I predict that cheap generic oral cladribine, fenebrutinib, prophylactic EBV vaccines and antiviral treatments for acute EBV-associated infectious mononucleosis will transform the MS landscape.
As a 25+ MS patient mainly affected by spinal cord lesions, now considered Secondary MS patient, due to walking difficulties after a huge c3 lesion that affected both my legs and slowly affecting my arms, I urge you to start puting NVG 291 into the picture because for some of us it appears to be the only regeneration therapy with strong science behind and efficacy on the horizon. I have done Mavenclad 4th year now with no new lesions, and I started valacyclovir. For me and many others, NVG 291 would be a life-changing option that we believe should be offered to us.
all these things are very exciting. Anything that could stop smouldering MS would be fantastic I do worry about whether my children will end up with MS so EBV vaccines/treatment would be great. Hopefully in years to come MS will be a disease that is consigned to the past.
This is some of the most encouraging analysis I’ve seen regarding DMTs.
Your treatment of oral cladribine and fenebrutinib, especially as regards their interaction with EBV, inspires a question: How close Is the MS world to scrapping the RRMS/PPMS/SPMS/uncertain-etiology paradigm?
The evidence seems to point to a different construct: 1) initially sub-clinical post-viral activity and immune response, 2) smouldering disease throughout, 3) CNS damage causing a mixture of breakthrough events and steady worsening, 4) loss of function mapped to CNS pathology.
This accords with my own experience as a late-onset (55, M) Dx RRMS who kept wondering when remission would show up. I too have acquired a bias; fair enough. Still, the more I learned, the more I became concerned that the phenotypes I didn’t fit into were devised primarily to whittle MS down into manageable targets for drug discovery, trials and funding.
Now I see you suggesting that a trial of a drug whose subjects are PPMS may have profound implications across the disease spectrum. It makes me wonder if phenotypes will soon be irrelevant for determining DMT eligibility and regarded as useful mainly for symptom management and helping the patient plan ahead.
Having mastered the use of a motorized wheelchair at the expense of assimilating principles of immunology, I don’t quite understand the case for a vaccine against a virus that nearly everyone acquires anyway. Surely the focus of prevention must be the well established genetic predispositions to initiation of MS disease activity, as well as further investigation of potential environmental factors.
As for treatment, I rarely miss an opportunity to beat the drum for rehabilitation. Rehab research must claim more attention in MS therapeutics. Rehab professions must have parity with medicine in MS clinical teams.
In the politics of MS, elevating the profile of rehab and smashing the tyranny of phenotypes in treatment and resource allocation seem to me to be the top priorities right now.
Whether or not I’m right, I’m sure that when the history of this period in MS is written, you and other human game changers will receive ample credit for the groundbreaking, influential work you’ve done.
As always, thanks for sharing your knowledge and wisdom!
Can you comment on how the Octupus trial is going. I’m not sure whether to take part or wait for the other med you refer to for SPMS. Smouldering. I’m sure that will be a couple of years. I’ve just been screened for octupus and my kidney function was just ok at 61. Cut off 60. This relates to the possibility of taking Metformin. A 1 in 3 chance of taking it. I’m in a slight dilemma now.
The Octopus trial is still in the recruitment phase, so it will be years before we get an answer. As with all trials, it involves some altruism in terms of getting randomised to the placebo arm. I always encourage my patients to participate in trials, as they help advance knowledge.
Yes. I’m happy to be in placebo too. I suppose if I end up on Metformin with unpleasant side effects I can stop. Or worsening kidney function. The tablets are like bullets so a little concerned over this. Sometimes it’s easy to over think everything.
I would be interested to know also. I took metformin also once a day for around 6 months and had my spinal leison disappear. I would love to know if others have seen the same or whether this was just a fluke and HSCT allowed time for the body to heal, although that’s not common with HSCT.
Regards spinal lesions. They’ve seen them on my scan then they’ve disappeared, then reappeared. I’m not being a party pooper however I was told lesions on the cord can be harder to see. 🤷♀️ or is this just someone who can’t read a scan? They were clear enough that I could see them. Correlated with my walking issues.
That’s something that Gavin can answer. I just know that now since HSCT if I get Covid or a bad cold etc it never flairs up old symptoms, where as before I would get tingling in my face or index finger and thumb.
Hi Helen, same here with spinal cord lesions. There, unfortunately, can be no doubt now! They even stopped checking for/on them. Nothing below c-spine, regardless of no legs..Too expensive? I don’t know! Smoulderingly yours…💐
Prof G, I wonder if there will ever be generics here in the states. There is always that tweaking of something to create an evergreen patent, much to our dismay! I’m going to continue my valacyclovir and hope for the best. I hope all is well with you!
A 30-day supply of generic teriflunomide can range from around $31.10 to over $2,000.
The price of generic dimethyl fumarate in the US varies significantly, but it's generally much lower than the brand-name version, Tecfidera. A month's supply can range from around $35 to over $2,000, depending on the pharmacy and whether you have insurance or use discount programs.
Generic Fingolimod:
GoodRx Gold: Prices can start around $279.33.
Cost Plus Drugs: A bottle of 30, 0.5mg capsules is listed at $77, plus pharmacy costs.
SingleCare: Using a discount card can bring the price down to around $150.09 for a 30-capsule supply.
Iv personally had no side effects other than gaining weight, however maybe that was because my weight and blood sugar levels are all well within the normal range anyhow, so as a result I did gain weight?? Who knows.
Maybe that’s also why chemo/HSCT works, because it wipes the gut micro bio and you have to rebuild it again. ?? Maybe ?? 🤔
That’s a thought. It’s like the most complex jig saw puzzle. Doing what we can whilst working with medics. I’ve always been interested in nutrition. So the Zoe thing is for me education. I don’t drink or dine out a lot so it’s money I can afford.
Never knew those cards existed, didn’t realise tysabri was more effective than ocrevus at slowing disability and relapses good to know thanks , with regards to mavenclad it would be my choice of next dmt if I become jcv+
Replying to myself to carry on with my response, even though I’m glad tysabri is an effective dmt it’s 20 years old yet still has not been bettered by modern dmts that itself if a pity
Yet many neurologists will not give it as a treatment due to possible long term side affects leaves people like me hoping that tysabri will do its thing and stop/slow progression
“Another advantage of cladribine is that, as a small molecule, it penetrates the CNS. Cerebrospinal fluid (CSF) levels are about 25% of what is found in the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. This explains why cladribine impacts smouldering MS and has been shown to reduce brain volume loss, retinal nerve fibre layer thinning, CSF NFL levels, CDF immunoglobulin and cytokine levels. In a small study, it has been shown to reduce both slowly expanding lesions on MRI and paramagnetic rim lesions.”
Sounds like a wonder drug! But is there any real world long term data to show what the long term outcomes are ie what percentage of patients (10, 15, 20 years later) see worsening disability or disability stability? Why aren’t neuros making more use of Cladribine (I’m assuming that the anti-CD20 therapies are way more popular)?
“Relapse-associated worsening (RAW) contributes about 10-20% of disability events in contemporary clinical trials. The remainder of the disability events are due to PIRA (progression independent of relapse activity). This is why we need CNS-penetrant DMTs to tackle the pathological processes driving smouldering MS.”
So why has the researched over the last 40 years+ (and still ongoing) focused on relapses and not smouldering MS which accounts for 80-90% of disability events? Why are we so concerned that BTK inhibitors may not be as good as some therapies at reducing relapses, when the big gap in the market is therapies which target the mechanisms driving smouldering MS? If the mechanisms driving smouldering MS are impacted by a therapy, perhaps relapses / focal inflammation will reduce (as it’s the immune system’s response to the smouldering).
Re: " But is there any real world long term data to show what the long term outcomes are ie what percentage of patients (10, 15, 20 years later) see worsening disability or disability stability?"
Yes, the 11 and 13-year follow-up of CIS and RRMS data is impressive.
As is the case with early open-label data on more advanced MS, which is why we are conducting the CHARIOT-MS study (EDSS 6.5-8.5), focusing on the preservation of hand function.
Re: "So why has the researched over the last 40 years+ (and still ongoing) focused on relapses and not smouldering MS which accounts for 80-90% of disability events?"
The billion-dollar question. The adoption of innovations is slow, even in science, particularly in neurology :-(
MS is one disease. PPMS is MS, just advanced MS, as pwPPMS missed out on the early relapsing stage of the disease. So, CD19-targeted CAR T-cells should have the same effect in PPMS as they do in early RMS.
Can cladabrine be used in a 60+ individual who had a history of relapsing but now mri’s haven’t picked up new lesions in years? I have needle fatigue and want to take a dmt that leaves me open for some of these new medications as they become available.
I think I will get some resistance from my neurologist who is not as familiar with all the options.
gut bacteria is a big research topic around the world at the moment and pwms care about what they can do to help themselves. Therefore this treatment option has been mentioned by many short term, on top of their usual treatment to see if it can reduce the inflammatory gut bacteria. What are your thoughts?? This reduces one of the gut bacteria’s found in the stomachs of people with MS and also that is an inflammatory bacteria. So is it worth trying this ivermectin to reduce it?
I’ve signed up to Zoe. Anything to help. They have an offer on making it more affordable. Not started yet. I’m waiting to finish a course of antibiotics.
It’s best if you read about it. If you click this link or google Zoe. Professor Tim Spector you can read about it. Just x out the sign up window. My typing isn’t very good so I won’t go into detail. It’s about eating for your gut microbiome. They test your poop and monitor your blood sugar levels. You keep a diary of your food and they work out which ones do and don’t suit you or you need more of. That’s basic info. I’ve been contemplating it for 2 years. I struggle with foods and gut response. Nothing to lose really.
It’s trying to get me to subscribe to read it, even though I have subscribed. What’s the overview of findings please? Safe but no real impact on ms? Safe but worsening? Safe with minimal impact?
I chose cladribine immediately after diagnosis, largely due to its convenience. Not much was known about it in 2018. Almost everything you say here matches my experience, right down to the chest infections soon after both rounds. I have stabilised, not noticed any significant smouldering, and even some improvements (I was slated to receive botox injections into my eye every 3 months, but only ever needed one). In a world that is full of terrible news everyday, Cladribine is surely one piece of good news. Well done for getting it on the WHO essential medicines list (I know it wasn't just you, but I'm sure your advocacy helped). In another life I'd like to campaign over DMT inequalities between the developing world and the developed.
Email response:
As a 25+ MS patient mainly affected by spinal cord lesions, now considered Secondary MS patient, due to walking difficulties after a huge c3 lesion that affected both my legs and slowly affecting my arms, I urge you to start puting NVG 291 into the picture because for some of us it appears to be the only regeneration therapy with strong science behind and efficacy on the horizon. I have done Mavenclad 4th year now with no new lesions, and I started valacyclovir. For me and many others, NVG 291 would be a life-changing option that we believe should be offered to us.
all these things are very exciting. Anything that could stop smouldering MS would be fantastic I do worry about whether my children will end up with MS so EBV vaccines/treatment would be great. Hopefully in years to come MS will be a disease that is consigned to the past.
This is some of the most encouraging analysis I’ve seen regarding DMTs.
Your treatment of oral cladribine and fenebrutinib, especially as regards their interaction with EBV, inspires a question: How close Is the MS world to scrapping the RRMS/PPMS/SPMS/uncertain-etiology paradigm?
The evidence seems to point to a different construct: 1) initially sub-clinical post-viral activity and immune response, 2) smouldering disease throughout, 3) CNS damage causing a mixture of breakthrough events and steady worsening, 4) loss of function mapped to CNS pathology.
This accords with my own experience as a late-onset (55, M) Dx RRMS who kept wondering when remission would show up. I too have acquired a bias; fair enough. Still, the more I learned, the more I became concerned that the phenotypes I didn’t fit into were devised primarily to whittle MS down into manageable targets for drug discovery, trials and funding.
Now I see you suggesting that a trial of a drug whose subjects are PPMS may have profound implications across the disease spectrum. It makes me wonder if phenotypes will soon be irrelevant for determining DMT eligibility and regarded as useful mainly for symptom management and helping the patient plan ahead.
Having mastered the use of a motorized wheelchair at the expense of assimilating principles of immunology, I don’t quite understand the case for a vaccine against a virus that nearly everyone acquires anyway. Surely the focus of prevention must be the well established genetic predispositions to initiation of MS disease activity, as well as further investigation of potential environmental factors.
As for treatment, I rarely miss an opportunity to beat the drum for rehabilitation. Rehab research must claim more attention in MS therapeutics. Rehab professions must have parity with medicine in MS clinical teams.
In the politics of MS, elevating the profile of rehab and smashing the tyranny of phenotypes in treatment and resource allocation seem to me to be the top priorities right now.
Whether or not I’m right, I’m sure that when the history of this period in MS is written, you and other human game changers will receive ample credit for the groundbreaking, influential work you’ve done.
As always, thanks for sharing your knowledge and wisdom!
My wife is diagnosed as primary progressive but a number of MRIs show no new lesions. Does this equate to smouldering MS?
If so would fenebrutinib deliver any benefits?
Yes, most worsening in someone with PPMS is due to smouldering MS.
Re: Fenebrutinib. We will have to wait for the trial results.
Thank you.
Can you comment on how the Octupus trial is going. I’m not sure whether to take part or wait for the other med you refer to for SPMS. Smouldering. I’m sure that will be a couple of years. I’ve just been screened for octupus and my kidney function was just ok at 61. Cut off 60. This relates to the possibility of taking Metformin. A 1 in 3 chance of taking it. I’m in a slight dilemma now.
The Octopus trial is still in the recruitment phase, so it will be years before we get an answer. As with all trials, it involves some altruism in terms of getting randomised to the placebo arm. I always encourage my patients to participate in trials, as they help advance knowledge.
Yes. I’m happy to be in placebo too. I suppose if I end up on Metformin with unpleasant side effects I can stop. Or worsening kidney function. The tablets are like bullets so a little concerned over this. Sometimes it’s easy to over think everything.
I would be interested to know also. I took metformin also once a day for around 6 months and had my spinal leison disappear. I would love to know if others have seen the same or whether this was just a fluke and HSCT allowed time for the body to heal, although that’s not common with HSCT.
Regards spinal lesions. They’ve seen them on my scan then they’ve disappeared, then reappeared. I’m not being a party pooper however I was told lesions on the cord can be harder to see. 🤷♀️ or is this just someone who can’t read a scan? They were clear enough that I could see them. Correlated with my walking issues.
This is likely a technical issue related to the scanner and positioning in the scanner.
I hope the HSCT stops you from getting smouldering MS. You were brave to go for it.
That’s something that Gavin can answer. I just know that now since HSCT if I get Covid or a bad cold etc it never flairs up old symptoms, where as before I would get tingling in my face or index finger and thumb.
Hi Helen, same here with spinal cord lesions. There, unfortunately, can be no doubt now! They even stopped checking for/on them. Nothing below c-spine, regardless of no legs..Too expensive? I don’t know! Smoulderingly yours…💐
I’ve never had a complete spinal mri. Only the C region. Twice. Once they were there and by magic they’d gone…. Not.
Prof G, I wonder if there will ever be generics here in the states. There is always that tweaking of something to create an evergreen patent, much to our dismay! I’m going to continue my valacyclovir and hope for the best. I hope all is well with you!
Yes, there are generics/biosimilars for teriflunomide, DMF, GA, Rituximab, and I think fingolimod.
Yes, I saw that quite a few are losing their patents. I wonder what the costs will be?
A 30-day supply of generic teriflunomide can range from around $31.10 to over $2,000.
The price of generic dimethyl fumarate in the US varies significantly, but it's generally much lower than the brand-name version, Tecfidera. A month's supply can range from around $35 to over $2,000, depending on the pharmacy and whether you have insurance or use discount programs.
Generic Fingolimod:
GoodRx Gold: Prices can start around $279.33.
Cost Plus Drugs: A bottle of 30, 0.5mg capsules is listed at $77, plus pharmacy costs.
SingleCare: Using a discount card can bring the price down to around $150.09 for a 30-capsule supply.
Interesting. I’m a little concerned over the potential side effects on the gut. I might not get Metformin. However I feel warey of it.
Iv personally had no side effects other than gaining weight, however maybe that was because my weight and blood sugar levels are all well within the normal range anyhow, so as a result I did gain weight?? Who knows.
Maybe that’s also why chemo/HSCT works, because it wipes the gut micro bio and you have to rebuild it again. ?? Maybe ?? 🤔
That’s a thought. It’s like the most complex jig saw puzzle. Doing what we can whilst working with medics. I’ve always been interested in nutrition. So the Zoe thing is for me education. I don’t drink or dine out a lot so it’s money I can afford.
How do I go about finding the ms cards, the updated version on the site?
Thank you
Via the MS-Selfie microsite: https://msselfie.co.uk/
https://msselfie.co.uk/wp-content/uploads/2024/06/MS-Selfie-Infocards-ver.-6.0-18-Feb-2024-3.pdf
Never knew those cards existed, didn’t realise tysabri was more effective than ocrevus at slowing disability and relapses good to know thanks , with regards to mavenclad it would be my choice of next dmt if I become jcv+
Replying to myself to carry on with my response, even though I’m glad tysabri is an effective dmt it’s 20 years old yet still has not been bettered by modern dmts that itself if a pity
In network analyses, alemtuzumab emerges as the most effective treatment.
Yet many neurologists will not give it as a treatment due to possible long term side affects leaves people like me hoping that tysabri will do its thing and stop/slow progression
Wow, you are fast! Thank you!
Your last post on Cladabrine was timely. I’m going to advocate for myself tomorrow.
“Another advantage of cladribine is that, as a small molecule, it penetrates the CNS. Cerebrospinal fluid (CSF) levels are about 25% of what is found in the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. This explains why cladribine impacts smouldering MS and has been shown to reduce brain volume loss, retinal nerve fibre layer thinning, CSF NFL levels, CDF immunoglobulin and cytokine levels. In a small study, it has been shown to reduce both slowly expanding lesions on MRI and paramagnetic rim lesions.”
Sounds like a wonder drug! But is there any real world long term data to show what the long term outcomes are ie what percentage of patients (10, 15, 20 years later) see worsening disability or disability stability? Why aren’t neuros making more use of Cladribine (I’m assuming that the anti-CD20 therapies are way more popular)?
“Relapse-associated worsening (RAW) contributes about 10-20% of disability events in contemporary clinical trials. The remainder of the disability events are due to PIRA (progression independent of relapse activity). This is why we need CNS-penetrant DMTs to tackle the pathological processes driving smouldering MS.”
So why has the researched over the last 40 years+ (and still ongoing) focused on relapses and not smouldering MS which accounts for 80-90% of disability events? Why are we so concerned that BTK inhibitors may not be as good as some therapies at reducing relapses, when the big gap in the market is therapies which target the mechanisms driving smouldering MS? If the mechanisms driving smouldering MS are impacted by a therapy, perhaps relapses / focal inflammation will reduce (as it’s the immune system’s response to the smouldering).
Re: " But is there any real world long term data to show what the long term outcomes are ie what percentage of patients (10, 15, 20 years later) see worsening disability or disability stability?"
Yes, the 11 and 13-year follow-up of CIS and RRMS data is impressive.
https://pubmed.ncbi.nlm.nih.gov/39690897/
https://pubmed.ncbi.nlm.nih.gov/37012898/
As is the case with early open-label data on more advanced MS, which is why we are conducting the CHARIOT-MS study (EDSS 6.5-8.5), focusing on the preservation of hand function.
https://journals.sagepub.com/doi/10.1177/17562864231200627
Re: "So why has the researched over the last 40 years+ (and still ongoing) focused on relapses and not smouldering MS which accounts for 80-90% of disability events?"
The billion-dollar question. The adoption of innovations is slow, even in science, particularly in neurology :-(
Hello, doctor. Could you please share your opinion on CAR T cells for primary progressive multiple sclerosis (PPMS)? All the best.
MS is one disease. PPMS is MS, just advanced MS, as pwPPMS missed out on the early relapsing stage of the disease. So, CD19-targeted CAR T-cells should have the same effect in PPMS as they do in early RMS.
https://gavingiovannoni.substack.com/p/will-cd19-targeted-car-t-cell-therapy?utm_source=publication-search
Can cladabrine be used in a 60+ individual who had a history of relapsing but now mri’s haven’t picked up new lesions in years? I have needle fatigue and want to take a dmt that leaves me open for some of these new medications as they become available.
I think I will get some resistance from my neurologist who is not as familiar with all the options.
Thank you
Yes, cladribine is rapidly becoming the go-to DMT for older people with MS as it is not associated with significant long-term immunosuppression.
And as garden lady asked, would clad leave the possibility open for the new BTK treatments?
Likewise, do the cd20 drugs leave the possibility open for the new BTK treatments? Thanks
Great news. I havd PPMS. Thanks for your insight.
Who will fund these interesting trials with cheap generic versions of oral cladribine?
I thought only drug companies working on new drugs can afford to run large trials
MS society are running the Octupus trial. They’re not DMTs. though. They’re for SPMS and PPMS. Meds that are already in use for other disease.
https://pubmed.ncbi.nlm.nih.gov/32539079/
https://pmc.ncbi.nlm.nih.gov/articles/PMC8245171/
https://www.sciencedirect.com/science/article/pii/S2666379125001284
gut bacteria is a big research topic around the world at the moment and pwms care about what they can do to help themselves. Therefore this treatment option has been mentioned by many short term, on top of their usual treatment to see if it can reduce the inflammatory gut bacteria. What are your thoughts?? This reduces one of the gut bacteria’s found in the stomachs of people with MS and also that is an inflammatory bacteria. So is it worth trying this ivermectin to reduce it?
It is going to take 20 years or more to generate the evidence that manipulating the microbiome is a DMT for MS. Let's wait for the evidence.
As for ivermectin, please see: https://gavingiovannoni.substack.com/p/q-and-a-80-ivermectin-as-a-treatment?utm_source=publication-search
Not as a treatment but as an add on to the dmd?
I’ve signed up to Zoe. Anything to help. They have an offer on making it more affordable. Not started yet. I’m waiting to finish a course of antibiotics.
Is that ivermectin or something completely different?
It’s best if you read about it. If you click this link or google Zoe. Professor Tim Spector you can read about it. Just x out the sign up window. My typing isn’t very good so I won’t go into detail. It’s about eating for your gut microbiome. They test your poop and monitor your blood sugar levels. You keep a diary of your food and they work out which ones do and don’t suit you or you need more of. That’s basic info. I’ve been contemplating it for 2 years. I struggle with foods and gut response. Nothing to lose really.
https://zoe.com/en-gb
It’s trying to get me to subscribe to read it, even though I have subscribed. What’s the overview of findings please? Safe but no real impact on ms? Safe but worsening? Safe with minimal impact?
I chose cladribine immediately after diagnosis, largely due to its convenience. Not much was known about it in 2018. Almost everything you say here matches my experience, right down to the chest infections soon after both rounds. I have stabilised, not noticed any significant smouldering, and even some improvements (I was slated to receive botox injections into my eye every 3 months, but only ever needed one). In a world that is full of terrible news everyday, Cladribine is surely one piece of good news. Well done for getting it on the WHO essential medicines list (I know it wasn't just you, but I'm sure your advocacy helped). In another life I'd like to campaign over DMT inequalities between the developing world and the developed.
Hello, doctor. Could you please share your opinion on CAR T cells for primary progressive multiple sclerosis (PPMS)? All the best.
Hello, doctor. Could you please share your opinion on CAR T cells for primary progressive multiple sclerosis (PPMS)? All the best.