Background

Alemtuzumab is an anti-CD52 monoclonal antibody therapy approved for treating RRMS. Although alemtuzumab is associated with non–MS-related secondary autoimmune events, the role pre-existing non-MS autoimmunity plays in secondary autoimmunity is unclear.

Objectives

To assess the impact of 1) pre-existing non-MS autoimmunity and 2) post-alemtuzumab thyroid autoimmunity on subsequent onset of new autoimmunity up to 9 years after initiating alemtuzumab.

Methods

In clinical trials (NCT00050778, NCT00530348, NCT00548405, NCT00930553, NCT02255656), patients were monitored for autoimmune adverse events (AEs). All patient- and investigator-reported AEs were recorded. An autoimmune event was pre-existing if it occurred prior to initiating alemtuzumab or was in the medical history database.

Results

A total of 1216 patients from the alemtuzumab clinical development program who received alemtuzumab 12 mg were included in the analysis. Ninety-six had pre-existing non-MS autoimmunity. Up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) pre-existing autoimmunity; similar percentages of patients with versus without pre-existing autoimmunity had ≥2 new autoimmune events (5.2% vs 8.2%, respectively). Most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab. Treatment-emergent thyroid autoimmunity after alemtuzumab Course 1 was not associated with subsequent nonthyroid autoimmunity after Course 2 (0% of patients with vs 3.0% of patients without thyroid autoimmunity after Course 1). Similarly, thyroid autoimmunity after Course 2 did not predict nonthyroid autoimmunity after Course 3 (1.8% vs 2.0%, respectively). Among 25,292 patients treated with alemtuzumab in the postmarketing setting as of 31 March 2019, additional events (occurring 18–36 months post treatment) included autoimmune hepatitis (10.7 in 10,000) and hemophagocytic lymphohistiocytosis (2.7 in 10,000).

Conclusions

Over 9 years after alemtuzumab initiation, pre-existing non-MS autoimmunity was not associated with subsequent new autoimmune disease. Emergence of thyroid autoimmunity after Courses 1 and 2 does not appear to predict subsequent serious autoimmune disease.

STUDY SUPPORT: Sanofi and Bayer HealthCare Pharmaceuticals.

Background

Masitinib (MAS) is a small molecule drug targeting KIT, LYN and CSF1R. Proof-of-concept that MAS slows progressive multiple sclerosis (MS) was previously demonstrated.

Objectives

Assessment of oral MAS as a treatment for progressive MS. Study AB07002 (NCT01433497) evaluated 2 independent parallel groups; 4.5 mg/kg/d vs matched placebo (PBO), and titrated MAS dose of 6.0 mg/kg/d vs PBO.

Methods

Randomized (2:1), double-blinded, placebo-controlled, 2-parallel group trial. Eligible patients (pts) aged 18­–75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0–6.0, regardless of time-from-onset, and diagnosed with primary progressive (PPMS) or non-active secondary progressive (nSPMS) MS, were treated for 96 weeks. Primary endpoint was overall EDSS change from baseline using repeated measures (GEE model, timeframe W12–W96, measured every 12 weeks). Results are expressed as least-squares means difference (δEDSS, positive value indicates worsening), with treatment-effect reported as between-group difference (ΔLSM, negative value favors MAS). A key sensitivity analysis was the 3-level ordinal EDSS model (±1 or 0, repeated measures), which simultaneously measures improved, stable, or worsening outcomes over duration of treatment.

Results

MAS (4.5mg/kg/d) (n=199, median EDSS=5.5, mean age=49.3±9.6 years) showed significant benefit over PBO (n=101) with δEDSS of 0.001 vs 0.098, respectively, and ΔLSM of -0.097(95%CI[-0.192,-0.002]);p=0.0256. This treatment-effect was numerically maintained for the subgroups of nSPMS (MAS n=120 vs 56) and PPMS (MAS n=79 vs 45) with ΔLSM of -0.104(95%CI[-0.198,-0.008]; p=0.032) and -0.128(95%CI [-0.285,0.0282];p=0.108), respectively. All EDSS sensitivity analyses were convergent with the primary outcome, including the conservative jump-to-reference approach with ΔLSM of -0.089 (95%CI[-0.173,-0.006];p=0.0367). Ordinal EDSS analysis showed a significant 39% relative probability of either reduction in EDSS progression or increase in EDSS improvement (hazard ratio (HR) 0.610 (95%CI[0.376,0.988];p=0·0446). Analysis of EDSS time-to-progression showed a significant reduced relative risk of 42% with MAS for first progression (HR 0.58, 95%CI[0.35,0.96];p=0.034), and a reduced relative risk of 37% with MAS for 12-week confirmed (HR 0.63, 95%CI[0.33,1.20];p=0.159). The proportion of pts presenting at least one adverse event (AE) was 94.5% for MAS (4.5 mg/kg/d) vs 87.1% for PBO. Safety was consistent with the known profile for MAS, common treatment-emergent AEs being diarrhea, nausea, rash, and hematological assessments. Efficacy results from the MAS high-dose parallel group (titrated 6.0 mg/kg/d) were inconclusive and no new safety signal was observed.

Conclusions

MAS (4.5 mg/kg/d), a first-in-class TKI targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity, may provide a new treatment option for PPMS and nSPMS

Background

Masitinib (MAS) is a small molecule drug targeting KIT, LYN and CSF1R. Proof-of-concept that MAS slows progressive multiple sclerosis (MS) was previously demonstrated.

Objectives

Assessment of oral MAS as a treatment for progressive MS. Study AB07002 (NCT01433497) evaluated 2 independent parallel groups; 4.5 mg/kg/d vs matched placebo (PBO), and titrated MAS dose of 6.0 mg/kg/d vs PBO.

Methods

Randomized (2:1), double-blinded, placebo-controlled, 2-parallel group trial. Eligible patients (pts) aged 18­–75 years, with baseline Expanded Disability Status Scale (EDSS) 2.0–6.0, regardless of time-from-onset, and diagnosed with primary progressive (PPMS) or non-active secondary progressive (nSPMS) MS, were treated for 96 weeks. Primary endpoint was overall EDSS change from baseline using repeated measures (GEE model, timeframe W12–W96, measured every 12 weeks). Results are expressed as least-squares means difference (δEDSS, positive value indicates worsening), with treatment-effect reported as between-group difference (ΔLSM, negative value favors MAS). A key sensitivity analysis was the 3-level ordinal EDSS model (±1 or 0, repeated measures), which simultaneously measures improved, stable, or worsening outcomes over duration of treatment.

Results

MAS (4.5mg/kg/d) (n=199, median EDSS=5.5, mean age=49.3±9.6 years) showed significant benefit over PBO (n=101) with δEDSS of 0.001 vs 0.098, respectively, and ΔLSM of -0.097(95%CI[-0.192,-0.002]);p=0.0256. This treatment-effect was numerically maintained for the subgroups of nSPMS (MAS n=120 vs 56) and PPMS (MAS n=79 vs 45) with ΔLSM of -0.104(95%CI[-0.198,-0.008]; p=0.032) and -0.128(95%CI [-0.285,0.0282];p=0.108), respectively. All EDSS sensitivity analyses were convergent with the primary outcome, including the conservative jump-to-reference approach with ΔLSM of -0.089 (95%CI[-0.173,-0.006];p=0.0367). Ordinal EDSS analysis showed a significant 39% relative probability of either reduction in EDSS progression or increase in EDSS improvement (hazard ratio (HR) 0.610 (95%CI[0.376,0.988];p=0·0446). Analysis of EDSS time-to-progression showed a significant reduced relative risk of 42% with MAS for first progression (HR 0.58, 95%CI[0.35,0.96];p=0.034), and a reduced relative risk of 37% with MAS for 12-week confirmed (HR 0.63, 95%CI[0.33,1.20];p=0.159). The proportion of pts presenting at least one adverse event (AE) was 94.5% for MAS (4.5 mg/kg/d) vs 87.1% for PBO. Safety was consistent with the known profile for MAS, common treatment-emergent AEs being diarrhea, nausea, rash, and hematological assessments. Efficacy results from the MAS high-dose parallel group (titrated 6.0 mg/kg/d) were inconclusive and no new safety signal was observed.

Conclusions

MAS (4.5 mg/kg/d), a first-in-class TKI targeting the innate immune system via inhibition of mast cell and microglia/macrophage activity, may provide a new treatment option for PPMS and nSPMS

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.

Background

Therapeutic options are growing for active RRMS patients, however, few prospective studies are available to compare the efficacy of those treatments. Best Escalation Strategy in MS (BEST MS) started in France in 2013 when natalizumab (NTZ) and fingolimod (FTY) were the two most employed second-line therapies in active RRMS.

Objectives

To compare the efficacy between natalizumab (NTZ) and fingolimod (FTY) in active relapsing-remitting multiple sclerosis (RRMS).

Methods

BEST-MS is a French prospective multicentric study.

Patients with active RRMS (defined as at least 1 relapse in the last 12 months on a well-conducted 1^st line treatment with at least 9 T2 hyperintensities on MRI, OR at least 2 relapses in the last 12 months with evidence of active disease on MRI for naïve patients) were enrolled to be treated either with NTZ or FTY. Treatments choice was at the discretion of the physician.

Relapses, EDSS and brain MRI were collected at baseline and at 12 months.

The main outcome measure was the proportion of patients reaching No Evidence of Disease Activity (NEDA) at 12 months, defined as the absence of relapses, absence of new T2 lesions, absence of new gadolinium enhancing lesions and a stable EDSS score.

Results

230 patients were included (age: 38.2 yrs, F/M: 3.1, FTY: 117, NTZ: 113). There was no statistical difference between groups regarding baseline characteristics.

Treatment drop out rate was higher in FTY group (22% vs 12%, p<0.0001) and most of thoses cases were related to a lack of efficacy.

At M12, 43% of patients treated with NTZ reached NEDA versus 27% in the FTY group (p=0.04)

NTZ indicated a better efficacy regarding new T2 lesions (0.7 vs 1.4, p=0.01) and gadolinium enhancing lesions (0.03 vs 0.5, p<0.0001).

Relapse rate (ARR) was lower in NTZ group (0.2 vs 0.27, p = 0.04), even if most relapses occurred during the first 4 months of treatment in both groups.

Conclusions

NTZ showed higher efficacy than FTY on MRI in active RRMS patients. ARR was also lower in favor of NTZ, but most relapses occurred early. However, the rate of drop out was higher for patients treated with FTY.

Background

Patients with relapsing-remitting multiple sclerosis (RRMS) often experience disease activity despite receiving a disease-modifying therapy (DMT). The Phase IIIb CASTING study (NCT02861014) of ocrelizumab evaluated the efficacy/safety in patients with RRMS who had a prior suboptimal response to one or two DMTs (primary endpoint: 2-year no evidence of disease activity [NEDA] rate).

Objectives

To evaluate CASTING 2-year NEDA outcomes by inclusion criteria, baseline characteristics and prior DMT.

Methods

Patients (Expanded Disability Status Scale [EDSS] score ≤4.0; discontinued prior DMT of ≥6 months’ duration due to suboptimal disease control) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. The primary endpoint of NEDA (with prespecified MRI re-baselining at Week 8) was defined as absence of: protocol-defined relapses, 24-week confirmed disability progression, T1‑weighted contrast-enhancing and new/enlarging T2-weighted lesions over 2 years.

Results

A total of 680 patients were evaluated (female, 64%; mean [SD] baseline EDSS score, 2.1 [1.1]; pretreated with one or two DMTs, including orals and injectables, n=411 [60.4%]/n=269 [39.6%]; enrolled due to activity of: MRI only, n=167 [24.6%]; relapse only, n=238 [35.0%]; MRI and relapse, n=275 [40.4%]). After 2 years, 74.8% (n/N=492/658) of patients had NEDA (with MRI re-baselined at Week 8). The NEDA rate was highest among patients enrolled due to MRI activity alone (80.6%) versus enrollment for relapse (75.1%) or relapse with MRI (70.5%). NEDA rates across disease-related subgroups were highest in the subgroups of baseline EDSS score <2.5 (77.2%), ≤1 relapse prior to enrollment (78.2%) and the event leading to enrollment occurring ≥6 months prior to study entry (75.8%) versus the counterpart subgroups of EDSS score ≥2.5 (70.8%), >1 relapse prior to enrollment (66.3%) and the event leading to enrollment occurring <6 months prior to entry (71.0%). The NEDA rate did not vary by baseline age (≤40 years, 74.7%; >40 years, 75.0%). NEDA rates were higher in patients receiving one prior DMT (77.6%) versus two prior DMTs (70.3%) and remained generally high when stratified by the last prior DMT received before enrollment: interferons, 81.1%; glatiramer acetate, 73.9%; dimethyl fumarate, 73.8%; teriflunomide 69.8%; fingolimod, 68.9%.

Conclusions

The NEDA rate was high overall and across a wide range of disease-related and demographic subgroups, regardless of prior treatment background.

Background

The efficacy and safety of ocrelizumab (OCR) in primary progressive multiple sclerosis were demonstrated vs placebo (PBO) in the Phase III ORATORIO study (NCT01194570).

Objectives

To assess the efficacy of switching to or maintaining OCR therapy on 48-week confirmed disability progression (CDP), in the open-label extension (OLE) of ORATORIO, over 7 years (360 weeks).

Methods

In the double-blind period (DBP), patients were randomized to OCR or PBO and followed for ≥120 weeks until a prespecified number of CDP events occurred. At DBP completion, patients remained on blinded treatment until the trial outcome was determined (extended controlled period; ECP). At OLE start, patients continued OCR (OCR-OCR) or switched from PBO to OCR (PBO-OCR). Time to 48-week CDP-EDSS (Expanded Disability Status Scale [EDSS] score increase from baseline [BL] of ≥1 point if BL EDSS ≤5.5 or ≥0.5 points if BL EDSS >5.5), time to 48-week CDP on the 9-Hole Peg Test (CDP-9HPT; ≥20% increase from BL in timed 9HPT) and time to 48-week confirmed EDSS≥7 (wheelchair requirement) are presented up to Week 360.

Results

Overall, 72% of patients entered the OLE. At Week 168 (12 weeks after the first patients entered the OLE), the proportion of patients with 48-week CDP-EDSS in the PBO-OCR and OCR-OCR groups was 44.4% vs 30.5% (Δ=13.9%; p<0.001), respectively; at Week 360 the corresponding proportions were 65.7% vs 54.2% (Δ=11.6%; p=0.006). At Week 168, the proportion of patients with 48-week CDP-9HPT in the PBO-OCR and OCR-OCR groups was 27.9% vs 15.8% (Δ=12.1%; p<0.001); at Week 360 the corresponding proportions were 41.6% vs 31.1% (Δ=10.6%; p=0.014), respectively. At Week 168 the proportion of patients with 48-week confirmed EDSS≥7 in the PBO-OCR and OCR-OCR groups was 9.1% vs 4.8% (Δ=4.3%; p=0.054), respectively; at Week 360 the proportions were 21.7% vs 12.3% (Δ=9.4%; p=0.009). During the DBP+ECP+OLE, compared with the PBO-OCR group, continuous OCR treatment reduced the risk of CDP-EDSS by 31% (HR [95% CI]: 0.69 [0.56–0.86]; p<0.001), CDP-9HPT by 34% (HR [95% CI]: 0.66 [0.50–0.87]; p=0.003) and 48-week confirmed EDSS≥7 by 44% (HR [95% CI]: 0.56 [0.37–0.85]; p=0.006). Timed 25-Foot Walk, composite CDP and 24-week CDP will also be presented. The OLE safety profile was consistent with the DBP.

Conclusions

After 7 years, 48-week CDP outcomes favoured those on earlier and continuous OCR treatment. Patients initiating OCR 3–5 years earlier had a significantly reduced risk of requiring a wheelchair vs those switching from PBO.

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 25^th–40^th 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 25^th–30^th 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.

Background

Subcutaneous interferon beta-1a (sc IFNβ-1a) is a well-established multiple sclerosis (MS) therapy with cumulative exposure of approximately 1,766,525 patient-years. Previous clinical trials demonstrate that patient age does not impact the efficacy of such therapy for treatment of MS.

Objectives

Using real-world data, we evaluated the effect of age on the effectiveness and discontinuation of sc IFNβ-1a, and healthcare utilization, in patients with MS.

Methods

This cohort study using MarketScan^© Databases included adult patients with MS newly initiated with sc IFNß-1a between Jul2010-Dec2015, with at least 6 months’ patient history before initiation (index date), and a recorded diagnosis of MS over the 6 months before or at initiation. Follow-up was until end of study period, end of insurance, or treatment discontinuation. Incidence rate (IR) per 100 person-years was used for discontinuation. Hazard ratio (HR) and 95% confidence internal (CI) were used to compare time to first relapse and discontinuation.

Results

Among 5,340 patients included, 14.5% were aged 18-30y, 27.5% 31-40y, 30.5% 41-50y, and 27.5% were 51+y. Relapse-free probability at 2-y ranged from 91.44% in 18-30y to 92.82% in 51+y. Compared with 18-30y, the HRs for relapse at 2-y (95%CI) were 31-40y: 1.00 (0.70, 1.43), 41-50y: 0.79 (0.55, 1.12), and 51+y: 0.86 (0.60, 1.24). In all age groups, hospitalizations due to MS were ≤0.01 and neurology visits were 0.2 patient per-month (PPM) over 2-y. Mean number (95%CI) of magnetic resonance imaging (MRI) scans performed PPM over 2-y ranged from 0.25 (0.16, 0.34) in 18-30y to 0.14 (0.12, 0.16) in 51y+ and outpatients visits due to MS from 0.68 (0.57, 0.78) to 0.75 (0.67, 0.82). Discontinuation IR at 2-y was 72.06 (65.12, 79.52) in 18-30y and 57.95 (53.76, 62.38) in 51+y. Compared to 18-30y, the HR of discontinuation decreased from 0.89 (0.79, 1.01) in 31-40y to 0.86 (0.76, 0.97) in 51+y.

Conclusions

Data suggest no effect of age on the effectiveness of sc IFNß-1a in the real-world setting, while treatment discontinuation decreased with increasing age. Older MS patients initiating sc IFNß-1a appear to have less active disease, reflected in lower relapses, and undergo MRI scanning less frequently than younger patients.

Background

The MAGNIFY-MS study (NCT03364036) aims to determine the onset of action of cladribine tablets 3.5 mg/kg over 2 years (CT3.5) in patients with relapsing multiple sclerosis (RMS). Efficacy data from the pivotal trial CLARITY showed that outcomes in CT3.5-treated patients were superior to placebo with regard to number and relative reduction of standardized combined unique active (CUA) lesions over the 96-week trial. Carrying out early and frequent magnetic resonance imaging (MRI) will provide valuable insights into the onset of action of CT3.5.

Objectives

To report on the onset of action of CT3.5 by observing changes in counts of CUA MRI lesions during the first 6 months of the MAGNIFY-MS study.

Methods

MRI scans were performed at screening, baseline, and at months 1, 2, 3 and 6 following CT3.5 treatment on patients with highly active RMS. Differences in CUA lesions between post-baseline periods (period 1, months 1–6, period 2, months 2–6, and period 3, months 3–6) were compared to the baseline period. CUA lesion count was standardized to period length and number of MRIs in a period. A mixed effects linear model was used to account for within pooled centre correlation and adjusted for CUA lesion count during the baseline period, age, and baseline expanded disability status scale (EDSS; >3, ≤3). Type-I-error inflation due to multiple testing was controlled by a gatekeeping procedure.

Results

The full analysis set considered for primary analysis included 270 patients. Reductions in mean CUA count were observed from month 1 onwards compared to baseline; by -1.193 in period 1, -1.500 in period 2 and -1.692 in period 3 (all p<0.0001). In particular, the mean T1 Gd+ lesion counts were decreased from month 2 onwards compared to baseline; by -0.857 at month 2, -1.355 at month 3 and -1.449 at month 6 (all p<0.0001). Sensitivity analysis using negative binomial distribution showed that the treatment effect increased with time measured as lack of CUA in subsequent periods; by 61% in period 1, 77% in period 2, and 87% in period 3 (all p<0.0001). The proportion of patients without any CUA lesions increased in the first 6 months; by 52% in period 1 (p=0.0241), 66% in period 2 (p<0.001), and 81% in period 3 (p<0.001).

Conclusions

MRI was used to assess disease activity in a group of highly active RMS on CT3.5 treatment from one month onwards. Data show an early onset of action on CUA lesions that was significant from month 1 versus baseline, with a treatment effect that increased over the first 6 months.

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.

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.

Background

MSProDiscuss^TM is a validated, physician-completed tool aimed at facilitating physician–patient conversation on signs of progression in multiple sclerosis (MS). A set of weighted questions on relapses, symptoms and their impacts as experienced by the patient generate a traffic light system output to aid the discussion. The tool is available online at www.msprodiscuss.com.

Objectives

Evaluate the usability and usefulness of MSProDiscuss in discussing disease progression in daily clinical practice.

Methods

An online qualitative survey consisting of individual questionnaires completed by healthcare professionals (HCPs) after using MSProDiscuss in patient consultations and a final questionnaire to capture overall experience on the tool was conducted in 34 countries. General feedback and recommendations for improving the tool were also collected.

Results

In total, 301 HCPs participated in the survey. The HCPs first completed individual questionnaires after using MSProDiscuss on 6974 MS patients and then a final questionnaire. In 97% (initial questionnaire, i) and 98% (final questionnaire, f) of the time MSProDiscuss was used, the time taken to complete the tool was considered satisfactory (1-4min). The questions were found to be comprehensible in 94% (i) to 97% (f) of cases, and HCPs are willing to use the tool again in the same patient 91% (i) of the time. MSProDiscuss was also useful in discussing MS symptoms and its impact on daily activities (88% i / 92% f) and cognitive function (79% both i and f) and in discussing progression in general (88% i / 90% f).

Moreover, in the final questionnaire, 95% agreed that the questions were similar to those asked by a HCP in a regular consultation. MSProDiscuss was also found to be helpful for understanding the impact of MS symptoms on daily activities (91%) and cognitive function (80%). Overall, 92% of the HCPs would recommend MSProDiscuss to a colleague; 92% think that it is feasible and 86% are willing to integrate MSProDiscuss into their clinical practice. Key recommendations were to allow for longitudinal follow-up, expand on cognitive assessments, and provide a patient-completed version. These have been considered for implementation in the updated version of MSProDiscuss.

Conclusions

The survey results established MSProDiscuss as useful and easy to use tool to facilitate patient-physician discussion of MS progression by structured capturing of patient clinical profile. Most HCPs were willing to integrate MSProDiscuss into their daily clinical practice.

Background

SymptoMScreen is a patient-reported outcome tool designed to rapidly assess symptom limitations across 12 symptoms commonly affected in people with multiple sclerosis (MS). Each domain is scored on a 7-point Likert scale (0 [not affected] to 6 [total limitation]) and domain scores are summed to calculate a total score ranging from 0 to 72. SymptoMScreen is used in the ongoing, open-label, single-arm, Phase IIIb CASTING clinical trial (NCT02861014).

Objectives

To report 2-year changes in SymptoMScreen scores among patients with relapsing-remitting MS (RRMS) from CASTING.

Methods

In CASTING, patients with RRMS (Expanded Disability Status Scale [EDSS] score ≤4.0 at screening; disease duration ≤10 years) and a prior suboptimal response to ≥6 months of treatment with one or two disease-modifying therapies (DMTs; including orals and injectables) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. SymptoMScreen was performed at baseline, Week 48 (1-year interim data) and Week 96 (2-year final data).

Results

A total of 680 patients (female, 64%; mean [SD] baseline EDSS score, 2.1 [1.1]) who were previously treated with one (n=414 [60.4%]) or two (n=269 [39.6%]) DMTs were enrolled (most frequently for MRI with relapse activity [40.4%]) and evaluated in the intent-to-treat population; 644 patients completed treatment. Total SymptoMScreen mean (SD) score reflected mild symptom burden at baseline (15.19 [12.67]) and improved significantly through Year 2 (13.62 [12.51]; p<0.001 [p values were not adjusted for multiplicity]). Statistically significant improvements after 2 years were observed for sensory symptoms (Δ-0.28; p<0.001), fatigue (Δ-0.23; p<0.001), vision (Δ-0.21; p<0.001), depression (Δ-0.15; p<0.01) and dizziness (Δ-0.14; p<0.01) domains. Non-significant improvements in symptom burden after 2 years (p>0.05) were observed in walking (Δ-0.1), cognition (Δ-0.10), anxiety (Δ-0.07), bodily pain (Δ-0.05), hand function (Δ-0.03) and bladder control (Δ-0.01), while a non-significant worsening was observed in the spasticity domain (Δ+0.04). The proportion of patients with at least one symptom causing at least moderate limitation (domain score ≥4) decreased from 31.6% at baseline to 26.3% at Year 2.

Conclusions

Patients with RRMS and a suboptimal response to therapy who switched to ocrelizumab experienced an improvement in symptom burden in the majority of SymptoMScreen domains after 2 years, which was most pronounced in sensory, fatigue and vision.

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.

Background

Subcutaneous interferon beta-1a (sc IFNβ-1a) is a well-established multiple sclerosis (MS) therapy with cumulative exposure of approximately 1,766,525 patient-years. Previous clinical trials demonstrate that patient age does not impact the efficacy of such therapy for treatment of MS.

Objectives

Using real-world data, we evaluated the effect of age on the effectiveness and discontinuation of sc IFNβ-1a, and healthcare utilization, in patients with MS.

Methods

This cohort study using MarketScan^© Databases included adult patients with MS newly initiated with sc IFNß-1a between Jul2010-Dec2015, with at least 6 months’ patient history before initiation (index date), and a recorded diagnosis of MS over the 6 months before or at initiation. Follow-up was until end of study period, end of insurance, or treatment discontinuation. Incidence rate (IR) per 100 person-years was used for discontinuation. Hazard ratio (HR) and 95% confidence internal (CI) were used to compare time to first relapse and discontinuation.

Results

Among 5,340 patients included, 14.5% were aged 18-30y, 27.5% 31-40y, 30.5% 41-50y, and 27.5% were 51+y. Relapse-free probability at 2-y ranged from 91.44% in 18-30y to 92.82% in 51+y. Compared with 18-30y, the HRs for relapse at 2-y (95%CI) were 31-40y: 1.00 (0.70, 1.43), 41-50y: 0.79 (0.55, 1.12), and 51+y: 0.86 (0.60, 1.24). In all age groups, hospitalizations due to MS were ≤0.01 and neurology visits were 0.2 patient per-month (PPM) over 2-y. Mean number (95%CI) of magnetic resonance imaging (MRI) scans performed PPM over 2-y ranged from 0.25 (0.16, 0.34) in 18-30y to 0.14 (0.12, 0.16) in 51y+ and outpatients visits due to MS from 0.68 (0.57, 0.78) to 0.75 (0.67, 0.82). Discontinuation IR at 2-y was 72.06 (65.12, 79.52) in 18-30y and 57.95 (53.76, 62.38) in 51+y. Compared to 18-30y, the HR of discontinuation decreased from 0.89 (0.79, 1.01) in 31-40y to 0.86 (0.76, 0.97) in 51+y.

Conclusions

Data suggest no effect of age on the effectiveness of sc IFNß-1a in the real-world setting, while treatment discontinuation decreased with increasing age. Older MS patients initiating sc IFNß-1a appear to have less active disease, reflected in lower relapses, and undergo MRI scanning less frequently than younger patients.