Alemtuzumab and multiple sclerosis: Is it safe? Dennis Bourdette Neurology published online June 11, 2014 DOI 10.1212/WNL.0000000000000554 This information is current as of June 11, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/early/2014/06/11/WNL.0000000000000554.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
EDITORIAL
Published Ahead of Print on June 11, 2014 as 10.1212/WNL.0000000000000554
Alemtuzumab and multiple sclerosis Is it safe?
Dennis Bourdette, MD, FAAN, FANA
Correspondence to Dr. Bourdette: [email protected] Neurology® 2014;83:1–2
The treatment of multiple sclerosis (MS) is complex. In the United States, we have 8 different classes of drugs approved for treating relapsing-remitting MS (RRMS).1 The first-generation therapies, glatiramer acetate and the b-interferons, have an impressive 20-year record of safety and many patients with RRMS have their disease well-controlled by these agents. Newer treatments, such as natalizumab, fingolimod, and dimethyl fumarate, may be more efficacious and convenient than the first-generation therapies. However, they lack a long-term safety record and some, such as natalizumab, have proved to be riskier than the first-generation therapies. In assessing any new therapy for RRMS, we must assess not just its efficacy but also its safety. Increased efficacy that comes with excessive risks is a Faustian bargain we should refuse. In this issue of Neurology®, Menge et al.2 review the key clinical trials of alemtuzumab for the treatment of RRMS. This review is timely given recent events. While regulatory agencies in Europe, Canada, Australia, and elsewhere have approved alemtuzumab for the treatment of RRMS, the US Food and Drug Administration (FDA) recently declined to register the therapy for MS.3 The divergent position of the FDA is partly based on the lack of subject blinding in the clinical trials but the FDA also raised concerns about the safety of the drug.4 Alemtuzumab is a humanized monoclonal antibody that rapidly depletes CD521 lymphocytes and monocytes following a short course of therapy.5 Repletion of cells occurs very slowly. Monocytes and B cells return to pretreatment levels within 3 months but T cells return much more slowly. CD81 T cells rise to pretreatment levels over a mean of 30 months and CD41 T cells remain below pretreatment levels for a mean of 5 years. Alemtuzumab’s prolonged effects on immune cells are the basis for its efficacy and also its risks. Menge et al.2 discuss the results of a phase 2 (CAMMS223) and 2 phase 3 trials (CARE-MS I and CARE-MS II) of alemtuzumab in RRMS.6–8 All 3 trials compared alemtuzumab with subcutaneous
interferon-b-1a (IFN-b-1a) and had coprimary outcomes of annualized relapse rate (ARR) and sustained disability worsening. Participants were not blinded to which treatment they received. CAMMS223 and CARE-MS I enrolled treatment-naive patients whereas CARE-MS II enrolled persons who had relapsed on glatiramer acetate or a b-interferon. All 3 studies showed lower ARR in subjects receiving alemtuzumab compared with IFN-b-1a. The ARR for alemtuzumab compared with IFN-b-1a for the trials were as follows: CAMMS223, 0.1 vs 0.36; CARE-MS I, 0.18 vs 0.39; CARE-MS II, 0.26 vs 0.52. The higher relapse rates in the CARE-MS II trial probably reflected enrollment of a more treatment-resistant group of participants, many of whom had had poorly controlled disease on b-interferon. Participants receiving alemtuzumab in the CAMMS223 and CARE-MS II trials had reductions in sustained disability worsening compared with those receiving IFN-b-1a (CAMMS233, 9% vs 26%, p , 0.001; CARE-MS II, 9% vs 22%, p 5 0.002). However, a difference in sustained disability worsening between the alemtuzumab and IFN-b-1a groups did not occur in CARE-MS I (8% vs 11%, p 5 0.22). This difference appears related to lower than expected disability progression in the placebo group. As reviewed by Menge et al., many secondary and post hoc clinical and magnetic resonance analyses have been performed on the data from these 3 trials, providing additional evidence that alemtuzumab is more efficacious than IFN-b-1a. However, their review also makes clear that alemtuzumab is substantially less safe than IFN-b-1a. Nearly 30% of patients with MS receiving alemtuzumab developed autoimmune thyroid disease, typically hyperthyroidism and Graves disease. While autoimmune thyroid disease is treatable, it is not trivial. Some patients required thyroidectomies and Graves disease may be a risk factor for thyroid cancer.9 Immune thrombocytopenia purpura occurred in 21 MS participants receiving alemtuzumab. One died from an intracranial hemorrhage while others were successfully treated, although some required treatment with immunosuppressants. A few cases of
See page 87 From the Department of Neurology, Oregon Health & Science University, Portland; and Multiple Sclerosis Center of Excellence–West, Portland Veterans Affairs Medical Center, OR. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the editorial. © 2014 American Academy of Neurology
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
immune-mediated hemolytic anemia and neutropenia also occurred and one person with agranulocytosis died. Finally, 4 cases of renal failure resulting from Goodpasture syndrome have been reported and 2 required renal transplantation. Thus a variety of autoimmune diseases have occurred in patients with MS following treatment with alemtuzumab, with fatal consequences in two. Other serious complications associated with alemtuzumab have appeared. There have been 4 malignancies attributable to alemtuzumab, 3 thyroid cancers, and a fatal case of Burkitt lymphoma. Herpes zoster developed more commonly among subjects receiving alemtuzumab compared with IFN-b-1a and single cases of Listeria meningitis, esophageal candidiasis, and pasturella suggest an increased risk for opportunistic infections. Despite the lack of blinding of participants, it appears that alemtuzumab is more effective in controlling RRMS than IFN-b-1a. However, alemtuzumab has a disturbing array of serious side effects and at least 3 deaths have occurred as a result of diseases complicating therapy with alemtuzumab. Menge et al. suggest the serious side effects of alemtuzumab might be mitigated by risk management programs but this notion is unproven. The authors also suggest that it might be appropriate to investigate alemtuzumab as an induction therapy in RRMS to be followed by a standard platform disease-modifying therapy. Given the long duration of immunosuppression induced by alemtuzumab and the serious diseases it may induce, we must question the wisdom of such an approach. If alemtuzumab has any role in treating RRMS, given the risks, it seems that one would only be justified using it in the rare patient with very active RRMS who has failed treatment with other, safer MS therapies. Alemtuzumab is efficacious in treating RRMS but its substantial risks demand considerable caution in its use. From the US perspective, the FDA’s decision to obtain further information about alemtuzumab before licensing reflects the extreme complexity of parsing efficacy and safety in the maelstrom of
2
Neurology 83
political, societal, administrative, and commercial influences. AUTHOR CONTRIBUTIONS Dennis Bourdette: drafting/revising the manuscript.
STUDY FUNDING No targeted funding reported.
DISCLOSURE D. Bourdette served on a scientific advisory board for the nonprofit entity NYSTEM; has received speaker honoraria from Biogen Idec, Teva Neurosciences, and Genzyme; has served as a consultant to Teva Neurosciences and Biogen Idec; has a use patent pending for the treatment of MS with cyclic peptide derivatives of cyclosporine, royalty payment from DebioPharma in 2012 and 2013; and receives research support from the US Department of Veterans Affairs. Go to Neurology.org for full disclosures.
REFERENCES 1. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 2014;89:225–240. 2. Menge T, Stüve O, Kieseier BC, Hartung HP. Alemtuzumab: the advantages and challenges of a novel therapy in MS. Neurology 2014;83:87–97. 3. FDA rejects MS drug Lemtrada. Available at: http://www. webmd.com/multiple-sclerosis/news/20131230/fda-rejects-msdrug-lemtrada. Accessed April 18, 2014. 4. FDA reviewers raise concern about alemtuzumab in MS. Available at: http://www.medscape.com/viewarticle/814121. Accessed April 18, 2014. 5. Coles AJ, Cox A, le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2006;253:98–108. 6. Coles AJ, Compston DA, Selmaj KW, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008;359:1786–1801. 7. 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. 8. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after diseasemodifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380:1829–1839. 9. Kraimps JL, Bouin-Pineau MH, Mathonnet M, et al. Multicentre study of thyroid nodules in patients with Graves disease. Br J Surg 2000;87:1111–1113.
July 1, 2014
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Alemtuzumab and multiple sclerosis: Is it safe? Dennis Bourdette Neurology published online June 11, 2014 DOI 10.1212/WNL.0000000000000554 This information is current as of June 11, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2014/06/11/WNL.00000 00000000554.full.html
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/early/2014/06/11/WNL.0000000000000554.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
EDITORIAL
Published Ahead of Print on June 11, 2014 as 10.1212/WNL.0000000000000554
Alemtuzumab and multiple sclerosis Is it safe?
Dennis Bourdette, MD, FAAN, FANA
Correspondence to Dr. Bourdette: [email protected] Neurology® 2014;83:1–2
The treatment of multiple sclerosis (MS) is complex. In the United States, we have 8 different classes of drugs approved for treating relapsing-remitting MS (RRMS).1 The first-generation therapies, glatiramer acetate and the b-interferons, have an impressive 20-year record of safety and many patients with RRMS have their disease well-controlled by these agents. Newer treatments, such as natalizumab, fingolimod, and dimethyl fumarate, may be more efficacious and convenient than the first-generation therapies. However, they lack a long-term safety record and some, such as natalizumab, have proved to be riskier than the first-generation therapies. In assessing any new therapy for RRMS, we must assess not just its efficacy but also its safety. Increased efficacy that comes with excessive risks is a Faustian bargain we should refuse. In this issue of Neurology®, Menge et al.2 review the key clinical trials of alemtuzumab for the treatment of RRMS. This review is timely given recent events. While regulatory agencies in Europe, Canada, Australia, and elsewhere have approved alemtuzumab for the treatment of RRMS, the US Food and Drug Administration (FDA) recently declined to register the therapy for MS.3 The divergent position of the FDA is partly based on the lack of subject blinding in the clinical trials but the FDA also raised concerns about the safety of the drug.4 Alemtuzumab is a humanized monoclonal antibody that rapidly depletes CD521 lymphocytes and monocytes following a short course of therapy.5 Repletion of cells occurs very slowly. Monocytes and B cells return to pretreatment levels within 3 months but T cells return much more slowly. CD81 T cells rise to pretreatment levels over a mean of 30 months and CD41 T cells remain below pretreatment levels for a mean of 5 years. Alemtuzumab’s prolonged effects on immune cells are the basis for its efficacy and also its risks. Menge et al.2 discuss the results of a phase 2 (CAMMS223) and 2 phase 3 trials (CARE-MS I and CARE-MS II) of alemtuzumab in RRMS.6–8 All 3 trials compared alemtuzumab with subcutaneous
interferon-b-1a (IFN-b-1a) and had coprimary outcomes of annualized relapse rate (ARR) and sustained disability worsening. Participants were not blinded to which treatment they received. CAMMS223 and CARE-MS I enrolled treatment-naive patients whereas CARE-MS II enrolled persons who had relapsed on glatiramer acetate or a b-interferon. All 3 studies showed lower ARR in subjects receiving alemtuzumab compared with IFN-b-1a. The ARR for alemtuzumab compared with IFN-b-1a for the trials were as follows: CAMMS223, 0.1 vs 0.36; CARE-MS I, 0.18 vs 0.39; CARE-MS II, 0.26 vs 0.52. The higher relapse rates in the CARE-MS II trial probably reflected enrollment of a more treatment-resistant group of participants, many of whom had had poorly controlled disease on b-interferon. Participants receiving alemtuzumab in the CAMMS223 and CARE-MS II trials had reductions in sustained disability worsening compared with those receiving IFN-b-1a (CAMMS233, 9% vs 26%, p , 0.001; CARE-MS II, 9% vs 22%, p 5 0.002). However, a difference in sustained disability worsening between the alemtuzumab and IFN-b-1a groups did not occur in CARE-MS I (8% vs 11%, p 5 0.22). This difference appears related to lower than expected disability progression in the placebo group. As reviewed by Menge et al., many secondary and post hoc clinical and magnetic resonance analyses have been performed on the data from these 3 trials, providing additional evidence that alemtuzumab is more efficacious than IFN-b-1a. However, their review also makes clear that alemtuzumab is substantially less safe than IFN-b-1a. Nearly 30% of patients with MS receiving alemtuzumab developed autoimmune thyroid disease, typically hyperthyroidism and Graves disease. While autoimmune thyroid disease is treatable, it is not trivial. Some patients required thyroidectomies and Graves disease may be a risk factor for thyroid cancer.9 Immune thrombocytopenia purpura occurred in 21 MS participants receiving alemtuzumab. One died from an intracranial hemorrhage while others were successfully treated, although some required treatment with immunosuppressants. A few cases of
See page 87 From the Department of Neurology, Oregon Health & Science University, Portland; and Multiple Sclerosis Center of Excellence–West, Portland Veterans Affairs Medical Center, OR. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the author, if any, are provided at the end of the editorial. © 2014 American Academy of Neurology
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
immune-mediated hemolytic anemia and neutropenia also occurred and one person with agranulocytosis died. Finally, 4 cases of renal failure resulting from Goodpasture syndrome have been reported and 2 required renal transplantation. Thus a variety of autoimmune diseases have occurred in patients with MS following treatment with alemtuzumab, with fatal consequences in two. Other serious complications associated with alemtuzumab have appeared. There have been 4 malignancies attributable to alemtuzumab, 3 thyroid cancers, and a fatal case of Burkitt lymphoma. Herpes zoster developed more commonly among subjects receiving alemtuzumab compared with IFN-b-1a and single cases of Listeria meningitis, esophageal candidiasis, and pasturella suggest an increased risk for opportunistic infections. Despite the lack of blinding of participants, it appears that alemtuzumab is more effective in controlling RRMS than IFN-b-1a. However, alemtuzumab has a disturbing array of serious side effects and at least 3 deaths have occurred as a result of diseases complicating therapy with alemtuzumab. Menge et al. suggest the serious side effects of alemtuzumab might be mitigated by risk management programs but this notion is unproven. The authors also suggest that it might be appropriate to investigate alemtuzumab as an induction therapy in RRMS to be followed by a standard platform disease-modifying therapy. Given the long duration of immunosuppression induced by alemtuzumab and the serious diseases it may induce, we must question the wisdom of such an approach. If alemtuzumab has any role in treating RRMS, given the risks, it seems that one would only be justified using it in the rare patient with very active RRMS who has failed treatment with other, safer MS therapies. Alemtuzumab is efficacious in treating RRMS but its substantial risks demand considerable caution in its use. From the US perspective, the FDA’s decision to obtain further information about alemtuzumab before licensing reflects the extreme complexity of parsing efficacy and safety in the maelstrom of
2
Neurology 83
political, societal, administrative, and commercial influences. AUTHOR CONTRIBUTIONS Dennis Bourdette: drafting/revising the manuscript.
STUDY FUNDING No targeted funding reported.
DISCLOSURE D. Bourdette served on a scientific advisory board for the nonprofit entity NYSTEM; has received speaker honoraria from Biogen Idec, Teva Neurosciences, and Genzyme; has served as a consultant to Teva Neurosciences and Biogen Idec; has a use patent pending for the treatment of MS with cyclic peptide derivatives of cyclosporine, royalty payment from DebioPharma in 2012 and 2013; and receives research support from the US Department of Veterans Affairs. Go to Neurology.org for full disclosures.
REFERENCES 1. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc 2014;89:225–240. 2. Menge T, Stüve O, Kieseier BC, Hartung HP. Alemtuzumab: the advantages and challenges of a novel therapy in MS. Neurology 2014;83:87–97. 3. FDA rejects MS drug Lemtrada. Available at: http://www. webmd.com/multiple-sclerosis/news/20131230/fda-rejects-msdrug-lemtrada. Accessed April 18, 2014. 4. FDA reviewers raise concern about alemtuzumab in MS. Available at: http://www.medscape.com/viewarticle/814121. Accessed April 18, 2014. 5. Coles AJ, Cox A, le Page E, et al. The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy. J Neurol 2006;253:98–108. 6. Coles AJ, Compston DA, Selmaj KW, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008;359:1786–1801. 7. 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. 8. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after diseasemodifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380:1829–1839. 9. Kraimps JL, Bouin-Pineau MH, Mathonnet M, et al. Multicentre study of thyroid nodules in patients with Graves disease. Br J Surg 2000;87:1111–1113.
July 1, 2014
ª 2014 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Alemtuzumab and multiple sclerosis: Is it safe? Dennis Bourdette Neurology published online June 11, 2014 DOI 10.1212/WNL.0000000000000554 This information is current as of June 11, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2014/06/11/WNL.00000 00000000554.full.html
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
