Alasdair Coles

Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.

BACKGROUND The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment. METHODS In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405. FINDINGS 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia. INTERPRETATION For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumabs main adverse effect of secondary autoimmunity. FUNDING Genzyme (Sanofi) and Bayer Schering Pharma.

Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial

BACKGROUND The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial. METHODS In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348. FINDINGS 187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32-0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40-1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma. INTERPRETATION Alemtuzumabs consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here. FUNDING Genzyme (Sanofi) and Bayer Schering Pharma.

Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis

The elective treatment of patients with multiple sclerosis, using a humanized anti-leukocyte (CD52) monoclonal antibody (Campath-1H), has illuminated mechanisms that underlie the clinical course of the disease. Twenty-seven patients were studied clinically and by magnetic resonance imaging (MRI) before and for 18 months after a single pulse of Campath-1H. The first dose of monoclonal antibody was associated with a transient rehearsal of previous symptoms caused by the release of mediators that impede conduction at previously demyelinated sites; this effect remained despite selective blockade of tumor necrosis factor-alpha. Disease activity persisted for several weeks after treatment but thereafter radiological markers of cerebral inflammation were suppressed for at least 18 months during which there were no new symptoms or signs. However, about half the patients experienced progressive disability and increasing brain atrophy, attributable on the basis of MRI spectroscopy to axonal degeneration, which correlated with the extent of cerebral inflammation in the pretreatment phase. These data support the formulation that inflammation and demyelination are responsible for relapses of multiple sclerosis; that inflammatory mediators, but not tumor necrosis factor-alpha, cause symptomatic reactivation of previously demyelinated lesions; and that axonal degeneration, conditioned by prior inflammation but proceeding despite its suppression, contributes to the progressive phase of disability. These results provide evidence supporting the emerging view that treatment in multiple sclerosis must be given early in the course, before the consequences of inflammation are irretrievably established.

The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy.

AbstractFrom 1991–2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath–1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing–remitting (RR) and secondary progressive (SP) stages of the illness, Campath–1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of patients with SP disease, treated with Campath–1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease. Patients with SPMS showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in patients with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, patients with RR disease showed an impressive reduction in disability at 6 months after Campath–1H (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on–going inflammation in these patients with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment.We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long–term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Campath–1H and IFN–beta in the treatment of drug–naïve patients with early, active RR MS.

Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis

Following lymphocyte depletion, homeostatic mechanisms drive the reconstitution of lymphocytes. We prospectively studied this process in 16 patients for 1 year after a single pulse of treatment with Campath‐1H, a humanised anti‐CD52 monoclonal antibody. We observed two phases of lymphocyte reconstitution. In the first 6 months after treatment the precursor frequency and proliferation index of the patients’ autologous mixed lymphocyte reaction increased; the depleted T cell pool was dominated by memory T cells, especially CD4+CD25high T cells, a putative regulatory phenotype; and there was a non‐significant rise in peripheral mononuclear cell FoxP3 mRNA expression and fall in constitutive cytokine mRNA expression. In the later phase, from 6‐to‐12 months after Campath‐1H, these changes reversed and there was a rise in ROG mRNA expression. However, total CD4+ numbers remained below 50% of pre‐treatment levels at 12 months, perhaps reflecting a failure in homeostasis. This was not due to an impaired IL‐7 response, as in rheumatoid arthritis, nor to a lack of IL‐7 receptors, which are found on fewer human CD4+CD25high than naive cells. We speculate that CCL21 and IL‐15 responses to lymphopaenia may be suboptimal in multiple sclerosis.

IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H)

Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity.

Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 Clinical Trial

Objective: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon β-1a (IFNβ-1a) through extended follow-up (up to 60 months from baseline). Methods: Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNβ-1a). Disability, relapses, and safety were assessed as in the original study period. Efficacy outcomes were analyzed from baseline of the original trial period to 60 months. Safety data extended beyond 60 months. Results: Over 5 years, alemtuzumab lowered the risk of sustained accumulation of disability by 72% and the rate of relapse by 69% compared with IFNβ-1a (both p < 0.0001). The annualized relapse rate from baseline to month 60 was 0.11 for alemtuzumab and 0.35 for IFNβ-1a. Complete safety follow-up reflected 988 and 376 person-years for alemtuzumab and IFNβ-1a patients, respectively. Serious infections were seen in 7% of alemtuzumab patients and 3% of IFNβ-1a patients, and thyroid disorders were seen in 30% of alemtuzumab patients vs 4% of IFNβ-1a patients. Immune thrombocytopenia occurred in 3% of alemtuzumab patients and 0.9% of IFNβ-1a patients during the initial study period; no additional events were reported during the extension phase. One alemtuzumab patient developed Goodpasture disease 39 months after the second annual cycle of alemtuzumab. Conclusions: Through extended follow-up, alemtuzumab remained significantly more efficacious than IFNβ-1a, with a safety profile consistent with previous reports. Classification of Evidence: This study provides Class III evidence that alemtuzumab is more effective than interferon β-1a in reducing relapses and disability in patients with RRMS in a long-term follow-up of a rater-blinded, randomized clinical trial with 59.5% of patients participating in the extended follow-up period.

Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort

Objective: To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). Methods: We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7–107.3). Results: Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12–18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02–17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50–6.19) were predictive of AID expression. Conclusions: Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment. Classification of evidence: This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.

Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity

Treatment of early relapsing-remitting multiple sclerosis with the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath [registered trade mark]) significantly reduced the risk of relapse and accumulation of disability compared with interferon β-1a in a phase 2 trial [Coles et al., (Alemtuzumab vs. interferon β-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786-801)]. Patients treated with alemtuzumab experienced an improvement in disability at 6 months that was sustained for at least 3 years. In contrast, those treated with interferon β-1a steadily accumulated disability. Here, by post hoc subgroup analyses of the CAMMS223 trial, we show that among participants with no clinical disease activity immediately before treatment, or any clinical or radiological disease activity on-trial, disability improved after alemtuzumab but not following interferon β-1a. This suggests that disability improvement after alemtuzumab is not solely attributable to its anti-inflammatory effect. So we hypothesized that lymphocytes, reconstituting after alemtuzumab, permit or promote brain repair. Here we show that after alemtuzumab, and only when specifically stimulated with myelin basic protein, peripheral blood mononuclear cell cultures produced increased concentrations of brain-derived neurotrophic factor, platelet-derived growth factor and ciliary neurotrophic factor. Analysis by reverse transcriptase polymerase chain reaction of cell separations showed that the increased production of ciliary neurotrophic factor and brain-derived neurotrophic factor after alemtuzumab is attributable to increased production by T cells. Media from these post-alemtuzumab peripheral blood mononuclear cell cultures promoted survival of rat neurones and increased axonal length in vitro, effects that were partially reversed by neutralizing antibodies against brain-derived nerve growth factor and ciliary neurotrophic factor. This conditioned media also enhanced oligodendrocyte precursor cell survival, maturation and myelination. Taken together, the clinical analyses and laboratory findings support the interpretation that improvement in disability after alemtuzumab may result, in part, from neuroprotection associated with increased lymphocytic delivery of neurotrophins to the central nervous system.

Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes

BACKGROUND Alemtuzumab is a humanised monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation. In a 3-year, rater-blinded phase 2 study (the CAMMS223 study) in patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab reduced relapse rate and the risk of sustained accumulation of disability compared with subcutaneous interferon beta-1a, and the mean expanded disability status scale (EDSS) score of the alemtuzumab cohort improved compared with baseline. Adverse events included infusion-associated reactions, predominantly mild to moderate infections, thyroid disorders, and immune thrombocytopenia. In this study, we further analysed the CAMMS223 data with the aim of determining whether demographic and baseline disease-related characteristics affect the beneficial effects of alemtuzumab. Additionally, we aimed to describe a new outcome measure in multiple sclerosis research: sustained reduction in disability. METHODS 334 treatment-naive patients with active, early RRMS were randomly assigned in a 1:1:1 ratio to receive interferon beta-1a (44 μg subcutaneously three times per week), or 24 mg per day or 12 mg per day alemtuzumab intravenously for 2 or 3 annual cycles. We analysed freedom from clinical disease activity (CDA; defined as no relapses and no sustained accumulation of disability) and occurrence of sustained reduction in disability (SRD; a ≥1 point decrease on the EDSS sustained for 6 consecutive months for patients with a baseline EDSS ≥2), and analysed efficacy outcomes for subgroups based on age, sex, geographic region, MRI-T1 brain volume, MRI-T2 lesion volume, disease duration, number of previous relapses within 2 years, and EDSS. FINDINGS 322 patients were analysed. 161 of 215 patients treated with alemtuzumab were free of CDA at 36 months (Kaplan-Meier estimate 71·8%, 95% CI 63·1-78·8%) compared with 52 of 107 patients treated with interferon beta-1a (42·6%, 32·4-52·4%; hazard ratio [HR]=0·31, 0·20-0·46; p<0·0001). For the 199 patients with a baseline EDSS score greater than or equal to 2, SRD was more likely (HR=2·61, 1·54-4·43; p=0·0004) among patients treated with alemtuzumab (66 of 133 patients, Kaplan-Meier estimate 51·6%, 95% CI 43·2-60·7%) than patients treated with interferon beta-1a (15 of 66 patients, 27·2%, 17·2-41·4%). All disability and relapse outcomes showed evidence of beneficial effects of alemtuzumab compared with interferon beta-1a across all analysed patient subsets, and no subgroup of patients consistently responded better than others to alemtuzumab. INTERPRETATION Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis. FUNDING Genzyme and Bayer Schering Pharma.