Background

Dimethyl fumarate (DMF) treatment is associated with a decrease in serum neurofilament light chain (sNfL) in patients with relapsing-remitting multiple sclerosis (RRMS). sNfL is an exploratory biomarker of MS disease activity. Additional data describing the association between sNfL and disease activity are needed to further investigate this biomarker as a potential predictor of treatment response, which could enable a more holistic disease monitoring approach to treatment.

Objectives

To describe variation in sNfL levels with respect to clinical and radiological disease activity in DMF-treated patients.

Methods

DMF-treated patients with RRMS and complete 2Y follow-up data were analyzed. Serum samples were collected, and routine clinical and radiological assessments were conducted at baseline (BL) and at regular intervals. sNfL concentrations were measured by Single Molecule Array (SiMoA). Normative sNfL data from a cohort of 135 healthy adult controls (age range 21-82 years) were used as a comparator. Age-normative sNfL cutoffs were defined based on the 95^th percentile of sNfL levels.

Results

Forty-one patients with 2Y follow-up data were included. Mean (SD) age and disease duration were 37.5 (10.1) and 6.0 (6.5) years, respectively, with mean (SD) time on DMF treatment 43.8 (9.15) months. Twenty-nine (70.7%) patients were treated with a previous MS therapy. Nineteen (46.3%) and 22 (53.7%) patients were below and above age-normative sNfL level at BL, respectively. Over 2Y, mean (95% CI) sNfL level decreased from 8.5 (7.1, 10.2) to 3.4 (2.0, 4.0) pg/ml, representing a 36.6% annual decrease, and 60% decrease over 2Y. Patients experienced a 71.1% (95% CI: 38.8%, 86.3%) reduction in ARR from 1Y prior to BL (0.463, 95% CI [0.279, 0.724]) to 2Y (0.134 [0.067, 0.24]), and 75.6% (59.4%, 87.1%) patients were free of new T2 lesions at 2Y. sNfL was below age-normative level in 53.7% (37.6%, 69%) of patients at BL vs 97.6% (85.6%, 99.9%) at 2Y. Patients with sNfL below age-normative level at BL generally remained below this threshold. At 2Y, patients both above and below age-normative sNfL level at BL experienced low cumulative ARR (95% CI) of 0.132 (0.043, 0.307) and 0.136 (0.05, 0.297), respectively, representing reductions of 75% and 66.7%.

Conclusions

DMF-treated patients reached NfL levels approaching that of healthy controls over 2Y with a reduction in disease activity, regardless of sNfL level at BL in this real-world setting. These data support a correlation between reductions in sNfL levels and decreased disease activity over 2Y of treatment, and potential of sNfL as a biomarker of treatment response that could be assessed during treatment in addition to standard of care monitoring.

Supported by: Biogen.

Background

Diroximel fumarate (DRF) is an oral fumarate recently approved in the United States for relapsing forms of multiple sclerosis (MS). DRF demonstrated favorable gastrointestinal (GI) tolerability in clinical studies of MS patients (pts). Discontinuations due to GI adverse events (AEs) were low (0.7%) in an open-label 2-year study. In a randomized study versus dimethyl fumarate (DMF), fewer pts reported GI AEs (35%, 88/253 DRF vs 49%,123/251 DMF) and GI AEs leading to discontinuation (0.8% DRF vs. 4.8% DMF); GI AEs were less frequently reported as moderate/severe for DRF (23%, 20/88) vs DMF (40%, 49/123). It is important to characterize DRF persistence in a real-world setting and effectiveness across different patient types and geographies.

Objectives

To describe the novel design of the DRF EXPERIENCE (EXPloring diroximEl fumarate Real-world experIENCE) Study Initiative.

Methods

A Phase IV DRF study should collect data on meaningful real-world outcomes, including treatment persistence, real-world tolerability, and clinical effectiveness, including cognitive changes, to align with evolving treatment goals. As DRF was designed to reduce treatment burden, impact on quality of life should also be assessed. Country-specific nuances due to unique healthcare environments, ethnicity, and cultural considerations diminish the utility of a single-study design.

Results

The DRF EXPERIENCE Study Initiative uses a novel design comprising 4 individual studies, each conducted in different regions but anchored by a core protocol to characterize the early experience in pts initiating DRF per routine care. The core protocol defines a set of required assessments for each study, but also allows flexibility to include others that address country-specific research questions. The primary objective is to characterize persistence to DRF at 1 year. Core protocol assessments include relapse, disability, cognitive changes, and pt-reported Neuro-QoL. Each study will enroll ~200 pts; the pooled total sample size of ~800 will improve ability for subgroup analyses. Pts will be followed for 2 years and include those newly initiating a disease modifying therapy (DMT) or switching from previous DMTs (including prior DMF).

Conclusions

The DRF EXPERIENCE Study Initiative uses a novel design to characterize the improved GI tolerability profile and effectiveness of DRF in MS pts in the real-world and will be informative to providers and patients when considering MS treatment goals together with the burden of therapy.

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