Thanks for the very interesting update, sounds like a lot has been happening and that thinking is slowly changing or rather being accepted more widely in the MS neurology community. Your view on neuros in the community having an interest in maintaining the status quo is perturbing, thanks for illuminating it, food for thought and maybe a conversation 🙂
I believe there was a talk from the Atara people about ATA188, the anti-EBV neurogenic t-cell therapy they've been trialling, it's in the Istanbul branch of the symposium, title is "Confirmed Disability Improvement And Sustainability In Secondary Progressive Multiple Sclerosis Placebo Arm Patients". Obviously as a member of the public and non-attendee I don't have access to this.
Would it be possible to take a look and see if there's anything interesting in there?
Yes, I was there. It had nothing to do with their trial results only an analysis to see what happens to patients with progressive disease from data in the placebo arms of other progressive trials. They showed that very subjects with progressive MS had improvement in disability. Hence the Lazarus effects they are seeing with the product must be real. Or not, it is amazing how effective the placebo effect can be in trials.
When you tell people with SPMS "there's nothing we can do for you, we just need to make you as comfortable as possible" - when someone comes with a drug for progression, particularly one that claims to target the process that underlies it all - yeah the force is gonna be pretty strong with that one? Placebo? Hopium?
Other "lifestyle" changes such as diet and the "other" Disease Modifying Therapy (exercise) and the time required for the brain to rewire itself when diet and exercise and everything else have helped reduce inflammation / smouldering?
Jun 29, 2022·edited Jun 29, 2022Liked by Gavin Giovannoni
Tks Dr G. I notice you mentioned btki,s do delete ebv infected B cells. Are you then saying ata188 is not needed? Also u m ention antu cd20 therapy as very effective even more than btki,s. So if we are on anti cd20 therapy, are btki,s unnecessary?
No, all I am saying is BTKi inhibit EBV signalling in infected B cells, which may be how they work in B cell lymphomas. This may not be relevant to MS. It needs to be studied.
the remylenation trials at Cambridge are not accepting patients post hsct, but are accepting those that were treated with alumtuzumab. any thoughts on this ?
The BTKis appear to be offering a beacon of hope for many but could still be 5 years from market and their are no UK based trials. The idea that CD20 plus BTKi as a combo therapy to deal with both elements of the disease is logical but is the theory that this will actually halt progression entirely or simply slow things down as per the current DMTs. HSCT which is BBB penetrant and takes out all or the majority of EBV infected cells still seems to be the most effective option for those not willing or able to wait would you agree?
> To me, the dose-dependent impact of evobrutinib on slowly expanding lesions is the most exciting DMT data this year.
Prof. G, what makes you sure this is true? The slide you posted seems to indicate that the results aren’t statistically significant. Even without looking at the p-values, those error bars definitely do not pass the smack-you-in-eye test.
It is a post-hoc analysis of phase 2 trial. The study was not powered for this outcome. The observation is an unbiased measure using a software algorithm. The observation and interpretation is not about statistics, but biology. If we only acted on properly-powered statistical data we will still be navel gazing in 2050 ;-)
Thank you! Could Covid reactivate EBV which in turns exacerbates symptoms. Could peptides in the form of Thymosin Alpha One and Thymosin Beta Four help? In my case, the y have. I have had Covid twice. The peptides have helped! What do you think, Dr. G?!
I really don't know. Thymosins modulate the immune system and hence could potentially impact EBV biology. I have done a quick search and there is nothing published on this. However, EBV transcription factors interact with prothymosin.
“I am still predicting a Black Swan event in MS and the odds of it being due to EBV are increasing rapidly.” In what sort of timescale is the Black Swan event likely to occur? I’m fed up with waiting for this pesky Black Swan!
Thank you for your thorough report - did not seem repetitive material to me! Certainly the first time I've read anything suggesting BTKi's might also inhibit latent EBV.
And since the understanding of MS seems to have long been defined by the available drugs to treat it, I'm excited as a pwMS that the BTKi's could usefully reshape the concept of our disease. Getting way ahead of the bridges yet to cross, but I am really enouraged by this (and also reminded elsewher of the urgency of shedding some of my pounds).
A small case series of 10 patients treated with AHSCT on St Petersburg; 3 with RRMS and 7 with progressive MS. Surprise surprise the pwRRMS had major improvement in their EDSS whereas the pwPMS stayed stable.
Thanks for the very interesting update, sounds like a lot has been happening and that thinking is slowly changing or rather being accepted more widely in the MS neurology community. Your view on neuros in the community having an interest in maintaining the status quo is perturbing, thanks for illuminating it, food for thought and maybe a conversation 🙂
Clear, concise reflections. Thank you for sharing
All very interesting, and hopeful. Thanks for the update.😀
I believe there was a talk from the Atara people about ATA188, the anti-EBV neurogenic t-cell therapy they've been trialling, it's in the Istanbul branch of the symposium, title is "Confirmed Disability Improvement And Sustainability In Secondary Progressive Multiple Sclerosis Placebo Arm Patients". Obviously as a member of the public and non-attendee I don't have access to this.
Would it be possible to take a look and see if there's anything interesting in there?
Yes, I was there. It had nothing to do with their trial results only an analysis to see what happens to patients with progressive disease from data in the placebo arms of other progressive trials. They showed that very subjects with progressive MS had improvement in disability. Hence the Lazarus effects they are seeing with the product must be real. Or not, it is amazing how effective the placebo effect can be in trials.
When you tell people with SPMS "there's nothing we can do for you, we just need to make you as comfortable as possible" - when someone comes with a drug for progression, particularly one that claims to target the process that underlies it all - yeah the force is gonna be pretty strong with that one? Placebo? Hopium?
Other "lifestyle" changes such as diet and the "other" Disease Modifying Therapy (exercise) and the time required for the brain to rewire itself when diet and exercise and everything else have helped reduce inflammation / smouldering?
ATA188 still looks very promising...
Tks Dr G. I notice you mentioned btki,s do delete ebv infected B cells. Are you then saying ata188 is not needed? Also u m ention antu cd20 therapy as very effective even more than btki,s. So if we are on anti cd20 therapy, are btki,s unnecessary?
Rob
No, all I am saying is BTKi inhibit EBV signalling in infected B cells, which may be how they work in B cell lymphomas. This may not be relevant to MS. It needs to be studied.
the remylenation trials at Cambridge are not accepting patients post hsct, but are accepting those that were treated with alumtuzumab. any thoughts on this ?
Not sure why. You would have to ask them why they have excluded patients previously treated with AHSCT.
Maybe they think pwMS treated with AHSCT have remyelinated themselves spontaneously and won't report out in the trial.
Wouldnt that be nice !
The BTKis appear to be offering a beacon of hope for many but could still be 5 years from market and their are no UK based trials. The idea that CD20 plus BTKi as a combo therapy to deal with both elements of the disease is logical but is the theory that this will actually halt progression entirely or simply slow things down as per the current DMTs. HSCT which is BBB penetrant and takes out all or the majority of EBV infected cells still seems to be the most effective option for those not willing or able to wait would you agree?
> To me, the dose-dependent impact of evobrutinib on slowly expanding lesions is the most exciting DMT data this year.
Prof. G, what makes you sure this is true? The slide you posted seems to indicate that the results aren’t statistically significant. Even without looking at the p-values, those error bars definitely do not pass the smack-you-in-eye test.
It is a post-hoc analysis of phase 2 trial. The study was not powered for this outcome. The observation is an unbiased measure using a software algorithm. The observation and interpretation is not about statistics, but biology. If we only acted on properly-powered statistical data we will still be navel gazing in 2050 ;-)
Thank you! Could Covid reactivate EBV which in turns exacerbates symptoms. Could peptides in the form of Thymosin Alpha One and Thymosin Beta Four help? In my case, the y have. I have had Covid twice. The peptides have helped! What do you think, Dr. G?!
I really don't know. Thymosins modulate the immune system and hence could potentially impact EBV biology. I have done a quick search and there is nothing published on this. However, EBV transcription factors interact with prothymosin.
“I am still predicting a Black Swan event in MS and the odds of it being due to EBV are increasing rapidly.” In what sort of timescale is the Black Swan event likely to occur? I’m fed up with waiting for this pesky Black Swan!
They are quite pesky and highly unpredictable.
Thank you for your thorough report - did not seem repetitive material to me! Certainly the first time I've read anything suggesting BTKi's might also inhibit latent EBV.
And since the understanding of MS seems to have long been defined by the available drugs to treat it, I'm excited as a pwMS that the BTKi's could usefully reshape the concept of our disease. Getting way ahead of the bridges yet to cross, but I am really enouraged by this (and also reminded elsewher of the urgency of shedding some of my pounds).
Thanks for sharing ! I didn't attend this year so it was a good summary for me ☺️
Thanks for summarising and sharing. Were there any updates/developments on AHSCT?!
A small case series of 10 patients treated with AHSCT on St Petersburg; 3 with RRMS and 7 with progressive MS. Surprise surprise the pwRRMS had major improvement in their EDSS whereas the pwPMS stayed stable.