Alemtuzumab was tested in progressive MS and peple got worse and in relapsing MS people got better .
This supported the view of a two stage disease process whereby relapsing MS was driven by the immune sysytem entering te CNS and progressive MS was driven by something else, that was not responsive to drugs that treated relapsing MS.
So there was no hope for these drugs in, or options for, progressive MS. There was only one problem with this idea and that is…….yep you guessed it.
The idea was a load of old jajce (clue translate this from Slovene and work it through .:-)
Sadly, it allowed neuros to do nothing, safe in the knowledge they were doing no harm. This gave rise to questions asking if the “real MS” would stand up etc. However, we did not pay enough attention to the biology. ProfG tried to explain it in this paper.
Giovannoni G, Cutter G, Sormani MP, Belachew S, Hyde R, Koendgen H, Knappertz V, Tomic D, Leppert D, Herndon R, Wheeler-Kingshott CAM, Ciccarelli O, Selwood D, di Cantogno EV, Ben-Amor AF, Matthews P, Carassiti D, Baker D, Schmierer K. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 ;12:70-78. doi: 10.1016/j.msard.2017.01.007.
This paper, which is abit of a stoggy read, but suggested two main things and that is the longer nerves (i.e. those going to the legs, will accumulate damage more quickly than the shorter nerves and therefore if we focus on head and hand functions rather focussing on lower limb function as the outcome in trials, we may be more likely to find something that works. This is because the “nerve reserve to tolerate damage” is more intact in the upper limbs. Secondly it takes time for the smouldering lesions, which may be created by the inflammatory attack. to go-out and therefore it takes time to see benefit.
As I have said over and over again, trial design is key to finding change and if the trial design is wrong you throw a potentially useful drug away. Sadly other people have said “you only get one chance” and that means if a trial fails, and some times this is possibly because of trial design, it is seen as a failure by the neuros. You don’t expose people to a percieved failure twice. This is very frustrating as a scientist becauuse you can see years of your life being thrown away.
For example every thing about tetrahydrocannabinol (the active ingredient of cannabis) and the cannabinoid system says that it should be neuroprotective and save nerves. We had showed this in cell culture assays, we had shown it works in animals in multiple systems, we had shown that if you stimulate the cannabinoid receptor with chemicals or using genetic engineering it gets better, we had shown if you block the receptor it gets worse and ever other scientist showed it should save nerves. We had planned a study, where we would load the trial with the subgroup of pwMS more likely to progress. However, other people did the trial before we get our act together and the trial fails and so years of study are flushed down the loo. This is because the approach is seen as a failure.
Sadly, the nuianse of the trial failure is lost and the view that it is a failure persists:-(
The tetrahydrocannabinol trial ended up by being loaded with people with more advanced disability. This is because these people kindly volunteered for the the study and the control group did not progress as predicted. We know that if you are in a trial, you do better even if you get the dummy drug (placebo), this is why it is important to have randomised, blinded trials. (In the top graph with alemtuzumab, who is to say that it didn’t have an effect and the deterioration may have been worse if there was an arm showing the effect of the dummy drug).
However, if the control does not get worse, how can you see an effect? Indeed, if you look in the groups that did progress, there was significant benefit and despite it not being a data hack, as the analysis was planned.
Pryce G, Riddall DR, Selwood DL, Giovannoni G, Baker D. Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids. J Neuroimmune Pharmacol. 2015 Jun;10(2):281-92
The trial is still seen as a failure and so when you try and put it back on the agenda, the idea gets binned and it is deemed better to try something new.
ASCENDING TO A NOSE-DIVE
Another example of a percieved glorious failure is the use of natalizumab and the ASCEND trial in secondary progressive MS. This trial failed. Therefore relapsing inhibiting drugs don’t work in progressive MS!
Biogen reports Top Line Results 2015 ……….”ASCEND Phase 3 Trial Did Not Meet Primary and Secondary Endpoints”
But these types of drugs are neuroprotective and we can see this by looking at neurofilament in the spinal fluid in people treated with natalizumab.
If you look on the left you can see there is more release of neurofilaments (nerve protein) than in healthy controls on the right (dark blue). This is the measure of disease-related nerve loss. Now if you give natalizumab and stop white cells getting into the brain and so you stop lesions forming, you stop getting the nerve loss as shown in the graph in the middle. This takes the new loss almost down to normal aging levels. This also exposes the level of nerve loss due to smouldering MS. We have heard this called the “real MS”.
So first I ask should people drop everything to study this “real MS” when we can do something about the lesional damage?…..I guess I would say yes now, but only because we can do someting about the inflammatory lesional damage. However, I hope you can see why I say if you go after the smouldering MS it needs to be in-addition to targeting the peripehral inflammatory response. Furthermore, you can see if you do not get this element under control the benefit you are seeking to achieve in controlling smouldering MS is within the experimental wobble (variation between people shown by the thin line above the graph. As you can see it is bigger in the graph on the left than than the therapeutic difference between the two graphs in the middle and the right ) .
So can neurofilament pick up progression that is not-dependent on disease activity and the most recent answer it seems is that if you look in the blood. The answer is No.
Gafson AR, Jiang X, Shen C, Kapoor R, Zetterberg H, Fox RJ, Belachew S. Serum Neurofilament Light and Multiple Sclerosis Progression Independent of Acute Inflammation. JAMA Netw Open. 2022;5(2):e2147588
Now one thing to note is that there is a lot less neurofilament in blood compared to the spinal fluid. So people suggest there is a perfect correlation between the levels in the blood verses the brain, but this is contentious. But this new study suggests it is not useful for monitoring progression, independent of disease activity due to lesion formation and relapses.
This suggests that looking for neurofilament light in biological fluids is abit like a brain scan. So just as you can measure fasting glucose to tell what is going on now (i.e. similar to the brain scan) to see if you have diabetes, if you look at HbA1c, which is derived from red blood cells which gives you a longer-term view (like neurofilament circulation). This is why we use neurofilament as evidence of disease activity to aid clinical descisions
However what is the ASCEND trial, it is a trial to see if blocking new lesions inhbited secondary progression. The primary endpoint of the trial in 2011 was “To investigate whether treatment with natalizumab slows the accumulation of disability not related to relapses in subjects with SPMS” but in 2013 it was changed to “Percentage of subjects experiencing confirmed progression of disability in one or more of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT)” (Check out History of Changes on Clinicaltrial.gov
The trial was reported
Kapoor R, Ho PR, Campbell N, Chang I, Deykin A, Forrestal F, Lucas N, Yu B, Arnold DL, Freedman MS, Goldman MD, Hartung HP, Havrdová EK, Jeffery D, Miller A, Sellebjerg F, Cadavid D, Mikol D, Steiner D; ASCEND investigators. Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol. 2018; 17(5):405-415.
It says “Had they selected hand function as the primary outcome the trial would have been positive and you would have had a treatment for progressive MS by now. So this is why I am so rabid about trial design.
However, what happened to nerve loss and neurofilaments? I was looking for this info the other day and did not find the new publication until today but remembered the ECTRIMS 2018 poster, that re-appeared again at the American Association of Neurology 2019
Natalizumab Reduces Serum Concentrations of Neurofilament Light Chain in Secondary Progressive Multiple Sclerosis Patients From the Phase 3 ASCEND Study (S12.008) Neurology, 2019; 92 (15 Supplement) S12.008
Kapoor R, Sellebjerg F, Hartung HP, Arnold DL, Freedman M et al. Natalizumab reduced serum levels of neurofilament light chain in secondary progressive multiple sclerosis patients from the phase 3 ASCEND study (P1740). Multiple Sclerosis Journal 2018; 24: (S2) 988
Background: Serum neurofilament light chain (sNfL) is a promising biomarker of disease activity and treatment response in relapsing-remitting multiple sclerosis (RRMS). However, data supporting the potential use of sNfL to measure disease progression or response to therapy in secondary progressive multiple sclerosis (SPMS) are comparatively scant.
Objectives: To report associations between sNfL and disease activity, disability progression, and response to natalizumab in SPMS patients enrolled in the ASCEND study.
Methods: sNfL levels were measured at baseline, week 48, and week 96 in 748 patients (randomized to natalizumab [n=379] or placebo [n= 365]) from the phase 3 ASCEND study of natalizumab in SPMS. sNfL levels were assessed using a Single Molecule Array (SIMOA) assay. Statistical analyses included Spearman correlation, mixed model for repeated measure, and ANCOVA.
Results: Baseline sNfL levels were significantly associated with baseline age (p< 0.05), number of Gd+ lesions (p< 0.0001), T2 lesion volume (p< 0.0001), Timed 25-Foot Walk time(T25FW, p< 0.0001), and 9-Hole Peg Test time (9HPT, p< 0.0001). Baseline sNfL levels were also associated with brain atrophy over 96 weeks (p< 0.0001). At week 96, sNfL levels were significantly higher in patients with progression compared to those without progression during the study, as defined using EDSS (p< 0.01), T25FW (p< 0.05), or 9HPT (p< 0.01 for both week 48 and week 96). Finally, sNfL levels at week 48 and week 96 were significantly lower in natalizumab-treated patients compared to those on placebo [ratio 0.84, 95% CI (0.79, 0.89), p< 0.001 and ratio 0.80, 95% CI (0.7, 0.85), p< 0.001, respectively]. Statistically significant differences in sNfL levels between natalizumab and placebo groups were observed in patients with and without enhancing lesions at baseline, relapses in the two years prior to the study enrollment, and inflammatory activity during the study.
Conclusions: Similar to previous observations in patients with RRMS, baseline sNfL levels of SPMS patients in the ASCEND study were associated with baseline disease activity measures and future brain atrophy rates. Natalizumab reduced sNfL levels compared to placebo in SPMS patients with and without acute inflammatory activity. Our findings suggest that sNfL might not only reflect inflammation driven neuro-axonal damage but also noninflammatory neurodegeneration in MS patients. Further studies are needed to corroborate our observations.
Serum Neurofilament Light and Multiple Sclerosis Progression Independent of Acute Inflammation.Gafson AR, Jiang X, Shen C, Kapoor R, Zetterberg H, Fox RJ, Belachew S.JAMA Netw Open. 2022 1;5(2):e2147588. doi: 10.1001/jamanetworkopen.2021.47588.
They say “using data from a large clinical trial of patients with secondary progressive MS (a phase 3, randomized, double-blind, placebo-controlled trial exploring the effect of natalizumab on disease progression in participants with Secondary Progressive Multiple Sclerosis [ASCEND in SPMS]; NCT01416181), we investigated whether sNfL could be used as a dynamic biomarker associated with progressive MS disease course. That is, we investigated whether longitudinal changes in sNfL concentration were associated with disability progression measures in the absence of relapses and magnetic resonance imaging (MRI) evidence of inflammatory activity.
Among 751 participants in the ASCEND population with serum neurofilament data, 214 individuals in the natalizumab group and 103 individuals in the placebo group had no inflammatory activity at baseline or throughout the study. There was no correlation at most time points for most assessments between changes in serum neurofilament concentration and current or future changes in EDSS, T25FW (25 foot timed walk), or 9HPT (9 hole peg test).
They say “Although the dynamics of serum neurofilament have been explored previously in populations with progressive MS, including the population from ASCEND, progression was not addressed independently of inflammatory activity, to our knowledge”. They say “These results are consistent with recent findings in relapsing-remitting MS in a large cohort of patients treated with natalizumab [Bridel et al.Neurology. 2021:97:e1898) in which sNfL similarly was not associated with progression independent of clinical or MRI signs of acute inflammatory disease activity”.
So neurofilament light is a marker of “active” disease.
I have to say we found this out the hard way in PROXIMUS trial where we were using neurofilament to look for the neuroprotective effect of oxcarbazepine on top of beta interferon with neurofilament in cerebrospinal fluid as the primary outcome measure.
COI: Multiple but not relevant
Disclaimer This report is the view of the author and has no relationship with any institution