I'm 56. I'll be dead before anything comes to market to help me lol. Good news for those coming up behind though and those who haven't yet been diagnosed.
Thanks! You are very sweet. I'm hanging in there, what other choice do we have? lol And I will co-sign your wish for a vaccine for us golden smouldies. Hope you find some joy in this day!
Please can I have some Frexalimab. I have been reading about MS research since I was diagnosed age 30 when my son was 2. He is now 38 and I have just filled in the form to claim my state pension. Just give me the drugs.....PX
Mars, are you willing to share your center? I have been followed by UTSW- Dallas for 20 years but this center is in sharp decline following the departure of Elliot Frohman in 2015. I subscribed to your Substack in an attempt to contact you there but that does not seem possible. Perhaps you could email your subscribers if this is something you are open to.
Felicity, I haven't logged in lately, I apologize for the delay, I experienced a MS attack last month, not happy with my life or with the process. I'm in-patient if I don't see action.
Not many real MS experts in the world.
My Dr is Annette Okai, I see her in Plano, Tx,
at 5150 Warren Parkway suite 100, phone # 972-403-8184, website is www.ntinh.com
Dr Okai is now in Private practice, she separated from Baylor a few years ago, she was Baylor's only MS specialist for over 10 years.
I think my comment got dropped when I edited one? My brain is smouldering away! In any event, the gist was I am far too old for this, but I’m extremely excited by this research. I also appreciate your approach is that MS is MS without differentiating. It reminds me of a physician’s opinion that “classic” trigeminal neuralgia and “atypical” TN are TN. End of. This such heartening news for younger pwMS. I like the adverse effects profile so far. Thank you as always for keeping us informed. Great news! 🌷
Prof. G, Any thoughts on whether this monoclonal antibody can theoretically be effective in treating SPMS or, daresay, subsequently reverse damage? I recognize it is early and speculative....that is why I included the word "theoretically" in the question. Thank you for all you do.
Yes, it will likely working in SPMS. I am in the camp of treating MS as one disease and not two, three or four diseases. You have MS not relapsing MS or SPMS.
Thanks as ever prof G for taking the time to inform and educate pwMS. And additional thanks to Simon Brown for all the explanations. News like this brings much needed hope to this parent of a child with MS.
Surprisingly the infection rate was low and patients dealt with infections well. There is a lot of redundancy in the immune system so PML infection risk is likely to be low and not in the same zone as natalizumab. We need to wait for the phase 3 trials and the extension data before drawing premature conclusions.
Prof G, is there any value in these existing therapeutics for CD04L?
An alternative antiplatelet agent that has been shown to reduce the activation-induced release of sCD04L from platelets is dipyridamole the; major way in which it inhibits platelets is via phosphodiesterase (PDE) inhibition.
Furthermore, ibudilast, an alternative PDE inhibitor, attenuated Tat-induced inflammatory responses in a murine microglial cell line [73] and it has been shown to control the release of sCD40L from platelets.
Source: 2013 Targeting platelet-derived soluble CD40 ligand: a new treatment strategy for HIV-associated neuroinflammation?
Lupus -> Frontal lobe lesions -> "Schizophrenia" / other similar conditions...
Treated with rituximab (same mechanism as Ocrevus).
Potentially the same cause, EBV? We know they're testing frex on lupus as well. This work could have implications far beyond MS in some very serious and seemingly intractable mental health cases...
What would be the risks/possibility of pwMS having anti virals outside a trial? As pointed out by others before patients with AIDs and Covid saw improvement in their MS symptoms while on anti virals.
Unlikely on the NHS. It will be difficult to justify anti-viral considering the current evidence base. We really need well designed definitive clinical trials that lead to licensed therapies that are properly reimbursed.
My *MS* fatigue resolves with valacyclovir. I’m on it for another reason unrelated to MS nor fatigue. Surprise! It supports my aging immune system (which keeps allowing EBV reactivations and reactivating MS).
Having recently joined a 2 year Ph3 BTKi trial, do the anti-CD40L revelations mean I've just boarded the wrong bus?
Facetious comment as an equivalent Frexalimab trial won't be ready in the lifetime of the trial I've joined and I'm hoping it makes a positive impact on my progression. However, it's tough on the pharmas if they are part-way to market on meds that could be virtually obsolete by the time they can release them to market.
No not at all. With every new compound, particularly first in class in relation to MS, may cause unexpected complications that results in the programme being pulled. There is a failure rate with all phase 3 drug development programmes. This is not exception. Who knows you may have backed the right horse.
May 31, 2023·edited May 31, 2023Liked by Gavin Giovannoni
Doesn't seem to deplete lymphocytes so we'd have almost fully-functional immune systems (apart from the broken bits which would be turned off by frex).
I appreciate that "MS is all one disease" but there is PIRA and progression in patients with full CD20-induced B cell depletion so there has to be SOMETHING making that happen. T cells with some kind of memory triggered by CD40 to CD40L (CD154) on the T cells maybe?
We know that antibodies are blocked by the blood brain barrier (BBB), whereas B & T cells, 1000x bigger than antibodies, are allowed across.
So presumably as this blocks CD40L rather than inducing apoptosis (killing the cell completely)...
CD40/L-blocked B & T cells are allowed in, across the BBB...
and then don't attack myelin as they've forgotten how to...
eventually allowing progression to stop...
and maybe even reverse a little bit?
Would there be attendant blood tests to see when EBV has been eradicated completely? Presumably at that point frex could be reduced to see if MS reactivates. And if it doesn't then the MS has, in effect, been (I hesitate to use the C word) rendered dormant?
I'm 56. I'll be dead before anything comes to market to help me lol. Good news for those coming up behind though and those who haven't yet been diagnosed.
wtf? You're only 56. I'm on a mavenclad support group chatting with some bloke who just finished his 2nd year at the age of 75.
If frex is any good it'll be licensed before 2030...
LOL. Yeah, I was mostly kidding but I am frustrated by the speed of research.
Me, me also! I’m much older than you. But I’m happy for the younger ones. I wish there were a vaccine for us golden smouldies. Hang in there, eh?🌷
Thanks! You are very sweet. I'm hanging in there, what other choice do we have? lol And I will co-sign your wish for a vaccine for us golden smouldies. Hope you find some joy in this day!
Please can I have some Frexalimab. I have been reading about MS research since I was diagnosed age 30 when my son was 2. He is now 38 and I have just filled in the form to claim my state pension. Just give me the drugs.....PX
Unfortunately, not. It is still in development and it will be a long time yet for it to get to market.
How long? :(
Could it not be fast tracked the way tysabri was afaik?
Dont worry. Being humourous.
Pam, I can relate. I wish I were a decade or two younger.🌷
Thank you Prof G.
You are one of the few leaders, leading the courageous fight against the MonSter, keep up the pressure and theorizing.
I Inform anyone who will listen to find you.
My MS Dr in Texas discuss's you quite often now, I've discussed your theories for years.
I hope we get to the remission promise land, too many of us are suffering, especially the younger MS patients need a bone.
Thank you for your support.
Mars, are you willing to share your center? I have been followed by UTSW- Dallas for 20 years but this center is in sharp decline following the departure of Elliot Frohman in 2015. I subscribed to your Substack in an attempt to contact you there but that does not seem possible. Perhaps you could email your subscribers if this is something you are open to.
Thank you.
Subscribers can email questions to ms-selfie@giovannoni.net
Felicity, I haven't logged in lately, I apologize for the delay, I experienced a MS attack last month, not happy with my life or with the process. I'm in-patient if I don't see action.
Not many real MS experts in the world.
My Dr is Annette Okai, I see her in Plano, Tx,
at 5150 Warren Parkway suite 100, phone # 972-403-8184, website is www.ntinh.com
Dr Okai is now in Private practice, she separated from Baylor a few years ago, she was Baylor's only MS specialist for over 10 years.
Goodluck,
Mars
I think my comment got dropped when I edited one? My brain is smouldering away! In any event, the gist was I am far too old for this, but I’m extremely excited by this research. I also appreciate your approach is that MS is MS without differentiating. It reminds me of a physician’s opinion that “classic” trigeminal neuralgia and “atypical” TN are TN. End of. This such heartening news for younger pwMS. I like the adverse effects profile so far. Thank you as always for keeping us informed. Great news! 🌷
Prof. G, Any thoughts on whether this monoclonal antibody can theoretically be effective in treating SPMS or, daresay, subsequently reverse damage? I recognize it is early and speculative....that is why I included the word "theoretically" in the question. Thank you for all you do.
Yes, it will likely working in SPMS. I am in the camp of treating MS as one disease and not two, three or four diseases. You have MS not relapsing MS or SPMS.
Thanks as ever prof G for taking the time to inform and educate pwMS. And additional thanks to Simon Brown for all the explanations. News like this brings much needed hope to this parent of a child with MS.
This seems to be aimed at RMS, do you think it will potentially help with smouldering MS?
Yes, I do. This is why I compare its mode of action to some of the IRTs that deplete T-cells.
Thanks for response Prof G, sounds promising.
I would also be interested to know if there’s any potential for SPMS? And does this drug immunosuppress and hence expose the patient to PML? Thankyou!
Surprisingly the infection rate was low and patients dealt with infections well. There is a lot of redundancy in the immune system so PML infection risk is likely to be low and not in the same zone as natalizumab. We need to wait for the phase 3 trials and the extension data before drawing premature conclusions.
Prof G, is there any value in these existing therapeutics for CD04L?
An alternative antiplatelet agent that has been shown to reduce the activation-induced release of sCD04L from platelets is dipyridamole the; major way in which it inhibits platelets is via phosphodiesterase (PDE) inhibition.
Furthermore, ibudilast, an alternative PDE inhibitor, attenuated Tat-induced inflammatory responses in a murine microglial cell line [73] and it has been shown to control the release of sCD40L from platelets.
Source: 2013 Targeting platelet-derived soluble CD40 ligand: a new treatment strategy for HIV-associated neuroinflammation?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906985/
2019 Dipyridamole as a new drug to prevent Epstein-Barr virus reactivation
https://www.sciencedirect.com/science/article/pii/S0166354219303304
Thanks. I will look into this in more detail.
Dipyridamole is being used for long covid, also suspected of being driven by reactivated EBV.
https://www.washingtonpost.com/wellness/2023/06/01/schizophrenia-autoimmune-lupus-psychiatry/
Lupus -> Frontal lobe lesions -> "Schizophrenia" / other similar conditions...
Treated with rituximab (same mechanism as Ocrevus).
Potentially the same cause, EBV? We know they're testing frex on lupus as well. This work could have implications far beyond MS in some very serious and seemingly intractable mental health cases...
Anti-CD40L is also being tested in lupus. The lupus programmes are further ahead, i.e. one is in phase 3.
What would be the risks/possibility of pwMS having anti virals outside a trial? As pointed out by others before patients with AIDs and Covid saw improvement in their MS symptoms while on anti virals.
Unlikely on the NHS. It will be difficult to justify anti-viral considering the current evidence base. We really need well designed definitive clinical trials that lead to licensed therapies that are properly reimbursed.
My *MS* fatigue resolves with valacyclovir. I’m on it for another reason unrelated to MS nor fatigue. Surprise! It supports my aging immune system (which keeps allowing EBV reactivations and reactivating MS).
Having recently joined a 2 year Ph3 BTKi trial, do the anti-CD40L revelations mean I've just boarded the wrong bus?
Facetious comment as an equivalent Frexalimab trial won't be ready in the lifetime of the trial I've joined and I'm hoping it makes a positive impact on my progression. However, it's tough on the pharmas if they are part-way to market on meds that could be virtually obsolete by the time they can release them to market.
No not at all. With every new compound, particularly first in class in relation to MS, may cause unexpected complications that results in the programme being pulled. There is a failure rate with all phase 3 drug development programmes. This is not exception. Who knows you may have backed the right horse.
I'm excited to read such news,however I am wondering if this includes All types of MS ..this wasn't made clear.
This trial was in relapsing MS. The phase 3 programme will include the same population.
We really need to get away from thinking of MS being 3 or 4 different diseases. The biology does not support this. MS is one disease.
Yes!!!
Thanks for the reply..much appreciated.
Doesn't seem to deplete lymphocytes so we'd have almost fully-functional immune systems (apart from the broken bits which would be turned off by frex).
I appreciate that "MS is all one disease" but there is PIRA and progression in patients with full CD20-induced B cell depletion so there has to be SOMETHING making that happen. T cells with some kind of memory triggered by CD40 to CD40L (CD154) on the T cells maybe?
We know that antibodies are blocked by the blood brain barrier (BBB), whereas B & T cells, 1000x bigger than antibodies, are allowed across.
So presumably as this blocks CD40L rather than inducing apoptosis (killing the cell completely)...
CD40/L-blocked B & T cells are allowed in, across the BBB...
and then don't attack myelin as they've forgotten how to...
eventually allowing progression to stop...
and maybe even reverse a little bit?
Would there be attendant blood tests to see when EBV has been eradicated completely? Presumably at that point frex could be reduced to see if MS reactivates. And if it doesn't then the MS has, in effect, been (I hesitate to use the C word) rendered dormant?
Wow great stuff doc!!!!
A question though: I never had Gad enh. Lesions. Does this mean cd40, cd40l does not apply to me? Rob
No. Gd-enhancing lesions are only the tip of the iceberg.
Do you know if there any plans for trials in primary progressive MS? Thanks
No, not yet. But PPMS is MS and hopefully the regulators will start treating MS as one disease.
Thanks and fingers crossed!