Clinical Trials in progressive MS. Is it time to bin Neurofilament Light?

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Many year ago I was having a conversation with NDG and neurofilaments and she said neurofilament light was the wrong outcome. I didn’t really get it because, surely as a nerve dies it releases its contents (i.e. neurofilaments).

However, I now think that neurofilament light is like a global MRI scan. If you can find neurofilaments then there is a lesion somewhere in the CNS. You may not find it because you don’t scan everywhere.

Therefore it is a very useful outcome, and indeed I think the neuros use it in their clinical practise as it shows disease activity.

However natalizumab treatment told us that when relapsing disease is controlled effectively that CSF neurofilament light levels goes virtually to healthy levels. We found out the hard way as we were ahead of our time in the PROXIMUS trial.

However, the Ibudilast trial tells me a few things. (A) Neurofilament light is not a good major outcome for progressive MS trials. In this trial, nothing happens with regards to neurofilament light.

This also happened in the PROXIMUS trial.

Some people (opinion leaders) have tried to convince us that the level of neurofilament in the blood reflects the neurofilament in the brain. This is lapped up by places where lumbar punctures are a scary thought. However, this study rather shows that this idea is, I think, BS. Maybe NDG can get us more on the virutes of lumar punctures.

Although not shown in this study, another idea that is trashed by the Ibudilast trials is (B) Brain atrophy on MRI is a clear biomarker for progression. Ibudilast fails to affect brain volume. This happened in PROXIMUS too.

So either ibudilast is rubbish or perhaps the MRI outcome is. In PROXIMUS trial brain volume effects failed to show a different of treatment, but clinical outcomes didn’t. Is this a fluke? With a group size of 15, surely it needs to be repeated. Anyway, contrary to my initial thoughts ibudilast looks like an interesting prospect for progressive MS

Fox RJ, Raska P, Barro C, Karafa M, Konig V, Bermel RA, Chase M, Coffey CS, Goodman AD, Klawiter EC, Naismith RT, Kuhle J. Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis. Mult Scler. 2021 Feb 26:1352458520986956. 

Background: Sensitive and specific biomarkers for use in progressive multiple sclerosis (MS) have not been established. We investigate neurofilament light (NfL) as a treatment response biomarker in progressive MS.

Objective: To evaluate whether ibudilast 100 mg/day alters serum and cerebrospinal fluid (CSF) levels of NfL in progressive MS.

Methods: In a protocol-defined exploratory analysis from a 2-year, phase 2 clinical trial of ibudilast in progressive MS (NCT01982942), serum samples were collected from 239 subjects and a subset contributed CSF and assayed using single-molecule assay (SIMOA) immunoassay. A mixed model for repeated measurements yielded log(NfL) as the response variable.

Results: The geometric mean baseline serum NfL was 31.9 and 28.8 pg/mL in placebo and ibudilast groups, respectively. The geometric mean baseline CSF NfL was 1150.8 and 1290.3 pg/mL in placebo and ibudilast groups, respectively. Serum and CSF NfL correlations were r = 0.52 and r = 0.78 at weeks 48 and 96, respectively. Over 96 weeks, there was no between-group difference in NfL in either serum (p = 0.76) or CSF (p = 0.46). After controlling for factors that may affect NfL, no effect of ibudilast on NfL in either serum or CSF was observed.

Conclusion: Ibudilast treatment was not associated with a change in either serum or CSF NfL.

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  • Do you know what happens at individual NFl levels when data before and after treatment are compared? I have seen for ocrelizumab or other drugs that people on DMTs have always a slightly (but non significant) higher value with respect to healthy controls. I wonder if that difference is a real difference or if it is truly non significant…

    • If it is a higher value across different studies then it is likely to be statistically significant, the difference can be little so requiring a large number of participants to show a lower enough p-value. However this still depends on the timing of NfL tests as it would take patients different amount of time to becoming stable on different DMTs.

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