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...
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
Re: "Do we know the level of immune suppression? And vaccine immune response. PML risks?"
It will be immunosuppressive, but we did not see a big infection risk in the phase 2 study. Subjects who had COVID seemed to handle it well.
Based on its mechanism of action it is likely to blunt vaccine, but not necessarily booster, responses.
PML outside of natalizumab treatment is very rare. It will take years of post-marketing surveillance to answer this question. There is a possibility you may not need this class of drug long-term if we can show it re-induces immune tolerance.
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?
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.
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
It is more complicated that this. EBV is a herpes virus and most people who get infected remain infected for life. There is more to getting MS than just having EBV.
Please remember EBV is necessary but not sufficient to develop MS.
The doctor says (as well as all other sources I've seen), that "most people who get infected remain infected for life". Don't also forget that most people do get infected, something like 97% (?, look that up). That's the big question- Why most people do not get MS even though they have had EBV infection and it is currently latent in their bodies? Not all people with MS have an active EBV infection going on, most don't (I think). But it "seems to appear", perhaps, that if you are extremely unusual and have avoided EBV all your life, you will not get MS. You have to have had it, but other stuff brings it forward (genes, lifestyle, environmental factors, other infections, etc.) "necessary but not sufficient". It's very complicated. {just trying to promote some basic, albeit confusing, knowledge.} I am not at all, an "expert" :-)
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.
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?
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:
Yes and no. The Frexalimab study was very small and only over 12 weeks. The ocrelizumab data is from large phase 3 trials over 96-120 weeks. I agree that there is reduction in NfL levels at 12 weeks, but this is to be expected with a potent anti-inflammatory such as anti-CD20. Anti-CD20s are very effective at suppressing focal inflammation, i.e. relapses and focal MRI activity, which is why they are so widely prescribed. The problem I have is that this is not sufficient to tackle smouldering MS and you need to go beyond this treatment target. I am just making the case for evolving the MS treatment landscape beyond anti-CD20s.
Who knows in 10 years time t he anti-CD20s may still be the mainstay of treatment, but as induction agents followed by maintenance therapies. Or anti-CD20s could be the platform on which to build a sandwich that will include neuroprotection, remyelination and neurorestorative therapies and anti-ageing drugs.
Dear Prof G., as you mentioned anti cd20 is not Long term Solution for pwms. Would you recommend to start with them as a newly diagnosed high Active Patient or would you recommend starting with Cladribin ?if anti cd20 are Safe Short run to start with until perhaps we have better Treatments in the next years? Perhaps less risky than Cladribin ? Thanks for your oppinion!
This is a million $ question and cannot be simply answered as being black and white. All DMT decisions need to be personalised as is one of the reasons I recommend reading through all the information on the microsite.
Every trial listing includes the dates. Phase 3 trials typically last 3 years. The Frexalimab trial for nrSPMS has Study Start 2023-12-27, Primary Completion 2026-12-23. That's the 3 years of patient treatment, but they may announce "top line" results so we will know if it worked. Then there is Study Completion 2028-03-24, another 15 months to analyze data, get it published, and go through FDA review to see if it can be approved.
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...
Yes, I suspect so. There is a trial recruiting subjects with non-relapsing SPMS:
https://clinicaltrials.gov/study/NCT06141486
I sincerely hope by the time the results are available in 4-5 years time the FDA and EMA will have merged MS into one category called MS.
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
Re: "Do we know the level of immune suppression? And vaccine immune response. PML risks?"
It will be immunosuppressive, but we did not see a big infection risk in the phase 2 study. Subjects who had COVID seemed to handle it well.
Based on its mechanism of action it is likely to blunt vaccine, but not necessarily booster, responses.
PML outside of natalizumab treatment is very rare. It will take years of post-marketing surveillance to answer this question. There is a possibility you may not need this class of drug long-term if we can show it re-induces immune tolerance.
One other follow up, do you think with the potential for crossing BBB it will affect smouldering MS?
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?
EBV bypasses CD40-CD40L signalling by using a CD40 mimic that signals constitutively.
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.
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 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?
Re: "Those who can’t get rid of EBV get MS."
It is more complicated that this. EBV is a herpes virus and most people who get infected remain infected for life. There is more to getting MS than just having EBV.
Please remember EBV is necessary but not sufficient to develop MS.
The doctor says (as well as all other sources I've seen), that "most people who get infected remain infected for life". Don't also forget that most people do get infected, something like 97% (?, look that up). That's the big question- Why most people do not get MS even though they have had EBV infection and it is currently latent in their bodies? Not all people with MS have an active EBV infection going on, most don't (I think). But it "seems to appear", perhaps, that if you are extremely unusual and have avoided EBV all your life, you will not get MS. You have to have had it, but other stuff brings it forward (genes, lifestyle, environmental factors, other infections, etc.) "necessary but not sufficient". It's very complicated. {just trying to promote some basic, albeit confusing, knowledge.} I am not at all, an "expert" :-)
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.
Re: "Any reason for the 300 mg frexi cohort having so much more COVID vs. 1200mg and placebo?"
Luck or bad luck. Unlikely to be due to the dose.
Re: "Care to drop a link? I, too, have a list. Would be interesting to see if/how they overlap."
The paper is in press.
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.
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 will depend on where she lives and whether or not she would eligible for the SPMS Frexalimab trial.
Ferroptosis
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
Yes and no. The Frexalimab study was very small and only over 12 weeks. The ocrelizumab data is from large phase 3 trials over 96-120 weeks. I agree that there is reduction in NfL levels at 12 weeks, but this is to be expected with a potent anti-inflammatory such as anti-CD20. Anti-CD20s are very effective at suppressing focal inflammation, i.e. relapses and focal MRI activity, which is why they are so widely prescribed. The problem I have is that this is not sufficient to tackle smouldering MS and you need to go beyond this treatment target. I am just making the case for evolving the MS treatment landscape beyond anti-CD20s.
Who knows in 10 years time t he anti-CD20s may still be the mainstay of treatment, but as induction agents followed by maintenance therapies. Or anti-CD20s could be the platform on which to build a sandwich that will include neuroprotection, remyelination and neurorestorative therapies and anti-ageing drugs.
Congratulations
Will Barts participate in the the phase 3 trials (RRMS and/or SPMS)?
Yes, we will be participating in at least the RMS trial. Dr Sharmilee Gnanapavan will be the lead.
Dear Prof G., as you mentioned anti cd20 is not Long term Solution for pwms. Would you recommend to start with them as a newly diagnosed high Active Patient or would you recommend starting with Cladribin ?if anti cd20 are Safe Short run to start with until perhaps we have better Treatments in the next years? Perhaps less risky than Cladribin ? Thanks for your oppinion!
This is a million $ question and cannot be simply answered as being black and white. All DMT decisions need to be personalised as is one of the reasons I recommend reading through all the information on the microsite.
https://msselfie.co.uk/questions-to-ask/questions-to-consider-about-managing-your-ms/
Indeed, great scientific news but i saw many along the years ;)
Every trial listing includes the dates. Phase 3 trials typically last 3 years. The Frexalimab trial for nrSPMS has Study Start 2023-12-27, Primary Completion 2026-12-23. That's the 3 years of patient treatment, but they may announce "top line" results so we will know if it worked. Then there is Study Completion 2028-03-24, another 15 months to analyze data, get it published, and go through FDA review to see if it can be approved.
Here is the trial listing https://clinicaltrials.gov/study/NCT06141486