Alemtuzumab CARE-MS I 5-year follow-up
Havrdova et al., 2017
The use of disease-modifying agents in MS is now commonplace, and a number of trials have demonstrated that a number of agents can reduce relapse rates and improve neuroimaging end-points. In the September 12th issue of Neurology (open access!), Havrdova and colleagues published the following 3 year extension to the team’s original 2 year phase III study (CARE-MS I), comparing alemtuzumab with IFN-beta1a.
I’ll start with a bit of PICO…
Patients with relapsing-remitting MS, 18-50yo, treatment-naive, with active disease defined as >=2 relapses in the previous 2 years and >= in the previous 1 year. Expanded disability status scale (EDSS) at baseline had to be =<3.
Of the 367 who completed the 2 year study, 349 entered this extension study.
Alemtuzumab, a humanised monoclonal antibody targeting CD52 (expressed on B and T lymphocytes), causing an initial depletion of the circulating pool of B and T cells, followed by re-population with slightly altered sub-types of T cells and associated cytokines and chemokines, known as “immune reprogramming” [ref].
Patients received 12mg/day for 5 days of IV alemtuzumab at baseline and 3 days at 12 months. Midway through the trial, these patients also started getting oral aciclovir during alemtuzumab infusions and for 28 days thereafter as prophylaxis against herpes. Patients in both groups received 1g per day of IV methylpred on 3 days at baseline and at month 12.
Patients in the alemtuzumab group were eligible to receive further treatment (12mg/day for 3 days) upon evidence of MS activity, provided their previous dose was at least 48 weeks prior to administration.
The initial trial compared alemtuzumab with subcutaneous IFN-beta1a, 3 times per week. This extension study was a longitudinal follow up of the alemtuzumab cohort, looking to see if the treatment effects were sustained. Therefore, when you look at the results, remember there is no comparator group
The initial trial was randomised, but rater-blinded, meaning the team of neurologists assessing to determine the patient’s current clinical status, or if a relapse had occurred, were blind to the treatments, but the patients and drug administrators knew which treatments were being given. This is different from double-blinded.
Annualised relapse rate (ARR) at 5 years post-treatment.
Relapse events were defined as objective signs on examination, lasting >48h, and/or MRI lesion activity. EDSS was assessed every 3 months using the same rater-blinded methods.
Note that data from 2 years was previously published in 2012, demonstrating a 54·9% improvement in relapse rate with alemtuzumab. While those in the alemtuzumab group on average had less “sustained accumulation of disability”, this effect did not reach significance (hazard ratio 0·70 [95% CI 0·40–1·23]; p=0·22) [ref].
Of the 367 who entered this extension study, 96% remained in the study until month 60. 110 patients received at least one re-treatment during the study period.
ARR remained low, consistent with the 2 year results (0.18 at 2 years vs. 0.16 at 5 years).
EDSS scores showed progressive decline from the initial improvement at 2 years. By year 5, 60% of patients were at their baseline, 17.8% had worsened, and 22.2% had improved.
By year 5, 62% of patients displayed no evidence of disease activity (NEDA).
One death during the extension period occurred due to sepsis secondary to pancytopenia, thought to be treatment-related.
No other serious AEs occurred during the extension. 99% of infections were mild-moderate nasopharyngitis, UTI, URTI or herpes zoster infection. The most common autoimmune AEs occurring during the extension were thyroid AEs.