First-line Disease-modifying Drugs Research Articles

Interferon Beta-1a versus Glatiramer Acetate: Changes of Innate Immunity in a Group of Women with Multiple Sclerosis

Introduction: Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease that secondarily leads to axonal loss and associated brain atrophy. Disease-modifying drugs (DMDs) have previously been studied for their ability to affect specific immunity. This study investigates the effect of interferon beta-1a (INF) and glatiramer acetate (GA) administration on changes in innate immunity cell populations. Methods: Sixty Caucasian female patients with relapsing-remitting MS undergo blood sample testing for 15 blood parameters at baseline, 1 month, 3 months, and 6 months after treatment by GA or IFN (started as their first-line DMD). Results: A statistically significant difference in the change after 6 months was found in the parameter monocytes (relative count) in the group of patients treated with IFN. The median increase was 27.8%. Changes in many of the other 15 parameters studied were 10–20%. Conclusion: Innate immunity has long been neglected in MS immunopathology. The findings suggest that IFN treatment may modulate the immune response in MS by affecting monocyte function and may provide insight into the mechanisms of action of IFN in MS.

Oral Cladribine in Patients who Change From First-Line Disease Modifying Treatments for Multiple Sclerosis: Protocol of a Prospective Effectiveness and Safety Study (CLAD CROSS).

BackgroundRecently, the number of available disease modifying therapies for multiple sclerosis (MS) has increased. However, a proportion of patients treated with these agents continue to experience relapses and disease progression. Cladribine tablets, approved in 2017 for highly active relapsing MS, comprise a sparsely administered oral treatment which exerts its therapeutic effect through a reduction and subsequent repletion of the lymphocyte population.Purpose/Study SampleHere we describe the design of CLAD CROSS, a prospective, non-interventional, multicenter, Phase IV study in patients with a confirmed diagnosis of RRMS who switch from first-line disease modifying drugs (DMDs) to treatment with cladribine tablets in routine clinical practice. 242 adult patients will be recruited in 61 sites (6 countries) over 30 months and will be followed up for 2 years following prescription of cladribine tablets per the decision of the treating physicians.Research DesignThe primary endpoint is the change in annualized relapse rate (ARR) between the 12-month pre-baseline period and over the 12-month period before end of study. Secondary endpoints are the percentage of patients with 6-month disability progression or improvement at the end of the study, measured by the Expanded Disability Status Scale, Timed 25 Foot Walk and 9-Hole Peg Test scales and quality of life, treatment satisfaction, and healthcare resource utilization, measured through the MSIS-29, TSQM 1.4, and EQ-5D-3L scales, respectively. MRI lesions will be compared in the exploratory setting between the 12-month pre-baseline period, baseline, and at years 1 and 2. Adverse events will be monitored throughout the study. Interim analyses are pre-planned when 30% and 60% of patients will complete the 12-month follow-up visit.ConclusionsCLAD CROSS will provide efficacy data on cladribine tablets, used as a follow-up treatment to first-line DMDs in the real-world setting, will further establish its safety profile and will collect information to support pharmacoeconomic studies.

Ten-year follow-up after mitoxantrone induction for early highly active relapsing-remitting multiple sclerosis: An observational study of 100 consecutive patients

BackgroundSix monthly courses of mitoxantrone were approved in France in 2003 for patients with highly active multiple sclerosis (MS). ObjectiveTo report the 10-year clinical follow-up and safety of mitoxantrone as an induction drug followed by maintenance therapy in patients with early highly active relapsing–remitting MS (RRMS) and an Expanded Disability Status Scale (EDSS) score<4, 12months prior to mitoxantrone initiation. MethodsIn total, 100 consecutive patients with highly active RRMS from the Rennes EDMUS database received monthly mitoxantrone 20mg combined with methylprednisolone 1g for 3 (n=75) or 6months (n=25) followed by first-line disease-modifying drug (DMD). The 10-year clinical impact was studied through clinical activity, DMD exposure, and adverse events. ResultsTwenty-four percent were relapse-free over 10years and the mean annual number of relapses was 0.2 at 10years. The mean EDSS score remained significantly improved for up to 10years, changing from 3.5 at mitoxantrone initiation to 2.7 at 10years. The probability of disability worsening and improvement from mitoxantrone initiation to 10years were respectively 27% and 58%, and 13% converted to secondary progressive MS. Patients only remained untreated or treated with a first-line maintenance DMD for 6.5years in average. In our cohort, mitoxantrone was generally safe. No leukemia was observed and six patients developed neoplasms, including 4 solid cancers. ConclusionMonthly mitoxantrone for 3 or 6months, followed by maintenance first-line treatment, may be an attractive therapeutic option for patients with early highly active RRMS, particularly in low-income countries.

Evaluation of the efficacy of MMX mesalazine therapy for moderate ulcerative colitis

Introduction. Treatment of patients with ulcerative colitis (UC) requires continuous anti-relapse therapy. Mesalazines are the firstline disease-modifying drugs for the treatment of mild to moderate UC to manage exacerbations and to induce and maintain remission.This paper is aimed at comparing the efficacy of treatment of patients with pancolitis and left-sided ulcerative colitis of moderate severity, who received MMX mesalazine as monotherapy and MMX mesalazine combined with mesalazines in the form of microclysters and suppositories.Materials and methods. A comparative clinical evaluation of the outcomes of treatment of patients with moderate UC who received MMX mesalazine as monotherapy (group 1) and MMX mesalazine combined with topical mesalazine (microclysters, suppositories) (group 2) was carried out. 40 patients with UC (group 1) and 46 (group 2) were examined.Results and discussion. Two weeks after MMX mesalazine therapy initiation, 92.8% of patients in group 1 responded to MMX mesalazine therapy and continued using the drugs as monotherapy (without microclysters and suppositories). In group 1, 95.6% of patients responded to MMX mesalazine therapy and continued treatment with topical mesalazines (microclysters and suppositories). At week 12, 54.3% of 35 patients in group 1, who responded to MMX mesalazine therapy, achieved clinical remission, 45.7% achieved clinical endoscopic remission. The Mayo Score decreased from 8.0 ± 0.17 to 2.3 ± 0.3 points. At week 12, 57.1% of patients with UC in group 2, who responded to MMX mesalazine therapy, achieved clinical remission, and 42.9% achieved clinical and endoscopic remission. The Mayo Score decreased from 7.85 ± 0.14 to 2.4 ± 0.3 points. There was no statistically significant difference in the level of laboratory findings between the groups of patients at 12 weeks and at 52 weeks (p&gt; 0.05).Conclusion. The long-term continuous administration of MMX mesalazine in patients with pancolitis and left-sided ulcerative colitis of moderate severity as monotherapy during the year is comparable in its efficacy with combined MMX mesalazine therapy and topical forms of mesalazine.

Adverse Drug Reaction Reporting Using a Mobile Device Application by Persons with Multiple Sclerosis: A Cluster Randomized Controlled Trial.

Patient reporting adds value to pharmacovigilance. Encouraging it to be done through a mobile device application (App) is a method that should be evaluated. This study aimed to determine whether the use of an App, compared to traditional use through e-mail, telephone, or the national website, increased suspected adverse drug reaction (ADR) reporting by persons with multiple sclerosis receiving a first-line disease-modifying drug. An open multi-centric, cluster-randomized controlled trial was conducted (VigipSEP study). Clusters were centers allocated (1:1) to the use of the My eReport France® App (experimental arm), and traditional reporting (control arm). Persons with multiple sclerosis initiating or switching to a first-line disease-modifying drug between April 2017 and April 2019 were included. The primary outcome was the mean number of ADR reports per patient for the center-level analysis, and the number of ADR reports per patient for the individual-level analysis using the hierarchical Poisson regression model. Twenty-four centers (12 per arm: six public neurologists from the multiple sclerosis academic expert centers, three public neurologists from general hospitals, and three private practice neurologists) were randomized, including 159 patients. The mean number of ADR reports per patient was significantly higher in centers that used the App: 0.47 vs 0.03 in control centers (p = 0.002). At an individual-level analysis, the experimental arm was significantly associated with a relative risk of ADR reports at 18.6 (95% confidence interval 4.1-84.2; p < 0.001), compared to the control arm, adjusted for sex and type of disease-modifying drug. The use of a mobile App increased the ADR reporting by persons with multiple sclerosis receiving a first-line disease-modifying drug. CLINICALTRIALS. NCT03029897, registered in 2017.

Long-term use of interferon-\u03b2 in multiple sclerosis increases V\u03b41\u2212V\u03b42\u2212V\u03b39\u2212 \u03b3\u03b4 T cells that are associated with a better outcome

BackgroundWe previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. Interferon-β (IFN-β) is one of the first-line disease-modifying drugs for MS. However, no previous studies have reported changes in γδ T cell subsets under IFN-β treatment. Therefore, we aimed to clarify the effects of the long-term usage of IFN-β on γδ T cell subsets in MS patients.MethodsComprehensive flow cytometric immunophenotyping was performed in 35 untreated MS and 21 MS patients on IFN-β for more than 2 years (IFN-β-treated MS) including eight super-responders fulfilling no evidence of disease activity criteria, and 44 healthy controls (HCs).ResultsThe percentages of Vδ2+Vγ9+ cells in γδ T cells were significantly lower in untreated and IFN-β-treated MS patients than in HCs. By contrast, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were markedly higher in IFN-β-treated MS patients than in HCs and untreated MS patients (both p < 0.001). A significant negative correlation between the percentages of Vδ2+Vγ9+ cells in γδ T cells and EDSS scores was confirmed in untreated MS but not evident in IFN-β-treated MS. Moreover, class-switched memory B cells were decreased in IFN-β-treated MS compared with HCs (p < 0.001) and untreated MS patients (p = 0.006). Interestingly, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were negatively correlated with class-switched memory B cell percentages in all MS patients (r = − 0.369, p = 0.005), and the percentages of Vδ1−Vδ2−Vγ9− cells in Vδ1−Vδ2− γδ T cells were negatively correlated with EDSS scores only in IFN-β super-responders (r = − 0.976, p < 0.001).ConclusionsThe present study suggests that long-term usage of IFN-β increases Vδ1−Vδ2−Vγ9− γδ T cells, which are associated with a better outcome, especially in IFN-β super-responders. Thus, increased Vδ1−Vδ2−Vγ9− cells together with decreased class-switched memory B cells may contribute to the suppression of disease activity in MS patients under IFN-β treatment.

First-line disease-modifying drugs in relapsing–remitting multiple sclerosis: an Italian real-life multicenter study on persistence

Objective: The introduction of oral disease-modifying drugs (DMDs) in addition to the available, injectable, ones for relapsing–remitting multiple sclerosis (RRMS) could be expected to improve medication persistence due to a greater acceptability of the route of administration. The aim of the study was to compare the proportion of patients discontinuing injectable DMDs (interferon beta 1a/1b, pegylated interferon, glatiramer acetate) with those discontinuing oral DMDs (dimethylfumarate and teriflunomide) during an observation period of at least 12 months. Secondary aims were to compare the time to discontinuation and the reasons for discontinuation between the two groups and to explore the demographic and clinical factors associated with DMD discontinuation.Methods: In this prospective, multi-center, real-life observational study, patients commencing any first-line DMD between 1 January 2015 and 31 July 2016 were enrolled and followed up for at least 12 months or until the drug was discontinued.Results: Of the 520 included patients, 262 (49.6%) started an injectable and 258 (50.4%) an oral DMD. There was no difference in the proportion of patients on oral (n = 62, 24%) or on injectable (n = 60, 23%) DMDs discontinuing treatment, the most frequent reason being adverse events/side-effects. Higher baseline Expanded Disability Status Scale (EDSS) scores and younger age increased the odds of treatment withdrawal. Time to treatment discontinuation was not different between the two groups and was not influenced by the initiated DMD (oral versus injectable), even after adjustment for baseline differences.Conclusion: The route of administration alone (i.e. oral versus injectable) was not a significant predictor of persistence with first-line DMDs in RRMS.

Dedicated mobile application for drug adverse reaction reporting by patients with relapsing remitting multiple sclerosis (Vigip-SEP study): study protocol for a randomized controlled trial

BackgroundThe reporting of adverse drug reactions (ADR) by patients represents an interesting challenge in the field of pharmacovigilance, but the reporting system is not adequately implemented in France. In 2015, only 20 MS patients in France reported ADR due to first-line disease-modifying drugs (DMD), while more than 3000 patients were initiated on DMD.The aim of this study is to validate a proof-of-concept as to whether the use of a mobile application (App) increases ADR reporting among patients with relapsing-remitting multiple sclerosis (RR-MS) receiving DMD.Methods/designWe designed a multi-centric, open cluster-randomized controlled trial, called the Vigip-SEP study (NCT03029897), using the App My eReport France® to report ADR to the appropriate authorities in E2B language, in accordance with European regulations. RR-MS patients who were initiated on, or switched, first-line DMD will be included. In the experimental arm, a neurologist will introduce the patient to the App to report ADR to the appropriate French authorities. In the control arm, the patient will be informed of the existence of the App but will not be introduced to its use and will then report ADR according to the usual reporting procedures. Primary assessment criteria are defined as the average number of ADR per patient and per center. We assume that the App will increase patient reporting by 10-fold. Therefore, we will require 24 centers (12 per arm: 6 MS academic expert centers, 3 general hospitals, 3 private practice neurologists), allowing for an expected enrollment of 180 patients (alpha risk 5%, power 90% and standard deviation 4%).DiscussionIncreasing patient reporting of ADR in a real-life setting is extremely important for therapeutic management of RR-MS, particularly for monitoring newly approved DMD to gain better knowledge of their safety profiles. To increase patient involvement, teaching patients to use tools, such as mobile applications, should be encouraged, and these tools should be tested rigorously.Trial registrationClinicalTrials.gov, ID: NCT03029897. Registered on 20 January 2017.

Assessing treatment outcomes in multiple sclerosis trials and in the clinical setting.

Increasing numbers of drugs are being developed for the treatment of multiple sclerosis (MS). Measurement of relevant outcomes is key for assessing the efficacy of new drugs in clinical trials and for monitoring responses to disease-modifying drugs in individual patients. Most outcomes used in trial and clinical settings reflect either clinical or neuroimaging aspects of MS (such as relapse and accrual of disability or the presence of visible inflammation and brain tissue loss, respectively). However, most measures employed in clinical trials to assess treatment effects are not used in routine practice. In clinical trials, the appropriate choice of outcome measures is crucial because the results determine whether a drug is considered effective and therefore worthy of further development; in the clinic, outcome measures can guide treatment decisions, such as choosing a first-line disease-modifying drug or escalating to second-line treatment. This Review discusses clinical, neuroimaging and composite outcome measures for MS, including patient-reported outcome measures, used in both trials and the clinical setting. Its aim is to help clinicians and researchers navigate through the multiple options encountered when choosing an outcome measure. Barriers and limitations that need to be overcome to translate trial outcome measures into the clinical setting are also discussed.

Erratum to: Health-Related Quality of Life in Patients with Multiple Sclerosis: Impact of Disease-Modifying Drugs.

Multiple sclerosis (MS) has a profound impact on health-related quality of life (HRQoL), a comprehensive subjective measure of the patient's health status. Assessment of HRQoL informs on the potential advantages and disadvantages of disease-modifying drugs (DMDs) beyond their effects on observer-based disability and magnetic resonance imaging abnormalities. This article reviews published data from randomized controlled trials and observational studies regarding the effects of currently available DMDs on HRQoL. Data indicate that DMD treatment is associated with prevention of worsening or with improvement of HRQoL, and that, in general, second-line DMDs may have a greater impact on HRQoL than first-line DMDs. In clinical practice, monitoring of HRQoL provides clinicians with unique information regarding disease impact and potential benefits and adverse effects of DMD treatment that may not be obtained otherwise; it might also permit early detection of an unfavorable disease course. It is suggested to assess HRQoL at the time of diagnosis and before starting or switching DMD treatment. Regular HRQoL measurements contribute to a comprehensive clinical evaluation, and may help to elucidate and quantify the patient's contribution to shared decision making regarding DMD treatment. Further studies are needed to better determine the role of HRQoL assessments in daily MS care.

Health-Related Quality of Life in Patients with Multiple Sclerosis: Impact of Disease-Modifying Drugs.

Multiple sclerosis (MS) has a profound impact on health-related quality of life (HRQoL), a comprehensive subjective measure of the patient’s health status. Assessment of HRQoL informs on the potential advantages and disadvantages of disease-modifying drugs (DMDs) beyond their effects on observer-based disability and magnetic resonance imaging abnormalities. This article reviews published data from randomized controlled trials and observational studies regarding the effects of currently available DMDs on HRQoL. Data indicate that DMD treatment is associated with prevention of worsening or with improvement of HRQoL, and that, in general, second-line DMDs may have a greater impact on HRQoL than first-line DMDs. In clinical practice, monitoring of HRQoL provides clinicians with unique information regarding disease impact and potential benefits and adverse effects of DMD treatment that may not be obtained otherwise; it might also permit early detection of an unfavorable disease course. It is suggested to assess HRQoL at the time of diagnosis and before starting or switching DMD treatment. Regular HRQoL measurements contribute to a comprehensive clinical evaluation, and may help to elucidate and quantify the patient’s contribution to shared decision making regarding DMD treatment. Further studies are needed to better determine the role of HRQoL assessments in daily MS care.

Discontinuation of disease modifying treatments in middle aged multiple sclerosis patients. First line drugs vs natalizumab

BackgroundSeveral disease-modifying drugs (DMD) are available for the treatment of MS, and most patients with relapsing-remitting disease are currently treated. Data on when and how DMD treatment can be safely discontinued are scarce. MethodsFifteen MS patients, treated with natalizumab for >5 years without clinical and radiological signs of inflammatory disease activity, suspended treatment and were monitored with MRI examinations and clinical follow-up to determine recurrence of disease activity. This group was compared with a retrospectively analysed cohort comprising 55 MS patients treated with first-line DMDs discontinuing therapy in the time period of 1998–2015 after an analogous stable course. ResultsNatalizumab discontinuers were followed for on average 19 months, and follow-up data for 56 months were available for first-line DMD quitters. Two-thirds of natalizumab treated patients experienced recurrent inflammatory disease activity, and one third had recurrence of rebound character. In contrast, 35% of first-line DMD quitters had mild recurrent disease activity, and no one exhibited rebound. ConclusionsWithdrawal of a first-line DMD after prolonged treatment in middle-aged MS patients with stable disease appears to be relatively safe, while natalizumab withdrawal in a similar group of patients cannot be safely done without starting alternative therapy.

Interferon‐β therapy specifically reduces pathogenic memory B cells in multiple sclerosis patients by inducing a FAS‐mediated apoptosis

Growing evidences put B lymphocytes on a central stage in multiple sclerosis (MS) immunopathology. While investigating the effects of interferon-β (IFN-β) therapy, one of the most used first-line disease-modifying drugs for the treatment of relapsing-remitting MS, in circulating B-cell sub-populations, we found a specific and marked decrease of CD27+ memory B cells. Interestingly, memory B cells are considered a population with a great disease-driving relevance in MS and resulted to be also target of B-cell depleting therapies. In addition, Epstein-Barr virus (EBV), associated with MS etiopathogenesis, harbors in this cell type and an IFN-β-induced reduction of the memory B-cell compartment, in turn, resulted in a decreased expression of the EBV gene latent membrane protein 2A in treated patients. We found that in vivo IFN-β therapy specifically and highly induced apoptosis in memory B cells, in accordance with a strong increase of the apoptotic markers Annexin-V and active caspase-3, via a mechanism requiring the FAS-receptor/TACI (transmembrane activator and CAML interactor) signaling. Thus, efficacy of IFN-β therapy in MS may rely not only on its recognized anti-inflammatory activities but also on the specific depletion of memory B cells, considered to be a pathogenic cell subset, reducing their inflammatory impact in target organs.

The Effect of Disease-Modifying Drugs on Brain Atrophy in Relapsing-Remitting Multiple Sclerosis: A Meta-Analysis.

BackgroundThe quantification of brain atrophy in relapsing-remitting multiple sclerosis (RRMS) may serve as a marker of disease progression and treatment response. We compared the association between first-line (FL) or second-line (SL) disease-modifying drugs (DMDs) and brain volume changes over time in RRMS.Materials and MethodsWe reviewed clinical trials in RRMS between January 1, 1995 and June 1, 2014 that assessed the effect of DMDs and reported data on brain atrophy in Medline, Embase, the Cochrane database and meeting abstracts. First, we designed a meta-analysis to directly compare the percentage brain volume change (PBVC) between FLDMDs and SLDMDs at 24 months. Second, we conducted an observational and longitudinal linear regression analysis of a 48-month follow-up period. Sensitivity analyses considering PBVC between 12 and 48 months were also performed.ResultsAmong the 272 studies identified, 117 were analyzed and 35 (18,140 patients) were included in the analysis. Based on the meta-analysis, atrophy was greater for the use of an FLDMD than that of an SLDMD at 24 months (primary endpoint mean difference, -0.86; 95% confidence interval: -1.57–-0.15; P = 0.02). Based on the linear regression analysis, the annual PBVC significantly differed between SLDMDs and placebo (-0.27%/y and -0.50%/y, respectively, P = 0.046) but not between FLDMDs (-0.33%/y) and placebo (P = 0.11) or between FLDMDs and SLDMDs (P = 0.49). Based on sensitivity analysis, the annual PBVC was reduced for SLDMDs compared with placebo (-0.14%/y and -0.56%/y, respectively, P<0.001) and FLDMDs (-0.46%/y, P<0.005), but no difference was detected between FLDMDs and placebo (P = 0.12).ConclusionsSLDMDs were associated with reduced PBVC slope over time in RRMS, regardless of the period considered. These results provide new insights into the mechanisms underlying atrophy progression in RRMS.

Cost-Effectiveness Modeling in Multiple Sclerosis: Playing Around with Non-Healthcare Costs?

Multiple sclerosis (MS) is a chronic disabling neurological disorder that affects more than two million people worldwide [1]. Accounting for more than half of the total population diagnosed with MS in the world, Europe is considered a high-prevalence region [1]. Patients with MS experience a wide range of signs and symptoms [2], which impair their capacity to perform day-to-day activities and thus quality of life [2, 3]. The onset of MS at an early age implies a substantial burden in terms of both healthcare and societal costs [2]. The drugs currently used to treat MS aim to alleviate symptoms, delay disease progression and, ultimately, disability. Steroidal anti-inflammatory drugs are traditionally used to inhibit the inflammatory process of MS, then various types of drugs can be used to alleviate the different symptoms (e.g., visual, motor, cognitive). However, the most important therapeutic group is the disease-modifying drugs (DMDs); drugs designed to delay the progression and the development of long-term disability. DMD prescription is still mainly restricted to patients with relapsing-remitting MS (RRMS), although there are some DMDs indicated for specific conditions of secondary progressive MS [4]. The two beta interferons (IFNb-1a and 1b) and glatiramer acetate (GA) have been the first-line DMDs for years. Indicated in patients with at least two relapses in the previous 2 years, they are all injectable (IFN b-1b and GA subcutaneous, IFN b-1a subcutaneous or intramuscular) [4]. More recently, other DMDs have been approved as second-line treatments: (1) natalizumab, a monoclonal antibody injected intravenously; (2) alemtuzumab, another monoclonal antibody for intravenous injection (initially marketed as an anticancer drug) that has recently proved to benefit MS patients, and (3) fingolimod, an oral drug that prevents lymphocyte migration to the central nervous system. Finally, the European Medicines Agency has very recently approved two oral first-line DMDs with different mechanisms of action [5]: teriflunomide and dimethyl fumarate. The pharmaceutical costs of MS have risen steeply over the previous few years, mainly owing to the introduction of new DMDs. Although medical evidence on the most dated DMDs is quite well established, the economic literature on these drugs is still controversial [6–9], casting doubts on their cost effectiveness. In this commentary, we assess the potential contribution of cost-effectiveness analyses to pricing and reimbursement decisions in Europe. In particular, we analyze the credibility of the major assumptions contained within the analyses.

Toxic cerebellar syndrome due to methotrexate

Methotrexate is a folate antagonist and one of several first-line disease-modifying drugs for treating rheumatoid arthritis. It can be given orally or parenterally: the bioavailability of oral doses of methotrexate...

Eligibility Criteria to Natalizumab Therapy in Patients with Relapsingremitting Multiple Sclerosis: A Real-life Study in an Italian Population-based Cohort

Background: Many patients with relapsing-remitting MS (RRMS) show a suboptimal response to first-line disease-modifying drugs. In these patients treatment with natalizumab is highly effective, however its use has been limited due to safety concerns. Objective: To evaluate the consistency between the eligibility to natalizumab according to Italian Drug Agency (AIFA), European Medicines Agency (EMA) and Food and Drug Administration (FDA) criteria, and its use in clinical practice. Methods: Medical records of 402 patients from four Italian MS Centres were reviewed to identify patients eligible to natalizumab according to AIFA, EMA, and FDA criteria and verify how many of them were currently treated or had been previously treated in practice. Results: Of 316 RRMS patients, 13.3% were currently or had been previously treated with natalizumab, while additional 7.0%, 14.2%, and 27.2% were not receiving the drug although they were eligible according to AIFA, EMA, and FDA criteria, respectively. Compared to patients treated with natalizumab, subject who were eligible but remained untreated were older and with shorter education. Conclusion: In a cohort of RRMS patients, 20.3%, 27.5%, and 40.5% were eligible to natalizumab according to AIFA, EMA, and FDA, respectively, although only part of them were actually treated.

Budget Impect Analysis.

To quantify the number and costs of relapses avoided over 2 years in the first-line treatment of RRMS based on the findings of the Cochrane report. An Excel-based financial model estimated the relapses and costs incurred by a hypothetical cohort of 1000 RRMS patients treated with first-line disease-modifying drugs (DMDs). The modelled cohort evaluated the consequences of treatment with subcutaneous (SC) interferon beta-1a versus intramuscular (IM) interferon beta-1a, as this was the only comparison whose data quality was assessed as ‘high’ by the Cochrane Review (Filippini et al., 2013). Risk of relapse was based on the 2-year data from the Cochrane Review network meta-analysis. The analysis was performed from a US payer perspective. The cost of a relapse was sourced from Panitch et al., 2005, and adjusted to 2012 US dollars. Net annual cost of therapy was based on wholesale acquisition cost. Given the model’s short time horizon, disability-related costs were not included as these tend to be an important economic driver only over the long-term progression of the disease. In order to test how variability in the model’s inputs might impact the analysis’ results, two-way sensitivity analyses were performed based on the reported 95% risk of relapse credible intervals for SC interferon beta-1a and IM interferon beta-1a In a hypothetical cohort of 1000 RRMS patients, treatment with SC interferon beta-1a is expected to result in the avoidance of 173 (sensitivity analysis range: -20 to 399) relapses versus IM interferon beta-1a over 2 years. Assuming a direct cost of relapse of $5141, this represents a savings of $890,212 (sensitivity analysis range: -$102,138 to $2,052,934) versus IM interferon beta-1a. Subcutaneous interferon beta-1a is likely to result in fewer relapses and lower direct costs of relapse versus IM interferon beta-1a over a 2-year period treatment.

New management algorithms in multiple sclerosis.

Our current treatment algorithms include only IFN-β and glatiramer as available first-line disease-modifying drugs and natalizumab and fingolimod as second-line therapies. Today, 10 drugs have been approved in Europe and nine in the United States making the choice of therapy more complex. The purpose of the review has been to work out new management algorithms for treatment of relapsing-remitting multiple sclerosis including new oral therapies and therapeutic monoclonal antibodies. Recent large placebo-controlled trials in relapsing-remitting multiple sclerosis have shown efficacy of new oral disease-modifying drugs, teriflunomide and dimethyl fumarate, with similar or better efficacy than the injectable disease-modifying drugs, IFN-β and glatiramer acetate. In addition, the new oral drugs seem to have a favorable safety profile. Further, the monoclonal antibody alemtuzumab, which in clinical trials has shown superiority to subcutaneous IFN-β 1a, has been approved in Europe, but not yet in the United States. In de novo-treated patients, the injectables, IFN-β and glatiramer acetate, will to a great extent be replaced by the new orals, dimethyl fumarate and teriflunomide. However, patients who are stable on an injectable with no or minor side-effects could continue their current therapy. Alemtuzumab should be used as a second-line therapy.

PND12 - A Budget Impact Analysis Of The Cochrane Collaboration Review Of First-Line Treatments For Relapsing-Remittimg Multiple Sclerosis

To quantify the number and costs of relapses avoided over 2 years in the first-line treatment of RRMS based on the findings of the Cochrane report. An Excel-based financial model estimated the relapses and costs incurred by a hypothetical cohort of 1000 RRMS patients treated with first-line disease-modifying drugs (DMDs). The modelled cohort evaluated the consequences of treatment with subcutaneous (SC) interferon beta-1a versus intramuscular (IM) interferon beta-1a, as this was the only comparison whose data quality was assessed as ‘high’ by the Cochrane Review (Filippini et al., 2013). Risk of relapse was based on the 2-year data from the Cochrane Review network meta-analysis. The analysis was performed from a US payer perspective. The cost of a relapse was sourced from Panitch et al., 2005, and adjusted to 2012 US dollars. Net annual cost of therapy was based on wholesale acquisition cost. Given the model’s short time horizon, disability-related costs were not included as these tend to be an important economic driver only over the long-term progression of the disease. In order to test how variability in the model’s inputs might impact the analysis’ results, two-way sensitivity analyses were performed based on the reported 95% risk of relapse credible intervals for SC interferon beta-1a and IM interferon beta-1a. In a hypothetical cohort of 1000 RRMS patients, treatment with SC interferon beta-1a is expected to result in the avoidance of 173 (sensitivity analysis range: -20 to 399) relapses versus IM interferon beta-1a over 2 years. Assuming a direct cost of relapse of $5141, this represents a savings of $890,212 (sensitivity analysis range: -$102,138 to $2,052,934) versus IM interferon beta-1a. Subcutaneous interferon beta-1a is likely to result in fewer relapses and lower direct costs of relapse versus IM interferon beta-1a over a 2-year period treatment.