ean 2015 alemtuzumab abstracts

ALEMTUZUMAB ABSTRACTS

Alemtuzumab Improves Quality of Life in Relapsing-Remitting Multiple Sclerosis Patients With Inadequate Efficacy Response to Prior Therapy: 4-Year Follow-up of CARE-MS II

Administration of Alemtuzumab on Nonconsecutive Days Does Not Impact Lymphocyte Depletion, Infusion-Associated Reactions, or Efficacy

Alemtuzumab Has a Durable Effect on Disability Improvement in Treatment-Naive Patients With Relapsing-Remitting Multiple Sclerosis: 4-Year Follow-up of CARE-MS I

Switching From Subcutaneous Interferon Beta-1a to Alemtuzumab Improves Relapse Outcomes in CARE-MS I

Infections in Alemtuzumab Patients Previously Treated With Subcutaneous Interferon Beta-1a

Lymphocyte Pharmacodynamics and Safety of Fingolimod Use in Patients Previously Treated With Alemtuzumab

Durable Effect of Alemtuzumab onDisease Activity in Patients With Relapsing-Remitting Multiple Sclerosis

Quality-of-Life Improvements With Alemtuzumab Are Maintained in Relapsing-Remitting Multiple Sclerosis Patients Who Develop Thyroid Adverse Events in CARE-MS II

ALEMTUZUMAB IMPROVES QUALITY OF LIFE IN RELAPSING-REMITTING MULTIPLE SCLEROSIS PATIENTS WITH INADEQUATE EFFICACY RESPONSE TO PRIOR THERAPY: 4-YEAR FOLLOW-UP OF CARE-MS II Rafael Arroyo González,1 Thibault Moreau,2 Jeffrey A Cohen,3 Gavin Giovannoni,4 David H Margolin,5 Linda Kasten,6 Eva Havrdova7; on behalf of the CARE-MS II Investigators

1Hospital Clinico San Carlos, Madrid, Spain; 2Burgundy University, Dijon University Hospital, Dijon, France; 3Cleveland Clinic, Cleveland, OH, USA; 4Queen Mary University of London, Barts and The London School of Medicine, London, UK; 5Genzyme, a Sanofi company, Cambridge, MA, USA; 6PROMETRIKA, LLC, Cambridge, MA, USA; 7First Medical Faculty, Charles University in Prague, Prague, Czech Republic

F2070 1st Congress of the European Academy of Neurology (EAN) June 20–23, 2015, Berlin, Germany

INTRODUCTION:

•In the CARE-MS II study, alemtuzumab demonstrated greater improvements in clinical, radiological, and quality of life (QoL) outcomes compared with subcutaneous interferon beta-1a (SC IFNB-1a) through 2 years in patients with active RRMS and an inadequate response, defined as at least one relapse, to a prior therapy with a consistent and manageable safety profile1,2

− In an ongoing open-label extension study, durable effects on efficacy were observed at Year 4 in CARE-MS II alemtuzumab patients, even though most (68%) did not receive any treatment since Month 123,4

− The most frequent adverse events (AEs) were infusion-associated reactions; other AEs of interest included autoimmune AEs (eg, thyroid AEs, immune thrombocytopenia, and nephropathies)1

•Patient-reported QoL outcomes complement clinical assessments from physicians, providing the patients’ own perspective on the burden of disease and treatment impact5

• In CARE-MS II, significant improvements in measures of physical, mental, and emotional QoL with alemtuzumab were maintained at Year 3 and were associated with 6-month sustained reduction in preexisting disability (SRD)6,7

OBJECTIVE:

•To examine the effect of alemtuzumab on QoL outcomes and the relationship between QoL and improvement in preexisting disability over 4 years in alemtuzumab-treated patients who had an inadequate response to a prior therapy

Title


METHODS:

•Patients with ≥1 relapse after ≥6 months of prior MS therapy received 2 annual treatment courses of alemtuzumab 12 mg (baseline and Month 12).

•In an extension study, patients could receive as-needed alemtuzumab retreatments ≥1 year apart. QoL endpoints included Functional Assessment of Multiple Sclerosis (FAMS), EuroQol 5-dimensions (EQ-5D) visual analogue scale (VAS), Short-Form 36-Item survey (SF-36; mental component summary [MCS] and physical component summary [PCS]), and QoL change by SRD (≥1-point EDSS decrease from baseline over ≥6 months [with baseline score ≥2.0]).

RESULTS:

Patients

•Of the 423 patients who completed the CARE-MS II core study, 393 (93%) entered the extension study

− Through Year 4, 68% of patients received only the initial 2 courses (no retreatment) of alemtuzumab; 5% of patients received another DMT during Years 3 or 4

•Baseline demographics and disease characteristics of patients entering the extension study were similar to those of patients in the core study3

Title


QoL Assessments

•Patients who had received alemtuzumab 12 mg in CARE-MS II showed stability in QoL assessments between Years 2 and 4, despite the low rate of retreatment with alemtuzumab through Year 4

•Mean FAMS scores improved from baseline to Year 4 (Figure 1)

Title


QoL Assessments

•There were significant improvements beginning in Year 1 and these effects were durable through Year 4 on 5 of 6 FAMS components: mobility (P=0.0032), symptoms (P=0.0446), emotional well-being (P=0.0012), general contentment (P=0.0005), and thinking and fatigue (P<0.0001) (data not shown)

•Mean SF-36 PCS scores in alemtuzumab-treated patients improved from baseline to Year 4 (Figure 2A)

− In Year 4, 33.1% of patients had improved SF-36 PCS scores (Figure 2B)

Title


QoL Assessments

•Significant improvements from baseline to Year 4 were also observed for 5 of 8 SF-36 subscales: general health (P=0.0003), physical functioning (P=0.0014), role-physical (P=0.0055), mental health (P=0.0098), and vitality (P=0.0004) (data not shown)

•Mean EQ-5D VAS scores in alemtuzumab-treated patients improved from baseline to Year 4 (Figure 3)

Title


QoL and Disability at Year 4

•Patients achieving 6-month SRD benefited from significantly greater improvements from baseline to Year 4 in FAMS, PCS, and EQ-5D VAS scores than patients who did not achieve 6-month SRD (P<0.05) (Figure 4)

Title


CONCLUSIONS:

•Improvements in QoL were observed within the first year of treatment and were sustained through 4 years in alemtuzumab-treated active RRMS patients with an inadequate response to a prior therapy, even though most patients did not receive any alemtuzumab treatment since Month 12

− Alemtuzumab-treated patients maintained greater QoL improvements than patients treated with SC IFNB-1a over 2 years in the core study, and these effects remained through 2 years of extension

•Improvements in preexisting disability were associated with greater improvements in physical aspects of QoL and demonstrate the impact of disability improvement on patient-reported outcomes

ADMINISTRATION OF ALEMTUZUMAB ONNONCONSECUTIVE DAYS DOES NOT IMPACT LYMPHOCYTE DEPLETION, INFUSION-ASSOCIATED REACTIONS, OR EFFICACY

Alexey N Boyko,1 Sibyl Wray,2 Tiffany J Braley,3 David H Margolin,4 Linda Kasten5; on behalf of the CARE-MS Investigators

1Russian Science and Research Medical University named after N. I. Pirogov, and Moscow Multiple Sclerosis Center, Moscow, Russian Federation; 2Hope Neurology, Knoxville, TN, USA; 3University of Michigan Multiple Sclerosis and Sleep Disorders Centers, Ann Arbor, MI, USA; 4Genzyme, a Sanofi company, Cambridge, MA, USA; 5PROMETRIKA, LLC, Cambridge, MA, USA


INTRODUCTION:

•For the treatment of relapsing-remitting multiple sclerosis (RRMS), the recommendation is that alemtuzumab be administered intravenously on 5 consecutive days (Course 1) and on 3 consecutive days 12 months later (Course 2). As adherence to this schedule may not always be feasible in clinical practice, we assessed infusion-associated reaction (IAR) frequency, efficacy, and lymphocyte pharmacodynamics of alemtuzumab administered on nonconsecutive days in the CARE-MS I and II studies.

METHODS:

•IARs (adverse events occurring during infusion or up to 24 hours post-infusion) were assessed following nonconsecutive infusions (Course 1: >5 days; Course 2: >3 days). Assessments included lymphocyte counts 1 month post-treatment; relapses and 6-month sustained accumulation of disability over 2 years (SAD, per Expanded Disability Status Scale [EDSS] score); gadolinium (Gd)-enhancing and new/enlarging T2-hyperintense lesions within year of treatment, in subjects completing Course 1 or 2 over 6–10 or 4–8 nonconsecutive days, respectively.

Title

RESULTS:

• A total of 811 patients were treated with alemtuzumab 12 mg in the CARE-MS studies

•771 patients (95.1%) completed Course 1 with 5 infusions on 5 consecutive days, and 762 patients (96.6%) completed Course 2 with 3 infusions on 3 consecutive days

•A total of 58 patients (7.2%) had a prolonged treatment course over nonconsecutive days (Course 1, n=40; Course 2, n=19; 1 patient had both courses prolonged)

− 25 patients completed Course 1 over 6–10 nonconsecutive days, and 15 completed Course 2 over 4–8 nonconsecutive days

IARs

•The incidence of IARs in the overall CARE-MS population was highest during Course 1 and declined in subsequent courses; serious IARs were infrequent (Figure 1)10,11

Title

10. Mayer L, Casady L, Clayton G, et al. Presented at: INS; May 3-8, 2014; Phoenix, AZ, USA. 11. Mayer L, Casady L, Clayton G, et al. Presented at: ACTRIMS-ECTRIMS; September 10-13, 2014; Boston, MA, USA, P880.

• The incidences of IARs and serious IARs with nonconsecutive infusions were similar to those observed in the overall study population (Table 1)

Title

12. Wray S,Boyko A, Margolin DH, et al. Presented at: AMCP; April 7-10, 2015; San Diego, CA, USA.

• Of patients receiving alemtuzumab Course 1 over 6−10 days or alemtuzumab Course 2 over 4−8 days, 1 patient (Course 1, 10 days) had 2 serious IARs (bradycardia, pleurisy); both were deemed probably related to alemtuzumab12

− These events occurred prior to the interruption in treatment

− Bradycardia resolved on the same day, and pleurisy resolved 3 days later

− Alemtuzumab treatment was resumed 5 days after IAR onset

• There were no Grade 3 or higher IARs or serious IARs when dosing resumed after the break in treatment (Figure 2)

Title


Lymphocyte Counts

•Depletion of total lymphocytes and CD4+, CD8+, and CD19+ subsets was similar with nonconsecutive infusions versus the total study population (Figure 3)

Title


Efficacy

•Most patients completing Course 1 over 6–10 nonconsecutive days or Course 2 over 4–8 nonconsecutive days remained free from clinical and MRI activity12

− Relapse-free over 2 years (Course 1, 12/18 patients; Course 2, 9/10 patients)

− Free from 6-month SAD over 2 years (Course 1, 13/18 patients; Course 2, 8/10 patients)

− Free of Gd-enhancing lesions (Course 1, 15/17 patients; Course 2, 9/10 patients)

− Free of new/enlarging T2 hyperintense lesions (Course 1, 12/16 patients; Course 2, 8/10 patients)

CONCLUSIONS:

•More than 95% of patients completed alemtuzumab infusions within the recommended time frame of 5 or 3 consecutive days

•Completion of a treatment course by up to an additional 5 days did not increase the overall incidence of IARs, affect the extent of lymphocyte depletion, or reduce treatment efficacy

•A break in treatment did not appear to increase serious or severe IARs after infusion was resumed

•These findings suggest that prolonging treatment courses of alemtuzumab by up to 5 additional days does not impact treatment outcomes among RRMS patients

Title


ALEMTUZUMAB HAS A DURABLE EFFECT ON DISABILITY IMPROVEMENT IN TREATMENT-NAIVE PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS: 4-YEAR FOLLOW-UP OF CARE-MS I

Oscar Fernandez,1 Hans-Peter Hartung,2 Christopher LaGanke,3 David H Margolin,4 Linda Kasten,5 Thibault Moreau,6 Gavin Giovannoni7; on behalf of the CARE-MS I Investigators

1Fundacion IMABIS, Hospital Universitario Carlos Haya, Malaga, Spain; 2Heinrich-Heine University, Düsseldorf, Germany; 3North Central Neurology Associates, Cullman, AL, USA; 4Genzyme, a Sanofi company, Cambridge, MA, USA; 5PROMETRIKA, LLC, Cambridge, MA, USA; 6Burgundy University, Dijon University Hospital, Dijon, France; 7Queen Mary University of London, Barts and The London School of Medicine, London, UK


INTRODUCTION:

•Alemtuzumab demonstrated a durable effect on disability over 3 years in treatment-naive patients with relapsing-remitting multiple sclerosis; mean Expanded Disability Status Scale (EDSS) score remained below pretreatment values. Here, we assess the 4-year durability of disability improvement in these patient

Patients

•349 patients (95%) from CARE-MS I entered the extension study

•Over 4 years (2 years of core study and 2 years of extension study), 74% of patients did not receive alemtuzumab treatment since Month 12

•Less than 2% received another DMT in Years 3 or 4; only 1 patient (0.3%) received both alemtuzumab retreatment and another DMT

Title


Disability Improvement

•25.8% of patients who had EDSS scores ≥2.0 at core study baseline and were treated with alemtuzumab in the core study had an EDSS score improvement of ≥1 point over 4 years

− 12.1% had 1.0-point improvement



•Mean EDSS scores remained stable over 4 years: 2.0 at core study baseline, 1.9 at Year 2 (end of core study), and 1.9 at Years 3 and 4 (Figure 1)

− Similar results were observed for the patients receiving only 2 courses (no retreatment) over 4 years

Title



•Most alemtuzumab patients had improved or stable EDSS from core study baseline through Year 4, but even higher proportions of patients were improved or stable who received only the initial 2 alemtuzumab courses (no retreatment) over 4 years (Figure 2)

− At Year 4, 76% of all alemtuzumab patients had EDSS scores that were stable (54.7%) or improved (21.7%) from Year 2 (data not shown)

− At Year 4, 79% of all alemtuzumab patients had EDSS scores that were stable (59.9%) or improved (19.4%) from Year 3 (data not shown)

Title



•Of patients who had an improved EDSS score from baseline to Year 2, 10.8% improved further from Year 2 to Year 4 (9.6% in patients receiving only 2 courses [no retreatment] over 4 years) (Figure 3)

− Of patients who had a stable EDSS score from baseline to Year 2, 22.5% improved from Year 2 to Year 4 (26.1% in patients receiving only 2 courses [no retreatment] over 4 years) (Figure 3)

•A minority of patients (n=77 [23.5%]) had an increased EDSS score in the core study; of those, 39.0% eventually improved in the extension (data not shown)

− Among patients receiving only 2 courses (no retreatment) over 4 years, 19.3% had an increased EDSS score in the core study; of those, 47.8% eventually improved in the extension (data not shown)

Title



•An additional 6% of patients achieved 6-month SRD from Year 2 to 4 (Figure 4)

− Of patients ever achieving 6-month SRD, 96% were free from 6-month sustained accumulation of disability through Year 4

Title


Introduction

•In the majority of patients with active RRMS who were treatment-naive, disability scores improved or remained stable over 4 years with alemtuzumab, with most patients having received their last alemtuzumab treatment 3 years prior

•Patients who did not receive retreatment in the extension study were more likely to have improved EDSS score over 4 years compared with the overall cohort

•An increasing number of patients achieved sustained reduction in preexisting disability over Years 0 to 4

•The durability of disability improvement following acute dosing of alemtuzumab may be the result of immunomodulatory effects due to the distinct pattern of lymphocyte repopulation following treatment and is a unique treatment approach for DMTs

Title


SWITCHING FROM SUBCUTANEOUS INTERFERON BETA-1A TO ALEMTUZUMAB IMPROVES RELAPSE OUTCOMES IN CARE-MS I

Oscar Fernandez,1 Hans-Peter Hartung,2 Christopher LaGanke,3 David H Margolin,4 Linda Kasten,5 Thibault Moreau,6 Gavin Giovannoni7; on behalf of the CARE-MS I Investigators

1Fundacion IMABIS, Hospital Universitario Carlos Haya, Malaga, Spain; 2Heinrich-Heine University, Düsseldorf, Germany; 3North Central Neurology Associates, Cullman, AL, USA; 4Genzyme, a Sanofi company, Cambridge, MA, USA; 5PROMETRIKA, LLC, Cambridge, MA, USA; 6Burgundy University, Dijon University Hospital, Dijon, France; 7Queen Mary University of London, Barts and The London School of Medicine, London, UK


INTRODUCTION:

•In the CARE-MS I study, alemtuzumab significantly reduced the annualized relapse rate (ARR) at 2 years by 55% compared with SC IFNB-1a in treatment-naive patients with active RRMS; there was no significant reduction in 6-month sustained accumulation of disability4

•The most frequent adverse events (AEs) with alemtuzumab were infusion-associated reactions; other AEs of interest included autoimmune AEs (eg, thyroid disorders, immune thrombocytopenia, and nephropathies)4

•In an ongoing, open-label extension study, CAMMS03409, patients who received SC IFNB-1a in CARE-MS I discontinued SC IFNB-1a and began treatment with alemtuzumab5,6

OBJECTIVE

•To examine relapse outcomes in patients who received SC IFNB-1a in the CARE-MS I core study and switched to alemtuzumab in the extension study

Title

4. Cohen JA, Coles AJ, Arnold DL, et al. Lancet 2012;380:1819-28. 5. Coles AJ, Arnold DL, Cohen JA, et al. Presented at: ACTRIMS-ECTRIMS; September 10-13, 2014; Boston, MA, USA, P090. 6. Fox EJ, Arnold DL, Cohen JA, et al. Neurology 2013;80:S41.001.

Study Design

•CARE-MS I was a phase 3, randomized, head-to-head, rater-blinded, 2-year study in treatment-naive patients4

− Eligible patients were aged 18–50 years, with active RRMS (≥2 relapses in the prior 2 years and ≥1 relapse in the prior year)

− Patients were randomized to SC IFNB-1a 44 μg 3 times per week, or 2 annual courses of alemtuzumab (12 mg/day intravenous on 5 consecutive days at baseline and on 3 consecutive days 12 months later)

•Patients completing CARE-MS I could enter the ongoing extension study5,6

− SC IFNB-1a–treated patients switched to alemtuzumab treatment (discontinued SC IFNB-1a and received 2 courses of alemtuzumab [12 mg/day intravenous on 5 consecutive days at extension study start and on 3 consecutive days 12 months later])

− No washout period from SC IFNB-1a was defined per protocol; upon entering the extension study, patients had 2 months to qualify for and receive alemtuzumab

Efficacy Assessments

•ARR

•During CARE-MS I, relapses were confirmed per the protocol definition by an independent, blinded relapse adjudication panel; in the extension study, relapses were confirmed per the protocol definition by the investigator

Statistical Analysis

•Analyses were based on all available data through Year 2 of the extension study

Title

4. Cohen JA, Coles AJ, Arnold DL, et al. Lancet 2012;380:1819-28. 5. Coles AJ, Arnold DL, Cohen JA, et al. Presented at: ACTRIMS-ECTRIMS; September 10-13, 2014; Boston, MA, USA, P090. 6. Fox EJ, Arnold DL, Cohen JA, et al. Neurology 2013;80:S41.001.

RESULTS:

Patients

•Of the 173 SC IFNB-1a–treated patients who completed the CARE-MS I core study, 144 (83%) enrolled in the extension study

− Of these, 132 received 2 courses of alemtuzumab at extension baseline and Month 12 (7 received only 1 course)

•Demographic and clinical characteristics at core study baseline were similar between all core study SC IFNB-1a patients and the subset who subsequently entered the extension study (Table 1)

Title


Relapse:

•Two years after entering the extension study, in which patients discontinued SC IFNB-1a and received alemtuzumab treatment at Months 0 and 12, ARR decreased (Figure 1A) and a higher proportion of patients were free of relapse (Figure 1B), compared with the previous 2 years on SC IFNB-1a in the core study

Title


Relapse:

•In the subset of patients who relapsed while on SC IFNB-1a during the core study (n=60; 32%), the ARR decreased and 68% were relapse-free 2 years after stopping SC IFNB-1a therapy and switching to alemtuzumab at Months 0 and 12 in the extension study (Figure 2)

− Similar results were observed in SC IFNB-1a patients who relapsed in the year prior to receiving alemtuzumab

Title


CONCLUSIONS:

•Relapse rates markedly improved after stopping SC IFNB-1a and switching to 2 annual courses of alemtuzumab in the CARE-MS I extension study

− Improvements were also seen in patients with disease activity while in the second year of the core study just prior to switching

•The efficacy of alemtuzumab on relapse outcomes in patients who switched from SC IFNB-1a was similar to that observed with alemtuzumab in the core study

•These findings support the favorable benefit-risk profile of alemtuzumab in patients who received prior disease-modifying therapy

Title


INFECTIONS IN ALEMTUZUMAB PATIENTS PREVIOUSLY TREATED WITH SUBCUTANEOUS INTERFERON BETA-1A

Jan Lycke,1 Jeffrey A Cohen,2 Edward J Fox,3 Hans-Peter Hartung,4 Eva Havrdova,5 Krzysztof W Selmaj,6 David H Margolin,7 Linda Kasten,8 and D Alastair S Compston9; on behalf of the CARE-MS I and II Investigators

1University of Gothenburg, Gothenburg, Sweden; 2Cleveland Clinic, Cleveland, OH, USA; 3Central Texas Neurology Consultants, Round Rock, TX, USA; 4Heinrich-Heine University, Düsseldorf, Germany; 5First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 6Medical University of Łódź, Łódź, Poland; 7Genzyme, a Sanofi company, Cambridge, MA, USA; 8PROMETRIKA LLC, Cambridge, MA, USA; 9University of Cambridge School of Clinical Medicine, Cambridge, UK


INTRODUCTION:

•In the core CARE-MS studies, infections were more common with alemtuzumab than with SC IFNB-1a over 2 years (alemtuzumab vs SC IFNB-1a group incidences: Year 1, 59.9% vs 44.2%; Year 2, 55.1% vs 42.5%), but were predominantly mild to moderate, mostly not serious (<3% serious), and responded well to conventional treatment1,2; yearly infection risk did not increase with alemtuzumab over 4 years3,4

•Alemtuzumab depletes circulating T and B lymphocytes, which is followed by a distinctive pattern of lymphocyte repopulation, potentially rebalancing the immune system7-10

− Innate immune cells appear to be minimally or transiently impacted by alemtuzumab treatment, and serum immunoglobulin levels are unaffected9-14

•Because treatment with SC IFNB-1a carries a risk for leukopenia,15 it is important to understand whether switching to alemtuzumab increases the risk for infection following treatment with SC IFNB-1a

OBJECTIVE

•To evaluate risk of infection in patients who received SC IFNB-1a in the core CARE-MS studies and then switched to 2 courses of alemtuzumab at baseline and Month 12 of the extension study

Title

1. Cohen JA et al. Lancet 2012;380:1819-28. 2. Coles AJ, et al. Lancet 2012;380:1829-39. 3. Coles AJ et al. Presented at: ACTRIMS-ECTRIMS; September 10-13, 2014; Boston, MA, USA, P090. 4. Hartung H et al. Presented at: ACTRIMS-ECTRIMS; September 10-13, 2014; Boston, MA, USA, P043. 7. Cox AL et al. Eur J Immunol 2005;35:3332-42. 8. Havari E et al. Immunology 2014;141:123-31. 9. Hu Y et al. Immunology 2009;128:260-70. 10. Kovarova I et al. Presented at: ENS; June 9-12, 2012; Prague, Czech Republic, P341 11. Coles AJ, al. Lancet 1999;354:1691-5. 12. McCarthy CL, Tuohy O, Compston DA, et al. Neurology 2013;81:872-6. 13. Turner MJ, et al. J Neuroimmunol 2013;261:29-36. 14. Turner MJ et al. Presented at: ECTRIMS; October 2-5, 2013; Copenhagen, Denmark, P1207. 15. Rebif (interferon beta-1a) for subcutaneous injection. Fullprescribing information. Rockland, MA: EMD Serono, Inc; 2015

METHODS:

•In the 2-year core CARE-MS I and II studies, SC IFNB-1a–treated patients received 44 μg 3 times/week, and then could enter an extension study and receive 2 courses of alemtuzumab 12 mg at extension Months 0 and 12.

RESULTS

•The extension enrolled 282 SC IFNB-1a–treated patients from the core studies; baseline demographics of patients who entered the extension study were similar to those of the full core study SC IFNB-1a–treated cohort16,17

•Patients who did not enter the extension had a similar incidence of infection during the core study to that in patients who did enter the extension (55% vs 57%)

•93.3% of patients who entered the extension study received 2 courses of alemtuzumab 12 mg over the 2-year period and 6.7% received 1 course

Title

16. Hartung HP, Giovannoni G, Arnold DL, et al. Neurology 2015;84:P7.270. 17. Fox EJ, Giovannoni G, Arnold DL, et al. Neurology 2015;84:P7.278.

• Infection incidence did not increase from Year 1 to Year 2 following alemtuzumab treatment in patients with prior SC IFNB-1a exposure (Figure 1)

• As in the core studies, infections were predominantly mild to moderate in severity (Table 1)

Title


• As in the core studies, the most common infection Aes included nasopharyngitis, urinary tract infection, upper respiratory tract infection, and sinusitis (Table 2)

• Among patients who received SC IFNB-1a and then switched to alemtuzumab, 47.2% had infections on both treatments

− Among patients with infections on both treatments (n=133), urinary tract infection was more common during alemtuzumab treatment than during SC IFNB-1a treatment (26.3% vs 15.0%), but other infections reported with both treatments had a similar incidence (nasopharyngitis, 39.8% vs 38.3%; upper respiratory tract infection, 24.8% vs 25.6%; sinusitis, 15.0% vs 10.5%)

Title


• During the 2 years after switching to alemtuzumab from SC IFNB-1a, the cumulative incidence of serious infections was 5.7%

− The most frequent serious infection was urinary tract infection, which is common in patients with MS18 (Table 3)

• One patient who switched to alemtuzumab from SC IFNB-1a developed a Grade 4 infection

− Ruptured appendix with infection was reported 5 months after the first course of alemtuzumab

− The patient was hospitalized, underwent laparoscopic appendectomy and antibiotic treatment, and recovered 7 days later

− Event was deemed unrelated to alemtuzumab by the investigator

• No deaths or treatment discontinuation due to infection occurred after switching to alemtuzumab

Title

18. Mahadeva A, Tanasescu R, Gran B. Am J Clin Exp Immunol 2014;3:57-67.

• Oral herpes and herpes zoster were the most common herpetic infections in alemtuzumab patients (Table 4)

Title

18. Mahadeva A, Tanasescu R, Gran B. Am J Clin Exp Immunol 2014;3:57-67.

CONCLUSION:

•Alemtuzumab-treated patients with prior SC IFNB-1a treatment in the CARE-MS core studies had a similar risk of infection as the patients who received alemtuzumab in the core studies. These findings support the consistent safety profile of alemtuzumab across clinical trials.

LYMPHOCYTE PHARMACODYNAMICS AND SAFETY OF FINGOLIMOD USE IN PATIENTS PREVIOUSLY TREATED WITH ALEMTUZUMAB

Krzysztof W Selmaj,1 Ann D Bass,2 Keith R Edwards,3 Per S Sørensen,4 David H Margolin,5 Linda Kasten,6 Jeffrey A Cohen7; on behalf of the CAMMS223 and CARE-MS I and II Investigators

1Medical University of Łódź, Łódź, Poland; 2Neurology Center of San Antonio, San Antonio, TX, USA; 3MS Center of NE New York, Latham, NY, USA; 4Danish Multiple Sclerosis Center, Rigshospitalet, Copenhagen, Denmark; 5Genzyme, a Sanofi company, Cambridge, MA, USA; 6PROMETRIKA, LLC, Cambridge, MA, USA; 7Cleveland Clinic, Cleveland, OH, USA


INTRODUCTION:

•Alemtuzumab depletes circulating T and B lymphocytes, after which a distinctive pattern of T- and B-cell repopulation begins within weeks6-8

− B-cell counts return to baseline levels within 6 months; T-cell counts generally reach the lower limits of normal (but not baseline) by 12 months9,10

•Depending on the clinical needs of the individual patient, physicians may want to use DMTs such as fingolimod; however, few data exist on the safety of this practice and effects on the immune system

•Because alemtuzumab8,10 treatment is associated with long-term effects on the immune system, and fingolimod is known to cause reductions in peripheral lymphocyte counts that persist with therapy,11 it is important to investigate how subsequent fingolimod is tolerated in alemtuzumab treated patients

OBJECTIVE

•To assess lymphocyte pharmacodynamics and safety of fingolimod use in RRMS patients previously treated with alemtuzumab

Title

6. Cox AL et al. Eur J Immunol 2005;35:3332-42. 7. Havari E, et al. Immunology 2014;141:123-31. 8. Hu Y et al. Immunology 2009;128:260-70. 9. LEMTRADA Summary of Product Characteristics. Oxford, United Kingdom: Genzyme Therapeutics, Ltd.; 2013. 10. Kasper LH, Arnold DL, Coles AJ, et al. Presented at: ECTRIMS; October 2-5, 2013; Copenhagen, Denmark, P531. 11. Francis G, Kappos L, O'Connor P, et al. Mult Scler 2014;20:471-80.

METHODS:

•In core studies, patients who were treatment-naive or had inadequate efficacy response to prior disease-modifying therapy (≥1 relapse after ≥6 months) received 2 annual courses of alemtuzumab 12 or 24 mg, or SC IFNB-1a 44 μg 3 times/week.

•In extension, alemtuzumab-treated patients could receive as-needed retreatment; SC IFNB-1a–treated patients switched to alemtuzumab.

•Other therapies, including fingolimod, were permitted in the extension. Lymphocyte counts were obtained every 3 or 6 months and in the month after each alemtuzumab course.

Title


RESULTS

Fingolimod Use

•Data cut-off for this analysis was October 4, 2013

•In the pooled study population (N=1486), there were 6483 total patient-years of follow-up, with a mean (SD) follow-up of 4.4 (1.7) years per patient

•Overall, few patients required treatment with another DMT such as fingolimod following alemtuzumab (6.5%)

•Fingolimod use was reported in 13 patients who entered the extension study

− 12 patients received alemtuzumab in the core studies; 1 patient received SC IFNB-1a in the CARE-MS I core study and alemtuzumab in the extension

− There were 22.0 total patient-years of follow-up after fingolimod initiation, with a mean (SD) follow-up of 1.7 (1.6) years per patient; mean (SD) time from most recent alemtuzumab dose to fingolimod initiation was 2.0 (1.5) years

− Overall, treatment with fingolimod after alemtuzumab in this small cohort of patients did not appear to positively impact clinical or MRI activity (data not shown)

Title


RESULTS

Lymphocyte Counts

•Lymphocyte count dynamics during core study alemtuzumab treatment in the overall study population are shown in Figure 1

Title


RESULTS

•As expected with the mechanism of action of each therapy, depletion and repopulation of CD4+ and CD8+ T-cell counts and CD19+ B-cell counts were observed after treatment with alemtuzumab; lymphocyte counts were decreased during treatment with fingolimod (Figure 2)

Title


Safety

•The incidence of AEs and serious AEs was not increased in patients receiving fingolimod treatment relative to the overall study population

•No AE type predominated during fingolimod treatment− Of the 13 patients who received fingolimod after alemtuzumab, 11 experienced AEs, including infections (n=9), thyroid AEs (n=2), cytopenia (n=4), and malignancy (AEs of basal cell carcinoma and papillary thyroid carcinoma after fingolimod treatment; n=1; described at right)

•There were no serious infections, thyroid AEs, nephropathies, or immune thrombocytopenia events

•Three patients experienced serious AEs after fingolimod initiation

− Patient 8: Vasovagal syncope (17 months after the last alemtuzumab dose and 4 months after starting fingolimod); patient recovered on the same day as the event and with no subsequent syncope episodes

− Patient 7: Grade 2 pericarditis (26 months after last dose of alemtuzumab and 9 months after starting fingolimod), Grades 2 and 3 basal cell carcinoma (31 and 41 months after last alemtuzumab dose and 5 and 15 months after stopping fingolimod), Grade 2 hyperthyroidism (32 months after last alemtuzumab dose and 15 months after starting fingolimod), which led to thyroidectomy and subsequent diagnosis of Stage 1 thyroid cancer

− Patient 10: Multiple sclerosis relapse (31 months after last dose of alemtuzumab and 13 months after starting fingolimod)

Title


CONCLUSIONS:

•Lymphocyte counts after switching from alemtuzumab to fingolimod were consistent with the known pharmacodynamic effects of fingolimod

•Overall AE profiles of fingolimod and alemtuzumab were consistent with the known safety profiles of each drug

•In this small group of patients, there were no safety findings to preclude use of fingolimod following alemtuzumab, although additional experience is needed

Title


DURABLE EFFECT OF ALEMTUZUMAB ONDISEASE ACTIVITY IN PATIENTS WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS

Heinz Wiendl,1 Douglas L Arnold,2,3 Raymond MM Hupperts,4 Gavin Giovannoni,5 David H Margolin,6 Linda Kasten,7 Eva Havrdova8; on behalf of the CARE-MS Investigators

1University of Münster, Münster, Germany; 2NeuroRx Research, Montréal, Québec, Canada; 3Montréal Neurological Institute, McGill University, Montréal, Québec, Canada; 4Orbis Medisch Centrum, Maastricht University Medical Center, Sittard, The Netherlands; 5Queen Mary University of London, Barts and The London School of Medicine, London, UK; 6Genzyme, a Sanofi company, Cambridge, MA, USA; 7PROMETRIKA, LLC, Cambridge, MA, USA; 8First Medical Faculty, Charles University in Prague, Prague, Czech Republic

P2164 1st Congress of the European Academy of Neurology (EAN) June 20–23, 2015, Berlin, Germany

OBJECTIVE

•In this follow-up of the CARE-MS studies and the ongoing extension study, we examine achievement of no evidence of disease activity in alemtuzumab-treated patients through Year 4

METHODS:

•In CARE-MS I (treatment-naive) and II (patients with ≥1 relapse after ≥6 months of prior therapy), the alemtuzumab 12-mg group received 2 annual treatment courses; in the extension study, patients could receive as-needed alemtuzumab retreatment ≥1 year apart.

•NEDA definition: absence of relapse, 6-month sustained accumulation of disability (Expanded Disability Status Scale score increase from baseline of ≥1.0 [≥1.5 if baseline EDSS=0]), new/enlarging T2 lesions, and gadolinium-enhancing lesions

Title


RESULTS:

CARE-MS I Core and Extension Study: Treatment-Naive Patients With Active RRMS

•The extension enrolled 349 (95%) alemtuzumab-treated patients from CARE-MS I; 97% of patients entering the extension remained in the study through Year 4

− During the first 2 years of the extension, most patients (74%) did not receive retreatment with alemtuzumab since the initial 2 courses at core study baseline and 12 months later

− 21% received 1 additional alemtuzumab course, either in Year 3 or 4, and 5% received 2 additional courses

− 98% did not receive other DMT in Years 3 and 4

•Baseline demographic characteristics of patients entering the extension study were similar to those of patients in the core study

Title


RESULTS:

Clinical Disease Activity

•Most alemtuzumab patients were free from clinical disease activity in Years 3 and 4, including those patients who did not receive retreatment (Figure 1)

− In Years 3 and 4, 76% of alemtuzumab patients were relapse-free7

− Over 4 years, 83% of alemtuzumab patients were free from 6-month SAD7

Title

7. Compston D, Giovannoni G, Arnold DL, et al. Presented at: AAN; April 18-25, 2015; Washington, DC, USA, S4.007

RESULTS:

MRI Activity

•Most CARE-MS I alemtuzumab patients were free from MRI activity in Years 3 and 4, including patients who were not retreated (Figure 2)

•In Years 3 and 4, the proportions of alemtuzumab patients free of Gd-enhancing (90% and 87%) and new/enlarging T2 hyperintense lesions (72% and 71%) remained stable compared with the core study8

Title

8. Arnold DL,Traboulsee A, Coles A, et al. Presented at: AAN; April 18-25, 2015; Washington, DC, USA, P7.246

RESULTS:

No Evidence of Disease Activity

•The proportion of alemtuzumab patients achieving no evidence of disease activity remained stable in Years 3 and 4 (Figure 3)

•Consistent with the overall study population, most of those patients who did not require alemtuzumab retreatment achieved no evidence of disease activity in Years 3 and 4

Title

RESULTS:

CARE-MS II Core and Extension Study: Patients With Active RRMS and an Inadequate Response to a Prior Therapy

•The extension enrolled 393 (93%) alemtuzumab-treated patients from CARE-MS II; 94% of patients entering the extension remained in the study through Year 4

− During the first 2 years of the extension, most patients (68%) did not receive retreatment with alemtuzumab since the initial 2 courses at core study baseline and 12 months later

− 24% received 1 additional alemtuzumab course, either in Year 3 or 4, and 7% received 2 additional courses

− 95% did not receive other DMT in Years 3 and 4

•Baseline demographic characteristics of patients entering the extension study were similar to those of patients in the core study

Title


RESULTS:

Clinical Disease Activity

•Most alemtuzumab patients were free from clinical disease activity in Years 3 and 4, including those patients who did not receive retreatment (Figure 4)

− In Years 3 and 4, 81% and 79% of alemtuzumab patients were relapse-free

− Over 4 years, 76% of alemtuzumab patients were free from 6-month SAD9

Title

9.Havrdova E, Giovannoni G, Arnold DL, et al. Presented at: AAN; April 18-25, 2015; Washington, DC, USA, P7.276

RESULTS:

MRI Activity

•Most CARE-MS II alemtuzumab patients were free from MRI activity in Years 3 and 4, including patients who were not retreated (Figure 5)

•In Years 3 and 4, the proportions of alemtuzumab patients free of Gd-enhancing lesions (87% and 89%) and new/enlarging T2 hyperintense lesions (69% and 70%) remained stable compared with the core study10

Title

10. Traboulsee A, Coles AJ, Cohen JA, et al. Presented at: AAN; April 18-25, 2015; Washington, DC, USA, P7.249

RESULTS:

No Evidence of Disease Activity

•The proportion of alemtuzumab patients achieving no evidence of disease activity remained stable in Years 3 and 4 (Figure 6)

•Consistent with the overall study population, most of those patients who did not require alemtuzumab retreatment achieved no evidence of disease activity in Years 3 and 4

Title


CONCLUSION:

•The proportion of alemtuzumab patients achieving NEDA remained stable in Years 3 and 4 of CARE-MS studies, irrespective of treatment-naive status or inadequate efficacy response to prior therapy. This durable effect was observed despite most patients not receiving alemtuzumab during the last 3 years of observation

Title


QUALITY-OF-LIFE IMPROVEMENTS WITH ALEMTUZUMAB ARE MAINTAINED IN RELAPSING-REMITTING MULTIPLE SCLEROSIS PATIENTS WHO DEVELOP THYROID ADVERSE EVENTS IN CARE-MS II

Tjalf Ziemssen,1 Krzysztof W Selmaj,2 Patrick Vermersch,3 Eva Havrdova,4 David H Margolin,5 Linda Kasten,6 Samuel F Hunter7; on behalf of the CARE-MS II Investigators

1Center of Clinical Neuroscience, Carl Gustav Carus University Hospital, Dresden, Germany; 2Medical University of Łódź, Łódź, Poland; 3University of Lille, Lille, France; 4First Medical Faculty, Charles University in Prague, Prague, Czech Republic; 5Genzyme, a Sanofi company, Cambridge, MA, USA; 6PROMETRIKA, LLC, Cambridge, MA, USA; 7Advanced Neurosciences Institute, Franklin, TN, USA

D229 1st Congress of the European Academy of Neurology (EAN) June 20–23, 2015, Berlin, Germany

OBJECTIVE

•To examine the relationship between QoL and thyroid AE occurrence in alemtuzumab-treated patients during the CARE-MS II study

METHODS:

•Patients with ≥1 relapse after ≥6 months prior therapy received 2 annual courses of alemtuzumab 12 mg/day or SC IFNB-1a 44 μg 3 times weekly. QoL assessments included Functional Assessment of Multiple Sclerosis (FAMS), Short-Form 36-Item (SF-36) survey physical component summary (PCS) and EuroQol 5-dimensions (EQ-5D) visual analogue scale (VAS). SF-36 mental component summary analysis was excluded due to no Year 2 group difference. Thyroid function testing (baseline and quarterly) was performed per comprehensive monitoring program

Title


Patients

•Among alemtuzumab-treated patients, 16% (70/435) had thyroid AEs over 2 years

•Baseline demographics were similar for alemtuzumab patients with and without thyroid AEs, except for gender; thyroid AEs were more likely to occur in women (Table 1)

Title


QoL Assessments by Thyroid AEs

•At Year 2, mean changes from baseline in QoL assessed by FAMS (Figure 1), SF-36 PCS (Figure 2A), and EQ-5D VAS (Figure 3) were similar in alemtuzumab-treated patients with or without thyroid Aes

•Proportions of alemtuzumab-treated patients with improved or stable SF-36 PCS scores over 2 years were similar in subgroups with and without thyroid AEs (Figure 2B)

− Mean changes from baseline in QoL scores in both thyroid subgroups were similar to those observed in the overall alemtuzumab cohort

Title


QoL Assessments by Thyroid AEs

Title


CONCLUSION:

•The development of thyroid AEs did not affect QoL scores in alemtuzumab-treated RRMS patients with an inadequate response to a prior therapy

•Alemtuzumab patients who developed thyroid Aes maintained greater QoL improvements than patients treated with SC IFNB-1a

•These findings support the favorable benefit-risk profile of alemtuzumab in active RRMS

ean 2015 alemtuzumab abstracts

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