The Shifting Landscape of Disease-Modifying Therapies for Relapsing Multiple Sclerosis

Multiple sclerosis (MS) is the most common nontraumatic neurological disorder of young adults, and roughly 85% of patients present with the relapsing form of the disease. Over the past 2 decades, the treatment arsenal for relapsing MS has expanded and evolved from mildly effective and relatively benign injectable agents to potent cell-depleting monoclonal agents. The latter have the potential to achieve disease remission coupled with risk of moderate to severe adverse events with which all MS care providers will need to acquaint themselves. This review is based on a detailed assessment of MS pivotal trials, extension studies, and expert reviews of the agents discussed. The following review should aid those practitioners directly and indirectly involved in the care of MS patients in understanding the benefits and risks associated with the medications they prescribe.

Disease of the Year: Multiple Sclerosis Section Editor: Fiona Costello, MD, FRCP(C) The Shifting Landscape of Disease-Modifying Therapies for Relapsing Multiple Sclerosis Jodie M. Burton, MD, MSc, FRCPC, Mark S. Freedman, MSc, MD, FAAN, FANA, FRCPC Background: Multiple sclerosis (MS) is the most common nontraumatic neurological disorder of young adults, and roughly 85% of patients present with the relapsing form of the disease. Over the past 2 decades, the treatment arsenal for relapsing MS has expanded and evolved from mildly effective and relatively benign injectable agents to potent cell-depleting monoclonal agents. The latter have the potential to achieve disease remission coupled with risk of moderate to severe adverse events with which all MS care providers will need to acquaint themselves. Methods: This review is based on a detailed assessment of MS pivotal trials, extension studies, and expert reviews of the agents discussed. Results/Conclusions: The following review should aid those practitioners directly and indirectly involved in the care of MS patients in understanding the benefits and risks associated with the medications they prescribe. Journal of Neuro-Ophthalmology 2018;38:210-216 doi: 10.1097/WNO.0000000000000659 © 2018 by North American Neuro-Ophthalmology Society P erhaps more so than in any other neurological disease, the treatment arsenal of disease-modifying therapies (DMTs) of disease modifying for multiple sclerosis (MS) Department of Clinical Neurosciences (JMB), Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; and Division of Neurology (MSF), The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada. J. M. Burton has participated in advisory boards for Novartis and EMD Serono, and has received unrestricted educational support and honoraria for educational presentations from Novartis, Sanofi Genzyme, BiogenIdec, and EMD Serono. M. S. Freedman is a member of advisory boards for Actelion, BayerHealthcare, BiogenIdec, Clene Nanomedicine, Hoffman La-Roche, Merck Serono, MedDay, Novartis, Sanofi-Aventis, has received honoraria and consultation fees from Actelion, BayerHealthcare, BiogenIdec, Chugai, Clene Nanomedicine, EMD Canada, Genzyme, Merck Serono, Novartis, Hoffman La-Roche, Sanofi-Aventis, Teva Canada Innovation, and has participated in Sanofi Genzyme's sponsored speaker's bureau. He has also received research/education grants from Genzyme. Address correspondence to Jodie M. Burton, MD, MSc, FRCPC, Health Sciences Centre, Room 1007c, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada; E-mail: [e-mail] 210 has evolved and expanded at a record pace. Before the 1990s, no viable preventative treatment options existed. A breakthrough came in 1993, when the first MS-specific drug, interferon beta-1b, was shown to change the natural history of MS and was approved in the United States (1). By 1998, another 3 self-injectable agents became available, of which 2 were variations of interferon beta-1a and 1 was a unique mixture of random peptide molecules called glatiramer acetate. All were approved on the basis of reducing relapses relative to placebo by a modest 30% (2-4). And, although their effectiveness has limitations, their safety profile (flulike side effects, skin irritation with extremely rare hepatic and hematological adverse events) was and remains a major selling point. The treatment landscape for MS since has broadened considerably; first, by recognizing that available treatments had the best impact if given early; and second, because gains in knowledge of MS pathophysiology coupled with evolution in drug development helped to yield more specific agents with improved outcomes, albeit while producing new and different inherent risks. Paradigm shifts in MS have moved from the "wait and see" approach to aggressively trying to curb all disease activity, buoyed by research showing that central nervous system (CNS) degeneration occurs at even the earliest possible time point of disease onset. With greater choice came the inevitable debate between targeting MS earlier and more aggressively vs escalating on an as need bases to avoid irreversible damage. With the introduction of natalizumab in 2004 and subsequent agents came a newly recognized complication offsetting improved efficacy-that of risk due to the development of opportunistic infections, the most worrisome being the often lethal and untreatable progressive multifocal leukoencephalopathy (PML). All current therapies for relapsing forms of MS are approved based on relapse reduction relative to a comparator (initially placebo, more recently a first-line agent); however, the ultimate goal is to slow or prevent impairment from cumulative CNS damage. Advanced Burton and Freedman: J Neuro-Ophthalmol 2018; 38: 210-216 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis neuroimaging and evolving biomarkers can help identify significant damage that does not clinically manifest but likely contributes to earlier disability (5). So, is it enough to simply reduce relapses or should the goal of therapy be to go as far as possible to stop all ongoing disease activity? To this end, treating neurologists have posited a different outcome measure-that of being free of detectable activity or no evidence of disease activity (NEDA). In its simplest and easiest form to measure, known as NEDA3, it is characterized by the absence of both relapse activity and sustained clinical disability progression, as well as the absence of new MRI activity (most commonly measured as new T2/gadolinium-enhancing lesions). Those treated patients meeting NEDA, especially early in their course, may have a lower risk of ultimate disability (2-year NEDA shows a 78% positive predictive value of no progression at Year 7) (6), but not all studies support this observation (6,7). We will provide an up-to-date review of current MS medications used most frequently and include examining their risks and benefits and suggestions on how they are being prescribed to optimize therapy. FIRST-LINE AGENTS (THE "ORIGINALS") The "first" first-line agents are the interferons (interferon beta-1a and-1b, interferon beta-1 b) and glatiramer acetate. These often are referred to as "immunomodulators" for their ability to alter the immune response specifically for MS, without suppressing host immunity. Pivotal 2-year placebo-controlled trials in relapsing MS showed relatively similar results for all the drugs, characterized by 18% (interferon beta-1a IM) to 34% (interferon beta-1a [SC]) relative relapse reduction and a 35% (glatiramer acetate) to .80% (interferon beta-1b SC) and (interferon beta-1a SC) reduction in new MRI lesion formation (1-4). Subsequent trials were not powered to show a treatment effect on slowing accumulation of sustained disability progression, but both the interferon beta-1a agents did demonstrate a significant reduction of 6-month sustained disability ranging from 22% to 37%, respectively (2,3). Long-term extension trials have suggested that even overall survival was better in patients originally assigned and maintaining treatment with interferon beta-1b, (8). In clinically isolated syndrome (CIS-or first clinical event MS) trials, all the "originals" showed roughly the same reduction in risk of the next relapse compared with placebo over the ensuing 2-3 years of approximately 45%-46%, compared with 30% in established MS; hence, the justification for treatment earlier in the disease course (9). The safety profile of the interferons is characterized by not uncommon, but relatively tolerable, flu-like symptoms (malaise, headache, arthralgia) and rare laboratory abnormalities in complete blood count (CBC) (mild leukopenia) and liver function tests (LFTs). Severe adverse events in the Burton and Freedman: J Neuro-Ophthalmol 2018; 38: 210-216 form of major perturbations in laboratory values and autoimmune hepatitis are exceedingly rare, and monitoring typically includes routine blood work every 6 months (1-3). Glatiramer acetate requires no monitoring and the most common adverse event is skin irritation, ranging from mild redness to rare, but disfiguring, lipoatrophy (4). In attempting to limit adverse events or avoid comorbidities that preclude the use of nerve agents, these "originals" are a reasonable first-choice therapy, particularly in patients with mild MS. Studies have shown continued benefit for many patients over decades, although early breakthrough disease does occur. So, early and relatively frequent monitoring is indicated for optimizing treatment. The inconvenience of self-injection, particularly in young and active patients, should not be discounted, and not surprisingly, the injectables are now considered a "hard sell" in the clinical setting. BEYOND THE SELF-INJECTABLE IMMUNOMODULATING AGENTS Based on studies in animal models of MS, natalizumab has the distinction of being the first monoclonal agent that prevents lymphocyte trafficking into the CNS (targeting the alpha-4 integrin) in MS, and also the DMT that heralded the real-world implications of severe adverse event awareness (10). Initially released in 2004, the agent was abruptly removed from market after it was discovered that 2 patient deaths in Phase III MS trials were due to PML (caused by the neurotropic JC virus entry into the CNS) (10). It is now well known that natalizumab treatment is associated with PML, a risk that increases with increasing duration of use (.24 months) and in patients previously exposed to immunosuppressive agents (11). High or rising titers of JC virus antibodies also are a risk factor for developing PML. Despite this, natalizumab is an effective and tolerable agent producing relapse reductions of 68% vs placebo, with virtually no day-to-day adverse events (12,13). MRI activity was also significantly reduced and disease progression slowed. Monitoring remains sacrosanct, however, with routine JC virus antibody serum testing, frequent MRI scanning, and immediate clinical assessment and cerebrospinal fluid testing in anyone with symptoms suggestive of PML. It also is wise to have the next agent in mind when starting natalizumab because in many patients, a switch due to 2 of the 3 risk factors (duration of use and JCV antibody positivity, something w60%-70% of us have) may become necessary (14). Sequencing the next therapy may be an issue, both because of the potential carry-over risk of early silent PML (particularly if the next agent is immunosuppressive) and because stopping an antitrafficking therapy such as natalizumab or fingolimod without timely substitution can lead to severe and even fatal rebound of MS activity because lymphocytes prevented from entering the CNS are suddenly able to do so en masse (15,16). 211 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis A STEP UP (THE "ORALS," PART 1) Each with their own somewhat unique mechanism of action, the oral DMTs offer an attractive alternative to self-injection. As the first approved oral medication for MS, fingolimod arrived in 2010, along with it came a shift toward the convenience of oral therapy for newly diagnosed patients. Fingolimod is not available as a first-line agent worldwide (in Canada and Europe, it is second line), and remains a second-line treatment owing to its inherent safety issues. Like natalizumab, fingolimod is an antilymphocyte trafficking agent that works by sequestering potentially disease-causing cells in lymph nodes. It does so by acting as an agonist to sphingosine-1-phosphate (S1P) receptors required for lymphocytes to egress lymph nodes (17). Binding the receptors leads to involution, but reexpression of S1P occurs on drug cessation. It is somewhat immunosuppressive and has been associated with a "rebound effect" if it is stopped without the timely introduction of a planned substitute. The efficacy data come from 3 major Phase III studies: FREEDOMS (18), FREEDOMS II (19), both placebo-controlled, and TRANSFORMS (20), a comparator study with interferon beta-1a (IM). Relative relapse rates compared with placebo broached 50% with significant reduction in MRI activity and slowing of disease progression (vs placebo only in FREEDOMS but not in FREEDOMS II) (19). Aside from the rebound issue, fingolimod's immunosuppressive properties have been linked to both herpetic lesions and PML. Given the widespread location of S1P receptors (e.g., cardiac muscle, the macula), adverse events include possible bradycardia and arrhythmias (often seen with the first dose, hence the first dose is done under monitoring) and, rarely, macular edema (necessitating close ophthalmological monitoring) (17). In 2012, teriflunomide was approved in the United States as a once daily oral medication (7 or 14 mg in the United States, 14 mg elsewhere). It works by depleting de novo purine pools necessary for rapidly dividing autoimmune cells. In the pivotal TEMSO trial, once daily teriflunomide vs placebo over 2 years resulted in a relative relapse reduction of 31%, with no clear difference between the doses on the clinical outcome, but a definite dose response in terms of MRI activity (21). Teriflunomide was studied in the largest clinical trial program to date, with 3 further Phase III studies TOWER, TOPIC, and TENERE (22-24). The higher dose consistently outperformed the lower dose of the drug, with significant effects on relapse reduction. Teriflunomide is the only oral agent to show an effect on slowing disease progression in both Phase III studies. Although relatively tolerable with rare abnormalities on laboratory monitoring of CBC and LFTs, the most notable adverse events associated with teriflunomide were mild hair thinning (telogen effluvium) and gastrointestinal disturbance (21,25). Its parent drug, leflunomide, was associated 212 with potential teratogenicity in animals, but to date, there has been no evidence of human teratogenicity in an ongoing pregnancy registry. Teriflunomide is the only DMT able to be flushed from the body with an elimination procedure removing 98% of the drug within 11 days (25). In 2013, dimethyl fumarate (DMF) was approved. It has an unclear mechanism of action, possibly acting more as a complex immunomodulator. It also is considered as a firstline oral agent with similar efficacy, but also concerning risks. The DEFINE trial studied DMF vs placebo, whereas the CONFIRM trial used a placebo and an active comparator, glatiramer acetate (26,27). A 53%-44% relative reduction in relapses vs placebo was noted in both studies, with a significant reduction in disability seen only in the DEFINE study (26,27). There was no statistically significant benefit in relapse reduction vs glatiramer acetate (26,27). The most common and sometimes intolerable adverse reactions associated with DMF include flushing, abdominal pain, and nausea/vomiting. In addition, between 2% and 9% of patients developed $Grade 3 lymphopenia (absolute lymphocyte count ,500/mL), which typically persists (26,28). Notably, the risk of DMF-associated lymphopenia increases with age, with more severe lymphocyte count reduction (Grade 2 or 3 lymphopenia) occurring in as many as 40% of DMF-treated patients with MS aged 55 years and older (26-28). This is of concern because in addition to numerous herpetic complications are at least 4 reported cases of PML, most commonly in patients with persistent lymphopenia and older than 50 years (28). Patients who demonstrate persistent lymphopenia early in their DMF course are typically switched to another agent. The oral first-line agents have simplified treatment and seem to have improved on the efficacy as well as drug adherence, but are offset by higher risks of worrisome adverse events that require ongoing monitoring. None of the DMT is proven safe in pregnancy or breastfeeding, requires diligence on both the patient's and provider's part to comply with required safety monitoring, and provides no lasting immunological modulation after discontinuation (25). INCREASING THE POWER (MORE "ORALS" AND THE ADVENT OF THE CELL-DEPLETING MONOCLONAL ANTIBODIES) When patients require a greater degree of disease control beyond immunomodulation or the blocking of lymphocyte trafficking, we tend to move toward cell-depleting therapies. Alemtuzumab is actually the first monoclonal antibody ever developed for human treatment and was approved for the treatment of MS in 2014. It also is the first agent that might truly induce remission of disease without the need for continual administration. This antibody binds to CD52 on T and B cells as well as monocytes, and activates cell death Burton and Freedman: J Neuro-Ophthalmol 2018; 38: 210-216 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis by complement binding and antibody-dependent cellmediated cytotoxicity (ADCC) (29). It is administered at baseline at 12 mg intravenously/day for 5 days, then again at Year 1 at the same dose for 3 days (29). In the CARE MS I trial (in treatment-naive patients), the risk reduction in relapses was 54.9%, whereas in the 5-year extension study, annualized relapse rates remained low, between 0.15 and 0.19, and through years 2-5, almost 61% of patients who received only 2 cycles of alemtuzumab achieved NEDA as well as slowing of median annual brain volume loss (29,30). In CARE MS II (treatment breakthrough patients), the risk reduction in relapses was 49.4%, with a 40% reduction in 6-month sustained disability (31). In CARE MS II 5-year extension study, annualized relapse rates remained low, between 0.18 and 022, and in the 58% of patients receiving only these 2 cycles, almost 50% achieved NEDA over this time (32). For breakthrough disease beyond Year 2, repeat 3-day cycles annually can be administered. But the downside of achieving remission after only 2 cycles is the very real issue of secondary autoimmune disease. There is 30+% risk of autoimmune thyroid disease, a 2% risk of idiopathic thrombocytopenic purpura, and rare antibody-mediated glomerular nephropathy syndromes (0.3%) (29-32). Emergence of secondary autoimmunity can occur up to 4 years after dosing, necessitating monthly laboratory monitoring for a minimum of 5-6 years (29,30). Infusion reactions are also likely (w90% of patients) and can range from myalgias, headaches to fever, urticarial and both symptomatic tachycardia and bradycardia, all reduced with concomitant administration of steroids and antihistamine drugs. Opportunistic infections, commonly herpetic eruptions, as well as cases of Listeria monocytogenes meningitis, also have been seen (4,5). Herpes prophylaxis is routine following each course. At present, no cases of PML have been reported in patients with MS treated with this agent (33). Alemtuzumab provides a unique opportunity to avoid chronic treatment, which allows for such things as eventual pregnancy. Ocrelizumab is a monoclonal agent targeting CD20 found on B cells, causing cell death similar to alemtuzumab by binding complement and inducing ADCC. It was approved in 2017 after 2 large Phase III trials showed a relative relapse reduction of 46%-47% (annualized relapse rate of 0.16) vs interferon beta-1a with a 40% risk reduction of 6-month disability progression (34). It also nearly shut down new lesion development on MRI relative to the interferon treatment with the very first infusion. Coupled with relatively mild infusion reactions and an infusion schedule of every 6 months, this agent provides powerful disease control with a relatively manageable regimen. Infections, including herpetic lesions, were more common in patients treated with ocrelizumab, as were an apparent increased number of malignancies (especially breast cancer) (34). At present, no cases of PML have been reported with this agent in the treatment of MS. Burton and Freedman: J Neuro-Ophthalmol 2018; 38: 210-216 The most recent addition to the array of cell-depleting therapies is oral cladribine. Cladribine, a purine analogue antimetabolite, was actually set to be the first oral agent on the market, but it was initially denied FDA approval due to a seemingly relatively high risk of malignancy (35). In truth, the risk was not significantly higher in treated patients, but the placebo group had surprisingly zero malignancies. A near 20-year safety registry was established to show no increased risk of malignancy and it was approved at a total dose of 3.5 mg/kg in 2017 in Canada and Europe. Cladribine induces a rapid and prolonged decrease in circulating B and T lymphocytes including both resting and dividing cells (35). It does so as a purine analogue that is activated, but not depleted in lymphocytes (owing to an absence of deactivating enzymes), whereas in all other cell types it is inactivated. Relative to placebo, cladribine reduced relapses by 55%-58% (36). Those who switched to cladribine in the extension study had an annualized relapse rate of 0.15. (vs 0.33 for the placebo) (37). Significant MRI reduction and slowing of disease progression were also noted in this trial with a 47% NEDA rate at 2 years (37). The CLARITY study extension showed that patients initially treated with 3.5 mg/kg of oral cladribine randomized for an additional 2 years to placebo did as well as those receiving an additional 2 years of 3.5 mg/kg treatment (38). Thus, similar to alemtuzumab, there seems to be a remission that can be long-lasting after only a 2-year treatment without the need for additional treatments. In the ORACLE CIS trial, there was a 67% (for the 3.5 mg/kg dose) reduction in risk of the next relapse, nearly twice the reduction than what had been described for the first-line injectable immunomodulators (39). Adverse events include persistent lymphopenia (which must resolve before redosing), and routine and opportunistic infections such as herpetic lesions and TB reactivation (35-37). In patients with more aggressive disease behavior, induction agents such as alemtuzumab and cladribine provide a good chance of remission. As well, pregnancy becomes a more manageable option after induction is complete. For those who need rapid disease control, ocrelizumab and the antitrafficking agents natalizumab and fingolimod are often selected, but stopping natalizumab or fingolimod requires advanced planning to deal with potential rebound activity. GO BIG OR GO HOME (TRANSPLANT AS A STANDARD MEMBER OF THE TREATMENT ARSENAL) At the far end of the inflammatory control spectrum is immunoablation followed by autologous hematopoietic stem cell transplant (AHSCT). In the early days of transplantation, regimens were either extremely weak or highly toxic, and performed in patients who were well into the degenerative phase of their disease with predictably poor 213 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year: Multiple Sclerosis FIG. 1. A suggested algorithm for DMT treatment optimization in relapsing-remitting MS (44). Patients with "low" risk of imminent disease progression are represented by the blue line, whereas those at high risk of imminent disease progression are represented by the red line. DMT, disease-modifying therapy; GA, glatiramer acetate; IFNB, inteferon beta; MS, multiple sclerosis. results (40). More recent trials and retrospective studies have made it clear that the ideal patient is a relatively young, able, and healthy relapsing patient who has active inflammatory disease despite adherence to a second-line agent, and that the ideal regimen for ablation is of intermediate or higher intensity (e.g., BEAM ATG, busulfan) (41-43). In relapsing MS, AHSCT is no longer an experimental therapy, but in the appropriate center, a viable option. With appropriate regimen and patient selection, patients have near-cessation of inflammatory disease activity, with a mean NEDA rate of up to 92% in the first 2 years. Risks are considerable, including infertility, febrile neutropenia, opportunistic infections, allergic and autoimmune complications, and a small, delayed risk of myelofibrosis (43). SO HOW TO CHOOSE: WHEN IS IT TIME TO CHANGE, AND TO WHAT? It is clear that treating MS has become much more complicated and probably should be the role of a trained MS neurologist. One approach has been to offer treatment escalation on an "as-needed" basis, starting with the safest agents first, particularly in a young adult who may live another 40-50 years. But, such a simplistic view of empirical therapy ignores what has been learned regarding disease behavior before DMT selection, which may predict the severity of MS and its prognosis-some patients clearly have a more aggressive disease warranting a more aggressive upfront treatment. One optimization scheme is depicted in (Fig. 1). Choice of first-line and subsequent treatment is based on the perceived propensity for a patient to have early disease progression, weighing in many prognostic factors. For example, after choosing a typical first-line treatment, 214 a patient's disease may be uncontrolled and his/her risk of progression changes from low to high, necessitating an escalation to a more effective but riskier therapy. After treatment with that therapy for a period, disease control may be adequately achieved, and a de-escalation is possible for longer-term safer treatment. Should the second escalated therapy be ineffective, further escalation is indicated, usually to a cell-depleting therapy (44). Ultimately, optimizing MS therapy truly requires a personalized approach, weighing in patient-specific factors that take into account disease severity, comorbidities, conception plans, and compliance with monitoring. 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