Background: The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated MSers with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial.
Methods: In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18—50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all MSers who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00530348 .
Findings: 187 (96%) of 195 MSers randomly allocated interferon beta-1a and 376 (97%) of 386 MSers randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) MSers in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) MSers in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32—0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of MSers in the interferon beta 1a group were relapse-free at 2 years compared with 78% of MSers in the alemtuzumab group (p<0·0001). 20 (11%) of MSers in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40—1·23]; p=0·22). 338 (90%) of MSers in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) MSers treated with alemtuzumab versus 85 (45%) MSers treated with interferon beta 1a. 62 (16%) MSers treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) MSers treated with interferon beta 1a. By 24 months, 68 (18%) MSers in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two MSers in the alemtuzumab group developed thyroid papillary carcinoma.
Interpretation: Alemtuzumab’s consistent safety profile and benefit in terms of reductions of relapse support its use for MSers with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here.
Funding: Genzyme (Sanofi) and Bayer Schering Pharma.
Very good news but let's hope the pricing is sensible rather than exploitative as as \many MSers as possible should have access.Piece in Independent today on this subject.I hope Sanofi/Genzyme are taking note!http://www.independent.co.uk/life-style/health-and-families/health-news/new-ms-wonder-drug-may-be-too-costly-to-use-8270024.html
Are these results good enough to call it a wonder drug?Relapse rate is halved but there isn't much difference in disability progression (11% for interferon vs 8% for alemtuzumab)
Convential wisdom is this is because the % of IFN relapsers was so small so the difference (8% vs 11%) isn't significant. This is,in part, because the trial used relatively newly diagnosed people (2 years mean post-diagnosis). If you looked at it another way and said you have less than a 1 in 10 chance of progression in disability in the first two years after Alemtuzumab (and I think the 5 year results weren't bad either) then that sounds more 'wonder-ful'!I'm really interested to see how the current extension trial looks when it concludes in Feb 2016 – they will give us, for some, 9 year data and then we're really getting a picture of how well this drug alters the natural history of MS. Hopefully, we'll be able to get some 7 year interim results in 2013/2014.
Sam, following your argument, IFN is a wonder-drug too. Roshni is right. A 3% decrease in disability progression is within the error margin of the analyses.
The interferon group in this study did better than expected. I suspect because MSers were relatively early in the course of their disease. What you need to look at is what happens after 2 years. The majority of MSers treated with alemtuzumab don't need any other treatment and their disability improves. Only a minority of MSers need to be retreated.What alemtuzumab offers in the future is what is so important. The only other drug in this class is cladribine!
This is a general point re: trial measures – do we ever measure the SEVERITY of relapses as opposed to the number of patients who relapse/the total number of relapses? I believe that DMTS have the capacity to not only reduce the numerical frequency of relapses but also the severity of them. i.e. an "un-modified" immune response in an invididual causes a severe demyelination and therefore very significant symptoms but a modified immune response still causes some demyelination (i.e. still, technically, a relapse) but the degree of demyelination is lessened and therefore the impact of the relapse is much less. i.e. an effective DMT could not make any impact on the number of relapses but the average increase in EDSS during the relapses could be moved from, say, 2 points to 0.25 or less. Is this ever looked at as an outcome? It links in to a wider point about the heterogenity of MS as a disease. I believe that disease activity/lesion location is not the only measure of disease severity. I think there are degrees of strength of the 'distorted' immune response in different people – some people's relapses are non-disabling, even when frequent, and are always likely to be so because the immune 'attack' on the myelin is relatively weak, causing only slight demyelination whereas others might have less frequent relapses but the immune attack, when it does occur, is really strong and strips the myelin away causing really severe symptoms. This is one reason I think some people have 'mild' MS and it stays mild (i.e. it is not a total lottery as to just where your lesions end up) and also why some people respond better to first line DMTs (their immune systems need less of a push to get back in line). Does that make sense and does it accord with current neurological thinking on the mechanisms of the heterogenity of MS?
I'm interested to hear the answer to the above. Prof G/MD? If a statistically significant number of trial candidates had significantly less disabling relapses under a DMT then surely that would be a valid measure? Number of lesions/number of relapses doesn't account for the potential difference in severity of those lesions/relapses etc? Do MSers have different levels of inherent severity of disease i.e. not just activity in terms of lesion number/relapse number but on how significant those relapses are? Is the analogy of some MSers having only slight demyelination at each relapse versus others having relapses that 'strip away' vast chunks with each relapses valid?
The EDSS is the scale we use to define relapses. Unfortunately, it is not a very good measure of severity. What we use as a surrogate for this is steroid usage. In most trials of DMTs they not only reduce the number of relapses, but the proportion that require steroids. Therefore we say that DMTs has an impact on the severity of relapses as well.
Is it right to say that some of the spectrum of disease variability in MS can be explained as per the above post? i.e. the attack of the immune system on the myelin is only weak in some (very little demyelination) and much stronger in others? i.e. aside from location of lesions and frequency, there is a kind of inherent "strength" to an inividuals immune response against the myelin which dictates some of whether an individual has a mild or a severe course?
I appreciate how much money Pharma has invested in getting Campath/Alemtuzumab/Lemtrada where it is today and the need to recoup expenses fro research, trials, etc, but please don't be greedy when pricing the drug. This is people's livelihoods here.
Let's not forget that CARE-MS I & II are virtually flowing into oceans of placebo, since there was no placebo group in neither. This yields the results totally unreliable.
?????????http://multiple-sclerosis-research.blogspot.co.uk/2012/01/what-is-your-story.html
This was a single-blinded study; all MSers new they were on alemtuzumab or interferon-beta-1a. It is not possible to blind MSers when alemtuzumab causes infusion reactions in almost everyone who gets the drug. So if you can't blind what is the point in comparing it to a placebo? Would it be ethical? Would MSers on an open-label placebo stay in the trial? No!
yeah, yeah, yeah, in Compston, Coles and Giovannoni's dream world maybe …. I can't find their explanation for how Alemtuzumab prevents the blood flow reversals that cause MS lesions by hitting the side the walls of the veins in our brains and spinal cords… (CCSVI offers a major explanation for this – that will be why the esteemed Compston et al dont like CCSVI – they've got their new Alemtuzumab (Lemtrada) baby coming off the production line…) Be a terrible disaster for Genzyme and Sanofi's share prices when everyone with MS finds out MRI shows that MS lesions are venodynamic MS lesions… Genzyme and Sanofi better get their marketing and PR ground troops at the MS Society on standby for the big sales push.. 'help us influence NICE' the MS Society will be asking us any day now.. Such a slick sales operation they have.
The picture Avatar is the one used on the article used to slate Team G.Therefore we know your world view.Why would one expect to see an explanation about how alemtuzumab has anything to do with side walls of veins? You would not because its effect is unrelated. Therefore this post adds little value.
The avatar should be an ostrich with its head in the sand.
I am not sure why alemtuzumab should have an effect on lesions in veins. To the best of my knowledge MSers have normal veins. If your are referring to Zamboni you should catch-up; his work has been discredited by recent studies.
Correction; in people with vasculitis alemtuzumab is effective and is used off-license by many to treat these diseases. MS is not due to a vasculitis; the latter requires inflammation to present within the walls of blood vessels. In MS the inflammatory cuff is outside of the vessel.
Regarding pricing; at the moment all we have heard is rumours. I suggest we wait to see what it is before we comment further on this.
I feel ignorant for asking but why does alemtuzumab have such an effect on the thyroid? Two cases of thyroid cancer, 18% thyroid-related adverse events?Congrats on the research. Early aggressive treatment before irreversible damage has occurred is quite a rallying cry.
The effect on thyroid is actually higher than this! With follow-up of longer duration up to 40% of woman MSers who have received the drug will develop thyroid disease and ~20% of male MSers.