The Role of Serum Biomarkers in the Management of MS

Jason Freeman, MD, MBA: Welcome to CMSC 2023. I'm your host, Dr Jason Freeman, Medical Director with Novartis Medical Affairs, providing you with updates from CMSC 2023. The information herein is provided for disease educational purposes only and is not intended to be nor does it imply medical or diagnostic advice.

Jason Freeman, MD, MBA: Joining me is Dr Gina Cox, Senior Medical Director with Novartis Pharmaceuticals. Today we will discuss key takeaways from the presentation by Dr Freedman on serum biomarkers. Dr Cox, welcome to the program.

Gina Cox: Thanks, Dr Freeman. It's great to join you.

Jason Freeman, MD, MBA: So, let's get started with a couple questions. The first being what do we know about serum neurofilament, and its use as a possible biomarker in MS?

Gina Mavrikis Cox, PhD: Sure, so serum neurofilament is certainly been a growing area of interest in the MS space for some time. And we've accumulated a lot of literature demonstrating that serum NfL may be a good readout of activity and damage within the CNS. And so, based on our understanding of NfL, and its ability, again to be measured within the blood compartment, for what's happening within the CNS, it’s really picked up a lot of interest. And as well, I think we've begun to have many conversations about how this marker may be utilized in clinical practice.

Jason Freeman, MD, MBA: Please note that the correlation between NfL and MS is still currently being studied. The FDA does not consider serum neurofilament a validated biomarker. So, no conclusion should be made regarding outcomes in MS based on the analogies or hypotheses discussed by the medical experts therein.

Jason Freeman, MD, MBA: And so, shifting a little bit, just how might it be use[d] clinically? What sort of information is being provided by CMSC and others about how to sort of roll this out in clinical practice?

Gina Mavrikis Cox, PhD: Sure. Well, I think as we've attended many of the congresses over the years, we've looked at a host of data that's been presented around NfL. But as I mentioned, more recently, the conversation, and including that at CMSC this year, has really shifted and began to look at ways to use NfL, as I mentioned. And so, some of the ways we're thinking about NfL are not only to measure current disease activity, because certainly, as I mentioned, it's a damage marker, and one that reads out on activity. But there is an evolving data around the use of NfL to predict future disease activity, as well. There's really a host of data telling us that there may be predictive value of NfL. That is, that we may be able to measure increases in NfL before we see disease activity. And this has been looked at in a number of ways where NfL spikes have preceded both relapse activity, as well as future and looks at more advanced and progressive specs of disease measurement.

Jason Freeman, MD, MBA: Great. So, I know that there are lots of different things that affectNfL. And obviously, there are a few different tests out there in the marketplace. But is there clearly a reference range or levels of NfL at which a clinical decision has to be made? And was this in particular discussed in the session hosted by Dr Freedman?

Gina Mavrikis Cox, PhD: Over the years, there have been a number of studies looking at the values of NfL, so the pure, the absolute values. And while we can identify and conduct analyses, looking at patients that are either elevated or normal, based on sort of these cutoffs that have been established within populations, as we move to progress this to use on an individual level, the conversation is still really evolving in terms of whether a single cutoff could be utilized within a particular population. We know age is certainly one of the biggest factors that drives NfL levels up over time. And so, are we able to use a single cutoff? The field is having a lot of discussions on whether a Z-score perhaps, what factors, as you mentioned, so BMI, age, how these factors may influence NfL and how we may need to take account for these, as we utilize this in the clinical setting. I think another piece, as well, that was mentioned was the value of looking at NfL in a longitudinal manner. So, the importance of understanding of baseline value for an individual patient, and really looking at how this changes over time. And these changes may actually be a secure indicator of that individual patient and what's happening. And so, there was a lot of discussion as well around the importance of baselining. And also the correlations between percent change over time in NfL and correlations with disease activity.

Jason Freeman, MD, MBA: So, so the answer clearly is no, there's no reference range yet, but it may be coming?

Gina Mavrikis Cox, PhD: Yes. So, from a reference perspective, I think we have a growing set of patient data that we can utilize to really evaluate the best manner to look at this over time. But again, based on some of the conversations happening now, just emphasizing the importance of baseline, and then looking longitudinally in patients and how informative that may be really in highlighting the underlying activity in that patient.

Jason Freeman, MD, MBA: And so, just to try and summarize that, I think, for maybe our neurologists who are not MS specialists, there's ongoing collection of data around NfL, the possibility of developing reference ranges, although you said, we may need to get more into statistics and Z-scores to do that, but it's coming over. And I think more importantly, longitudinally, looking at time point A, B, and C and change therein seems rather important rather than just a single time point.

Gina Mavrikis Cox, PhD: Exactly. There are a number of assays that some neurologists are accessing today, certainly in the clinical trial space. NfL has been measured for some time.And we hear a lot more about this being implemented within clinical practice. So I think we'll hear more as the experience grows around NfL, and we begin to get a real good handle on, again, sort of how we can individualize care with NfL and utilizing that sort of holistically as a biomarker both to look at disease activity currently, as well as, I think, the novel aspect here is really what NfL can tell us about the future, which we talk about the tip of the iceberg with disease activity. I should add that there are a number of other biomarkers that are being looked at and advanced in the MS space. So, looking at the differential benefit of looking at those biomarkers, perhaps, alongside of NfL as well, too. So, the biomarker space is really growing at this time.

Jason Freeman, MD, MBA: You started to get into it, but are there specifics that you can share with us? That we in the clinical community need to be on the watch out for? I know I hear a lot about GFAP or but are there others or panels or what else is sort of coming down the pike?

Gina Mavrikis Cox, PhD: So, there are some multimodal approaches that are being explored, looking at groups of biomarkers more holistically, as a way to sort of gauge again, change over time, and how patients are doing. The GFAP, as you mentioned, is another one that gets a lot of attention. Some of the data presented at CMSC, and I think, if you think sort of about some of the data that's also been presented previously, GFAP is really looking, I think, more deeply at -and a little bit better at- predicting progression. And so, there's a lot of conversation, could NfL be combined with GFAP? What would those things tell us together versus separately, as well? And then I think from a biomarker perspective, we're talking about serum biomarkers here. But certainly, there are a number of non-conventional MRI as well as MRI modalities that can be combined. So, NfL is really looking like it's going to be another tool, I would say, to work alongside of these other biomarker assessments that are being conducted today to give us additional clues on what's happening at the individual patient level.

Jason Freeman, MD, MBA: And last question: anything that we can sort of reference, as we are out there in clinical practice and trying to figure out, when and how and sort of where to implement these tools?

Gina Mavrikis Cox, PhD: The CMSC does have a consensus panel that was put together several years ago, and there is an NfL consensus statement that was put out. This consensus statement largely summarizes a lot of the literature that exists, as well as talking about the clinical utility that's been identified for NfL. There is further work being done to really, I would say, hone the guidelines and make them more clinically applicable, which really to get from this place of literature to clinical application, I think, the community is certainly asking for more specificity in terms of how to integrate this into clinical practice. So, we do look forward to seeing more there.

Jason Freeman, MD, MBA: Well, Dr Cox, thank you so much for your time today. We appreciate you being here and sharing your knowledge about this particular presentation.

Gina Mavrikis Cox, PhD: Thanks Dr Freeman again, pleasure to be here today.

Jason Freeman, MD, MBA: Thank you for watching CMSC 2023 updates with Novartis US Medical Affairs.

Transcript Edited for Clarity