Jai Perumal

Emerging Disease-Modifying Therapies in Multiple Sclerosis

Opinion statementThe past two decades have seen tremendous expansion in therapeutic options for multiple sclerosis (MS). While the growing armamentarium of therapies provides physicians and patients an array of available options, it also brings in its wake the challenging responsibility of choosing the optimal therapy for an individual patient. In a newly diagnosed patient with relapsing disease, the current practice is to start one of the interferons (interferon-beta) or glatiramer acetate. With increasing experience and if there are no new safety concerns, use of fingolimod as a first-line agent in relapsing-remitting MS could expand. BG-12 appears to have a safety and efficacy profile that would make it a first-line agent, while tolerability would need to be considered. Teriflunomide is another oral agent that is under review by the US Food and Drug Administration and, apart from the pregnancy concerns, seems a potential first-line choice as well. For patients with high disease activity at onset or those refractory to current first-line agents, natalizumab and fingolimod are the two options considered most often at present. With the potential availability of alemtuzumab in the near future, that will provide an additional option considered highly efficacious. Its efficacy would have to be weighed carefully against its safety profile. Advances in genetics and biomarkers may allow the development of personalized medicine, and thus, the determination of the “best therapy” for an individual patient. Risk stratification strategies such as serum JC virus antibody status and pre-determination an individual’s risk of autoimmune disease on alemtuzumab may facilitate early initiation of optimal therapies. Treatments for MS have come a long way and the future looks even more promising and will provide us with better and greater options in treating patients, meaning we can hope to see even less of an impact of the disease in the lives of patients with MS.

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

BACKGROUND Primary 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. METHODS SPRINT-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. RESULTS A 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. CONCLUSION SPRINT-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.

Subcutaneous administration of alemtuzumab in patients with highly active multiple sclerosis.

Alemtuzumab is an anti-CD52 monoclonal antibody with remarkable efficacy in relapsing multiple sclerosis (MS). In clinical trials and off-label use in MS, alemtuzumab has been administered intravenously (IV). Alemtuzumab is approved for chronic lymphoid leukemia as IV. Oncology guidelines recommend alemtuzumab subcutaneous (SC) over IV. There is no report of alemtuzumab SC in MS. We report two patients with highly active relapsing MS who were treated with SC alemtuzumab, had significant improvement and tolerated SC alemtuzumab well without the typical infusion-associated adverse events. SC alemtuzumab in MS warrants further studies as this may enhance patient convenience and minimize infusion-associated adverse events.

Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation

OBJECTIVE The objective of this study is to longitudinally analyze the uptake of [11C]PK11195-PET in multiple sclerosis patients after 3 and 6 months of natalizumab treatment. METHODS Eighteen MS patients, starting treatment with monocloncal anti-VLA-4, were enrolled in a longitudinal PK-PET study. PK uptake was quantified by volume of distribution (VT) calculation using image-derived input function at baseline, 3 and 6 months. Pharmacokinetic quantification was done using a segmented MRI, and selected areas included white matter, gadolinium enhancing lesions, non-enhancing lesions, cortical grey matter and thalamus. VTs of lesions were calculated in reference to each patients white matter (VT ratio=VTr), to consider physiologic variability. RESULTS Test-retest variability was stable for healthy control (HC). Quantification of PK uptake was completed in 18 patients, and baseline uptake was compared to 6-month uptake. After the start of natalizumab VTr significantly decreased in 13 individual enhancing lesions present within 5 patients (p=0.001). Moreover, VTr of the sum of non-enhancing lesions showed a moderate decrease (p=0.03). No longitudinal changes were detected in normal appearing white matter, the thalamus and cortical grey matter. CONCLUSION A reduction in PK11195 uptake was observed in both enhancing and chronic lesions after the start of natalizumab. PK11195 PET can be used as tool to assess the longitudinal change in MS lesions.

Comparative efficacy of alemtuzumab and established treatment in the management of multiple sclerosis

Alemtuzumab is the newest disease-modifying therapy approved for the treatment of relapsing multiple sclerosis. Alemtuzumab is an anti-CD52 targeted antibody that causes lysis of T and B lymphocytes, monocytes, natural killer cells, macrophages, and dendritic cells. Following its administration, a prolonged T-cell lymphopenia results with emergence of a reconstituted immune system that differs in its composition from that pretreatment. In clinical trials, alemtuzumab has shown impressive efficacy with regard to clinical and radiological outcomes in relapsing multiple sclerosis, along with sustained long-term beneficial effects, and it is attractive for its once-yearly administration. Despite this, the occurrence of serious secondary autoimmune disorders, infections, and a potential risk of malignancy necessitates a careful evaluation of risks versus benefits for an individual patient prior to its use. The requirement of patient commitment to the intense mandatory monitoring program is also a factor to be considered when incorporating alemtuzumab into the treatment regimen.

Immediate transient thrombocytopenia at the time of alemtuzumab infusion in multiple sclerosis

Background: Alemtuzumab is a monoclonal antibody approved for relapsing-remitting multiple sclerosis (RRMS). Although Immune thrombocytopenia (ITP) has been reported as a secondary autoimmune phenomenon following alemtuzumab infusion, immediate thrombocytopenia during the infusion has not been reported. Objective: We report transient, reversible, self-limiting acute-onset thrombocytopenia during the first course with alemtuzumab. Results and conclusion: In total, 3 of 22 paitents developed mild self-limited bruising associated with a drop in platelet count from their baseline during the intial 5-day course of alemtuzumab. Upon chart review, all 22 patients who received alemtuzumab developed an immediate mostly asymptomatic drop in platelet count which returned to normal within 2 months post-infusion.

Differential Impact of Multiple Sclerosis on Cortical and Deep Gray Matter Structures in African Americans and Caucasian Americans.

African Americans with multiple sclerosis (AAwMS) have different disease phenotypes when compared to Caucasians Americans with MS (CAwMS). The pathologic basis of this difference in disease presentation is unknown.

Fingolimod and cardiac risk: latest findings and clinical implications.

Fingolimod is an oral medication approved for the treatment of relapsing multiple sclerosis (MS). It is unique compared with other approved disease-modifying therapies for MS in that it is the first oral agent and it has a novel mechanism of action. In clinical trials and postmarket use, it demonstrates clear therapeutic efficacy. However, it is associated with certain risks including cardiac concerns. The recent reports of cardiac events potentially associated with the drug prompted a regulatory agencies review of the use of fingolimod for MS in the USA and Europe. After completion of their review, the US Food and Drug Administration and the European Medicines Agency concluded that its benefits outweighed the risks. However, certain recommendations were made for appropriate patient selection for fingolimod and for more cautious first-dose monitoring. We review the use of fingolimod for MS in light of the recently reported potential cardiac risks. We conclude that with appropriate patient selection and careful monitoring, it appears to have a favorable benefits/risks profile and can be a valuable treatment option for relapsing MS. Continued postmarketing surveillance and data from the extension phase of its clinical trials will be very important in understanding the long-term efficacy and safety of fingolimod and to help determine its place in the treatment algorithm for multiple sclerosis.

A study of patients with aggressive multiple sclerosis at disease onset

Objective Identify aggressive onset multiple sclerosis (AOMS) and describe its clinical course. Methods AOMS patients were identified from a multiple sclerosis (MS) database based on a set of criteria. The subsequent clinical course of AOMS patients was then reviewed with the goal of potentially identifying the best approaches to manage these patients. Results Fifty-eight of 783 (7.4%) patients in the MS database met the criteria for AOMS, and 43 patients who had complete data for the duration of their follow-up were included in the subsequent analysis. The mean duration of the follow-up was 54 months. Thirty-five patients (81%) were started on a conventional first-line agent (injectable therapies for MS). Only two of these 35 patients (5.7%) had no evidence of disease activity. Twenty-two of 35 patients suffering from refractory disease were switched to a more aggressive treatment (natalizumab, rituximab, alemtuzumab, cyclophosphamide). Eight patients were started on aggressive treatment as their initial therapy, and seven of these eight (87.5%) patients showed no evidence of disease activity. Conclusion With recognition of the crucial significance of early optimal treatment during the potential window of opportunity for best long-term outcomes, we describe AOMS within 1 year of disease onset and discuss possible treatment considerations for these patients.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll‐like receptor 4 and can cross the blood–brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal‐appearing brain tissue, the thickness of the retinal nerve‐fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was ‐0.0010 per year with ibudilast and ‐0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain‐tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT‐MS ClinicalTrials.gov number, NCT01982942.)