Late-breaking study results reported at ECTRIMS 2013 indicate that neurofilament levels may be reliable biomarkers of nerve damage and disease progression in patients with relapsing multiple sclerosis.
Copenhagen, Denmark — October 5, 2013 – Late breaking results were reported here today that point to neurofilament levels as reliable biomarkers of nerve damage and disease progression in patients with relapsing multiple sclerosis (MS). Neurofilament levels, as measured by the presence of neurofilament light chains, were also found to reflect fingolimod activity in these patients.
Jens Kuhle, MD, Barts and London School of Medicine presented results October 5 during the “Late Breaking News” session of the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the 18th Annual Conference of Rehabilitation in MS.
According to Kuhle, the effect of immunomodulatory treatments on neuroaxonal damage and degeneration has been difficult to assess due to the lack of reliable, quantitative biomarkers. Neurofilaments are highly specific major structural proteins of neurons. “Neurofilaments are promising biomarkers in multiple sclerosis and increased levels in cerebrospinal fluid (CSF) indicate axonal damage or degeneration,” said Kuhle. In this study, the light chains of neurofilaments were measured before and after treatment with fingolimod to determine an association between their levels and drug efficacy. Fingolimod is an oral sphingosine1-phosphate receptor modulator that has been approved as a treatment for relapsing MS; the phase 3 FREEDOMS study demonstrated that fingolimod significantly improved relapse rates compared with either placebo or intramuscular interferon beta in patients with relapsing MS. Preclinical findings and effects on brain volume loss suggest that fingolimod may also have neuroprotective properties within the CNS.
This study looked at 36 patients participating in the FREEDOMS study; in this cohort, nine patients received fingolimod 0.5 mg, 15 patients were given fingolimod 1.25 mg, and 12 received placebo. CSF samples were drawn at baseline and at 12 months following the start of the study. Neurofilament levels were determined by commercially available ELISA (UmanDiagnostics NF-light® assay) in blinded fashion. Clinical and magnetic resonance imaging (MRI) were also done.
Neurofilament levels at baseline did not differ substantially between patients receiving fingolimod 0.5 mg or 1.25 mg or placebo; median neurofilament levels for the three groups were 644 pg/ml, 617 pg/ml, and 886 pg/ml, respectively (P=0.677). After 12 months of treatment, patients treated with fingolimod at either dose showed much lower neurofilament levels compared to baseline and to placebo patients; fingolimod patients had median 321 pg/ml compared to 738 pg/ml in placebo patients (P=0.011). Both doses of fingolimod were associated with a reduction, but neurofilament levels were lower in patients receiving a higher dose; patients at the 0.5 mg dose had levels of 644 pg/ml and patients receiving 1.25 mg had levels of 401 pg/ml. The median change from baseline in neurofilament levels for the respective fingolimod groups was -346 pg/ml (P=0.027) and -326 pg/ml (P<0.001) When both doses were combined, the median change from baseline in neurofilament levels was -339 pg/ml (P<0.001).
Patients receiving placebo experienced a smaller, statistically non-significant change in neurofilament levels of -214 pg/ml (P=0.470). An association was also determined between baseline neurofilament levels across treatment groups and the number and volume of T1 godolin-enhancing lesions (r=0.518 and 0.427 respectively), and T2 volume (r=0.448) at baseline.
After 12 months of fingolimod treatment, neurofilament levels were decreased compared to placebo (P=0.015). Kuhle noted that this represented a 50% reduction of CSF neurofilament levels with fingolimod treatment (P=0.001), compared a 17% reduction in patients treated with placebo (P=0.470). Neurofilament levels appear to correlate with baseline measures of disease activity, including the number of lesions.
“We have previously been able to show that neurofilament heavy chain levels in CSF correlate with relapses and disability in multiple sclerosis — these data strengthen and support the evaluation of neurofilament levels, which provide a useful surrogate for measuring the rate of neurodegeneration in MS,“ said Kuhle.
Responding to a question from the audience, Kuhle said that work on this project was done analyzing both heavy and light chains. He said that “Both have differential relevance, but in this study we used only light chains because serum measurement was more successful.”
No external support was reported for this study.