitor for one component of the disease. Progression will, in the main, be unavoidable, though I suspect alemtuzumab may, in some cases,marginally delay patho-clinical progressive symptoms.

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    2. Is there a way this information can be pulled out of the currently available data?

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  6. Important thinking. Keep up the running.

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  7. I would be curious to know the exact methodology that was used when measuring brain atrophy for the results you posted above. In particular, if the same equipment and process was used for each patients scan. This is a major factor in the results obtained:

    "...We emphasize that in the longitudinal study of any single subject, highest scan-rescan reproducibility is of particular importance. As an example, a change from the 12- to the 32-channel coil caused a shift in the whole brain BSI of ~0.5%."

    "We conclude, however, that for highest scan-rescan accuracy and maximized power to detect brain changes in clinical investigations and population studies, the imaging protocol and hardware should be kept as consistent as possible over time."

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432691/

    Without some control over the methods and equipment used and the fact that this analysis was done unblinded leaves the conclusions highly questionable.

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    1. "This study refers to Alzheimer's. Can we assume that the same applies for MS"

      The same issues occur whether you are talking about Alzheimers or MS atrophy measurments:

      www.ajnr.org/content/early/2012/07/12/ajnr.A3107.full.pdf

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  8. Can Alemtuzumab help reduce the rate of brain atrophy in SPMS?

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    1. Can it stop? = No. Can it reduce? dont know but possibly as there is still active inflammation going on. We would need a formal study.

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  9. Prof G, is there a possibility that previous treatment with IFN or GA influence outcome of subsequent treatment with alemtuzumab somehow? Did they compare outcomes of patient treated previously with IFN who then switched to alemz with patients treated with GA and then with alem, is there any difference in sense of atrophy rates between those groups?
    Or could this data be easily pulled.
    Thanks.

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    1. Re: "...is there a possibility that previous treatment with IFN or GA influence outcome of subsequent treatment with alemtuzumab somehow?"

      I am not aware that previous DMTs affect the outcome with Alemtuzumab; it was clear from the clinical results that both groups benefit. I suspect that when the brain atrophy data comes out this will be looked into. I suspect there will less pseudoatropy in MSers moving from IFNbeta/GA onto Alem as they would have gone through this already.

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