Keywords::
Alemtuzumab (Campath-1H) is a humanized monoclonal antibody under investigation for multiple sclerosis (MS) Citation[1]. Alemtuzumab is directed against the CD52 antigen, which is expressed on the surface of T cells, B cells, natural killer cells, monocytes and dendritic cells Citation[2]. Alemtuzumab leads to complement and antibody-dependent cytoxicity of lymphocytes Citation[3,4]. The result is a profound depletion of circulating T and B cells. The mechanism of action of alemtuzumab in MS is more complex, and is probably not solely related to lymphocyte depletion. Interplay of increased regulatory T cells and decreased memory T cells is the more likely mechanism leading to prolonged efficacy in MS Citation[5]. In addition, lymphocytes appearing after alemtuzumab treatment secrete increased levels of brain-derived neurotrophic factor, which may have neuroprotective effects Citation[6].
Alemtuzumab was approved to treat chronic lymphocytic leukemia in 2006 Citation[7], and was tested in vasculitis with promising results Citation[8]. Open-label studies in secondary progressive MS demonstrated marked and prolonged reduction of relapses and MRI lesion activity Citation[9], but a lack of benefit on gradual progression, leading to the investigation of alemtuzumab in relapsing–remitting (RR) MS Citation[10]. In CAMMS223, a Phase II clinical trial to evaluate the efficacy and safety of alemtuzumab in previously untreated subjects Citation[11], alemtuzumab reduced the annualized relapse rate by 74% and reduced the risk of sustained accumulation of disability, measured by the Expanded Disability Status Scale (EDSS), by 71% compared with subcutaneous IFN-β1a. The benefit on disability was sustained for up to 5 years Citation[12]. Alemtuzumab therapy was suspended in this trial after three subjects developed immune thrombocytopenia and one died with a fatal brain hemorrhage.
The Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II Phase III clinical trials were recently published. CARE-MS I was a randomized, rater-masked, clinical trial comparing alemtuzumab with IFNβ-1a in previously untreated subjects with RRMS Citation[13]. Alemtuzumab was administered intravenously at a dose of 12-mg daily for 5 days at baseline followed by a 3-day course at month 12. IFNβ-1a (44 µg) was administered subcutaneously three-times per week after initial dose titration. Subjects were followed for 2 years, and the primary analysis included 376 subjects in the alemtuzumab arm and 187 subjects in the IFNβ-1a arm. Alemtuzumab treatment was associated with a 55% reduction in relapses and the proportion of subjects free of relapse was significantly higher in the alemtuzumab arm (78 vs 59%, respectively). A trend favoring alemtuzumab was observed for reduction in EDSS worsening, confirmed over 6 months. A reduction in gadolinium enhancing lesions was also seen. T2 lesion volume did not differ between the two groups. Alemtuzumab decreased brain volume loss over 2 years compared with IFNβ-1a. A difference in clinical and MRI disease-free status was also seen, favoring alemtuzumab (39 vs 27%).
CARE-MS II had a similar design, but compared alemtuzumab and subcutaneous IFN-β1a in subjects with RRMS who had experienced a relapse on IFN-β or glatiramer acetate Citation[14]. Initially, two doses of alemtuzumab were studied; either 12 or 24 mg administered by intravenous infusion daily for 5 days at baseline and 3 days at 12 months. The 24‑mg dose was abandoned due to slow recruitment, and the primary analysis cohorts included 202 subjects on IFNβ-1a and 426 subjects on alemtuzumab 12 mg. Alemtuzumab showed a significant reduction in relapses (49%) and 6-month confirmed EDSS progression (42%). Relapse freedom was also higher in the alemtuzumab arm (65 vs 47%), as was clinical and MRI disease freedom (60 vs 41%). Positive effects were seen in MRI metrics, including gadolinium enhancing lesions and new or enlarged T2 lesions. Brain volume loss was slowed with alemtuzumab compared with IFNβ-1a.
In the Phase III trials, most subjects experienced infusion reactions (90–97%), mostly mild–moderate in severity. Infusion reactions have been previously described with alemtuzumab and are thought to result from abrupt release of cytokines, including TNF-α and IFN-γ, with cell lysis Citation[15]. Pretreatment with an antipyretic and antihistamine decreased the intensity of these reactions.
The most notable adverse event in the alemtuzumab trials was secondary humoral autoimmunity Citation[13,14], thought to result from reconstitution of B cells prior to regulatory T cells Citation[16]. The return of B cells occurs within 6 months of treatment, while the return of T cells may take years to occur. Increased levels of IL-21 have been postulated as a response to treatment, which favors proliferation of self-reactive T cells and contribute to autoimmunity Citation[17]. In the Phase III clinical trials, autoimmune thyroid disease developed in 16–19% of the alemtuzumab-treated subjects Citation[13,14]. Idiopathic thrombocytopenic purpura occurred in <1% of the patients in Phase III trials of alemtuzumab Citation[13,14,18]. Several cases of antiglomerular basement membrane disease (Goodpasture syndrome) have also been identified Citation[13,19]. Because secondary autoimmune disorders can occur up to 5 years after alemtuzumab therapy Citation[12], the incidence of these disorders may have been underestimated in the clinical trials.
The incidence of infections with alemtuzumab was similar to IFNβ-1a in the Phase III trials, with the exception of increased herpes virus infections Citation[13,14]. There were two cases of tuberculosis in Phase III trials, both occurring in patients from endemic areas. Overall, increased risk of opportunistic infection was not seen. Although alemtuzumab produces profound depletion of circulating lymphocytes, innate immune mechanisms and tissue-resident memory T cells, key aspects of immune surveillance, are preserved, which may explain the relatively low incidence of infection with alemtuzumab.
Cases of basal cell carcinoma were similar across treatment arms in Phase III trials. A higher incidence of thyroid cancer was seen, but these may have been a by-product of increased ultrasound screening of the thyroid. Single cases of vulvar and colon cancer were seen in the 24‑mg arm of the CARE-MS II trial Citation[14].
Alemtuzumab has been submitted for regulatory approval in MS and a decision is expected in 2013. Its convenient dosing schedule and potent efficacy are attractive features. Alemtuzumab showed consistent, robust benefit on relapses, MRI lesion activity and whole brain atrophy compared with an active comparator in a Phase II and two Phase III clinical trials in RRMS, with positive results in both treatment-naive subjects as well as subjects with continued disease activity on first-line agents. Benefit on slowing accrual of 6-month confirmed EDSS worsening was shown in the Phase II trial and CARE-MS II, again relative to an active comparator. Superiority on this end point was not demonstrated in CARE-MS I. This negative finding was, at least in part, due to the low number of patients in the IFNβ-1a arm with confirmed EDSS worsening (11%), substantially less than the anticipated rate of 26% based on the Phase II study. Reduction in disability (improvement) was seen in a subset of patients treated with alemtuzumab in CARE-MS II. Whether this observation results from the anti-inflammatory actions of alemtuzumab or represents direct repair-promoting actions remains uncertain.
However, the advantage of alemtuzumab’s potent efficacy is somewhat mitigated by safety concerns. Subject and clinician education concerning potential adverse effects and a comprehensive monitoring plan implemented in alemtuzumab trials facilitated early detection of secondary autoimmunity and effective intervention. It is likely that similar approaches will be stipulated by regulatory agencies postmarketing, including, for example, baseline and serial complete blood counts and thyroid function tests. Monitoring for antiglomerular basement membrane disease (via serial urinalysis or serum creatinine determination) may also be considered. However, the efficiency of these tests to detect this very rare complication remains unclear, and urinalysis is anticipated to lead to a large number of false positives. Monitoring will need to be continued for at least several years after the last treatment cycle, which will require approaches to maintain follow-up. Thus, the convenience of administering alemtuzumab via short annual courses will be counterbalanced by the practical aspects of monitoring for secondary autoimmunity.
The appropriate placement of alemtuzumab in the MS treatment algorithm remains unclear. All three alemtuzumab trials recruited patients early in the disease course, based on a hypothesized therapeutic window in which treatment would be most effective. The Phase II study and CARE-MS I showed benefit in treatment-naive patients. However, it is unlikely that most clinicians will utilize alemtuzumab broadly as a first-line agent, despite its greater potency and advantages in terms of treatment adherence relative to IFN-β and probably glatiramer acetate. Alemtuzumab will face stiff competition as a second-line agent from natalizumab (particularly in John Cunningham virus seronegative patients) and from oral agents, fingolimod and dimethyl fumarate (when approved). A method for assessing the risk of alemtuzumab-associated secondary autoimmunity would help clarify when to utilize alemtuzumab. Pretreatment serum IL-21 level has been proposed as one approach Citation[17], but the predictive value of this test has not been fully validated. Thus, selection of patients for alemtuzumab therapy will initially be based on a determination of whether its potent efficacy justifies its risk on a case-by-case basis. In most cases it will be used in a subgroup of patients with highly active, treatment-refractory disease who are considered to be at high risk for future disability.
Financial & competing interests disclosure
This publication was made possible by the Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the NIH and NIH roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. D Ontaneda is supported by a NIH KL2 Award and a National Multiple Sclerosis Sylvia Lawry Physician Fellowship Award (FP 1769-A-1). D Ontaneda has received consulting or speaking fees from Acorda Therapeutics, Biogen Idec and Novartis. JA Cohen has received consulting and speaking fees in the last three years from Biogen Idec, Elan, Lilly, Novartis, Receptos, Teva and Vaccinex. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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