It is clear to me, and it should be clear to my colleagues, that anti-CD20 therapies have a limited shelf-life as a treatment for MS and will not be the mainstay of MS treatment in 10 years time.
Thanks. Some much needed hope after all the failures in the last few months.
So what is a realistic timeline for the completion of phase 3 here?
Also, any chance this will help in PPMS? I'm on Ocrelizumab (actually had an infusion yesterday and still feel the comedication) without too much belief that actually does much, thankfully at least the side effects are negligible (aside of that pesky vaccination issue). Having an exit strategy for that sure would be good...
"As you are aware, I have taken a very strong position on EBV, and I have been convinced that EBV causes MS and is the driver of MS disease activity. "
I agree EBV is a driver to MS disease activity 100%, but is it the only one?
MS (like all disease) is nothing more than a cluster group of dysfunctional gene variants that set off a domino effect of systematic dysfunction that creates susceptibility to opportunistic pathogens like EBV.
In other words, the difference between someone who develops MS and someone who doesn’t boils down to genetic variants that create a weakened ability to fight the heightened infection, and/or repair the damage. Environment and lifestyle factors that feed these defects further aggravate immune/repair dysfunction.
Understanding this, why would EBV be the only one to take advantage? Could there be co-infections adding to the load? Lyme has been studied as well as Nematode filarial. I’d love your thoughts.
I’ve told myself I am not getting excited unless phase 3 meets the endpoint going forward
So would this be an ongoing therapy like a Tysabri or an IRT?
If successful thru phase 3-4 based on data I would assume then the aim would be for folks to get off DMTs like Tysabri and ocrevus and switch over?
Do we know the level of immune suppression? And vaccine immune response. PML risks?
All of these would need to be answered and laid out. All in all looks very promising but I’ll keep expectations in check as been burned already with BTKs and ATA188
Another thought/question as I re-read your post regarding the future of MS treatments. If we know genetic variables create a susceptibility for MS (with contributing environment and lifestyle factors), why aren’t we looking at therapies that repair what’s ‘broken’ at root level instead of tinkering with fully functional aspects further up the long and complicated immune chain?
Hi Gavin. When do you reckon there could be Frexalimab trials for PPMS candidates?
I participated on a PPMS -brutinib trial but had to stop after a few months due to liver toxicity. Evidence is emerging that I'm not alone and liver damage could be a limiting factor on the usefulness of some/all of the -brutinibs from now on. Now on ocrelizumab which doesn't seem to be having an effect, so keen to be considered for a Frexalimab trial as soon as it becomes available.
As a person of 66 years old and 13 years with MS, will these pharmo companies ever address the efficiency for these new drugs for what I consider the "forgotten" MS population. I ask so insurance / Medicare providers will have more confidence in covering these new drugs.
Any reason for the 300 mg frexi cohort having so much more COVID vs. 1200mg and placebo?
"I have just completed a review article on potential EBV antivirals, and there are a lot of drugs that need to be tested in MS." Care to drop a link? I, too, have a list. Would be interesting to see if/how they overlap.
Anti-CD20 can have only ever been a starting point (it's anyways baffling to me how the MS field took so long to start trialling them, they wasted years before getting of their assess) as anyone in the RA field would have known.
To see how far this route goes one should have been far more aggressive in pursuing this route and looking to target what RTX doesn't target (LLPCs). I agree that CD19 CAR T-cells (or CAR-NK CD19 at much higher doses?) might get us there, but one could have tried targeting those cekks that don't just express CD20 much earlier already. What about CD19+BCMA? Hopefully B-cell targeting with CAAR-T therapy will eventually get us there.
I'm lost here. If "EBV infection induces CD40L/CD40 signaling in host cells, which appears to play an essential role in its persistent infection and malignancies of lymphocytes", then are you saying the CD40L is responsible for lysis of EBV, as latent infection doesn't seem to affect the general population?
A close relation "Karen" with non-active SPMS progressed significantly while on Rituxan/Ocrevus for 7 years AND she progressed while in the phase 2 ATA 188 study, which was a crossover study (she completed the study, thus received treatment). As you know, ATA 188 was a bust. Assuming she meets the inclusion criteria, would you encourage Karen to try and enroll in the Frexalimab phase 3 study?
That’s such exciting most promising news ProfG, I’m exceptionally hopeful for my daughter who’s 25yo and was diagnosed at 22yo. She was initially on Cladribine for 2 treatments then switched to Kesimpta
Yes I am concerned with long term side effects of Kesimpta as she’s very young and anything that has the potential of remission without more dosage “(establish immune tolerance)” and reducing brain atrophy & preventing smouldering MS would be incredible outcomes
I am very excited about this drug. But from what I have seen published so far frexalimab is not superior to ocrelizumab. Frexalimab has higher T1 rates and decreased NFL levels to a much smaller extent than ocrelizumab did over same measurement length. I looked at the published paper myself. Just compare the paper you discuss here with:
Thanks. Some much needed hope after all the failures in the last few months.
So what is a realistic timeline for the completion of phase 3 here?
Also, any chance this will help in PPMS? I'm on Ocrelizumab (actually had an infusion yesterday and still feel the comedication) without too much belief that actually does much, thankfully at least the side effects are negligible (aside of that pesky vaccination issue). Having an exit strategy for that sure would be good...
"As you are aware, I have taken a very strong position on EBV, and I have been convinced that EBV causes MS and is the driver of MS disease activity. "
I agree EBV is a driver to MS disease activity 100%, but is it the only one?
MS (like all disease) is nothing more than a cluster group of dysfunctional gene variants that set off a domino effect of systematic dysfunction that creates susceptibility to opportunistic pathogens like EBV.
In other words, the difference between someone who develops MS and someone who doesn’t boils down to genetic variants that create a weakened ability to fight the heightened infection, and/or repair the damage. Environment and lifestyle factors that feed these defects further aggravate immune/repair dysfunction.
Understanding this, why would EBV be the only one to take advantage? Could there be co-infections adding to the load? Lyme has been studied as well as Nematode filarial. I’d love your thoughts.
I’ve told myself I am not getting excited unless phase 3 meets the endpoint going forward
So would this be an ongoing therapy like a Tysabri or an IRT?
If successful thru phase 3-4 based on data I would assume then the aim would be for folks to get off DMTs like Tysabri and ocrevus and switch over?
Do we know the level of immune suppression? And vaccine immune response. PML risks?
All of these would need to be answered and laid out. All in all looks very promising but I’ll keep expectations in check as been burned already with BTKs and ATA188
Another thought/question as I re-read your post regarding the future of MS treatments. If we know genetic variables create a susceptibility for MS (with contributing environment and lifestyle factors), why aren’t we looking at therapies that repair what’s ‘broken’ at root level instead of tinkering with fully functional aspects further up the long and complicated immune chain?
Hi Gavin. When do you reckon there could be Frexalimab trials for PPMS candidates?
I participated on a PPMS -brutinib trial but had to stop after a few months due to liver toxicity. Evidence is emerging that I'm not alone and liver damage could be a limiting factor on the usefulness of some/all of the -brutinibs from now on. Now on ocrelizumab which doesn't seem to be having an effect, so keen to be considered for a Frexalimab trial as soon as it becomes available.
As a person of 66 years old and 13 years with MS, will these pharmo companies ever address the efficiency for these new drugs for what I consider the "forgotten" MS population. I ask so insurance / Medicare providers will have more confidence in covering these new drugs.
I have a question
-Those who can’t get rid of EBV get MS.
-Those who can’t get rid of SARS-CoV-2 get long-COVID.
Can we learn from SARS-CoV-2?
Any reason for the 300 mg frexi cohort having so much more COVID vs. 1200mg and placebo?
"I have just completed a review article on potential EBV antivirals, and there are a lot of drugs that need to be tested in MS." Care to drop a link? I, too, have a list. Would be interesting to see if/how they overlap.
Gonna slightly disagree on this one.
Anti-CD20 can have only ever been a starting point (it's anyways baffling to me how the MS field took so long to start trialling them, they wasted years before getting of their assess) as anyone in the RA field would have known.
To see how far this route goes one should have been far more aggressive in pursuing this route and looking to target what RTX doesn't target (LLPCs). I agree that CD19 CAR T-cells (or CAR-NK CD19 at much higher doses?) might get us there, but one could have tried targeting those cekks that don't just express CD20 much earlier already. What about CD19+BCMA? Hopefully B-cell targeting with CAAR-T therapy will eventually get us there.
I'm lost here. If "EBV infection induces CD40L/CD40 signaling in host cells, which appears to play an essential role in its persistent infection and malignancies of lymphocytes", then are you saying the CD40L is responsible for lysis of EBV, as latent infection doesn't seem to affect the general population?
A close relation "Karen" with non-active SPMS progressed significantly while on Rituxan/Ocrevus for 7 years AND she progressed while in the phase 2 ATA 188 study, which was a crossover study (she completed the study, thus received treatment). As you know, ATA 188 was a bust. Assuming she meets the inclusion criteria, would you encourage Karen to try and enroll in the Frexalimab phase 3 study?
Ferroptosis
That’s such exciting most promising news ProfG, I’m exceptionally hopeful for my daughter who’s 25yo and was diagnosed at 22yo. She was initially on Cladribine for 2 treatments then switched to Kesimpta
Yes I am concerned with long term side effects of Kesimpta as she’s very young and anything that has the potential of remission without more dosage “(establish immune tolerance)” and reducing brain atrophy & preventing smouldering MS would be incredible outcomes
Thank you for sharing 💝💝💝
I am very excited about this drug. But from what I have seen published so far frexalimab is not superior to ocrelizumab. Frexalimab has higher T1 rates and decreased NFL levels to a much smaller extent than ocrelizumab did over same measurement length. I looked at the published paper myself. Just compare the paper you discuss here with:
https://www.ocrevus-hcp.com/rms/efficacy.html
https://www.cuba.dialogoroche.com/content/dam/roche-dialogo/global-assets/downloadable-assets/neurology/roche-ectrims-2020/posters/ACTRIMS-ECTRIMS-2020-poster-bar-or-ocrelizumab-treatment-induces-a-sustained-blood-NfL-reduction-in-patients-with-PPMS-and-RMS.pdf
Congratulations
Will Barts participate in the the phase 3 trials (RRMS and/or SPMS)?