Early use of high-efficacy therapies in multiple sclerosis in the United States: benefits, barriers, and strategies for encouraging adoption.

Multiple sclerosis (MS) is characterized by progressive neuroinflammation and neurodegeneration from disease onset that, if left untreated, can result in the accumulation of irreversible neurological disability. Early intervention with high-efficacy therapies (HETs) is increasingly recognized as the best strategy to delay or mitigate disease progression from the earliest stages of the disease and to prevent long-term neurodegeneration. Although there is growing clinical and real-world evidence supporting early HET intervention, foregoing this strategy in favor of a traditional escalation approach prioritizing lower-efficacy disease-modifying therapies remains a common approach in clinical practice. This review explores potential health care professional- and patient-related barriers to the early use of HETs in patients with MS in the United States. Barriers can include regulatory and reimbursement restrictions; knowledge gaps and long-term safety concerns among health care professionals; and various individual, cultural, and societal factors affecting patients. Potential strategies for overcoming these barriers and encouraging early HET use are proposed.

Review Of The Safety, Efficacy And Tolerability Of Fingolimod In The Treatment Of Pediatric Patients With Relapsing-Remitting Forms Of Multiple Sclerosis (RRMS).

Pediatric-onset multiple sclerosis (POMS) is an immune-mediated, demyelinating, neurodegenerative disease that accounts for 3-5% of all multiple sclerosis (MS) cases. Although evidence suggests that it has similar risk factors and disease pathophysiology as adult-onset MS (AOMS), there are distinctive features in disease characteristics and patient demographics of POMS that require unique therapeutic development and treatment considerations. Gilenya® (Novartis International AG, Basel, Switzerland) (fingolimod) is a sphingosine-1-phosphate (S1P) receptor modulator that prevents lymphocytic outflow from peripheral lymph nodes. It has demonstrated efficacy in AOMS. In POMS, there have been three observational studies and one pivotal clinical trial evaluating the efficacy, safety, and tolerability of fingolimod. Currently, fingolimod is the only Food and Drug Administration and European Medicines Agency approved disease-modifying therapy to treat POMS. This review will critically evaluate the available evidence of fingolimod in the treatment of POMS in detail, as well as discussing its treatment implications.

Serum neurofilament light chain concentration in a phase 1/2 trial of autologous mesenchymal stem cell transplantation.

BACKGROUND: Serum neurofilament light chain concentration is a proposed biomarker of axonal injury in multiple sclerosis. Mesenchymal stem cells have anti-inflammatory and repair-promoting activities, making them of interest for potential multiple sclerosis treatment. OBJECTIVES: The purpose of this study was to assess correlation of serum neurofilament light chain concentration and measures of multiple sclerosis disease activity/severity, longitudinal stability of serum neurofilament light chain concentration, and treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration. METHODS: Twenty-four multiple sclerosis patients underwent intravenous infusion of autologous mesenchymal stem cells. Clinical assessments, serum collection, and brain magnetic resonance imaging were performed at months -1, 0 (transplant), 1, 3, and 6. Matched control serum was collected once (n = 10). Serum neurofilament light chain concentration was measured by single-molecule array. Serum neurofilament light chain concentration correlations with disease measures were analyzed by Spearman correlations and linear mixed effect models. Pre-post transplant serum neurofilament light chain concentration was compared by Wilcoxon signed rank testing. RESULTS: There were significant (p<0.01) correlations between serum neurofilament light chain concentration and gadolinium-enhancing lesion number (rho = 0.55) and volume (rho = 0.65), and new/enlarging T2 lesions (rho = 0.65). Patients without disease activity had lower fluctuation in serum neurofilament light chain concentration (p = 0.01). Mean pre- versus post-treatment serum neurofilament light chain concentration values were not significantly different. CONCLUSIONS: Serum neurofilament light chain concentration correlated with magnetic resonance imaging measures of disease activity cross sectionally and longitudinally, and was stable in patients without disease activity. There was no clear treatment effect of mesenchymal stem cell transplantation on serum neurofilament light chain concentration.

Tuberculosis screening in multiple sclerosis: effect of disease-modifying therapies and lymphopenia on the prevalence of indeterminate TB screening results in the clinical setting.

BACKGROUND: Tuberculosis screening is recommended in multiple sclerosis patients starting certain disease-modifying therapies. Disease-modifying therapies may affect interferon-gamma release assay results. OBJECTIVE: To determine the effects of multiple sclerosis disease-modifying therapies on interferon-gamma release assay results. METHODS: Indeterminate interferon-gamma release assay results among multiple sclerosis patients were compared across disease-modifying therapies by Fisher's exact test. Logistic regression evaluated the effects of lymphopenia on interferon-gamma release assay results. RESULTS: A total of 1058 patients underwent interferon-gamma release assay: 2.0% (21) positive, 6.1% (65) indeterminate, with 59.4% (628) on disease-modifying therapies. Results were significantly different across disease-modifying therapies (P = 0.002). Absolute lymphocyte count less than 0.5 k/µL had 9.39 times (95% confidence interval 5.2-17.0) increased odds of indeterminate interferon-gamma release assay results. CONCLUSIONS: Disease-modifying therapies affecting lymphocytes had a higher risk of indeterminate interferon-gamma release assay results.

Newer Treatment Approaches in Pediatric-Onset Multiple Sclerosis.

PURPOSE OF REVIEW: With the recognition that pediatric-onset multiple sclerosis (POMS) is characterized by more prominent disease activity, earlier age at onset of disability milestones, and more prominent cognitive impairment compared with physical disability earlier in the disease course compared with adult-onset multiple sclerosis (AOMS), there has been increasing interest in identifying optimal and safe treatment approaches to achieve better disease control in this group. Injectable therapies have been traditionally used as first line in this population, although not formally approved. This review focuses on current treatment and monitoring approaches in POMS. RECENT FINDINGS: In the past few years, and despite the paucity of FDA-approved medications for use in POMS, an increasing trend toward using newer disease-modifying therapies (DMTs) in this group is observed. However, escalation (as opposed to induction) remains the most frequent approach, and many children continue to be untreated before age 18, particularly before age 12. The only FDA- and EMA-approved disease-modifying therapy in POMS is fingolimod; however, dimethyl fumarate, teriflunomide, natalizumab, ocrelizumab, and alemtuzumab either have been evaluated in observational studies or are being currently investigated in formal randomized controlled trials for use in POMS and appear to be safe in this group. Autologous hematopoietic stem cell transplantation has also been evaluated in a small series. Clinical outcome measures and MS biomarkers have been poorly studied in POMS; however, the use of composite functional scores, neurofilament light chain, optical coherence tomography, and imaging findings is being increasingly investigated to improve early diagnosis and efficient monitoring of POMS. Off-label use of newer DMTs in POMS is increasing, and based on retrospective data, and phase 2 trials, this approach appears to be safe in children. Results from ongoing trials will help clarify the safety and efficacy of these therapies in the future. Fingolimod is the only FDA-approved medication for use in POMS. Outcome measures and biomarkers used in AOMS are being studied in POMS and are greatly needed to quantify treatment response in this group.

Exploratory MRI measures after intravenous autologous culture-expanded mesenchymal stem cell transplantation in multiple sclerosis.

BACKGROUND: Mesenchymal stem cells (MSC) have immunomodulatory and neuro-protective properties and are being studied for treatment of multiple sclerosis (MS). Tractography-based diffusion tensor imaging (DTI), cortical thickness (Cth) and T2 lesion volume (T2LV) can provide insight into treatment effects. OBJECTIVE: The objective of this study was to analyse the effects of MSC transplantation in MS on exploratory MRI measures. METHODS: MRIs were obtained from 24 MS patients from a phase 1 open-label study of autologous MSC transplantation. DTI metrics were obtained in lesions and normal-appearing white matter motor tracts (NAWM). T2LV and Cth were derived. Longitudinal evolution of MRI outcomes were modelled using linear mixed effects. Pearson's correlation was calculated between MRI and clinical measures. RESULTS: Lesional radial diffusivity (RD) and axial diffusivity (AD) decreased pre-transplant and showed no changes post-transplant. There were mixed trends in NAWM RD and AD pre/post-transplant. Transplantation stabilized T2LV growth. NAWM RD and AD correlated with Cth, T2LV and with leg and arm function but not with cognition. Lesional DTI demonstrated similar but less robust correlations. CONCLUSIONS: Microstructural tissue integrity is altered in MS. DTI changes pre-transplant may be influenced by concomitant lesion accrual. Contributor to DTI stabilization post-transplant is multifactorial. DTI of major motor tracts correlated well with clinical measures, highlighting its sensitivity to clinically meaningful changes.

Developing therapeutic strategies to promote myelin repair in multiple sclerosis.

Introduction: Approved disease-modifying therapies for multiple sclerosis (MS) lessen inflammatory disease activity that causes relapses and MRI lesions. However, chronic inflammation and demyelination lead to axonal degeneration and neuronal loss, for which there currently is no effective treatment. There has been increasing interest in developing repair-promoting strategies, but there are important unanswered questions regarding the mechanisms and appropriate methods to evaluate these treatments. Areas covered: The rationale for remyelinating agents in MS is discussed, with an overview of both myelin physiology and endogenous repair mechanisms. This is followed by a discussion of the identification and development of potential remyelinating drugs. Potential biomarkers of remyelination are reviewed, including considerations regarding measuring remyelination in clinical trials. Information and data were obtained from a search of recent literature through PubMed. Peer-reviewed original articles and review articles were included. Expert opinion: There are several obstacles to the translation of potential remyelinating agents to clinical trials, particularly uncertainty regarding the most appropriate study population and method to monitor remyelination. Refinements in clinical trial design and outcome measurement, potentially via advanced imaging techniques, are needed to optimize detection of repair in patients with MS.

Treating primary-progressive multiple sclerosis: potential of ocrelizumab and review of B-cell therapies.

Multiple sclerosis (MS) therapy has evolved rapidly with an increased availability of several immunomodulating therapies over the past two decades. Disease-modifying therapies have proven to be effective in treating relapse-remitting MS (RRMS). However, clinical trials involving some of the same agents for secondary-progressive and primary-progressive MS (SPMS and PPMS) have been largely negative. The pathogenesis of progressive MS remains unclear, but B-cells may play a significant role in chronic compartmentalized inflammation, likely contributing to disease progression. Biologics targeted at B-cells, such as rituximab, are effective in treating RRMS. Ocrelizumab is a humanized monoclonal antibody to CD20+ B-cells that has shown positive results in PPMS with a significant reduction in disease progression. This review aims to discuss in detail the involvement of B-cells in MS pathogenesis, current progress of currently available and investigational biologics, with focus on ocrelizumab, and future prospects for B-cell therapy in PPMS.

PEGylated rhFGF-2 conveys long-term neuroprotection and improves neuronal function in a rat model of Parkinson's disease.

Fibroblast growth factor 2 (FGF-2) has a neurotrophic effect on dopaminergic neurons in vitro and in vivo, and exhibits beneficial effects in animal models of neurodegenerative disorders such as Parkinson's disease (PD). The poor stability and short half-life of FGF-2, however, have hampered its clinical use for neurological diseases. In the present study, we modified native recombinant human FGF-2 (rhFGF-2) by covalently attaching polyethylene glycol (PEG) polymers, named PEGylation, to enhance its neuroprotection efficacy in 6-hydroxydopamine (6-OHDA)-induced model of PD. In vitro, PEG-rhFGF-2 performed better biostability in 6-OHDA-induced PC-12 cells than native rhFGF-2. The in vivo data showed that, compared with native rhFGF-2, PEGylated rhFGF-2 was more efficacious in preventing 6-OHDA-induced lesion upon tyrosine hydroxylase-positive neurons in the substantia nigra (SN), improving the apomorphine-induced rotational behavior and the 6-OHDA-induced decline in tissue concentration of dopamine (DA) and its metabolites. Importantly, our data showed that the superior pharmacological activity of PEGylated rhFGF-2 is probably due to its greater permeability through the blood-brain barrier and better in vivo stability compared to native rhFGF-2. The enhanced stability and bioavailability of PEGylated rhFGF-2 make this molecule a great therapeutic candidate for neurodegenerative diseases such as PD and mood disorders.