IM IFNβ-1a Research Articles

Why are the First-Line Therapies Used as Injections Discontinued in the Treatment of Multiple Sclerosis?

Objective: Immunomodulatory therapies (IMTs) are used in the treatment of multiple sclerosis (MS) considering their efficacy and safety. Although other effective treatments have been used in recent years, the use of IMTs still continues. In this study, we aimed to reveal the reasons for the discontinuation of IMTs used as injections. Method: IMTs data of 1464 patients were collected and analysed from the Imed database, where 20-year data of the patients were entered by us. Groups were divided as; Interferon beta-1a subcutaneous (IFN-β1a SC), Interferon beta-1a intramuscular (IFN-β1a IM), glatiramer acetate (GA) and Interferon beta-1b (IFN-β1b). Age, gender, duration of illness, types of disease onset, time to start the injection, duration of injection therapy, and reason for discontinuation of patients were analysed. Results: The most common reason for discontinuation of treatments was found to be disease progression (20.13%, 28.14%, 19.64%, 23.87%). Side effects, increased attack frequency, patient demand, disease activity detection in imaging methods, and pregnancy planning followed the disease progression respectively. Conclusion: IMTs as an injection form are used in the treatment of MS, considering their effectiveness and reliability. The most common reason for discontinuing treatment is disease progression.

A method to compare prospective and historical cohorts to evaluate drug effects. Application to the analysis of early treatment effectiveness of intramuscular interferon-β1a in multiple sclerosis patients

BackgroundDisease modifying therapy have changed the natural evolution of multiple sclerosis (MS), with efficacy demonstrated in randomized clinical trials. Standard-of-care effectiveness is needed to complement clinical trial data and highlight outcomes in real-world practice, but comparing prospective patients with historical cohorts likely introduces biases. To address these potential biases, assigning a patient with a score that expresses his/her disease prognosis before starting a therapy may make it possible to evaluate the unbiased ability of the therapy to modify disease natural history. Thus, we aimed at analyzing the effectiveness of intramuscular interferon-β1a (im IFN-β1a) matching by BREMSO score (Bayesian Risk Estimate for Multiple Sclerosis at Onset) a prospective real-world cohort of treated patients with a historical cohort of untreated patients. Material and methodsWe observed 108 newly diagnosed, treatment naïve MS patients over 12 months of treatment with im IFN-β1a. BREMSO score was used to assign a value to each patient, giving the real-world treated patients comparable with the Historical untreated patients, on the basis of the same risk to have unfavorable evolution. ResultsA significantly higher percentage of relapse-free patients is observed in IFN-β1a treated cohort vs. Historical untreated cohort (79.6% vs. 59.3%, p < 0.01). Clinical relapses risk is reduced by 2.2 times in treated patients (p = 0.01). ConclusionsWe propose a promising method to manage observational data in a relatively unbiased way, in order to analyze real-world treatment effectiveness.

Uveitis in Patients with Multiple Sclerosis in Clinical Trials of Fingolimod: Incidence, Prevalence, and Impact on Disease Course

To determine the incidence and prevalence of uveitis and its effect on multiple sclerosis (MS) disease activity and outcomes in patients with MS who participated in the fingolimod clinical trial program. Analysis of pooled data (N= 27 528) from patients enrolled in fingolimod clinical studies and their extensions. Patients were stratified into 4 cohorts based on the history of uveitis at baseline and uveitis events during the observation period: no history and no uveitis events ("no uveitis"); history and no uveitis events ("history"); no history and uveitis events ("first event"); history and uveitis events ("recurrent event"). Adult patients diagnosed with relapsing or primary progressive MS. Patients received fingolimod (0.5, 1.25, or 5 mg/day), placebo, or intramuscular interferon beta-1a (IFNβ-1a IM) during the core studies; patients receiving placebo or IFNβ-1a IM were switched to fingolimod 0.5mg therapy for study extensions. Incidence and prevalence of uveitis, and MS outcome measures, including annualized relapse rate (ARR), time to first relapse, change in Expanded Disability Status Scale (EDSS) score from baseline, and proportion of patients with 6-month confirmed disability progression. A total of 189 patients in the analysis population had uveitis. Of these, 162 patients had a history of uveitis (prevalence, 0.59%). Uveitis occurred as a first event in 27 patients (incidence, 0.1 per 100 patient-years) and as a recurrent event in 10 of 162 patients (prevalence, 6.17%). Patients with uveitis had a significantly shorter time to first relapse (mean, 2.11 vs. 8.12 years; P= 0.047) and a significantly higher ARR (0.31 vs. 0.21; P= 0.025) than those without uveitis. Mean increase in EDSS score at month 120 and the proportions of patients with 6-month confirmed disability progression, and with EDSS score ≥4 during follow-up, were similar in patients with uveitis compared with those without uveitis. This pooled analysis involving a large patient cohort showed that patients with MS and uveitis had increased MS relapse activity compared with those without uveitis.

Relapse rates in patients with multiple sclerosis treated with fingolimod: Subgroup analyses of pooled data from three phase 3 trials

BackgroundFingolimod is a once-daily, orally administered therapy for relapsing forms of MS. It has been shown to reduce relapse rates significantly in all phase II and phase III clinical trials when compared with placebo and intramuscular interferon β-1a (IFNβ-1a IM). MethodsThis study compared annualized relapse rates (ARRs) associated with fingolimod, placebo and IFNβ-1a IM, in patient subgroups from the pooled FREEDOMS, FREEDOMS II, and TRANSFORMS populations. This provided a large data set in which the efficacy of fingolimod could be assessed across a range of patient subgroups, including clinically relevant subgroups not previously analysed. ResultsCompared with placebo, fingolimod was associated with significantly lower ARRs across all patient subgroups with relative reductions in ARRs ranging from 35% (patients who had previously received treatment for their MS for up to 1 year; P<0.05) to 69% (patients with symptoms for less than 3 years before study entry; P<0.001). Other relative reductions in ARR compared with placebo included 64% in patients aged 40 years or younger and 63% in those naïve to treatment (P<0.001 for both). Compared with IFNβ-1a IM, the greatest benefits to ARR were seen in patients aged 40 years or younger (55% relative ARR reduction, P<0.001) and in a small subgroup of patients who had previously received IFNβ and glatiramer acetate (55% relative ARR reduction; P<0.05). Reductions in ARR compared with IFNβ-1a IM were not statistically significant in men (33%, P=0.081), in patients aged over 40 years (23%, P=0.230) and in those who had received treatment prior to the study for 1 year or less (35%, P=0.108). Fingolimod was associated with significantly lower ARRs compared with placebo and with IFNβ-1a IM irrespective of treatment status (treatment-naïve and previously treated for MS), and regardless of type of previous therapy. ConclusionsFingolimod provided consistent efficacy benefits over placebo and IFNβ-1a IM across a range of subgroups of patients with relapsing MS. The magnitude of the beneficial effect of fingolimod over IFNβ-1a IM may depend on age, sex, and duration of previous treatment. These findings suggest that most benefit will be gained by patients who start fingolimod early in the disease course, but the findings also suggest that fingolimod treatment will benefit patients later in the disease course when they have already accrued disability.

Disease-modifying drugs reduce cortical lesion accumulation and atrophy progression in relapsing-remitting multiple sclerosis: results from a 48-month extension study.

Cortical lesions (CLs) and atrophy are pivotal in multiple sclerosis (MS) pathology. This study determined the effect of disease modifying drugs (DMDs) on CL development and cortical atrophy progression in patients with relapsing-remitting MS (RRMS) over 48 months. Patients (n = 165) were randomized to sc IFN β-1a 44 μg, im IFN β-1a 30 μg, or glatiramer acetate 20 mg. The reference population comprised 50 DMD-untreated patients with RRMS. After 24 months, 43 of the untreated patients switched to DMDs. The four groups of patients were followed up for an additional 24 months. At 48 months the mean standard deviation number of new CLs was significantly lower in patients treated with sc IFN β-1a (1.4 ± 1.0, range 0–5) compared with im IFN β-1a (2.3 ± 1.3, range 0–6, P = 0.004) and glatiramer acetate (2.2 ± 1.5, range 0–7, P = 0.03). Significant reductions in CL accumulation and new white matter and gadolinium-enhancing lesions were also observed in the 43 patients who switched to DMDs after 24 months, compared with the 24 months of no treatment. Concluding, this study confirms that DMDs significantly reduce CL development and cortical atrophy progression compared with no treatment.

Effect of switching from intramuscular interferon β-1a to oral fingolimod on time to relapse in patients with relapsing–remitting multiple sclerosis enrolled in a 1-year extension of TRANSFORMS

BackgroundIn the absence of controlled, parallel-group studies, statistical methods developed to estimate treatment effects in patients receiving alternative/rescue treatment in clinical trials may be used to estimate the effects of multiple sclerosis (MS) therapy switch using available clinical trial data. ObjectiveTo use TRANSFORMS data and parametric models to assess the time to first confirmed relapse in MS patients who switched from intramuscular interferon β-1a (IFNβ-1a IM) 30μg/mL once weekly to oral fingolimod 0.5 or 1.25mg once daily vs. remaining on IFNβ-1a IM. MethodsPost hoc analyses were conducted using data from the intent-to-treat population. The Branson and Whitehead switch model with iterative parameter estimation was used to estimate the ratio of the observed time to first confirmed relapse over the estimated time. ResultsLog-linear regression model results showed that fingolimod 0.5 and 1.25mg prolonged time to relapse, with an estimated median time to first relapse of 5.07years (P=0.0026 vs. IFNβ-1a IM) and 4.11years (P=0.0113), respectively, versus 2.26years with IFNβ-1a IM. The estimated ratio of observed time to first confirmed relapse to the estimated time had the patient remained on IFNβ-1a IM was 2.09 (95% CI, 1.45–3.04) for switching to fingolimod 0.5mg and 1.84 (95% CI, 1.30–2.65) for switching to fingolimod 1.25mg. ConclusionDuring the extension, time to first confirmed relapse was approximately doubled in patients switching from IFNβ-1a IM to fingolimod. These analytic methods may be useful in evaluating treatment switch effects in clinical trials with extension data.

P032 - Consistent reduction in the annualized rate of brain volume loss across phase 3 core and extension trials of fingolimod in relapsing multiple sclerosis

Background/objective In phase 3 trials, fingolimod 0.5 mg or 1.25 mg daily reduced brain atrophy versus placebo over 2 years (FREEDOMS and FREEDOMS II), and versus interferon beta-1a IM (IFNβ-1a) over 1 year (TRANSFORMS). Rates of brain atrophy on continuous fingolimod treatment were sustained in extension studies, but diminished number of completers might limit interpretability. We estimated the continuous effect of fingolimod treatment on brain volume (BV) loss, using all data from phase 3 and extension trials. Design/methods We determined annualized percentage BV change (PBVC) for all patients individually, to account for variable treatment-time exposures. During phase 3 studies and extensions, annualized PBVC was calculated for each patient from fingolimod treatment initiation until last available scan. Descriptive analyses included cohorts of patients receiving fingolimod 0.5 mg continuously, and all patients receiving fingolimod (combined-dose group) continuously, for up to 60 months from phase 3 baseline. Further analyses, using these dose-group definitions, were also conducted for up to 24 months from extension baseline to compare annualized PBVC among patients after switching to fingolimod from placebo or IFNβ-1a, with that determined on long-term fingolimod treatment. Results Respectively, mean annualized PBVC in the long-term continuous fingolimod 0.5 mg and combined-dose groups was FREEDOMS, ?0.45% ( n =372), ?0.42% ( n =718); FREEDOMS II, ?0.41% ( n =279), ?0.38% ( n =553); TRANSFORMS, ?0.31% ( n =379), ?0.31% ( n =728); and after switching was FREEDOMS, ?0.49% ( n =135), ?0.44% ( n =259); FREEDOMS II, ?0.47% ( n =47), ?0.43% ( n =103); TRANSFORMS, ?0.25% ( n =130), ?0.19% ( n =267). Conclusion Annualized PBVC during fingolimod phase 3 and extension studies demonstrate a consistent low rate of brain atrophy, supporting previous observations from individual studies. After switching to fingolimod from the comparator, patients exhibited similar atrophy rates to those initially randomized to fingolimod. Annualized PBVC calculation incorporates all available PBVC data, despite varying treatment-time exposures, and partly addresses discontinuation bias that may occur in long-term analyses.

Efficacy and safety of fingolimod in Hispanic patients with multiple sclerosis: pooled clinical trial analyses.

The disease characteristics of multiple sclerosis (MS) appear to differ between Hispanic and Caucasian patients, with Hispanic patients having a younger age at onset, and a higher prevalence of optic nerve and spinal cord involvement. Fingolimod, the first-in-class oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing MS, has been shown to significantly reduce annualized relapse rates (ARRs), lesion-based magnetic resonance imaging (MRI) activity, confirmed disability, and brain volume loss, compared with placebo or intramuscular interferon beta-1a (IFNβ-1a IM) in randomized, double-blind, controlled clinical studies. Here, the efficacy and safety profile of fingolimod in Hispanic patients was compared to that observed in the overall study populations. This was a post hoc analysis of relapses and safety data for Hispanic patients with relapsing-remitting MS (RRMS) randomized to receive daily fingolimod 0.5 mg, weekly IFNβ-1a IM (30 mg) or placebo, in the phase 3, controlled FREEDOMS, FREEDOMS II, and TRANSFORMS fingolimod studies. The ARR was estimated for each treatment group; only relapses that were confirmed by an independent examining neurologist were included in these analyses. Safety assessments included the incidence of adverse events and serious adverse events. Eligible Hispanic patients aged 18-55 years (n=181) had been treated as follows: fingolimod 0.5 mg (n=89), IFNβ-1a IM (n=65), and placebo (n=27). Hispanic patients treated with fingolimod for up to 2 years had lower ARRs (ARR: 0.22, 95% confidence interval [CI]: 0.14-0.35) than those receiving placebo (ARR: 0.46, 95% CI: 0.24-0.88) or IFNβ-1a IM (ARR: 0.34, 95% CI: 0.18-0.63), with relative reductions of 52% and 35%, respectively. A transient decrease in heart rate that started to attenuate 6 h after fingolimod administration was observed, consistent with the well-characterized pharmacologic effect following fingolimod treatment initiation. No cases of symptomatic bradycardia were reported in Hispanic patients. The incidence of first-degree atrioventricular block was low and similar across all treatment groups (3.1-4.5%). The safety profile of fingolimod in Hispanic patients was consistent with that reported in the overall population of each study. Overall, this study demonstrates that fingolimod is efficacious and well tolerated in Hispanic patients with RRMS.

Early MRI activity predicts treatment nonresponse with intramuscular interferon beta-1a in clinically isolated syndrome

ObjectiveDetermine whether MRI activity 6 months after treatment initiation in the Controlled High-Risk Subjects Avonex® Multiple Sclerosis Prevention Study (CHAMPS) predicted progression to clinically definite multiple sclerosis (CDMS) over the subsequent 30 months in intramuscular interferon beta-1a (IM IFNβ-1a)-treated patients vs placebo-treated patients. MethodsCHAMPS patients were randomized to once-weekly IM IFNβ-1a 30μg or placebo for up to 36 months. MRI was performed every 6 months until CDMS confirmation. Patient groups were defined based on new T2 and/or Gd+ lesions at 6 months. ResultsThirteen IM IFNβ-1a patients (6.7%) and 24 placebo patients (12.6%) developed CDMS prior to month 6 and did not undergo the 6-month MRI. At 6 months, 29.7% of IM IFNβ-1a-treated patients vs 40.9% of placebo-treated patients were defined as having high MRI activity levels (≥2 new T2 and/or ≥2 Gd+ lesions). In this subgroup, estimated cumulative probabilities of CDMS were similar between groups (HR=0.88 [0.44–1.77], p=0.7227). A significant treatment response was seen for patients with <2 new T2 and <2 Gd+ lesions at 6 months (HR=0.39 [0.19–0.82], p=0.0120). ConclusionMRI scans 6 months after IM IFNβ-1a initiation in CIS patients predict early treatment non-response. Standardized scanning and monitoring may facilitate early disease management.

Treatment satisfaction in multiple sclerosis.

Disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) are associated with inconvenient methods of administration, significant side effects, and low adherence rates. This study was undertaken to compare treatment satisfaction in MS patients treated with interferon beta-1a intramuscular (IFNβ-1a IM), interferon beta-1a subcutaneous (IFNβ-1a SC), glatiramer acetate (GA), and natalizumab (NTZ), and to examine the associations between treatment satisfaction ratings and adherence to therapy. Two hundred twenty-six treated MS patients completed the Treatment Satisfaction Questionnaire for Medicine. Multivariable models were used to compare treatment satisfaction across groups. There were no statistically significant differences in overall treatment satisfaction. The NTZ group reported greater satisfaction with the ability of the medication to treat or prevent MS than the IFNβ-1a IM group. The NTZ group also reported higher overall convenience scores than the IFNβ-1a IM group and greater satisfaction with ease of use of the medication than the interferon and GA groups. Patients in the IFNβ-1a IM group reported less satisfaction with ease of planning when to use the medication than those in the other groups. Convenience was associated with adherence in IFNβ-1a SC- and GA-treated patients, with lower convenience scores associated with lower adherence. These results may be useful to MS patients and health-care providers facing decisions about DMT use.

Cognitive impairment in multiple sclerosis: An 18 year follow-up study

BackgroundCognitive impairment occurs in 40–65% of patients with multiple sclerosis (MS). Less is known about the rate and pattern of cognitive decline over the course of the illness. ObjectiveTo examine long-term changes in cognition among patients enrolled in the phase III clinical trial of intramuscular interferon beta-1a (IM IFNβ-1a). MethodsTwenty-two patients underwent a longitudinal investigation comparing neuropsychological test performance at study entry and 18-year follow-up. ResultsOver the 18 year interval, significant declines were observed on measures of information processing speed, simple and complex auditory attention, episodic learning and memory, and visual construction. Nine patients (41%) were found to be cognitively impaired at study entry. At follow-up 13 patients (59%) were cognitively impaired. While both the impaired and unimpaired patients at baseline experienced declines on these measures, only one measure, the Symbol Digit Modalities Test (SDMT), demonstrated a group (cognitively impaired versus intact at baseline)×time interaction. This interaction was characterized by a steeper decline in the unimpaired than the impaired group at baseline. ConclusionsOver an 18 year period, our results suggest that cognitive impairment in MS progresses, with declines being most evident on measures known to be most sensitive to MS-related cognitive difficulties both cross-sectionally and longitudinally.

A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis

The phase III placebo-controlled BRAVO study assessed laquinimod effects in patients with relapsing-remitting MS (RRMS), and descriptively compared laquinimod with interferon beta (IFNβ)-1a (Avonex(®) reference arm). RRMS patients age 18-55 years with Expanded Disability Status Scale (EDSS) scores of 0-5.5 and documented pre-study relapse (≥ 1 in previous year, 2 in previous 2 years, or 1 in previous 1-2 years and ≥ 1 GdE lesion in the previous year) were randomized (1:1:1) to laquinimod 0.6 mg once-daily, matching oral placebo, or IFNβ-1a IM 30 μg once-weekly (rater-blinded design), for 24 months. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included percent brain volume change (PBVC) and 3-month confirmed disability worsening. In all, 1,331 patients were randomized: laquinimod (n = 434), placebo (n = 450), and IFNβ-1a (n = 447). ARR was not significantly reduced with laquinimod [-18 %, risk ratio (RR) = 0.82, 95 % CI 0.66-1.02; p = 0.075] vs. placebo. Laquinimod significantly reduced PBVC (28 %, p < 0.001). Confirmed disability worsening was infrequent (10 % laquinimod, 13 % placebo). The change in confirmed disability worsening with laquinimod measured using EDSS was -31 % [hazard ratio (HR) 0.69, p = 0.063], and using Multiple Sclerosis Functional Composite (MSFC) z-score was -77 % (p = 0.150), vs. placebo. IFNβ-1a reduced ARR 26 % (RR = 0.74, 95 % CI 0.60-0.92, p = 0.007), showed no effect on PBVC loss (+11 %, p = 0.14), and changes in disability worsening were -26 and -66 % as measured using the EDSS (HR 0.742, p = 0.13) and MSFC (p = 0.208), respectively. Adverse events occurred in 75, 82, and 70 % of laquinimod, IFNβ-1a, and placebo patients, respectively. Once-daily oral laquinimod 0.6 mg resulted in statistically nonsignificant reductions in ARR and disability progression, but significant reductions in brain atrophy vs. placebo. Laquinimod was well-tolerated.

Treatment Discontinuation and Disease Progression with Injectable Disease-Modifying Therapies

Injectable first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS) are generally prescribed for continuous use. Accordingly, the various factors that influence patient persistence with treatment and that can lead some patients to switch medications or discontinue treatment may affect clinical outcomes. Using data from the North American Research Committee on Multiple Sclerosis (NARCOMS) database, this study evaluated participants' reasons for discontinuation of injectable DMTs as well as the relationship between staying on therapy and sustained patient-reported disease progression and annualized relapse rates. Participants selected their reason(s) for discontinuation from among 16 possible options covering the categories of efficacy, safety, tolerability, and burden, with multiple responses permitted. Both unadjusted data and data adjusted for baseline age, disease duration, disability, and sex were evaluated. Discontinuation profiles varied among DMTs. Participants on intramuscular interferon beta-1a (IM IFNβ-1a) and glatiramer acetate (GA) reported the fewest discontinuations based on safety concerns, although GA was associated with reports of higher burden and lower efficacy than other therapies. Difficulties with tolerability were more often reported as a reason for discontinuing subcutaneous (SC) IFNβ-1a than as a reason for discontinuing IM IFNβ-1a, GA, or SC IFNβ-1b. In the persistent therapy cohort, less patient-reported disability progression was reported with IM IFNβ-1a treatment than with SC IFNβ-1a, IFNβ-1b, or GA. These findings have relevance to clinical decision making and medication compliance in MS patient care.

Swiss Analysis of Multiple Sclerosis: A Multicenter, Non-Interventional, Retrospective Cohort Study of Disease-Modifying Therapies

Background: There is a scarcity of reports comparing efficacy and tolerability of the multiple sclerosis (MS) disease-modifying therapies [DMTs; intramuscular interferon-β1a (IM IFNβ-1a), subcutaneous (SC) IFNβ-1a, SC IFNβ-1b, SC glatiramer acetate (GA)] in a real-world setting. Methods: This multicenter, non-interventional, retrospective cohort study analyzed data from 546 patients with clinically isolated or relapsing-remitting MS constantly treated with one DMT for 2 years. Annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) scores, and DMT tolerability were assessed. Results: Demographic data were comparable across DMTs. There were no significant differences between DMT groups in ARR during study year 1 (p = 0.277) or study year 2 (p = 0.670), or in EDSS change between years 1 and 2 (p = 0.624). Adverse events were frequent (39-56%) in all groups. Flu-like symptoms were less frequent with GA treatment (2.3% vs. IM IFNβ-1a, 46.7%; SC IFNβ-1a, 39.8%; SC IFNβ-1b, 25.8%; p < 0.05). Injection site reactions were less often reported with IM IFNβ-1a (10.5% vs. SC IFNβ-1a, 33.9%; SC IFNβ-1b, 38.3%; GA, 26.1%; p < 0.05). Conclusions: All DMTs showed comparable effects on MS relapse rate and EDSS change, with IM IFNβ-1a and GA being more tolerable with respect to injection site reactions and flu-like symptoms, respectively.

Fingolimod versus intramuscular interferon in patient subgroups from TRANSFORMS

In the 12-month phase 3 TRANSFORMS study, fingolimod showed greater efficacy than intramuscular interferon beta (IFNβ)-1a in patients with relapsing-remitting multiple sclerosis (RRMS). This study analyzed fingolimod efficacy compared with IFNβ-1a in patient subgroups from TRANSFORMS. Patients were randomized to receive fingolimod or weekly IM IFNβ-1a for 12 months. Analyses of efficacy included annualized relapse rate (ARR), and magnetic resonance imaging (MRI) measures [gadolinium (Gd)-enhancing T1 lesions, new/newly enlarged (active) T2 lesions, brain volume change]. Subgroups were defined based on demographics, disease characteristics (baseline EDSS score, relapse rate, and MRI parameters), and response to previous therapy. Fingolimod 0.5 mg reduced ARR over 12 months by 32-59 % relative to IFNβ-1a in all subgroups defined by demographic factors or baseline disease characteristics. Fingolimod also reduced the number of new Gd-enhancing lesions, active T2 lesions, and the rate of brain volume loss, versus IFNβ-1a in most (95 %) subgroups. In patients with high disease activity despite IFNβ treatment in the year before study, fingolimod 0.5 mg reduced ARR by 61 % relative to IFNβ-1a. Reductions in lesion counts and brain volume loss also favored fingolimod in these patients. In conclusion, consistently better efficacy was observed for fingolimod compared with IFNβ-1a across different subgroups of patients with RRMS.

Cost-effectiveness of injectable disease-modifying therapies for the treatment of relapsing forms of multiple sclerosis in Spain

To compare the cost-effectiveness of injectable disease-modifying therapies (DMTs) for the first-line treatment of relapsing-remitting multiple sclerosis (RRMS) in Spain. A Markov model was developed to estimate the cost-effectiveness of intramuscular interferon beta-1a (IM IFNβ-1a), subcutaneous interferon beta-1a (SC IFNβ-1a), interferon beta-1b (IFNβ-1b) and glatiramer acetate (GA) relative to best supportive care in a hypothetical cohort of 1,000 RRMS patients in Spain. The model was developed from a societal perspective with a time horizon of 30 years. Natural history and clinical trial data were used to model relapse rates and disease progression. Cost and utility data were obtained from a published survey of multiple sclerosis patients in Spain. The primary outcome measure was cost per quality-adjusted life year (QALY) gained. Univariate and probabilistic sensitivity analyses were performed. Compared to best supportive care, the base case cost-effectiveness was <euro>168,629 per QALY gained for IM IFNβ-1a, <euro>231,853 per QALY gained for IFNβ-1b, <euro>295,638 per QALY gained for SC IFNβ-1a, and <euro>318,818 per QALY gained for GA. Results were most sensitive to changes in DMT cost, utility values and treatment effect. In our cost-effectiveness analysis of first-line injectable DMTs in Spain, we found IM IFNβ-1a to be more cost-effective than SC IFNβ-1a, IFNβ-1b or GA. Sensitivity analyses confirmed the robustness of these results.

Aggressive relapsing multiple sclerosis characterized by rapid disability progression

BackgroundCriteria for identifying relapsing multiple sclerosis (RMS) patients with aggressive disease, which would be useful for clinical decision making, are currently unavailable. ObjectiveIdentify RMS patients with aggressive disease characterized by rapid disability progression. MethodsData from a 2-year, phase 3, double-blind, placebo-controlled trial with long-term follow-up evaluations of RMS patients taking either intramuscular interferon beta-1a (IM IFNβ-1a, 30μg) or placebo with baseline Expanded Disability Status Scale (EDSS) scores of 1.0–3.5 were retrospectively analyzed. Patients with a ≥2.0-point increase in EDSS score, resulting in a score ≥4.0 by study end, were considered to have aggressive RMS. The risk of a poor long-term outcome, defined as an EDSS score ≥8.0 at 8 years of follow-up, was calculated as an odds ratio from a logistic regression model comparing patients with and without aggressive RMS. ResultsOnly 25 patients met the criteria for aggressive RMS. Among these patients, mean disease duration was 5.1±3.85 years, mean baseline age was 37.2±6.35 years, and mean baseline EDSS score was 2.8±0.74. Fewer IM IFNβ-1a-treated than placebo-treated patients met the criteria for aggressive RMS at 2 years (7% vs 22% on placebo, p=0.0072). Thirteen patients reached the EDSS milestone of ≥8.0 by the end of the 8-year follow-up. The odds ratio for attaining severe disability was 86.4 (95% CI, 10.3–726.4; p<0.0001) for patients with aggressive RMS compared to patients without aggressive RMS. ConclusionsDefining aggressive RMS based on rapid EDSS progression was useful in identifying patients at risk for more severe disease course.

Treatment patterns in multiple sclerosis: administrative claims analysis over 10 years

Objective:Treatment patterns for the MS disease-modifying therapies (DMT) have changed over time. The objective of this study was to examine and describe treatment patterns in MS over a 10-year period.Methods:MS patients who filled a DMT prescription between January 1, 2001 and December 31, 2010 were identified from Clinformatics for DataMart affiliated with OptumInsight. Two cohorts were identified: those with a DMT prescription in 2003 and those with a DMT prescription in 2008. Treatment patterns were examined 2 years before and after the anchor prescriptions for each cohort.Results:Comparing treatment patterns prior to the two anchor prescriptions, interferon-beta (IFNβ)-1a IM (Avonex) and IFNβ-1b (Betaseron) gained the most users in 2001–2003, while IFNβ-1a IM and IFNβ-1a SC (Rebif) gained the most users from 2006–2008. In the 2 years following the two anchor prescriptions, treatment patterns changed. From 2003–2005, 21.2% of IFNβ-1a SC users and more than 15.0% of IFNβ-1a IM and IFNβ-1b users changed to another interferon or glatiramer acetate (GA; Copaxone), while 12.5% of GA users changed to an interferon, most often IFNβ-1a SC. From 2008–2010 the largest proportion of changes from each of the interferons and natalizumab (NZ; Tysabri) were to GA, while those switching from GA were most often changed to IFNβ-1a SC. Those with a 2008 anchor prescription for NZ were most often changed (57%) to GA.Limitations:In retrospective database analyses the presence of a claim for a filled prescription does not indicate that the drug was consumed, and reasons for changes in therapy are not available. The study design looking forward and backward from the anchor prescriptions may have contributed to differences in the proportion of patients seen with no observable change in DMT. Claims-based data are also constrained by coverage limitations that determine the data available and limit the generalizability of results to managed care patients.Conclusions:Changes in treatment patterns in the first half of the observation period were reflective of the addition of IFNβ-1a SC to the market in 2002. Following the 2003 and 2008 anchor prescriptions there were differences in treatment patterns, with more IFNβ-1a IM users being changed to IFNβ-1a SC after the 2003 anchor DMT, and more of each of the interferons and NZ being changed to GA following the 2008 anchor DMT. With the introduction of oral therapies for MS, treatment patterns will again be impacted.

Impact of Natalizumab on Ambulatory Improvement in Secondary Progressive and Disabled Relapsing-Remitting Multiple Sclerosis

BackgroundThere is an unmet need for disease-modifying therapies to improve ambulatory function in disabled subjects with multiple sclerosis.Objectives:Assess the effects of natalizumab on ambulatory function in disabled subjects with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS).MethodsWe retrospectively reviewed ambulatory function as measured by timed 25-foot walk (T25FW) in clinical trial subjects with an Expanded Disability Status Scale score ≥3.5, including RRMS subjects from the phase 3 AFFIRM and SENTINEL trials, relapsing SPMS subjects from the phase 2 MS231 study, and nonrelapsing SPMS subjects from the phase 1b DELIVER study. For comparison, SPMS subjects from the intramuscular interferon beta-1a (IM IFNβ-1a) IMPACT study were also analyzed. Improvement in ambulation was measured using T25FW responder status; response was defined as faster walking times over shorter (6–9-month) or longer (24–30-month) treatment periods relative to subjects’ best predose walking times.ResultsThere were two to four times more T25FW responders among disabled MS subjects in the natalizumab arms than in the placebo or IM IFNβ-1a arms. Responders walked 25 feet an average of 24%–45% faster than nonresponders.ConclusionNatalizumab improves ambulatory function in disabled RRMS subjects and may have efficacy in disabled SPMS subjects. Confirmation of the latter finding in a prospective SPMS study is warranted.

Intramuscular interferon beta-1a and evolving treatment options and outcomes measurement for MS: considerations for managed care.

Intramuscular interferon beta-1a and evolving treatment options and outcomes measurement for MS: considerations for managed care.