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The Current Landscape and Unmet Needs in Multiple Sclerosis
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Abstract
When introduced in the early and middle 1990s, current first-line pharmacologic therapies for multiple sclerosis (MS)-interferon beta-1a, interferon beta-1b, and glatiramer acetate-constituted a major advancement in MS treatment. Nevertheless, disease progression, although typically delayed with these agents, remains inevitable in most patients and constitutes a significant limitation of the currently available treatments. Moreover, the first-line therapies all require frequent subcutaneous or intramuscular injections, delivery modalities that are associated with subpar treatment adherence. The demand for more effective agents has produced a new generation of MS therapies with impressive efficacy profiles-although their long-term safety and tolerability remain largely unknown. Some of the new agents have been formulated for oral administration, which will likely have a positive impact on treatment adherence. These new agents are appearing during a time of major change in MS research. As the old expectation of inevitable disease progression is being reconsidered, the notion of sustained disease inactivity has become a credible, still somewhat elusive, goal. Neuroprotection may also be possible with new and existing treatments. At the same time, new imaging techniques, such as measuring disease progression via T1-hypointense lesions ("black holes"), and a better understanding of pathophysiologic factors in MS-such as the role of neurotrophic growth factors and oxidative stress-are changing the ways that efficacy is measured and how new agents are developed.
(Am J Manag Care. 2010;16:S211-S218)
The treatment landscape for multiple sclerosis (MS) is currently undergoing very significant changes. For nearly a decade and a half, 3 therapies have dominated MS practice: interferon beta-1a (IF NB-1a), interferon-1b (IF NB-1b), and glatiramer acetate (GA). A fourth therapy, natalizumab, has demonstrated a high degree of efficacy, but its use has been limited by risk of progressive multifocal leukoencephalopathy (PML).1,2 Although the current armamentarium for MS has improved patients' quality of life, there is certainly room for improvement in terms of efficacy, convenience, and adherence.
A new generation of MS therapies is emerging, with novel mechanisms of action and new delivery modalities (eg, infrequent infusion and oral administration), which could have important ramifications for adherence to MS therapies. Several therapies are under review by the US Food and Drug Administration (FDA) and some are in the later stages of development.
The notion of what constitutes adequate efficacy in MS has begun to shift. When current first-line agents were introduced in the 1990s, they represented a marked improvement in the treatment of MS. Gradually, however, treatment expectations began to rise. After all, most patients were not getting better; they were just deteriorating at a less rapid rate. Unfortunately, this is still the case. Nevertheless, the conceptual framework, and ambition, for what constitutes a high degree of efficacy in MS has migrated from a model of slowing disease progression to a model of disease remission and neuroprotection. As the expectations for treatment efficacy have evolved, so have the means of measuring efficacy. Efficacy can now be measured using new sophisticated imaging techniques, and there are novel markers for disease progression and neuroprotection.
At present, new ambitions for treatment efficacy in MS have yet to be fulfilled. Limited evidence suggests that it may be possible, however, at least in a significant subset of patients, to achieve sustained remission.3-5 It remains to be seen whether new MS agents will be able to provide patients with a higher standard of efficacy, and greater reason for optimism, compared with current treatments. Also, it will have to be determined whether the safety profiles of new agents allow for use in the entire patient population.
The Efficacy of Current MS Treatments
All 3 first-line MS agents, as well as natalizumab, demonstrate clinically significant efficacy in treating MS. Many MS experts feel that none of the 3 first line agents demonstrates superior efficacy over another, and each confers particular advantages and disadvantages.
Interferon Beta-1b
IFNB-1b was approved by the FDA in 1993, and it was the first disease-modifying drug (DMD) available for the treatment of MS. It is indicated for treating relapsing forms of MS and is administered by subcutaneous (SC) injection every other day.6 IFNB-1b has been shown to significantly reduce the occurrence of relapses versus placebo and to limit magnetic resonance imaging (MRI )-detected deterioration in patients with relapsing-remitting MS (RRMS).7,8
In addition to reducing relapses and improving MRI variables, IFNB-1b was studied in the BENEFIT (Betaferon/Betaseron in Newly Emerging MS For Initial Treatment) trial over a period of 5 years to determine the consequences of early treatment versus delayed treatment with IFNB-1b.9 Patients were randomized to receive either IF NB-1b (n = 292) or placebo (n = 176) within 60 days of the first neurological event suggestive of MS. Patients were also required to have at least 2 clinically silent T2 MRI lesions. In the second phase of the study, patients in the placebo group were switched to IFNB-1b after 2 years elapsed or a diagnosis of clinically definite MS (CDMS) (whichever occurred first).
Figure 1
Figure 2
After 5 years, significantly more (46%) patients who received early IFNB-1b received a diagnosis of CDMS compared with those who received delayed treatment (57%) (P = .003) (). Thus, treatment with IF NB-1b appeared to significantly delay the onset of CDMS. The number needed to treat (NNT) to prevent 1 CDMS diagnosis was 9.9 Over the course of 5 years, disability progression, as measured by the Expanded Disability Status Scale (EDSS), was lower in the early-treatment group, but the difference was not significant ().
Interferon Beta-1a
IFNB-1a is indicated in RRMS for the reduction of relapses and to slow the onset of disability.10,11 IFNB-1a is available in 2 formulations: (1) as a 3-times weekly SC injection and (2) as a once-weekly intramuscular (IM) injection.10,11
The IM formulation of IFNB-1a has been shown to reduce the annualized rate of relapse compared with placebo.12 IM IFNB-1a also delays the time to sustained disability progression, based on EDSS scores, versus placebo.12 Similarly, the SC injection formulation of IF NB-1a has been shown to reduce relapses and delay disability progression compared with placebo.13
In the 2-year INCOMIN (Independent Comparison of Interferon) trial (n = 188), IFNB-1b (250 μg every other day as an SC injection) was significantly more effective than IFNB-1a (30 μg once weekly as an IM injection) with respect to the proportion of patients who remained relapse free (51% vs 36%) and free of new T2 lesions on MRI (55% vs 26%); significantly fewer patients in the SC IFNB-1b group experienced disease progression.14 In the EVIDENCE (Evidence of Interferon Dose-Response-European North American Comparative Efficacy) study (n = 677), SC IFNB-1a (44 μg 3 times a week) was more effective than IM IFNB-1a (given once weekly) in keeping patients with RRMS relapse free and reducing MRI measures of disease activity over a period of 1 year; furthermore, patients receiving IM IFNB-1a every week experienced further reductions in relapse rates and T2-lesion activity when switched to therapy with SC IFNB-1a 3 times a week.15-18
The CHAMPS (Controlled High-Risk-Subjects Avonex MS Prevention Study) study was initially designed to determine the effects of IM IF NB-1a compared with placebo on the risk of onset of CDMS in patients who had previously experienced a first acute optical, cerebral, or spinal cord demyelinating event in addition to having 2 clinically silent MRI lesions.19 Patients were randomized to receive weekly IM IFNB-1a (n = 193) or placebo (n = 190) for up to 3 years.19 At the end of the study, the cumulative probability of developing CDMS was 35% in patients receiving IFNB-1a compared with 50% for those receiving placebo (P = .002). Patients given IFNB-1a experienced a median increase of 1% in lesion volume versus 16% of those given placebo (P <.001). Similarly, patients given IF NB-1a had fewer new or enlarging T2 lesions and T1 gadolinium-enhancing lesions than those given placebo (P <.001 for both).19
In an open-label extension trial of CHAMPS, called CHAMPIONS (Controlled High-Risk Avonex MS Prevention Study In Ongoing Neurologic Surveillance), all patients received IF NB-1a for a follow-up period totaling 5 years (including the approximately 3 years' duration with CHAMPS). A total of 53% (n = 203) of patients enrolled in the CHAMPS study took part in the CHAMPIONS study.20 The likelihood of developing CDMS was significantly lower in the early-treatment group (ie, those who had received IF NB-1a at the start of CHAMPS) compared with those who received delayed treatment (ie, those receiving IFNB-1a at the onset of CDMS or otherwise after the end of CHAMPS).20 The 5-year incidence of CDM S was 36% (±9%) in the early-treatment group versus 49% (±10%) in the delayedtreatment group (P = .03).20
Glatiramer Acetate
GA is indicated for the reduction of the frequency of relapses in RRMS, including patients who have experienced a first clinical episode and have MRI features consistent with MS. Like the interferons, GA is effective in MS, at least in part, because it reduces inflammatory processes in the central nervous system (CNS).21 This anti-inflammatory activity, however, is achieved by a different means than that of the interferons. While the interferons appear to produce anti-inflammatory changes in the CNS primarily by preventing autoaggressive T-cell migration through the blood-brain barrier (BBB), GA has no such limiting effect on penetration of the BBB.22 Instead, GA appears to function via the infiltration of GA-specific T helper 2 cells which produce "bystander suppression" of the autoreactive process.21
Figure 3
In the clinical trial setting, GA has demonstrated significant superiority to placebo in reducing the rate of relapses and in slowing the rate of disability progression (based on EDSS scores).23 Compared with placebo, patients given GA had significantly fewer new and enhanced lesions or lesions that converted to "black holes."24 The PRECISE trial was an early- versus delayed-treatment study in which patients with clinically isolated syndrome, and at least 2 T2-weighted cerebral lesions (≥6 mm), were randomized to receive SC GA (n = 243) or placebo (n = 238) once daily for 3 years. If they were diagnosed with CDMS, they were given GA.25 Treatment with GA was associated with a 45% reduction in the risk of CDMS ().25 The NNT to prevent a single patient from converting to CDMS was 5.
In the parallel-group, open-label REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study, GA was compared with IFNB-1a in RRMS.26 Patients (n = 764) who had had at least 1 relapse within the past 12 months were randomized to receive GA (20 mg once daily) or interferon beta-1a (44 μg 3 times per week) for 96 weeks. No significant difference was observed between groups for time to first relapse (the primary end point). There were no significant differences in the number and change in volume of T2 active lesions, or in the change in the volume of gadolinium-enhancing lesions, although patients given IFNB-1a had significantly fewer gadolinium-enhancing lesions (P = .0002). The incidence and severity of adverse events (AEs) were similar among those given GA and those given INFB-1a.
In a recent head-to-head trial of GA versus IFNB-1b, the BEYOND (Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose) study, 2447 patients with RRMS were randomized to receive IFNB-1b (250 μg or 500 μg every other day) or GA (20 mg once daily) for between 2 and 3.5 years with quarterly evaluations.27 For MRI parameters, GA and IFNB-1b conferred similar benefits. Risk of relapse, the primary outcome, was not significantly different between any of the 3 treatment groups.27 The main secondary outcomes, EDSS progression and change in volume of T1 black hole lesions, were also not significantly different between treatment groups. Changes in brain volume were similar for both IFNB-1b doses and GA, with small volume increases from baseline at years 2 and 3.27 At year 1, all 3 treatment groups had substantial reductions in brain volume from baseline (significantly more so for GA vs the IFNB-1b groups), but this was likely a result of water loss associated with initial anti-inflammatory treatment rather than tissue loss, a phenomenon known as "pseudoatrophy."27,28 IFNB-1b and GA were well tolerated; injection-site reactions were the most common AE.27 Elevated liver enzyme levels and flulike symptoms occurred significantly more often in patients receiving IFNB-1b than in those receiving GA.
Natalizumab
A fourth DMD for MS, the monoclonal antibody natalizumab, is currently available and is indicated to "delay the accumulation of physical disability and reduce the frequency of clinical exacerbations."29 In the 2-year phase 3 AFFIRM (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis) trial, natalizumab was highly effective in RRMS.2 Patients given natalizumab experienced a 68% relative reduction in the annualized relapse rate (P <.001), whereas the mean number of new or enhancing T2-weighted hyperintense lesions was 83% lower than that among patients given placebo (P <.001).2 Gadolinium-enhanced lesions were reduced by 92% compared with placebo (P <.001).
At 2 years, the sustained disability progression rate was significantly lower in patients given natalizumab compared with those given placebo. The cumulative probability of 12-week sustained progression of disability was 17% in the natalizumab group versus 29% in the placebo group (hazard ratio, 0.58; 95% confidence interval, 0.43-0.77; P <.001), which represented a 42% reduction in risk of disability progression with natalizumab.
Despite these data, natalizumab's use has been limited by its association with the low, but definite, risk for PML. At present, it is regarded primarily as a second-line therapy.1
Safety and Tolerability Issues With MS Agents
While injection-site reactions and flulike symptoms are fairly common AEs with current first-line MS therapies, these and other AEs are rarely serious. The interferons and GA are relatively well tolerated. Although some of the emerging MS therapies show the potential for significantly improved efficacy, their side-effect profiles are less well understood. Until these new agents are widely used in the MS population, their tolerability and long-term safety will remain uncertain.
Limitations of Existing First-Line Therapies
Although the efficacy of the current first-line MS agents (ie, IF NB-1b, IF NB-1a, and GA) is substantial, sustained remission from symptoms is rare and stopping disease progression altogether remains an unmet treatment goal. Compared with previous options for MS, these first-line therapies represent very significant improvements. However, disease progression is more or less inevitable even though all 3 agents can provide substantial reductions in relapse rate and disability. Some of these agents may also possess some measure of neuroprotection. Ultimately, however, current options for MS fall well short of ideal treatment.
In addition to their limitations in efficacy, current first-line MS agents all require SC or IM injections, which many patients regard as inconvenient, and thereby impact treatment adherence. Adherence rates for the interferons and GA have been estimated between 50% and 80%.30-32 Natalizumab requires infusion in the clinical setting over a 1-hour period every 4 weeks.29 Although natalizumab cannot be self-administered, once-monthly administration is advantageous over the more frequent administration schedules of first-line therapies.
The emergence of oral therapies for MS-such as laquinimod, cladribine, fingolimod, BG-12, and teriflunomide-would likely improve treatment adherence in MS since oral therapies overcome the barriers of inconvenience, discomfort, and time associated with injection/infusion delivery.33,34 Other factors that suppress MS treatment adherence, and are related to the use of injections, include simple disinclination to perform an injection, "being tired" of taking injections, as well as skin and pain reactions to injections.
Among the new generation of MS therapies are monoclonal antibody therapies, such as alemtuzumab, rituximab, and daclizumab, all of which, like natalizumab, require delivery by infusion (although not necessarily at the same infrequent dosing schedule).35,36
Emerging Concepts in Defining Treatment Success
Disease Remission
To date, an MS agent has been regarded as effective in RRMS if it reduces the relapse rate and slows the progression of disability. The assumption has been that MS will progress even if phases of remission occur. At present, that assumption prevails, but the possibility of achieving greater efficacy, of stopping disease activity in a significant portion of patients, has become a credible goal.3
The introduction of immunomodulatory biologic therapies for the treatment of rheumatoid arthritis-which, like MS, possesses an immunemodulated pathophysiology-and the consequent shift in treatment expectations toward remission provide a model for the future of MS treatment.
With the exception of the BEYOND study, first-line MS agents have not been studied for their ability to stop all disease progression. The possibility of achieving freedom from disease activity was examined in a post hoc analysis of data from the AFFIRM study. Patients with RRMS were randomized to receive natalizumab or placebo for 2 years. The primary end points of AFFIRM -rate of clinical relapse and probability of sustained disability progression-both significantly favored natalizumab.2 The post hoc analysis defined absence of disease activity 3 ways: (1) absence of clinical disease: no relapses or disability progression (sustained for 12 weeks); (2) absence of radiologic disease: no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions; and (3) a combined criterion (ie, meeting both the radiologic and clinical thresholds).4
Natalizumab performed well in the AFFIRM study based on all 3 post hoc criteria. After 2 years, 64% of patients receiving natalizumab experienced no clinical disease activity compared with 39% receiving placebo (P <.0001).4 No radiologic disease activity occurred in 58% of patients in the natalizumab group compared with 14% in the placebo group (P <.0001). Using the combined criteria measure, a total of 37% of patients given natalizumab had no disease activity compared with 7% of patients given placebo (P <.0001). A recently published Italian postmarketing observational study of natalizumab, which included 285 patients with MS, defined clinical absence of disease activity exclusively in terms of lack of relapses, while radiologic disease inactivity was defined as the absence of new and enlarging T2 lesions and gadolinium-enhancing lesions.5 After 2 years of follow-up, 78% of patients were relapse free and 69% achieved radiologic disease inactivity.
These data are certainly promising, but constitute information about 1 agent for a period of only 2 years. The long-term effects of DMDs in MS remain to be determined.37 Although patients receiving long-term DMDs have clearly achieved longer intervals before the onset of both clinically definite disease as well as irreversible disability, the best available clinical data rarely extend beyond 5 years. In the case of emerging treatments, there are no long-term data.
Neuroprotection
Explanations for the efficacy of agents in MS have, until recently, largely focused on the role of inflammatory processes and how the various available therapies address inflammation in the CNS. But as the expectations for more robust efficacy increase, so the search for a deeper and more nuanced understanding of disease processes in MS has been extended. The role of oxidative stress, for example, has emerged as a more prominent area of research in both the pathophysiology of MS and its relationship to the efficacy of pharmacologic agents. This research includes examining the importance of proteins such as metallothioneins and nuclear receptor coactivator 7 alternate start transcript (NCOA7-AS), which may protect cells in the CNS from oxidative stress.38,39 The importance of nerve growth, or neurotrophic factors, which are related to remyelination, has been an area of interest for at least a decade and will continue to be.40
Neuroprotection has increasingly become the focus of research and debate in MS. Neuroprotection describes an ambitious treatment goal of limiting, or even arresting, the neurodegenerative processes that characterize MS, including axonal degeneration and demyelination. At present, neuroprotection is poorly understood. Much effort has been made toward designating reliable markers of neuroprotection in MS, which would give clinicians an opportunity to track disease progression and allow clinical researchers to evaluate, and compare, the benefits of pharmacologic agents in the treatment of MS.
Figure 4
Several recent randomized clinical trials have been designed to better evaluate the evolution of markers of neuroprotection. New and existing imaging techniques, as well as markers of inflammation, oxidative stress, and neurotrophic factors, may indirectly allow for the assessment of neuroprotective effects of MS therapies. A recent review by Barkhof et al summarized the prevailing wisdom on the subject of imaging to measure neuroprotection and concluded that the best available imaging techniques for measuring neuroprotection are whole-brain volume, lesion measurement, and optical coherence tomography (OCT).28 Whole-brain volume is associated with atrophy in MS and has been shown to decline less with MS therapies,27 although there are confounding influences, including inflammation and "pseudoatrophy" ().28 Regarding measurement of lesions, numerous techniques are currently available, the most reliable being evolution of permanent black holes (PBH) in T1-weighted images, diffusion tensor imaging, T1 and T2 relaxometry, and magnetization transfer ratio.28 OCT is a novel technology that measures infrared light reflection patterns off the retinal layers to quantify the thickness of the retinal nerve fiber layer (RNFL) and macular volume. RNFL measurement describes the status of unmyelinated retinal axons and correlates with EDSS, brain parenchymal fraction, and visual acuity. Macular volume evaluation allows for an analysis of axonal status and their ganglion cell bodies.41-44
The efficacy of MS agents in reducing the development of black holes has been assessed in a handful of studies, including AFFIRM . The protocol for most studies included MRI scans at baseline, and after each year of treatment. In AFFIRM , natalizumab was associated with a 76% reduction in new T1-hypointense lesions at 2 years (P <.001 vs placebo).45 More patients given natalizumab (63%) had no new T1-hypointense lesions compared with those given placebo (27%). Most new T1-hypointense lesions were nonenhancing, likely reflecting PBHs. Patients given natalizumab had fewer of these lesions, suggesting that natalizumab may reduce the accumulation of axonal loss. More frequent MRI scans, however, may provide a better assessment of neuroprotection associated with MS agents.
The use of lesion measurement to assess neuroprotection was applied in the BEC OME (Betaseron vs Copaxone in Multiple Sclerosis with Triple-Dose Gadolinium and 3-Tesla MRI Endpoints) study, which measured the occurrence of new and enhancing lesions every month in patients receiving IFNB-1b or GA for up to 2 years.46 The MRI protocol included the use of T1-weighted images and T2/fluid-attenuated inversion recovery (FLAIR) to measure nonenhancing new lesions. At the end of years 1 and 2, the number of new lesions was similar for both treatment groups, with T2/FLAIR lesions occurring relatively infrequently.46 The number of relapse-free patients was not significantly different between treatment groups. An additional analysis based on the BEC OME data, focusing exclusively on new acute black holes and PBHs, found similar rates of black hole development in both treatment groups with the exception of newly enhancing lesions converting to PBHs after at least 1 year- these occurred more frequently in the GA group (15.2% vs 9.8% with IFNB-1b; P = 0.02).47
Conclusion
Existing first-line therapies for MS provide meaningful treatment efficacy and relatively few side effects. Emerging agents have demonstrated potentially greater efficacy and sustained cessation of disease activity. Safety issues with several of these emerging treatments, however, may be a cause for concern and will require long-term use to determine how widely they may be applied to the MS population. The new oral agents promise greater convenience and will likely contribute to improved treatment adherence with consequent beneficial effects on treatment outcomes. As new therapies emerge for MS, the paradigm for measuring treatment success has been shifting in recent years, particularly with the development of novel means of measuring neuroprotection. Taken together, the newer treatments and new imaging techniques for measuring efficacy point to a new era in the treatment of MS, with greater efficacy accompanied by greater ambitions for what constitutes treatment success.
Author Affiliation: Multiple Sclerosis Center, University of Pennsylvania, Philadelphia, PA.
Funding Source: Financial support for this work was provided by Teva Neurosciences, Inc.
Author Disclosure: Dr Markowitz reports consultancy/lectureship with Bayer, Biogen Idec, EMD Serono, Novartis, Teva, and Wyeth. He has received grants from Bayer, Biogen Idec, EMD Serono, Novartis, and Teva.
Authorship Information: Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.
Address correspondence to: Clyde E. Markowitz, MD, Multiple Sclerosis Center, University of Pennsylvania, 3400 Spruce St, 3 W Gates Bldg, Philadelphia, PA 19104. E-mail: cmarkowi@mail.med.upenn.edu.
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