Thursday, 1 May 2014

AAN 2014: alemtuzumab treatment results in sustained improvement

Let the experiment run; year 3 and beyond. #MSBlog #MSResearch

"The following is my poster from the AAN on alemtuzumab and sustained improvement. You can click on the SlideShare icon to get a better view."





"This poster and abstract (below) generated a lot of discussion about how durable and long-term the alemtuzumab treatment effect lasts. Only 1 in 5 MSers required a further course in year 3. The important observation is that the disability scores (EDSS) flat-lines. Inevitably this data leads to the discussion on how far out do we need to go to claim long-term remission or an MS cure? I co-authored editorial last year and we used the opportunity to put out a preliminary definition of a cure. I think it is a reasonable starting point. If we don't start thinking about this issue how are we going to find the needle? The downside may be that all we do is push out the start of SPMS and provide the neurodegenerative camp with part of the proof they crave."





Banwell et al. Editors' welcome and a working definition for a multiple sclerosis cure. Multiple Sclerosis and Related Disorders. 2013; 2(2):65-67.

.... Defining a cure in MS is a difficult task. How long should we wait before declaring a victory; 15, 20 or 25 years? Oncologists have back-tracked on this issue and instead of a cure they now prefer to use the term NEDD, or no evidence of detectable disease, at a specific time-point knowing full well that a limited number of subjects will relapse and present with recurrent disease after this point. We propose using the term NEDA, or no evident disease-activity, at 15 years as a starting point for defining a cure. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a usual end point. In addition, the median time to the onset of secondary progressive MS is ~10-11 years (Kremenchutzky, Rice et al. 2006) and is well within the 15 year time window of our proposed definition of a cure. At present NEDA is defined using a composite of a) no relapses, or b) no EDSS progression, or c) no MRI activity (new or enlarging T2 lesions or no Gd-enhancing lesions) (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). This description is currently based on data that is routinely collected in contemporary clinical trials (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). The definition of NEDA will evolve with technological innovations and clinical practice, and in the future it will almost certainly include MSer-related outcomes, grey matter disease activity, an index of brain atrophy and hopefully a CSF biomarker profile.....



References:

Giovannoni, G., S. Cook, et al. (2011). "Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis." Lancet Neurol 10(4): 329-337.


Havrdova, E., S. Galetta, et al. (2009). "Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study." Lancet Neurol 8(3): 254-260


Kremenchutzky, M., G. P. Rice, et al. (2006). "The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease." Brain 129(Pt 3): 584-594.


AAN Abstract

Giovannoni et al. Sustained Improvement in Disability Outcomes with Alemtuzumab in Active Relapsing-Remitting Multiple Sclerosis Patients Who Participated in CARE-MS II: Three-year Follow-up. AAN P3.165; Tuesday, April 29, 2014 3:00 PM.

OBJECTIVE: Examine durability of disability improvement in the first year of an extension for active relapsing-remitting multiple sclerosis (RRMS) patients who received alemtuzumab in CARE-MS II.

BACKGROUND: In CARE-MS II, alemtuzumab 12 mg given annually showed superior efficacy over 2 years versus high-dose subcutaneous IFNB-1a in active RRMS patients who relapsed on prior therapy.

DESIGN/METHODS: On completion of CARE-MS II (NCT00548405), patients could enter an extension study (NCT00930553). Alemtuzumab-treated patients could receive an additional treatment course if they experienced ≥1 relapse or ≥2 new/enlarging lesions on MRI. Expanded Disability Status Scale (EDSS) scores were assessed by blinded raters at baseline and quarterly; worsening and improvement were defined as ≥0.5 point increase or decrease from core study baseline EDSS score. Sustained reduction in disability (SRD) was defined as a decrease from core study baseline by ≥1 EDSS point over 3, 6, or 12 months, if baseline EDSS score ≥2.0.

RESULTS: 393/423 (93%) of alemtuzumab 12 mg patients who completed CARE-MS II enrolled in the extension; 80% did not receive re-treatment during Year 3. Mean EDSS scores remained below pre-treatment values during Year 3. At Year 3, 70% of patients' EDSS scores were stable or improved from core study baseline (value at Year 2: 76%), whereas 74% of patients had a stable or improved EDSS score relative to the extension baseline (end of Year 2). The cumulative proportion of patients attaining 3-, 6-, and 12-month SRD increased in Year 3 (43%, 35%, and 27%, respectively).

CONCLUSIONS: Alemtuzumab demonstrated a durable improvement in disability over 3 years, with the majority of patients not receiving a third course of alemtuzumab.
Study Supported by: Genzyme, a Sanofi company, and Bayer Healthcare Pharmaceuticals

CoI: multiple, the poster was kindly produced by Evidence Scientific and I am co-chief editor of MSARDs the journal in which the above excerpt was published.

4 comments:

  1. In Robin Franklin's talk he said that most people seem to progress in their early 40's no matter how long they'd had the disease and he speculated that this might be because we begin to lose our ability to remyelinate effectively as we age. How does this tie in with your above working definition?

    Also, I see those treated in the study had a baseline EDSS of 2.7. If your baseline EDSS was only 1 or 1.5, would you be more likely to have sustained benefit for longer, or would it depend upon how long you'd had MS irrespective of your EDSS.

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    Replies
    1. Very true, Lexie. My neurologist said that alemtuzumab may stop relapses but neuro-degeneration is a separate process and the evidence thus far suggests alemtuzumab has no effect on that.

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    2. There does appear to be an age related effect to progression such that people with primary progressive MS get their MS as Relapsing remitting MSers are becoming secondary progressive and so aging is an issue is progression pre-destined

      In the age of high effective DMT only time will tell.

      In terms of EDSS the lower you are when you start I would suspect the better, in the animals I think it relates to thedegree of accumulation of damage rather than time

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    3. "Evidence thus far suggests alemtuzumab has no effect on that".

      Not sure you can come to this conclusion.

      Do people with secondary progressive MS progress on Alemtuzumab the answer appears yes, does it change the rate of progression I think the answer is unknown.

      Does the effect of immune process that drive relapsing MS pre condition progression or are they totally independent?

      Does it affect the rate of change to secondary progression?

      All questions

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