Over a 2-year treatment period, no clear effects of dimethyl fumarate were identified on clinical or MRI outcomes in patients with progressive multiple sclerosis.
Dimethyl fumarate (Tecfidera; Biogen), an FDA-approved therapy for relapsing forms of multiple sclerosis (MS), failed to show any effect on clinical nor MRI outcomes or changes in serum concentrations of neurofilament light (NfL) in an open-label extension (OLE) study (NCT02959658) of patients with progressive MS. Despite this, there was a group of patients that improved to an extent, which investigators noted warrants further investigation.
In the placebo-controlled portion of the trial, the therapy did not meet its primary end point of change in cerebrospinal fluid (CSF) concentrations of NfL over a 48-week period. In total, 42 patients with progressive MS entered the OLE, and 33 (61%) patients had complete data at week 96. Similar to the double-blind period, results showed no between-group differences or significant changes in serum NfL levels. Although CSF levels of Nfl were significantly increased compared with controls, serum levels were mainly within normal range, with only 12% of patients having a serum NfL ration above 1.0 at screening.
Senior investigator Finn Sellebjerg, MD, head of the Danish Multiple Sclerosis Center at Copenhagen University, and colleagues reported data at screening, week 48, and week 96. Each individual underwent clinical evaluations using the Expanded Disability Status Scale (EDSS) score, 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW) test, Symbol Digit Modalities Test (SDMT), California Verbal Learning Test (CVLT-II), and Brief Visuospatial Memory-Revised (BVMT-R).
In the OLE period, from week 48 to 96, investigators observed no significant change in disability at a group level upon treatment with dimethyl fumarate, except for a worsening in non-dominant 9HPT in the group originally randomized to placebo (P = .024). Although dimethyl fumarate failed to meet its primary end point, there was mixed results in terms of clinical outcomes. Fourteen (42%) patients had physical disease progression assessed with either EDSS, T25FW, or 9HPT at week 96; however, another 15 (46%) patients showed improvement in at least 1 physical domain at the same time point.
Six (18%) of the 7 patients with EDSS worsening was confirmed from week 72 to 96, and 5 (15%) of the 6 with EDSS improvements were confirmed from week 72 to 96. When investigators applied a cut-off of 8 points on the SDMT, 2 (6%) patients worsened, 25 (78%) did not change, and 5 (16%) improved. Chow et al noted that a follow-up time of 2 years is short in terms of recording progression, and that improvements may be possibly explained by repeated testing, even though different versions of the SDMT were applied.
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"The physical improvements seen in collectively 46% of the patients are likely explained by optimization of supportive measures by the trial personnel, e.g., referral for physical therapy and perhaps some degree of learning effects," the study authors wrote. "No patients initiated fampridine therapy during the trial. This treatment was tested and initiated in relevant subjects before screening, and all eligible patients remained on fampridine treatment throughout the trial. Reports of physical improvements in longitudinal studies in progressive MS are sparse."
Over the 96-week treatment, in terms of physical, cognitive, and MRI changes, patients were “remarkably stable,” but increases were observed in T2 lesion volume, as well as increases in mean diffusivity in normal-appearing white matter and putamen. The adverse events (AEs) observed in the OLE portion of the trial were similar to that experienced in the DB period, except for a decrease in flu-like symptoms and fewer reports of flushing. Serious AEs, which were rare in the study, were similar in both phases, with 1 case of basal cell carcinoma in the OLE.
During the DB period, 2 patients in the dimethyl fumarate-treated group each developed 1 new lesion. For the placebo group, 1 patient developed 3 new lesions, and 2 developed 1 new lesion each. In the OLE, 1 patient had 2 new lesions, and 2 patients had 1 new lesion each in the group originally randomized to placebo. In terms of those who continued treatment with dimethyl fumarate into the OLE, 1 patient showed 2 new lesions during this time.