IMPORTANCE Alemtuzumab, a CD52-depleting monoclonal antibody, effectively inhibits relapsing multiple sclerosis (MS) but is associated with a high incidence of secondary B-cell autoimmunities that limit use. These effects may be avoided through control of B-cell hyperproliferation.OBJECTIVE To investigate whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase 3 trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS. DESIGN, SETTING, AND PARTICIPANTS Lymphocyte reconstitution data from regulatory submissions of the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests. Data used in this study were reported from June 22 to October 12, 2016. MAIN OUTCOMES AND MEASURES Tabulated data from T-and B-lymphocyte subset analysis and antidrug antibody responses were extracted from the supplied documents.RESULTS Alemtuzumab depleted CD4 + T cells by more than 95%, including regulatory cells (−80%) and CD8 + T cells (>80% depletion), which remained well below reference levels throughout the trials. However, although CD19 + B cells were initially also depleted (>85%), marked (180% increase) hyperrepopulation of immature B cells occurred with conversion to mature B cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and -neutralizing antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyperrepopulation of B cells masked a marked, long-term depletion of CD19 + memory B cells that may underpin efficacy in MS.CONCLUSIONS AND RELEVANCE Although blockade of memory T and B cells may limit MS, rapid CD19 + B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell-depleting agents.

Objective:To understand the efficacy of cladribine (CLAD) treatment in MS through analysis of lymphocyte subsets collected, but not reported, in the pivotal phase III trials of cladribine and alemtuzumab induction therapies.Methods:The regulatory submissions of the CLAD Tablets Treating Multiple Sclerosis Orally (CLARITY) (NCT00213135) cladribine and Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, study one (CARE-MS I) (NCT00530348) alemtuzumab trials were obtained from the European Medicine Agency through Freedom of Information requests. Data were extracted and statistically analyzed.Results:Either dose of cladribine (3.5 mg/kg; 5.25 mg/kg) tested in CLARITY reduced the annualized relapse rate to 0.16–0.18 over 96 weeks, and both doses were similarly effective in reducing the risk of MRI lesions and disability. Surprisingly, however, T-cell depletion was rather modest. Cladribine 3.5 mg/kg depleted CD4+ cells by 40%–45% and CD8+ cells by 15%–30%, whereas alemtuzumab suppressed CD4+ cells by 70%–95% and CD8+ cells by 47%–55%. However, either dose of cladribine induced 70%–90% CD19+ B-cell depletion, similar to alemtuzumab (90%). CD19+ cells slowly repopulated to 15%–25% of baseline before cladribine redosing. However, alemtuzumab induced hyperrepopulation of CD19+ B cells 6–12 months after infusion, which probably forms the substrate for B-cell autoimmunities associated with alemtuzumab.Conclusions:Cladribine induced only modest depletion of T cells, which may not be consistent with a marked influence on MS, based on previous CD4+ T-cell depletion studies. The therapeutic drug-response relationship with cladribine is more consistent with lasting B-cell depletion and, coupled with the success seen with monoclonal CD20+ depletion, suggests that B-cell suppression could be the major direct mechanism of action.

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BackgroundThe use of alemtuzumab in people with relapsing MS (pwRMS) is limited by the high risk of secondary B cell autoimmunity (SAI). Data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase III trials has never been comprehensively reported. We hypothesised this data may reveal mechanisms explaining efficacy as well as SAI with alemtuzumab.MethodsLymphocyte data from regulatory submissions of the pivotal CARE-MS I and II trials was obtained from the European Medicines Agency, and analysed.ResultsAlemtuzumab depleted CD4+ T cells by 95%, including regulatory (−80%) and CD8+ T cells (−85%), all remaining below normal throughout the trials. Whilst CD19+ B cells were initially depleted (−90%) marked (+180%) hyper-repopulation occurred of immature B cells, converting to mature B cells. This was associated with alemtuzumab-binding and neutralising antibodies and SAI. Hyper-repopulation of B cells masked long-term depletion of CD19+ memory B cells that may underpin efficacy in MS.ConclusionWhilst depletion of memory T and B cells by alemtuzumab may limit MS, rapid CD19+ B cell subset repopulation in the absence of effective T cell regulation may reduce efficacy and cause SAI. Controlling B cell proliferation until T cell regulation recovers may limit SAI.