Barts-MS rose-tinted-odometer N/A
Yesterday’s PMSA meeting was very interesting. It is clear the field of MS is at a cross-roads and that Pharma needs the wider MS community to help them change the game. If we don’t I suspect we won’t see the next generation of treatments being developed to target the ‘real MS’ or ‘smouldering disease’.
It was clear that combination therapies are needed, but how we make them happen is another story. Regulators need to understand that we need to go beyond inflammation and treat MS as one disease. I tried to convey this message in my presentation. What I am staying is the real MS is essentially primary progressive MS or smouldering MS. Our anti-inflammatory therapies convert relapsing forms of MS into primary progressive MS and we, therefore, need to combine these groups, i.e. those who are NEDA-2 and getting worse into one group for add-on trials.
My proposal to oncologise MS and create a trials platform was presented by both Jeremy Chataway and Ludwig Kappos. It is reassuring that these two giants of the MS world are supportive of the idea. I have therefore designed the skeleton of an O’ADD-ON and DADD platform for discussion. In reality, these platforms should have been set-up yesterday.
Doing registry-type trials is now the norm in most fields of oncology. I, therefore, see no reason why we can’t steal their ideas and apply them to MS. The question which fish will bite first; Roche or Biogen? There is nothing like a bit of competition and the fear of missing out (FOMO) to get people to act.
What do you think of these platforms? I am very interested to hear if you think this is feasible or not? An ocrelizumab and/or DMF platform will at least create the base for Roche and Biogen to develop their own add-on compounds but will allow them to partner with other Pharma companies, for example, Abbvie and elezanumab, and with academia. Although these platforms will be expensive I am sure the investment will pay massive dividends down the line for pwMS, society and industry.
CoI: multiple
P.S. In response to some of the comments below. The following infographic is a crude attempt to explain what I mean when I say that current DMTs convert RRMS into PPMS or smouldering MS. PwPPMS simply have a much longer asymptomatic and prodromal phase so that when they present with symptoms and get diagnosed they have lost more brain and spinal cord. In other words, pwPPMS have more advanced MS and have less reserve compared to people with early relapse-onset MS. The latter explains why the treatment response is less in both SPMS and PPMS.
Prof G,
“What I am staying is the real MS is essentially primary progressive MS or smouldering MS. Our anti-inflammatory therapies convert relapsing forms of MS into primary progressive MS”.
I thought I was unlucky to get MS, but my neuro told me that at least I was lucky to get RRMS rather than PPMS “which was the worst version of MS”. Now it looks like I was unlucky to get MS and unlucky to get PPMS!
But I’m in no mood to rant today. I was one of those who followed the advice of experts like you and went for the hit it hard and early approach (Alemtuzumab) – some 13 years ago. After my two infusions I have had no other treatment. How does add-on therapies help people like me who are not on a therapy? How would people like me get just the add-on given that my MRIs show no active disease?
I have added a post-script above to explain things. It is not all bad news.
A stake to the heart for anyone who has been injecting themselves with a DMT each day or popping a DMT pill. Looks like we have all been wasting our time!
Is your advice to stop taking our DMTs, as I prefer being RRMS than PPMS?
I’m guessing the proposed add on trials will take years to set up and it will be a decade before any results are known. I can’t wait that long so will be praying for that Black Swan to appear and also pinning my dwindling hope on the work of Prof Pender. Something is in the brain which can uses smouldering MS and the subsequent involvement of the immune system resulting in focal inflammation and relapses. For too long MS research has focused on the latter and now the chickens are coming home to roost. Until the actual cause of smouldering MS is addressed we are still pi$$ing in the wind.
Currently in a ocrelizumab trial (https://clinicaltrials.gov/ct2/show/NCT03972306) so I’m putting my money on Roche to step up to the innovation plate here.
I’m currently on ocrevus (having infusion as I type). Is this a different trial to find something else out?
As a trial manager – I’ve worked on a cohort study for about 5 years that has embedded RCTS. It works really well as a model. In silo/traditional trials, realistically, it is always the same sites that open and under this design you can keep the same staff in post and you don’t lose momentum between studies. It works both ways, and you can cherry pick the interventions that align with your local pathways (and your PIs biases), so there isn’t really a negative. The research output has been excellent and answered several previously unanswered questions, with benefits for patients and cost-savings for the NHS. The cohort has run it’s course and the new focus is getting funding for a platform study (apparently it’s in vogue). Hopefully NIHR funding, with some industry input. We are relying on NHS digital (easier as an IP speciality I suspect) and a HQIP audit that has a section 251, whilst repurposing much of the infrastructure (personnel, and database) from the cohort.
As a patient – One of the sad truths of MS research is that it creates a divide between those with the condition and researchers; MS is devastating to live with, but as a researcher, MS is a playground or at least a well-loved occupation. This trial should be well received by those with MS, as it’s takes attempts to respond to the frustrations patients have about research (1. Trials take too long, 2. Trials cost too much, 3. Patient benefits aren’t tangible, 4. They have narrow eligibility criteria so I can’t take part, 5. This trial isn’t relevant to an NHS setting, 6. The trial doesn’t ask the question I’m interested in). I think this more pragmatic design, feels like an attempt to work with us; rather than work around us whilst looking away. I would be delighted to take part; I am sure most would.
You asked if it was feasible – why wouldn’t it be?? You have an exceptionally engaged group of patients, huge academic resource, and access to industry funding. What I think would be useful:
1) I hope you are working closely with the MS registry; that is a lovely platform – very accessible and easy to operate for PROMS
2) Can this trial offer something to the NHS. Researchers are very blue sky thinking, but the shop-floor care is often poor (due to lack of resource, not talent). There has been the Variance project and GIRFT project, which showed huge problems in care. Could you embed some KPIS onto this platform and look at how inefficiencies in care impact outcomes – I suspect it would have a much greater treatment effect that some of the other interventions outlined on your slide. Perhaps the KPIs could be aligned with financial penalties which may get hospital management to provide greater resource to the care community. You mentioned the National Cancer Audit – would be great to get the national MS audit. The audit used for our trial has an aligned dataset with agreement for data sharing, which again prevents duplication and reduces need for resource.
Thanks for the comment. My ambition would for this to be international. The MS Society is starting a progressive MS platform. My worry is that the UK platform will be targeting pwMS when they are in the later stages of their disease, where it is much harder to show a treatment effect. The idea of this platform is to target the pathology that drives progressive or smouldering MS much earlier on and as an add-on strategy. The MS Society platform may or may not be add-on.
“The idea of this platform is to target the pathology that drives progressive or smouldering MS much earlier on and as an add-on strategy.”
As someone with around 2 decades of slow PPMS, smouldering MS, I’m sad to say I lose interest right there.
We have just had a programme grant to tackle smouldering MS rejected by the MS Society. The peer-reviewers didn’t like it and they were unhappy with our public engagement around the grant. Not sure if the MS Society (UK) would buy into these platforms. At least the clinical scientists at Roche and Biogen understand smouldering MS and are working on it themselves. In other words, there is no need to make the scientific case to Roche and Biogen only the financial case. However, we would need to convince the MS Society that smouldering MS exists, MS is one disease and that an add-on paradigm is the one to back. I am not sure the MS Society is on the same page as us.
What about the other MS Pharma companies? In particular Novartis?
Novartis is too secretive and they don’t really collaborate with these types of projects. Novatians are very conservative and there are too many layers of decision-makers within the company to do this kind of thing, i.e. too many chiefs. Novartians also like to come up with their own ideas. In addition, fingolimod is about to come off patent so the financial incentive or the incentive to create new IP in relation to a fixed combination with fingolimod is not there. Maybe they will be interested once ofatumumab is licensed and established. However, if Roche can come up with a winning ocrelizumab add-on combination then ofatumumab will be a non-starter.
I have now added a new platform called FADD to cover Novartis.
This type of platform would not really work for IRTs, i.e. alemtuzumab or cladribine. However, platforms to test sequencing options post-alemtuzumab or -cladribine could be supported. We did propose such a platform to Genzyme-Sanofi to deal with secondary autoimmunity, i.e. to test multiple agents in parallel to see if we could derisk alemtuzumab. The latter proposal dates back 5 years and nothing has happened, which is a tragedy because the results of the rituximab and teriflunomide arms of that proposal would have reported by now. Can you imagine how different life would be if we could prevent alemtuzumab-induced secondary autoimmunity?
How are you defining smouldering MS on the platform?
It depends on the mode of action of the drug and the therapeutic target. It could be SELs, cognition, brain volume loss, demyelination, intrathecal B cells and plasma cells. Please note the deep phenotyping will provide biomarkers of several pathogenic processes that we think are driving smouldering MS.
Can this platform be used to test symptomatic treatments?
Yes, the platform(s) will allow symptomatic treatments to be tested as well.
Why isn’t research focused on identifying the ROOT CAUSE of MS rather than trying to find Pharma cocktails for downstream fallout? Seems rather inefficient, ineffective, and expensive. You may as well be saying “I wonder what happens if you put ketchup AND mustard on those PWMS.” Let Pharma do Pharma. It’s incomprehensible that we don’t really know what MS is. Tax/charity funded researchers need to find the cause so we know if we are actually helping or hurting as we BUMBLE AROUND with these Pharma products.
We think we have found the root cause and working on it as well. But we still need to deal with MS once it has started.
Ooo. That’s exciting! What is the root cause then? What is MS?
I think you mean well but how realistic are your platforms in terms time to available treatment and cost to the MS patient/taxpayer?
Would you think if EBV causes MS then Dr. Pender’s primed CD8 T-cells against EBV controlled memory B-cells in the meninges of the CNS would be a better base for your treatment pyramid for all stages of MS followed by neuro-protection, remyelination and neuro-restoration if needed? Immunosuppressants only needed to treat relapses with clinical or Gd+ changes.
But all effective DMTs target memory B cells that are the cell that houses latent EBV. They may be immunosuppressive, but they are all potentially anti-viral. Please remember that not all immunosuppressive agents are effective in MS; it is a select few.
I do not understand this logic? Please explain if possible.
These primed CD8 T-cells against EBV laden B cells in follicles in the meninges of the CNS can easily cross the BBB and destroy these type of B-cells that have already accumulated.
Alemtuzumab, ocrezulimab cannot cross the BBB and will have little to no effect on these accumulated EBV controlled memory B-cells in the CNS.
Fingolimod, siponimod can cross the BBB but will have no effect on these B-cells as they only stop egress of B-cells from peripheral lymph nodes. As well, Tysabri cannot destroy the already built up EBV laden B-cells in the CNS and, like S1P modulators, can only stop new B-cells from migrating in.
This leaves DMF and cladribine which may have a possible effect on these EBV controlled B-cells as they are both CNS penetrant.
Hi there;
I’ve been following a study on elenazumab in which some patients are already on ocrevus.
It is happening in the States and some of the patients have a FB group where they share their improvements (or the lack of them).
Maybe it can show Roche that there is a market for their add on…
Why blood spots, saliva and urine?
Saliva – biomarkers in particular EBV shedding
Blood spots – biomarkers, in particular, neurofilament levels
Urine – biomarkers, in particular, inflammatory markers, e.g. neopterin
Why just ocrelizumab with an add on? Why not cladribine (i watched a video of you singing its praises before it was approvec) or alemtuzemab? Or are you just using ocrelizumab as an example? Thanks
We are proposing three DMTs; ocrelizumab, DMF and fingolimod. Common to these is that they are all maintenance treatments and suitable for combination therapy and creating new IP (intellectual property) for Pharma. The latter is the carrot. Cladribine and alemtuzumab are IRTs and not maintenance treatments hence their platforms will be sequencing platforms. Sequencing can be done, but breakthrough activity will need to be addressed, i.e. re-treatment or switching. There also needs to be the necessary numbers of patients to make the platforms feasible. At the moment the treatment landscape is being dominated by DMF, ocrelizumab and fingolimod. For some reason, the wider MS community don’t like IRTs and that includes HSCT.
Could you please elaborate further on the “sequencing” scenario after Cladribine?
I remember some slides of you suggesting the idea of using a BKT innibitor or Teri, bit I don’t know if that is what you mean by sequencing.
Thanks as always for your time!
Thank you for taking the time to the reply Prof G. I thought IRT was the best possible treatment? but now I’m second guessing my decision if they’re not suitable for add-on treatment. I’ll happily re take cladribine every 4 years (no reports on post 4 year so that’s why I say 4) if it keeps me stable, with no new activity. But I would like some add on that will stop any damage already done getting worse or the holy grail, reversing any damage.
IRT could be the best optionfor an add-on as the IRT may be gone quickly in the case of cladribine this is within 24h and so the body is only dealing with one drug and so there is no drug-drug interaction between the treatments
Thanks MD but of course pharma aren’t interested in doing that with IRT are they? 🤷♀️
It depends it they see the light and secondly it depends on who has a neuroprotective. Dealing with two companies is a problem
Not at the moment because they are making money out of DMT and they dont have the neuroptorectives, but once the DMT start to go out of patent and the price falls the neuroprotective becomes the commodity and importantly if clinicans get a backbone and do these studies and they are successful then it will happen.
Wouldn’t it be great if they all just worked together? Just imagine the possibilities…… the answers are out there, if they pooled all their info …well, as I said, just imagine
Good point
Prof G
are you not simply trying to say, that people convert to PPMS from RRMS in spite of taking DMTS.
by saying that DMTs convert you from RRMS to PPMS suggests it acts as catalyst to the process, which I believe is the opposite.
what they do is mask the visible signs (i.e. relapses (which also overtime reduces build up of reserve damage) but they do not stop the unseen damage in the background (i.e. what you call the shredder/ or now smouldering MS?).
If I have misunderstood this, apologies but I just think you should be aware that what you are writing appears to suggest that taking a DMT could increase the time to PPMS from RRMS and this taken out of context, with insufficient follow up, could lead someone to not take a DMT. Which I believe is why you are keen to ensure you have explained what you really meant and to prevent any misunderstanding.
correction* (shorten not increase)
what you are writing appears to suggest that taking a DMT could shorten the time to PPMS from RRMS and this taken out of context….
my overall point being, DMTs do not speed up the process to PPMS, right?
Could this be a genuine option for remylination? If so, why can’t all MS patients be put on this, it appears the earlier the better
https://multiplesclerosisnewstoday.com/news-posts/2019/10/11/diabetes-drug-metformin-promotes-myelin-repair-in-rats
I am trying to understand exactly what you mean by stating that the current DMT’s convert RMS into PPMS. Do you mean, that the DMT is an agent in the RMS turning to PPMS, or just that it doesn’t prevent the progressive stage in the end?
Also can you tell a little more about what you mean by MS being one disease instead og three?
RMMS converting to PPMS…means if you get rid of the relapses that it stopps being RRMS, however there is a view that underneath the relapses there is the smoulddering MS that is common in PPMS..remove the relapses and yu are left with the smouldering MS. The question is. Is the smoulderingMS conditioned by the active relapses or is it an entirely independent process. I think the former