Contributions
Abstract: EP1600
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 25 Biomarkers
Background: Dimethyl fumarate (DMF) has been approved for the treatment of patients with relapsing forms of multiple sclerosis (MS). Investigation of DMF in secondary progressive MS (SPMS) is supported by its mechanism of action, which appears to be mediated, at least in part, through activation of the nuclear factor (erythroid derived 2)-related factor 2 (Nrf2). Nonclinical studies have shown DMF to have both cytoprotective and anti‑inflammatory effects. Studies in SPMS patients and pre-clinical models show that the active metabolite of DMF, monomethyl fumarate (MMF), penetrates the CNS; however, the effect of DMF on neuronal and glial CSF biomarkers is unknown.
Objectives: To explore the effect of DMF on neuronal and glial biomarkers in the CSF of SPMS patients.
Methods: Sixteen SPMS patients were treated with oral DMF 120 mg twice daily (BID) for 4 weeks, followed by oral DMF 240 mg BID for 24 weeks. CSF levels of neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1) were measured by the Single Molecule Array (SIMOA) assay at baseline, week 6 and week 28. CSF samples from four healthy controls were also analyzed.
Results: At baseline patients had a mean EDSS of 4.4, disease duration of 22.5 years, and no Gd+ lesions. Baseline CSF NfL levels (mean±SD) in SPMS patients were 572±296 pg/mL and in healthy subjects 303±193 pg/mL. Mean EDSS decreased to 3.4, reflecting clinical improvement in 9 of 13 patients; NfL remained stable over the course of DMF treatment to week 28 (569±316 pg/mL), except for one patient who had disease exacerbation at week 18 when NfL levels increased to 1950 pg/mL and then decreased to 823 pg/mL by week 28. Levels of tau, GFAP and UCH-L1 remained stable over the 28 weeks.
Conclusions: In this small group of SPMS patients, baseline CSF NfL was relatively low, consistent with absence of Gd+ lesions, remained stable during DMF treatment, and increased upon exacerbation in one patient. These data are consistent with the proposed value of NfL as a marker of MS disease activity and treatment monitoring.
Supported by: Biogen.
Disclosure:
Keith R. Edwards: Grant/Research support: Biogen, Eli Lilly, Genentech, Genzyme/Sanofi, Merz Pharmaceuticals, Novartis.
Jessica Suita: none.
Judy Button: none.
Bing Zhu: employee of and holds stock/stock options in Biogen.
Tatiana Plavina: employee of and holds stock/stock options in Biogen.
Jason P. Mendoza: employee of and holds stock/stock options in Biogen.
Natalia Penner: employee of and holds stock/stock options in Biogen.
Abstract: EP1600
Type: ePoster
Abstract Category: Pathology and pathogenesis of MS - 25 Biomarkers
Background: Dimethyl fumarate (DMF) has been approved for the treatment of patients with relapsing forms of multiple sclerosis (MS). Investigation of DMF in secondary progressive MS (SPMS) is supported by its mechanism of action, which appears to be mediated, at least in part, through activation of the nuclear factor (erythroid derived 2)-related factor 2 (Nrf2). Nonclinical studies have shown DMF to have both cytoprotective and anti‑inflammatory effects. Studies in SPMS patients and pre-clinical models show that the active metabolite of DMF, monomethyl fumarate (MMF), penetrates the CNS; however, the effect of DMF on neuronal and glial CSF biomarkers is unknown.
Objectives: To explore the effect of DMF on neuronal and glial biomarkers in the CSF of SPMS patients.
Methods: Sixteen SPMS patients were treated with oral DMF 120 mg twice daily (BID) for 4 weeks, followed by oral DMF 240 mg BID for 24 weeks. CSF levels of neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1) were measured by the Single Molecule Array (SIMOA) assay at baseline, week 6 and week 28. CSF samples from four healthy controls were also analyzed.
Results: At baseline patients had a mean EDSS of 4.4, disease duration of 22.5 years, and no Gd+ lesions. Baseline CSF NfL levels (mean±SD) in SPMS patients were 572±296 pg/mL and in healthy subjects 303±193 pg/mL. Mean EDSS decreased to 3.4, reflecting clinical improvement in 9 of 13 patients; NfL remained stable over the course of DMF treatment to week 28 (569±316 pg/mL), except for one patient who had disease exacerbation at week 18 when NfL levels increased to 1950 pg/mL and then decreased to 823 pg/mL by week 28. Levels of tau, GFAP and UCH-L1 remained stable over the 28 weeks.
Conclusions: In this small group of SPMS patients, baseline CSF NfL was relatively low, consistent with absence of Gd+ lesions, remained stable during DMF treatment, and increased upon exacerbation in one patient. These data are consistent with the proposed value of NfL as a marker of MS disease activity and treatment monitoring.
Supported by: Biogen.
Disclosure:
Keith R. Edwards: Grant/Research support: Biogen, Eli Lilly, Genentech, Genzyme/Sanofi, Merz Pharmaceuticals, Novartis.
Jessica Suita: none.
Judy Button: none.
Bing Zhu: employee of and holds stock/stock options in Biogen.
Tatiana Plavina: employee of and holds stock/stock options in Biogen.
Jason P. Mendoza: employee of and holds stock/stock options in Biogen.
Natalia Penner: employee of and holds stock/stock options in Biogen.