|under&over – ProfG’s #1 non-scientific highlight at #ECTRIMS2018|
|Raju Kapoor with ProfG’s #1 scientific highlight at #ECTRIMS2018|
The avalanche of neurofilament data, in particular, the serum neurofilament results from the natalizumab SPMS, or ASCEND, trial. This was presented by Dr Raj Kapoor as a late-breaking poster. In summary, it showed that peripheral blood neurofilament levels were responsive to natalizumab therapy regardless of whether or not SPMSers had baseline Gd-enhancing lesions (aka baseline activity).
Why is this so important?
Please remember that the population of SPMSers in the ASCEND trial were very advanced with more than 60% needing a walking stick or sticks, i.e. they were almost off their feet and had markedly reduced reserve in the neuronal system supplying their legs. This study was negative on lower limb function (EDSS and timed-25 foot walk), but positive on upper limb function (9-hole peg test) at 2-years becoming positive at 3 years in the extension study. These results are consistent with MS being a length-dependent central axonopathy. The good news is that these results are now backed-up with data from the hottest biomarker in town.
An interesting observation that has yet to be published from the ASCEND trial is the data showing that natalizumab-treated SPMSers are more likely to have a confirmed disability improvement compared to placebo-treated subjects in the 2-year period of blinded observation. Could the drop of peripheral blood NFL levels indicate not only a reversal of the neurodegenerative pathology but possibly be a marker of neuroregeneration? Pity we don’t have CSF from this trial it would be fascinating to look at regenerative biomarkers, i.e. is there any evidence of axonal sprouting and synaptogenesis on natalizumab?
What this new blood NFL analysis tells us that so-called non-relapsing advanced MS is inflammatory and this inflammation is modifiable by a highly effective MDT such as natalizumab. Please note that this was not seen in the data presented on the effect of siponimod on peripheral blood NFL levels at the AAN earlier this year.
I am now convinced that natalizumab is an effective treatment for SPMS. It also further validates serum NFL as a surrogate marker of neuroaxonal damage in MS. Is there now enough data for the regulators, i.e. the FDA and EMA, to evaluate NFL as a surrogate end-point for MS? I personally think so, which is why we have been using CSF NFL levels in clinical practice at Barts-MS for about 3-4 years to aid clinical decision making. We use CSF NFL as an inflammatory biomarker and include it in our treatment target for more advanced MSers.
Once the FDA and EMA accept NFL as a surrogate end-point in MS I would urge Biogen to go back to the regulators to discuss natalizumab getting a label for progressive forms of MS. If Biogen don’t think they have a chance of getting a label change via this route I would urge them to do ASCEND-2 or ASCEND-HAND, i.e. trial of natalizumab in advanced MS only this time extending recruitment into MSers in wheelchairs. Another option is to do the randomised withdrawal study that I proposed last year. The latter would have to be done in the UK, where we are being forced to stop DMTs in MSers who become wheelchair bound. The idea is to randomise people to placebo or natalizumab with the primary outcome being time to confirmed relapse or evident disease activity using MRI and serum NFL levels. Some of you may ask, what about PML? Yes, what about PML? This can potentially be derisked using the current tools including extended interval dosing (EID) in the trial. I have also made the point that JCV and PML are biological problems and they will be cracked with time. We need to keep up on the pressure on the scientific community to solve these problems.
I was asked by a colleague at ECTRIMS if I envisage NFL replacing MRI as an assessment of MS disease activity? Potentially, yes. The good thing about NFL monitoring is that it is an integrator of MS disease activity and will assess both brain and spinal cord activity. This is important because most of us don’t include spinal cord imaging in our monitoring protocols. NFL is also potentially cheaper and easier to standardise and as it is a lab-based immunoassay could really help in resource-poor environments with limited access to MRI. It will also be more convenient for patients; having a blood test is quicker and easier than coming in for an MRI scan. At the moment one company have the monopoly on peripheral blood NFL measurements and are charging an extortionist price for their assays, reagents and the maintenance of their platform. The other good news at ECTRIMS is that competition will be arriving soon in the NFL space. Hopefully from at least another two platforms, one of which who has a large footprint in routine laboratories. We need some good old competition to drive down prices.
In support of NFL replacing MRI monitoring was a poster from Tjalf Ziemssen’s group in Dresden showing that when you do monthly blood NFL levels, NFL levels were noted to rise prior to detecting MRI activity or clinical relapse. This is not surprising; I have data from my PhD on daily urinary neopterin levels, an inflammatory marker, showing the same thing. So yes, I envisage a world in the not so distant future when MSers will be having frequent blood neurofilament levels measured, hopefully, using home finger-prick technology to monitor their MS disease activity. Once we get to this stage then we will be able to apply true precision medicine to individual patients and we will be able to optimise treatments based on real-time biomarker measurements.
We have been working on NFL in MS for over 15 years and to see it transforming MS research and translating so fast into clinical practice makes the work we have done seem worthwhile.
13 thoughts on “Early reflections on ECTRIMS 2018”
"What this new blood NFL analysis tells us that so-called non-relapsing advanced MS is inflammatory and this inflammation is modifiable by a highly effective MDT such as natalizumab."No doubting this. It's just it seems subtle. Why can't it ever bethat someone goes down 1.5 EDSS points on Tysabri w/ SPMS.
Re: "Why can't it ever be that someone goes down 1.5 EDSS points on Tysabri w/ SPMS."Because they have lost too many nerve fibres and tend to older. You need reserve capacity and the biology of youth to make a significant recovery. However, as ageing is biological we may be able to reprogramme cells in the future from being old to becoming young again.
"So yes, I envisage a world in the not so distant future… "Takeaway from the 2018 ECTRIMS vintage: a lot of wishful thinking.
Wishful thinking maybe; but what started 18 years ago is now becoming a reality. If you don't imagine, or dream, of a better future for people with MS what is there to aim for?
"of a better future for people with MS what is there to aim for?"Hmmm..maybe any kind of therapy for ALS and ALZ.A non-immunotherapy for MS.
Thanks for banging the drum for natalizumab. Biogen must have a tough time with Roche taking the lead with ocrelizumab, only two decades after rituximab went to market. Taking pharma's inefficiency aside, I'd really like to see somebody nailing this disease with an anti-EBV treatment (or is this rituximab/ocrelizumab by any chance?).
No we should seek a non antibody antiviral. However it is not clear if this ultimately will be a good thing. I will make a post on a recent paper pointing the finger at EBV. However the question i have is where is the specificity coming from and what is it.
Did you notice the ocrelizumab brain atrophy data at ECTRIMS 2018? Not as good as alemtuzumab's nor natalizumab's. Why? There is more to treating MS that the B-cell.
"However the question i have is where is the specificity coming from and what is it."How specific is the knowledge of process by which EBV causescancers..?
"Did you notice the ocrelizumab brain atrophy data at ECTRIMS 2018? Not as good as alemtuzumab's nor natalizumab's. Why? There is more to treating MS that the B-cell. "ProfG or MD would you mind to post on that?
CSF from this trial would indeed be sweet.Doesn't the whole NFL line of thought take us in the direction of the elusive MS blood test?
Ocrevus apparently does less for brain atrophy than Natal. Just my luck after a recent switch; and my neuro says no going back to Natal.
Interesting blog! Thanks! I know of the one competitor you mentioned with serum NF-L detection. Who are the other two that came out at ECTRIMS?