Additional efficacy endpoints from pivotal natalizumab trials in relapsing-remitting MS.

Standard clinical endpoints in multiple sclerosis (MS) studies, such as disability progression defined by the expanded disability status scale (EDSS) and annualized relapse rate, may not fully reflect all aspects of therapeutic benefit experienced by patients. Pivotal studies showed that natalizumab is effective both as monotherapy (AFFIRM study) and in combination with interferon beta-1a (IFNß-1a) (SENTINEL study) in patients with relapsing MS. We present AFFIRM and SENTINEL data demonstrating the efficacy of natalizumab on prespecified tertiary endpoints, including extent of confirmed change in EDSS score from baseline, time to sustained progression to EDSS milestone scores, hospitalizations, corticosteroid use, and time to confirmed progression of cognitive deficits. Natalizumab significantly reduced changes in EDSS scores (P < 0.001) and proportion of patients progressing to an EDSS score ≥4.0 (P < 0.001) and ≥6.0 (P = 0.002) compared with placebo. Natalizumab + IFNß-1a significantly reduced changes in EDSS scores compared with placebo + IFNß-1a (P = 0.011). Based on 0.5 standard deviation change in paced auditory serial addition test-3 score, natalizumab treatment reduced the risk of confirmed progression of cognitive deficits by 43% compared with placebo (HR 0.57 [95% CI 0.37, 0.89], P = 0.013); however, no significant difference between groups was seen in SENTINEL. Natalizumab, both as monotherapy and in combination with IFNß-1a, significantly reduced the annualized rate of MS-related hospitalizations (by 64 and 61%, respectively) and the annualized rate of relapses severe enough to require steroid treatment (by 69 and 61%, respectively) compared with placebo and placebo + IFNß-1a (P < 0.001). These analyses underline beneficial effects of natalizumab therapy in relapsing MS patients.

Efficacy of natalizumab therapy in patients of African descent with relapsing multiple sclerosis: analysis of AFFIRM and SENTINEL data.

BACKGROUND: Patients with multiple sclerosis (MS) who are of African descent experience a more aggressive disease course than patients who are of white race/ethnicity. In phase 3 clinical trials (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] and Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis [SENTINEL]), natalizumab use significantly improved clinical and magnetic resonance imaging outcomes over 2 years in patients with relapsing MS. Because patients of African descent may be less responsive to interferon beta treatment than patients of white race/ethnicity, the efficacy of natalizumab therapy in this population is clinically important. OBJECTIVE: To evaluate the efficacy of natalizumab use in patients of African descent with relapsing MS. DESIGN: Post hoc analysis. SETTING: Academic research. PATIENTS: Patients of African descent with relapsing MS who received natalizumab or placebo in the phase 3 AFFIRM study and those who received natalizumab plus intramuscular interferon beta-1a or placebo plus intramuscular interferon beta-1a in the phase 3 SENTINEL study. MAIN OUTCOME MEASURE: Efficacy of natalizumab use in patients of African descent with relapsing MS who participated in the AFFIRM or SENTINEL trial. RESULTS: Forty-nine patients of African descent participated in AFFIRM (n = 10) or SENTINEL (n = 39). Demographic and baseline disease characteristics were similar between patients treated with natalizumab (n = 21) or placebo (n = 28). Natalizumab therapy significantly reduced the annualized MS relapse rate by 60% (0.21 vs 0.53 in the placebo group, P = .02). Compared with placebo use, natalizumab therapy also significantly reduced the accumulation of lesions observed on magnetic resonance imaging over 2 years: the mean number of gadolinium-enhancing lesions was reduced by 79% (0.19 vs 0.91, P = .03), and the mean number of new or enlarged T2-weighted lesions was reduced by 90% (0.88 vs 8.52, P = .008). CONCLUSION: Natalizumab therapy significantly improved the relapse rate and accumulation of brain lesions in patients of African descent with relapsing MS.

Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis.

The SENTINEL study showed that the addition of natalizumab improved outcomes for patients with relapsing multiple sclerosis (MS) who had experienced disease activity while receiving interferon beta-1a (IFNbeta-1a) alone. Previously unreported secondary and tertiary magnetic resonance imaging (MRI) measures are presented here. Patients received natalizumab 300 mg (n=589) or placebo (n=582) intravenously every 4 weeks plus IFNbeta-1a 30 microg intramuscularly once weekly. Annual MRI scans allowed comparison of a range of MRI end points versus baseline. Over 2 years, 67% of patients receiving natalizumab plus IFNbeta-1a remained free of new or enlarging T2-lesions compared with 30% of patients receiving IFNbeta-1a alone. The mean change from baseline in T2 lesion volume over 2 years decreased in patients receiving natalizumab plus IFNbeta-1a and increased in those receiving IFNbeta-1a alone (-277.5mm(3) versus 525.6mm(3); p<0.001). Compared with IFNbeta-1a alone, add-on natalizumab therapy resulted in a smaller increase in mean T1-hypointense lesion volume after 2 years (1821.3mm(3) versus 2210.5mm(3); p<0.001), a smaller mean number of new T1-hypointense lesions over 2 years (2.3 versus 4.1; p<0.001), and a slower rate of brain atrophy during the second year of therapy (-0.31% versus -0.40%; p=0.020). Natalizumab add-on therapy reduced gadolinium-enhancing, T1-hypointense, and T2 MRI lesion activity and slowed brain atrophy progression in patients with relapsing MS who experienced disease activity despite treatment with IFNbeta-1a alone.

The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL.

The AFFIRM and SENTINEL studies showed that natalizumab was effective both as monotherapy and in combination with interferon beta (IFNbeta)-1a in patients with relapsing multiple sclerosis (MS). Further analyses of AFFIRM and SENTINEL data were conducted to determine the efficacy of natalizumab in prespecified patient subgroups according to baseline characteristics: relapse history 1 year before randomization (1, 2, > or = 3), Expanded Disability Status Scale score (< or = 3.5, > 3.5), number of T2 lesions (< 9, > or = 9), presence of gadolinium-enhancing (Gd+) lesions (0, > or = 1), age (< 40, > or = 40) and gender (male, female). A post hoc analysis was conducted to determine the efficacy of natalizumab in patients with highly active disease (i. e., > or = 2 relapses in the year before study entry and > or = 1 Gd+ lesion at study entry). In both AFFIRM and SENTINEL studies natalizumab reduced the annualized relapse rates across all subgroups (except the small subgroups with < 9 baseline T2 lesions) over 2 years. In AFFIRM, natalizumab significantly reduced the risk of sustained disability progression in most subgroups. In SENTINEL, natalizumab significantly reduced the risk of sustained disability progression in the following subgroups: > or = 9 T2 lesions at baseline, > or = 1 Gd+ lesions at baseline, female patients and patients < 40 years of age. Natalizumab reduced the risk of disability progression by 64 % and relapse rate by 81 % in treatment- naive patients with highly active disease and by 58 % and 76 %, respectively, in patients with highly active disease despite IFNbeta-1a treatment. These results indicate that natalizumab is effective in reducing disability progression and relapses in patients with relapsing MS, particularly in patients with highly active disease.

Health-related quality of life in multiple sclerosis: effects of natalizumab.

OBJECTIVE: To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. METHODS: HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300 mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-beta-1a) plus natalizumab 300 mg (n = 589), or IFN-beta-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. RESULTS: Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. INTERPRETATION: HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab.

Combination therapy for the treatment of multiple sclerosis: challenges and opportunities.

OBJECTIVE: Multiple sclerosis (MS) is a complex, heterogeneous disease. Standard treatment of relapsing MS includes interferon beta (IFNbeta) and glatiramer acetate. These agents reduce relapse rates, and IFNbeta-1a is associated with a slowing of disease progression. Despite treatment, many patients experience disease progression, prompting neurologists to use combination therapies to delay this progression. Agents that may be considered for combination therapy are those with unique mechanisms of action that exert additive or synergistic efficacy. This article reviews combination treatment with immunosuppressive therapies and new agents for the management of MS. METHODS: The Medline and EMBASE databases were searched for clinical trials using the following search terms: multiple sclerosis, interferon, Avonex, Betaseron, Rebif, glatiramer, copolymer 1, Copaxone, immunosuppressant, cytotoxic, corticosteroid, azathioprine, cyclophosphamide, methotrexate, mitoxantrone, natalizumab, combination therapy. The National MS Society website was searched for clinical trials of combination therapies. RESULTS: Several small studies have analyzed the effects of immunosuppressive therapy added to IFNbeta treatment, and some encouraging results have been obtained. Few data are available on combination therapy with new drug classes; however, current data suggest that combination therapy with new agents is effective. Although the available data on combination regimens are promising, interpretation is limited by lack of controlled study design, small patient population, and short study duration. CONCLUSIONS: Combination of standard therapies with immunosuppressive agents or with new therapies may provide synergistic effects that will likely benefit patients with MS. Larger, well-controlled trials need to be conducted.

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.

BACKGROUND: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. METHODS: We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. RESULTS: Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan-Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T(2)-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. CONCLUSIONS: Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.).

Selecting a disease-modifying agent as platform therapy in the long-term management of multiple sclerosis.

Multiple sclerosis (MS) is a complex, incurable disease. Treatment consists of lifelong disease and symptom management. FDA-approved therapies for relapsing MS include subcutaneous (SC) interferon beta-1b (IFNbeta1b, Betaseron), IM interferon-beta-1a (Avonex), SC interferon-beta-1a (Rebif), glatiramer acetate (Copaxone), and mitoxantrone (Novantrone), all of which are known as disease-modifying agents (DMAs). DMAs that can be initiated and continued on a long-term basis can be referred to as platform therapies. During periods of disease instability with increased disease activity, corticosteroids or immunosuppressive agents can be used in combination with appropriate DMA platform therapy to help control symptoms. To date, long-term comparative studies of DMAs are not available. However, based on the effects of these agents on disability progression, relapse rates, MRI outcomes, and neutralizing antibodies observed in phase III randomized clinical trials, IFNbeta1a products are the DMAs of choice for platform therapy for MS. Evidence indicates that IFNbeta1a may also be beneficial in the early stages of the disease. Research is ongoing to identify other appropriate add-on agents (e.g., antigen-specific therapies) to be used in combination with existing DMAs to effectively manage MS.

Concomitant therapy for multiple sclerosis.

Interferon beta (IFNbeta) is the first-line treatment for patients diagnosed with multiple sclerosis (MS). In patients with MS who experience breakthrough disease while receiving treatment with IFNbeta, it is common clinical practice to administer additional therapeutic agents. The rationale for use of concomitant therapies in the long-term management of MS is derived from the heterogeneous and multifactorial etiology of this disease. Agents used concomitantly have the potential to exert synergistic effects and slow the progression of disease in patients who experience breakthrough disease. Concomitant therapies that have been reported in patients with MS are reviewed here.

Clinical management of multiple sclerosis: the treatment paradigm and issues of patient management.

OBJECTIVE: To summarize the conclusions of an expert panel of neurologists specializing in multiple sclerosis (MS) convened for the purpose of creating a treatment algorithm with regard to the clinical management of MS. The panel was sponsored by the Health Science Center for Continuing Medical Education and the University of Medicine and Dentistry of New Jersey and supported by an educational grant from Biogen Idec, Inc. SUMMARY: MS is a chronic demyelinating disease characterized by a variable clinical course. Currently, there is no cure for MS, and the management of MS requires lifelong treatment with disease-modifying agents. Some patients respond well to therapy for many years, whereas others may have aggressive disease that is more difficult to manage. Hence, given the variable nature in the course of MS and patients. response to treatment, neurologists must individualize care for their patients. An MS treatment algorithm was recently developed by a panel of neurologists who are MS experts to provide community neurologists with best-practice protocols for treating and managing their MS patients. The panel of experts categorized MS into 3 different stages, with patients transitioning between the stages based on their response to therapy and disease progression. Stage I represents MS early in the progression of the disease, during which platform drug therapy is recommended (i.e., interferon beta-1b [IFNbeta-1b], IFNbeta-1a, or glatiramer acetate). The results of randomized, controlled clinical trials suggest that IFNbeta is the optimal choice for platform therapy. Despite treatment with platform therapy, it is common for patients to experience some ongoing symptoms and periodic exacerbations of the disease (annual relapse rate of 0.59 to 0.84 on treatment); such relapses should not be considered treatment failures and are best managed with steroids. Stage II represents acute breakthrough disease (i.e., when the clinical activity becomes more frequent or severe). This stage is best managed by the addition of pulse corticosteroids to the platform drug. Stage III represents continued breakthrough disease and is best managed by the addition of immunosuppressants to the platform drug. CONCLUSION: The MS treatment algorithm provides an educational resource for physicians. It should assist all health care professionals involved in the management of MS patients and enhance their ability to improve quality of life for these patients over the course of the disease.

Stepped-care approach to treating MS: a managed care treatment algorithm.

OBJECTIVE: To introduce a model treatment algorithm for use in the managed care setting as a strategy to provide ongoing disease management and long-term care for patients with multiple sclerosis (MS), with the goal of delaying disease progression and the associated disability and cognitive dysfunction. SUMMARY: MS is a chronic inflammatory disorder of the central nervous system that is associated with progressive disability and cognitive dysfunction. Currently, management of MS involves planning an effective long-term treatment strategy that can delay the progression of the disease. This article reviews a typical stepped-care approach to treating MS that is based on the concept of a platform drug, which is an agent that provides baseline immunomodulatory action throughout the course of the disease. Considerations for selecting a platform therapy include the effect on the full spectrum of MS (disability, relapses, lesion load, and atrophy as well as patient compliance and the potential impact of neutralizing antibodies [NAbs]). Currently, 4 first-line therapies are approved for relapsing MS: the 3 interferon beta (IFNbeta) products and glatiramer acetate. Of these, the IFNbetas are generally recommended as platform therapy because all have shown significant effects on relapses, magnetic resonance imaging parameters of the disease, and because intramuscular (i.m.) IFNbeta-1a (Avonex) and subcutaneous (s.c.) IFNbeta-1a (Rebif) have been shown to slow the progression of sustained disability. Patients being treated with IFNbetas can develop NAbs to the drug, which can lead to a loss of efficacy and subsequent occurrence of breakthrough disease. The 3 different formulations of IFNbeta are associated with a varying incidence of NAbs (i.m. IFNbeta-1a, 5%; s.c. IFNbeta-1a, 24%; IFNbeta-1b [Betaseron], 45%). Antibodies also form against glatiramer acetate, although their clinical significance needs to be elucidated. As the disease progresses or has periods of aggressive activity, the stepped-care approach is to add other agents onto the platform therapy to improve control of the disease. CONCLUSION: Stepped care, as outlined in this model treatment algorithm for the managed care setting, is an effective method to achieve the fundamental goal of MS treatment, that is, to delay disease progression and the associated disability and cognitive impairment.