Alemtuzumab – A New Efficacy Benchmark in Relapsing–Remitting Multiple Sclerosis?

both T- and B-lymphocytes. Importantly, because CD52 is found less frequently on innate immune cells, such as natural killer cells and phagocytes, alemtuzumab does not appear to disrupt other immune system functions. This could explain the relatively low rates of serious infections reported for alemtuzumab in clinical trials.

Pre-clinical mechanism of action studies on alemtuzumab have been limited by a lack of cross-reactivity between human and mouse CD52. However, significant insights into alemtuzumab’s mechanism of action have been gained via studies in the recently developed transgenic mouse that expresses human CD52 (hCD52) under control of the hCD52 promoter.58

The tissue distribution of hCD52 and

immune function in the transgenic mice were normal. Treating the mice with alemtuzumab transiently increased serum cytokines and reduced blood lymphocytes in a manner that was similar to the response seen in humans. However, lymphocyte depletion was not as marked in lymphoid organs including the spleen, thymus and lymph nodes; this could explain why patients receiving alemtuzumab show a lower incidence of infection than might be anticipated. In mice, eliminating populations of natural killer cells and neutrophils with antibodies to Gr-1 or asialo-GM-1, respectively, markedly reduced the effects of alemtuzumab but removal of complement using cobra venom factor had no effect. These findings indicate that lymphocyte depletion resulting from alemtuzumab therapy relies primarily on antibody-dependent cell-mediated cytotoxicity as opposed to complement-dependent cytotoxicity. An overview of these potential mechanisms of action is shown in Table 2.

After alemtuzumab treatment, immune reconstitution follows a unique characteristic pattern in which B cells return towards baseline levels within three months while T cells take up to five years to recover.59,60

Figure 1: Annualised Relapse Rates and the Percentage of Patients Without Relapse in the CAMMS223 Trial

0.1 0.2 0.3 0.4 A 0.5

0

IFNβ-1a (n=111)

B

90 80

70 60 50

40 30

10 20

0

IFNβ-1a (n=111)

Following peripheral lymphocyte depletion, it has been postulated that naïve myelin-specific T cells could be tolerised, preventing their neurodegenerative activity.56

Furthermore, in vitro analysis has

Alemtuzumab 12mg/day (n=112)

Alemtuzumab 24mg/day (n=110)

Alemtuzumab pooled (n=222)

This property could

provide alemtuzumab with immunomodulatory properties in addition to depleting lymphocytes.59

shown that alemtuzumab may increase the lymphocytic delivery of neurotrophins to the central nervous system promoting survival of neurons and increased axonal length.54

This potential neurorestorative

action may partly explain the observed improvement in disability after alemtuzumab administration, although much work is required to further elucidate this effect. Overall, it appears that the benefits of alemtuzumab therapy in MS rest not on lymphocyte depletion per se, but rather in a long-term shift in the lymphocyte repertoire.

Alemtuzumab Clinical Trial Data

Initial pilot studies (1991–2002) consisting of 58 patients with MS showed that alemtuzumab significantly reduced relapse rates in both RRMS and secondary progressive MS (SPMS) (2.2–0.19 and 0.7–0.001 relapses per year, respectively, both p<0.001).61

A: Annualised relapse rates; B: proportion of patients without relapses when receiving interferon beta-1a (IFNβ-1a) (44µg continuously, subcutaneous injection) or alemtuzumab (12 or 24mg per day, intravenous infusion*) in the Campath-1H in Multiple Sclerosis (CAMMS223) trial (three-year data). *Alemtuzumab dosing regimen is initially for five days, then for three days after 12 months. Source: CAMMS223 Trial Investigators, 2008.62

doses of alemtuzumab with a current standard DMD treatment (IFNβ-1a SC) in a total of 334 DMD-naïve patients with early, active RRMS. Patients had an expanded disability status scale (EDSS) ≤3 and at least two clinical episodes during the previous two years.62

Patients

received intravenous alemtuzumab 12 (n=108) or 24mg per day (n=108, both doses were administered initially as a five-day course then a three-day course at 12 months and an optional 24 months) or IFNβ-1a 44µg SC three times weekly throughout the study (n=107). In CAMMS223, alemtuzumab showed markedly superior efficacy compared with IFNβ-1a in both the time to sustained accumulation of disability and the rate of relapse.62

An analysis at 36 months Moreover, in

alemtuzumab-treated patients with either RRMS or SPMS there was no new lesion formation. It also produced sustained and significant reductions in disability progression in RRMS, but not in SPMS where disability accumulation was sustained.61

Data from these pilot studies

suggest that alemtuzumab may be more effective in treating MS in early active patients.

The phase II Campath-1H in Multiple Sclerosis (CAMMS223) trial provided the first well-designed controlled trial evidence in favour of alemtuzumab treatment in MS. This randomised study compared two

EUROPEAN NEUROLOGICAL REVIEW

demonstrated that the annualised relapse rates for patients receiving IFNβ-1a, or alemtuzumab 12 or 24mg per day and the pooled alemtuzumab analysis were 0.36, 0.11, 0.08 and 0.10, respectively (see Figure 1). Compared with IFNβ-1a, alemtuzumab both 12 and 24mg per day reduced the rate of relapse by 69 and 79%, respectively (p<0.001 for both comparisons). For six-month sustained accumulation of disability (SAD), greater improvements were observed for alemtuzumab-treated patients compared with those treated with IFNβ-1a. An estimated 26.2, 8.5, 9.5 and 9% of patients had SAD in the IFNβ-1a, the alemtuzumab 12 and 24mg per day groups and the pooled alemtuzumab analysis, respectively. Compared with IFNβ-1a, the alemtuzumab 12 and 24mg per day and pooled groups reduced the risk of sustained accumulation of disability (six-months’ criteria) by 75,

85

Alemtuzumab 12mg/day (n=112)

Alemtuzumab 24mg/day (n=110)

Alemtuzumab pooled (n=222)

% patients without relapse

Annualised relapse rate