I will be optimistic and give fenebrutinib a 40% chance (range 30-50%) of being superior to ocrelizumab in primary progressive MS. However, the dark horse is remibrutinib. What about tolebrutinib?
Possibly quite a lot. All the BTKi will be anti-EBV in that EBV uses BTK to keep infected cells alive. Blocking BTKi is likely to remove a pro B-cell survival signal that leads to B-cell death and the gradual purging of infected B-cells from the body. This is an hypothesis that needs to be tested in subjects with MS treated with these agents.
You have been saying for some time that the BTKi might be effective at depleting EBV infested B-cells. It would have been nice if the current trials had measured EBV levels. Is there any chance a post study could be done to measure EBV, and compare between treated and placebo groups?
If the BTKis are allowing apoptosis of latently infected B-Cells, why aren't we seeing a greater effect on relapses(if this is the MOA of b-cell depleters...killing EBV infected B-cells)? Is it possible that the relapse rate might go down with greater length of treatment with a BTKi? It should be interesting to see.
Perhaps we should also consider extended dosing B-cell depletion to cover RAW and then use the BTKis to reduce/eliminate any PIRA.
HERCULES data show a 31% lower risk of disability progression for patients. What does this mean for the layman? Does it mean you’ll still become increasingly disabled, but it will take a third longer to get to the EDSS level you would have got to if you hadn’t had the treatment? Is this level of slowing good (reminds me of the c.30% reduction in relapses from the first DMTs)? Could the effect be better the longer you are on the drug?
MS stat - looks like a complete failure and a waste of money and time. Similar situation to MS Smart. Why do we persist with these hit and hope studies (Octopus the next trial)? Now there is a better understanding of the mechanisms driving disability (smouldering MS) shouldn’t future MS society funded trials be targeting these mechanisms rather than trialing drugs which don’t appear to have any likely impact on the biology of this disease?
Re: "HERCULES data show a 31% lower risk of disability progression for patients. What does this mean for the layman?"
If you look at the 25% incidence, i.e. one in 4 people reached this milestone in about 18 months and it took those on Tolebrutinib about 36 months or longer to reach this milestone. Yes, the effects are likely to get better with time. There will also be variability around the mean with some people doing better than others. You are right in that most people will gradually get worse, but more slowly that if they were not on the drug.
Re: "MS stat - looks like a complete failure and a waste of money and time."
Yes, you are right. But hindsight is perfect vision. I agree that the MS Society should not be funding these trials. I think drug development at the stage of phase 3 should be done by Pharma. The MS Society should be funding proof-of-concept studies that move the dial.
Let's hope for the best on the tolebrutinib PPMS trial but honestly, after 5 years of Ocr for PPMS I am still declining and the infection frequency is climbing so I am leaning towards switching (off label if need be) even if it is just comparable...
The liver toxicity aside, this all sounds really exciting because it begins to prove that MS is just not one disease process and there are drugs coming through to prove and address this. Plus these drugs could be used profitably earlier on in MS than waiting until the SPMS label is applied.
Yes, it is very exciting and opens the door for a lot more research. The data confirms several hypotheses related to smouldering MS.
I think dealing with liver toxicity will something we do and as long as we can protect patients from DILI we should be okay. However, the regulators have to see the data in the same way we see it, otherwise they may say there is no unmet need.
DILI looks like a hypersensitivity or allergic reaction. I will happen a few patients who will have to stop taking the drug. It is manageable and happens with other drugs.
well this time is too hard to deny/ignore/misleading? I had this opinion in mind when you tried to picture Ofa & Ocr have different long term treatment outcome.
About 12 months in the US and 18-24 months in Europe. Please be aware a licensed product does not mean it will be available as healthcare systems still have many hurdles in relation to access; for example, in the England there is NICE and NHSE guidelines.
Please be aware because of the liver toxicity signal it may not be straightforward that this class of drug gets a license. The FDA will want to make sure patients are safe.
You say leisons are not the real MS, as you know I have agreed with this, but even at Ectrims as you know they are all saying the leison is first that causes the damage. Not that there’s underlying disease happening first. * it all just feels like pye in the sky, no one actually knows, so I don’t know how they can all dismiss it
Interesting that relapses and smoldering are being more clearly identified as independent processes. Is it possible we will see combination of therapies which might address both? Wondering about something like a traditional DMT alongside a BTKi.
I would be surprised about combination therapies, more likely to be sequential. I suspect BTKi's will be more effective when used after a B-cell depleting DMT.
Is anybody worried about cardiotoxicity of those new BTKi? Ibrutinib is known to cause cardiotoxicty and other 2nd gen BTKi used in oncology are known to cause heart issues.
> Although less than ibrutinib, newer BTK inhibitors still appear to link with residual cardiotoxic risks.
> However, a growing number of cardiac-focused reports have suggested a residual increase in cardiovascular risk even with next-generation BTK inhibitor therapies.
We haven't seen a signal yet. I suspect this is due to off target effects of the oncology BTKI's on other kinases. The newer agents are very selective. We probably should not be referring to them as being 2nd generation BTKi's, but probably as 3rd generation selective BTKi's. Saying this Tolebrutinib has known off-target effects.
Email question: "What is this saying about EBV?"
Possibly quite a lot. All the BTKi will be anti-EBV in that EBV uses BTK to keep infected cells alive. Blocking BTKi is likely to remove a pro B-cell survival signal that leads to B-cell death and the gradual purging of infected B-cells from the body. This is an hypothesis that needs to be tested in subjects with MS treated with these agents.
You have been saying for some time that the BTKi might be effective at depleting EBV infested B-cells. It would have been nice if the current trials had measured EBV levels. Is there any chance a post study could be done to measure EBV, and compare between treated and placebo groups?
I don't think so. Pharma are not interested in showing their drugs work via EBV mechanisms. Doing this would lower the bar for the competition.
Thank you Australia & Norway, for starting several EBV antiviral trials Q4 2024!
If the BTKis are allowing apoptosis of latently infected B-Cells, why aren't we seeing a greater effect on relapses(if this is the MOA of b-cell depleters...killing EBV infected B-cells)? Is it possible that the relapse rate might go down with greater length of treatment with a BTKi? It should be interesting to see.
Perhaps we should also consider extended dosing B-cell depletion to cover RAW and then use the BTKis to reduce/eliminate any PIRA.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10444716/
HERCULES data show a 31% lower risk of disability progression for patients. What does this mean for the layman? Does it mean you’ll still become increasingly disabled, but it will take a third longer to get to the EDSS level you would have got to if you hadn’t had the treatment? Is this level of slowing good (reminds me of the c.30% reduction in relapses from the first DMTs)? Could the effect be better the longer you are on the drug?
MS stat - looks like a complete failure and a waste of money and time. Similar situation to MS Smart. Why do we persist with these hit and hope studies (Octopus the next trial)? Now there is a better understanding of the mechanisms driving disability (smouldering MS) shouldn’t future MS society funded trials be targeting these mechanisms rather than trialing drugs which don’t appear to have any likely impact on the biology of this disease?
Re: "HERCULES data show a 31% lower risk of disability progression for patients. What does this mean for the layman?"
If you look at the 25% incidence, i.e. one in 4 people reached this milestone in about 18 months and it took those on Tolebrutinib about 36 months or longer to reach this milestone. Yes, the effects are likely to get better with time. There will also be variability around the mean with some people doing better than others. You are right in that most people will gradually get worse, but more slowly that if they were not on the drug.
Re: "MS stat - looks like a complete failure and a waste of money and time."
Yes, you are right. But hindsight is perfect vision. I agree that the MS Society should not be funding these trials. I think drug development at the stage of phase 3 should be done by Pharma. The MS Society should be funding proof-of-concept studies that move the dial.
Let's hope for the best on the tolebrutinib PPMS trial but honestly, after 5 years of Ocr for PPMS I am still declining and the infection frequency is climbing so I am leaning towards switching (off label if need be) even if it is just comparable...
The liver toxicity aside, this all sounds really exciting because it begins to prove that MS is just not one disease process and there are drugs coming through to prove and address this. Plus these drugs could be used profitably earlier on in MS than waiting until the SPMS label is applied.
Yes, it is very exciting and opens the door for a lot more research. The data confirms several hypotheses related to smouldering MS.
I think dealing with liver toxicity will something we do and as long as we can protect patients from DILI we should be okay. However, the regulators have to see the data in the same way we see it, otherwise they may say there is no unmet need.
"liver toxicity aside" - can it be put aside?
Are there good ways of dealing with it?
Or will liver toxicity be reason enough to move off this treatment?l
DILI looks like a hypersensitivity or allergic reaction. I will happen a few patients who will have to stop taking the drug. It is manageable and happens with other drugs.
I've developed this theory that you don't like Roche and your opinions over their products just have that extra subjective tone.
On the contrary. I think their BTKi fenebrutinib is likely to be best in class ;-)
well this time is too hard to deny/ignore/misleading? I had this opinion in mind when you tried to picture Ofa & Ocr have different long term treatment outcome.
How long will it take for the BTK's to be on the market and in what order will they be available?
About 12 months in the US and 18-24 months in Europe. Please be aware a licensed product does not mean it will be available as healthcare systems still have many hurdles in relation to access; for example, in the England there is NICE and NHSE guidelines.
Please be aware because of the liver toxicity signal it may not be straightforward that this class of drug gets a license. The FDA will want to make sure patients are safe.
Thanks so much for explaining the new drugs! I have been waiting to hear your account of Tolebrutinib.
Exciting stuff! Thank you for your diligent reporting on these developments!
Out of interest why do they compare to low efficacy treatments all the time? Why don’t they just compare Ocrevus to these straight away ?
You say leisons are not the real MS, as you know I have agreed with this, but even at Ectrims as you know they are all saying the leison is first that causes the damage. Not that there’s underlying disease happening first. * it all just feels like pye in the sky, no one actually knows, so I don’t know how they can all dismiss it
https://gavingiovannoni.substack.com/p/multiple-sclerosis-develops-long
https://gavingiovannoni.substack.com/p/hot-topic-aan-2023-smoldering-ms
https://gavingiovannoni.substack.com/p/can-you-have-a-relapse-affecting
https://gavingiovannoni.substack.com/p/is-it-ethical-to-use-teriflunomide
Interesting that relapses and smoldering are being more clearly identified as independent processes. Is it possible we will see combination of therapies which might address both? Wondering about something like a traditional DMT alongside a BTKi.
I would be surprised about combination therapies, more likely to be sequential. I suspect BTKi's will be more effective when used after a B-cell depleting DMT.
Is anybody worried about cardiotoxicity of those new BTKi? Ibrutinib is known to cause cardiotoxicty and other 2nd gen BTKi used in oncology are known to cause heart issues.
> Although less than ibrutinib, newer BTK inhibitors still appear to link with residual cardiotoxic risks.
> However, a growing number of cardiac-focused reports have suggested a residual increase in cardiovascular risk even with next-generation BTK inhibitor therapies.
https://www.jacc.org/doi/10.1016/j.jaccao.2023.09.002
We haven't seen a signal yet. I suspect this is due to off target effects of the oncology BTKI's on other kinases. The newer agents are very selective. We probably should not be referring to them as being 2nd generation BTKi's, but probably as 3rd generation selective BTKi's. Saying this Tolebrutinib has known off-target effects.
Ok so this shows it can target smouldering MS
Can we not combine btks and other treatments then to tackle both “best of both worlds” approach
Eg tysabri+ btk or ocrevus + btk?