Author Of 1 Presentation
FC02.05 - Safety and Efficacy in Patients Treated With Dimethyl Fumarate and Followed For 13 Years: Final Results of ENDORSE
Abstract
Background
DMF is a well-established therapy for relapsing forms of multiple sclerosis (RMS); data from ENDORSE, an extension to phase 3 studies DEFINE and CONFIRM, has enabled >10 years follow-up.
Objectives
We report safety/efficacy of DMF in patients with RMS treated with DMF and followed for 13 years in ENDORSE (NCT00835770) (2 years DEFINE/CONFIRM, and >10 years ENDORSE).
Methods
Incidence of serious AEs (SAEs), discontinuations due to AEs, annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg BID: placebo (PBO)/DMF (PBO, years 0–2 /DMF, years 3–10) or continuously (DMF/DMF). Efficacy outcomes were assessed in patients up to 10 years due to sample size considerations. For lymphocyte analysis, data from first DMF exposure were analysed for patients in DEFINE/CONFIRM/ENDORSE.
Results
At 23 January 2020, 1736 patients enrolled/received ≥1 dose DMF. Of 1736 patients, 760 completed. Patients were followed for a median (min,max) of 6.76(0.04,10.98) years in ENDORSE, and 2 years in DEFINE/CONFIRM. Overall, 551 (32%) patients experienced SAEs; most were MS relapse and fall. There was one case of PML in this study. There was no increased incidence of other infections or serious infections. Sixteen percent (n=282) patients discontinued due to AEs; 2% relapse, 2% disease progression, and 4% GI disorders. ALC decreased over the first 48 weeks, and then remained generally stable for the majority of the study. The proportion of patients with other AEs of special interest (including opportunistic infection, malignancy, and serious herpes zoster) was similar regardless of ALC. For patients continuously treated (n=501), overall ARR remained low (0.141[95% CI, 0.119,0.167]), while for PBO/DMF patients (n=249) ARR decreased after initiating DMF (ARR 0–2 years, 0.330[95% CI, 0.266,0.408]; ARR overall, 0.149[95% CI, 0.116,0.190]). Overall, 60% of DMF/DMF and 66% of PBO/DMF patients remained relapse-free; 20% and 17% of patients had 1 relapse, respectively. Walking abilities were maintained throughout the study; the number of patients with EDSS scores ≤3.5 was 413/479(86%) DMF/DMF (179/217[82%] PBO/DMF) at Year 2, and 173/226(77%) DMF/DMF (67/90[74%] PBO/DMF) at Year 10. Seventy-two percent and 73% of DMF/DMF and PBO/DMF patients, respectively, had no 24-week confirmed disability progression over 10 years.
Conclusions
These safety and efficacy data in patients followed for 13 years, support DMF as a long-term option for patients with RMS.
Presenter Of 1 Presentation
FC02.05 - Safety and Efficacy in Patients Treated With Dimethyl Fumarate and Followed For 13 Years: Final Results of ENDORSE
Abstract
Background
DMF is a well-established therapy for relapsing forms of multiple sclerosis (RMS); data from ENDORSE, an extension to phase 3 studies DEFINE and CONFIRM, has enabled >10 years follow-up.
Objectives
We report safety/efficacy of DMF in patients with RMS treated with DMF and followed for 13 years in ENDORSE (NCT00835770) (2 years DEFINE/CONFIRM, and >10 years ENDORSE).
Methods
Incidence of serious AEs (SAEs), discontinuations due to AEs, annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg BID: placebo (PBO)/DMF (PBO, years 0–2 /DMF, years 3–10) or continuously (DMF/DMF). Efficacy outcomes were assessed in patients up to 10 years due to sample size considerations. For lymphocyte analysis, data from first DMF exposure were analysed for patients in DEFINE/CONFIRM/ENDORSE.
Results
At 23 January 2020, 1736 patients enrolled/received ≥1 dose DMF. Of 1736 patients, 760 completed. Patients were followed for a median (min,max) of 6.76(0.04,10.98) years in ENDORSE, and 2 years in DEFINE/CONFIRM. Overall, 551 (32%) patients experienced SAEs; most were MS relapse and fall. There was one case of PML in this study. There was no increased incidence of other infections or serious infections. Sixteen percent (n=282) patients discontinued due to AEs; 2% relapse, 2% disease progression, and 4% GI disorders. ALC decreased over the first 48 weeks, and then remained generally stable for the majority of the study. The proportion of patients with other AEs of special interest (including opportunistic infection, malignancy, and serious herpes zoster) was similar regardless of ALC. For patients continuously treated (n=501), overall ARR remained low (0.141[95% CI, 0.119,0.167]), while for PBO/DMF patients (n=249) ARR decreased after initiating DMF (ARR 0–2 years, 0.330[95% CI, 0.266,0.408]; ARR overall, 0.149[95% CI, 0.116,0.190]). Overall, 60% of DMF/DMF and 66% of PBO/DMF patients remained relapse-free; 20% and 17% of patients had 1 relapse, respectively. Walking abilities were maintained throughout the study; the number of patients with EDSS scores ≤3.5 was 413/479(86%) DMF/DMF (179/217[82%] PBO/DMF) at Year 2, and 173/226(77%) DMF/DMF (67/90[74%] PBO/DMF) at Year 10. Seventy-two percent and 73% of DMF/DMF and PBO/DMF patients, respectively, had no 24-week confirmed disability progression over 10 years.
Conclusions
These safety and efficacy data in patients followed for 13 years, support DMF as a long-term option for patients with RMS.
Author Of 12 Presentations
P0013 - Modeling a long-term virtual placebo arm for SPMS population in the EXPAND study: Comparing different statistical methods (ID 1774)
Abstract
Background
Siponimod significantly reduced the risk of 3-/6-month confirmed disability progression (3m/6mCDP) versus placebo by 21% and 26%, respectively in patients with secondary progressive multiple sclerosis (SPMS), during the core part of the EXPAND study. At the end of EXPAND-Core, patients were offered a switch to open-label siponimod in the ongoing EXPAND-Extension allowing follow-up for up to an additional 7 years; therefore, a long-term comparison between siponimod and placebo was not possible and a modeling for the placebo long-term trajectory was proposed using different statistical methodology.
Objectives
To estimate the long-term effect of siponimod versus placebo by modeling placebo treatment corrected for switch at the end of EXPAND-Core.
Methods
In the EXPAND-Extension part, 6mCDP was analyzed to assess disability. Time to 6mCDP to account for the switch to siponimod in placebo-treated patients was modeled by 3 methods: 1) Rank Preserving Structural Failure Time (RPSFT) model that uses the actual time to 6mCDP for switchers to compute a hypothetical time to 6mCDP as if they had never switched; 2) simulating the hypothetical time from the switch to 6mCDP based on core part data as if patients had never switched (Two-stage method); and 3) a parametrical model (Weibull distribution) to extrapolate a placebo survival curve.
Results
As of 6 April 2019, 878 patients (siponimod, n=593; placebo-siponimod switch, n=285) were still ongoing in the EXPAND-Extension. All 3 methods confirmed the long-term effect of siponimod versus placebo in the EXPAND population. The RPSFT model seems to provide the more accurate estimate for time to 6mCDP (hazard ratio [95% confidence interval]: 0.69 [0.53; 0.90]) vs the Two-stage (0.76 [0.64; 0.92]) and Weibull modeling methods (0.58 [0.49; 0.67]). The RPSFT results were indicative of a persistent treatment effect over 5 years with a ~50–60% increase in the time to 6mCDP in siponimod versus placebo-corrected switch (median time to 6mCDP: 42.5 months for placebo-corrected switch as opposed to 51.7 months for uncorrected placebo; median not reached with siponimod). Accuracy of RPSFT is supported by simulations conducted under conditions similar to the EXPAND study, which included waning and increasing treatment effects, that found very low difference between the true hazard ratio and the hazard ratio obtained with RPSFT.
Conclusions
The results support the reliability of RPSFT to model a virtual placebo arm in the long-term in a SPMS population. RPSFT results confirmed a long-term benefit of siponimod over placebo with a preserved hazard ratio on 6mCDP and ~50‒60% prolongation of time to 6mCDP.
P0238 - Sustained reduction of disability and cognitive decline with long-term siponimod treatment in patients with active SPMS: EXPAND data up to 5 years (ID 1471)
Abstract
Background
In the EXPAND Core part, in the subgroup of patients with active secondary progressive multiple sclerosis (aSPMS: presence of relapses in the 2 years prior to screening and/or ≥1 T1 gadolinium-enhancing (Gd+) lesion at baseline), siponimod reduced the risk of 3-/6-month confirmed disability progression on Expanded Disability Status Scale (3m/6mCDP) by 31% and 37%, respectively, and the risk of decline in cognitive processing speed (CPS, 6-month confirmed cognition worsening of ≥4-point on Symbol Digit Modalities Test [6mCCW]) by 27% versus placebo.
Objectives
To assess the long-term efficacy and safety of siponimod in patients with aSPMS in the Core and Extension parts of the EXPAND study.
Methods
In patients with aSPMS who had received ≥1 dose of randomized treatment during Core part, and who entered the Extension (36 month extension data cut-off [6 April 2019]; total study duration ≤5 years), time to 3m/6mCDP, 6mCCW, and annualized relapse rate (ARR) were assessed for the Continuous (siponimod in the Core and Extension) and Switch (placebo in the Core and switched to open-label siponimod in the Core/Extension) groups.
Results
Of the 1651 patients randomized in the EXPAND Core part, 779 were with aSPMS (Continuous group: N=516; Switch group: N=263), of which 582 entered the Extension. The risk of 6mCDP was reduced by 29% (0.71 [0.57‒0.90]; p=0.0044) for the Continuous versus Switch group, corresponding to an about 70% delay in time to 6mCDP across the 25th–40th percentile). Median time to 6mCDP was 48 months for the Switch group and was not reached for the Continuous group. The risk of 6mCCW for the Continuous versus Switch group was reduced by 33% (0.67 [0.53‒0.86]); p=0.0018), corresponding to an about 70% delay in time to 6mCCW across the 25th–30th percentile, median time to 6mCCW (55.5 months) was reached only for the Switch group. In patients without active disease, a nonsignificant trend for reduced risk of disability progression and cognitive worsening was observed for the Continuous vs Switch groups. A significant reduction in ARR for the Continuous versus Switch groups was observed in patients with (0.08 vs 0.12; p=0.0023) or without active disease (0.03 vs 0.08; p<0.0001).
Conclusions
In EXPAND, long-term data analyses in the Continuous versus Switch groups showed that siponimod treatment effects on disability, cognitive processing speed, and relapse outcomes in patients with active SPMS are sustained for up to 5 years, and highlight the value of early treatment initiation.
P0263 - Serum neurofilament predicts clinical progression and increases diagnostic accuracy in patients with early multiple sclerosis (ID 1336)
- S. Bittner
- F. Steffen
- T. Uphaus
- M. Muthuraman
- V. Fleischer
- A. Salmen
- F. Luessi
- A. Berthele
- L. Klotz
- S. Meuth
- A. Bayas
- F. Paul
- H. Hartung
- R. Linker
- C. Heesen
- M. Stangel
- B. Wildemann
- F. Then Bergh
- B. Tackenberg
- T. Kuempfel
- F. Weber
- U. Zettl
- U. Ziemann
- H. Tumani
- S. Groppa
- M. Mühlau
- C. Lukas
- B. Hemmer
- H. Wiendl
- R. Gold
- F. Zipp
Abstract
Background
Up to date prognostic estimation in newly diagnosed patients is hardly possible while the differentiation between disabling versus more benign courses is of utmost relevance. Reliable blood-based biomarkers that are associated with diagnosis and prognosis of multiple sclerosis (MS) have not been established.
Objectives
Can serum neurofilament light chain measurements serve as a reliable biomarker for diagnostic accuracy and prognosis for multiple sclerosis patients at the time point of diagnosis?
Methods
In a multicenter prospective longitudinal observational cohort, patients with a first diagnosis of multiple sclerosis (MS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers and assessed yearly with a standardized protocol. Patients were offered standard immunotherapies according to national treatment guidelines. Serum NfL concentrations were measured using an ultrasensitive single-molecule array (Simoa).
Results
A possible association between sNfL levels and clinical diagnosis, relapses, MRI parameters and treatment decisions was tested in 814 patients classified according to current (2017) and older (2010) McDonald criteria at time point of diagnosis and two years after study inclusion sNfL levels correlated with number of T2 and Gd+ lesions and clinical relapses. After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036) and increased accuracy of distinction between CIS and RRMS, when including ≥ 90th percentile of sNfL values. Patients receiving disease-modifying treatment (DMT) during the first two years had higher sNfl baseline levels (11.8 pg/ml, 7.5-20.9 pg/ml, n = 727) than patients never receiving DMT (9.5 pg/ml, IQR 6.4-14.1 pg/ml, n = 87, p = 0.002). Longitudinal sNfL levels reflected treatment decisions within the first four years.
Conclusions
sNfL is associated with diagnosis and prognosis of MS patients at the time point of first diagnosis and may be of use for initial treatment stratification.
P0303 - Calculated steroid dose needed for multiple scleroses relapses (ID 1456)
Abstract
Background
Glucocorticoid (GC) pulse therapy is used for Multiple Sclerosis (MS) relapse treatment. At the same time GC resistance often mandates timely introduction of plasma exchange (PLEX). There are yet no well established predictors for the GC dose needed to treat MS relapses.
Objectives
The aim of this study is to establish a predictive model basing on clinical data to support clinicians in estimating the maximum GC dose above which no additional therapeutic value can be expected.
Methods
We retrospectively screened clinical registries at University Hospital Bern and Ruhr University Hospital Bochum for MS patients treated with GC. We performed a multivariate regression analysis with GC dose as dependent variable and Vitamin D (25D) level, sex, age, expanded disability status scale (EDSS), contrast enhancement on cranial and/or spinal MRI, immunotherapy and clinical involvement of optic nerve as independent variables.
Results
In this explorative cohort, 113 MS patients were included (Bern/Bochum: n = 63/47). Our model in total significantly predicted GC dose, however within the independent variables only 25D serum concentration and presence of optic neuritis were independent predictors of the GC dose needed to treat the present MS relapse ([25D]: -25.95 (95% CI: -47.40 - -4.49), p=0.018; optic neuritis: 2040.51 (95% CI: 584.64 – 3496.36), p=0.006).
Conclusions
Considering that GC dosing appears to be individual with several response-influencing factors, we established a predictive model, which supports clinicians to estimate GC dose needed to treat MS relapses. A second validation cohort is needed to proof our analysis.
P0317 - Dual mode of action of siponimod in secondary progressive multiple sclerosis: A hypothesis based on the relevance of pharmacological properties (ID 1380)
Abstract
Background
Siponimod, a potent and selective sphingosine 1-phosphate (S1P1,5) receptor modulator, is the first oral disease-modifying therapy shown to reduce disability progression, cognitive decline, and total brain volume loss in secondary progressive multiple sclerosis (SPMS) patients. Recently presented data further suggest a favorable impact on more specific measures of neurodegeneration such as gray matter atrophy and myelin density assessed by magnetization transfer ratio. New preclinical insights further substantiate the dual mode of action (MoA) of siponimod demonstrating peripheral and central action targeting both inflammation and neurodegeneration.
Objectives
To propose a working hypothesis of a dual MoA for siponimod based on its unique specific pharmacological profile versus other S1P modulators.
Methods
Recent preclinical results with siponimod in pharmacokinetic/pharmacodynamic (PK/PD), mechanistic, and disease models were reviewed and placed in perspective.
Results
Preclinical data demonstrate that siponimod triggers S1P1-dependent anti-inflammatory effects on pathogenic lymphocytes and glial cells in the central nervous system (CNS), and S1P5-dependent promyelination effects on oligodendrocytes. Concomitant optimal S1P1- and S1P5-dependent effects are therefore required, in both blood and CNS compartments, for translation into clinical efficacy. Preclinical data indicate that the S1P1- and S1P5-dependent CNS effects follow non-classical pharmacology (“bell-shaped”), resulting in lowering of efficacy for agonists at supramaximal doses. This suggests an overall particularly complex drug dose-effect relationship. Recent preclinical PK/PD studies show that a CNS/blood drug exposure ratio (CNS/bloodDER) of ~6 allows siponimod to approach the top nadir of both S1P1- and S1P5-dependent dose-response curves in the blood and CNS compartments.
Hence, the CNS/bloodDER might be a key factor impacting therapeutic efficacy of an S1P-modulator. Fingolimod-phosphate has a higher CNS/bloodDER of 20–30, which might result in a potential therapeutic disadvantage compared to siponimod regarding S1P1- and S1P5-mediated CNS effects.
Conclusions
Preclinical findings show that siponimod has the pharmacological characteristics required for its dual S1P1/S1P5 MoA in both blood and CNS compartments, which may be of relevance for its clinical efficacy in SPMS. Translational and clinical studies are warranted to further validate this hypothesis.
P0507 - Treatment of multiple sclerosis during lactation with interferon-beta 1a or glatiramer acetate (ID 877)
Abstract
Background
Interferon-betas (IFN-β) are cytokines, glatiramer acetate (GA) is a synthetic polypeptide. Both substances are large molecules and lack oral bioavailability. As of September 2019, IFN-β are the first and up to now the only multiple sclerosis (MS) therapy approved also during lactation. Published data are restricted but show only minimal concentrations of the drug in human milk. No data on GA excretion are available, but it seems unlikely the substance would pass into breast milk. Although the risk for the infant is most likely negligible, data on breastfeeding under IFN-β or GA are very restricted. The effects on infant development and health as well as on maternal relapse risk postpartum are yet unknown.
Objectives
To assess the safety of maternal IFN-β 1a or GA administration during lactation for the breastfed infant as well as to assess its effect on the occurrence of postpartum relapses.
Methods
So far, we identified 34 infants (one pair of twins) who were breastfed under GA and 28 infants who were breastfed under IFN-β 1a from the German MS and pregnancy registry (DMSKW). Cases were followed-up for at least one year postpartum. Data was generated via standardized interviews, conducted with the mother during pregnancy as well as at 1, 3, 6 and 12 months postpartum.
Results
Identification, inclusion and follow-up of additional cases are still ongoing; updated data as well as analysis of the total cohorts will be presented at the congress. Among the infants breastfed under GA there was no case of developmental delay, in the IFN-β 1a cohort there was one report of a delay regarding motor skills (4 %). Medians of weight, length and head circumference at several medical check-ups during the first year of life lay within the normal range (3rd and 97th percentile) of reference values for both cohorts. Hospitalizations and antibiotic treatments occurred only rarely. Within the first year postpartum 7 (21 %) women relapsed in the GA cohort as well as 7 (25 %) in the IFN-β 1a cohort.
Conclusions
Our preliminary analysis revealed no hints that treatment with GA or IFN-β 1a during lactation negatively affects development or health of breastfed infants. The effect on postpartum relapses has still to be determined. Our results support the recent label extension of IFN-β and suggest that treatment with GA is probably compatible with breastfeeding as well.
P0587 - Impact of siponimod on myelination as assessed by MTR across SPMS subgroups: Post-hoc analysis from the EXPAND MRI substudy (ID 1588)
Abstract
Background
Changes in magnetization transfer ratio (MTR) are a marker of changes in myelin density and associated tissue integrity in the brain. Siponimod improved MTR recovery in lesions and demonstrated a significant effect on MTR decrease in normal-appearing brain tissue (NABT) and cortical grey matter (cGM) with a more pronounced effect on normal-appearing white matter (NAWM) in the overall EXPAND secondary progressive multiple sclerosis (SPMS) population, as reported previously.
Objectives
To investigate the effect of siponimod vs placebo (PBO) on MTR changes in NABT, cGM, and NAWM in subgroups of SPMS patients.
Methods
This prospective MTR substudy assessed the effect of siponimod versus PBO on median normalized MTR (nMTR) in NABT, cGM and NAWM assessed by absolute change from baseline (BL) to Month (M) 24 using repeated measures models. Patient subgroups were defined by: disease history and severity (age [≤45/>45 years], disease duration [≤15/>15 years], Expanded Disability Status Scale (EDSS) score [≤5.5/≥6.0], Symbol Digit Modalities Test score (≤43/>43); and inflammatory disease activity (active/non-active SPMS, with/without relapse in 2 years before screening, with/without gadolinium-enhancing lesions). Data from the per-protocol set (n=443) are presented.
Results
The subgroup analysis indicated that absolute changes from BL in median nMTR for NAWM ranged from –0.124 to –0.034 in the PBO group and from –0.016 to 0.040 in the siponimod group, which corresponds to 79–198% attenuation in median nMTR decrease versus PBO across all the subgroups studied (all p<0.05 except EDSS≥6 subgroup, p=0.064). The results were consistent for NABT (70–170%) and cGM (44–188%) although slightly less pronounced (p>0.05 for some subgroups). In the active SPMS subgroup, siponimod attenuated median nMTR decrease across NABT, cGM and NAWM by 91–109% (p<0.01 all); and in the non-active SPMS subgroup by 170–198% (p=0.0151 for NAWM, p>0.05 for NABT, cGM).
Conclusions
Over 24 months, siponimod attenuated the decrease in median nMTR in brain tissues across the patient subgroups characterized by disease activity and severity. The effect of siponimod was most pronounced in NAWM. These data support preclinical studies of siponimod, showing direct beneficial CNS effects on myelination.
P0741 - Pain, depression and quality of life in adults with MOG-antibody associated disease (ID 1622)
Abstract
Background
Myelin oligodendrocyte glycoprotein-antibody (MOG-ab) associated disease (MOGAD) is an inflammatory autoimmune condition of the CNS, clinically resembling seropositive neuromyelitis spectrum disorder (NMOSD). Despite severe pain is one of the most frequent and disabling symptoms in NMOSD, data on pain in MOGAD are scarce and clinical case reports and series often ignore it as a severe symptom.
Objectives
To assess features of chronic pain, depression, and their impact on health-related quality of life (hr-QoL) in MOG-antibody associated disease (MOGAD).
Methods
Patients with MOGAD were identified in the Neuromyelitis Optica Study Group (NEMOS) registry. Data were acquired by a questionnaire, including clinical, demographic, pain (PainDetect, Brief Pain Inventory - short form, McGill Pain Questionnaire - short form), depression (Beck Depression Inventory-II), and hr-QoL (Short Form-36 Health Survey) items.
Results
Forty-three patients (29 female, 14 male) were included. Twenty-two patients suffered from disease-related pain (11 nociceptive, 8 definite neuropathic, 3 possible neuropathic pain). Patients with neuropathic pain reported higher pain intensity compared to those with nociceptive (pain severity index (PSI)±SD: 5.7±2.0 vs. 2.8±1.3, p=0.003) and more profound impairment of activity of daily living (ADL). Fifteen patients reported spasticity-associated pain, including four with short lasting painful tonic spasms. Twelve patients received pain medication, still suffering from moderate pain (PSI±SD: 4.6±2.3). Only four out of 10 patients with moderate to severe depression took antidepressants. Physical QoL was more affected in pain-sufferers (p<0.001) than in patients without pain, being most severely reduced in patients with neuropathic pain (p=0.016) compared to other pain-sufferers. Pain severity (B=-5.455, SE=0.810, p<0.001), visual impairment (B=-8.163, SE=1.742, p<0.001), and gait impairment (B=-5.756, SE=1.875, p=0.005) were independent predictors of low physical QoL. Depressive state (B=-15.484, SE=2.896, p<0.001) was the only predictor for reduced mental QoL.
Conclusions
Being highly prevalent, pain and depression strongly reduce QoL and ADL in MOGAD. Although treatable, both conditions remain insufficiently controlled in real-life clinical practice
P0742 - Pain, depression and quality of life in NMOSD: a cross-sectional study of 166 AQP4-antibody seropositive patients in Europe (ID 1645)
Abstract
Background
“Spinal pain”, girdle-like dysesthesia, and painful spasms were noted already in earliest disease descriptions in the 18th century. Nowadays it has become clear that pain is a frequent and one of the most disabling symptoms in these patients. Due to the rarity of NMOSD most previous studies of pain and depression were relatively small or included a mixed population AQP4-IgG-seropositive and seronegative patients, while recent clinical trials clearly indicate that pathogenetic mechanisms are different in these forms.
Objectives
To evaluate prevalence, clinical characteristics and predictive factors of pain, depression and their impact on the quality of life (QoL) in a large European seropositive neuromyelitis optica spectrum disease (NMOSD) cohort.
Methods
We included 166 patients with aquaporin-4-seropositive NMOSD from 13 tertiary referral centers of Neuromyelitis Optica Study Group (NEMOS). Clinical data, including expanded disability status scale and localization of spinal lesions on MRI, were retrieved from the NEMOS database or local electronic patient records. Data on pain, depression and quality of life were captured by self-reporting questionnaires.
Results
125 (75.3%) patients suffered from chronic NMOSD-associated pain. Of these, 65.9% had neuropathic pain, 68.8% reported spasticity-associated pain and 26.4% painful tonic spasms. Number of previous myelitis attacks (OR 1.27, p=0.018) and involved upper thoracic segments (OR 1.31, p=0.018) were the only predictive factors for chronic pain. Interestingly, the latter was specifically associated with spasticity-associated (OR 1.36, p=0.002), but not with a neuropathic pain. 39.8% suffered from depression (moderate to severe in 51.5%). Pain severity (OR 1.81, p<0.001) and especially neuropathic character (OR 3.44, P<0.001) were strongly associated with depression. 70.6% of patients with moderate or severe depression and 42.5% of those with neuropathic pain had no specific medications. 64.2% of those under symptomatic treatment still reported moderate to severe pain. Retrospectively, 39.5% of pain-sufferers reported improvement of pain after start of immunotherapy: 37.3% under rituximab, 40.0% under azathioprine, 33.3% under mycophenolate mofetil and 66.7% under tocilizumab. However, there was no difference in terms of pain prevalence or intensity in patients with different immunotherapies. Pain intensity, walking impairment and depression could explain 56% of the physical QoL variability, while depression was the only factor, explaining 46% of the mental QoL variability.
Conclusions
Myelitis episodes involving upper thoracic segments are main drivers of pain in NMOSD. Although pain intensity was lower than in previous studies, pain and depression remain undertreated and strongly affect QoL. Interventional studies on targeted treatment strategies for pain are urgently needed in NMOSD.
P0806 - Effect of siponimod on cognitive processing speed in SPMS patients with active and non-active disease (ID 1251)
Abstract
Background
Siponimod significantly reduced the relative risk of 3-month (m) confirmed disability progression (CDP) by 21% and 6mCDP by 26% versus placebo in the EXPAND core study. Siponimod also showed a significant benefit on cognitive processing speed (CPS) as measured by change in the Symbol Digit Modalities Test (SDMT).
Objectives
To evaluate the effect of siponimod on CPS in subgroups of patients with active (aSPMS) and non-active (naSPMS) disease from the EXPAND core study.
Methods
EXPAND (N=1651) was a double-blind Phase 3 study that randomized a broad range of SPMS patients to siponimod or placebo (2:1). This subgroup post-hoc analysis included patients with aSPMS (siponimod, n=516; placebo, n=263; defined as presence of relapses in the 2 years before screening and/or ≥1 T1 gadolinium-enhancing lesions at baseline) and naSPMS (siponimod, n=557; placebo, n=270; counterpart of aSPMS). The outcomes analyzed were change in SDMT score from baseline to M24 derived from the mixed model for repeated measures; time to 6m confirmed ≥4-points cognitive worsening/improvement (6mCW/6mCI) on SDMT and a categorical analysis showing the proportion of patients with worsened, stable and improved SDMT scores (worsened/improved by ≥4 points since baseline and until the end of the trial, or otherwise stable) at M24.
Results
Change in SDMT (95% CI) versus placebo from baseline to M24 in the aSPMS and naSPMS groups was 2.34 (0.66; 4.02) and 2.44 (0.67; 4.22; p<0.01 for both), respectively, consistent with the overall EXPAND core population (2.28 [1.09; 3.48]; p<0.001). In patients with aSPMS, siponimod reduced the risk of 6mCW by 27% (hazard ratio [95% CI]: 0.73 [0.53; 1.01]; p=0.06) and improved the chance of 6mCI by 62% (1.62 [1.14; 2.29]; p=0.007) versus placebo. Corresponding values in the naSPMS group were: 6mCW, 24% (0.76 [0.53; 1.09]; p=ns) and 6mCI, 19% (1.19 [0.86; 1.65]; p=ns). In the aSPMS group, a lower proportion of patients worsened (27.3% vs 38.2%, p=0.002) and a higher proportion of patients improved (34.1% vs 22.9%, p=0.001) on SDMT versus placebo. Corresponding proportions for the naSPMS group were: worsened, 21.2% vs 23.7%, p=ns; improved, 35.6 vs 31.2%, p=ns.
Conclusions
Siponimod was associated with relevant benefits in CPS as measured by change in SDMT in patients with active and non-active SPMS. In patients with active disease, both a reduced risk for clinically relevant worsening and an increased chance for clinically relevant improvement were observed.
P1065 - Treatment Satisfaction Across Age Groups in Patients Who Switched to Teriflunomide: Analysis of the Real-world Teri-PRO Study (ID 814)
Abstract
Background
Teriflunomide is a once-daily oral immunomodulator approved for treating relapsing forms of MS (RMS) and relapsing-remitting MS, depending on the local label. In the phase 4, real-world Teri-PRO study (NCT01895335), patient-reported outcomes in RMS patients showed significantly improved satisfaction with teriflunomide versus prior disease-modifying therapy (DMT) at Week 48; safety was consistent with prior teriflunomide trials.
Objectives
To assess changes in treatment satisfaction stratified by age in Teri-PRO patients who switched to teriflunomide 14 mg from prior DMTs.
Methods
Patients switching to teriflunomide 14 mg were stratified by age at baseline (≤35 years [n=85]; >35 to ≤45 years [n=167]; >45 to ≤55 years [n=175]; >55 years [n=129]). Assessment: Treatment Satisfaction Questionnaire for Medication (TSQM version 1.4 [4 domains: Global Satisfaction, Effectiveness, Side Effects, and Convenience; scores: 0-100, higher scores indicate improved satisfaction]) at baseline versus Week 48.
Results
Compared with baseline, mean scores in each TSQM domain were significantly increased at Week 48 in patients aged >35 to ≤45 years (least-squares mean change [LS]: Global Satisfaction, 15.0, P<0.0001; Effectiveness, 6.3, P=0.0157; Side Effects, 20.6, P<0.0001; Convenience, 31.6, P<0.0001), >45 to ≤55 years (LS: Global Satisfaction, 15.4, P<0.0001; Effectiveness, 8.3, P<0.0001; Side Effects, 20.4, P<0.0001; Convenience, 31.0, P<0.0001), and >55 years (LS: Global Satisfaction, 11.3, P=0.0001; Effectiveness, 9.3, P=0.0001; Side Effects, 11.7, P<0.0001; Convenience, 29.8, P<0.0001). In patients aged ≤35 years, significantly improved mean TSQM scores at Week 48 versus baseline were observed in the Side Effects (LS: 26.2, P<0.0001) and Convenience (LS: 28.7, P<0.0001) domains. Across age groups, similar improvements in treatment satisfaction were also seen at Week 4 versus baseline, except for the Effectiveness domain in patients aged ≤35 years.
Conclusions
Over 48 weeks across age groups, patients aged >35 years who switched to teriflunomide 14 mg had significant improvements in all 4 TSQM domains versus baseline, and patients aged ≤35 years experienced significant improvements in the Side Effects and Convenience domains. These findings indicate teriflunomide improves treatment satisfaction regardless of age in RMS patients switching from other DMTs, with improvements occurring as early as Week 4 and persisting at Week 48 of treatment.
STUDY SUPPORT: Sanofi.
P1126 - Impact of interferon-beta exposure during early pregnancy on relapse rate (ID 1074)
Abstract
Background
In disease modifying therapy (DMT)-unexposed pregnancies of multiple sclerosis (MS) patients, relapse rate decreases significantly during pregnancy, followed by an increase in the first 12 weeks postpartum, but little is known about the relapse pattern and the associated steroid use in interferon-β (IFN-β) -exposed pregnancies, which might not show the typical disease course.
Objectives
To determine disease activity during pregnancy in women with MS and IFN-β treatment 12 months prior to the last menstrual period (LMP).
Methods
Pregnancies were prospectively collected in the German MS and pregnancy registry up to 10.2018. Pregnancies with a duration of at least 22 gestational weeks and IFN-β treatment 12 months prior to conception were compared in two groups: pre-LMP group stopping IFN-β between 365 and 1 day before LMP and post-LMP group stopping IFN-β between LMP and 84 days afterwards.
Results
We identified 47 pregnancies in pre-LMP group and 165 pregnancies in post-LMP group, without differences in baseline characteristics (age, BMI, disease duration, IFN-β treatment duration, annualized relapse rate (ARR) before pregnancy) and a median postpartum follow up of 610 days (range 17 – 2,799). 35 of 212 women (16.5%) had at least one relapse during pregnancy, 14 (29.8%) in pre-LMP group and 21 (12.7%) in post-LMP group (p=0.011). 14 (6.6%) women experienced a relapse in trimester 1, 21 (9.9%) in trimester 2 and 7 (3.3%) in trimester 3. Notably, significantly more women in the pre-LMP group experienced a relapse in trimester 2 (OR= 4.68, CI[1.82;12.2], p=0.002). Corticosteroid use did not differ significantly between groups; neither in overall pregnancy (p= 0.399) nor per trimena (trimester 1: p= 0.686, trimester 2: p= 0.266, trimester 3: p= 0.124).
214 pregnancy outcomes were observed (including two twin pregnancies). Preterm births differed significantly with more preterm births in the pre-LMP group (pre-LMP: 8/17.02%; post-LMP: 10/6.06%; OR 3.12, p=0.03). Medically confirmed major malformations did not differ between groups (pre-LMP: 1/47 (2.13%); post-LMP: 7/167 (4.20%); OR: 0.433, p=0.687)). No stillbirth was observed.
Conclusions
The withdrawal of IFN-β before pregnancy is associated with a higher relapse risk, especially in trimester 2 and a higher chance of preterm birth, though not higher steroid use during pregnancy, but more data is needed. At the time of the meeting, updated results on disease activity especially relapse rates will be presented.