Relapsing Forms Of Multiple Sclerosis Research Articles

Reversible oxidation/reduction steps in the metabolic degradation of the glycerol side chain of the S1P1 modulator ponesimod

1. Ponesimod is a selective modulator of the sphingosine 1-phosphate receptor 1 (S1P1) approved for the treatment of active relapsing forms of multiple sclerosis. The chemical structure of ponesimod contains a glycerol side chain which is the major target of drug metabolism in humans. 2. The two major metabolic pathways give the acids M12 (-OCH2CH(OH)COOH) and M13 (-OCH2COOH). While the former results from oxidation of the terminal alcohol, the mechanism yielding the chain-shortened acid M13 is less obvious. A detailed mechanistic study with human liver microsomes and hepatocytes using ponesimod, M12 and some of the suspected intermediates revealed an unexpectedly complex pattern of enzyme-mediated and chemical reactions. 3. Metabolic pathways for both acids were not independent and several of the transformations were reversible, depending on reaction conditions. Formation of M13 occurred either via initial oxidation of the secondary alcohol, or as a downstream process starting from M12. 4. The phenol metabolite M32 was produced as part of several pathways. Control experiments at various pH values and in the absence of metabolizing enzymes support the conclusion that its formation resulted from chemical degradation rather than from metabolic processes.

Successful treatment of multiple sclerosis with refractory rheumatoid arthritis using ofatumumab: A case report

AbstractBackgroundOfatumumab is an anti‐CD20 human monoclonal antibody that is approved in several countries worldwide for the treatment of relapsing forms of multiple sclerosis (MS). Recent studies have shown promising results of ofatumumab therapy for rheumatoid arthritis (RA). We report a case with both MS and refractory RA that was successfully treated with ofatumumab.Case PresentationA 44‐year‐old woman with a history of RA since the age of 40, and prior treatment with methotrexate, prednisolone, and several disease‐modifying antirheumatic drugs (DMARDs), including salazosulfapyridine, iguratimod, tacrolimus, presented with a recent onset of visual acuity loss in the left eye. Ophthalmic examination revealed a decreased central flicker frequency (CFF) and central scotoma. Brain magnetic resonance imaging (MRI) revealed periventricular multiple lesions and contrast enhancement of the left optic nerve. Cerebrospinal fluid analysis revealed mild lymphocytic pleocytosis, elevation of protein, and oligoclonal bands. Serum anti‐aquaporin‐4 (AQP4) antibodies, anti‐myelin oligodendrocyte glycoprotein (MOG) antibodies, and other serological tests for optic neuritis were unremarkable. She was diagnosed with relapsing and remitting MS at 10 months after development of optic neuritis when she experienced a relapse, accompanied by new asymptomatic lesions detected on brain MRI. After ofatumumab administration, we discontinued all DMARDs and maintained remission over a 12‐month period.ConclusionThere is growing evidence of significant involvement of B‐cells in the pathogenesis of RA and the effectiveness of B‐cell depletion therapy in managing RA. Ofatumumab is an effective treatment for patients with MS and refractory RA.

Meaningful Change Thresholds and Fatigue Severity Points on Patient-Reported Outcomes by the Fatigue Symptoms and Impacts Questionnaire in Patients With Relapsing Multiple Sclerosis

ObjectivesThe Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a new content-valid, concise, and reliable 20-item patient-reported outcome measure to evaluate the symptoms and impacts of fatigue in patients with relapsing forms of multiple sclerosis. Analyses were performed to derive meaningful change thresholds (MCTs) on patient-reported outcomes as measured by FSIQ-RMS and generate receiver operating characteristic (ROC) curves to determine fatigue severity cut points at baseline and change in severity at post-baseline and supplement the anchor-based MCT results. MethodsAnalyses were based on data from the OPTIMUM trial (NCT02425644). An anchor-based approach using uncollapsed changes on the Patient Global Impression of Severity at week 108 were used to determine the MCT for only the FSIQ-RMS Symptoms domain; distribution-based MCT estimations were conducted using baseline FSIQ-RMS Impacts scores. ROC curves with calculation of area under the curve were used to identify the best cut point. ResultsBased on the evidence provided by the anchor-based analyses using the Patient Global Impression of Severity as an anchor for the FSIQ-RMS Symptoms domain, meaningful score changes for improvement and deterioration were −6.3 and 6.3, respectively. Meaningful score changes for the FSIQ-RMS Physical, Cognitive/Emotional, and Coping Impacts domains using distribution-based methods were 10.8, 8.4, and 9.8, respectively. These results are supported by the ROC analyses. ConclusionsThresholds to support interpretation of the FSIQ-RMS, such as MCTs, can be used to determine and categorize patients who have experienced a meaningful change in their MS-related fatigue (eg, responder analyses) in future clinical research studies.

P687 Ozanimod as a once-daily oral therapy for Japanese patients with ulcerative colitis: results from the induction period of a Phase 2/3 study (J-True North)

Abstract Background Ozanimod is an oral, small molecule sphingosine 1-phosphate (S1P) receptor modulator that selectively targets the S1P1 and S1P5 receptor subtypes. Ozanimod is approved in multiple countries outside Japan for the treatment of moderately to severely active ulcerative colitis (UC) and/or relapsing forms of multiple sclerosis. We herein report the efficacy and safety results during the induction period of J-True North, a multi-centre, randomised, double-blind, placebo-controlled clinical Phase 2/3 study consisting of a 12-week induction period, followed by a 40-week maintenance period and an open-label extension period in Japanese patients with moderately to severely active UC. Methods Japanese male and female UC patients aged 18 to 75 years with moderately to severely active UC (defined as Mayo score of 6 to 12, with endoscopic subscore ≥2, rectal bleeding score (RBS) ≥1, and stool frequency score ≥1) were randomised in a 1:1:1 ratio to receive either 0.46 mg or 0.92 mg ozanimod, or placebo capsules orally once daily. All patients had received prior treatment with aminosalicylates or corticosteroids. The primary endpoint was clinical response at Week 12 (defined as a reduction from baseline in the complete Mayo score of ≥ 3 points and ≥ 30%, and a reduction from baseline in the RBS of ≥ 1 point or an absolute RBS of ≤ 1 point), and key secondary endpoints were clinical remission, clinical response, endoscopic improvement, mucosal healing and safety at Week 12 and 52. Results Patients were randomised to the ozanimod 0.46 mg group (n=68), 0.92 mg group (n=65), and the placebo group (n=65). At baseline, 36.4% of patients were female, mean age was 42.6 y and mean complete Mayo score was 8.4. The clinical response rate at Week 12 was 52.9%, 61.5%, and 32.3% in the ozanimod 0.46 mg, 0.92 mg, and placebo groups, respectively, demonstrating a statistically significant improvement of ozanimod vs placebo (Figure 1). Similarly, higher improvement rates were observed in all key secondary clinical and endoscopic endpoints in the ozanimod groups compared with the placebo group at Week 12. Frequent adverse events (AEs) observed in the induction period were nasopharyngitis, headache, et.al. (Table 1). AEs observed in the study were similar to those in the global phase 3 True North study with 0.92 mg ozanimod, and there were no new safety signals with ozanimod in the J-True North study. Conclusion Ozanimod as a once-daily oral therapy was effective as induction therapy for Japanese patients with moderately to severely active UC, and the safety profile was consistent with the results of previous studies. Figure 1 Table 1

Real-world treatment patterns and effectiveness of cladribine tablets in patients with relapsing forms of multiple sclerosis in the United States.

Real-world evidence on the use of cladribine tablets (CladT) for relapsing forms of multiple sclerosis (RMS) in the United States is emerging. The objective of this study was to assess the real-world treatment patterns and effectiveness of CladT in RMS. Adults with RMS initiating CladT were selected from the Symphony Integrated Dataverse. Baseline and follow-up periods were the 12 months before and 24 months after CladT initiation (index date). Switching to another disease-modifying therapy (DMT) and number of CladT courses were described during follow-up. Annualized relapse rate (ARR), MS disease severity, Expanded Disability Status Scale-Derived Disability Indicators (EDSS-DDI), corticosteroid use, and healthcare resource utilization (HRU) were described during Years 1 and 2 of follow-up and compared with baseline. A total of 539 CladT-treated patients were included (mean age: 49.9 years; 77.6% female). Over the 2-year follow-up, 91% and 59% of patients had one and two CladT courses, respectively, and 7% of patients had evidence of switching to another DMT. ARR, MS disease severity score, and corticosteroid use decreased significantly during follow-up compared with baseline, while EDSS-DDI remained stable. All-cause and MS-related HRU decreased during follow-up. CladT-treated patients with RMS had low switch rates, reduced ARR, disease severity, corticosteroid use, and HRU.

Practical Clinical Guidelines for Natalizumab Treatment in Patients With Relapsing Multiple Sclerosis.

Natalizumab (TYSABRI®) was the first high-efficacy monoclonal antibody disease-modifying therapy (DMT) approved as a monotherapy for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS. Because natalizumab is administered by intravenous infusion, infusion nurses play a key role in the care of natalizumab-treated patients. In the 16 years since approval, substantial data have been gathered on the long-term, real-world effectiveness and safety of natalizumab. This article provides a synopsis of this data, as well as practical information for optimizing patient care. This includes information on strategies to mitigate the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients, natalizumab use during pregnancy, and use with vaccines. It also includes guidance on the preparation and administration of natalizumab and monitoring of natalizumab-treated patients.

Effectiveness and Safety of Teriflunomide in Relapsing-Remitting Multiple Sclerosis and Improvements in Quality of Life: Results from the Real-World TERICARE Study.

Teriflunomide is a once-daily oral immunomodulator approved for relapsing forms of multiple sclerosis (MS) or relapsing-remitting multiple sclerosis (RRMS; depending on the local label), based on extensive evidence from clinical trials and a real-world setting on efficacy, tolerability and patient-reported benefits. The TERICARE study assessed the impact of teriflunomide treatment over 2years on health-related quality of life (HRQoL) and some of the most common and disabling symptoms of MS, such as fatigue and depression. This prospective observational study in Spain included RRMS patients treated with teriflunomide for ≤ 4weeks. The following patient-reported outcomes (PROs) were collected at baseline and every 6months for 2years: the 29-item Multiple Sclerosis Impact Scale version 2 (MSIS-29), the 21-item Modified Fatigue Impact Scale (MFIS-21), the Beck Depression Inventory (BDI-II), the Short Form (SF)-Qualiveen and theTreatment Satisfaction Questionnaire for Medication v1.4 (TSQM). Annualised relapse rate (ARR), disability progression according to the Expanded Disability Status Scale (EDSS), and no evidence of disease activity (NEDA-3) were also assessed. A total of 325 patients were analysed. Patients had a mean (SD) age of 43.2years (10.4), a mean baseline EDSS score of 1.75 (1.5), a mean number of relapses in the past 2years of 1.5 (0.7), and 64% had received prior disease-modifying therapy (DMT). Patients showed significant improvements in the psychological domain of MSIS-29 from 35.9 (26.6) at baseline to 29.4 (25.5) at 18months (p = 0.004) and 29.0 (24.6) at 24months (p = 0.002). Levels of fatigue and depression were also reduced. After 2years of treatment with teriflunomide, ARR was reduced to 0.17 (95% CI 0.14-0.21) from the baseline of 0.42 (95% CI 0.38-0.48), representing a 60.1% reduction. Mean EDSS scores remained stable during the study, and 79.9% of patients showed no disability progression. 54.7% of patients achieved NEDA-3 in the first 12months, which increased to 61.4% during months 12-24. Patients reported increased satisfaction with treatment over the course of the study, regardless of whether they were DMT naive or not. Teriflunomide improves psychological aspects of HRQoL and maintains low levels of fatigue and depression. Treatment with teriflunomide over 2years is effective in reducing ARR and disability progression.

Relapse recovery in relapsing-remitting multiple sclerosis: An analysis of the CombiRx dataset.

Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery. The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS). Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time to unconfirmed and confirmed relapse recovery. CombiRx included 1008 participants. We investigated 240 relapses. Median time to relapse recovery was 111 days. Most recovery events took place within 1 year of relapse onset: 202 of 240 (84%) individuals recovered during follow-up, 161 of 202 (80%) by 180 days, and 189 of 202 (94%) by 365 days. Relapse severity was the only factor associated with relapse recovery. Recovery from relapses takes place up to approximately 1 year after the event. Relapse severity, but no other patient factors, was associated with the speed of relapse recovery. Our findings inform clinical practice and trial design in RRMS.

Meta‐analysis of the use of Ofatumumab in the treatment of relapsing‐remitting multiple sclerosis

AbstractBackgroundOfatumumab is the first monoclonal antibody developed specifically for treating relapsed multiple sclerosis (RMS). This disease (Multiple Sclerosis) includes relapsing–remitting multiple sclerosis (RRMS), a chronic autoimmune illness that affects the central nervous system (CNS), including the brain and spinal cord. The purpose of this study is to determine whether Ofatumumab is efficacious and safe in the treatment of relapsing–remitting multiple sclerosis.MethodsAn analysis of studies comparing Ofatumumab with placebo in people with relapsing‐remitting multiple sclerosis was done in accordance with PRISMA guidelines. We looked up information in MEDLINE, SciSearch, BIOSIS Previews, Derwent Drug File, Embase, and International Pharmaceutical Abstracts. In patients with relapsing–remitting multiple sclerosis, randomized double‐blind and non‐randomized trials contrasting Ofatumumab with placebo were found by two independent investigators. Utilizing Review Manager 5.4.1, data were examined. The main results were total gadolinium‐enhancing (Gd+) T1 lesions, annualized relapse rate, and new or expanding total T2 lesions. Secondary outcomes concentrated on general adverse events and adverse events related to infections.ResultsThree studies were included involving 334 patients, and the meta‐analysis indicated that Ofatumumab showed good efficacy and safety in patients with relapsing forms of multiple sclerosis. The annual rate of relapse was significantly reduced by Ofatumumab (OR 0.51; 95% CI 0.27, 0.98; P = 0.04). Ofatumumab reduced the number of gadolinium‐enhancing (Gd+) T1 lesions per scan (Mean difference −0.59; 95% CI −0.63, −0.55; P < 0.05). Ofatumumab treatment decreased new or enlarging total T2 lesions significantly (Mean difference −1.03; 95% CI −1.29, −0.76; P < 0.05). Infection‐related adverse effects were seen more frequently with Ofatumumab shown by the odd ratio 0.48; 95% CI 0.22, 1.04; P = 0.06. Infection is, thus, a major limitation to its use.ConclusionThe meta‐analysis indicated that Ofatumumab is efficacious and safe for patients with relapsing forms of multiple sclerosis.

FTY720 in immuno-regenerative and wound healing technologies for muscle, epithelial and bone regeneration.

In 2010, the FDA approved the administration of FTY720, S1P lipid mediator, as a therapy to treat relapsing forms of multiple sclerosis. FTY720 was found to sequester pro-inflammatory lymphocytes within the lymph node, preventing them from causing injury to the central nervous system due to inflammation. Studies harnessing the anti-inflammatory properties of FTY720 as a pro-regenerative strategy in wound healing of muscle, bone and mucosal injuries are currently being performed. This in-depth review discusses the current regenerative impact of FTY720 due to its anti-inflammatory effect stratified into an assessment of wound regeneration in the muscular, skeletal, and epithelial systems. The regenerative effect of FTY720 in vivo was characterized in three animal models, with differing delivery mechanisms emerging in the last 20years. In these studies, local delivery of FTY720 was found to increase pro-regenerative immune cell phenotypes (neutrophils, macrophages, monocytes), vascularization, cell proliferation and collagen deposition. Delivery of FTY720 to a localized wound environment demonstrated increased bone, muscle, and mucosal regeneration through changes in gene and cytokine production primarily by controlling the local immune cell phenotypes. These changes in gene and cytokine production reduced the inflammatory component of wound healing and increased the migration of pro-regenerative cells (neutrophils and macrophages) to the wound site. The application of FTY720 delivery using a biomaterial has demonstrated the ability of local delivery of FTY720 to promote local wound healing leveraging an immunomodulatory mechanism.

Results of a Phase III, Multinational, Double-blind, Placebo-controlled Study in Subjects with Relapsing Forms of Multiple Sclerosis (RMS) to Assess the Efficacy, Safety, and Tolerability of GA Depot, a Long-Acting IM Injection of Glatiramer Acetate, Administered Once Every Four Weeks (P6-3.014)

Results of a Phase III, Multinational, Double-blind, Placebo-controlled Study in Subjects with Relapsing Forms of Multiple Sclerosis (RMS) to Assess the Efficacy, Safety, and Tolerability of GA Depot, a Long-Acting IM Injection of Glatiramer Acetate, Administered Once Every Four Weeks (P6-3.014)

Long-Term Safety and Effectiveness of Delayed-release Dimethyl Fumarate in Multiple Sclerosis Patients Treated in Routine Medical Practice, an updated analysis of the ESTEEM Study (P7-3.009)

<h3>Objective:</h3> To assess long-term safety and effectiveness of delayed-release dimethyl fumarate (DMF) in patients with relapsing forms of multiple sclerosis (MS) in clinical practice. <h3>Background:</h3> DMF has demonstrated a favorable benefit–risk profile in patients with relapsing forms of MS in clinical trials and real-world studies. To provide information on long-term exposure in clinical practice, the ESTEEM study (NCT02047097) was conducted. <h3>Design/Methods:</h3> In this ongoing study, patients treated with DMF were recruited from ~380 sites. The primary objective was to assess the incidence and type of serious adverse events (SAEs) and AEs leading to discontinuation. Secondary objectives included assessment of DMF effectiveness on annualized relapse rate (ARR) and patient-reported outcomes (PROs). <h3>Results:</h3> As of April 2021, 5251 patients had received &gt;1 dose of DMF. Mean (SD) age of patients at enrollment was 40.1 (11.2) years; 74.0% were female. Patients received DMF for a mean (SD) duration of 30.4 (20.4) months. Primary reasons for discontinuation were AEs (1066/5251; 20.3%), of which the most common were gastrointestinal AEs (442/1066; 41.5%), and efficacy reasons (439/5251, 8.4%). Of 5251 patients, 173 (3.3%) patients discontinued due to lymphopenia. SAEs were reported in 326 (6.2%) patients, most commonly infections and infestations (n=86; 1.6%). No PML was reported. Adjusted ARR (95% CI) remained low, ranging from 0.16 (0.14–0.17) after Year 1 to 0.05 (0.04–0.08) after Year 5. Mean scores for measures of physical and psychological impact, fatigue, overall health outcomes, and work productivity and activity impairment remained stable at 5.5 years compared with baseline. <h3>Conclusions:</h3> In this interim analysis, DMF demonstrated a safety profile in real-world clinical practice consistent with the known profile of DMF. Similarly, relapse rates were low and both ARR and PROs remained stable over time. This indicates a sustained effectiveness for patients who remain on DMF treatment for up to 5 years. <b>Disclosure:</b> Dr. Pandey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Pandey has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi Genzyme. Dr. Pandey has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech . Dr. Pandey has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for BMS. Dr. Pandey has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen . Dr. Pandey has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion. Dr. Pandey has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Genentech . Dr. Pandey has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Horizon Therapeutics . The institution of Dr. Pandey has received research support from NIH. The institution of Dr. Pandey has received research support from CMSC. Kathryn Giles has stock in Synderdisc. The institution of Kathryn Giles has received research support from Biogen. Dr. Balashov has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Macdonell has nothing to disclose. Jorg Windsheimer has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck, Biogen,BMS,Janssen,Roche,Hexal. Jorg Windsheimer has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen,Teva,BMS. Mikel Martinez has nothing to disclose. Dr. Bozin has received personal compensation for serving as an employee of Biogen. Dr. Bozin has received personal compensation for serving as an employee of Arvelle Therapeutics. Dr. Bozin has stock in Biogen. Xiaotong Jiang has nothing to disclose. Dr. Lyons has received personal compensation for serving as an employee of Biogen. Dr. Lyons has received stock or an ownership interest from Biogen. Oksana Mokliatchouk has received personal compensation for serving as an employee of Biogen. Oksana Mokliatchouk has received stock or an ownership interest from Biogen. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Okai has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Okai has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Serono. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Okai has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi Genzyme. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alexion. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for EMD SERONO . Dr. Okai has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Sanofi Genzyme .

Use of individual measure and Z-scores to monitor disease course in Relapsing Multiple Sclerosis: A 1-year Prospective Study in a Single Center (P5-3.012)

<h3>Objective:</h3> To assess the performance of individual serum neurofilament (sNFL) values vs. Z-score to monitor inflammation in persons with relapsing forms of MS (pwRMS) <h3>Background:</h3> Population-based standards of sNFL levels have been recently proposed to detect activity in pwRMS. However, sNFL levels are variable, and the exact algorithm to diagnose individual-based disease activity is not defined yet. <h3>Design/Methods:</h3> A prospective cohort of 114 pwRMS were followed for 1 year. Clinical examination and sNFL assessment were performed and registered every three months. MRIs were performed annually. Baseline sNFL was the sNFL level measured at study inclusion in the absence of disease activity. Reference sNFL level was the lowest individual sNFL measure obtained during follow-up in the absence of disease activity. BMI-adjusted Z-score was registered for baseline, reference, and activity points. Non-parametric tests were used because data did not follow a normal distribution. <h3>Results:</h3> Median baseline sNFL levels were 6.85 (5.15 – 9.09); Z score 0.64 (−0.33 – 1.49). Median reference sNFL levels were 4.71 (4 – 5.87); Z score −0.36 (−1.13 – 0.42). Twenty-four patients (21.1%) had disease activity during follow-up. Median sNFL in these patients was 8.67 pg/ml (6.91 – 13) with an increase of 14.7% over the baseline level: 1.01 (−0.71 – 2.67; P = 0.66) and of 77% over the reference level: 3.63 (2.09 – 6.25; P = 0.001). Z-score during disease activity was 1.13 (0.45 – 2.27), overlapping with control levels in the population-based normogram. In our cohort, none of the individual sNFL measures or baseline Z-score predicted disease activity during the first year of follow-up, but patients with relapse at inclusion were more prone to have disease activity. <h3>Conclusions:</h3> Establishment of an individual sNFL reference value in the first year of follow-up might help to better diagnose ongoing inflammation. Baseline sNFL was not as good comparator for this outcome. <b>Disclosure:</b> Mr. Solís-Tarazona has received personal compensation for serving as an employee of Novo Nordisk A/S. Salma Reddam has nothing to disclose. Dr. Gil-Perotin has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck.

Ublituximab: First Approval.

Ublituximab (ublituximab-xiiy; BRIUMVI™) is a glycoengineered anti-CD20 monoclonal antibody developed by TG Therapeutics, Inc. for the treatment of multiple sclerosis (MS). The mechanism of action of ublituximab involves the depletion of B cells via antibody-dependent cellular cytotoxicity, as B cells have a key role in the pathogenesis of MS. Ublituximab is the first anti-CD20 treatment that is administered twice-yearly as one hour infusions, following the initial doses. In December 2022, ublituximab received its first global approval in the USA for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. This article summarizes the milestones in the development of ublituximab leading to this first approval in this indication.

Ublituximab (Briumvi) for Relapsing Multiple Sclerosis

The FDA has approved the recombinant chimeric anti-CD20 antibody ublituximab-xiiy (Briumvi – TG Therapeutics) for IV treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome (initial neurological episode), relapsing-remitting disease, and active secondary progressive MS (SPMS). Two other anti-CD20 antibodies, IV ocrelizumab (Ocrevus) and SC ofatumumab (Kesimpta), are also FDA-approved for these indications.

Comparative efficacy and safety of ozanimod and ponesimod for relapsing multiple sclerosis: A matching-adjusted indirect comparison.

Ozanimod and ponesimod are sphingosine 1-phosphate receptor modulators approved by the U.S. Food and Drug Administration for treatment of relapsing forms of multiple sclerosis (MS). Given that no head-to-head trials have assessed these two treatments, we performed a matching-adjusted indirect comparison (MAIC) to compare efficacy and safety outcomes between ozanimod and ponesimod for MS. A MAIC compared efficacy and safety of ozanimod and ponesimod at 2 years. Outcomes included annualized relapse rate (ARR) and percentage change from baseline in brain volume loss (BVL) as well as rates of any treatment-emergent adverse events (TEAEs), serious adverse events (AEs), AEs leading to discontinuation, and other safety outcomes. Individual patient-level data were obtained for ozanimod from the RADIANCE-B trial, while aggregate-level patient data were obtained for ponesimod from the OPTIMUM trial. The MAIC was not anchored owing to lack of a common comparator across the two trials. The following characteristics were matched between the trials' populations: age, sex, time since MS symptom onset, relapses in prior year, Expanded Disability Status Scale score, disease-modifying therapies received in the prior 2 years, absence of gadolinium-enhancing T1 lesions, and percentage of patients from Eastern Europe. After matching, key baseline characteristics were balanced between patients receiving ozanimod and ponesimod. Compared with ponesimod, ozanimod had a numerically lower ARR (rate ratio: 0.80 [95% CI: 0.57, 1.10]) and was associated with a significant reduction in BVL (% change difference: 0.20 [95% CI: 0.05, 0.36]). Additionally, ozanimod was associated with a significantly lower risk of TEAEs (risk difference: -11.9% [95% CI: -16.8%, -7.0%]), AEs leading to discontinuation (-6.1% [95% CI: -8.9%, -3.4%]), and lymphocyte count <0.2K/μL (-2.3% [95% CI: -4.2%, -0.5%]). There were no statistically significant differences in the other safety outcomes. The MAIC results suggest that, compared with ponesimod, ozanimod is more effective in preserving brain volume, is comparable in terms of reducing relapse rates, and has a favorable safety profile.

Stability and Activity of Interferon Beta to Treat Idiopathic Pulmonary Fibrosis with Different Nebulizer Technologies.

Background: Idiopathic pulmonary fibrosis (IPF) is a serious lung disease characterized by lung scarring, which results in breathing difficulty. Currently, patients with IPF exhibit a poor survival rate and have access to very limited therapeutic options. Interferon beta (IFN-β) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing forms of multiple sclerosis, and it has also been shown to exhibit therapeutic potential in IPF. However, clinical use of IFN-β did not lead to improved overall survival in IPF patients in existing studies. One possibility is the limited efficiency of IFN-β delivery through intravenous or subcutaneous injection. Materials and Methods: The aerosol particle size distribution was determined with a laser diffraction particle size analyzer to characterize the droplet size and fine particle fraction generated by three types of nebulizers: jet, ultrasonic, and mesh. A breathing simulator was used to assess the delivery efficiency of IFN-β, and the temperature in the medication reservoirs was monitored with a thermocouple during nebulization. To further evaluate the antifibrotic activity of IFN-β pre- and postnebulization, bleomycin (BLM)- or transforming growth factor-beta (TGF-β)-treated human lung fibroblast (HLF) cells were used. Cell viability was measured by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Transwell migration assay and Q-PCR analysis were used to evaluate cell migration and the myofibroblast differentiation ability, respectively. IFN-β protein samples were prepared using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) sample loading buffer, and the expression of IFN-β was assessed by western blotting. Results: Among the current drug delivery systems, aerosolized medication has shown increased efficacy of drug delivery for treating respiratory diseases when compared with parenteral drugs. It was found that neither the structural integrity nor the biological function of nebulized IFN-β was compromised by the nebulization process of the mesh nebulizer. In addition, in BLM dose-response or TGF-β-induced lung fibroblast proliferation assays, these effects could be reversed by both parenteral and inhaled IFN-β nebulized with the mesh nebulizer. Nebulized IFN-β with the mesh nebulizer also significantly inhibited the migration and myofibroblast differentiation ability of TGF-β-treated HLF cells. Conclusions: The investigations revealed the potential efficacy of IFN-β in the treatment of IPF with the mesh nebulizer, demonstrating the higher efficiency of IFN-β delivered through the mesh nebulizer.

A plain language summary of the impact of vaccines against flu and chickenpox in people with multiple sclerosis treated with cladribine tablets.

This is a summary of an article originally published in the Multiple Sclerosis Journal. Cladribine tablets (MAVENCLAD®) are an oral (taken by mouth) medication, approved for the treatment of people with relapsing forms of multiple sclerosis (MS, with episodes of new or worsening symptoms). They are administered for a maximum of 10 days per year, over a period of 2 years. Cladribine tablets work by temporarily reducing the number of lymphocytes, which are immune cells that help to fight off infections. Because of this, people with MS (also called PwMS) may have concerns about the effect of cladribine tablets on vaccines, as these work via immune cells to build protection against infection. A study called MAGNIFY-MS investigated how long it takes for cladribine tablets to begin to work in people with a type of MS called highly active relapsing MS. During the study, some participants received their usual vaccinations against flu (influenza) and against the chickenpox virus (also called varicella zoster virus) as part of their routine medical care. The MAGNIFY-MS study gave the researchers an opportunity to look at how cladribine tablets affect the way the flu and chickenpox virus vaccines work in the body. Cladribine tablets do not affect how well the body responds to flu and chickenpox vaccines. PwMS taking cladribine tablets who are vaccinated against chickenpox, flu or both can be protected against these diseases.

Ponesimod for the treatment of relapsing multiple sclerosis

Ponesimod (Ponvory) is a new sphingosine 1‐phosphate receptor modulator for the treatment of adults with relapsing forms of multiple sclerosis (MS). This article discusses its mode of action, efficacy and adverse effects.

S812 Hepatic Safety of Ozanimod in Ulcerative Colitis and Relapsing Multiple Sclerosis Phase 3 Trials

Introduction: Ozanimod (OZA) is a sphingosine 1-phosphate (S1P) receptor modulator approved for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing forms of multiple sclerosis (MS) in the United States and European Union. Other S1P receptor modulators have shown substantial elevations in hepatic enzymes. Methods: The impact of OZA on liver function tests was assessed in this safety analysis from phase 3 UC and MS trials. In the 52-week (10-week induction period and 42-week maintenance period), randomized True North (TN) trial, patients (pts) with moderately to severely active UC were treated with placebo (n=216) or OZA 0.92 mg (equivalent to OZA HCl 1 mg) (n=796). In the randomized MS trials (SUNBEAM and RADIANCE), MS pts were treated with interferon beta-1a 30 µg (n=885) or OZA (n=882) for 12 and 24 months, respectively. Hepatic enzymes were assessed at baseline and Weeks 5, 10, 18, 28, 40, and 52 in TN, and at baseline and every 3 months for the MS trials. In the UC and MS trials, enzyme elevations were confirmed with a repeated test within 14 days. Results: Percentages of pts on OZA 0.92 mg with elevations in alanine transaminase (ALT), aspartate aminotransferase (AST), and bilirubin are shown in the Table; < 6% and < 2% of pts had ALT and AST elevations ≥3 x upper limit of normal (ULN), respectively, and < 2% had bilirubin elevations >2 x ULN. Of those with ALT ≥3 x ULN, 86.4% (19/22) of UC pts and 85.4% (41/48) of MS pts recovered to ALT < 3 x ULN within 3 months. Most hepatic treatment-emergent adverse events (TEAEs) were mild to moderate in UC and MS pts. In TN, 3 (0.4%) pts on OZA reported a hepatobiliary disorder TEAE, 1 (0.1%) of whom had hyperbilirubinemia. In the MS trials, 15 (1.7%) pts on OZA 0.92 mg reported a hepatobiliary disorder TEAE, 3 (0.3%) of whom had hyperbilirubinemia. Hepatic-related events leading to discontinuation, which were generally asymptomatic laboratory abnormalities, were reported in 4 (0.5%) UC pts and in 11 (1.2%) MS pts on OZA 0.92 mg. No serious hepatic TEAEs, Hy’s law cases, or severe drug-induced hepatocellular injuries occurred with OZA 0.92 mg in any of the trials. Conclusion: In this analysis of phase 3 UC and MS trials with OZA, elevations of aminotransferases and bilirubin occurring with OZA were infrequent, generally asymptomatic, and transient. These elevations, which generally resolved without study drug discontinuation, did not meet the criteria for Hy’s law or protocol-defined serious AEs. Table 1. - Maximum postbaseline ALT, AST, and bilirubin levels with OZA 0.92 mg Parameter TN (UC)(n=783) Sunbeam/Radiance (MS) (n=878) ALT >1 × ULN 215 (27.5) 373 (42.5) ≥3 × ULN 22 (2.8) 48 (5.5) ≥5 × ULN 8 (1.0) 14 (1.6) AST >1 × ULN 136 (17.4) 185 (21.1) ≥3 × ULN 14 (1.8) 9 (1.0) ≥5 × ULN 5 (0.6) 5 (0.6) Bilirubin >1 × ULN 32 (4.1) 122 (13.9) >2 × ULN 3 (0.4) 14 (1.6) >3 × ULN 1 (0.1) 3 (0.3)