INVITED REVIEW ARTICLE
Newer Agents in the Treatment of Multiple Sclerosis Siddharama Pawate, MD* and Francesca Bagnato, MD, PhDw
Background: Multiple sclerosis (MS) is the most common cause of nontraumatic neurological disability in young adults. There is great need for developing effective treatments to arrest the disease. As of today, there is no cure for MS but several agents mitigating its effects are available. The era of disease-modifying therapy began with the use of interferon beta and glatiramer acetate in the 1990s. Given the injectable nature and the limited efficacy of these agents, efforts are ongoing to develop new treatments. Summary of Review: We provide an overview of the ongoing developments in MS therapy. After considering the clinical features and measures of drug efficacy in MS clinical trials, we report the phase-III clinical trials results of: (1) 3 oral agents approved within the last 5 years, fingolimod (Gilenya), dimethylfumarate (Tecfidera), and teriflunomide (Aubagio); (2) the oral agent laquinimod; and (3) the monoclonal antibodies daclizumab, ocrelizumab, and alemtuzumab. We will then briefly mention remyelinating and neuroprotective agents that are in very early studies. We will end with a possible approach to different clinical scenarios to guide the choice of disease-modifying therapy in patients. Conclusions: The newer agents offer the convenience of oral administration (for the oral agents) and potentially higher efficacy, but their long-term safety profile remains unknown. All available agents attack only 1 aspect of MS, that is, inflammatory demyelination. Arresting or reversing the progression of disability will be feasible only with agents affecting remyelination and neuroprotection, still in relatively early research. Key Words: multiple sclerosis, treatment, inflammation, demyelination, neuroprotection
(The Neurologist 2015;19:104–117)
M
ultiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system (CNS), affecting approximately 2.1 million people worldwide (400,000 in the United States).1 MS begins in young adulthood and is a life-long disease. Therefore, its socioeconomic impact is probably greater than that of other chronic and disabling neurological conditions such as Alzheimer’s disease and stroke.2 As of today, there is no cure for MS but several immunomodulatory agents mitigating its effects are available. Immunomodulatory therapies in MS are directed against the presumed autoimmune pathogenic mechanism of the disease (reviewed by Bar-Or and colleagues3–5). The first diseasemodifying treatment (DMT) approved by the Food and Drug From the *Department of Neurology, Multiple Sclerosis Center, Vanderbilt University Medical Center, Nashville, TN; and wDepartment of Neurology, University of Maryland, Baltimore, MD. The authors declare no conflict of interest. Reprints: Francesca Bagnato, MD, PhD, Department of Neurology, University of Maryland, 110 S Paca St., Baltimore, MD 21201. E-mail: [email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1074-7931/15/1904-0104 DOI: 10.1097/NRL.0000000000000020
104 | www.theneurologist.org
Administration (FDA) was interferon beta-1b (IFNb-1b) (Betaseron) in 1993.6–8 IFNb-1b was followed by IFNb-1a (Avonex and Rebif),9–13 and glatiramer acetate (GA, Copaxone).14 Both IFNs and GA reduce the number of clinical relapses in the relapsing-remitting phase of the disease, and the formation of new lesions assessed by magnetic resonance imaging (MRI). However, both IFNs and GA are largely ineffective in preventing or delaying disability progression. Natalizumab (Tysabri) is about twice as efficacious than IFNb and GA in reducing MS relapses,15,16 and is given by monthly infusions, making it easy to monitor compliance. It is generally well tolerated. Unfortunately, patients treated with natalizumab are at risk of developing progressive multifocal leukoencephalopathy (PML) due to reactivation of the John Cunningham virus (JCV) in the brain.17,18 Detection of anti-JC virus antibody testing,19 which may predict the risk of PML,20 has allowed for stratification of the risk of PML. The main risk factors for PML development are: (1) presence of anti-JCV antibody, (2) duration of natalizumab therapy, with risk increasing after 24 months, and (3) a history of prior immunosuppression. As more information about PML risk becomes available, the safety profile of natalizumab will be more clearly defined. It will then be possible that it will find a wider use. Mitoxantrone (Novantrone) is efficacious in highly active disease and is approved for secondary progressive MS with superimposed relapses. Mitoxantrone suffers from high adverse reactions including leukemia (1 in 500) and cardiotoxicity.21 With the availability of newer agents it will likely have an extremely limited indication. The limitations of the approved therapies as detailed above indicate the need for more options in treating MS. The needs include superior efficacy, better compliance through ease of use and lack of serious adverse effects (AEs), and longterm safety. The recent availability of oral medications for MS is therefore an important development. Within the last 5 years the FDA has approved 3 oral agents, fingolimod (Gilenya), teriflunomide (Aubagio), and dimethylfumarate (Tecfidera), and the anti-CD52 monoclonal antibody alemtuzumab (Lemtrada) for use in MS. Other agents are in various stages of clinical trials and FDA approval. These agents include the oral agent laquinimod, and the monoclonal antibodies daclizumab and ocrelizumab. In the present manuscript, we will briefly overview the clinical manifestations of MS and the clinical and radiologic means used to assess drug efficacy in MS patients during the course of experimental clinical trials. We will then review the current status of all the above-mentioned newer therapies, appraising the results of all the phase-III clinical trials published as of January 2014. The IFNs, GA, and natalizumab have been extensively reviewed elsewhere.22–27 We will not discuss oral cladribine, recently reviewed,28 which was not approved for MS therapy in the United States and Europe because of safety concerns, although it is approved as an MS therapy in Russia and Australia. Results reported in the pivotal clinical trials, which led to the approval of each medication are summarized in Table 1. The Neurologist
Volume 19, Number 4, April 2015
The Neurologist
Volume 19, Number 4, April 2015
New Treatments for Multiple Sclerosis
TABLE 1. Efficacy and Safety of MS Therapies That Have been Approved or Undergone Phase-III Clinical Trials (Data Refer to the Studies That Lead the Medication Approval)
Agent/Pivotal Clinical Trial
Clinical Outcome Measures: ARR and CDP
MRI Outcome Measures: CELs, WM-Ls on T2-w MRI, cBHs, and BPF
IFNb-1b (Betaseron)6,7
ARR: 34% reduction (P
Newer Agents in the Treatment of Multiple Sclerosis Siddharama Pawate, MD* and Francesca Bagnato, MD, PhDw
Background: Multiple sclerosis (MS) is the most common cause of nontraumatic neurological disability in young adults. There is great need for developing effective treatments to arrest the disease. As of today, there is no cure for MS but several agents mitigating its effects are available. The era of disease-modifying therapy began with the use of interferon beta and glatiramer acetate in the 1990s. Given the injectable nature and the limited efficacy of these agents, efforts are ongoing to develop new treatments. Summary of Review: We provide an overview of the ongoing developments in MS therapy. After considering the clinical features and measures of drug efficacy in MS clinical trials, we report the phase-III clinical trials results of: (1) 3 oral agents approved within the last 5 years, fingolimod (Gilenya), dimethylfumarate (Tecfidera), and teriflunomide (Aubagio); (2) the oral agent laquinimod; and (3) the monoclonal antibodies daclizumab, ocrelizumab, and alemtuzumab. We will then briefly mention remyelinating and neuroprotective agents that are in very early studies. We will end with a possible approach to different clinical scenarios to guide the choice of disease-modifying therapy in patients. Conclusions: The newer agents offer the convenience of oral administration (for the oral agents) and potentially higher efficacy, but their long-term safety profile remains unknown. All available agents attack only 1 aspect of MS, that is, inflammatory demyelination. Arresting or reversing the progression of disability will be feasible only with agents affecting remyelination and neuroprotection, still in relatively early research. Key Words: multiple sclerosis, treatment, inflammation, demyelination, neuroprotection
(The Neurologist 2015;19:104–117)
M
ultiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system (CNS), affecting approximately 2.1 million people worldwide (400,000 in the United States).1 MS begins in young adulthood and is a life-long disease. Therefore, its socioeconomic impact is probably greater than that of other chronic and disabling neurological conditions such as Alzheimer’s disease and stroke.2 As of today, there is no cure for MS but several immunomodulatory agents mitigating its effects are available. Immunomodulatory therapies in MS are directed against the presumed autoimmune pathogenic mechanism of the disease (reviewed by Bar-Or and colleagues3–5). The first diseasemodifying treatment (DMT) approved by the Food and Drug From the *Department of Neurology, Multiple Sclerosis Center, Vanderbilt University Medical Center, Nashville, TN; and wDepartment of Neurology, University of Maryland, Baltimore, MD. The authors declare no conflict of interest. Reprints: Francesca Bagnato, MD, PhD, Department of Neurology, University of Maryland, 110 S Paca St., Baltimore, MD 21201. E-mail: [email protected]. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 1074-7931/15/1904-0104 DOI: 10.1097/NRL.0000000000000020
104 | www.theneurologist.org
Administration (FDA) was interferon beta-1b (IFNb-1b) (Betaseron) in 1993.6–8 IFNb-1b was followed by IFNb-1a (Avonex and Rebif),9–13 and glatiramer acetate (GA, Copaxone).14 Both IFNs and GA reduce the number of clinical relapses in the relapsing-remitting phase of the disease, and the formation of new lesions assessed by magnetic resonance imaging (MRI). However, both IFNs and GA are largely ineffective in preventing or delaying disability progression. Natalizumab (Tysabri) is about twice as efficacious than IFNb and GA in reducing MS relapses,15,16 and is given by monthly infusions, making it easy to monitor compliance. It is generally well tolerated. Unfortunately, patients treated with natalizumab are at risk of developing progressive multifocal leukoencephalopathy (PML) due to reactivation of the John Cunningham virus (JCV) in the brain.17,18 Detection of anti-JC virus antibody testing,19 which may predict the risk of PML,20 has allowed for stratification of the risk of PML. The main risk factors for PML development are: (1) presence of anti-JCV antibody, (2) duration of natalizumab therapy, with risk increasing after 24 months, and (3) a history of prior immunosuppression. As more information about PML risk becomes available, the safety profile of natalizumab will be more clearly defined. It will then be possible that it will find a wider use. Mitoxantrone (Novantrone) is efficacious in highly active disease and is approved for secondary progressive MS with superimposed relapses. Mitoxantrone suffers from high adverse reactions including leukemia (1 in 500) and cardiotoxicity.21 With the availability of newer agents it will likely have an extremely limited indication. The limitations of the approved therapies as detailed above indicate the need for more options in treating MS. The needs include superior efficacy, better compliance through ease of use and lack of serious adverse effects (AEs), and longterm safety. The recent availability of oral medications for MS is therefore an important development. Within the last 5 years the FDA has approved 3 oral agents, fingolimod (Gilenya), teriflunomide (Aubagio), and dimethylfumarate (Tecfidera), and the anti-CD52 monoclonal antibody alemtuzumab (Lemtrada) for use in MS. Other agents are in various stages of clinical trials and FDA approval. These agents include the oral agent laquinimod, and the monoclonal antibodies daclizumab and ocrelizumab. In the present manuscript, we will briefly overview the clinical manifestations of MS and the clinical and radiologic means used to assess drug efficacy in MS patients during the course of experimental clinical trials. We will then review the current status of all the above-mentioned newer therapies, appraising the results of all the phase-III clinical trials published as of January 2014. The IFNs, GA, and natalizumab have been extensively reviewed elsewhere.22–27 We will not discuss oral cladribine, recently reviewed,28 which was not approved for MS therapy in the United States and Europe because of safety concerns, although it is approved as an MS therapy in Russia and Australia. Results reported in the pivotal clinical trials, which led to the approval of each medication are summarized in Table 1. The Neurologist
Volume 19, Number 4, April 2015
The Neurologist
Volume 19, Number 4, April 2015
New Treatments for Multiple Sclerosis
TABLE 1. Efficacy and Safety of MS Therapies That Have been Approved or Undergone Phase-III Clinical Trials (Data Refer to the Studies That Lead the Medication Approval)
Agent/Pivotal Clinical Trial
Clinical Outcome Measures: ARR and CDP
MRI Outcome Measures: CELs, WM-Ls on T2-w MRI, cBHs, and BPF
IFNb-1b (Betaseron)6,7
ARR: 34% reduction (P
