Biomarker Report from the Phase II Lamotrigine Trial in Secondary Progressive MS – Neurofilament as a Surrogate of Disease Progression

Abstract

ObjectiveLamotrigine trial in SPMS was a randomised control trial to assess whether partial blockade of sodium channels has a neuroprotective effect. The current study was an additional study to investigate the value of neurofilament (NfH) and other biomarkers in predicting prognosis and/or response to treatment.MethodsSPMS patients who attended the NHNN or the Royal Free Hospital, UK, eligible for inclusion were invited to participate in the biomarker study. Primary outcome was whether lamotrigine would significantly reduce detectable serum NfH at 0-12, 12–24 and 0–24 months compared to placebo. Other serum/plasma and CSF biomarkers were also explored.ResultsTreatment effect by comparing absolute changes in NfH between the lamotrigine and placebo group showed no difference, however based on serum lamotrigine adherence there was significant decline in NfH (NfH 12–24 months p = 0.043, Nfh 0–24 months p = 0.023). Serum NfH correlated with disability: walking times, 9-HPT (non-dominant hand), PASAT, z-score, MSIS-29 (psychological) and EDSS and MRI cerebral atrophy and MTR. Other biomarkers explored in this study were not found to be significantly associated, aside from that of plasma osteopontin.ConclusionsThe relations between NfH and clinical scores of disability and MRI measures of atrophy and disease burden support NfH being a potential surrogate endpoint complementing MRI in neuroprotective trials and sample sizes for such trials are presented here. We did not observe a reduction in NfH levels between the Lamotrigine and placebo arms, however, the reduction in serum NfH levels based on lamotrigine adherence points to a possible neuroprotective effect of lamotrigine on axonal degeneration.

Serum neurofilament is associated with progression of brain atrophy and disability in early MS

“…A previous study in secondary progressive MS reported serum NfH levels to correlate with brain atrophy and clinical measures such as EDSS and MSFC. 4 Future studies will show if these discrepancies relate to differences in disease stage or analytical performance of bioassays with higher sensitivity like ECL or single molecule analysis technologies vs conventional ELISA. 8 Analyses of changes in brain volume require considerable follow-up and are affected by different factors not directly related to axonal loss such as fluid shifts, aging, remyelination, and astrogliosis.…”

“…Immunoassays for both NfL and NfH have been extensively published and have short-term and long-term prognostic value in various neurologic disorders. [2][3][4][5] The phase II riluzole trial in participants with early multiple sclerosis (MS) was a randomized, double-blind, placebo-controlled study assessing the putative neuroprotective effect of riluzole. The primary outcome of the trial, brain atrophy, was negative.…”

Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?

“…In addition, serum NF-H levels were shown to decrease during SPMS, when patients were treated with Na + channel blocker, lamotrigine (based on serum lamotrigine adherence) [67]. The serum levels of NF-H were shown to correlate with clinical disability, EDSS and MRI cerebral atrophy [67] which further supports the notion that serum NF-H levels can manifest during disease progression and more likely in chronic MS (Figure 1).…”

Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids

“…Sodium channel inhibitors can exhibit marked neuroprotective effects in induced-relapsing EAE through effects on nerves and microglia (Waxman 2002;Al-Izki et al 2014;Morsali et al 2013). Sodium channel blockers used to treat epilepsy may also have some neuroprotective potential in MS (Gnanapavan et al 2013). This is perhaps consistent with the mechanism of action of CBD, although clinically CBD does not appear to have the side-effect potential of some clinical sodium channel blockers, which limited drug compliance and the perceived success of clinical trials of this compound class in MS (Kapoor et al 2010;Gnanapavan et al 2013).…”