Prof G- Is it possible to have a newsletter to compare top DMTs - BTKi vs ocrevus vs cladribine vs CAR-T . And practicalities in getting on them etc, hurdles etc.
We don't have enough data for that. The critical observation is that we are now moving towards CNS therapies, and I suspect when it comes to protecting the end-organ (brain and spinal cord), these will supplant the peripherally acting treatments.
I can appreciate we don’t have a complete picture, but beggars can’t be choosers and SPMS/ PPMS/ Smouldering MS are indeed beggars. We have to make risk/based decisions if need be. Perhaps go with off label medication if possible. Just because our disease is not terminal or deadly doesn’t make it carry any less weight. I personally think poor quality of life/ loss of basic independence should be classified as terminal. Maybe then the medical community will be more radical or less conservative with their prescriptions. No-one should be prescribing 30% effective DMTs anymore. Its shocking that this still happens. Yes research is really moving but not fast enough. We are effectively rotting veg, and keeping us in the fridge to slow the rot is not good enough anymore. We now know too much. My point is ii hope the medical community tries think outside the box and come up with really innovative approaches to deal with the collateral damage of pwMS having been treated with low grade DMT for the majority of their ms just because there was nothing available back then. Those group of pwMS i call collateral damage as we are the collateral damage of time vacuum, when nothing was known about ms. These groups may as well be forgotten as the new therapies will have most impact on newly diagnosed pwMS.
Honestly this is so infuriating. There needs to be urgent action within the medical community so everyone is on the SAME page. Its unacceptable.
We all know better now, so there is no excuse.
The lack of urgency from the medical community is because MS is not a terminal or deadly disease. Unfortunately, most think “oh theyre still alive, so its all good”. Or they see those 1% percenters running marathons or climbing mount everest and think “ oh ms is grand! No that is not good enough! The medical community needs to try harder! There needs to be a movement. The ONLY person who is trying to make things better for people with MS is prof G! and a couple of other individuals in medical community. Thats it.
We dont live in the future. We live in the now. We need a treatment to apply now OR a script to use to educate archaic neurologists on how to treat MS. Yes some are bound by NICE regulations and what not but there must be a way to use these borderline therapies out of compassionate use. Our quality of life DEMANDS use of these borderline therapies out of compassionate use, just as is sometimes done on other rare diseases.
We need the medical community to change gears. The science has changed gears, now its time for science advocates to follow suit.
I was not given a choice my neuro prescribed Copaxone. I was 59 at the time and he thinks I've had MS for years. He said my MS is probably burnt out and then a new lesion was found.
I am smouldering and desperate since my ocrelizumab failed to keep me stable although i dont have new MRI lesions but my EDSS went from 3.5 to 6 in 1 year time while under ocrelizumab
Thats what im talking about, MS will “always“ progress or become smouldering . We need something that actually combats or halts smouldering, and that seems to be BTKi at the moment. Lack of new MRI lesions does NOT mean the treatment is being effective.
I would love to see another biomarker measure of effectiveness these drugs are being measured against . Perhaps one that gives us a measure of EBV activity in the body?
Exciting news but there are still a couple of hurdles to overcome. NICE to select it and will it be available to me, 71 years old, smouldering MS with no history of relapses but struggling with numerous disabilities.
Sorry to sound a bit negative but I do feel that people like my self are ignored and I suspect there are quite a lot of us who just have to get on with it.
Thank you for delivering and explaining the good news! Is Fenebrutinib going to have an advantage over B-cell therapies for addressing RAW and PIRA? For RRMS, PPMS? And do the results of PPMS translate also to SPMS?
Exciting news!! When do you think this will be available via the NHS? And would be available to SPMS??…i assume yes as labelling of ms is becoming more flexible now after ECTRIMs… neurologists are not being too Jurassic in their ways of thinking anymore. However, the PAYE / NIHR market authorisation process may take some adjusting .. or allow prescribing neurologists some flexibility in “off label “ prescriptions perhaps?
It will take approximately 2 years to clear all the hurdles, including those with the MHRA, NICE, and NHS England. Please note that there is still one outstanding trial to report.
Not only me. I think you should thank the Roche-Genentech team behind fenebrutinib - they have done a fantastic job and took significant risks with their development programme. I would like to give a shout-out to the medicinal chemists who invented the compound. They designed the molecule to possess specific attributes, and these trials validate their creativity and hard work. I would vote for them to win a version of the Academy Awards for MS research.
That’s exactly what im thinking about. Im currently on ocrevus, but considering jumping on the CAR-T clinical trial as that’s like a more targeted approach than full blown mass destruction of aHSCT therapy. But this new breakthrough has me thinking twice now
In the case of PPMS, the data on conventional AHSCT (even full blown myelo-ablative regimes) is not great to begin with - bad enough in fact that the local center does not do it anymore in PPMS.
I just so happens that I have a neuro appointment tomorrow, topic is pretty obvious now :)
Yes you are correct. I did AHSCT very early in the disease course (RRMS) active inflammatory disease. I wouldn’t have done it if I was PPMS and had MS for many years
Thanks. Am I the only one who finds it difficult to interpret the results relating to disability progression? Tolebrutinib (HERCULES - SPMS without relapses) delayed the time to onset of 6-month confirmed disability progression (CDP) by 31% compared to placebo. Ocrelizumab (as I understand it) was only tested in PPMS patients. Ditto Fenebrutinib (results above). So we have different patient groups (NR SPMS and PPMS) and a c.30% reduction in disability progression for all three drugs when tested in ‘progressive’ patients. Are progressive patients in the future going to be in a similar position as RRMS patients 25-30 years ago ie you have X drugs all offering a 30% reduction in xxx? 30% is a start in slowing disability progression, but what will be needed to boost this to 75%+ eg other add on therapies?
We need to wait for the full results to see how effective fenebrutinib is relative to ocrelizumab in PPMS and teriflunomide in RMS before we can comment.
Moreover, I'd appreciate an analysis of Frenebtutanib data versus the Ocrevus O'Hand data, if possible. Has the O'Hand data been somewhat glossed over (I do know you discussed quite comprehensively Prof. G) in the MS community in general? In my mind, the O'Hand trial results were significant as it showed preservation of upper extremity function in *older* cohort.
I think O'HAND is also a game-changer as it proves several theories we put forward about MS and also changes the way we do clinical trials and treat MS. I think things will gradually change once the results are published.
Thank you for your latest update! It sounds really encouraging. I live with a smouldering form of MS - clinically stable more or less for the past 4 years, EDDS now at 6.5, treated with Tysabri for the past 2 yerars +.
My question is whether, if inflammation can be more effectively controlled with treatments like fenebrutinib, combining that with focused physical training could help the body repair itself over time and possibly reduce disability, even if the medication itself doesn’t repair nerve damage. And what about adding creatine to this combination?
Thank you again for your ongoing work and for the hope it brings to us, pwMS.
Re: "My question is whether, if inflammation can be more effectively controlled with treatments like fenebrutinib..."
Yes, because it is CNS penetrant and targets central processes driving smouldering MS. Tolebrutinib will be licensed first. So if you have smouldering MS you may want to consider tolebrutinib and it will be some time before fenebrutinib becomes available.
I see that BTK inhibitors are being discussed at this week’s European Charcot Foundation meeting “SESSION III — Addressing progression by BTK Inhibition: Hype or Hope?”. Are the outcomes of these discussions made public? A very relevant discussion for MSers who are considering a BTK inhibitor as a possible future treatment to address their smouldering MS.
VERY, VERY, VERY disappointing and discouraging to see yet another clinical trial for an "MS DMT" where the primary endpoint was ARR, when there is research that has found no association between relapses and long-term progression and CDW in MS (UCSF EPIC Study, Confavreux article/research, etc).
The disability progression endpoint is also not meaningful over such a short duration of time, when we know that irreversible disability accumulation in MS occurs over a long period of time and generally in the progressive phases of MS.
To me, the press release is just another example of propaganda and hype.
You will need to speak to the regulators. We initially aimed for the primary endpoint to be confirmed disability progression, but the regulators preferred it to be ARR. But the PPMS trial was CDP so that you will have the data ;-)
I suggest we wait for the complete data set before jumping to premature conclusions about the impact of fenebrutinib on progression. I am expecting it to be superior to teriflunomide, similar to what was observed with tolebrutinib.
Agreed @kb! Am just so tired of seeing endless drug trials that continue to show inferior results to HSCT. And already CAR T- cell is looking superior to drugs in trials in China… time to persuade the neurologists to quit the drugs!
Re: "To me, the press release is just another example of propaganda and hype."
I am not sure it is. Roche-Genentech has a legal obligation to release the results, as they are market-sensitive. They need to do this to prevent insider trading. I am not sure it is hype. What have they hyped?
That’s disappointing I was actually excited for the first time of a chance of a new bullet for the gun against ms, I thought (wrongly) that as it doesn’t work like anti cd20 meds it would be an option
Last question on this regarding ms & crohns , ocrevus is not advised as it stays in the system for so long so if an ibs event happens it’s a bad situation to be in , does fenebrutinib leave the system a lot sooner so if an event occurs it would possibly be easier to treat , I’m grasping at straws here .
Thanks for replying, I’ve seen it’s also being looked at as a treatment for rheumatoid arthritis, I wonder if it will work for psoriatic arthritis also ? I will ask my rheumatologist.
Perhaps there’s still away of being able to receive it when it’s made available on the nhs 🤞
Thank you very much foe the info. Do you know I'd that are working on the drug approval in other countries? For example Canada? If so, can we estimate how long it could take?
I have been taiking Fingolimod for years. Do you think Fenebrutinib is likely to be more effective? Do you know at this stage what side effects it may exhibit? Many thanks for reading, Christina Willetts
Yes, I suspect fenebrutinib will be superior to fingolimod and other licensed MS DMTs. The side effect profile is reasonable, with the liver toxicity being the most significant. However, this can be mitigated through monitoring. Please read the phase 2 trial paper in Lancet Neurology.
Prof G- Is it possible to have a newsletter to compare top DMTs - BTKi vs ocrevus vs cladribine vs CAR-T . And practicalities in getting on them etc, hurdles etc.
We don't have enough data for that. The critical observation is that we are now moving towards CNS therapies, and I suspect when it comes to protecting the end-organ (brain and spinal cord), these will supplant the peripherally acting treatments.
I can appreciate we don’t have a complete picture, but beggars can’t be choosers and SPMS/ PPMS/ Smouldering MS are indeed beggars. We have to make risk/based decisions if need be. Perhaps go with off label medication if possible. Just because our disease is not terminal or deadly doesn’t make it carry any less weight. I personally think poor quality of life/ loss of basic independence should be classified as terminal. Maybe then the medical community will be more radical or less conservative with their prescriptions. No-one should be prescribing 30% effective DMTs anymore. Its shocking that this still happens. Yes research is really moving but not fast enough. We are effectively rotting veg, and keeping us in the fridge to slow the rot is not good enough anymore. We now know too much. My point is ii hope the medical community tries think outside the box and come up with really innovative approaches to deal with the collateral damage of pwMS having been treated with low grade DMT for the majority of their ms just because there was nothing available back then. Those group of pwMS i call collateral damage as we are the collateral damage of time vacuum, when nothing was known about ms. These groups may as well be forgotten as the new therapies will have most impact on newly diagnosed pwMS.
Very well said, Sal!
Some of us are still being prescribed these 30% effective DMT’s because are Neuro’s refuse to get on board.
Honestly this is so infuriating. There needs to be urgent action within the medical community so everyone is on the SAME page. Its unacceptable.
We all know better now, so there is no excuse.
The lack of urgency from the medical community is because MS is not a terminal or deadly disease. Unfortunately, most think “oh theyre still alive, so its all good”. Or they see those 1% percenters running marathons or climbing mount everest and think “ oh ms is grand! No that is not good enough! The medical community needs to try harder! There needs to be a movement. The ONLY person who is trying to make things better for people with MS is prof G! and a couple of other individuals in medical community. Thats it.
We dont live in the future. We live in the now. We need a treatment to apply now OR a script to use to educate archaic neurologists on how to treat MS. Yes some are bound by NICE regulations and what not but there must be a way to use these borderline therapies out of compassionate use. Our quality of life DEMANDS use of these borderline therapies out of compassionate use, just as is sometimes done on other rare diseases.
We need the medical community to change gears. The science has changed gears, now its time for science advocates to follow suit.
I was not given a choice my neuro prescribed Copaxone. I was 59 at the time and he thinks I've had MS for years. He said my MS is probably burnt out and then a new lesion was found.
I am smouldering and desperate since my ocrelizumab failed to keep me stable although i dont have new MRI lesions but my EDSS went from 3.5 to 6 in 1 year time while under ocrelizumab
Thats what im talking about, MS will “always“ progress or become smouldering . We need something that actually combats or halts smouldering, and that seems to be BTKi at the moment. Lack of new MRI lesions does NOT mean the treatment is being effective.
I would love to see another biomarker measure of effectiveness these drugs are being measured against . Perhaps one that gives us a measure of EBV activity in the body?
Exciting news but there are still a couple of hurdles to overcome. NICE to select it and will it be available to me, 71 years old, smouldering MS with no history of relapses but struggling with numerous disabilities.
Sorry to sound a bit negative but I do feel that people like my self are ignored and I suspect there are quite a lot of us who just have to get on with it.
Thank you for delivering and explaining the good news! Is Fenebrutinib going to have an advantage over B-cell therapies for addressing RAW and PIRA? For RRMS, PPMS? And do the results of PPMS translate also to SPMS?
Yes, that is the implication. That is addressed in the press release and suggests the data on PIRA is very good.
Thank you for this article. Could you provide a comment on Fenebrutinib in relation to Cladribine?
Too early. Let's wait for the results to be presented and published.
Exciting news!! When do you think this will be available via the NHS? And would be available to SPMS??…i assume yes as labelling of ms is becoming more flexible now after ECTRIMs… neurologists are not being too Jurassic in their ways of thinking anymore. However, the PAYE / NIHR market authorisation process may take some adjusting .. or allow prescribing neurologists some flexibility in “off label “ prescriptions perhaps?
It will take approximately 2 years to clear all the hurdles, including those with the MHRA, NICE, and NHS England. Please note that there is still one outstanding trial to report.
😣
Thank you doctor Giovannoni for giving us hope
Not only me. I think you should thank the Roche-Genentech team behind fenebrutinib - they have done a fantastic job and took significant risks with their development programme. I would like to give a shout-out to the medicinal chemists who invented the compound. They designed the molecule to possess specific attributes, and these trials validate their creativity and hard work. I would vote for them to win a version of the Academy Awards for MS research.
Finally some good news.
Commendable that FENtrepid tested against ocrelizumab. I'll even skip my usual gripes about the Oratorio data...
Now I am trying to make up my mind if I should try to get on the BMS CAR-T trial or wait for fen...
I would go for the here and now - a bird in hand is worth two in the bush. It will take 18-24 months for fenebrutinib to become available.
That’s exactly what im thinking about. Im currently on ocrevus, but considering jumping on the CAR-T clinical trial as that’s like a more targeted approach than full blown mass destruction of aHSCT therapy. But this new breakthrough has me thinking twice now
In the case of PPMS, the data on conventional AHSCT (even full blown myelo-ablative regimes) is not great to begin with - bad enough in fact that the local center does not do it anymore in PPMS.
I just so happens that I have a neuro appointment tomorrow, topic is pretty obvious now :)
Yes you are correct. I did AHSCT very early in the disease course (RRMS) active inflammatory disease. I wouldn’t have done it if I was PPMS and had MS for many years
Thanks. Am I the only one who finds it difficult to interpret the results relating to disability progression? Tolebrutinib (HERCULES - SPMS without relapses) delayed the time to onset of 6-month confirmed disability progression (CDP) by 31% compared to placebo. Ocrelizumab (as I understand it) was only tested in PPMS patients. Ditto Fenebrutinib (results above). So we have different patient groups (NR SPMS and PPMS) and a c.30% reduction in disability progression for all three drugs when tested in ‘progressive’ patients. Are progressive patients in the future going to be in a similar position as RRMS patients 25-30 years ago ie you have X drugs all offering a 30% reduction in xxx? 30% is a start in slowing disability progression, but what will be needed to boost this to 75%+ eg other add on therapies?
We need to wait for the full results to see how effective fenebrutinib is relative to ocrelizumab in PPMS and teriflunomide in RMS before we can comment.
Moreover, I'd appreciate an analysis of Frenebtutanib data versus the Ocrevus O'Hand data, if possible. Has the O'Hand data been somewhat glossed over (I do know you discussed quite comprehensively Prof. G) in the MS community in general? In my mind, the O'Hand trial results were significant as it showed preservation of upper extremity function in *older* cohort.
I think O'HAND is also a game-changer as it proves several theories we put forward about MS and also changes the way we do clinical trials and treat MS. I think things will gradually change once the results are published.
https://gavingiovannoni.substack.com/p/ectrims-2025-blowing-my-own-horn
This is why I did AHSCT very early
I was wondering your thoughts on Fenebrutinib vs CAR T cell therapy vs aHSCT and if you could do a newsletter on this ☺️ x
Too early. We need to see the full set of results.
Is it too early to compare Fenebrurtinib to aHSCT also? Thank you for your reply. C
Yes, too early. Let's wait for the results. I can say that fenebrutinib is safer than AHSCT.
Thank you! Do you know a guess estimate how long before fenebrutinib will be available? C
Thank you for your latest update! It sounds really encouraging. I live with a smouldering form of MS - clinically stable more or less for the past 4 years, EDDS now at 6.5, treated with Tysabri for the past 2 yerars +.
My question is whether, if inflammation can be more effectively controlled with treatments like fenebrutinib, combining that with focused physical training could help the body repair itself over time and possibly reduce disability, even if the medication itself doesn’t repair nerve damage. And what about adding creatine to this combination?
Thank you again for your ongoing work and for the hope it brings to us, pwMS.
Re: "My question is whether, if inflammation can be more effectively controlled with treatments like fenebrutinib..."
Yes, because it is CNS penetrant and targets central processes driving smouldering MS. Tolebrutinib will be licensed first. So if you have smouldering MS you may want to consider tolebrutinib and it will be some time before fenebrutinib becomes available.
I see that BTK inhibitors are being discussed at this week’s European Charcot Foundation meeting “SESSION III — Addressing progression by BTK Inhibition: Hype or Hope?”. Are the outcomes of these discussions made public? A very relevant discussion for MSers who are considering a BTK inhibitor as a possible future treatment to address their smouldering MS.
Yes. However, I believe the ECF requires a subscription to access the online (live) and recorded material.
VERY, VERY, VERY disappointing and discouraging to see yet another clinical trial for an "MS DMT" where the primary endpoint was ARR, when there is research that has found no association between relapses and long-term progression and CDW in MS (UCSF EPIC Study, Confavreux article/research, etc).
The disability progression endpoint is also not meaningful over such a short duration of time, when we know that irreversible disability accumulation in MS occurs over a long period of time and generally in the progressive phases of MS.
To me, the press release is just another example of propaganda and hype.
You will need to speak to the regulators. We initially aimed for the primary endpoint to be confirmed disability progression, but the regulators preferred it to be ARR. But the PPMS trial was CDP so that you will have the data ;-)
I suggest we wait for the complete data set before jumping to premature conclusions about the impact of fenebrutinib on progression. I am expecting it to be superior to teriflunomide, similar to what was observed with tolebrutinib.
Agreed @kb! Am just so tired of seeing endless drug trials that continue to show inferior results to HSCT. And already CAR T- cell is looking superior to drugs in trials in China… time to persuade the neurologists to quit the drugs!
Re: "To me, the press release is just another example of propaganda and hype."
I am not sure it is. Roche-Genentech has a legal obligation to release the results, as they are market-sensitive. They need to do this to prevent insider trading. I am not sure it is hype. What have they hyped?
Awesome news , will this be offered to patients like myself who can’t take anti cd20 medication due to crohns ?
Unlikely as HCPs are likely to extrapolate the anti-CD20 results to inflammatory bowel disease.
That’s disappointing I was actually excited for the first time of a chance of a new bullet for the gun against ms, I thought (wrongly) that as it doesn’t work like anti cd20 meds it would be an option
Last question on this regarding ms & crohns , ocrevus is not advised as it stays in the system for so long so if an ibs event happens it’s a bad situation to be in , does fenebrutinib leave the system a lot sooner so if an event occurs it would possibly be easier to treat , I’m grasping at straws here .
Yes. fenebrutinib washes out within days, and the B-cells are then functional.
It has multiple actions. One of its actions is to inhibit B-cells.
Thanks for replying, I’ve seen it’s also being looked at as a treatment for rheumatoid arthritis, I wonder if it will work for psoriatic arthritis also ? I will ask my rheumatologist.
Perhaps there’s still away of being able to receive it when it’s made available on the nhs 🤞
Thank you very much foe the info. Do you know I'd that are working on the drug approval in other countries? For example Canada? If so, can we estimate how long it could take?
Canada is likely to be on the same timeline as the UK. I would estimate 18-124 months.
I have been taiking Fingolimod for years. Do you think Fenebrutinib is likely to be more effective? Do you know at this stage what side effects it may exhibit? Many thanks for reading, Christina Willetts
Yes, I suspect fenebrutinib will be superior to fingolimod and other licensed MS DMTs. The side effect profile is reasonable, with the liver toxicity being the most significant. However, this can be mitigated through monitoring. Please read the phase 2 trial paper in Lancet Neurology.
linkinghub.elsevier.com/retrieve/pii/S1474-4422(25)00174-7
Bar-Or A, Dufek M, Budincevic H, Drulovic J, Habek M, Hua LH, Weber MS, Thomas P, Napieralski J, Mitzner MC, Ratchford JN, Clayton D, Harp CT, Kuruvilla D, Qi Q, Chen YF, Xu Y, Goodyear A, Oh J; FENopta Study Group. Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study. Lancet Neurol. 2025 Aug;24(8):656-666. doi: 10.1016/S1474-4422(25)00174-7. PMID: 40683275.
Exciting news. Can drug-induced liver injury be managed if signs of liver problems are detected?
Yes, with frequent liver function test monitoring in the first 12 weeks after starting the drug.
Does the patient have to stop taking the drug or can it be managed in another way? Thanks
The patient has to stop taking the drug.