BERLIN – Neurofilament light chain (Nf-L) levels are higher in the plasma of patients with secondary progressive multiple sclerosis (SPMS) than primary progressive multiple sclerosis (PPMS) irrespective of age, according to an analysis of blood samples from two large phase 3 trials.
“Our data suggest that Nf-L should be considered as an informative endpoint for phase 2 studies in SPMS,” said the presenting study author Ludwig Kappos, MD, at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Much of the research on using Nf-L as a biomarker in MS to date has looked at patients with relapsing-remitting MS and the researchers wanted to see if Nf-L might be a useful biomarker in progressive MS because drug development in this area needs long-term and large trials to show an effect of a drug on disability. Conventional magnetic resonance imaging measures show only a modest association with disease evolution in SPMS and PPMS, and, as Nf-L is specific to neuronal damage, it should reflect damage to the brain and spinal cord, Dr. Kappos explained.
The aim of thewas to compare Nf-L levels in the two progressive subtypes of MS – SPMS and PPMS – and to see if it had any predictive value in determining the degree of brain atrophy or disability. Other objectives were to measure the sensitivity for Nf-L to detect treatment effects, and to estimate how big a sample size would be needed in a phase 2 study if it was used as a primary endpoint.
Blood samples from 1,830 patients who had participated in one of two phase 3 studies of siponimod in SPMS () and fingolimod (Gilyena) in PPMS ( ). Nf-L levels were measured retrospectively in plasma using the SIMOA Nf-L immunoassay and categorized as being low (less than 30 pg/mL), medium (30-60 pg/mL), or high (greater than 60 pg/mL). Brain volume change on MRI was calculated using the (Structural Image Evaluation, using Normalization, of Atrophy) method, and disability changes assessed were evaluated by the Expanded Disability Status Scale (EDSS) score
“One of the confounders of measuring Nf-L is age,” Dr. Kappos acknowledged, “but we see a difference between SPMS and PPMS that is robust along the spectrum of ages.” The geometric mean of Nf-L at baseline was 32.1 pg/mL in patients with SPMS (n = 1,452) and 22.0 pg/mL in those with PPMS (n = 378).
Multiple regression analysis showed that, in both SPMS and PPMS patients, higher Nf-L levels were associated with older age and higher disease activity (increased EDSS score, more gadolinium-enhancing (Gd+) lesions and higher T2 lesion load).
Greater brain loss was seen at both 12 and 24 months in patients with high versus low Nf-L levels at baseline in both the SPMS and PPMS groups. For example, comparing high versus low Nf-L in SPMS, the mean brain volume change from baseline was –0.8% vs. –0.2% (P less than .0001) at 12 months and –1.5% vs. –0.5% at 24 months (P less than .0001). Corresponding values for PPMS were –0.8% vs. –0.4% (P = .0044) and –1.9% vs. –0.8% (P less than .0001).
Nf-L levels of 30 pg/mL were associated with a 32% increased risk of disability progression in patients with SPMS (P = .0055) and a 49% increased risk of disability progression in patients with PPMS (P = .0268).
In both groups of progressive MS patients, Nf-L levels were reduced in response to treatment at both 12 and 24 months, which remained significant.
“So, what about sample size calculation for a 1-year, phase 2 study with Nf-L as a primary endpoint?” Dr. Kappos queried. Assuming a reduction in Nf-L of 20% with a test drug, such a study would be likely to need to include 188 patients, or 94 patients per single arm to have 80% statistical power. To see a 30% reduction in Nf-L, fewer total and single-arm numbers would be needed, at 74 and 37 participants, respectively.
The study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Kappos disclosed that his institution (University Hospital Basel) had received steering committee, advisory board, and consultancy fees in the last 3 years that had been used exclusively for research support at the department from Novartis and a number of other pharmaceutical manufacturers. The Research of the MS Centre in Basel has been supported by grants from Bayer, Biogen, Novartis, the Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations.
SOURCE: Kuhle J et al. ECTRIMS 2018..