Background

Diroximel fumarate (DRF) is a novel oral fumarate approved in the United States for relapsing forms of multiple sclerosis (MS). DRF undergoes pre-systemic hydrolysis to monomethyl fumarate (MMF), the same pharmacologically active metabolite as dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of MMF and are expected to have similar efficacy and safety profiles. In DMF-treated patients, annual rates of brain volume loss over 6 years ranged from -0.19 to -0.37, approaching rates observed in healthy adults (-0.1% to -0.3%).

Objectives

To report percent brain volume change (PBVC) and impact on disability in patients from EVOLVE-MS-1 who have received DRF treatment for up to 2 years.

Methods

EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, phase 3 study to assess the long-term safety, tolerability, and efficacy of DRF 462 mg over 96 weeks in adults with relapsing-remitting MS. Normalized brain volume was assessed at baseline and used to calculate PBVC at Weeks 48 and 96. Confirmed Disability progression (CDP) was measured using the Expanded Disability Status Scale (≥1.5-, ≥1.0-, or ≥0.5-point increase from a baseline score of 0, 1.0-5.5, or 6.0, respectively), with changes sustained for 12 weeks. Estimated proportion of patients with CDP was calculated by the Kaplan-Meier method. No evidence of disease activity (NEDA)-3 was defined as no relapses, no 12-week CDP, and no new/enlarging T2 or new gadolinium-enhancing lesions. This post hoc analysis was conducted in a subgroup of patients who had brain volume scan measurements at baseline, Week 48, and Week 96. The Week 48 and Week 96 visits occurred within an analysis window of ±12 weeks.

Results

As of 2 July 2019, a total of 1051 patients were enrolled in EVOLVE-MS-1 and 365 patients were included in this analysis. Median (range) exposure was 96 (75-100) weeks. Mean (SD) PBVC was -0.36 (0.60) from baseline to Week 48 and -0.35 (0.55) from Week 48 to Week 96. Estimated proportion of patients who were free of CDP was 94.3% at Week 48 and 90.7% at Week 96. The proportion of patients with NEDA-3 at Week 48 and Week 96 was 44.7% (163/365) and 25.2% (91/361), respectively.

Conclusions

Interim findings from the ongoing EVOLVE-MS-1 study demonstrate that yearly PBVC in DRF-treated patients approached the rate observed in healthy adults and was consistent with previous studies of DMF. Most patients remained free of CDP at 2 years.

Supported by: Biogen

Background

Diroximel fumarate (DRF) is a novel oral fumarate approved for relapsing forms of multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF demonstrated improved gastrointestinal (GI) tolerability vs DMF, with significantly fewer days with a score of ≥2 on the patient-assessed Individual Gastrointestinal Symptom and Impact Scale (IGISIS).

Objectives

To determine whether an IGISIS score ≥2 is an appropriate threshold for comparing GI tolerability and detecting clinically meaningful quality of life (QoL) improvements in EVOLVE-MS-2.

Methods

EVOLVE-MS-2 (NCT03093324) was a 5-week, randomized study comparing GI tolerability of DRF vs DMF in patients with relapsing-remitting MS. Patients self-assessed severity of 5 key GI symptoms by completing IGISIS and Global GISIS (GGISIS) questionnaires. GGISIS assessed interference of GI symptoms on daily activities and missed work. The association between worst IGISIS score ≥2 and measures of treatment burden (worst interference with daily activities, missed work due to GI symptoms, and use of concomitant symptomatic medication to treat GI AEs) by treatment group was assessed using risk ratios (RR; DRF/DMF).

Results

Overall, 253 patients received DRF and 251 received DMF. Fewer DRF-treated patients reported any IGISIS score ≥2 (DRF, 43.1% [109/253]; DMF, 51.4% [128/249]). IGISIS score ≥2 detected moderate/severe GI AEs of IGISIS with 90% sensitivity and 59% specificity. Among patients reporting GI symptoms as “Quite a Bit” or “Extremely” interfering with daily activities (n=47) or missing ≥ 1 hour work due to GI symptoms (n=46) using GGISIS, 89.4% and 91.3% reported a worst IGISIS score ≥2, respectively. In patients with worst IGISIS score ≥2, DRF was associated with lower likelihood of GI symptoms interfering with daily activities “Quite a bit” or “Extremely” (RR 0.88; 95% CI 0.51–1.53), leading to missed work (RR 0.88; 95% CI 0.51–1.53), and resulting in concomitant symptomatic medication use for GI AEs (RR 0.57; 95% CI 0.32–1.00).

Conclusions

Fewer patients reported IGISIS score ≥2 with DRF vs DMF, and an IGISIS score ≥2 was sensitive for identifying moderate/severe GI AEs and clinically meaningful GI symptoms that could impact QoL from a patient perspective.

Supported by: Biogen

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 2019, the FDA changed the prescribing information to include active SPMS for siponimod, in addition to natalizumab, ocrelizumab, cladribine, fingolimod, dimethyl fumarate, interferons, and glatiramer acetate.

Objectives

Evaluate how US Neurologists are diagnosing secondary progressive (SP) multiple sclerosis (MS) over time. Determine how treatment choices for SPMS are evolving.

Methods

US Neurologists contributed online chart reviews for a cross-sectional audit of patients with SPMS in Q3 2018 (n=168 physicians; 431 SPMS patients) and Q3 2019 (n=147 physicians; 423 SPMS patients).

Results

SPMS transition was diagnosed most commonly by a progressive accumulation of disability independent of relapse activity (57% of patients). SPMS diagnosis in 2019 relied more upon confirmed disability progression (CDP) over 6 months (25% vs. 16% in 2018) and increased rate of brain atrophy (15% vs. 9%). Neurologists relied less upon absence of relapses (12% vs. 24% in 2018), length of time since MS diagnosis (11% vs. 16%), and a decreased annualized relapse rate (6% vs. 11%). In 2019, MS Specialists (n=85) were more likely to identify SPMS by CDP-6M (33% vs. 14%), whereas General Neurologists (n=61) relied more on worsening MRI findings (50% vs. 30%) and decreased walking speed (26% vs. 14%). Compared to the prior year, the proportion with active SPMS increased (66% vs. 58%), with MS Specialists more likely to categorize SPMS patients active compared to General Neurologists (73% vs. 59%). SPMS patients were most likely to be treated with an oral DMT (34%), followed closely by monoclonal antibodies (32%). Siponimod and cladribine use was introduced in 2019, while fingolimod and dimethyl fumarate use declined from 2018 levels.

Conclusions

US Neurologists continue to evolve in diagnosing SPMS, using the active SPMS subtype, and in treatment choices for such patients.

Background

Natalizumab extended interval dosing (EID) is associated with lower risk of progressive multifocal leukoencephalopathy than every-4-week standard interval dosing (SID). Independent real-world (RW) studies suggest that natalizumab effectiveness is maintained in patients who switch from SID to EID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a learning health system comprised of a collaborative network of healthcare institutions that provides access to RW clinical and MRI data collected using standardized acquisition protocols.

Objectives

Compare the effectiveness of natalizumab EID and SID using quantitative MRI metrics from highly standardized RW images in MS PATHS.

Methods

An MRI segment was defined as 2 MRI acquisitions and associated interval duration. MS PATHS patients with ≥1 MRI segment, ≥2 infusion cycles (infusion interval >21 days and ≤84 days), and complete covariate information were eligible. MRI segments with average infusion cycle (AIC) ≤35 days and >35 days were defined as SID and EID, respectively. For each MRI segment, new T2 lesions and changes in T2 lesion volume (T2LV) and brain parenchymal fraction (BPF) were compared for SID and EID using inverse probability weighting (IPW) with logistic regression and robust linear regression.

Results

IPW analysis included 327 SID patients (596 MRI segments) and 67 EID patients (85 MRI segments). The mean AIC for SID was 29.5 (standard deviation [SD] 1.8) days and 40.8 (4.9) days for EID. Mean MRI segment duration for SID and EID was 9.7 (SD 5.5) and 9.6 (5.3) months, respectively. Proportions of patients with no new T2 lesions were similar for the SID and EID groups (75.6% vs 75.3%; adjusted odds ratio for 0 vs ≥1 lesion=0.967 [95% CI 0.500, 1.871]; P=0.921). SID and EID patients did not differ significantly in adjusted T2LV change (−0.070 [95% CI −0.129, 0.111] mL vs 0.022 [−0.132, 0.180] mL; P=0.233) or BPF change (−0.1222% [95% CI −0.1524%, −0.0921%] vs −0.1442% [−0.2234%, −0.0649%]; P=0.617).

Conclusions

MRI activity was low in SID and EID MS PATHS patients, and there were no significant differences in MRI outcomes between the 2 groups. These results confirm and extend previous RW studies of natalizumab EID effectiveness. Study limitations include modest EID sample size and potential channeling bias. The ongoing phase 3b randomized trial NOVA (clinicaltrials.gov NCT03689972) will further evaluate the effectiveness of natalizumab EID versus SID.

MS PATHS is supported by Biogen.

Background

Background: Multiple sclerosis (MS) incidence in Hispanic Americans (HA) is increasing, highlighting the need to understand disease features and clinical course trends among this subpopulation.

Objectives

Objective: To compare demographic features and clinical characteristics of a large population of HA and non-Hispanic Caucasian Americans (NHCA) with MS.

Methods

Methods: MS PATHS is a network of MS Centers in the United States (n=7) and Europe (n=3) contributing standardized data acquired during routine care. US-based MS PATHS participants who self-reported as HA (irrespective of race) or as NHCA, and compared the groups according to demographic (sex, years of education, smoking status, BMI, employment, and insurance status), MS clinical (self-reported disability via Patient Determined Disease Steps [PDDS]), and neuro-performance (via the MS Performance Test (MSPT): walking, manual dexterity, and processing speed) features. Odds ratios and mean differences for PDDS and neuro-performance outcomes were adjusted for age, sex, disease duration and subtype, smoking status, BMI, insurance status, employment status, and years of education. Z-score is compared to a representative healthy population.

Results

Results: Compared to NHCA (n=9003), HA (n=609) had earlier MS symptom onset (mean 28.6y [SD:10.7y] vs 33.6y [11.3y]; p<0.001) and younger age at diagnosis (31.6y [10.9y] vs 36.6y [10.9y]; p<0.001). HA were more likely to have mild disability by the PDDS, compared to NHCA (OR 0.62, 95% CI [-0.89, -0.06], p=0.02). However, HA had worse performance on both manual dexterity times (z score: 0.31 [0.14, 0.47], p<0.001), and cognitive processing speed score (# correct: 0.37 [0.27-0.47], p<0.0001). 25-foot walking speed was not different between the groups (z score:0.09 [-0.23,0.41], p=0.56).

Conclusions

Conclusion: Using standardized data collection in this large MS sample, HA compared to NHCA patients were found to have younger age of onset and diagnosis and higher levels of cognitive and manual dexterity slowing. However, HA were less likely to rate themselves with severe disability on the PDDS. As the groups did not differ in walking speed, this may reflect the scale relatively weighting ambulation over other functions or other language/cultural differences.