Objective: Presentation of top line clinical efficacy and safety results from phase 3 pivotal study: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I)
Background: Alemtuzumab is an anti-CD52 humanized monoclonal antibody that alters the circulating lymphocyte pool. Alemtuzumab was significantly more effective than subcutaneous interferon-beta-1a (SC IFNB-1a) in a phase 2 trial (CAMMS223) with relapsing-remitting multiple sclerosis (RRMS) patients. CARE-MS I is a phase 3 trial designed to confirm the efficacy and safety of alemtuzumab versus SC INFB-1a.
Methods: CARE-MS I is a 2-year, randomised, rater-blinded, active-comparator, global trial comparing the safety and efficacy of alemtuzumab to IFNB-1a in active, treatment-naïve RRMS patients. Patients received 2 annual short cycles (5 days and 3 days) of 12 mg/day intravenous alemtuzumab or 44 mcg SC IFNB-1a 3 x weekly for 24 months. Entry criteria included: age 18-50 years; MS symptom onset <= 5 years; baseline Expanded Disability Status Score (EDSS) <=3; 2 or more relapses in the 24 months prior to study entry; and at least 1 attack in the 12 months prior to study entry. The primary efficacy endpoints are relapse rate and time to sustained accumulation of disability (SAD). SAD is defined as an >=1 point increase in EDSS lasting >=6 months (or >=1.5 point increase if baseline EDSS <1). Blinded raters assessed EDSS quarterly, and relapses as needed. Safety was assessed continuously. The protocol included a safety education and monitoring program for early detection of identified secondary autoimmune disorders as part of a proactive risk mitigation strategy.
Results:
Alemtuzumab reduced the annualised relapse rate compared to IFNβ-1a by 55% (P<0.0001). 8% alemtuzumab and 11% IFNβ-1a treated subjects showed disability progression (confirmed at 6 months). This was not statistically significant (P=0.22) due to the unexpected low rate of sustained disability in IFNβ-1a treated arm. There was a significant slowing in brain atrophy on alemtuzumab vs. IFNβ-1a ; brain volume change -1.5% IFNβ-1a vs -0.8% alemtuzumab.
Headline adverse events:
No alemtuzumab treatment discontinuations occurred due to adverse events. 18% of subjects developed autoimmune thyroid disease with alemtuzumab compared to 6% on IFNβ-1a. 0.8% of subjects treated with alemtuzumab developed autoimmune thrombocytopenia (3 cases). 67% of subjects developed infections (1.9% serious) on alemtuzumab compared to 46% (1.1% serious) on IFNβ-1a. There were 2 cases of thyroid carcinoma with alemtuzumab.
Conclusions: CARE-MS confirmed alemtuzumab’s ability to reduce relapses compared to IFNβ-1a. It did not slow the progression of diability compared to IFNβ-1a due to low event rate.
“Some people felt let down by these results after the hype of the phase 2 results. Not me. I still think Alemtuzumab is the most effective treatment in late stage development, but it comes with risks that for some will be worth taking. The fact that the trial did not show an impact on disability progression is not important; the subjects in this study were very early in the course of the disease.”
“More worrying was the reporting of two thyroid cancers in Alemtuzumab treated subjects. It seems likely that one of the cancers pre-dated the trial as the subject had a thyroid nodule documented before entering the study. Fortunately, both were detected early and excised.”
“After my experience with Cladribine and the regulatory decisions concerning the cancer risk associated with this drug I sincerely hope the regulators don’t take the same view in relation to these cancers!”
CoI: Multiple
What is the conclusion of the CARE-MS1 phase 3 trial? I thought this was it, but it says in conclusion 'if positive, CARE MS 1 will confirm…', and there is nothing in this or in the extract from Coles et al at the top that mentions thyroid cancers?
Prof,I wasn't at the conference, but my reading of the abstracts suggests a bit of a damp squib. There appear to be more effective treatments in the pipeline, but with the exception of BG 12, the price is more serious side-effects. Was there anything new re pathology or cause? Anything on stopping progression or promoting repair?
There's a rumour that Prof G and Prof B are still in Amsterdam (stumbled across the Red Light district) – I don't believe a word of it. But Prof G very quiet.
Hate to Scotch the rumour, but Prof G is on tour…educating!. Won't say where, in case he gets flashmobbed after last weeks tirade on Facebook and other nonsense that he had to put up with.(If your are going to insult him, please try and get your facts correct!)Prof G has poor internet availability, so can't post that often, but posting he is. But may does not have time to repond to everything yet. Plus he has to sort through the year that was ECTRIMS 2011, to seperate the Wheat from the chaff.Prof B on the other hand is off to another Sin City to discuss studies aimed at progresive MSers.P.S. This will be a trip from hell (5am start)so no comments about a jolly please… it will fall on deaf ears.
There were a few studies on future candidates for progressive MS at ECTRIMS and results of a small scale trial. However nothing with a big fanfare yet.As for repair there are more candidates that were reported to be useful, but these studies are someway off reaching the NHS and where at early stage development.However there was a lot to digest.
Could you explain 'Database lock will occur in June, 2011; final clinical efficacy and safety results including relapse and disability outcomes will be presented' 1. June 2011 has passed. 2. What is 'Database lock'?
Apologies; the abstract that was posted is the incorrect version. I have now included the headline results.
Re: "Anything on stopping progression or promoting repair?"Yes, several presentations showed that early treatment with DMTs reduced disease progression and slowed brain atrophy. Unfortunately, there was nothing on reversing disability in MS'ers with progressive MS.
Re: "Anything on stopping progression or promoting repair?"Yes, several presentations showed that early treatment with DMTs reduced disease progression and slowed brain atrophy. Unfortunately, there was nothing on reversing disability in MS'ers with progressive MS.
Prof G,You say that Alemtuzumab looks the most effective treatment in late stage development (I would agree having received it in an earlier trial). What catches your eye in earlier stage development.On the issue of thyroids, I had a thyroid condition which pre-dated my MS dx. When I read MS Bitch, I recall the author saying that she had a thyroid problem before her MS dx. Has any research been undertaken on the possible involvement of the thyroid (thyroid conditions) in MS?
Re: "Has any research been undertaken on the possible involvement of the thyroid (thyroid conditions) in MS?"Yes, thyroid disease is a very common problem in the general population and is increased in family members of people with MS. There is an apparent increase risk of thyroid disorders in people with MS, but this has not been shown in all studies. Therefore some of the problems can predate the treatment. Dr Coles mentioned to us that in one case of thyroid cancer the patient had a nodule before going into the trial; therefore in this case it is likely to have predated the treatment. As will all issues in relation to cancers on treatments we need large numbers to see if it is a risk. In my opinion MS'ers with active disease would be willing to take a undefined risk, that appears low, to reap the benefits of Alemtuzumab.
Is there any research going on as to whether there should be any further treatment after 2 courses of alemtuzumab? I vaguely recall some talk about trying copaxone. Would BG12 be a possibility bearing in mind its neuroprotective element, your fears that inflammation may not be the whole story, and it is not an immunosuppresive?
Re: "Is there any research going on as to whether there should be any further treatment after 2 courses of alemtuzumab? …"Yes, we have the option of giving 3rd and 4th courses depending on response. If you are disease activity free after the 2nd course you don't need additional courses. Regards to adding in BG12; this is an interesting suggestion and may work. However, we would need to do a study to show that sequential therapies work. I am not sure who would fund this sort of study. It would be very expensive, unless we used biomarkers as an outcome; for example atrophy on MRI or changes in CSF neurofilament levels.