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.
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: "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.
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.
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.
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...
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.
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.
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.
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: "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.
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.
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.
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...
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.
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.