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The objective of this study is to assess whether elevation of serum inflammatory markers levels may indicate the progression of clinical impairment in Parkinson’s disease (PD) patients. In 47 PD patients, the serum levels of the C3 and C4 part of the complement and Interleukin-6 (IL-6) were measured. The results at baseline and after 2 years were correlated with scales measuring memory, depression, motor symptoms, and quality of life. Patients with higher levels of C3 and C4 at baseline had decreased quality of life, verbal ability, and memory. Patients with higher IL-6 at baseline showed worse depression scores at 2 years. Patients with persistently higher levels of C3 and C4 at 2 years had worse quality of life and memory ability. Uncorrected p values are reported due to the exploratory nature of the study. The results indicate an impact of inflammation on non-motor signs and quality of life in PD. The increase of levels of serum inflammatory biomarkers may indicate the progression of non-motor impairment in PD.

Objectives. The association between abnormal serum immunomarkers and mortality in 53 consecutive Parkinson’s disease patients was studied. Materials and Methods. The plasma level of specific inflammatory cytokines was investigated: mannan-binding lectin (MBL), interleukin- (IL-) 6, and tumor necrosis factor-alpha (TNF-α). The baseline serum immunomarkers obtained from patients who died (n=16) during a four-year follow-up period were compared with the data of patients who survived (n=37). Results. The baseline level of IL-6 was significantly higher in the deceased patients than in the survivors. Elevated IL-6 levels and age were major independent contributors to disease mortality. Differences between other plasma cytokine level abnormalities were not significant. Conclusion. This study showed that IL-6 elevation may be a marker of increased mortality risk in Parkinson’s disease patients. The inflammation may act in association with other factors and comorbidities in progressive neurodegenerative pathology.

Background: The research of primary progressive multiple sclerosis (PPMS) has not been able to capitalize on recent progresses in advanced magnetic resonance imaging (MRI) protocols. Objective: The presented cross-sectional study evaluated the utility of four different MRI relaxation metrics and diffusion-weighted imaging in PPMS. Methods: Conventional free precession T1 and T2, and rotating frame adiabatic T1ρ and T2ρ in combination with diffusion-weighted parameters were acquired in 13 PPMS patients and 13 age- and sex-matched controls. Results: T1ρ, a marker of crucial relevance for PPMS due to its sensitivity to neuronal loss, revealed large-scale changes in mesiotemporal structures, the sensorimotor cortex, and the cingulate, in combination with diffuse alterations in the white matter and cerebellum. T2ρ, particularly sensitive to local tissue background gradients and thus an indicator of iron accumulation, concurred with similar topography of damage, but of lower extent. Moreover, these adiabatic protocols outperformed both conventional T1 and T2 maps and diffusion tensor/kurtosis approaches, methods previously used in the MRI research of PPMS. Conclusion: This study introduces adiabatic T1ρ and T2ρ as elegant markers confirming large-scale cortical gray matter, cerebellar, and white matter alterations in PPMS invisible to other in vivo biomarkers.

Background: A poor patient adherence often limits the real-world effectiveness of an oral disease-modifying therapy (DMT) for multiple sclerosis (MS). In the present study, we aimed to map patient preferences, attitudes toward treatment, and quality of life to identify the predictors of non-adherence to teriflunomide. Methods: This was a single-arm, non-interventional, multicenter study (Czech Act 378/2007 Coll.) consisting of three visits: the first at treatment initiation (teriflunomide 14 mg), and then after 3 and 9 months of therapy. We enrolled both DMT-naïve and patients who had undergone a DMT diagnosed with a clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS). The functional status and MS activity were estimated using the Expanded Disability Status Scale (EDSS) and annualized relapse rate (ARR); the quality of life via the Multiple Sclerosis Impact Scale (MSIS-29); the medication adherence with the Morisky Medication Adherence Scale (MMAS-8); the confidence in the ability to take medications by the Self-Efficacy for Appropriate Medication Score (SEAMS); and the attitude to the therapy via the Beliefs about Medicines Questionnaire (BMQ). After nine months of therapy, we predicted the adherence to teriflunomide (MMAS-8) by fitting a multivariate ordinal logistic model with EDSS changes, gender, previous DMT, MSIS-29, BMQ, and SEAMS as the explanatory variables. Results: Between 2018 and 2019, 114 patients were enrolled at 10 sites in the Czech Republic. The mean age was 41.2 years, 64.8% were diagnosed with a CIS, 52.4% were DMT-naïve, and 98.1% of patients preferred an oral administration at the baseline. The mean EDSS baseline was 1.97 and remained constant during the 9 months of therapy. The ARR baseline was 0.72 and dropped to 0.19 and 0.15 after 3 and 9 months, respectively. Despite a more than 4-fold higher ARR baseline, the treatment-naïve patients achieved an ARR at 9 months comparable with those previously treated. There were ten non-serious adverse reactions. After nine months of teriflunomide therapy, 63.3%, 21.2%, and 15.4% of patients had a high, medium, and low adherence, respectively, as per the MMAS-8; 100% of patients preferred an oral administration. The SEAMS score (odds ratio (OR) = 0.91; p = 0.013) and previous DMT (OR = 4.28; p = 0.005) were the only significant predictors of non-adherence. The disability, the quality of life, and beliefs about medicines had no measurable effect on adherence. Conclusion: After nine months of teriflunomide therapy, both the disability and quality of life remained stable; the relapse rate significantly decreased, 63.3% of patients had a high adherence, and 100% of patients preferred an oral administration. A low adherence was associated with previous DMT experiences and a low self-efficacy for the appropriate medication (i.e., the confidence in one’s ability to take medication correctly).

Background Cladribine, a selective immune reconstitution therapy, is approved for the treatment of adult patients with highly active multiple sclerosis (MS). Objectives Provide experience with cladribine therapy in a real-world setting. Methods This is a registry-based retrospective observational cohort study. First, using data from the Czech nationwide registry ReMuS, we analysed patients who initiated cladribine from September 1, 2018 to December 31, 2021. Second, we analysed a subgroup of patients who initiated cladribine between September 1, 2018 to June 30, 2020, thus possessing a follow-up period of at least 2 years. We evaluated demographic and MS characteristics including disease-modifying therapies (DMTs) before and after cladribine administration, relapses, Expanded Disability Status Scale (EDSS), and adherence. Results In total, 617 patients (335 with follow-up of at least 2 years) started cladribine therapy in the study period (mean age 37.0, mean disease duration 8.4 years, 74.1% females). In most cases, cladribine was administered as a second-line drug, a total of 80.7% had been escalated from a platform DMT. During 2 years before cladribine initiation, the average annualised relapse rate (ARR) was .67. Following cladribine initiation, the ARR decreased to .28 in the first year and .22 in the second year. Overall, across the entire two-year treatment period, 69.0% of patients were relapse-free and the average ARR was .25. As for EDSS development, the median baseline EDSS was 2.5 and remained stable even after 24 months. The adherence to treatment ranged of around 90%. Conclusion This nationwide study confirms the efficacy of cladribine in real-world settings, especially in patients who are not treatment-naïve. In addition, the study shows an exceptionally high adherence rate, a finding that underscores the invaluable role of cladribine, but also the value of registry-based studies in capturing real-world clinical practice.

The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis. In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab. Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches. In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).

BackgroundFenebrutinib is a potent, highly selective, noncovalent, reversible Bruton’s tyrosine kinase inhibitor. In the Phase II FENopta study (NCT05119569), participants received Fenebrutinib 200mg orally BID or placebo. Fenebrutinib reduced inflammatory disease activity in RMS and demonstrated CNS penetrance during the 12-week double blind treatment period. Here we present open label extension study results through Week 48, during which all participants received Fenebrutinib 200 mg BID.Results99 participants enrolled in the OLE; and 96 (97%) remain. At OLE week 48, 96% of participants were relapse free (ARR 0.04) and mean T1 Gd+ lesions were 0.015 lesions per scan (n=67), with 99% of participants free of T1Gd+ lesions. T2 lesion volume decreased in both groups during the OLE.Median EDSS change from baseline was 0 for each arm.The most common AEs were UTI (8%), COVID-19 (7%) and pharyngitis (5%). Serious AEs occurred in one participant (1%) as did asymptomatic ALT elevation (1%), which resolved with treatment discontinuation.Conclusions1 year of fenebrutinib treatment resulted in low ARR, stable EDSS and low MRI activity in participants with RMS, with a favourable safety profile. Ongoing Phase III trials will better characterise the effects of fenebrutinib on disease progression across MS phenotypes.sophie.wrigley@roche.com

The prospect for Bruton's tyrosine kinase (BTK) inhibition to meaningfully affect relapsing multiple sclerosis has recently been questioned due to inconsistent findings in the magnitude and sustainability of the effect of BTK inhibitors on disease activity. We assessed the safety, efficacy, and CSF drug concentrations of fenebrutinib, a highly selective, noncovalent, reversible BTK inhibitor, in patients with relapsing multiple sclerosis. This multicentre, double-blind, randomised, placebo-controlled, phase 2 trial (FENopta) was conducted at 18 community centres and hospitals across six countries in Europe and North America. Patients with relapsing multiple sclerosis aged 18–55 years with an Expanded Disability Status Scale (EDSS) score of 0·0–5·5, and recent documented disease activity, were randomly assigned (2:1) to oral fenebrutinib (200 mg twice daily) or placebo for 12 weeks, using permuted blocks and stratified by the presence or absence of T1 gadolinium-enhancing (Gd+) lesions on the brain MRI at screening. The randomisation sequence was generated by an interactive voice or web response system and both patients and investigators were masked to treatment allocation. Participants could enter an optional open-label extension study to receive fenebrutinib for up to 192 weeks. The primary efficacy endpoint was the total number of new T1 Gd+ lesions on brain MRI at weeks 4, 8, and 12; with additional MRI assessments at 48-week intervals during the open-label extension. Efficacy analyses were done on randomised patients with evaluable post-baseline MRIs; safety analyses used the safety-evaluable population. This study is registered with ClinicalTrials.gov, NCT05119569, and EudraCT, 2021–003772–14; recruitment is closed and the trial is ongoing. Between March 1, 2022 and March 29, 2023, 109 patients with relapsing multiple sclerosis were randomly assigned treatment: 73 received fenebrutinib and 36 received placebo. 106 patients had evaluable post-baseline brain MRI scans and were assessed for efficacy in the fenebrutinib group (n=70) and placebo group (n=36). The combined number of new T1 Gd+ lesions at weeks 4, 8, and 12 were 0·077 (95% CI 0·043–0·135) in the fenebrutinib group and 0·245 (0·144–0·418) in the placebo group (69% relative reduction [95% CI 34–85]; p=0·0022). During the open-label extension, through week 48, the unadjusted annualised relapse rate was 0·04 and 95 (96%) of 99 patients were relapse-free. During the double-blind treatment phase, the most common adverse events that were more frequent in the fenebrutinib group than in the placebo group were hepatic enzyme elevations (four [6%] vs 0), headache (three [4%] vs one [3%]), and nasopharyngitis (two [3%] vs 0); no serious adverse events or deaths occurred. Fenebrutinib was well tolerated and exerted an early, robust, and sustained effect of limiting new focal brain lesions. Further studies are needed to better characterise the safety and efficacy of fenebrutinib on both relapsing multiple sclerosis and non-relapsing progressive multiple sclerosis. F. Hoffmann-La Roche.

BackgroundClinical guidelines for relapsing remitting multiple sclerosis (RRMS) do not recommend disease modifying therapy (DMT) escalation after a single on-treatment clinically silent MRI lesion (CSL).MethodsFrom the MSBase international registry, we studied adults with RRMS who had MRI brain scans 6-18 months apart while clinically stable and established on a DMT. Cox models compared outcomes (relapse and 6 month confirmed disability worsening [CDW]) in those with and without CSLs, adjusted for sex, age, calendar year, MS duration, EDSS score, relapses in the prior 2 years, DMT efficacy and country health expenditure. In those with CSLs on platform or moderate-efficacy DMTs, an emulated a target trial compared DMT escalation within 6 months of a silent lesion versus unchanged DMT (unless a post-MRI clinical event occurred).ResultsAmong 10,308 people with RRMS, 2-year hazard ratios (HR [95% confidence interval]) comparing CSL with no CSL were 1.78 [1.59–2.00] for relapse and 1.38 [1.18–1.61] for CDW. Associations were similar in people with both single and multiple CSLs, on platform and moderate-efficacy baseline DMTs, and regardless of disease duration. In 2,295 people with CSLs on platform and moderate-efficacy DMTs, DMT escalation (n=288) reduced the median 4-year relapse risk from 38.9% to 17.0% (HR 0.34 [0.23–0.48]).ConclusionsPeople with RRMS with single or multiple on-treatment clinically silent MRI lesions have higher subsequent risks of relapse and disability worsening than those without CSLs. DMT escalation mitigates the relapse risk. Contrary to clinical guidelines, DMT escalation should be considered even after a single CSL.cyrus.daruwalla@nhs.net

Background/ObjectivesFrexalimab, a second-generation anti-CD40L antibody, blocks the CD40/CD40L pathway, which is important in regulating adaptive and innate immunity. During the 12-week (W) double-blind period of the phase-2 trial (NCT04879628) in participants with relapsing multiple sclerosis (pwRMS), frexalimab was well-tolerated and efficacious, with 1200-mg intravenous (IV) arm showing an 89% reduction in new gadolinium-enhancing (Gd+) T1-lesions vs placebo. Here, we report W96 results in the open-label extension (OLE).Methods129 participants were randomised (4:4:1:1) to frexalimab1200mg/IV every-4-weeks (q4w) or frexalimab300mg/subcutaneous (SC) q2w or matching placebo. After W12, participants receiving placebo switched to frexalimab arms. During OLE, the SC dose was increased to 1800-mg q4w, resulting in similar frexalimab exposure as with 1200-mg q4w IV dose; 36/57 participants in SC arms received high-dose and underwent W96 MRI assessments. Key endpoints: safety and efficacy (Gd+ T1-lesions, new/enlarging T2-lesions, annualised relapse rate [ARR]).Results106 participants (82%) remained on treatment at W96. Total number of Gd+ T1-lesions (mean±SD) remained low at W96 in participants who continued receiving frexalimab and who switched from placebo to frexalimab at W12 (IV arms: frexalimab1200mg/IV: 0.1±0.5, placeboIV/frexalimab1200mg/IV: 0.1±0.3; all SC arms: ≤0.4). New/enlarging T2-lesion monthly count remained low with frexalimab1200mg/IV through W96. ARR (baseline-W96) was low (0.08 [95% CI, 0.03–0.18]) in frexalimab1200mg/IV arm; 92% of participants were relapse-free. Most common adverse events were nasopharyngitis, headache, and COVID-19.ConclusionsFrexalimab continues to show favourable safety and sustained reduction in disease activity in pwRMS through W96, supporting its further development in phase-3 trials as a potential high-efficacy, non-lymphocyte-depleting therapy.