Thank you so much for the update Gavin. I agree that the real MS is smouldering MS. Myself and many others in middle age are experiencing new symptoms and progression without new activity seen on MRI. There is a research study taking place in the UK about smouldering MS called the SAW project. I’m taking part in the hope that smouldering MS becomes accepted as the real MS. Thank you for all the work you are doing for PwMS it is appreciated! Jane
“So for people with smouldering MS in the UK, I would not expect tolebrutinib to be available until late 2026.”
Q1: I’m guessing there are tens of thousands of patients in the U.K. with SPMS. Most of these patients probably rarely see a neuro as there are no treatment options. If tolebrutinib becomes available in late 2026, how will MS clinics gear up for this? Will they contact SPMS patients? This will be a huge extra workload eg MRIs, bloods….
Q2: I think I read that tolebrutinib reduced the risk of progression / disability by c.30%. If the drug is addressing the real MS, why only 30%? Will higher doses be required, or will a longer time on the drug see greater effectiveness?
Q3: The MS team in Cambridge is gearing up to start a trial of Car T cell therapy. (An educated guess) which therapy (BTK v Cart T cells) is likely to have the greater effect on addressing the real MS?
Q4: Do we still need to treat relapses if they are not the real MS? Could the future be induction therapy (anti-CD20) followed by a BTKi?
Re: "Q3: The MS team in Cambridge is gearing up to start a trial of Car T cell therapy. (An educated guess) which therapy (BTK v Cart T cells) is likely to have the greater effect on addressing the real MS?"
Is it CD19-targeted CAR T-cells? If yes, it is likely to be better than BTKi's at purging EBV infected B-cells. The data from SLE is truly amazing and we are all anticipating similar results in MS.
Re: "Q2: I think I read that tolebrutinib reduced the risk of progression / disability by c.30%. If the drug is addressing the real MS, why only 30%? Will higher doses be required, or will a longer time on the drug see greater effectiveness?"
I suspect more time is necessary to see its longterm impact. I think Tole is working as an anti-EBV drug and its impact will be via latently infected cells and it may take time to purge the virus from the latently infected pool.
Re: "Q1: I’m guessing there are tens of thousands of patients in the U.K. with SPMS. Most of these patients probably rarely see a neuro as there are no treatment options. If tolebrutinib becomes available in late 2026, how will MS clinics gear up for this? Will they contact SPMS patients? This will be a huge extra workload eg MRIs, bloods…."
Yes, a good, caring MS centre will contact their patients. We did this for ocrelizumab and sipinimod in active PPMS and active SPMS, respectively.
Q5: “The real MS is what is happening in the tissue of the brain and spinal cord, i.e. smouldering disease and that we should be targeting the disease and not the immune response to the disease”. Are BTK inhibitors really targeting the disease, or are they just targeting the immune response (smouldering inflammation) within the CNS? The activity of microglia / macrophages could be just the innate immune system's response to what’s happening in the tissue of the brain and spinal cord.
Re: "Q5: “The real MS is what is happening in the tissue of the brain and spinal cord, i.e. smouldering disease and that we should be targeting the disease and not the immune response to the disease”. Are BTK inhibitors really targeting the disease, or are they just targeting the immune response (smouldering inflammation) within the CNS? The activity of microglia / macrophages could be just the innate immune system's response to what’s happening in the tissue of the brain and spinal cord."
I think BTKi's are selectively targeting EBV infected B-cells, which is what the real MS is.
Re: "Q4: Do we still need to treat relapses if they are not the real MS? Could the future be induction therapy (anti-CD20) followed by a BTKi?"
Yes. If you treat what is causing relapses and focal MRI activity then they will disappear. This is tole's Achille's heel; it is no that effective at suppressing focal inflammation. I suspect it will need to be used as part of an induction-maintenance strategy in MS.
Any form of MS is bad news. At first it is unpredictable then it gets a real hold on you and disabilities, hidden and visible are permanent. Yup smouldering MS is ghastly. The question for quite a few of us is simple, will we be eligible for toletbrutninb? I'm 70, retired and smouldering or at least 10 years, frankly I do not rate my chance of ever receiving treatment but none the less it will be a big help for thousands of other people
I suspect it will be limited to the non-relapsing SPMS population that is still mobile. NICE and the MHRA rarely expand the label and use of drugs past the trial population.
Mobile is a very wide definition. I can walk but must use a 4 wheeled walker and I cannot stand on my feet without holding onto something. Personally I think I am mobile but will the decision makers agree
Again as someone with ppms, slow moving ppms as my neurologist calls it, I want to call it smouldering MS. So I have to ask, how does one get on Tolebrutinb.
Very insightful Newsletter. Are you suggesting that DMTs may be symptom relievers and just slowing down the time until disability is reached ? And how long is too long to have been smoldering to get this treatment ? Will it reverse or stop and slow further by the 30%.
Most of these treatments get more effective with time as the survival curves continue to separate. The 30% is likely to floor effect and its true impact will be greater than this.
This is good news, however, having been smouldering for years, I don’t see treatment at age 70 with comorbidities happening in a case like mine. However, I am thrilled for others. Thank you for this!
Thank you very much for the update. I hope we have one more weapon in our short pockets...seeing the plot about confirmed improvemen in your post, this speaks about a portion of patients that improved and this lasted over months correct, which is different from disability progression as a metric, correct?
It's surprising that a CNS-penetrating drug does not outperform another treatment for relapsing forms of MS and yet proves more effective than a placebo in controlling disability. I wonder if it would have been a nought if it were pitted against teriflunomide, the comparator drug that was used in the relapsing remitting MS study (Oh et al).
34-yr-old female RRMS waiting to choose DMT. Initially drawn to Ocrevus as a one-shot, high-dose solution, blood/brain barrier etc., but now results that a higher dose is not more effective, is there anything really to differentiate from the lower maintenance type dose of kesimpta in this scenario, if you were choosing your first DMT and really wanted to kickstart the best course of action right from the off with RRMS? (symptoms: optic neuritis Feb '25, vertigo episodes and tingling feet starting circa 2019). Thank you.
Will this be looked at as an immune modulator or an immune suppressor ? As this is relevant for all of us that have or had cancer, and currently most effective DMTs are contra indicated in cancer
And I hope that you have a good break away from all the hard work
Immune suppressor. BTKi's block B-cell responses and downregulate macrophage biology. It is likely to block vaccine responses in a similar way to anti-CD20 therapies.
Thank you I thought that, that would be the answer. I just live in hope of newer immune modulators that can be used with caution in people who have had cancer.
Thank you so much, Dr. G. I would also like to ask you, please, why was the study protocol designed to only report "Increase in ALT level to greater than 3x ULN"? I am wondering why increases in ALT level to greater than 2x ULN were not reported in this trial (from what I have seen). Thank you so much! -K
This is based on Hy's law. Hy's Law is a clinical guideline used to assess the risk of a drug-induced liver injury (DILI) leading to acute liver failure (ALF). It's based on the observation that significant elevation in liver enzymes (ALT or AST) along with jaundice (elevation of total bilirubin) is a strong indicator of severe DILI.
Key Components of Hy's Law:
Elevated ALT or AST: A significant increase in these liver enzymes (3 times or more the upper limit of normal - ULN) indicates hepatocellular damage.
Elevated Total Bilirubin: An increase in total bilirubin (2 times or more the ULN) indicates jaundice, which is a sign of liver dysfunction and bilirubin build-up.
Different numbers reported for 3-month CDP, 6-month CDP and 6-month CDI. I think the discrepancy is maybe explained by different median follow-up times of the 2 reports (median follow-up time of 113 weeks in the NEJM article vs what appears to be 45 weeks in the ECTRIMS 2024 report); however, I am not sure
Sorry, but I don't see where you see different numbers. They are essentially the same in both reports. Maybe you just read something the wrong way. I'm really trying to see where the numbers are different, or where they might be transposed or mistakes, because I want to make sure I'm not missing something important. But I'm just not finding anything like what you're describing.
The results for 3 month CDP, 6 month CDP and 6 month CDI. You need to look at the actual findings, such as 37.2% for placeo and 26.9% for tolebrutinib for "cumulative incidence of 6-month CDP" In the ECTRIMS 2024 report vs 22.6% for tolebrutinib and 30.7% for placebo for the same end point ("confirmed disability that was sustained for at least 6 months, assessed in a time-to-treat analysis")in NEJM article.
"The NEJM figure uses the actual number of trial participants who reached the primary endpoint, while the data presented at ECTRIMS in Copenhagen uses the Kaplan-Meier estimates. The K-M data is based on a model that considers the entire time course of the outcomes, while the NEJM used the point estimate at the end of the study."
Hi Dr. G. Thank you SO MUCH for inquiring with Sanfoi and finding out this information. But now I am further confused because the NEJM article states: "The corresponding Kaplan-Meier estimates at 24 months (for 6-month sustained CDP) were 21.9% for tolebrutinib and 30.2% for placebo, but the Kaplan-Meier estimates for this same end point in the ECTRIMS 2024 report were 26.9% for tolebrutinib and 37.2% for placebo. Maybe these different numbers are explained by the median follow up length of the trials, which appear to have been 133 weeks in the NEJM article and 45 weeks in the ECTRIMS 2024 report? Thanks so much for your kind assistance with trying to help me understand the HERCULES tolebrutinib results, Dr. G. I very much appreciate it. I try as hard as I can to understand them on my own, but I am confused at this point. -KB
It has now been 11yrs since I was diagnosed with MS. I have repeated my observation that MRIs often conflict with disability hundreds of times. A high lesion load does not always equal high disability; a low lesion load can actually cause far more disability. Thus since 2014 I have argued that HSCT should not only be offered based on lesion presentation. We know HSCT works despite no active lesions; gradually the proof of smouldering MS being the real enemy is now being proven.
Thank you so much for the update Gavin. I agree that the real MS is smouldering MS. Myself and many others in middle age are experiencing new symptoms and progression without new activity seen on MRI. There is a research study taking place in the UK about smouldering MS called the SAW project. I’m taking part in the hope that smouldering MS becomes accepted as the real MS. Thank you for all the work you are doing for PwMS it is appreciated! Jane
“So for people with smouldering MS in the UK, I would not expect tolebrutinib to be available until late 2026.”
Q1: I’m guessing there are tens of thousands of patients in the U.K. with SPMS. Most of these patients probably rarely see a neuro as there are no treatment options. If tolebrutinib becomes available in late 2026, how will MS clinics gear up for this? Will they contact SPMS patients? This will be a huge extra workload eg MRIs, bloods….
Q2: I think I read that tolebrutinib reduced the risk of progression / disability by c.30%. If the drug is addressing the real MS, why only 30%? Will higher doses be required, or will a longer time on the drug see greater effectiveness?
Q3: The MS team in Cambridge is gearing up to start a trial of Car T cell therapy. (An educated guess) which therapy (BTK v Cart T cells) is likely to have the greater effect on addressing the real MS?
Q4: Do we still need to treat relapses if they are not the real MS? Could the future be induction therapy (anti-CD20) followed by a BTKi?
Re: "Q3: The MS team in Cambridge is gearing up to start a trial of Car T cell therapy. (An educated guess) which therapy (BTK v Cart T cells) is likely to have the greater effect on addressing the real MS?"
Is it CD19-targeted CAR T-cells? If yes, it is likely to be better than BTKi's at purging EBV infected B-cells. The data from SLE is truly amazing and we are all anticipating similar results in MS.
Many thanks for your responses to all my questions.
Re: "Q2: I think I read that tolebrutinib reduced the risk of progression / disability by c.30%. If the drug is addressing the real MS, why only 30%? Will higher doses be required, or will a longer time on the drug see greater effectiveness?"
I suspect more time is necessary to see its longterm impact. I think Tole is working as an anti-EBV drug and its impact will be via latently infected cells and it may take time to purge the virus from the latently infected pool.
Re: "Q1: I’m guessing there are tens of thousands of patients in the U.K. with SPMS. Most of these patients probably rarely see a neuro as there are no treatment options. If tolebrutinib becomes available in late 2026, how will MS clinics gear up for this? Will they contact SPMS patients? This will be a huge extra workload eg MRIs, bloods…."
Yes, a good, caring MS centre will contact their patients. We did this for ocrelizumab and sipinimod in active PPMS and active SPMS, respectively.
Sorry - one more question / observation:
Q5: “The real MS is what is happening in the tissue of the brain and spinal cord, i.e. smouldering disease and that we should be targeting the disease and not the immune response to the disease”. Are BTK inhibitors really targeting the disease, or are they just targeting the immune response (smouldering inflammation) within the CNS? The activity of microglia / macrophages could be just the innate immune system's response to what’s happening in the tissue of the brain and spinal cord.
Re: "Q5: “The real MS is what is happening in the tissue of the brain and spinal cord, i.e. smouldering disease and that we should be targeting the disease and not the immune response to the disease”. Are BTK inhibitors really targeting the disease, or are they just targeting the immune response (smouldering inflammation) within the CNS? The activity of microglia / macrophages could be just the innate immune system's response to what’s happening in the tissue of the brain and spinal cord."
I think BTKi's are selectively targeting EBV infected B-cells, which is what the real MS is.
Re: "Q4: Do we still need to treat relapses if they are not the real MS? Could the future be induction therapy (anti-CD20) followed by a BTKi?"
Yes. If you treat what is causing relapses and focal MRI activity then they will disappear. This is tole's Achille's heel; it is no that effective at suppressing focal inflammation. I suspect it will need to be used as part of an induction-maintenance strategy in MS.
Any form of MS is bad news. At first it is unpredictable then it gets a real hold on you and disabilities, hidden and visible are permanent. Yup smouldering MS is ghastly. The question for quite a few of us is simple, will we be eligible for toletbrutninb? I'm 70, retired and smouldering or at least 10 years, frankly I do not rate my chance of ever receiving treatment but none the less it will be a big help for thousands of other people
I suspect it will be limited to the non-relapsing SPMS population that is still mobile. NICE and the MHRA rarely expand the label and use of drugs past the trial population.
Mobile is a very wide definition. I can walk but must use a 4 wheeled walker and I cannot stand on my feet without holding onto something. Personally I think I am mobile but will the decision makers agree
Am in your shoes, unfortunately..
Again as someone with ppms, slow moving ppms as my neurologist calls it, I want to call it smouldering MS. So I have to ask, how does one get on Tolebrutinb.
You need to wait for the PPMS trial results to report out.
Any idea on the timing of that?
It is an event driven study, which was slow to recruit. So in about 12 months time.
Very insightful Newsletter. Are you suggesting that DMTs may be symptom relievers and just slowing down the time until disability is reached ? And how long is too long to have been smoldering to get this treatment ? Will it reverse or stop and slow further by the 30%.
Most of these treatments get more effective with time as the survival curves continue to separate. The 30% is likely to floor effect and its true impact will be greater than this.
This is great news, although the availability of the drug will be delayed in the US. Thank you for the info!
This is good news, however, having been smouldering for years, I don’t see treatment at age 70 with comorbidities happening in a case like mine. However, I am thrilled for others. Thank you for this!
Hallelujah for Tolebrutinib! I'm excited for the future ☺️
Thank you very much for the update. I hope we have one more weapon in our short pockets...seeing the plot about confirmed improvemen in your post, this speaks about a portion of patients that improved and this lasted over months correct, which is different from disability progression as a metric, correct?
These are great news. I hope that tolebrutinib will really help with smoldering MS, and I hope that it will be available in my country as well.
And I'm really happy that neurologists around the world understand that MS management should not be oriented only on relapse prevention.
It's surprising that a CNS-penetrating drug does not outperform another treatment for relapsing forms of MS and yet proves more effective than a placebo in controlling disability. I wonder if it would have been a nought if it were pitted against teriflunomide, the comparator drug that was used in the relapsing remitting MS study (Oh et al).
34-yr-old female RRMS waiting to choose DMT. Initially drawn to Ocrevus as a one-shot, high-dose solution, blood/brain barrier etc., but now results that a higher dose is not more effective, is there anything really to differentiate from the lower maintenance type dose of kesimpta in this scenario, if you were choosing your first DMT and really wanted to kickstart the best course of action right from the off with RRMS? (symptoms: optic neuritis Feb '25, vertigo episodes and tingling feet starting circa 2019). Thank you.
Alem or AHSCT
Very unlikely to find a neurologist willing to help you with either of them in the nhs , that’s been my experience so far anyway
Amazing - some good news for smoulderers and a seeming acceptance by wider medical audience that smouldering is real. Thanks Gavin.
Frustrated that my age always seems to be against me :-(
First, thank you for keeping us informed.
Will this be looked at as an immune modulator or an immune suppressor ? As this is relevant for all of us that have or had cancer, and currently most effective DMTs are contra indicated in cancer
And I hope that you have a good break away from all the hard work
Immune suppressor. BTKi's block B-cell responses and downregulate macrophage biology. It is likely to block vaccine responses in a similar way to anti-CD20 therapies.
Thank you I thought that, that would be the answer. I just live in hope of newer immune modulators that can be used with caution in people who have had cancer.
Hi Dr. G: Can you please explain the discrepancies in the results reported about the tolebrutinib Phase 3 HERCULES trial in the recent NEJM article (https://www.nejm.org/doi/pdf/10.1056/NEJMoa2415988) vs. the report of this trial presented at ECTRIMS 2024 (https://congress.sanofimedical.com/s3fs-public/2024-09/Efficacy%20and%20Safety%20of%20Tolebrutinib%20Versus%20Placebo%20in%20Non-Relapsing%20Secondary%20Progressive%20Multiple%20Sclerosis%20Results%20From%20the%20Phase%203%20HERCULES%20Trial.pdf?VersionId=duChB4x7ecZduMeQ9v4rSSp8ZeNuci1f)? Thanks so much! -K
Thanks for highlighting this. I will find out and get back to you.
Thank you so much, Dr. G. I would also like to ask you, please, why was the study protocol designed to only report "Increase in ALT level to greater than 3x ULN"? I am wondering why increases in ALT level to greater than 2x ULN were not reported in this trial (from what I have seen). Thank you so much! -K
This is based on Hy's law. Hy's Law is a clinical guideline used to assess the risk of a drug-induced liver injury (DILI) leading to acute liver failure (ALF). It's based on the observation that significant elevation in liver enzymes (ALT or AST) along with jaundice (elevation of total bilirubin) is a strong indicator of severe DILI.
Key Components of Hy's Law:
Elevated ALT or AST: A significant increase in these liver enzymes (3 times or more the upper limit of normal - ULN) indicates hepatocellular damage.
Elevated Total Bilirubin: An increase in total bilirubin (2 times or more the ULN) indicates jaundice, which is a sign of liver dysfunction and bilirubin build-up.
What discrepancies?
Different numbers reported for 3-month CDP, 6-month CDP and 6-month CDI. I think the discrepancy is maybe explained by different median follow-up times of the 2 reports (median follow-up time of 113 weeks in the NEJM article vs what appears to be 45 weeks in the ECTRIMS 2024 report); however, I am not sure
Sorry, but I don't see where you see different numbers. They are essentially the same in both reports. Maybe you just read something the wrong way. I'm really trying to see where the numbers are different, or where they might be transposed or mistakes, because I want to make sure I'm not missing something important. But I'm just not finding anything like what you're describing.
The results for 3 month CDP, 6 month CDP and 6 month CDI. You need to look at the actual findings, such as 37.2% for placeo and 26.9% for tolebrutinib for "cumulative incidence of 6-month CDP" In the ECTRIMS 2024 report vs 22.6% for tolebrutinib and 30.7% for placebo for the same end point ("confirmed disability that was sustained for at least 6 months, assessed in a time-to-treat analysis")in NEJM article.
This is the reply I received from Sanofi:
"The NEJM figure uses the actual number of trial participants who reached the primary endpoint, while the data presented at ECTRIMS in Copenhagen uses the Kaplan-Meier estimates. The K-M data is based on a model that considers the entire time course of the outcomes, while the NEJM used the point estimate at the end of the study."
Hi Dr. G. Thank you SO MUCH for inquiring with Sanfoi and finding out this information. But now I am further confused because the NEJM article states: "The corresponding Kaplan-Meier estimates at 24 months (for 6-month sustained CDP) were 21.9% for tolebrutinib and 30.2% for placebo, but the Kaplan-Meier estimates for this same end point in the ECTRIMS 2024 report were 26.9% for tolebrutinib and 37.2% for placebo. Maybe these different numbers are explained by the median follow up length of the trials, which appear to have been 133 weeks in the NEJM article and 45 weeks in the ECTRIMS 2024 report? Thanks so much for your kind assistance with trying to help me understand the HERCULES tolebrutinib results, Dr. G. I very much appreciate it. I try as hard as I can to understand them on my own, but I am confused at this point. -KB
It has now been 11yrs since I was diagnosed with MS. I have repeated my observation that MRIs often conflict with disability hundreds of times. A high lesion load does not always equal high disability; a low lesion load can actually cause far more disability. Thus since 2014 I have argued that HSCT should not only be offered based on lesion presentation. We know HSCT works despite no active lesions; gradually the proof of smouldering MS being the real enemy is now being proven.