Clinical evidence of interventions assessed in Friedreich ataxia: a systematic review.

Objectives: The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature review (SLR) was carried out to understand and summarize the published efficacy and safety of therapeutic interventions in this disease. Methods: Database searches were carried out in MEDLINE, Embase, and Cochrane by two independent reviewers. In addition, trial registries and conference proceedings were hand-searched. Results: Thirty-two publications were deemed eligible according to PICOS criteria. Twenty-four publications detail randomized controlled trials. The most frequently identified therapeutic intervention was idebenone (n = 11), followed by recombinant erythropoietin (n = 6), omaveloxolone (n = 3), and amantadine hydrochloride (n = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743). These studies included patients from 8 to 73 years old, and disease duration varied from 4.7 to 19 years. Disease severity as per the mean GAA1 and GAA2 allele repeat length ranged from 350 to 930 and 620 to 987 nucleotides, respectively. Most frequently reported efficacy outcomes were the International Cooperative Ataxia Rating Scale (ICARS, n = 10), the Friedreich Ataxia Rating Scale (modified FARS and FARS-neuro, n = 12), the Scale for Assessment and Rating of Ataxia (SARA, n = 7), and the Activities of Daily Living scale (ADL, n = 8). Each of these assesses the severity of disability in FA patients. In many studies, patients with FA deteriorated according to these severity scales regardless of treatment, or inconclusive results were found. Generally, these therapeutic interventions were well-tolerated and safe. Serious adverse events were atrial fibrillation (n = 1), craniocerebral injury (n = 1), and ventricular tachycardia (n = 1). Conclusion: Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.

A systematic review investigating the effectiveness and safety of treatments for Friedreich ataxia What is Friedreich ataxia? Friedreich ataxia (FA) is a rare genetic condition that causes nervous system damage and movement problems, including muscle weakness and impaired coordination (ataxia). Heart problems, vision problems, spine problems, and diabetes can occur, too. Within 10 to 20 years of the first symptoms, an individual with FA generally requires a wheelchair. Why was this study done? Currently there are no approved treatments for FA. Current treatments focus on relieving symptoms. This study was carried out to obtain a landscape view of all the published evidence about FA treatments. What did the researchers find? • Two scales were most frequently used to assess disease severity: the International Cooperative Ataxia Rating Scale (ICARS) and the FA Rating Scale (modified FARS and FARS-neuro). • Patients on idebenone at 1350 to 2550 mg per day showed improvement in ICARS and FARS scores over 6 months, but scores deteriorated after 12 months in ambulatory patients with FA. • Omaveloxolone at doses of 2.5 to 300 mg per day showed significant improvement in mFARS scores and FA Activity of Daily Living scores at 48 weeks compared with placebo. • Patients treated with vatiquinone showed significant improvements in FARS-neuro scores at 24 months versus natural disease progression. • Other treatments did not show evidence of significant improvement. What does this mean? FA leads to nervous system damage slowly, over an extended period. It is important to keep in mind that many of the studies reviewed here were of fairly short duration, meaning that the effects of a treatment may not have been detectable. Why is this important? This study was undertaken in the hopes that a comprehensive picture of the current treatment landscape for FA will help promote research that will eventually lead to effective treatments to slow down or reverse the damage caused by disease, which are vitally needed.

How have Economic Evaluations in Relapsing Multiple Sclerosis Evolved Over Time? A Systematic Literature Review.

INTRODUCTION: The introduction of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) over the last two decades has prompted the economic assessments of these treatments by reimbursement authorities. The aim of this systematic literature review was to evaluate the modeling approach and data sources used in economic evaluations of DMTs for RMS, identify differences and similarities, and explore how economic evaluation models have evolved over time. METHODS: MEDLINE®, Embase®, and EBM Reviews databases were searched using Ovid® Platform from database inception on 25 December 2019 and subsequently updated on 17 February 2021. In addition, health technology assessment agency websites, key conference proceedings, and gray literature from relevant websites were screened. The quality of included studies was assessed using the Drummond and Philips checklists. RESULTS: A total 155 publications and 30 Health Technology Assessment (HTA) reports were included. Most of these were cost-utility analysis (73 studies and 25 HTA reports) and funded by medicines manufacturers (n = 65). The top three countries where studies were conducted were the USA (n = 29), the UK (n = 16), and Spain (n = 10). Studies predominantly used Markov cohort models (94 studies; 25 HTAs) structured based on the Expanded Disability Status Scale (EDSS) with 21 health states (20 studies; 12 HTA reports). The London Ontario and British Columbia data sets were commonly used sources for natural history data (n = 33; n = 13). Twelve studies and ten HTAs from the UK assumed a waning of DMT effect over the long term, while this was uncommon in studies from other countries. Nineteen studies adjusted for multiple sclerosis (MS)-specific mortality estimates, while 18 studies used data from the national life table without adjustment. Studies prominently referred to mortality data that were about two decades old. The data on treatment effect was generally obtained from randomized controlled trials (43 studies; 7 HTAs) or from published evidence synthesis (23 studies; 24 HTAs). Utility estimates were derived from either published studies and/or supplemented with data from RCTs. Most of the models used the lifetime horizon (n = 37) with a 1-year cycle length (n = 63). CONCLUSION: As expected, similarities as well as differences were observed across the different economic models. Available evidence suggests models should continue using the Markov cohort model with 21 EDSS-based states, however, allowing the transition to a lower EDSS state and assuming a sustained treatment effect. With reference to the data sources, models should consider using a contemporary MS-specific mortality data, recent natural history data, and country-specific utility data if available. In case of data unavailability, a sensitivity analysis using multiple sources of data should be conducted. In addition, future models should incorporate other clinically relevant outcomes, such as the cognition, vision, and psychological aspects of RMS, to be able to present the comprehensive value of DMTs.

Protective effect of Etoricoxib against middle cerebral artery occlusion induced transient focal cerebral ischemia in rats.

Stroke is the third leading cause of global death and disability. Cyclooxygenase-2 mRNA has been shown to be up-regulated after stroke and also the time window of its expression extends from 4 to 12 h. The objective of this study was to elucidate the protective effect of Etoricoxib (a selective Cyclooxygenase-2 inhibitor) against transient middle cerebral artery occlusion induced behavioral, biochemical and histological alterations. Transient ischemia reperfusion significantly caused behavioral (neurological deficits, decreased locomotor activity and rotarod performance), biochemical (increased lipid peroxidation and nitrite concentration, while decreased superoxide dismutase and catalase activity) and histological (increased infarct volume) changes. Etoricoxib (3 and 10 mg/kg, i.p.) significantly reversed the alterations caused by cerebral ischemia however, 1 mg/kg dose was not found effective in any of the parameters. Finally, we can conclude that Etoricoxib has beneficial effects against transient middle cerebral artery occlusion model in rats. The present study indicates that Etoricoxib may be considered as a potential candidate in the treatment of stroke, clinically.