psing–
Drug Evaluation For reprint orders, please contact: [email protected]
Alemtuzumab for the treatment of relapsing–remitting multiple sclerosis
Alemtuzumab, a humanized monoclonal antibody that targets CD52, was recently approved in the EU and Canada for the treatment of patients with active relapsing– remitting multiple sclerosis. Alemtuzumab induces rapid depletion of circulating Band T-lymphocytes followed by repopulation that leads to a distinctive lymphocyte profile, including an increased proportion of regulatory T-lymphocytes and memory B- and T-lymphocytes. In early open-label studies, alemtuzumab treatment reduced the number of clinical relapses and new MRI lesions in participants with secondary progressive MS. However, most participants had continued worsening of disability, which led to the evaluation of alemtuzumab in patients with early stages of disease in the Genzyme (MA, USA)-sponsored clinical development program in MS. In one Phase II and two Phase III trials, alemtuzumab reduced the number of clinical relapses versus the active comparator, subcutaneous IFN-β-1a, in treatment-naive and treatment-experienced participants with relapsing–remitting multiple sclerosis. Two of these trials showed reduction in risk of confirmed worsening of disability, and all showed reduction in cerebral atrophy. Safety issues include infusion reactions that are mitigated by pretreatment with corticosteroids in addition to symptomatic management with antihistamines; mild to moderate infections; and autoimmune adverse events. In this context, post-marketing risk mitigation strategies will be needed so that potential adverse events can be identified and managed early and effectively.
Carrie M Hersh*,1 & Jeffrey A Cohen1 Mellen Center for Multiple Sclerosis Treatment & Research, Neurological Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA *Author for correspondence: Tel.: +1 216 444 3653 Fax: +1 216 445 6259 hershc@ ccf.org
1
Keywords: alemtuzumab • autoimmune adverse events • CD52 • monoclonal antibody • relapsing–remitting multiple sclerosis
Background Overview of multiple sclerosis
Multiple sclerosis (MS) is an inflammatory disease of the CNS that is a major cause of neurological impairment and disability. Approximately 80–85% of patients with MS initially present with a relapsing–remitting (RR) course that is thought to reflect the development of focal inflammatory lesions. Periodic relapses represent new or worsening neurological manifestations typically developing over days to weeks followed by a period of neurological recovery [1] . Eventually, the course in most patients evolves into gradual worsening (progression) with the cessation of relapses, thought to represent a shift to a neu-
10.2217/IMT.14.7 © 2014 Future Medicine Ltd
rodegenerative process. This clinical evolution reflects a complex interplay of inflammation, demyelination and axonal degeneration in the CNS [2,3] . Crucial associated manifestations in this latter phase include accumulation of disability in gait, motor function, balance and cognition. Body of review Overview of the market
The first disease-modifying therapies (DMTs) approved to treat RRMS were IFN-β (now comprising four preparations) and glatiramer acetate (GA). There is abundant evidence from formal studies and clinical practice supporting the long-term efficacy and safety of
Immunotherapy (2014) 6(3), 249–259
part of
ISSN 1750-743X
249
Drug Evaluation Hersh & Cohen these agents. The most common side effects of IFN-β include injection site reactions and flu-like symptoms, which tend to resolve after a few months of treatment. Other potential adverse effects include hematological abnormalities, elevated liver enzymes, thyroid disease and exacerbation in pre-existing spasticity and headache disorders. Potential side effects with GA include local injection-site reactions, post-injection systemic reactions and cutaneous lipoatrophy with chronic use. Owing to the extensive experience with these agents and their good safety record, they remain the most common first-line therapies for RRMS. However, shortcomings include modest efficacy for patients as a group and administration by frequent injection. Natalizumab, a humanized monoclonal antibody directed against the adhesion molecule α4-integrin [4] , was approved in the USA in November 2004, and in other regions afterwards, for the treatment of patients with relapsing MS. Phase III trials of natalizumab alone or in combination with intramuscular IFN-β-1a showed that natalizumab reduced the frequency of relapses, MRI lesion formation and worsening of disability in patients with relapsing MS [5,6] . No head-to-head trials comparing natalizumab to IFN-β or GA have been conducted, but the magnitude of therapeutic effect on relapse rate in the pivotal trials suggests it has more potent efficacy. Although natalizumab is highly efficacious, its use is primarily limited to second line by the associated risk of progressive multifocal leukoencephalopathy. Three oral medications recently received regulatory approval to treat RRMS: fingolimod, teriflunomide and dimethyl fumarate. They provide effective reduction in disease activity and disability progression. However, they have adverse effects that may compromise tolerability. Fingolimod is associated with cardiac effects with treatment initiation, increased blood pressure, macular edema, elevated liver enzymes and infections, particularly with herpes viruses [7,8] . Common side effects of teriflunomide are ALT elevation, mild or moderate transient gastrointestinal symptoms and hair thinning, which is usually transient [9] . Dimethyl fumarate is associated with cutaneous flushing and gastrointestinal symptoms [10,11] . With the currently available medication options, patients and physicians have the ability to select treatment not only based on efficacy and safety, but also patient factors, prior experience and personal preference. In this context, alemtuzumab, which is approved in Europe and Canada, represents an additional option with several unique features. Introduction to alemtuzumab
Alemtuzumab (being developed by Genzyme, a Sanofi company, MA, USA) is a humanized monoclonal anti-
250
Immunotherapy (2014) 6(3)
body previously approved for the treatment of B-cell chronic lymphocytic leukemia (CLL). It was subsequently evaluated in patients with active RRMS in three active-controlled studies versus subcutaneous (sc.) IFN-β-1a. Alemtuzumab was recently approved in Europe as a first-line agent and in Canada as a second-line agent for the treatment of adult patients with RRMS with active disease defined by clinical or imaging features. The Biologics License Application was not approved by the US FDA, leaving the future of alemtuzumab in the USA uncertain at this time. Alemtuzumab selectively targets CD52, a protein expressed at high levels on T and B lymphocytes, with resultant lymphocyte depletion and subsequent recovery of cell populations at variable rates [12,13] . B lymphocytes recover within 6 months of the treatment course, while T lymphocytes recover more slowly, approaching the lower limit of normal within 12 months of initial administration. CD4 + T lymphocytes are particularly slow to repopulate, with peripheral counts increasing over time but generally remaining below baseline levels for several years after a single 5-day exposure. This repopulation process leads to prolonged changes in the lymphocyte repertoire and long-lasting changes in immune function that may help explain the therapeutic effects of alemtuzumab in RRMS [14–16] . Chemistry
Alemtuzumab has an approximate molecular weight of 150 kDa and is part of the IgG1k antibody subclass. Its target is the CD52 molecule, a 28kD glycoprotein, consisting of 12 amino acids, attached to the cell surface by a glycosylphosphatidylinositol anchor [13,17] . CD52 is expressed at high levels on lymphocytes and to varying levels on monocytes, macrophages, NK cells, eosinophils and mature spermatozoa [18] . There is little to no CD52 expression on neutrophils and bone marrow stem cells [19] . The physiological function of CD52 is not known for certain. It is theorized to be involved in cell adhesion or activation. Pharmacodynamics
Alemtuzumab administration leads to rapid, long-term lymphopenia. Within minutes of infusing a single dose of 3 mg, peripheral lymphocytes are depleted, which is associated with almost immediate release of serum cytokines, including TNF-α, IL-6, and IFN-γ, that peaks at 2–6 hours after infusion [20] . This process is responsible for infusion-associated reactions and is mitigated by pretreatment with steroids, antihistamines and antipyretics [21] . The depleted lymphocyte pool is initially dominated by regulatory T lymphocytes, other memory T lymphocytes and B lymphocytes. There is a gradual return of naive T lymphocytes
future science group
Alemtuzumab for the treatment of relapsing–remitting multiple sclerosis
and memory B lymphocytes. It takes on average a median of 3 years for mean CD4 + T-lymphocyte numbers to reach the lower limit of normal range and at least 5 years to return to baseline. The mechanism of lymphocyte depletion was investigated in a transgenic mouse model expressing human CD52 and supported a predominantly antibody-dependent cell-mediated cytolysis rather than complement-dependent lysis [19] . The efficacy of alemtuzumab is prolonged, outlasting lymphocyte depletion, and appears to result from the distinctive lymphocyte profile that emerges during the repopulation process, resulting in a functionally different subset of lymphocytes. For example, in vitro studies demonstrated that IL-7 induced an expansion of CD4 + CD25 + CD127low regulatory T lymphocytes and decreased percentages of Th17 and Th1 lymphocytes. The results suggest that differential reconstitution of T-lymphocyte subsets and selectively delayed CD4 + T-lymphocyte repopulation may contribute to long-lasting suppression of disease activity following alemtuzumab administration [22] . Additionally, in vitro studies showed increased production of bioactive neurotrophic factors including brain-derived neurotrophic factor, ciliary neurotrophic factor, FGF and PDGF by lymphocytes collected 12 months after alemtuzumab administration, which may contribute to clinical efficacy by promoting neuronal survival, axon growth and proliferation of oligodendrocytes [23] . Pharmacokinetics & metabolism
Alemtuzumab is delivered in an isotonic (pH 6.8–7.4) solution for intravenous (iv.) injection [17] . In Phase III clinical trials, initial dosing was scheduled as iv. infusion of 12 mg or 24 mg/day on 5 consecutive days. The second course was scheduled as iv. infusion of the same dose on 3 consecutive days 1 year later [24,25] . Alemtuzumab serum concentration peaks 15–30 minutes following iv. infusion with a steady state distribution volume of 0.185 l/kg and a terminal half-life of 15–21 days [26] . Alemtuzumab follows nonlinear elimination and demonstrates complex pharmacokinetics that likely differ between MS and leukemia given the marked differences in dosing regimen [27–29] . Clearance is reduced with repeated administration due to loss of receptormediated clearance. Pharmacokinetics have not been studied in the pediatric population or in patients with liver or renal impairment. Antialemtuzumab antibodies are known to develop after alemtuzumab treatment. After the first alemtuzumab course in a Phase III trial, the proportion of participants positive for antialemtuzumab antibodies peaked at month 3 (63%) and decreased to 29.3% at month 12. Of the participants who tested positive for
future science group
Drug Evaluation
antialemtuzumab antibodies, the proportion of participants with inhibitory antibodies was highest 1 month after the first course (87.7%), and approached baseline levels (1.6%) prior to receiving a second course of treatment at month 12. Presence of antialemtuzumab antibodies did not impact the pattern and time course of lymphocyte depletion and repopulation or efficacy outcomes, possibly because the rate and/or affinity of interaction of alemtuzumab with CD52 exceeds that with antialemtuzumab antibodies. In addition, no difference was seen in the overall incidence of infusionassociated reactions or serious infusion-associated reactions among alemtuzumab-treated participants who were always negative for antialemtuzumab antibodies and patients who were ever positive [30] . Clinical efficacy History, development & early studies
Kohler and Milstein led the seminal discovery of monoclonal antibodies in 1975 [31] , which paved the way for the development of monoclonal antibodies that targeted T cells [32] . A subset of antibodies that could bind to CD52 was identified, with IgM being the most effective at activating human complement. This was subsequently named the ‘Cambridge Pathology-1’ or ‘Campath-1M’ antibody. This led to the development of Campath-1G in 1989, a monoclonal antibody of the IgG2b isotype that could clear leukemic cells from blood, for the treatment of CLL [33] . However, use of this rodent antibody was limited by its immunogenicity. Therefore, a humanized form, Campath-1H, was developed for therapeutic indications [34] . Regulatory approval for Campath/MabCampath to treat refractory B-lymphocyte CLL occurred in 2001 [35] and as first-line therapy for B-lymphocyte CLL in 2007. Alemtuzumab was initially tested in MS in the 1990s in a series of open-label studies [36,37] . Licensed disease-modifying agents at the time were effective in reducing the number of clinical relapses but had minimal effects on the long-term accumulation of disability and disease progression. In this context, treatment with alemtuzumab was first targeted for patients with a secondary progressive course. Results showed decreased cerebral inflammation as demonstrated by a reduction in the number of clinical relapses and new lesions on cranial MRI. However, most patients had continued worsening of disability and brain volume loss on MRI. These early studies suggested that disability accrual in progressive MS is not due to ongoing inflammation, which is successfully treated with alemtuzumab, but is due to different, possibly noninflammatory mechanisms in later stages. The authors speculated that clinical efficacy may be more robust if started at earlier stages of the disease
www.futuremedicine.com
251
Drug Evaluation Hersh & Cohen before the consequences of inflammatory damage are irretrievably established [38] . An uncontrolled, open-label study targeting patients with aggressive, early RRMS was reported in 2006 [39] . Twenty-two participants were enrolled with a mean disease duration of 2.7 years, mean Expanded Disability Status Scale (EDSS) score of 4.8. In the year prior to treatment with alemtuzumab, the mean annualized relapse rate (ARR) was 2.9 with mean increase in EDSS score by 2.2 points. Following alemtuzumab, there was a 91% reduction in ARR to 0.2 (p < 0.001) and reduction in disability with mean improvement of 1.2 points on the EDSS score. Phase II trial
A summary of alemtuzumab clinical trials are provided in Table 1. CAMMS223, a randomized, multisite, raterblinded Phase II trial, compared alemtuzumab at 12 and 24 mg doses with high dose sc. IFN-β-1a in treatmentnaive patients with early RRMS [40] . Over 36 months, the risks of clinical relapse and confirmed worsening of disability were reduced by over 70% in alemtuzumabtreated participants. Cranial MRI showed a reduction in T2 lesion load compared with sc. IFN-β-1a but was not statistically significant. The reduction in brain volume, measured on T1-weighted images, between baseline and month 36 was significantly less among subjects receiving alemtuzumab than among those allocated sc. IFN-β-1a (-0.5 and -1.8%, respectively; p = 0.05). As atrophy measures may be confounded by early acceleration of brain volume loss following initiation of antiinflammatory therapies, so-called ‘pseudoatrophy’, the investigators analyzed brain volume between months 12 and 36. During these months, brain volume increased by 0.9% in the alemtuzumab group and decreased by 0.2% in the sc. IFN-β-1a group (p = 0.02). However, these findings may have been affected by the use of T1-weighted images leading to misclassification of active lesions as cerebrospinal fluid on baseline scans with subsequent classification as brain parenchyma on follow-up scans. In the CAMMS223 extension trial, alemtuzumab continued to suppress relapses more than sc. IFN-β-1a and demonstrated improved disability at month 60 compared with baseline [41] . In the CAMMS223 trial, the majority of alemtuzumab-treated participants were not eligible to receive a third course of therapy at 24 months due to a dosing suspension that resulted from a fatal index case of immune thrombocytopenic purpura (ITP, see section on ‘Safety and Tolerability’ for further discussion) that occurred prior to the implementation of the safety monitoring program. Thereby, outcome data were predominantly from two planned courses of drug therapy. The CAMMS223 trial was also not powered
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Immunotherapy (2014) 6(3)
to detect late-appearing and/or low-frequency events, which necessitated further investigation in Phase III trials. Finally, masking of both patients and treating clinicians to treatment assignment was not considered feasible due to different treatment schedules, routes of administration and side-effect profiles of the study drugs. To mitigate this potential source of bias, raters who were masked to treatment assignment performed the EDSS and MRI assessments. Phase III trials
CARE-MS I was a randomized, rater-masked, multicenter Phase III trial, in which patients with early, treatment-naive RRMS were enrolled with mean ARR 1.8 and EDSS 2.0 at baseline [25] . Participants were randomly allocated either sc. IFN-β-1a at the approved dose for treatment of MS (44 ug) or alemtuzumab (12 mg). Coprimary endpoints were relapse rate and time to 6-month confirmed worsening of disability. Over 24 months, alemtuzumab reduced the rate of relapse compared with sc. IFN-β-1a (hazard ratio: 0.45; 95% CI 0.33–0.61; p < 0.0001). Eleven percent of participants in the sc. IFN-β-1a group had 6-month confirmed worsening of disability compared with 8% in the alemtuzumab group, but the difference was not statistically significant (hazard ratio: 0.70; 95% CI 0.40–1.23; p = 0.22). Forty percent of participants in the sc. IFN-β-1a group relapsed, compared with 22% of participants in the alemtuzumab group (p < 0.0001), corresponding to a 54.9% reduction in risk of relapse with alemtuzumab. Up until this point, most of the recent clinical trials assessed the clinical efficacy of alemtuzumab in treatment-naive patients. Few published studies in the literature rigorously investigated the efficacy and risks of escalation to a potentially more effective treatment in patients who relapsed on prior DMT. In this context, the CARE-MS II trial was a randomized controlled, multicenter, rater-masked study that compared sc. IFN-β-1a and alemtuzumab in patients with RRMS who previously relapsed on DMT [24] . Of 628 participants randomized to either sc. IFN-β-1a or alemtuzumab 12 mg, 518 (82.5%) had prior IFN-β and 215 (34.2%) had GA; an additional 22 participants (3.5%) had prior treatment with natalizumab in addition to IFN-β or GA [42] . There was a 49.4% reduction in relapse rate with alemtuzumab 12 mg compared with the sc. IFN-β-1a group, and 65% of participants in the alemtuzumab 12 mg group were relapse-free at 2 years compared with 47% in the sc. IFN-β-1a group (p < 0.001). Additionally, there was 42% reduction in 6-month confirmed worsening of disability with alemtuzumab compared with sc. IFN-β-1a (p = 0.008). Cranial MRI showed fewer new/enlarging lesions on T2-weighted scans and gadolinium enhancing lesions (p < 0.0001) with a statistically
future science group
Alemtuzumab for the treatment of relapsing–remitting multiple sclerosis
Drug Evaluation
Table 1. Summary of alemtuzumab clinical trials. Trial
Study design
CAMMS223, Phase II, n = 334 randomized, multisite, raterblinded trial in early, treatmentnaive RRMS; 3-year trial
Treatment arms
Primary clinical Other clinical outcome outcomes
• Sustained Three arms: EDSS alemtuzumab disability: 12 or 24 mg/ 9.0% day iv. cycles: combined year 1, 5 alemtuzumab days; years 2 vs 26.2% and 3, 3 days IFN-β-1a vs IFN-β-1a 44 (p < 0.001) mcg sc. three • ARR: 0.10 times per alemtuzumab week; 1:1:1 vs 0.36 ratio
MRI outcomes
• Decreased T2 Mean EDSS: lesion burden in improved by alemtuzumab vs 0.39 points IFN-β-1a group for combined (p = 0.005) alemtuzumab vs worsened by • After 1 year, increased brain 0.38 points for volume with IFN-β-1a alemtuzumab vs decreased brain volume with IFN‑β1a
IFN-β-1a
(p
Drug Evaluation For reprint orders, please contact: [email protected]
Alemtuzumab for the treatment of relapsing–remitting multiple sclerosis
Alemtuzumab, a humanized monoclonal antibody that targets CD52, was recently approved in the EU and Canada for the treatment of patients with active relapsing– remitting multiple sclerosis. Alemtuzumab induces rapid depletion of circulating Band T-lymphocytes followed by repopulation that leads to a distinctive lymphocyte profile, including an increased proportion of regulatory T-lymphocytes and memory B- and T-lymphocytes. In early open-label studies, alemtuzumab treatment reduced the number of clinical relapses and new MRI lesions in participants with secondary progressive MS. However, most participants had continued worsening of disability, which led to the evaluation of alemtuzumab in patients with early stages of disease in the Genzyme (MA, USA)-sponsored clinical development program in MS. In one Phase II and two Phase III trials, alemtuzumab reduced the number of clinical relapses versus the active comparator, subcutaneous IFN-β-1a, in treatment-naive and treatment-experienced participants with relapsing–remitting multiple sclerosis. Two of these trials showed reduction in risk of confirmed worsening of disability, and all showed reduction in cerebral atrophy. Safety issues include infusion reactions that are mitigated by pretreatment with corticosteroids in addition to symptomatic management with antihistamines; mild to moderate infections; and autoimmune adverse events. In this context, post-marketing risk mitigation strategies will be needed so that potential adverse events can be identified and managed early and effectively.
Carrie M Hersh*,1 & Jeffrey A Cohen1 Mellen Center for Multiple Sclerosis Treatment & Research, Neurological Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA *Author for correspondence: Tel.: +1 216 444 3653 Fax: +1 216 445 6259 hershc@ ccf.org
1
Keywords: alemtuzumab • autoimmune adverse events • CD52 • monoclonal antibody • relapsing–remitting multiple sclerosis
Background Overview of multiple sclerosis
Multiple sclerosis (MS) is an inflammatory disease of the CNS that is a major cause of neurological impairment and disability. Approximately 80–85% of patients with MS initially present with a relapsing–remitting (RR) course that is thought to reflect the development of focal inflammatory lesions. Periodic relapses represent new or worsening neurological manifestations typically developing over days to weeks followed by a period of neurological recovery [1] . Eventually, the course in most patients evolves into gradual worsening (progression) with the cessation of relapses, thought to represent a shift to a neu-
10.2217/IMT.14.7 © 2014 Future Medicine Ltd
rodegenerative process. This clinical evolution reflects a complex interplay of inflammation, demyelination and axonal degeneration in the CNS [2,3] . Crucial associated manifestations in this latter phase include accumulation of disability in gait, motor function, balance and cognition. Body of review Overview of the market
The first disease-modifying therapies (DMTs) approved to treat RRMS were IFN-β (now comprising four preparations) and glatiramer acetate (GA). There is abundant evidence from formal studies and clinical practice supporting the long-term efficacy and safety of
Immunotherapy (2014) 6(3), 249–259
part of
ISSN 1750-743X
249
Drug Evaluation Hersh & Cohen these agents. The most common side effects of IFN-β include injection site reactions and flu-like symptoms, which tend to resolve after a few months of treatment. Other potential adverse effects include hematological abnormalities, elevated liver enzymes, thyroid disease and exacerbation in pre-existing spasticity and headache disorders. Potential side effects with GA include local injection-site reactions, post-injection systemic reactions and cutaneous lipoatrophy with chronic use. Owing to the extensive experience with these agents and their good safety record, they remain the most common first-line therapies for RRMS. However, shortcomings include modest efficacy for patients as a group and administration by frequent injection. Natalizumab, a humanized monoclonal antibody directed against the adhesion molecule α4-integrin [4] , was approved in the USA in November 2004, and in other regions afterwards, for the treatment of patients with relapsing MS. Phase III trials of natalizumab alone or in combination with intramuscular IFN-β-1a showed that natalizumab reduced the frequency of relapses, MRI lesion formation and worsening of disability in patients with relapsing MS [5,6] . No head-to-head trials comparing natalizumab to IFN-β or GA have been conducted, but the magnitude of therapeutic effect on relapse rate in the pivotal trials suggests it has more potent efficacy. Although natalizumab is highly efficacious, its use is primarily limited to second line by the associated risk of progressive multifocal leukoencephalopathy. Three oral medications recently received regulatory approval to treat RRMS: fingolimod, teriflunomide and dimethyl fumarate. They provide effective reduction in disease activity and disability progression. However, they have adverse effects that may compromise tolerability. Fingolimod is associated with cardiac effects with treatment initiation, increased blood pressure, macular edema, elevated liver enzymes and infections, particularly with herpes viruses [7,8] . Common side effects of teriflunomide are ALT elevation, mild or moderate transient gastrointestinal symptoms and hair thinning, which is usually transient [9] . Dimethyl fumarate is associated with cutaneous flushing and gastrointestinal symptoms [10,11] . With the currently available medication options, patients and physicians have the ability to select treatment not only based on efficacy and safety, but also patient factors, prior experience and personal preference. In this context, alemtuzumab, which is approved in Europe and Canada, represents an additional option with several unique features. Introduction to alemtuzumab
Alemtuzumab (being developed by Genzyme, a Sanofi company, MA, USA) is a humanized monoclonal anti-
250
Immunotherapy (2014) 6(3)
body previously approved for the treatment of B-cell chronic lymphocytic leukemia (CLL). It was subsequently evaluated in patients with active RRMS in three active-controlled studies versus subcutaneous (sc.) IFN-β-1a. Alemtuzumab was recently approved in Europe as a first-line agent and in Canada as a second-line agent for the treatment of adult patients with RRMS with active disease defined by clinical or imaging features. The Biologics License Application was not approved by the US FDA, leaving the future of alemtuzumab in the USA uncertain at this time. Alemtuzumab selectively targets CD52, a protein expressed at high levels on T and B lymphocytes, with resultant lymphocyte depletion and subsequent recovery of cell populations at variable rates [12,13] . B lymphocytes recover within 6 months of the treatment course, while T lymphocytes recover more slowly, approaching the lower limit of normal within 12 months of initial administration. CD4 + T lymphocytes are particularly slow to repopulate, with peripheral counts increasing over time but generally remaining below baseline levels for several years after a single 5-day exposure. This repopulation process leads to prolonged changes in the lymphocyte repertoire and long-lasting changes in immune function that may help explain the therapeutic effects of alemtuzumab in RRMS [14–16] . Chemistry
Alemtuzumab has an approximate molecular weight of 150 kDa and is part of the IgG1k antibody subclass. Its target is the CD52 molecule, a 28kD glycoprotein, consisting of 12 amino acids, attached to the cell surface by a glycosylphosphatidylinositol anchor [13,17] . CD52 is expressed at high levels on lymphocytes and to varying levels on monocytes, macrophages, NK cells, eosinophils and mature spermatozoa [18] . There is little to no CD52 expression on neutrophils and bone marrow stem cells [19] . The physiological function of CD52 is not known for certain. It is theorized to be involved in cell adhesion or activation. Pharmacodynamics
Alemtuzumab administration leads to rapid, long-term lymphopenia. Within minutes of infusing a single dose of 3 mg, peripheral lymphocytes are depleted, which is associated with almost immediate release of serum cytokines, including TNF-α, IL-6, and IFN-γ, that peaks at 2–6 hours after infusion [20] . This process is responsible for infusion-associated reactions and is mitigated by pretreatment with steroids, antihistamines and antipyretics [21] . The depleted lymphocyte pool is initially dominated by regulatory T lymphocytes, other memory T lymphocytes and B lymphocytes. There is a gradual return of naive T lymphocytes
future science group
Alemtuzumab for the treatment of relapsing–remitting multiple sclerosis
and memory B lymphocytes. It takes on average a median of 3 years for mean CD4 + T-lymphocyte numbers to reach the lower limit of normal range and at least 5 years to return to baseline. The mechanism of lymphocyte depletion was investigated in a transgenic mouse model expressing human CD52 and supported a predominantly antibody-dependent cell-mediated cytolysis rather than complement-dependent lysis [19] . The efficacy of alemtuzumab is prolonged, outlasting lymphocyte depletion, and appears to result from the distinctive lymphocyte profile that emerges during the repopulation process, resulting in a functionally different subset of lymphocytes. For example, in vitro studies demonstrated that IL-7 induced an expansion of CD4 + CD25 + CD127low regulatory T lymphocytes and decreased percentages of Th17 and Th1 lymphocytes. The results suggest that differential reconstitution of T-lymphocyte subsets and selectively delayed CD4 + T-lymphocyte repopulation may contribute to long-lasting suppression of disease activity following alemtuzumab administration [22] . Additionally, in vitro studies showed increased production of bioactive neurotrophic factors including brain-derived neurotrophic factor, ciliary neurotrophic factor, FGF and PDGF by lymphocytes collected 12 months after alemtuzumab administration, which may contribute to clinical efficacy by promoting neuronal survival, axon growth and proliferation of oligodendrocytes [23] . Pharmacokinetics & metabolism
Alemtuzumab is delivered in an isotonic (pH 6.8–7.4) solution for intravenous (iv.) injection [17] . In Phase III clinical trials, initial dosing was scheduled as iv. infusion of 12 mg or 24 mg/day on 5 consecutive days. The second course was scheduled as iv. infusion of the same dose on 3 consecutive days 1 year later [24,25] . Alemtuzumab serum concentration peaks 15–30 minutes following iv. infusion with a steady state distribution volume of 0.185 l/kg and a terminal half-life of 15–21 days [26] . Alemtuzumab follows nonlinear elimination and demonstrates complex pharmacokinetics that likely differ between MS and leukemia given the marked differences in dosing regimen [27–29] . Clearance is reduced with repeated administration due to loss of receptormediated clearance. Pharmacokinetics have not been studied in the pediatric population or in patients with liver or renal impairment. Antialemtuzumab antibodies are known to develop after alemtuzumab treatment. After the first alemtuzumab course in a Phase III trial, the proportion of participants positive for antialemtuzumab antibodies peaked at month 3 (63%) and decreased to 29.3% at month 12. Of the participants who tested positive for
future science group
Drug Evaluation
antialemtuzumab antibodies, the proportion of participants with inhibitory antibodies was highest 1 month after the first course (87.7%), and approached baseline levels (1.6%) prior to receiving a second course of treatment at month 12. Presence of antialemtuzumab antibodies did not impact the pattern and time course of lymphocyte depletion and repopulation or efficacy outcomes, possibly because the rate and/or affinity of interaction of alemtuzumab with CD52 exceeds that with antialemtuzumab antibodies. In addition, no difference was seen in the overall incidence of infusionassociated reactions or serious infusion-associated reactions among alemtuzumab-treated participants who were always negative for antialemtuzumab antibodies and patients who were ever positive [30] . Clinical efficacy History, development & early studies
Kohler and Milstein led the seminal discovery of monoclonal antibodies in 1975 [31] , which paved the way for the development of monoclonal antibodies that targeted T cells [32] . A subset of antibodies that could bind to CD52 was identified, with IgM being the most effective at activating human complement. This was subsequently named the ‘Cambridge Pathology-1’ or ‘Campath-1M’ antibody. This led to the development of Campath-1G in 1989, a monoclonal antibody of the IgG2b isotype that could clear leukemic cells from blood, for the treatment of CLL [33] . However, use of this rodent antibody was limited by its immunogenicity. Therefore, a humanized form, Campath-1H, was developed for therapeutic indications [34] . Regulatory approval for Campath/MabCampath to treat refractory B-lymphocyte CLL occurred in 2001 [35] and as first-line therapy for B-lymphocyte CLL in 2007. Alemtuzumab was initially tested in MS in the 1990s in a series of open-label studies [36,37] . Licensed disease-modifying agents at the time were effective in reducing the number of clinical relapses but had minimal effects on the long-term accumulation of disability and disease progression. In this context, treatment with alemtuzumab was first targeted for patients with a secondary progressive course. Results showed decreased cerebral inflammation as demonstrated by a reduction in the number of clinical relapses and new lesions on cranial MRI. However, most patients had continued worsening of disability and brain volume loss on MRI. These early studies suggested that disability accrual in progressive MS is not due to ongoing inflammation, which is successfully treated with alemtuzumab, but is due to different, possibly noninflammatory mechanisms in later stages. The authors speculated that clinical efficacy may be more robust if started at earlier stages of the disease
www.futuremedicine.com
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Drug Evaluation Hersh & Cohen before the consequences of inflammatory damage are irretrievably established [38] . An uncontrolled, open-label study targeting patients with aggressive, early RRMS was reported in 2006 [39] . Twenty-two participants were enrolled with a mean disease duration of 2.7 years, mean Expanded Disability Status Scale (EDSS) score of 4.8. In the year prior to treatment with alemtuzumab, the mean annualized relapse rate (ARR) was 2.9 with mean increase in EDSS score by 2.2 points. Following alemtuzumab, there was a 91% reduction in ARR to 0.2 (p < 0.001) and reduction in disability with mean improvement of 1.2 points on the EDSS score. Phase II trial
A summary of alemtuzumab clinical trials are provided in Table 1. CAMMS223, a randomized, multisite, raterblinded Phase II trial, compared alemtuzumab at 12 and 24 mg doses with high dose sc. IFN-β-1a in treatmentnaive patients with early RRMS [40] . Over 36 months, the risks of clinical relapse and confirmed worsening of disability were reduced by over 70% in alemtuzumabtreated participants. Cranial MRI showed a reduction in T2 lesion load compared with sc. IFN-β-1a but was not statistically significant. The reduction in brain volume, measured on T1-weighted images, between baseline and month 36 was significantly less among subjects receiving alemtuzumab than among those allocated sc. IFN-β-1a (-0.5 and -1.8%, respectively; p = 0.05). As atrophy measures may be confounded by early acceleration of brain volume loss following initiation of antiinflammatory therapies, so-called ‘pseudoatrophy’, the investigators analyzed brain volume between months 12 and 36. During these months, brain volume increased by 0.9% in the alemtuzumab group and decreased by 0.2% in the sc. IFN-β-1a group (p = 0.02). However, these findings may have been affected by the use of T1-weighted images leading to misclassification of active lesions as cerebrospinal fluid on baseline scans with subsequent classification as brain parenchyma on follow-up scans. In the CAMMS223 extension trial, alemtuzumab continued to suppress relapses more than sc. IFN-β-1a and demonstrated improved disability at month 60 compared with baseline [41] . In the CAMMS223 trial, the majority of alemtuzumab-treated participants were not eligible to receive a third course of therapy at 24 months due to a dosing suspension that resulted from a fatal index case of immune thrombocytopenic purpura (ITP, see section on ‘Safety and Tolerability’ for further discussion) that occurred prior to the implementation of the safety monitoring program. Thereby, outcome data were predominantly from two planned courses of drug therapy. The CAMMS223 trial was also not powered
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to detect late-appearing and/or low-frequency events, which necessitated further investigation in Phase III trials. Finally, masking of both patients and treating clinicians to treatment assignment was not considered feasible due to different treatment schedules, routes of administration and side-effect profiles of the study drugs. To mitigate this potential source of bias, raters who were masked to treatment assignment performed the EDSS and MRI assessments. Phase III trials
CARE-MS I was a randomized, rater-masked, multicenter Phase III trial, in which patients with early, treatment-naive RRMS were enrolled with mean ARR 1.8 and EDSS 2.0 at baseline [25] . Participants were randomly allocated either sc. IFN-β-1a at the approved dose for treatment of MS (44 ug) or alemtuzumab (12 mg). Coprimary endpoints were relapse rate and time to 6-month confirmed worsening of disability. Over 24 months, alemtuzumab reduced the rate of relapse compared with sc. IFN-β-1a (hazard ratio: 0.45; 95% CI 0.33–0.61; p < 0.0001). Eleven percent of participants in the sc. IFN-β-1a group had 6-month confirmed worsening of disability compared with 8% in the alemtuzumab group, but the difference was not statistically significant (hazard ratio: 0.70; 95% CI 0.40–1.23; p = 0.22). Forty percent of participants in the sc. IFN-β-1a group relapsed, compared with 22% of participants in the alemtuzumab group (p < 0.0001), corresponding to a 54.9% reduction in risk of relapse with alemtuzumab. Up until this point, most of the recent clinical trials assessed the clinical efficacy of alemtuzumab in treatment-naive patients. Few published studies in the literature rigorously investigated the efficacy and risks of escalation to a potentially more effective treatment in patients who relapsed on prior DMT. In this context, the CARE-MS II trial was a randomized controlled, multicenter, rater-masked study that compared sc. IFN-β-1a and alemtuzumab in patients with RRMS who previously relapsed on DMT [24] . Of 628 participants randomized to either sc. IFN-β-1a or alemtuzumab 12 mg, 518 (82.5%) had prior IFN-β and 215 (34.2%) had GA; an additional 22 participants (3.5%) had prior treatment with natalizumab in addition to IFN-β or GA [42] . There was a 49.4% reduction in relapse rate with alemtuzumab 12 mg compared with the sc. IFN-β-1a group, and 65% of participants in the alemtuzumab 12 mg group were relapse-free at 2 years compared with 47% in the sc. IFN-β-1a group (p < 0.001). Additionally, there was 42% reduction in 6-month confirmed worsening of disability with alemtuzumab compared with sc. IFN-β-1a (p = 0.008). Cranial MRI showed fewer new/enlarging lesions on T2-weighted scans and gadolinium enhancing lesions (p < 0.0001) with a statistically
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Alemtuzumab for the treatment of relapsing–remitting multiple sclerosis
Drug Evaluation
Table 1. Summary of alemtuzumab clinical trials. Trial
Study design
CAMMS223, Phase II, n = 334 randomized, multisite, raterblinded trial in early, treatmentnaive RRMS; 3-year trial
Treatment arms
Primary clinical Other clinical outcome outcomes
• Sustained Three arms: EDSS alemtuzumab disability: 12 or 24 mg/ 9.0% day iv. cycles: combined year 1, 5 alemtuzumab days; years 2 vs 26.2% and 3, 3 days IFN-β-1a vs IFN-β-1a 44 (p < 0.001) mcg sc. three • ARR: 0.10 times per alemtuzumab week; 1:1:1 vs 0.36 ratio
MRI outcomes
• Decreased T2 Mean EDSS: lesion burden in improved by alemtuzumab vs 0.39 points IFN-β-1a group for combined (p = 0.005) alemtuzumab vs worsened by • After 1 year, increased brain 0.38 points for volume with IFN-β-1a alemtuzumab vs decreased brain volume with IFN‑β1a
IFN-β-1a
(p
