Oh my.. I believe I have smoldering MS, altho when I talk to my doc about this I am looked at like I have 6 heads. Same if I mention EBV in correlation to MS.. But thats another story. My first question here is will this trial be available in the US or is this strictly for UK residents? I have worsening disability but cannot pin point actual relapses and the MRI's are showing worsening numbers of lesions as well as enlarging lesions. I am also 65 and have already been told I am well into SPMS, but they are keeping my offical record to say I am still RRMS. I assume this is for possibilities of certain DMT's that arent available to pwMS that are anything other than RRMS. Anyway, I would love to get more info on this trial and whether it will be open to US residents as well as UK (or whatever country). My doc is currently pushing Ocrevus less than a year coming off of Mayzent, which nearly killed me with the suppression of my immune system.I find this all very exciting!
Hi Karin, same here in the states. I believe I’m too elderly and secondary blood issues would preclude my using a DMT at this point. But it certainly sounds exciting, and if I had a resurgence of blood counts, I’d go for it! These cerebellar issues are nooo fun and not going anywhere. Good to see you again! 🌸
I also have other health issues and feel I have an additional underlying disease that has been dismissed and overlooked. I have many symptoms that do not fir with MS but are often blown off as MS related. I dont believe it but I cannot get anyone to look further. As to low blood counts.. While on the Mayzent, my white counts were so low that without knowledge of the DMT, one doctor wanted me tested for leukemia. I had so many infections, often opportunistic ones like abscessed teeth, infected hang nails to the constant flares of herpes outbreaks to at least monthly UTI's. It was horrible. It took over a year for my white counts to all come back to normal levels and they are even now sometimes iffy. I also have chronic anemia to deal with. UGH. These DMT's are brutal on us.. especially being older.. (65 now) when immune system is not the best anyway
I understand completely. I’d like to at least use an older drug, though not interferon, but I’m so weary of differing opinions on this anemia thing. It makes me hesitant to do anything. After 65 also in the states, if you mention anything “negative”, such as feeling blue, your PCP can’t seem to get it that it can be that way from MS, or being ill, or frightened from not knowing what’s happening! The medical complex is tiring!🌷
Prof - interested in this comment 'I suspect in these pwMS, their immune systems get rid of, or at least control, the cause of MS without needing an exogenous treatment' is this potential inhibited by starting on a DMT, which supresses the immune system and its ability to get rid of the offending cause?
Also, have you observed any miracles yet in your sizomus trial? i know the results are down the track but wondered whether the patients were reporting changes even though you wouldnt know which arm of the trial they were on
I was initially accepted onto the Sizomus trial last year and I was so excited to be part of it. Unfortunately the lumbar puncture came back as negative. I did have a positive lumbar puncture result at diagnosis and Wafa contacted my hospital who confirmed this but sadly I could not continue with the trial. I did not know if was possible for the bands to disappear. Would this result prevent me from applying for the smouldering ms trial? Thanks
I am a healthy 60 year old female who was diagnosed with ppms over 20 years ago. I have never heard of smouldering ms but now I have it explains so much. I have had no relapses but my symptoms have SLOWLY progressed. I am on no medication. & would love to volunteer for the SIZOMUS study. It sound very exciting
Hi Sarah, I am also. But it’s pretty exciting. I’m hoping something will emerge from these trials for a drug that may help those of us whom are older.🌷
BTKi's are an unknown entity. Their positioning will depend on the benefit-risk profile. In terms of their anti-EBV effects I see them being used sequentially as part of a induction-maintenance paradigm; for example, induction with anti-CD20 therapy for say 2 years followed by a long-term maintenance phase with a BTKi.
I hope I am not hijacking this tread, I don't understand, if latent form of EBV resides in B-cells and those cells are depleted with anti-CD20 drugs, problem would be solved or I am very stupid/naive?
Prof G is there any update on the trial you were planning with Laura Airas – Turku University Hospital (Finland) Exploring the role of A2A adenosine receptor in the pathogenesis of progressive MS.
Prof G - thanks for sharing and reminding us of this. The Kletzl et al paper you refer to states “risk reductions in 12-/24-week CDP was exposure-dependent”. Is 12/24 weeks enough and what sort of CDP do they mean? Also, should we be taking the Kletzl et al paper seriously as they are paid by Roche and some even own Roche stocks? My CD19 levels are still 0 at 10 months post Ocrelizumab infusion. I’m keen to halt/reduce any smouldering MS, so would having another Ocrevus infusion now have any benefit seeing as CD19 is currently 0?
CDP confirmed disability progression means worsening EDSS and confirmed at 12 and 24 weeks. The latter 24 week CDP is more robust and less likely to revert. The treatment effect of anti-CD20 therapies is poorly correlated with peripheral B-cell levels, which is why I don't use adaptive dosing; i.e. all my patients are dose 6-monthly. The latter may change when better data emerges.
I have to confess I've never heard of smouldering MS. I was only diagnosed in May 2022 and only started having symptoms about a year ago. I am on a DMT (Ocrevus) and I know that won't stop my current symptoms but these have got much worse very quickly. No new symptoms but old existing ones getting rapidly worse. I am not due to see my neurologist again until September 2024. Is this something the treatments you are trialling could help with?
Yes, this is what smouldering MS is; worsening despite being on an 'effective DMT' and being NEIDA (no evident inflammatory disease activity). Yes, this treatment is meant to target smouldering MS.
Oh my #2 - this article blew my socks off - I've had MS for over 30 years and have never heard of "smoldering MS" - like Karin asked below will this trial be available in Canada? My diagnosis is SPMS and my symptoms have worsened considerably in the last two years. My recent MRI (one year ago) showed no new lesions. My neurologist at the MS Clinic has not suggested any DMT so I'm just plugging along - thank you for sharing this - can I share it with my FB Group, MS stands for Mindset Shift?
It would be interesting if we could get to try a combination approach between an established DMT and a BTKi, especially as it's looking like BTK inhibitors may not be as potent as high efficacy DMTs.
The title of the post brought hope, quickly killed by ‘only in Finland’. Why are MSers always in no man’s land when it comes to treating the real MS (EBV / smouldering MS)? Smouldering MS has been known about for some time, yet trials of therapies are always at the planning stage eg Octopus, early phase trials, or later phase trials which won’t report for 2-3 years (and if effective will have to go through long lead times for licensing). When will MSers actually have a pill in their hand which addresses smouldering MS? 2030?
I think this shows that the effort to tackle smouldering MS is an International one. Unfortunately the wheels of science turn very slowly from a vantage point of 1, 2 or 3 years. But as soon as you take a longer term view say over decades you realise how much progress has been made.
“the wheels of science turn very slowly” - that old chestnut! I’m not convinced. Science wasn’t slow developing an atomic bomb, getting a man on the moon, developing effective treatments for AIDS and developing a range of Covid vaccines. Unfortunately, a therapy which shut down MS would mean an end to ECTRIMS, ACTRIMS, mega pharma profits and the hundreds of MS research teams around the world etc. The link between EBV and MS was first highlighted in the early 1980s, yet no researcher is willing to (or is prevented from) undertake a trial of an anti-viral or HAART. Until the mechanisms destroying nerve tissue are halted, the word progress should be used very carefully.
Hi Prof G, I’ve completed the survey. It didn’t ask for my name / details so I assume it’s just collecting general info & not looking for individuals to register for it? Is that right?
That is correct. If we collect personal details in these sorts of surveys we have to get ethics approval, etc. Online surveys that don't request personal details are not classed as medical research.
For EBV treatment in this post you mention BTKi and Ixazomib. Will you still be investigating all the therapeutics targeting EBV that you discussed in this earlier post?
Not me or my group specifically, but the wider MS community will attempt to do so. The BTKi and drugs such as glofitamab will be done by a pharmaceutical company. When it comes to CD19-targeted CAR T-cells we will hopefully do this as a partnership between academia and pharma.
Can you share when the results of your famciclovir trial will be public? What are your thoughts on the case studies showing multi-year NEDA in MS patients on antiretrovirals? This is supported by cell-assay studies showing effectiveness against EBV, especially TAF. Should this be investigated with a short-term biomarker trial like you are doing for famciclovir? If either showed effectiveness would it make sense to do a human trial that takes a few years, or would the other therapies like the BTKis reaching ph 4 starting in 2026 deal with EBV just as well as antivirals or antiretrovirals? These are intriguing because if effective, they could be had off-label, as an EBV mitigant while we wait for the truly effective therapies to get through the development pipeline.
Oh my.. I believe I have smoldering MS, altho when I talk to my doc about this I am looked at like I have 6 heads. Same if I mention EBV in correlation to MS.. But thats another story. My first question here is will this trial be available in the US or is this strictly for UK residents? I have worsening disability but cannot pin point actual relapses and the MRI's are showing worsening numbers of lesions as well as enlarging lesions. I am also 65 and have already been told I am well into SPMS, but they are keeping my offical record to say I am still RRMS. I assume this is for possibilities of certain DMT's that arent available to pwMS that are anything other than RRMS. Anyway, I would love to get more info on this trial and whether it will be open to US residents as well as UK (or whatever country). My doc is currently pushing Ocrevus less than a year coming off of Mayzent, which nearly killed me with the suppression of my immune system.I find this all very exciting!
Karin, I’m the same. I would be classed officially as SPMS but the DMTs are only for RRMS
Hi Karin, same here in the states. I believe I’m too elderly and secondary blood issues would preclude my using a DMT at this point. But it certainly sounds exciting, and if I had a resurgence of blood counts, I’d go for it! These cerebellar issues are nooo fun and not going anywhere. Good to see you again! 🌸
I also have other health issues and feel I have an additional underlying disease that has been dismissed and overlooked. I have many symptoms that do not fir with MS but are often blown off as MS related. I dont believe it but I cannot get anyone to look further. As to low blood counts.. While on the Mayzent, my white counts were so low that without knowledge of the DMT, one doctor wanted me tested for leukemia. I had so many infections, often opportunistic ones like abscessed teeth, infected hang nails to the constant flares of herpes outbreaks to at least monthly UTI's. It was horrible. It took over a year for my white counts to all come back to normal levels and they are even now sometimes iffy. I also have chronic anemia to deal with. UGH. These DMT's are brutal on us.. especially being older.. (65 now) when immune system is not the best anyway
I understand completely. I’d like to at least use an older drug, though not interferon, but I’m so weary of differing opinions on this anemia thing. It makes me hesitant to do anything. After 65 also in the states, if you mention anything “negative”, such as feeling blue, your PCP can’t seem to get it that it can be that way from MS, or being ill, or frightened from not knowing what’s happening! The medical complex is tiring!🌷
Prof - interested in this comment 'I suspect in these pwMS, their immune systems get rid of, or at least control, the cause of MS without needing an exogenous treatment' is this potential inhibited by starting on a DMT, which supresses the immune system and its ability to get rid of the offending cause?
Also, have you observed any miracles yet in your sizomus trial? i know the results are down the track but wondered whether the patients were reporting changes even though you wouldnt know which arm of the trial they were on
No miracles from Sizomus that I am aware of. What do you mean by miracle?
I was initially accepted onto the Sizomus trial last year and I was so excited to be part of it. Unfortunately the lumbar puncture came back as negative. I did have a positive lumbar puncture result at diagnosis and Wafa contacted my hospital who confirmed this but sadly I could not continue with the trial. I did not know if was possible for the bands to disappear. Would this result prevent me from applying for the smouldering ms trial? Thanks
I am a healthy 60 year old female who was diagnosed with ppms over 20 years ago. I have never heard of smouldering ms but now I have it explains so much. I have had no relapses but my symptoms have SLOWLY progressed. I am on no medication. & would love to volunteer for the SIZOMUS study. It sound very exciting
I am too old
Hi Sarah, I am also. But it’s pretty exciting. I’m hoping something will emerge from these trials for a drug that may help those of us whom are older.🌷
Do you see these BTK inhibitors being a replacement or an add on to existing MS DMT?
BTKi's are an unknown entity. Their positioning will depend on the benefit-risk profile. In terms of their anti-EBV effects I see them being used sequentially as part of a induction-maintenance paradigm; for example, induction with anti-CD20 therapy for say 2 years followed by a long-term maintenance phase with a BTKi.
Why anti-C20 over cladribine for induction?
Because they deplete memory B-cells, the cells in which resides in its latent form.
I hope I am not hijacking this tread, I don't understand, if latent form of EBV resides in B-cells and those cells are depleted with anti-CD20 drugs, problem would be solved or I am very stupid/naive?
I thought cladribine also depleted those?
Prof G is there any update on the trial you were planning with Laura Airas – Turku University Hospital (Finland) Exploring the role of A2A adenosine receptor in the pathogenesis of progressive MS.
I am told that Prof Airas and her team are hard at work to make this study a success. However, things take time.
Prof G - thanks for sharing and reminding us of this. The Kletzl et al paper you refer to states “risk reductions in 12-/24-week CDP was exposure-dependent”. Is 12/24 weeks enough and what sort of CDP do they mean? Also, should we be taking the Kletzl et al paper seriously as they are paid by Roche and some even own Roche stocks? My CD19 levels are still 0 at 10 months post Ocrelizumab infusion. I’m keen to halt/reduce any smouldering MS, so would having another Ocrevus infusion now have any benefit seeing as CD19 is currently 0?
CDP confirmed disability progression means worsening EDSS and confirmed at 12 and 24 weeks. The latter 24 week CDP is more robust and less likely to revert. The treatment effect of anti-CD20 therapies is poorly correlated with peripheral B-cell levels, which is why I don't use adaptive dosing; i.e. all my patients are dose 6-monthly. The latter may change when better data emerges.
I have to confess I've never heard of smouldering MS. I was only diagnosed in May 2022 and only started having symptoms about a year ago. I am on a DMT (Ocrevus) and I know that won't stop my current symptoms but these have got much worse very quickly. No new symptoms but old existing ones getting rapidly worse. I am not due to see my neurologist again until September 2024. Is this something the treatments you are trialling could help with?
Yes, this is what smouldering MS is; worsening despite being on an 'effective DMT' and being NEIDA (no evident inflammatory disease activity). Yes, this treatment is meant to target smouldering MS.
Oh my #2 - this article blew my socks off - I've had MS for over 30 years and have never heard of "smoldering MS" - like Karin asked below will this trial be available in Canada? My diagnosis is SPMS and my symptoms have worsened considerably in the last two years. My recent MRI (one year ago) showed no new lesions. My neurologist at the MS Clinic has not suggested any DMT so I'm just plugging along - thank you for sharing this - can I share it with my FB Group, MS stands for Mindset Shift?
Yes, please share with anyone you want. The principle behind MS-Selfie is self-management and self-actualisation.
I filled in the form; I would absolutely sign up for the trial if they do one in the UK.
It would be interesting if we could get to try a combination approach between an established DMT and a BTKi, especially as it's looking like BTK inhibitors may not be as potent as high efficacy DMTs.
Is this feasible? Is there interest in it?
We won't know how effective they are until the results come in. It is difficult to extrapolate phase 2 data to phase 3 data. We usually get surprised.
The title of the post brought hope, quickly killed by ‘only in Finland’. Why are MSers always in no man’s land when it comes to treating the real MS (EBV / smouldering MS)? Smouldering MS has been known about for some time, yet trials of therapies are always at the planning stage eg Octopus, early phase trials, or later phase trials which won’t report for 2-3 years (and if effective will have to go through long lead times for licensing). When will MSers actually have a pill in their hand which addresses smouldering MS? 2030?
I think this shows that the effort to tackle smouldering MS is an International one. Unfortunately the wheels of science turn very slowly from a vantage point of 1, 2 or 3 years. But as soon as you take a longer term view say over decades you realise how much progress has been made.
“the wheels of science turn very slowly” - that old chestnut! I’m not convinced. Science wasn’t slow developing an atomic bomb, getting a man on the moon, developing effective treatments for AIDS and developing a range of Covid vaccines. Unfortunately, a therapy which shut down MS would mean an end to ECTRIMS, ACTRIMS, mega pharma profits and the hundreds of MS research teams around the world etc. The link between EBV and MS was first highlighted in the early 1980s, yet no researcher is willing to (or is prevented from) undertake a trial of an anti-viral or HAART. Until the mechanisms destroying nerve tissue are halted, the word progress should be used very carefully.
What you said is basically the cold hard truth.
We cannot cure ms because it's a cashcow.
It needs to provide the milk for btki next and whatever else.
God forbid we just asked pharma to help us take 5 people and put them on antivirals to find out what happens.
I entirely give up, it's nothing but a money game.
I'm going to go on coimbra like i decided before.
Indeed ! I like your comments. Pls share your opinions more often if possible :-)
Please can you consider me for theAHSCT trial ?
The STAR-MS or AHSCT trial has very strict recruitment criteria. You would need to check if you are eligible using the following tool.
https://sites.google.com/sheffield.ac.uk/starms/the-starms-trial/am-i-eligible?authuser=0
Hi Prof G, I’ve completed the survey. It didn’t ask for my name / details so I assume it’s just collecting general info & not looking for individuals to register for it? Is that right?
That is correct. If we collect personal details in these sorts of surveys we have to get ethics approval, etc. Online surveys that don't request personal details are not classed as medical research.
For EBV treatment in this post you mention BTKi and Ixazomib. Will you still be investigating all the therapeutics targeting EBV that you discussed in this earlier post?
EBV immunotherapy for MS: glofitamab induction
https://gavingiovannoni.substack.com/p/ebv-immunotherapy-for-ms-glofitamab#details
Not me or my group specifically, but the wider MS community will attempt to do so. The BTKi and drugs such as glofitamab will be done by a pharmaceutical company. When it comes to CD19-targeted CAR T-cells we will hopefully do this as a partnership between academia and pharma.
Can you share when the results of your famciclovir trial will be public? What are your thoughts on the case studies showing multi-year NEDA in MS patients on antiretrovirals? This is supported by cell-assay studies showing effectiveness against EBV, especially TAF. Should this be investigated with a short-term biomarker trial like you are doing for famciclovir? If either showed effectiveness would it make sense to do a human trial that takes a few years, or would the other therapies like the BTKis reaching ph 4 starting in 2026 deal with EBV just as well as antivirals or antiretrovirals? These are intriguing because if effective, they could be had off-label, as an EBV mitigant while we wait for the truly effective therapies to get through the development pipeline.
The FamV trial is about to finish and then there is all the laboratory work to be done. Hopefully the results will be available by ECTRIMS.