PARIS — A blood test for monitoring the treatment effect of drugs in multiple sclerosis (MS) is making good progress, with latest data showing that it correlates with MS lesions, number of relapses, brain volume loss, and disability progression.
The test involves measuring blood levels of neuronal structural proteins known as neurofilament light chains (NfLs). It has previously been suggested that blood levels of these NfLs may be a promising biomarker of neuroaxonal loss in MS, and the latest study suggests that blood NfL levels correlate well with markers of disease progression.
“Our study has the novelty of comparing patients treated with placebo to patients treated with an active drug in a randomized context, showing that NfL in the blood is able to detect a treatment effect,” lead author, Maria Pia Sormani, PhD, University of Genoa, Italy, commented to Medscape Medical News.
“This is very important to validate NfL as a measure sensitive to monitor the efficacy of drugs in MS,” she added. “Our results show that NfL can be used as an endpoint to assess treatment effects on both inflammatory and degenerative aspects of MS in clinical trials.”
The study was presented at the recent 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017.
Dr Sormani and colleagues analyzed blood samples from the FREEDOMS study with fingolimod in relapsing-remitting MS to assess how NfL levels correlated with other measures of disease progression, including T2 lesion formation, relapse activity, brain volume loss, and disability progression.
They found that fingolimod significantly reduced blood NfL levels compared with placebo at 6 months and that 6-month NfL levels were correlated to standard measures of disease activity and severity after 2 years.
In addition, blood NfL levels at 6 months captured a similar effect of fingolimod treatment on the number of relapses at 2 years as T2 lesions on MRI and correlated better with the effect of fingolimod treatment on brain volume loss at 2 years.
Commenting on these results in a round-up of clinical highlights of the ECTRIMS/ACTRIMS meeting, Robert Fox, MD, Cleveland Clinic Foundation, Ohio, said the study represented “very encouraging news on NfL as a predictor of treatment responses. It appears to be a better predictor of what patients will do and the treatment response than typically used brain MRI.”
Jeffrey Cohen, MD, also from the Cleveland Clinic, told Medscape Medical News that NfL was a very interesting biomarker of MS disease activity that can be measured in blood.
“There is now a very consistent body of evidence showing that it reflects CNS [central nervous system] damage and predicts disability,” he said. “This new study shows it reflects beneficial treatment effects of medication, and it is now starting to be used as a measure of drug effect in new clinical trials. I believe it will eventually also be used in the clinic to track disease activity.”
Dr Cohen explained that having an easy to measure blood marker of disease activity such as NfL would help personalize treatment approaches.
“Right now we have a ‘one size fits all’ approach to treatment, but the goal is to tailor therapy so those patients with the most aggressive disease receive the most efficacious therapies early on,” he said. “To do this, we need to regularly monitor disease activity, and having a blood test that reflects disease progression will enable this to be done much more easily.”
Dr Sormani said the routine use of NfL to monitor patients in clinical practice needs further research. “Standardization of the technique is a first requirement, to have reference values that can be interpreted by everyone.”
She added: “I think it will be very useful in complementing MRI, but I don’t think it will replace MRI, which gives a morphological and functional picture of the brain. Initially NfL will be used as a quick and easy screening tool to assess the activity of new drugs.”
She noted that a great advantage of NfL is that it can be assessed retrospectively. “We have a large amount of clinical trial data that can be reanalyzed if blood samples have been properly stored. I hope pharma companies will do their best to reassess these precious data, from which we can get very relevant information about NfL levels and its relationship with other clinical variables.”
For the current study, the researchers analyzed data on all patients enrolled in the FREEDOMS study who provided consent for exploratory biomarker analysis and had an NfL assessment at month 6 (n = 258; placebo: 117; fingolimod 0.5 mg: 141).
Results showed that blood NfL levels at baseline were similar in the two groups; median levels were 26 pg/mL in the placebo group and 28 pg/mL in the fingolimod group. After 6 months’ treatment, levels were significantly lower in the fingolimod group; they remained at 26 pg/mL in the placebo group and fell to 18 pg/mL in treated patients (P < .001).
NfL at 6 months was correlated to measures of disease activity and severity at 24 months. These included the number of T2 lesions (r = 0.46; P < .001), the number of relapses (r = 0.25; P < .001), brain volume loss (r = −0.41; P < .001), and 6-month confirmed disability progression (hazard ratio, 1.7; P = .02).
The percentage treatment effect on month 24 relapses explained by the effect on NfL levels at 6 months was 30% — the same as that explained by the effect on number of T2 lesions at 6 months.
The percentage treatment effect on month 24 brain volume loss explained by the effect on NfL at 6 months was 58% compared with 39% for that explained by the number of T2 lesions at 6 months.
The number of patients needed for a 6-month phase 2 study (for a drug with efficacy similar to that of fingolimod vs placebo at 90% power) is in the range of 60 to 130 patients.
This study was supported by Novartis. Dr Sormani has received compensation for serving on Scientific Advisory Boards from TEVA, Genzyme, Novartis, Roche, and Vertex; funding for travel or speaker honoraria from Merck Serono, TEVA, Genzyme, Novartis, Biogen, and Roche; consultancy from Merck Serono, Biogen, TEVA, Genzyme, Roche, GeNeuro, Medday and Novartis; and Speakers´ Bureaus from Teva, Merck Serono, Biogen, Novartis, and Genzyme.
7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017. Abstract 277. Presented October 28, 2017.
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