Balancing Early Aggression Against Risk of Progression in Multiple Sclerosis.

Multiple sclerosis is a chronic demyelinating disease characterized by focal and diffuse inflammation of the central nervous system resulting in significant physical and cognitive disabilities. Disease-modifying therapies targeting the dysfunctional immune response are most effective in the first few years after disease onset, indicating that there is a limited time window for therapy to influence the disease course. No evidence of disease activity is emerging as a new standard for treatment response and may be associated with improved long-term disability outcomes. An aggressive management strategy, including earlier use of more potent immunomodulatory agents and close monitoring of the clinical and radiologic response to treatment, is recommended to minimize early brain volume loss and slow the progression of physical and cognitive impairments in patients with relapsing-remitting multiple sclerosis.

Canadian Experience with Fingolimod: Adherence to Treatment and Monitoring.

BACKGROUND: The Canadian GILENYA® Go ProgramTM provides education and support to people with relapsing-remitting multiple sclerosis during fingolimod treatment. METHODS: Data were collected and analyzed from the time of the first individual enrolled in March 2011 to March 31, 2014. Individuals were excluded if they withdrew from the program prior to receiving the first dose, or had not completed the first dose observation (FDO) at the time of data cut-off. Reports of adverse effects were validated with a database of adverse events reported to Novartis Pharmaceuticals Canada Inc. RESULTS: A total of 2,399 individuals had completed FDO at the end of the three-year observation period. Mean age was 41.2 years; 75.2% were female. The most recent prior therapies reported were interferon-ß agents (50.2%), glatiramer acetate (31.1%), natalizumab (14.2%), no prior therapy (3.3%), and other agent (1.1%). Reasons for switching to fingolimod were lack of efficacy (34.9%), side effects (34.6%), and dissatisfaction with injections/infusion (30.4%). Continuation rates with fingolimod at 12, 24 and 30 months were 80.7%, 76.6% and 76.0%, respectively. The discontinuation rate due to reported lack of efficacy during the three-year period was 1.3%. There was 94.4% adherence to the scheduled ophthalmic examination. CONCLUSIONS: The GILENYA® Go ProgramTM captures data for virtually all fingolimod-treated patients in Canada, enabling the evaluation of fingolimod use in routine practice. Ongoing patient support and reminders to take the medication, in conjunction with physicians' and/or patients' perception of the efficacy and tolerability of fingolimod, resulted in a high rate of continuation during longer-term therapy.

Cost-effectiveness of fingolimod versus interferon-ß1a for the treatment of pediatric-onset multiple sclerosis in Canada.

AIMS: To evaluate the cost-effectiveness of fingolimod versus interferon (IFN)-ß1a at a dose of 30 µg per week for the treatment of relapsing pediatric-onset multiple sclerosis (POMS) in Canada. MATERIAL AND METHODS: A discrete-time Markov model was developed to compare fingolimod with IFN ß-1a over a time horizon of two years representing patients followed up to mean age of 18 years from a Canadian health care system perspective. Twenty-one health states based on the Expanded Disability Status Scale (EDSS) were considered: EDSS 0‒9 for relapsing multiple sclerosis (MS), EDSS 0‒9 for secondary progressive MS, and "Death." Relative treatment efficacy for fingolimod versus IFN-ß1a was estimated from the PARADIGMS study. Costs and resource use were obtained from published literature and Canadian sources. Utilities were estimated by mapping the Pediatric Quality of Life inventory data onto the Child Health Utility Index-9 Dimension using a published mapping algorithm. Future costs and benefits were discounted at 1.5% per annum. RESULTS: Compared with IFN ß-1a, fingolimod led to an increase in quality-adjusted life-years (QALYs) (0.125) with incremental costs (Canadian dollars [CAD] 2,977) and to an incremental cost-effectiveness ratio (ICER) of CAD 23,886/QALY over a time horizon of two years representing patients followed up to mean age of 18 years. The monetary benefits of fingolimod treatment versus IFN ß-1a at a willingness-to-pay (WTP) threshold of CAD 50,000 per QALY gained were higher than the costs. One-way sensitivity analysis and probabilistic sensitivity analysis (PSA) both confirmed the robustness of the results. LIMITATIONS: The main limitations of this analysis primarily stem from the limited data availability in POMS. CONCLUSIONS: Fingolimod is cost effective compared with IFN ß-1a for the treatment of POMS over a time horizon of two years representing patients followed up to a mean age of 18 years in Canada.

A retrospective claims analysis: Compliance and discontinuation rates among Canadian patients with multiple sclerosis treated with disease-modifying therapies.

BACKGROUND: Compliance to disease modifying therapy (DMT) is associated with a reduced risk of relapse, lower healthcare resource utilization, and improved health-related quality of life in patients with multiple sclerosis (MS). Our objective was to assess the compliance and discontinuation rates of fingolimod relative to other oral, injectable, and infusible DMTs available on the market at the time of the study in Canada in patients with relapsing-remitting MS (RRMS). METHODS AND FINDINGS: We conducted a retrospective claims analysis. Patients with RRMS with ≥ 1 prescription for each DMT were included. Compliance (medication possession ratio of ≥ 80%) and discontinuation (gap > 30 days from the end of the index prescription) were calculated at the 6-, 12- and 24-month time points. Compliance with fingolimod at the 6-, 12- and 24-month time points was 75%, 75% and 70%, respectively; compared with DMF [70% (P < 0.001), 68% (P < 0.001), and 56% (P < 0.001), respectively], and BRACE [53% (P < 0.001), 47% (P < 0.001), and 35% (P < 0.001), respectively]. Compliance with fingolimod was comparable to teriflunomide at each time point, but was higher compared to natalizumab [70% versus 57% (P < 0.001)] at the 24-month time point. At the 6-, 12- and 24-month time points, patients on fingolimod had the lowest discontinuation rate (26%, 24%, and 29%, respectively) compared to BRACE [49% (P < 0.001), 44% (P < 0.001), and 57% (P < 0.001)], respectively], and natalizumab [33% (P < 0.001), 29% (P < 0.001), and 45% (P < 0.001), respectively], and was similar to teriflunomide (26%, 25%, and 31%, respectively). CONCLUSIONS: The compliance rate in fingolimod treated patients at the 24 month time point was higher than that observed in natalizumab treated patients. The discontinuation rate was lower with fingolimod compared to other DMTs at all time points but was similar to teriflunomide.

Diagnosis and management of secondary-progressive multiple sclerosis: time for change.

Identifying the transition of relapsing-remitting multiple sclerosis (MS) to the secondary-progressive MS form remains a clinical challenge due to the gradual nature of the transition, superimposed relapses, the heterogeneous course of disease among patients and the absence of validated biomarkers and diagnostic tools. The uncertainty associated with the transition makes clinical care challenging for both patients and physicians. The emergence of new disease-modifying treatments for progressive MS and the increasing emphasis of nonpharmacological strategies mark a new era in the treatment of progressive MS. This article summarizes challenges in diagnosis and management, discusses novel treatment strategies and highlights the importance of establishing a clear diagnosis and instituting an interdisciplinary management plan in the care of patients with progressive MS.

Sequencing of disease-modifying therapies for relapsing-remitting multiple sclerosis: a theoretical approach to optimizing treatment.

Multiple sclerosis (MS) is a chronic disease which usually begins in young adulthood and is a lifelong condition. Individuals with MS experience physical and cognitive disability resulting from inflammation and demyelination in the central nervous system. Over the past decade, several disease-modifying therapies (DMTs) have been approved for the management of relapsing-remitting MS (RRMS), which is the most prevalent phenotype. The chronic nature of the disease and the multiple treatment options make benefit-risk-based sequencing of therapy essential to ensure optimal care. The efficacy and short- and long-term risks of treatment differ for each DMT due to their different mechanism of action on the immune system. While transitioning between DMTs, in addition to immune system effects, factors such as age, disease duration and severity, disability status, monitoring requirements, preference for the route of administration, and family planning play an important role. Determining a treatment strategy is therefore challenging as it requires careful consideration of the differences in efficacy, safety and tolerability, while at the same time minimizing risks of immune modulation. In this review, we discuss a sequencing approach for treating RRMS, with importance given to the long-term risks and individual preference when devising a treatment plan. Evidence-based strategies to counter breakthrough disease are also addressed.

Sequencing of high-efficacy disease-modifying therapies in multiple sclerosis: perspectives and approaches.

Multiple sclerosis (MS) is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting course that later transitions to secondary progressive MS. Currently available disease-modifying therapies (DMTs) for relapsing MS have been demonstrated to reduce disease activity, however most patients require a change in therapy over the course of their disease. Treatment goals include the prevention of relapses and disability accumulation and to achieve this objective requires careful planning. Sequencing of DMTs for individual patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes.

Real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease: the EMBRACE study.

OBJECTIVE: To assess the real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease (AD) in Canada. RESEARCH DESIGN AND METHODS: Eighteen-month observational, prospective, multi-center, open-label study conducted on AD patients with Standardized Mini-Mental State Examination (SMMSE) score of 10-26 and Global Deterioration Scale (GDS) score of 4-6. Patients were treated with the rivastigmine transdermal patch (Exelon patch*) 5 cm² (4.6 mg/24 hours) or 10 cm² (9.5 mg/24 hours), once daily. MAIN OUTCOME MEASURES: Primary outcome was change in SMMSE from baseline to 18 months. Secondary outcomes included change in SMMSE at 6 and 12 months and change in GDS, Assessment of Patient Ability (APA-C), Overall Patient Assessment Rating (OPAR), caregiver-reported compliance and treatment satisfaction at 6, 12, and 18 months. RESULTS: Among the 1204 patients enrolled, 969 were included in the ITT analysis. Mean (SD) age was 80.2 (8.00) years, disease duration was 0.6 (1.26) years, 62.0% of patients were women, 80.4% were living in the community, and 69.3% were treatment naïve. Mean (SD) baseline SMMSE and GDS scores were 21.8 (3.98) and 4.2 (0.61), respectively. Over 18 months of treatment there were no clinically significant changes in SMMSE and GDS. The majority of patients showed improvement or no change in GDS, APA-C and OPAR over 18 months. The proportion with reported improvement in GDS, APA-C and OPAR was higher than the proportion that deteriorated. Compliance improved from baseline to 18 months and for 88.2% of patients caregivers preferred the transdermal patch to oral medications. CONCLUSIONS: The rivastigmine transdermal patch is effective in maintaining cognitive function over 18 months of treatment in patients with mild-to-moderate AD. The safety profile was comparable to the data in the Canadian product monograph. Lack of a comparator group is a potential limitation of the study.

Effects of rivastigmine on common symptomatology of Alzheimer's disease (EXPLORE).

OBJECTIVE: To evaluate, in a real-world clinical setting, the efficacy of rivastigmine in the management of six symptoms commonly associated with Alzheimer's disease (AD). METHODS: This was a naturalistic, prospective, open-label, multi-centre, post-marketing, observational study. Data were collected by the participating study physicians at their practices across Canada. Subjects had a clinical diagnosis of mild-to-moderate AD and were prescribed rivastigmine by their treating physician. Efficacy was primarily evaluated by a physician-assessed, abbreviated Clinical Global Impression of Change (CGI-C) scale, focusing on six symptoms: attention, apathy, anxiety, agitation, irritability and sleep disturbance. Changes were assessed at months 3, 6 and 12. Several other patient-, physician- and caregiver-related assessments were also included. RESULTS: A total of 4460 patients were recruited by 353 study physicians; 3800 were deemed evaluable, having taken at least one dose of rivastigmine and with at least one post-baseline assessment. At baseline, attention problems were present in 86.0% of evaluable patients, anxiety in 77.3%, apathy in 68.3%, irritability in 64.0%, agitation in 54.6% and sleep disturbance in 54.5%. At both month 6 and month 12, for each symptom, the percentage of patients experiencing an improvement was considerably larger than the percentage of patients who experienced symptom worsening. Among evaluable patients, the proportions improving vs. deteriorating at month 6 were 46.4 vs. 8.8% for attention; 42.8 vs. 7.2% for apathy; 41.1 vs. 9.4% for anxiety; 33.8 vs. 7.7% for agitation; 35.1 vs. 10.1% for irritability; and 30.8 vs. 5.4% for sleep disturbance. LIMITATIONS: Open-label studies have an inherent potential for bias by both the caregiver and the physician. CONCLUSIONS: This study demonstrates that a considerable proportion of rivastigmine-treated patients experience improvements on each of the six symptoms studied. These findings add further support to previous randomised, clinical studies showing benefit of rivastigmine in AD.

A large, naturalistic, community-based study of rivastigmine in mild-to-moderate AD: the EXTEND Study.

BACKGROUND: Previous studies in Alzheimer's Disease (AD) suggest a benefit from switching from one cholinesterase (ChE) inhibitor to another in the event of treatment failure on the index agent. This observational, open-label study sought to evaluate the efficacy of the ChE inhibitor rivastigmine on cognition, functional autonomy and behavior in patients with mild-to-moderate AD previously treated with other ChE inhibitors (switched patients) as well as in those previously ChE-inhibitor-naive (de novo users). METHODS: Patients were eligible for a switch if they experienced a lack or loss of efficacy or had experienced intolerance to prior ChE inhibitor therapy. Rivastigmine was initiated at a dose of 1.5 mg b.i.d. and titration was done as per standard medical practice. Efficacy was assessed using the mini-mental state examination (MMSE) and an abbreviated version of the Clinician's Global Impression of Change (CGI-C) at Month 3 and Month 6. Caregiver burden was also assessed at Month 6 using a self-rated scale. RESULTS: Overall, 2633 subjects were enrolled in this study. The mean MMSE improved from 20.6 at baseline to 21.5 at Month 6. More patients improved than deteriorated on every domain of the CGI-C. Caregivers felt less burdened after the 6 month evaluation period. Efficacy parameters demonstrated favorable results for both de novo and switched patients, but more so in the first group. LIMITATIONS: Open-label studies have an inherent potential for bias by both the caregiver and the physician. In this study, there was also a large percentage of missing patient records for each of the follow-up visits (Months 3 and 6). CONCLUSIONS: Patients with mild-to-moderate AD switched from previous ChE inhibitor therapy to rivastigmine can obtain measurable benefits, although the treatment effect may be less than in de novo patients. Further research into switching cholinesterase inhibitors is warranted.