Expert Review of Clinical Immunology
ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: http://www.tandfonline.com/loi/ierm20
Alemtuzumab for the treatment of relapsingremitting multiple sclerosis: a review of its clinical pharmacology, efficacy and safety David E Jones & Myla D Goldman To cite this article: David E Jones & Myla D Goldman (2014) Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis: a review of its clinical pharmacology, efficacy and safety, Expert Review of Clinical Immunology, 10:10, 1281-1291, DOI: 10.1586/1744666X.2014.951332 To link to this article: http://dx.doi.org/10.1586/1744666X.2014.951332
Published online: 22 Aug 2014.
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Date: 14 December 2016, At: 05:26
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Alemtuzumab for the treatment of relapsingremitting multiple sclerosis: a review of its clinical pharmacology, efficacy and safety Expert Rev. Clin. Immunol. 10(10), 1281–1291 (2014)
David E Jones and Myla D Goldman* Department of Neurology, James Q. Miller MS Clinic, University of Virginia Health System, 500 Ray C. Hunt Drive, Charlottesville, VA 22908, USA *Author for correspondence: [email protected]
Multiple sclerosis (MS) is an inflammatory condition of the CNS presumably induced by an environmental trigger(s) in a genetically susceptible individual. Inflammation is prominent and most susceptible to intervention early in MS, so early treatment with disease-modifying therapies is recommended to reduce relapses and new MRI activity (both markers of inflammation) with the goal of delaying disability progression. Unfortunately, the response to the disease-modifying therapies is variable and often falls short of stopping observable disease activity, so the search for more effective agents continues. Alemtuzumab is a monoclonal antibody against CD52 that has exhibited significant efficacy throughout its clinical trial program in MS; uniquely, some of the studies have demonstrated a sustained reduction in disability in MS patients. Countering this impressive efficacy is an associated high risk of autoimmune events (especially thyroid) and concerns for infection or malignancy given prolonged immunosuppression after treatment with alemtuzumab. KEYWORDS: alemtuzumab • monoclonal antibody • multiple sclerosis
Multiple sclerosis (MS) is a chronic inflammatory condition of the CNS that is presumed to occur when a genetically susceptible individual is exposed to an as-yet unconfirmed environmental trigger. It is a very common cause of non-traumatic disability in young adults, affecting over 400,000 individuals in the USA [1]. Most cases start as relapsing-remitting (RR) disease, in which there are inflammatory episodes of neurologic dysfunction, often accompanied by gadolinium enhancement on MRI followed by some functional recovery and resolution of this enhancement; however, MRI activity can also occur in the absence of new neurologic symptoms [2]. Although degeneration is demonstrable early in RR-MS, it is likely the driving process later in the disease, as the patient clinically transitions into secondary progressive MS; however, our understanding of
informahealthcare.com
10.1586/1744666X.2014.951332
the pathophysiology of progressive MS is less robust. If this degeneration is not directly driven by the inflammatory component of MS, it may relate to other processes, including Wallerian degeneration due to previous damage to myelin or axons, compartmentalized inflammation possibly attributable to the innate immune system behind an intact blood–brain barrier, the presence of reactive oxygen species and/or a mitochondrial bioenergetics deficit as the brain attempts to compensate for additional damage after depletion of its functional reserve [3,4]. MS disease activity is often measured by relapse assessment, which are defined as episodes of new or worsening neurologic dysfunction occurring in the absence of fever or infection and lasting over 24 h, or quantitating MRI change, including new or enlarging
2014 Informa UK Ltd
ISSN 1744-666X
1281
Drug Profile
Jones & Goldman
T2 hyperintensities, new T1 hypointensities (‘black holes’), gadolinium enhancement and brain atrophy. Standard measures of disease progression include Kurtzke’s Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC). The EDSS is a ordinal scale between 0 and 10 that measures disability in seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bladder/ bowel, cerebral); it is often criticized for being non-linear, having intra- and inter-rater variability, placing excessive weight on ambulation and de-emphasizing both upper extremity function and the silent symptoms of MS (fatigue, depression, cognitive dysfunction) [5]. The MSFC includes measurements of three tasks: the timed 25-foot walk, the timed 9-hole PEG test and the cognitive Paced Auditory Sequential Addition Test; some have suggested modifying the MSFC by replacing the Paced Auditory Sequential Addition Test with the Symbol Digit Modalities Test and adding a test of visual contrast sensitivity with Sloan low contrast letter charts [6–8].
The DMTs have inconsistent data for reduction in disability progression in the short term; indeed, one analysis of historical, contemporary treated and contemporary untreated cohorts of MS patients suggests that IFN-b may not confer a long-term disability benefit [17]. Of the three Phase III studies of fingolimod, only FREEDOMS met its disability end point; likewise, only one of the two Phase III dimethyl fumarate trials met this end point [14,18,19]. Conversely, both Phase III studies of teriflumomide (TEMSO and TOWER) met their disability end point, and the laquinimod studies suggest that it is possible for an MS drug to have a more robust effect on disability than relapses, although this drug is years away from potential approval [20–23]. A post hoc analysis of the natalizumab AFFIRM data suggests that reversal of disability as measured by improvement in the EDSS or health-related quality of life may be an obtainable goal in at least the short term in some patients with RR-MS [24]. Halting the progression of disability or even reversal of pre-existing disability is arguably one of the biggest unmet needs in MS therapeutics.
Overview of the market
There are currently 11 US FDA-approved disease-modifying therapies (DMTs) for relapsing forms of MS, including six injectable medications (subcutaneous [sc.] and intramuscular IFN-b-1a, 2 sc. IFN-b-1bs and 2 doses of sc. glatiramer acetate), two intravenous [iv.] medications (mitoxantrone, natalizumab) and three oral medications (fingolimod, teriflunomide and dimethyl fumarate). All of these have good data for reduction in annualized relapse rate (ARR) and MRI activity; however, their data for reduction in disability progression is less robust. As may be imagined, defining a suboptimal response to a partially effective medication is challenging, although some argue that we should strive to stop all disease activity. A post hoc analysis of the natalizumab AFFIRM data suggests that ‘freedom of disease activity’ (FDA) is an achievable end point in some patients; however, it has been suggested that ‘no evidence of disease activity’ (NEDA) is a more appropriate term for this end point as not all disease activity in MS is easily measured [9,10]. Unfortunately, the goal of either FDA or NEDA remains elusive in many patients. Compounding this difficulty is a paucity of head-to-head trials comparing the DMTs: the EVIDENCE trial suggests initial superiority of sc. IFN-b-1a, while the BEYOND and REGARD trials suggests similar efficacy between glatiramer acetate and high-dose IFN-b [11–13]. Although technically glatiramer acetate was a reference comparator in the CONFIRM study, dimethyl fumarate did not achieve statistically significant superiority for the primary end point (ARR) and some secondary end points of the trial; similarly, TENERE did not show superiority of teriflunomide over sc. IFN-b-1a [14,15]. The TRANSFORMS trial suggests superiority of fingolimod over intramuscular IFN-b-1a, albeit with the caveat that almost 50% of patients randomized to IFN-b were previously treated with an interferon [16]. These comparator trials set a precedent for rater-blinded studies in MS, and several ongoing clinical trials in MS are utilizing this methodology. 1282
Introduction to the drug
Alemtuzumab (LemtradaTM ) is a humanized monoclonal antibody directed against CD52, a 12-amino acid glycophosphatidylinositollinked surface protein that is primarily expressed on B- and T-lymphocytes with limited expression on monocytes, dendritic cells and NK cells; however, it is not significantly expressed by hematopoietic progenitor cells or neutrophils. The function of CD52 is not well characterized, although some data suggest that it may be involved with T-cell activation or induction of CD4+ Tregs. Although alemtuzumab’s original indication was for treatment of B-cell chronic lymphocytic leukemia, its use has been explored in other autoimmune diseases, including rheumatoid arthritis [25–28]. Treatment with alemtuzumab causes a rapid depletion of immune cells expressing CD52 in the blood by complementdependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity; however, this effect seems limited in lymphoid tissue. Mouse models exploring the mechanism of action and safety of alemtuzumab were of limited value, as alemtuzumab does not interact with mouse CD52; however, this was overcome by developing a human CD52 (hCD52) transgenic mouse that appeared physically and immunologically normal. The distribution of hCD52 in this transgenic mouse was similar to that of CD52 in humans, and treatment with alemtuzumab effected a similar depletion of circulating B- and T-lymphocytes. There was limited depletion of lymphocytes in the lymphoid tissue and a relative sparing of Tregs; as in humans, treatment with alemtuzumab did not seem to affect hematopoietic progenitor cells in the hCD52 transgenic mouse [29]. This model also suggests that alemtuzumab does not negatively impact the function of the innate immune system (NK cells, macrophages, neutrophils) and demonstrates both that a normal T-cell-independent antibody response could be triggered 3 days after alemtuzumab and that a normal T-cell-dependent antibody response could be triggered 21 days Expert Rev. Clin. Immunol. 10(10), (2014)
Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis
after alemtuzumab. T-cells extracted from the mouse spleen 3 days after alemtuzumab treatment exhibited normal proliferation and cytokine responses to stimulation. Memory T cells were relatively spared from depletion after alemtuzumab, and memory T-cell responses remained intact after treatment [30]. Conversely to this very rapid lymphocyte depletion, the recovery of lymphocytes after alemtuzumab is very slow, even though the drug’s mean terminal phase half-life is 4–5 days in MS patients [31]. In one analysis of lymphocyte reconstitution in 36 MS patients treated with alemtuzumab, the median recovery time for B lymphocytes to the lower limit of normal was 8.4 months, for CD8 T lymphocytes it was 20 months and for CD4 lymphocytes it was 35 months [32]. For several months after treatment, the T-lymphocyte population is predominantly made up of memory T cells and Tregs [33]. B-cell depletion recovers more rapidly and actually overshoots its baseline; indeed, in another study, B-cell counts were 165% of baseline 12 months after alemtuzumab, perhaps in response to a persistent elevation in B-cell activating factor. In an analysis of B-cell recovery, the predominant B-cells after alemtuzumab were naı¨ve immature and then naı¨ve mature B cells; even at 12 months, the number of CD27+ memory B cells was only 25% of baseline [34]. The aforementioned mouse model showed similarly slow lymphocyte recovery kinetics, with B-cell recovery within 7–10 weeks and incomplete T-cell recovery at 25 weeks. It also suggests that partial depletion of thymocytes by alemtuzumab may be a potential reason for this slow T-cell recovery [29]. In the Phase II and III trials of alemtuzumab for MS, the drug was infused for 5 consecutive days in course one; a second course of 3 consecutive days was given 12 months later, and additional courses of 3 consecutive days could be given not more often than annually as deemed appropriate for breakthrough disease (although this was uncommon) [35,36]. An immediate post-infusion reaction of pyrexia, urticarial rash, headache and temporary reoccurrence of previous neurologic deficits is recognized with alemtuzumab. This reaction seems to be induced by increased expression of TNF-a, IL-6 and IFN-g, perhaps by the cross-linking of NK cells, and it may be limited by pretreatment with corticosteroids and antihistamines [37,38]. All patients receiving alemtuzumab in these trials also received iv. methylprednisolone 1 g daily for the first 3 days of each alemtuzumab course, and other medications for infusion reactions could be given as the investigator deemed appropriate. Clinical efficacy Early investigations
The first observation of alemtuzumab for MS was initiated in 1991 and explored its effect on secondary progressive-MS. The drug was administered to 36 patients; initially, there was some dose variability (60–120 mg total dose given over 5–10 days), but a dosing regimen of 20 mg iv. daily 5 days was used in subsequent patients. Intravenous methylprednisolone was given to most in an attempt to mitigate the aforementioned informahealthcare.com
Drug Profile
recrudescence of previous neurologic symptoms and postinfusion cytokine release. Despite a strong reduction of MRI activity and relapses, these patients continued to accrue disability, suggesting an ‘uncoupling’ of the inflammatory and degenerative components of MS pathophysiology [39]. Alemtuzumab was subsequently given to 22 patients with RR-MS. This relapsing cohort had a relapse rate of 2.94 relapses per patient in the year before treatment and a posttreatment relapse rate of 0.19, representing a 91% reduction (p < 0.0001). After 12 months, the mean EDSS improvement from baseline in this cohort was 1.4 points [40]. Phase II studies
CAMMS223 [41] was a Phase II, randomized, rater-blinded trial comparing alemtuzumab with IFN-b-1a 44 mg (Rebif) sc. three-times weekly (subsequently abbreviated as IFN-b SC) in patients with early RR-MS. Inclusion criteria included a diagnosis of RR-MS per the 2001 McDonald criteria; symptom onset within 36 months of enrollment; being treatmentnaı¨ve; having an EDSS £ 3; experiencing ‡2 relapses in the preceding 2 years and having ‡1 enhancing lesion on a screening MRI. Patients with a prior history of autoimmunity or antithyrotropin-receptor antibodies were excluded. Patients were randomized to alemtuzumab 12 mg/day, alemutuzumab 24 mg/day or IFN-b SC in a 1:1:1 fashion [42]. CAMMS223 enrolled 334 patients, of whom 216 received alemtuzumab. One of the co-primary end points, ARR, was reduced by 74% (p < 0.001) in the alemtuzumab group (ARR of 0.10) compared with the IFN-b SC group (ARR of 0.36); indeed, the ARR of the alemtuzumab group equates to one relapse every 10 years. The other co-primary end point (6-month sustained accumulation of disability [SAD] as measured by EDSS performed by a blinded rater) was reduced by 71% (p < 0.001) in the alemtuzumab group (9.0%) versus IFN-b SC (26.2%). It is notable that the alemtuzumab group had a mean improvement in disability of 0.39 points on the EDSS, while the IFN-b SC group had a mean worsening of 0.38 points. There were also significant reductions in T2 lesion volume (p = 0.005) and atrophy (p = 0.05) favoring alemtuzumab. Furthermore, brain volume decreased by 0.2% in the IFN-b SQ group, but increased by 0.9% in the alemtuzumab group between months 12 and 36 [42]. Sixty-eight percent (n = 198) of the patients enrolled in CAMMS223 continued in an extension phase of the study. After 5 years, the rate of SAD was reduced by 72% (p < 0.0001) and the ARR was reduced by 69% (p < 0.0001) compared with IFN-b SC. Between 36 and 60 months, only 9 of the 151 alemtuzumab patients who entered the extension phase qualified for additional courses of alemtuzumab by experiencing breakthrough clinical disease, suggesting a durable effect of this medication [43]. A post hoc analysis of CAMMS223 explored two additional measures: freedom from clinical disease activity, defined as the absence of relapses and 6-month sustained disability progression during this 36-month trial, and sustained reduction in 1283
Drug Profile
Jones & Goldman
Table 1. Phase II and III alemtuzumab data
[42,50,51].
CAMMS223
CARE-MS I
CARE MS-2
Number of patients on ALM
216
376
426
Relapse rate reduction of ALM compared with IFN-b SC
74% (p < 0.001)
55% (p < 0.0001)
49% (p < 0.0001)
Risk reduction of 6-month SAD with ALM compared with IFN-b SC
71% (p < 0.001)
NS
42% (p = 0.008)
Mean EDSS change with ALM (IFN-b SC)
-0.39 (+0.38)
-0.14 (-0.14)
-0.17 (+0.24)
Proportion of patients with new/enlarging T2 hyperintensities with ALM (IFN-b SC)
–
48% (56%; p = 0.04)
46% (68%; p < 0.0001)
Free of clinical and radiographic disease with ALM (IFN-b SC)
72% (43%)†
39% (27%)
32% (14%)
Percent infection with ALM (IFN-b SC)
66% (47%)
67% (45%)
77% (66%)
Percent serious infection with ALM (IFN-b SC)
4% (2%)
2% (1%)
4% (1%)
Percent thyroid autoimmunity with ALM (IFN-b SC)
23% (3%)
18% (6%)
16% (5%)
Number ITP with ALM (IFN-b SC)
6 (1)
3 (0)
7 (0)
‡
Number renal autoimmunity with ALM (IFN-b SC)
0
1
1
Number malignancy with ALM (IFN-b SC)
3 (1)
2 (0)
3 (1)
†
Post hoc analysis. ‡ One case of anti-GBM disease 39 months after second course of alemtuzumab. ALM: Alemtuzumab; IFN-b SC: IFN-b-1a subcutaneous three-times weekly (Rebif); ITP: Idiopathic thrombocytopenic purpura.
disability (SRD), defined as a 1 point improvement from baseline EDSS sustained for 6 months in patients with a baseline EDSS ‡2. Almost 72% of the alemtuzumab patients achieved freedom from clinical disease activity at 36 months compared with approximately 43% of those receiving IFN-b SC (p < 0.0001). Likewise, Kaplan–Meier estimates suggested 52% of alemtuzumab patients (and 27% of IFN-b SC patients) achieved SRD (p < 0.004). Subset analysis suggested that all measured patient subgroups had a beneficial effect with alemtuzumab compared with placebo [44]. Substudies of CAMMS223 also supported functional improvement with alemtuzumab: 273 of the 334 patients in CAMMS323 participated in a study of visual contrast sensitivity measured by Pelli-Robson charts, and the alemtuzumab group showed higher rates of sustained visual improvements at 3 and 6 months [35]. Twenty patients in CAMMS223 underwent magnetic transfer resonance (MTR) imaging as did 18 untreated RR-MS patients from a historical cohort; the MTR values in normal appearing gray and white matter were relatively unchanged in the alemtuzumab group, but the untreated patients had MTR reductions, suggesting ongoing loss of myelin and axonal integrity [36]. A post hoc analysis explored other potential mechanisms of alemtuzumab in a group of CAMMS223 patients who did not have evidence of significant disease activity, but had disability improvement during the trial. The authors hypothesized that this improvement did not relate entirely to alemtuzumab’s anti-inflammatory effect and demonstrated that peripheral blood mononuclear cells from alemtuzumab-treated patients secreted more brain-derived neurotrophic factor, ciliary neurotrophic factor, PDGF and FGF 12 months after treatment with alemtuzumab than healthy controls or patients treated with IFN-b SC. They also showed 1284
that these neurotrophic factors appeared to be secreted by T cells and may promote neuronal and oligodendrocyte progenitor cell survival [45]. Other studies
A small, 2-year open-label trial of alemtuzumab 24 mg daily enrolled 45 patients with RR-MS who had experienced breakthrough disease on an interferon. The ARR was reduced by 94% (p < 0.0001) in this 2-year study compared with the 2 years before the patients received alemtuzumab. There was a trend suggesting disability improvement as measured by the year 2 EDSS compared with baseline (-0.38; p = 0.0542); although the difference in mean MSFC composite scores were not statistically significant, the MSFC composite was stable or improved in 70% of patients [46]. A similar study of 39 patients with aggressive RR-MS (mean ARR of 2.48 and EDSS of 4.45 despite mean disease duration of only 2.92 years) showed a 92.3% reduction in ARR compared with pretreatment (p < 0.0001) and a mean improvement in EDSS of 0.36 points [47]. Phase III studies
Two large randomized, rater-blinded, comparator trials (vs IFN-b SC) investigated the utility of alemtuzumab in RR-MS; one was a treatment-naı¨ve trial [48], and the other included patients who had experienced a breakthrough relapse on a previous DMT [49]. In CARE-MS I, 581 treatment-naı¨ve patients with RR-MS were randomized to receive either alemtuzumab 12 mg/day or IFN-b SC in a 2:1 ratio. Inclusion criteria included a diagnosis of RR-MS by MacDonald 2005 criteria, symptom onset within 5 years of screening, ‡2 relapses in the Expert Rev. Clin. Immunol. 10(10), (2014)
Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis
past 2 years and ‡1 relapse in the past year, EDSS £3 and an MRI consistent with demyelinating disease. Exclusion criteria included progressive disease, prior use of a DMT or immunosuppressive medication and significant autoimmune comorbidity. In this 2-year trial, the co-primary end points were relapse rate reduction and 6-month SAD. The alemtuzumab group experienced a 54.9% reduction in ARR (0.18 vs 0.39; p < 0.0001) compared with the IFN-b SC. SAD did not significantly differ between the groups; however, only 11% of the patients in the IFN-b SC had disability progression (compared with 8% with alemtuzumab), which was much less than predicted when the study was designed. Both groups experienced a mean EDSS improvement of 0.14 points, but it is unclear if this is a true signal or statistical noise. There was a trend for improvement in MSFC, but due to pre-specified statistical plan, a p-value could not be formally computed. Although the change in T2 lesion volume (secondary end point) did not differ between the groups, the alemtuzumab group demonstrated a reduction in the proportions of patients with new and enlarging T2 lesions (p = 0.04) and gadolinium-enhancing lesions (p < 0.0001); brain atrophy was also reduced in the alemtuzumab arm (p < 0.0001). The MRI response to alemtuzumab was more robust in the second year. Antibodies to alemtuzumab did not seem to affect the efficacy of the drug [50]. Similarly, CARE-MS II was a randomized, rater-blinded, active-comparator trial of alemtuzumab and IFN-b SC in patients who experienced a relapse on a previous DMT for RR-MS. Patients were randomized in 1:2:2 ratio to receive IFN-b SC, alemtuzumab 12 mg/day or alemtuzumab 24 mg/ day; however, this last group was later eliminated to accelerate enrollment. Inclusion criteria were a diagnosis of RR-MS via 2005 McDonald criteria, disease duration
ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: http://www.tandfonline.com/loi/ierm20
Alemtuzumab for the treatment of relapsingremitting multiple sclerosis: a review of its clinical pharmacology, efficacy and safety David E Jones & Myla D Goldman To cite this article: David E Jones & Myla D Goldman (2014) Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis: a review of its clinical pharmacology, efficacy and safety, Expert Review of Clinical Immunology, 10:10, 1281-1291, DOI: 10.1586/1744666X.2014.951332 To link to this article: http://dx.doi.org/10.1586/1744666X.2014.951332
Published online: 22 Aug 2014.
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Article views: 202
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ierm20 Download by: [University of California, San Diego]
Date: 14 December 2016, At: 05:26
Drug Profile
Alemtuzumab for the treatment of relapsingremitting multiple sclerosis: a review of its clinical pharmacology, efficacy and safety Expert Rev. Clin. Immunol. 10(10), 1281–1291 (2014)
David E Jones and Myla D Goldman* Department of Neurology, James Q. Miller MS Clinic, University of Virginia Health System, 500 Ray C. Hunt Drive, Charlottesville, VA 22908, USA *Author for correspondence: [email protected]
Multiple sclerosis (MS) is an inflammatory condition of the CNS presumably induced by an environmental trigger(s) in a genetically susceptible individual. Inflammation is prominent and most susceptible to intervention early in MS, so early treatment with disease-modifying therapies is recommended to reduce relapses and new MRI activity (both markers of inflammation) with the goal of delaying disability progression. Unfortunately, the response to the disease-modifying therapies is variable and often falls short of stopping observable disease activity, so the search for more effective agents continues. Alemtuzumab is a monoclonal antibody against CD52 that has exhibited significant efficacy throughout its clinical trial program in MS; uniquely, some of the studies have demonstrated a sustained reduction in disability in MS patients. Countering this impressive efficacy is an associated high risk of autoimmune events (especially thyroid) and concerns for infection or malignancy given prolonged immunosuppression after treatment with alemtuzumab. KEYWORDS: alemtuzumab • monoclonal antibody • multiple sclerosis
Multiple sclerosis (MS) is a chronic inflammatory condition of the CNS that is presumed to occur when a genetically susceptible individual is exposed to an as-yet unconfirmed environmental trigger. It is a very common cause of non-traumatic disability in young adults, affecting over 400,000 individuals in the USA [1]. Most cases start as relapsing-remitting (RR) disease, in which there are inflammatory episodes of neurologic dysfunction, often accompanied by gadolinium enhancement on MRI followed by some functional recovery and resolution of this enhancement; however, MRI activity can also occur in the absence of new neurologic symptoms [2]. Although degeneration is demonstrable early in RR-MS, it is likely the driving process later in the disease, as the patient clinically transitions into secondary progressive MS; however, our understanding of
informahealthcare.com
10.1586/1744666X.2014.951332
the pathophysiology of progressive MS is less robust. If this degeneration is not directly driven by the inflammatory component of MS, it may relate to other processes, including Wallerian degeneration due to previous damage to myelin or axons, compartmentalized inflammation possibly attributable to the innate immune system behind an intact blood–brain barrier, the presence of reactive oxygen species and/or a mitochondrial bioenergetics deficit as the brain attempts to compensate for additional damage after depletion of its functional reserve [3,4]. MS disease activity is often measured by relapse assessment, which are defined as episodes of new or worsening neurologic dysfunction occurring in the absence of fever or infection and lasting over 24 h, or quantitating MRI change, including new or enlarging
2014 Informa UK Ltd
ISSN 1744-666X
1281
Drug Profile
Jones & Goldman
T2 hyperintensities, new T1 hypointensities (‘black holes’), gadolinium enhancement and brain atrophy. Standard measures of disease progression include Kurtzke’s Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC). The EDSS is a ordinal scale between 0 and 10 that measures disability in seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bladder/ bowel, cerebral); it is often criticized for being non-linear, having intra- and inter-rater variability, placing excessive weight on ambulation and de-emphasizing both upper extremity function and the silent symptoms of MS (fatigue, depression, cognitive dysfunction) [5]. The MSFC includes measurements of three tasks: the timed 25-foot walk, the timed 9-hole PEG test and the cognitive Paced Auditory Sequential Addition Test; some have suggested modifying the MSFC by replacing the Paced Auditory Sequential Addition Test with the Symbol Digit Modalities Test and adding a test of visual contrast sensitivity with Sloan low contrast letter charts [6–8].
The DMTs have inconsistent data for reduction in disability progression in the short term; indeed, one analysis of historical, contemporary treated and contemporary untreated cohorts of MS patients suggests that IFN-b may not confer a long-term disability benefit [17]. Of the three Phase III studies of fingolimod, only FREEDOMS met its disability end point; likewise, only one of the two Phase III dimethyl fumarate trials met this end point [14,18,19]. Conversely, both Phase III studies of teriflumomide (TEMSO and TOWER) met their disability end point, and the laquinimod studies suggest that it is possible for an MS drug to have a more robust effect on disability than relapses, although this drug is years away from potential approval [20–23]. A post hoc analysis of the natalizumab AFFIRM data suggests that reversal of disability as measured by improvement in the EDSS or health-related quality of life may be an obtainable goal in at least the short term in some patients with RR-MS [24]. Halting the progression of disability or even reversal of pre-existing disability is arguably one of the biggest unmet needs in MS therapeutics.
Overview of the market
There are currently 11 US FDA-approved disease-modifying therapies (DMTs) for relapsing forms of MS, including six injectable medications (subcutaneous [sc.] and intramuscular IFN-b-1a, 2 sc. IFN-b-1bs and 2 doses of sc. glatiramer acetate), two intravenous [iv.] medications (mitoxantrone, natalizumab) and three oral medications (fingolimod, teriflunomide and dimethyl fumarate). All of these have good data for reduction in annualized relapse rate (ARR) and MRI activity; however, their data for reduction in disability progression is less robust. As may be imagined, defining a suboptimal response to a partially effective medication is challenging, although some argue that we should strive to stop all disease activity. A post hoc analysis of the natalizumab AFFIRM data suggests that ‘freedom of disease activity’ (FDA) is an achievable end point in some patients; however, it has been suggested that ‘no evidence of disease activity’ (NEDA) is a more appropriate term for this end point as not all disease activity in MS is easily measured [9,10]. Unfortunately, the goal of either FDA or NEDA remains elusive in many patients. Compounding this difficulty is a paucity of head-to-head trials comparing the DMTs: the EVIDENCE trial suggests initial superiority of sc. IFN-b-1a, while the BEYOND and REGARD trials suggests similar efficacy between glatiramer acetate and high-dose IFN-b [11–13]. Although technically glatiramer acetate was a reference comparator in the CONFIRM study, dimethyl fumarate did not achieve statistically significant superiority for the primary end point (ARR) and some secondary end points of the trial; similarly, TENERE did not show superiority of teriflunomide over sc. IFN-b-1a [14,15]. The TRANSFORMS trial suggests superiority of fingolimod over intramuscular IFN-b-1a, albeit with the caveat that almost 50% of patients randomized to IFN-b were previously treated with an interferon [16]. These comparator trials set a precedent for rater-blinded studies in MS, and several ongoing clinical trials in MS are utilizing this methodology. 1282
Introduction to the drug
Alemtuzumab (LemtradaTM ) is a humanized monoclonal antibody directed against CD52, a 12-amino acid glycophosphatidylinositollinked surface protein that is primarily expressed on B- and T-lymphocytes with limited expression on monocytes, dendritic cells and NK cells; however, it is not significantly expressed by hematopoietic progenitor cells or neutrophils. The function of CD52 is not well characterized, although some data suggest that it may be involved with T-cell activation or induction of CD4+ Tregs. Although alemtuzumab’s original indication was for treatment of B-cell chronic lymphocytic leukemia, its use has been explored in other autoimmune diseases, including rheumatoid arthritis [25–28]. Treatment with alemtuzumab causes a rapid depletion of immune cells expressing CD52 in the blood by complementdependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity; however, this effect seems limited in lymphoid tissue. Mouse models exploring the mechanism of action and safety of alemtuzumab were of limited value, as alemtuzumab does not interact with mouse CD52; however, this was overcome by developing a human CD52 (hCD52) transgenic mouse that appeared physically and immunologically normal. The distribution of hCD52 in this transgenic mouse was similar to that of CD52 in humans, and treatment with alemtuzumab effected a similar depletion of circulating B- and T-lymphocytes. There was limited depletion of lymphocytes in the lymphoid tissue and a relative sparing of Tregs; as in humans, treatment with alemtuzumab did not seem to affect hematopoietic progenitor cells in the hCD52 transgenic mouse [29]. This model also suggests that alemtuzumab does not negatively impact the function of the innate immune system (NK cells, macrophages, neutrophils) and demonstrates both that a normal T-cell-independent antibody response could be triggered 3 days after alemtuzumab and that a normal T-cell-dependent antibody response could be triggered 21 days Expert Rev. Clin. Immunol. 10(10), (2014)
Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis
after alemtuzumab. T-cells extracted from the mouse spleen 3 days after alemtuzumab treatment exhibited normal proliferation and cytokine responses to stimulation. Memory T cells were relatively spared from depletion after alemtuzumab, and memory T-cell responses remained intact after treatment [30]. Conversely to this very rapid lymphocyte depletion, the recovery of lymphocytes after alemtuzumab is very slow, even though the drug’s mean terminal phase half-life is 4–5 days in MS patients [31]. In one analysis of lymphocyte reconstitution in 36 MS patients treated with alemtuzumab, the median recovery time for B lymphocytes to the lower limit of normal was 8.4 months, for CD8 T lymphocytes it was 20 months and for CD4 lymphocytes it was 35 months [32]. For several months after treatment, the T-lymphocyte population is predominantly made up of memory T cells and Tregs [33]. B-cell depletion recovers more rapidly and actually overshoots its baseline; indeed, in another study, B-cell counts were 165% of baseline 12 months after alemtuzumab, perhaps in response to a persistent elevation in B-cell activating factor. In an analysis of B-cell recovery, the predominant B-cells after alemtuzumab were naı¨ve immature and then naı¨ve mature B cells; even at 12 months, the number of CD27+ memory B cells was only 25% of baseline [34]. The aforementioned mouse model showed similarly slow lymphocyte recovery kinetics, with B-cell recovery within 7–10 weeks and incomplete T-cell recovery at 25 weeks. It also suggests that partial depletion of thymocytes by alemtuzumab may be a potential reason for this slow T-cell recovery [29]. In the Phase II and III trials of alemtuzumab for MS, the drug was infused for 5 consecutive days in course one; a second course of 3 consecutive days was given 12 months later, and additional courses of 3 consecutive days could be given not more often than annually as deemed appropriate for breakthrough disease (although this was uncommon) [35,36]. An immediate post-infusion reaction of pyrexia, urticarial rash, headache and temporary reoccurrence of previous neurologic deficits is recognized with alemtuzumab. This reaction seems to be induced by increased expression of TNF-a, IL-6 and IFN-g, perhaps by the cross-linking of NK cells, and it may be limited by pretreatment with corticosteroids and antihistamines [37,38]. All patients receiving alemtuzumab in these trials also received iv. methylprednisolone 1 g daily for the first 3 days of each alemtuzumab course, and other medications for infusion reactions could be given as the investigator deemed appropriate. Clinical efficacy Early investigations
The first observation of alemtuzumab for MS was initiated in 1991 and explored its effect on secondary progressive-MS. The drug was administered to 36 patients; initially, there was some dose variability (60–120 mg total dose given over 5–10 days), but a dosing regimen of 20 mg iv. daily 5 days was used in subsequent patients. Intravenous methylprednisolone was given to most in an attempt to mitigate the aforementioned informahealthcare.com
Drug Profile
recrudescence of previous neurologic symptoms and postinfusion cytokine release. Despite a strong reduction of MRI activity and relapses, these patients continued to accrue disability, suggesting an ‘uncoupling’ of the inflammatory and degenerative components of MS pathophysiology [39]. Alemtuzumab was subsequently given to 22 patients with RR-MS. This relapsing cohort had a relapse rate of 2.94 relapses per patient in the year before treatment and a posttreatment relapse rate of 0.19, representing a 91% reduction (p < 0.0001). After 12 months, the mean EDSS improvement from baseline in this cohort was 1.4 points [40]. Phase II studies
CAMMS223 [41] was a Phase II, randomized, rater-blinded trial comparing alemtuzumab with IFN-b-1a 44 mg (Rebif) sc. three-times weekly (subsequently abbreviated as IFN-b SC) in patients with early RR-MS. Inclusion criteria included a diagnosis of RR-MS per the 2001 McDonald criteria; symptom onset within 36 months of enrollment; being treatmentnaı¨ve; having an EDSS £ 3; experiencing ‡2 relapses in the preceding 2 years and having ‡1 enhancing lesion on a screening MRI. Patients with a prior history of autoimmunity or antithyrotropin-receptor antibodies were excluded. Patients were randomized to alemtuzumab 12 mg/day, alemutuzumab 24 mg/day or IFN-b SC in a 1:1:1 fashion [42]. CAMMS223 enrolled 334 patients, of whom 216 received alemtuzumab. One of the co-primary end points, ARR, was reduced by 74% (p < 0.001) in the alemtuzumab group (ARR of 0.10) compared with the IFN-b SC group (ARR of 0.36); indeed, the ARR of the alemtuzumab group equates to one relapse every 10 years. The other co-primary end point (6-month sustained accumulation of disability [SAD] as measured by EDSS performed by a blinded rater) was reduced by 71% (p < 0.001) in the alemtuzumab group (9.0%) versus IFN-b SC (26.2%). It is notable that the alemtuzumab group had a mean improvement in disability of 0.39 points on the EDSS, while the IFN-b SC group had a mean worsening of 0.38 points. There were also significant reductions in T2 lesion volume (p = 0.005) and atrophy (p = 0.05) favoring alemtuzumab. Furthermore, brain volume decreased by 0.2% in the IFN-b SQ group, but increased by 0.9% in the alemtuzumab group between months 12 and 36 [42]. Sixty-eight percent (n = 198) of the patients enrolled in CAMMS223 continued in an extension phase of the study. After 5 years, the rate of SAD was reduced by 72% (p < 0.0001) and the ARR was reduced by 69% (p < 0.0001) compared with IFN-b SC. Between 36 and 60 months, only 9 of the 151 alemtuzumab patients who entered the extension phase qualified for additional courses of alemtuzumab by experiencing breakthrough clinical disease, suggesting a durable effect of this medication [43]. A post hoc analysis of CAMMS223 explored two additional measures: freedom from clinical disease activity, defined as the absence of relapses and 6-month sustained disability progression during this 36-month trial, and sustained reduction in 1283
Drug Profile
Jones & Goldman
Table 1. Phase II and III alemtuzumab data
[42,50,51].
CAMMS223
CARE-MS I
CARE MS-2
Number of patients on ALM
216
376
426
Relapse rate reduction of ALM compared with IFN-b SC
74% (p < 0.001)
55% (p < 0.0001)
49% (p < 0.0001)
Risk reduction of 6-month SAD with ALM compared with IFN-b SC
71% (p < 0.001)
NS
42% (p = 0.008)
Mean EDSS change with ALM (IFN-b SC)
-0.39 (+0.38)
-0.14 (-0.14)
-0.17 (+0.24)
Proportion of patients with new/enlarging T2 hyperintensities with ALM (IFN-b SC)
–
48% (56%; p = 0.04)
46% (68%; p < 0.0001)
Free of clinical and radiographic disease with ALM (IFN-b SC)
72% (43%)†
39% (27%)
32% (14%)
Percent infection with ALM (IFN-b SC)
66% (47%)
67% (45%)
77% (66%)
Percent serious infection with ALM (IFN-b SC)
4% (2%)
2% (1%)
4% (1%)
Percent thyroid autoimmunity with ALM (IFN-b SC)
23% (3%)
18% (6%)
16% (5%)
Number ITP with ALM (IFN-b SC)
6 (1)
3 (0)
7 (0)
‡
Number renal autoimmunity with ALM (IFN-b SC)
0
1
1
Number malignancy with ALM (IFN-b SC)
3 (1)
2 (0)
3 (1)
†
Post hoc analysis. ‡ One case of anti-GBM disease 39 months after second course of alemtuzumab. ALM: Alemtuzumab; IFN-b SC: IFN-b-1a subcutaneous three-times weekly (Rebif); ITP: Idiopathic thrombocytopenic purpura.
disability (SRD), defined as a 1 point improvement from baseline EDSS sustained for 6 months in patients with a baseline EDSS ‡2. Almost 72% of the alemtuzumab patients achieved freedom from clinical disease activity at 36 months compared with approximately 43% of those receiving IFN-b SC (p < 0.0001). Likewise, Kaplan–Meier estimates suggested 52% of alemtuzumab patients (and 27% of IFN-b SC patients) achieved SRD (p < 0.004). Subset analysis suggested that all measured patient subgroups had a beneficial effect with alemtuzumab compared with placebo [44]. Substudies of CAMMS223 also supported functional improvement with alemtuzumab: 273 of the 334 patients in CAMMS323 participated in a study of visual contrast sensitivity measured by Pelli-Robson charts, and the alemtuzumab group showed higher rates of sustained visual improvements at 3 and 6 months [35]. Twenty patients in CAMMS223 underwent magnetic transfer resonance (MTR) imaging as did 18 untreated RR-MS patients from a historical cohort; the MTR values in normal appearing gray and white matter were relatively unchanged in the alemtuzumab group, but the untreated patients had MTR reductions, suggesting ongoing loss of myelin and axonal integrity [36]. A post hoc analysis explored other potential mechanisms of alemtuzumab in a group of CAMMS223 patients who did not have evidence of significant disease activity, but had disability improvement during the trial. The authors hypothesized that this improvement did not relate entirely to alemtuzumab’s anti-inflammatory effect and demonstrated that peripheral blood mononuclear cells from alemtuzumab-treated patients secreted more brain-derived neurotrophic factor, ciliary neurotrophic factor, PDGF and FGF 12 months after treatment with alemtuzumab than healthy controls or patients treated with IFN-b SC. They also showed 1284
that these neurotrophic factors appeared to be secreted by T cells and may promote neuronal and oligodendrocyte progenitor cell survival [45]. Other studies
A small, 2-year open-label trial of alemtuzumab 24 mg daily enrolled 45 patients with RR-MS who had experienced breakthrough disease on an interferon. The ARR was reduced by 94% (p < 0.0001) in this 2-year study compared with the 2 years before the patients received alemtuzumab. There was a trend suggesting disability improvement as measured by the year 2 EDSS compared with baseline (-0.38; p = 0.0542); although the difference in mean MSFC composite scores were not statistically significant, the MSFC composite was stable or improved in 70% of patients [46]. A similar study of 39 patients with aggressive RR-MS (mean ARR of 2.48 and EDSS of 4.45 despite mean disease duration of only 2.92 years) showed a 92.3% reduction in ARR compared with pretreatment (p < 0.0001) and a mean improvement in EDSS of 0.36 points [47]. Phase III studies
Two large randomized, rater-blinded, comparator trials (vs IFN-b SC) investigated the utility of alemtuzumab in RR-MS; one was a treatment-naı¨ve trial [48], and the other included patients who had experienced a breakthrough relapse on a previous DMT [49]. In CARE-MS I, 581 treatment-naı¨ve patients with RR-MS were randomized to receive either alemtuzumab 12 mg/day or IFN-b SC in a 2:1 ratio. Inclusion criteria included a diagnosis of RR-MS by MacDonald 2005 criteria, symptom onset within 5 years of screening, ‡2 relapses in the Expert Rev. Clin. Immunol. 10(10), (2014)
Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis
past 2 years and ‡1 relapse in the past year, EDSS £3 and an MRI consistent with demyelinating disease. Exclusion criteria included progressive disease, prior use of a DMT or immunosuppressive medication and significant autoimmune comorbidity. In this 2-year trial, the co-primary end points were relapse rate reduction and 6-month SAD. The alemtuzumab group experienced a 54.9% reduction in ARR (0.18 vs 0.39; p < 0.0001) compared with the IFN-b SC. SAD did not significantly differ between the groups; however, only 11% of the patients in the IFN-b SC had disability progression (compared with 8% with alemtuzumab), which was much less than predicted when the study was designed. Both groups experienced a mean EDSS improvement of 0.14 points, but it is unclear if this is a true signal or statistical noise. There was a trend for improvement in MSFC, but due to pre-specified statistical plan, a p-value could not be formally computed. Although the change in T2 lesion volume (secondary end point) did not differ between the groups, the alemtuzumab group demonstrated a reduction in the proportions of patients with new and enlarging T2 lesions (p = 0.04) and gadolinium-enhancing lesions (p < 0.0001); brain atrophy was also reduced in the alemtuzumab arm (p < 0.0001). The MRI response to alemtuzumab was more robust in the second year. Antibodies to alemtuzumab did not seem to affect the efficacy of the drug [50]. Similarly, CARE-MS II was a randomized, rater-blinded, active-comparator trial of alemtuzumab and IFN-b SC in patients who experienced a relapse on a previous DMT for RR-MS. Patients were randomized in 1:2:2 ratio to receive IFN-b SC, alemtuzumab 12 mg/day or alemtuzumab 24 mg/ day; however, this last group was later eliminated to accelerate enrollment. Inclusion criteria were a diagnosis of RR-MS via 2005 McDonald criteria, disease duration
