Treatment Of Progressive Multiple Sclerosis Research Articles

Progressive MS trials: Lessons learned

Up to very recently, no treatments had proved effective in progressive multiple sclerosis (MS). In 2016, four drugs, two tested in phase 3 and two in phase 2 trials, showed a beneficial effect in primary or secondary progressive MS. Although this could indicate a turning point in progressive MS treatment, most of these successes have been modest and mainly restricted to patients with active inflammation, in the context of trials with powerful anti-inflammatory agents. This paper summarises these reasons, particularly focusing on the main lessons learned for the design of future trials. First, a drug’s mechanism of action should tackle the specific pathogenic mechanisms that characterise progressive MS. Second, trial populations where new drugs are to be tested should be carefully chosen, possibly including younger patients with shorter disease durations, which have greater chances of showing active deterioration during the trial, therefore increasing the power to detect treatment effects. Third, outcome measures used in future phase 2 and phase 3 trials should be highly sensitive and be accompanied by smart trial designs.

High dose biotin as treatment for progressive multiple sclerosis

BackgroundPublished data suggested high dose biotin improved patients with progressive MS. We wished to determine benefits and side effects of administering daily high dose biotin to patients with progressive multiple sclerosis in a large MS specialty clinic. MethodsForty-three patients with progressive multiple scleroses were prescribed pharmaceutical grade biotin as a single daily dose of 300mg/day. Brain MRIs were performed at baseline and after one year on biotin. Quantitative neurologic exams (EDSS) and blood work monitoring for biotin toxicity were performed at baseline and every three months thereafter. ResultsHigh dose biotin was safe, and well tolerated, with no evidence of toxicity on blood work and no new lesions on brain MRIs. None of the patients’ EDSS scores improved. One-third of patients (38–43%) worsened, most often with increased lower extremity weakness, worsened balance, and more falling, with two patients worsening sufficiently to increase their EDSS scores by 0.5. Several worsened patients improved after stopping biotin. ConclusionHigh dose biotin was safe and well tolerated, but of no demonstrable long-term benefit. More than one-third of patients worsened while on biotin, most likely due to their disease, but in some patients also possibly due to the inability of their injured central nervous systems to respond to the increased metabolic demands induced by biotin.

Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial

SummaryBackgroundIn the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures.MethodsWe did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348.FindingsBaseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6–7·8; p<0·0001) and non-verbal memory (decline of 6·8 points, 4·8–8·7; p<0·0001). At 24 months, the FAB score was 1·2 points higher in the simvastatin-treated group than in the placebo group (95% CI 0·2–2·3). The simvastatin group also had a 2·5 points better mean physical component score of the SF-36 (95% CI 0·3–4·8; p=0·028). A treatment effect was not noted for any other outcomes.InterpretationTo our knowledge, this SPMS cohort is the largest studied to date with comprehensive longitudinal cognitive, neuropsychiatric, and HRQoL assessments. We found evidence of a positive effect of simvastatin on frontal lobe function and a physical quality-of-life measure. Although we found no effect of simvastatin on the other outcome measures, these potential effects warrant confirmation and underline the importance of fully assessing cognition and quality of life in progressive multiple sclerosis treatment trials.FundingThe Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, a personal contribution from A W Pidgley CBE, and the National Institute for Health Research University College London Hospitals Biomedical Research Centre and University College London.

Pharmacological Approaches to the Management of Secondary Progressive Multiple Sclerosis.

It is well recognised that the majority of the impact of multiple sclerosis (MS), both personal and societal, arises in the progressive phase where disability accumulates inexorably. As such, progressive MS (PMS) has been the target of pharmacological therapies for many years. However, there are no current licensed treatments for PMS. This stands in marked contrast to relapsing remitting MS (RRMS) where trials have resulted in numerous licensed therapies. PMS has proven to be a more difficult challenge compared to RRMS and this review focuses on secondary progressive MS (SPMS), where relapses occur before the onset of gradual, irreversible disability, and not primary progressive MS where disability accumulation occurs without prior relapses. Although there are similarities between the two forms, in both cases pinpointing when PMS starts is difficult in a condition in which disability can vary from day to day. There is also an overlap between the pathology of relapsing and progressive MS and this has contributed to the lack of well-defined outcomes, both surrogates and clinically relevant outcomes in PMS. In this review, we used the search term 'randomised controlled clinical drug trials in secondary progressive MS' in publications since 1988 together with recently completed trials where results were available. We found 34 trials involving 21 different molecules, of which 38% were successful in reaching their primary outcome. In general, the trials were well designed (e.g. double blind) with sample sizes ranging from 35 to 1949 subjects. The majority were parallel group, but there were also multi-arm and multidose trials as well as the more recent use of adaptive designs. The disability outcome most commonly used was the Expanded Disability Status Scale (EDSS) in all phases, but also magnetic resonance imaging (MRI)-measured brain atrophy has been utilised as a surrogate endpoint in phase II studies. The majority of the treatments tested in SPMS over the years were initially successful in RRMS. This has a number of implications in terms of targeting SPMS, but principally implies that the optimal strategy to target SPMS is to utilise the prodrome of relapses to initiate a therapy that will aim to both prevent progression and slow its accumulation. This approach is in agreement with the early targeting of MS but requires treatments that are both effective and safe if it is to be used before disability is a major problem. Recent successes will hopefully result in the first licensed therapy for PMS and enable us to test this approach.

Phase I Clinical Trial Demonstrates Safety and Efficacy of Intrathecal Autologous Mesenchymal Stem Cell-Derived Neural Progenitors (MSC-NPs) for the Treatment of Progressive Multiple Sclerosis (P5.378)

Phase I Clinical Trial Demonstrates Safety and Efficacy of Intrathecal Autologous Mesenchymal Stem Cell-Derived Neural Progenitors (MSC-NPs) for the Treatment of Progressive Multiple Sclerosis (P5.378)

Intrathecal Injection of Peripherally Mobilized Blood Stem Cells to Treat Multiple Sclerosis.

In this study, we analyzed 70 patients with worseningmultiple sclerosis despite pharmacologic treatment who were treated with several intrathecal injections of peripheral blood cells harvested by apheresis after granulocyte-colony stimulating factor treatment. Thirty-seven patients (52%) had a reduction of Expanded Disability Status Scale score; 10 patients had relapses, although these were milder than usual and more easily controlled by corticosteroids. Because mesenchymal cells increase in the peripheral blood after granulocyte-colony stimulating factor stimulation, a peripheral blood harvest seems easier and less costly than mesenchymal cell cultivation before injection. This seems to be a reasonable treatment for progressive multiple sclerosis.

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study

Background: Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. Objective: To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. Methods: Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5–7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6–7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. Results: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. Conclusion: MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.

Progressive MS Alliance Industry Forum: Maximizing Collective Impact To Enable Drug Development

The Progressive MS Alliance Industry Forum describes a new approach to address barriers to developing treatments for progressive multiple sclerosis (MS). This innovative model promises to facilitate robust collaboration between industry, academia, and patient organizations and accelerate research towards the overarching goal of developing safe and effective treatments for progressive MS.

Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis

BackgroundPrimary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and −10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. MethodsSPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100mg/day) or placebo for 96weeks. Imaging is conducted every 24weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. ResultsA total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. ConclusionSPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials.

E.07 The role of the neurologist in advanced multiple sclerosis: the patient’s perspective

Background: Few evidence-based disease-modifying treatments exist for progressive multiple sclerosis (MS). How can neurologists best care for patients with advanced MS? Little is known about how patients with progressive MS view their relationship with their treating neurologist, and if the role of the neurologist matches their needs and preferences. Methods: A qualitative cross-sectional analysis of patient preferences regarding the role of the neurologist in their care. Patients with progressive MS and an EDSS score of 6 or more were invited to participate. Patients and caregivers completed separate written questionnaires and were then interviewed by one of the authors. Data were subjected to thematic coding to group common themes and the distribution of themes among different disability sub-groups was analyzed. Results: Full results will be available at the time of the conference. Preliminary results suggest that the neurologist has an important role in updating patients on the progress of their disease and responding to questions. Patients are fearful of becoming dependent on others for their care. The concept of palliative care is unfamiliar to most patients. Conclusions: Despite a lack of disease-modifying treatments for progressive multiple sclerosis, patients believe that the neurologist has an important role in their care.

Pharmacokinetics and pharmacodynamics of MD1003 (high-dose biotin) in the treatment of progressive multiple sclerosis

ABSTRACTIntroduction: Multiple sclerosis (MS) is a chronic, potentially highly disabling neurological disorder. No disease-modifying treatments are approved in the progressive and not active forms of the disease.Areas covered: High doses of biotin were tested in an open-label pilot study involving 23 patients with progressive MS and reported positive results. A randomized, double-blind, placebo-controlled trial in 154 progressive MS patients confirmed the beneficial effect of MD1003 (high-dose biotin) on reversing or stabilizing disability progression, with a good safety profile. It is proposed that MD1003 in progressive MS 1) increases energy production in demyelinated axons and/or 2) enhances myelin synthesis in oligodendrocytes. Biotin is highly bioavailable; absorption and excretion are rapid. The major route of elimination is urinary excretion.Expert opinion: A high oral dose of biotin seems generally well tolerated but a few important safety concerns were identified: 1) teratogenicity in one species and 2) interference with some biotin-based laboratory immunoassays. The animal toxicity data are limited at such high doses. Further preclinical studies would be useful to address the mechanism of action of MD1003. Assessment of clinical benefit duration in responders will be also very important to set. Results of randomized, placebo-controlled trial are reassuring and provide hope for the treatment of progressive MS.

Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis.

Inaccessibility of the inflammation compartmentalized to the central nervous system (CNS) may underlie the lack of efficacy of immunomodulatory treatments in progressive multiple sclerosis (MS). The double blind combination of Rituximab by IntraVenous and IntraThecAl injection versus placebo in patients with Low-Inflammatory SEcondary progressive MS (RIVITALISE; NCT01212094) trial was designed to answer: (1) Whether an induction dose of intravenous and intrathecal rituximab efficiently depletes CNS B cells? and (2) If so, whether this leads to global inhibition of CNS inflammation and slowing of CNS tissue destruction? Patients aged 18-65years were randomly assigned to rituximab or placebo. Protocol-stipulated interim analysis quantified the efficacy of B-cell depletion. The efficacy on cerebrospinal fluid (CSF) biomarkers failed to reach criteria for continuation of the trial. B-cell-related CSF biomarkers (sCD21 and B-cell activating factor) changed only in the active-treatment arm. While CSF B cells were killed robustly (median -79.71%, P=0.0176), B cells in CNS tissue were depleted inadequately (~-10-20%, P<0.0001). Consequently, the T-cell-specific CSF biomarker sCD27 decreased slightly (-10.97%, P=0.0005), while axonal damage marker, neurofilament light chain did not change. Insufficient saturation of CD20, lack of lytic complement, and paucity of cytotoxic CD56(dim) NK cells contribute to decreased efficacy of rituximab in the CNS. Biomarker studies reliably quantified complementary pharmacodynamic effects of rituximab in the CNS, exposed causes for poor efficacy and determined that RIVITALISE trial would be underpowered to measure efficacy on clinical outcomes. Identified mechanisms for poor efficacy are applicable to all CNS-inflammation targeting monoclonal antibodies.

Search for progressive multiple sclerosis treatment is gathering momentum

Search for progressive multiple sclerosis treatment is gathering momentum

Treatment of progressive MS – are we any closer?

Over the last twenty years, Multiple Sclerosis (MS) has moved from being an untreatable condition, with few therapeutic options to a position of active management underpinned by a range of oral and injectable treatments. These advances however are restricted to patients with the relapsing/remitting form of MS (RRMS), while for those with the progressive forms of the condition there are virtually no treatments available. These patients constitute over 50% of the 2.3 million people with MS worldwide and addressing their needs is all the more important as progression is the main determinant of disability in MS and carries the greatest economic burden. The reasons behind this therapeutic vacuum include (1) poor understanding of the mechanisms underlying neurodegeneration and the identification of potential treatment targets (2) lack of clarity in defining the progressive phenotype (3) developing appropriate trial design with effective biomarkers and clinical outcomes (4) the need for improved symptom management and rehabilitation. A number of initiatives have emerged including the International Progressive MS Alliance (PMSA), which has united MS Societies and clinical academics worldwide. We are now seeing important insights into pathological mechanisms, greater clarity over clinical phenotypes and innovative trial designs. Results from clinical trials have been mixed, with some cause for optimism. However, the imminent outcome from several major studies has the potential to change the direction of travel irrevocably. If we are to have the same impact on progressive MS as seen in RRMS, we will need a focused, global and consistent approach going forward.

Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally.

Objective:We are conducting an open-label phase 1b study on the efficacy of intrathecal (IT) administration of rituximab, provided via an Ommaya reservoir, for the treatment of progressive multiple sclerosis (PMS). The objective of this initial study was to monitor B lymphocytes in peripheral blood (PB) and CSF from the first 10 patients 1 year posttreatment.Methods:Dose titration was performed with daily escalation from 1 mg to 25 mg IT rituximab (n = 3). Lymphocyte subpopulations were monitored daily during dose escalation in PB by flow cytometry and subsequently every 3 months for 1 year, after a total dose of 3 × 25 mg. PB B-lymphocyte subpopulations for the remaining patients (n = 7) were monitored at regular intervals. CSF lymphocyte subpopulations for all patients were monitored by flow cytometry every 2–3 months.Results:The PB B-lymphocyte count dropped rapidly after the first 2 injections (total dose of 3.5 mg IT rituximab) to undetectable levels. Three 25-mg doses given once per week depleted peripheral B lymphocytes entirely for the following 3–6 month period.Conclusions:Monoclonal antibodies seem to rapidly redistribute to the peripheral compartment following IT injection. Ultra-low doses of rituximab given IT are sufficient to cause complete depletion of peripheral B lymphocytes, indicating that low-dose IT treatment has the potential to be effective in both the CNS and systemic compartments.Classification of evidence:This study provides Class IV evidence that for patients with PMS, rituximab provided via an Ommaya reservoir depletes peripheral blood B lymphocytes.

The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis.

The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. The CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. Twenty-seven UK sites. Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. Three and 6 months, and then 6-monthly up to 36 or 42 months. Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). Effectiveness - recruitment targets were achieved. Of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. The CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. Current Controlled Trials ISRCTN62942668. The National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

Understanding Multiple Sclerosis Better in 2014 – Environmental Factors, Remyelination, Diagnostic Techniques, Treatment Decisions and the Future Focus of Multiple Sclerosis Treatment

Epidemiological factors, such as vitamin D, Epstein–Barr virus, smoking and adolescent obesity, are associated with multiple sclerosis (MS) susceptibility and may be involved in MS aetiology. There is also evidence of gene–environment interactions. Both validated predictive biomarkers and gene-expression data will play a crucial role in future diagnosis of MS and prognosis facilitating early treatment and improving management. Understanding the mode of action of disease-modifying therapies (DMTs) should also enhance MS management by identifying the best treatment for different stages of the disease course. Magnetic resonance imaging (MRI) plays a significant role in both diagnosis and monitoring of patients and is likely to become part of the daily MS practice using standardised protocols and software to increase reproducibility. A future goal of MS treatment is to facilitate neuron repair and remyelination. In this respect, animal models of remyelination could be useful in identifying potential therapies. Diagnosis of radiological syndrome is now simpler, but its management is controversial and it does not always convert to MS. In addition, treatment for progressive MS is problematic as current DMTs are indicated only for relapsingremitting MS. Symptomatic treatment is a neglected aspect of MS management, which is often the main concern of both patients and neurologists. Neurologists need to collaborate in trials and consider repurposed drugs that could provide treatment for these symptoms. The second MS Days meeting provided a valuable platform for these critical topics to be discussed and novel solutions to be considered.

MS and related disorders: looking for markers of phenotypes

Multiple sclerosis (MS) research addressed several challenges in 2014, including progressive MS. Despite advances in other forms of MS, there are no approved treatments for progressive MS because of the scarcity of reliable methods to test when, how, and why MS progresses. Nonetheless, post-hoc analyses of placebo-controlled trials1,2 suggest that a subset of patients with progressive MS might benefit from immune-directed therapies, which are usually effective in the management of relapsing–remitting MS.

Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis.

Currently available immunomodulatory therapies do not stop the pathogenesis underlying multiple sclerosis (MS) and are only partially effective in preventing the onset of permanent disability in patients with MS. Identifying a drug that stimulates endogenous remyelination and/or minimizes axonal degeneration would reduce the rate and degree of disease progression. Here, the effects of the highly selective estrogen receptor (ER) β agonist indazole chloride (Ind-Cl) on functional remyelination in chronic experimental autoimmune encephalomyelitis (EAE) mice were investigated by assessing pathologic, functional, and behavioral consequences of both prophylactic and therapeutic (peak EAE) treatment with Ind-Cl. Peripheral cytokines from autoantigen-stimulated splenocytes were measured, and central nervous system infiltration by immune cells, axon health, and myelination were assessed by immunohistochemistry and electron microscopy. Therapeutic Ind-Cl improved clinical disease and rotorod performance and also decreased peripheral Th1 cytokines and reactive astrocytes, activated microglia, and T cells in brains of EAE mice. Increased callosal myelination and mature oligodendrocytes correlated with improved callosal conduction and refractoriness. Therapeutic Ind-Cl-induced remyelination was independent of its effects on the immune system, as Ind-Cl increased remyelination within the cuprizone diet-induced demyelinating model. We conclude that Ind-Cl is a refined pharmacologic agent capable of stimulating functionally relevant endogenous myelination, with important implications for progressive MS treatment.

Natalizumab in progressive MS

Natalizumab inhibits the migration of systemic immune cells to the CNS and may be beneficial in progressive multiple sclerosis (MS). The objective of the study was to examine the effects of natalizumab in progressive MS. In an open-label phase 2A study, 24 patients with progressive MS were included to receive natalizumab treatment for 60 weeks. Response to natalizumab was assessed in CSF and MRI studies. The primary endpoint was change in CSF osteopontin, a biomarker of intrathecal inflammation, from baseline to week 60. Seventeen patients completed the study. No new safety issues were encountered. CSF osteopontin decreased by 65 ng/mL (95% confidence interval 34-96 ng/mL; p = 0.0004) from baseline to week 60 in conjunction with decreases in other CSF biomarkers of inflammation, axonal damage, and demyelination. Magnetization transfer ratio increased in both cortical gray and normal-appearing white matter and correlated with decreases in CSF neurofilament light chain. Natalizumab treatment of progressive MS reduces intrathecal inflammation and tissue damage, supporting a beneficial effect of natalizumab treatment in progressive MS and suggesting that systemic inflammation contributes to the pathogenesis. Moreover, the study establishes the feasibility of using CSF biomarkers in proof-of-concept trials, allowing a low number of participants and short study duration. This study provides Class IV evidence that in patients with progressive MS, natalizumab reduces biomarkers of intrathecal inflammation.