Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial

Alasdair J Coles, Douglas L Arnold, Ann D Bass, Aaron L Boster, D Alastair S Compston, Óscar Fernández, Eva Kubala Havrdová, Kunio Nakamura, Anthony Traboulsee, Tjalf Ziemssen, Alan Jacobs, David H Margolin, Xiaobi Huang, Nadia Daizadeh, Madalina C Chirieac, Krzysztof W Selmaj, Alasdair J Coles, Douglas L Arnold, Ann D Bass, Aaron L Boster, D Alastair S Compston, Óscar Fernández, Eva Kubala Havrdová, Kunio Nakamura, Anthony Traboulsee, Tjalf Ziemssen, Alan Jacobs, David H Margolin, Xiaobi Huang, Nadia Daizadeh, Madalina C Chirieac, Krzysztof W Selmaj

Abstract

Background: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline.

Methods: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab.

Results: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups.

Conclusion: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups.

Clinicaltrialsgov identifiers: NCT00530348; NCT00548405; NCT00930553.

Keywords: CD52; MRI; alemtuzumab; brain volume; disability; disease activity; efficacy; extension; multiple sclerosis; relapse; safety.

Conflict of interest statement

Conflict of interest statement: AJC reports receiving consulting fees, lecture fees, and institutional grant support from Sanofi prior to 2017. DLA reports receiving consulting fees and/or grants from Acorda, Adelphi, Alkermes, Biogen, Celgene, Frequency Therapeutics, Genentech, Genzyme, Hoffmann-La Roche, Immune Tolerance Network, Immunotec, MedDay, Merck Serono, Novartis, Pfizer, Receptos, Roche, Sanofi-Aventis, Canadian Institutes of Health Research, MS Society of Canada, International Progressive MS Alliance, and an equity interest in NeuroRx Research. ADB reports receiving research funding, compensation for medical advisory boards, and compensation for speakers bureaus from Actelion, Biogen, EMD Serono, Genentech-Roche, Mallinckrodt, Novartis, Sanofi, and TG Therapeutics. ALB reports receiving consulting fees and/or speaking fees for non-CME services from Biogen, Mallinckrodt, Medtronic, Novartis, Sanofi, and Teva. DASC reports receiving consulting fees, grant, and research support from Sanofi, and lecture fees from Bayer-Schering Pharma and Sanofi, prior to 2017. ÓF reports receiving speaking and/or consulting fees for Allergan, Almirall, Bayer-Schering Pharma, Biogen, Merck Serono, Novartis, Sanofi, and Teva, and research support from the Hospital Foundation FIMABIS; he also serves as editor of the Revista Española de Esclerosis Múltiple. EKH reports receiving honoraria and grant support from Actelion, Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi, and Teva, and is supported by the Ministry of Education of the Czech Republic, project PROGRES Q27/LF1. KN reports speaking fees and research support from Biogen and Sanofi, along with royalty fees for licenses with Biogen. AT reports receiving consulting and/or speaking fees, along with grant and research support, from Biogen, Chugai, Roche, Sanofi, and Teva. TZ reports receiving consulting and/or speaking fees from Almirall, Bayer, Biogen, Merck, Novartis, Roche, Sanofi, and Teva, along with grant and research support from Biogen, Novartis, Sanofi, and Teva. AJ, DHM, XH, and MCC report being employees of Sanofi during the time of the analysis. ND reports receiving personal compensation as an employee of Sanofi. KWS reports receiving consulting and/or speaking fees from Biogen, Merck, Novartis, Roche, Sanofi, and Synthon.

© The Author(s), 2021.

Figures

Figure 1.
Figure 1.
CARE-MS I and II patient disposition. Schematic of the as-randomized patient population from the core CARE-MS studies through the extension study, CAMMS03409. Patients randomized to SC IFNB-1a 44 μg who received treatment in the core studies discontinued SC IFNB-1a before initiating alemtuzumab 12 mg in the extension. (A) CARE-MS I patients who were randomized to either alemtuzumab or SC IFNB-1a at core study start. (B) CARE-MS II patients who were randomized to either alemtuzumab or SC IFNB-1a at core study start. CARE-MS, Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; IFN, interferon; SC IFNB-1a, subcutaneous interferon beta-1a.
Figure 2.
Figure 2.
Efficacy outcomes in CARE-MS I patients through year 6. Results are shown for the CARE-MS I alemtuzumab-only and IFN–alemtuzumab groups. (A) Yearly ARR from year 2 of the core study to the end of the CAMMS03409 extension study, and cumulative ARR from core study baseline through year 6. Core study ARR values are presented for year 2 only in this analysis, and were reported previously for years 0–2 cumulatively (alemtuzumab: 0.18; SC IFNB-1a: 0.39). (B) Change in mean (SE) EDSS score from core study baseline through year 6. (C) Percentages of patients with improved, stable, and worsened EDSS scores at year 2 and year 6 from core study baseline. Percentages may not sum to 100% due to rounding. (D) Kaplan–Meier estimates of the percentages of patients free of 6-month CDW. (E) Kaplan–Meier estimates of the percentages of patients with 6-month CDI. (F) Percentages of patients free of MRI disease activity each year from core study baseline through year 6. For IFN–alemtuzumab patients, MRI disease activity values for year 1 and year 2 are presented only for patients who entered the extension only. (G) Percentages of patients free of new Gd-enhancing lesions each year from core study baseline through year 6. Core study values for proportions of patients free of new Gd-enhancing lesions are presented separately for year 1 and year 2 in this analysis, and were reported previously for year 2 only (alemtuzumab: 93%; SC IFNB-1a: 81%). (H) Percentages of patients free of new/enlarging T2 hyperintense lesions each year from core study baseline through year 6. Core study values for proportions of patients free of new/enlarging T2 hyperintense lesions are presented separately for year 1 and year 2 in this analysis, and were reported previously for years 0–2 cumulatively (alemtuzumab: 52%; SC IFNB-1a: 42%). For IFN–alemtuzumab patients, values for proportions free of Gd-enhancing lesions and new/enlarging T2 lesions for year 1 and year 2 are presented for patients who entered the extension only, and were reported previously for all patients who received SC IFNB-1a in the core study. (I) Median cumulative percentage BVL from core study baseline to the end of CAMMS03409. (J) Median annual percentage BVL. Alemtuzumab-only group versus IFN–alemtuzumab group: *p < 0.05 indicates significant between-treatment group differences in favor of the alemtuzumab-only group and †p < 0.05 indicates significant between-treatment group differences in favor of the IFN–alemtuzumab group. Year 2 of SC IFNB-1a treatmentversus each year (years 3–6) after initiating alemtuzumab treatment: ‡p < 0.05. ARR, annualized relapse rate; BPF, brain parenchymal fraction; BVL, brain volume loss; CARE-MS, Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CDI, confirmed disability improvement; CDW, confirmed disability worsening; CI, confidence interval; EDSS, Expanded Disability Status Scale; Gd, gadolinium; IFN, interferon; MRI, magnetic resonance imaging; SC IFNB-1a, subcutaneous interferon beta 1-a; SE, standard error; Y, year.
Figure 3.
Figure 3.
Efficacy outcomes in CARE-MS II patients through year 6. Results are shown for the CARE-MS II alemtuzumab-only and IFN–alemtuzumab groups. (A) Yearly ARR from year 2 of the core study to the end of the CAMMS03409 extension study, and cumulative ARR from core study baseline through year 6. Core study ARR values are presented for year 2 only in this analysis, and were reported previously for years 0–2 cumulatively (alemtuzumab: 0.26; SC IFNB-1a: 0.52). (B) Change in mean (SE) EDSS score from core study baseline through year 6. (C) Percentages of patients with improved, stable, and worsened EDSS scores at year 2 and year 6 from core study baseline. Percentages may not sum to 100% due to rounding. (D) Kaplan–Meier estimates of the percentages of patients free of 6-month CDW. (E) Kaplan–Meier estimates of the percentages of patients with 6-month CDI. (F) Percentages of patients free of MRI disease activity each year from core study baseline through year 6. For IFN–alemtuzumab patients, MRI disease activity values for year 1 and year 2 are presented for patients who entered the extension only. (G) Percentages of patients free of new Gd-enhancing lesions each year from core study baseline through year 6. Core study values for proportions of patients free of new Gd-enhancing lesions are presented separately for year 1 and year 2 in this analysis, and were reported previously for year 2 only (alemtuzumab: 91%; SC IFNB-1a: 77%). (H) Percentages of patients free of new/enlarging T2 hyperintense lesions each year from core study baseline through year 6. Core study values for proportions of patients free of new/enlarging T2 hyperintense lesions are presented separately for year 1 and year 2 in this analysis, and were reported previously for years 0–2 cumulatively (alemtuzumab: 54%; SC IFNB-1a: 32%). For IFN–alemtuzumab patients, values for proportions free of Gd-enhancing lesions and new/enlarging T2 lesions for year 1 and year 2 are presented for patients who entered the extension only, and were reported previously for all patients who received SC IFNB-1a in the core study. (I) Median cumulative percentage BVL from core study baseline to the end of CAMMS03409. (J) Median annual percentage BVL. Alemtuzumab-only group versus IFN–alemtuzumab group: *p < 0.05 indicates significant between-treatment group differences in favor of the alemtuzumab-only group and †p < 0.05 indicates significant between-treatment group differences in favor of the IFN–alemtuzumab group. Year 2 of SC IFNB-1a treatmentversus each year (years 3–6) after initiating alemtuzumab treatment: ‡p<0.0001, §p<0.001, and ¶p<0.05. ARR, annualized relapse rate; BPF, brain parenchymal fraction; BVL, brain volume loss; CARE-MS, Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CDI, confirmed disability improvement; CDW, confirmed disability worsening; CI, confidence interval; EDSS, Expanded Disability Status Scale; Gd, gadolinium; IFN, interferon; MRI, magnetic resonance imaging; SC IFNB-1a, subcutaneous interferon beta 1-a; SE, standard error; Y, year.

References

    1. Gajofatto A, Benedetti MD. Treatment strategies for multiple sclerosis: when to start, when to change, when to stop? World J Clin Cases 2015; 3: 545–555.
    1. Cox AL, Thompson SA, Jones JL, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005; 35: 3332–3342.
    1. Hu Y, Turner MJ, Shields J, et al. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009; 128: 260–270.
    1. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012; 380: 1819–1828.
    1. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012; 380: 1829–1839.
    1. Lemtrada (alemtuzumab). Prescribing information: Genzyme Corporation, Cambridge, MA, 2020.
    1. Lemtrada. Summary of product characteristics: Sanofi Belgium, Diegem, Belgium, 2020.
    1. Coles AJ, Jones J, Vermersch P, et al. Autoimmunity and other long-term safety and efficacy of alemtuzumab treatment of multiple sclerosis. In preparation.
    1. Holmoy T, von der Lippe H, Leegaard TM. Listeria monocytogenes infection associated with alemtuzumab – a case for better preventive strategies. BMC Neurol 2017; 17: 65.
    1. Canham LJW, Manara A, Fawcett J, et al. Mortality from Listeria monocytogenes meningoencephalitis following escalation to alemtuzumab therapy for relapsing-remitting multiple sclerosis. Mult Scler Relat Disord 2018; 24: 38–41.
    1. Holmoy T, Fevang B, Olsen DB, et al. Adverse events with fatal outcome associated with alemtuzumab treatment in multiple sclerosis. BMC Res Notes 2019; 12: 497.
    1. Clerico M, De Mercanti S, Artusi CA, et al. Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab. Mult Scler 2017; 23: 874–876.
    1. Russo CV, Sacca F, Paternoster M, et al. Post-mortem diagnosis of invasive pulmonary aspergillosis after alemtuzumab treatment for multiple sclerosis. Mult Scler 2020; 26: 123–126.
    1. Penkert H, Delbridge C, Wantia N, et al. Fulminant central nervous system nocardiosis in a patient treated with alemtuzumab for relapsing-remitting multiple sclerosis. JAMA Neurol 2016; 73: 757–759.
    1. Sheikh-Taha M, Corman LC. Pulmonary nocardia beijingensis infection associated with the use of alemtuzumab in a patient with multiple sclerosis. Mult Scler 2017; 23: 872–874.
    1. Yiannopoulou KG, Papadimitriou D, Anastasiou AI, et al. Neutropenia with fatal outcome in a multiple sclerosis patient 23 days after alemtuzumab infusion. Mult Scler Relat Disord 2018; 23: 15–16.
    1. Saarela M, Senthil K, Jones J, et al. Hemophagocytic lymphohistiocytosis in 2 patients with multiple sclerosis treated with alemtuzumab. Neurology 2018; 90: 849–851.
    1. Pfeuffer S, Beuker C, Ruck T, et al. Acute cholecystitis during treatment with alemtuzumab in 3 patients with RRMS. Neurology 2016; 87: 2380–2381.
    1. Croteau D, Flowers C, Kulick CG, et al. Acute acalculous cholecystitis: a new safety risk for patients with MS treated with alemtuzumab. Neurology 2018; 90: e1548–e1552.
    1. Ferraro D, Camera V, Vitetta F, et al. Acute coronary syndrome associated with alemtuzumab infusion in multiple sclerosis. Neurology 2018; 90: 852–854.
    1. Azevedo CJ, Kutz C, Dix A, et al. Intracerebral haemorrhage during alemtuzumab administration. Lancet Neurol 2019; 18: 329–331.
    1. Havrdova E, Arnold DL, Cohen JA, et al. Alemtuzumab CARE-MS I 5-year follow-up: durable efficacy in the absence of continuous MS therapy. Neurology 2017; 89: 1107–1116.
    1. Coles AJ, Cohen JA, Fox EJ, et al. Alemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings. Neurology 2017; 89: 1117–1126.
    1. Ziemssen T, Thomas K. Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord 2017; 10: 343–359.
    1. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83: 278–286.
    1. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet Neurol 2011; 10: 338–348.
    1. Rudick RA, Fisher E, Lee JC, et al. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 1999; 53: 1698–1704.
    1. Liu GF, Wang J, Liu K, et al. Confidence intervals for an exposure adjusted incidence rate difference with applications to clinical trials. Stat Med 2006; 25: 1275–1286.
    1. Phelps R, Winston JA, Wynn D, et al. Incidence, management, and outcomes of autoimmune nephropathies following alemtuzumab treatment in patients with multiple sclerosis. Mult Scler 2019; 25: 1273–1288.
    1. Brown JWL, Coles A, Horakova D, et al. Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis. JAMA 2019; 321: 175–187.
    1. Horakova D, Boster A, Bertolotto A, et al. Alemtuzumab-treated patients with relapsing-remitting MS show low rates of conversion to secondary progressive MS: 6-year follow-up of CARE-MS I and II. Mult Scler 2017; 23: P1195.
    1. Cuker A, Bass AD, Nadj C, et al. Immune thrombocytopenia in alemtuzumab-treated MS patients: incidence, detection, and management. Mult Scler 2020; 26: 48–56.
    1. US Food and Drug Administration. FDA warns about rare but serious risks of stroke and blood vessel wall tears with multiple sclerosis drug Lemtrada (alemtuzumab), (accessed 17 September 2020).
    1. European Medicines Agency. Measures to minimise risk of serious side effects of multiple sclerosis medicine Lemtrada [press release], (accessed 17 September 2020).
    1. Jones JL, Thompson SA, Loh P, et al. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proc Natl Acad Sci U S A 2013; 110: 20200–20205.
    1. Turner MJ, Lamorte MJ, Chretien N, et al. Immune status following alemtuzumab treatment in human CD52 transgenic mice. J Neuroimmunol 2013; 261: 29–36.
    1. Gross CC, Ahmetspahic D, Ruck T, et al. Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2016; 3: e289.
    1. Kim Y, Kim G, Shin HJ, et al. Restoration of regulatory B cell deficiency following alemtuzumab therapy in patients with relapsing multiple sclerosis. J Neuroinflammation 2018; 15: 300.
    1. Chan JK, Taylor C, Traboulsee A, et al. Durable neuroprotective effects of alemtuzumab over 5 years on retinal nerve fibre layer and ganglion cell layers in relapsing-remitting multiple sclerosis (RRMS) patients. Mult Scler 2017; 23: P1082.
    1. Vavasour IM, Tam R, Li DK, et al. A 24-month advanced magnetic resonance imaging study of multiple sclerosis patients treated with alemtuzumab. Mult Scler 2019; 25: 811–818.
    1. Button T, Altmann D, Tozer D, et al. Magnetization transfer imaging in multiple sclerosis treated with alemtuzumab. Mult Scler 2013; 19: 241–244.
    1. Brown JWL, Prados Carrasco F, Eshaghi A, et al. The effect of alemtuzumab on periventricular magnetisation transfer ratio gradients. Mult Scler 2017; 23: P1877.
    1. Ziemssen T, Bass AD, Berkovich R, et al. Efficacy and safety of alemtuzumab through 9 years of follow-up in patients with highly active disease: post hoc analysis of CARE-MS I and II patients in the TOPAZ extension study. CNS Drugs 2020; 34: 973–988.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel