It would be a travesty if in 20 years' time the next generation of MS researchers discover that antivirals are a very effective treatment for MS when we have the tools to answer this question now.
There has only been one EBV vaccine trial with a single lyric antigen GP350 and it didn't fail. It reduced the incidence of IM by 78%. GSK licensed it to Medimmune who then decided to not to develop it.
There are ways to flush out EBV using CTLs, CAR T-cells and potentially EBNA1 inhibitors.
GSK's VZV vaccine works very well at boosting anti VZV responses and keeps VZV silent. Why won't an EBV vaccine work? EBV and VZV are related to each other; they are both human herpes viruses.
EBV is a biological agent with many targets. Don't you trust science?
“Would you volunteer to participate in a clinical trial of an antiviral drug cocktail to suppress MS disease activity, in particular smouldering MS?” Why ask questions you already know the answer to? The travesty is: (i) we now have good evidence that ebv is the main cause of MS; (ii) patients (those who keep up to date with MS research) want treatments to address ebv / smouldering MS; (iii) patients have no influence on determining which types of drugs eg anti-virals go into trial. You can keep posting this stuff until you are blue in the face, but someone (it might not be you) needs to drive this through to completion rather than keep writing about it. There are two types of people in this world - those who talk about doing something and those who actually do something. Writing endless news letters falls into the former. Getting a trial up and running falls into the latter. Yes I know my post will come across as rude, but I find the excuses for not doing something which will really change the future of MSers tiresome. This MS-Selfie has annoyed me so I’m taking the dog out to get some fresh air. Perhaps when I’m out you can sketch out a plan for a trial of an anti- rial and get the ball rolling,
I have had MS for 22 years. I heard terms such as 'tantalisingly close' and 'within the next ten years' so many times that it has almost driven a kind a cynicism within me. I don't wish to decry the hard work of anyone trying to better understand this disease, its just feels as though barking up the same tree for 30 years has not really got us that much closer. I very thankfully benefitted from being in the first wave of RRMS'ers to take DMT's. This kept me pretty stable and largely relapse free. Not being nibbled away by regular relapses afforded me a great 15 years. Sadly like so many in my position I hit that cliff edge where the transition to SPMS, (or the one process overtaking the other) was very abrupt and over a handful of years has taken me from walks in the countryside to being wheelchair bound. I took great interest In Dr Gold's hypothesis and and am so pleased that there is still the will to study it further. I would be more than willing to be involved in any studyies. Sadly I know no wealthy philanthropists. I was connected with GSK anti infectives but sadly everyone I knew has moved on or retired. Would crowdfunding be an option? I assume a lot of these meds are generics by now.
I will start writing to my insurance and MS societies to show support for anti-virals and huge cost savings, then the cat is out of the bag.
The cost of Lemtrada x 2 rounds paid by insurance was over $200,000 dollars total, anti-virals would cost a fraction vs Lemtrada cost.
IF anti-virals are the treatment of choice for MS, who would question the logic of reducing high costs of treating MS patients ? Reduce the cost by a ratio of 200,000 : 1, just one example.
Most HIV anti-viral drugs are generic in the USA, Meaning if manufacturing isn't difficult /issue, the anti-virals may cost pennies per tablet to produce, just guessing on cost of tablets made.
If you were to bet on which antiretroviral(s) are most likely to be of benefit in MS, which would you investigate? Is there a pattern in the case reports of people who have HIV and MS improvement? I would have thought that drug companies would be clamouring to extend their patents by finding new indications for their products, but maybe the patents have already elapsed? Are there any epidemiological studies looking at MS and PrEP yet, or is it too new?
Yes. Prof Gold and I are about to start making the rounds again to all the HIV companies. However, my money is on therapeutic EBV vaccines and EBV specific or targeted antivirals. Contrary to what Ian says we have been working on the Charcot Project for years. The problem is people don't realise that science is a slow process.
But if the immune system is intact (which it isn’t when taking disease modifiers), why would vaccination be better than the EBV infection response. We’ve been told that CoVID infection response is better than vaccination, so why do you think EBV will be the other way around? Also, having been hospitalised for three weeks by CoVID, because Ocrelizumab blocked my antibody production to 3 Pfizer BioNTech CoVID vaccinations, I can’t see any other vaccines having the desired effect. My money is on the T cell therapies that bypass the inadequate genetics like Atara’s Allogeneic T‑Cell Immunotherapies. I can see EBV vaccination preventing MS, partly through herd immunity, once added to the childhood immunisations for future generations, but that doesn’t help pwMS now.
Oh yes. It's not just double blind, it's triple blinded. There was a 50% chance that I was on placebo. I'm assuming I was. Had I remained in the study, I would have definitely received the drug in a following year. But I couldn't hang. My walking severely deteriorated.
I remember referring an haemophiliac for plastic surgery for his lipodystrophy, many years ago, because homosexual men were recognising his antiretroviral fat pad and trying to pick him up inappropriately as he walked around in public with his wife and young daughter. Rather than approaching the HIV drug companies to see who will back this research, you probably need an idea of which compounds are most likely to provide fruitful studies.
Is there anything we could do to nudge our neurologist to get them to give us a prescription for these antivirals?
Mine is very firmly a believer of the EBV aspect and as such has pushed Lemtrada (outside of ahsct as I can’t get it here) and tbf I am a bit too nervous of the side affects of Lemtrada and why I’m switching to Mavenclad instead from Tysabri
What antivirals could we request? I’m in Australia so we are more open to trying things outside the norm to an extent
I think that case reports are not sufficient to move a big pharma to invest money on antivirals for MS. If you and your colleagues want to have real trial up and running I am afraid that you will need to collect much more case reports to push pharma to spend money.
Personally, I would take an antiviral but I can't because a prescription is needed and no physician is going to prescribe it and also because the prices of the branded versions are quite high. I could decide to buy and take the drug (and responsibility for adverse events and consequences) from India where it is way cheaper but I would still need a prescription nobody will make to buy and import events drug even for personal use. So we are all stuck to pharma not investing, charities not funding, and doctors not prescribing while we really want to do something for ourselves.
Crowdfunding could work if you source generics or from place like India. If one year treatment is in the thousands euros range with the registered drug, it will be impossible to get enough money in a reasonable time to do the trial
What about neurologists prescribing antivirals - off-label - now, in addition to regular DMDs? I’m sure I’m not the only one that would be willing to take them. There have already been a few studies but then they stopped.
Thanks! If patients are willing to try - with an anti-viral that has a lengthy safe history- say, an antiviral that’s been used for lupus for years? Just grasping for how from an ms’er.
But how do you show the antiviral is working when you are on a high-efficacy DMT? I would suggest a induction-maintenance strategy, i.e. to see if the antiviral keeps you in remission after induction with a high efficacy DMT. Another strategy is to start pwMS on natalizumab on an antiviral and see if it can prevent natalizumab rebound. Do we have equipoise for the latter?
Feb 26, 2022·edited Feb 26, 2022Liked by Gavin Giovannoni
Last I checked, high efficacy DMT (with the excepton of some lucky alemtuzumab takers, for cladribine it seems too early to tell) did not prevent progression, only slowed it down.
So if the antiviral does something as an addon, we will see it. Might need a bigger study this way to get enough statistical power but presumably it would be easier to recruit people than telling them they need to stop their DMT.
Not sure if we have equipoise for the natalizumab discontinuation (never really looked into natalizumab).
Cladribine followed with antiviral or nothing sounds like it would achieve equipoise in as far as people would surely be no worse than standard of care. Same argument with alemtuzumab but given the rarity of its prescription, I really doubt you could conceivably do that study.
Come to think of it, I guess you could get equipoise for people who wanted to stop anti cd20 either way but again not convinced there would be enough recruits... Personally would most likely not sign up for that design.
I am sure many, myself included, would volunteer for a trial. Would some like Crowdacure help to fund it or could participants pay for their own costs and is this ethical? I am clearly no expert but would a HIV drug that is a combination therapy like Combivir gove a better chance of success?
alafenamide (TAF), couldn't like minded, willing doctors / patients try this in the meantime? I also found a report of an HIV positive person who also has Multiple Sclerosis who was on Tenofovir alafenamide as part of her HIV treatment, while she was taking it her MS symptoms were in remission and as soon as they stopped it and put her on Tenofovir disoproxil fumarate instead her MS was active again.
Geneuro is expected to report results of their anti-HERV-W monoclonal antibody temelimab in March (I'm guessing end of March). Results from an initial phase 2 were partially positive, albeit with no evident anti-inflammatory properties.
That being said, are neurologists tied up regarding prescribing HAART off label? How was Rituximab discovered to be efficient in MS?
Dr. G: I didn’t think Ocrelizumab nor Rituximab were able to deplete memory cells? That memory cells don’t present with CD19/20 cell surface protein. Could you please confirm for me?
I’m just coming out of AHSCT as I type. I had found this research EBV/HERV connection a few years ago and decided on a few drugs to pursue under supervision of my neuro who you know. My body didn’t tolerate them, yet at this stage I think I need to really ensure - moving forward - that I’ve got enough pharma under my belt to prevent disease reactivation. Please let me know your thoughts on specific anti-retroviral therapies….if you feel comfortable to? Thanks 🙏
I am really happy to volunteer as a participant for an anti retrovirus trial. Currently on Sizomus trial which is fascinating and very motivating. I gain so much knowledge from this and I would urge anyone who can travel confortably to Barts every 4 weeks, to take part. Once my engagement in this has ended, I would love to engage in an anti retrovirus trial. Prof G thankyou so much for all your ideas and for all the hard work you put in over many years, to bring these ideas to fruition.
I'd sign up for that trial, especially if I could stay on my DMT. I recently dropped out of ATA188 trial due to progression. Trying my third DMT now - Tysabri and it's definitely helping. But as I'm JC-positive, my time limit on the drug will sunset at some point because of the PML risk.
Are there significant differences between an antiviral like Valacyclovir and antiretrovirals? I'd read about that guy with HIV a while back, but never heard anything more.
Feb 26, 2022·edited Feb 26, 2022Liked by Gavin Giovannoni
“Would you volunteer to participate in a clinical trial of an antiviral drug cocktail to suppress MS disease activity, in particular smouldering MS?”
Since you are asking this (it seems) in the context of any “stage” of MS, I’ll comment: I’m 64 and have made it this far, which means for many like me, we are concerned about not adding another thing to the mix of things we may have already added, that can contribute to things going wrong, when you are not a “spring chicken”. The immune system is the way it is; fine tuning has been happening by random luck I might add, over millions of years. The overall system has good reason to be exactly the way it is.
And you do a great job of trying to describe the outcome of all this in terms of MS, to us laypeople and/or others. I am reluctant to throw a wrench into the gears unless there is good evidence and reason to believe and trust that doing so, won’t screw things up even more. Not in MS terms, but in terms of other things that will eventually turn sour. And I say this in the context of us already seeing what happens when a new virus comes along and your B cell depleter med has wiped out sufficient parts of your immune system that would normally fight it. What also happens, socially, is that some of the people who manufacture the DMT just “blow through” the valid questions as if nothing were happening, leaving the consequences it seams, almost to random selection again- that is, who survives and why will be studied by someone else. B cells may do more than carry EBV, they may fight some types of cancer (I read), for example. So while I am a big believer in science I would be extremely hesitant to enroll in a study at this stage of my game, unless I was given some good reassurance. If I were 30, you’d get a different answer as things for me have already largely played out. Don’t get me wrong, I would like to hear and learn more. But, for “survival’s” sake, I am beyond the guinea pig stage.
There has only been one EBV vaccine trial with a single lyric antigen GP350 and it didn't fail. It reduced the incidence of IM by 78%. GSK licensed it to Medimmune who then decided to not to develop it.
There are ways to flush out EBV using CTLs, CAR T-cells and potentially EBNA1 inhibitors.
GSK's VZV vaccine works very well at boosting anti VZV responses and keeps VZV silent. Why won't an EBV vaccine work? EBV and VZV are related to each other; they are both human herpes viruses.
EBV is a biological agent with many targets. Don't you trust science?
“Would you volunteer to participate in a clinical trial of an antiviral drug cocktail to suppress MS disease activity, in particular smouldering MS?” Why ask questions you already know the answer to? The travesty is: (i) we now have good evidence that ebv is the main cause of MS; (ii) patients (those who keep up to date with MS research) want treatments to address ebv / smouldering MS; (iii) patients have no influence on determining which types of drugs eg anti-virals go into trial. You can keep posting this stuff until you are blue in the face, but someone (it might not be you) needs to drive this through to completion rather than keep writing about it. There are two types of people in this world - those who talk about doing something and those who actually do something. Writing endless news letters falls into the former. Getting a trial up and running falls into the latter. Yes I know my post will come across as rude, but I find the excuses for not doing something which will really change the future of MSers tiresome. This MS-Selfie has annoyed me so I’m taking the dog out to get some fresh air. Perhaps when I’m out you can sketch out a plan for a trial of an anti- rial and get the ball rolling,
I have had MS for 22 years. I heard terms such as 'tantalisingly close' and 'within the next ten years' so many times that it has almost driven a kind a cynicism within me. I don't wish to decry the hard work of anyone trying to better understand this disease, its just feels as though barking up the same tree for 30 years has not really got us that much closer. I very thankfully benefitted from being in the first wave of RRMS'ers to take DMT's. This kept me pretty stable and largely relapse free. Not being nibbled away by regular relapses afforded me a great 15 years. Sadly like so many in my position I hit that cliff edge where the transition to SPMS, (or the one process overtaking the other) was very abrupt and over a handful of years has taken me from walks in the countryside to being wheelchair bound. I took great interest In Dr Gold's hypothesis and and am so pleased that there is still the will to study it further. I would be more than willing to be involved in any studyies. Sadly I know no wealthy philanthropists. I was connected with GSK anti infectives but sadly everyone I knew has moved on or retired. Would crowdfunding be an option? I assume a lot of these meds are generics by now.
I very much hope this can gain traction again.
Regards
RV
I will start writing to my insurance and MS societies to show support for anti-virals and huge cost savings, then the cat is out of the bag.
The cost of Lemtrada x 2 rounds paid by insurance was over $200,000 dollars total, anti-virals would cost a fraction vs Lemtrada cost.
IF anti-virals are the treatment of choice for MS, who would question the logic of reducing high costs of treating MS patients ? Reduce the cost by a ratio of 200,000 : 1, just one example.
Most HIV anti-viral drugs are generic in the USA, Meaning if manufacturing isn't difficult /issue, the anti-virals may cost pennies per tablet to produce, just guessing on cost of tablets made.
If you were to bet on which antiretroviral(s) are most likely to be of benefit in MS, which would you investigate? Is there a pattern in the case reports of people who have HIV and MS improvement? I would have thought that drug companies would be clamouring to extend their patents by finding new indications for their products, but maybe the patents have already elapsed? Are there any epidemiological studies looking at MS and PrEP yet, or is it too new?
Yes. Prof Gold and I are about to start making the rounds again to all the HIV companies. However, my money is on therapeutic EBV vaccines and EBV specific or targeted antivirals. Contrary to what Ian says we have been working on the Charcot Project for years. The problem is people don't realise that science is a slow process.
But if the immune system is intact (which it isn’t when taking disease modifiers), why would vaccination be better than the EBV infection response. We’ve been told that CoVID infection response is better than vaccination, so why do you think EBV will be the other way around? Also, having been hospitalised for three weeks by CoVID, because Ocrelizumab blocked my antibody production to 3 Pfizer BioNTech CoVID vaccinations, I can’t see any other vaccines having the desired effect. My money is on the T cell therapies that bypass the inadequate genetics like Atara’s Allogeneic T‑Cell Immunotherapies. I can see EBV vaccination preventing MS, partly through herd immunity, once added to the childhood immunisations for future generations, but that doesn’t help pwMS now.
If EBV vaccines appear, we would have to get off anti cd20 to benefit...
Much like you, I am intrigued by Atara. That's the other trial I would seriously consider.
I dropped out of ATA188 due to progression. Though I could have been on placebo.
I didn’t think there was a placebo trial yet?
Oh yes. It's not just double blind, it's triple blinded. There was a 50% chance that I was on placebo. I'm assuming I was. Had I remained in the study, I would have definitely received the drug in a following year. But I couldn't hang. My walking severely deteriorated.
Me too
I dropped out of ATA188 due to progression. Though I could have been on placebo.
I remember referring an haemophiliac for plastic surgery for his lipodystrophy, many years ago, because homosexual men were recognising his antiretroviral fat pad and trying to pick him up inappropriately as he walked around in public with his wife and young daughter. Rather than approaching the HIV drug companies to see who will back this research, you probably need an idea of which compounds are most likely to provide fruitful studies.
Re PrEP too soon.
I wonder if the confidentiality requirements of the Venereal diseases act will impede this research in the future.
Vitamin D is an antiviral‼️
Is there anything we could do to nudge our neurologist to get them to give us a prescription for these antivirals?
Mine is very firmly a believer of the EBV aspect and as such has pushed Lemtrada (outside of ahsct as I can’t get it here) and tbf I am a bit too nervous of the side affects of Lemtrada and why I’m switching to Mavenclad instead from Tysabri
What antivirals could we request? I’m in Australia so we are more open to trying things outside the norm to an extent
Not sure we should be doing this outside of trials. We need to do randomised controlled trials.
That’s a fair point, hopefully you can get these trials out ASAP!
I’m also hoping Mavenclad can by me time for a few years before this is available.
I think that case reports are not sufficient to move a big pharma to invest money on antivirals for MS. If you and your colleagues want to have real trial up and running I am afraid that you will need to collect much more case reports to push pharma to spend money.
Personally, I would take an antiviral but I can't because a prescription is needed and no physician is going to prescribe it and also because the prices of the branded versions are quite high. I could decide to buy and take the drug (and responsibility for adverse events and consequences) from India where it is way cheaper but I would still need a prescription nobody will make to buy and import events drug even for personal use. So we are all stuck to pharma not investing, charities not funding, and doctors not prescribing while we really want to do something for ourselves.
Hmm. So crowdfund it is?
Crowdfunding could work if you source generics or from place like India. If one year treatment is in the thousands euros range with the registered drug, it will be impossible to get enough money in a reasonable time to do the trial
Yes I would, very much, thank you.
What about neurologists prescribing antivirals - off-label - now, in addition to regular DMDs? I’m sure I’m not the only one that would be willing to take them. There have already been a few studies but then they stopped.
But where is the class 1 or 2 evidence to justify off-label prescribing?
Thanks! If patients are willing to try - with an anti-viral that has a lengthy safe history- say, an antiviral that’s been used for lupus for years? Just grasping for how from an ms’er.
I take VALTREX 1 gram since 2014 for shingle prophylaxis, HINT HINT.
Would happily take part in a trial IF it let's me stay on a high efficacy DMT.
A trial with a cross-over design would be my favorite so to be sure to get the antiviral.
RE: "... stay on a high efficacy DMT.."
But how do you show the antiviral is working when you are on a high-efficacy DMT? I would suggest a induction-maintenance strategy, i.e. to see if the antiviral keeps you in remission after induction with a high efficacy DMT. Another strategy is to start pwMS on natalizumab on an antiviral and see if it can prevent natalizumab rebound. Do we have equipoise for the latter?
Last I checked, high efficacy DMT (with the excepton of some lucky alemtuzumab takers, for cladribine it seems too early to tell) did not prevent progression, only slowed it down.
So if the antiviral does something as an addon, we will see it. Might need a bigger study this way to get enough statistical power but presumably it would be easier to recruit people than telling them they need to stop their DMT.
Not sure if we have equipoise for the natalizumab discontinuation (never really looked into natalizumab).
Cladribine followed with antiviral or nothing sounds like it would achieve equipoise in as far as people would surely be no worse than standard of care. Same argument with alemtuzumab but given the rarity of its prescription, I really doubt you could conceivably do that study.
Come to think of it, I guess you could get equipoise for people who wanted to stop anti cd20 either way but again not convinced there would be enough recruits... Personally would most likely not sign up for that design.
I am sure many, myself included, would volunteer for a trial. Would some like Crowdacure help to fund it or could participants pay for their own costs and is this ethical? I am clearly no expert but would a HIV drug that is a combination therapy like Combivir gove a better chance of success?
To answer your question, yes!
There is a trial starting soon with Tenofovir
alafenamide (TAF), couldn't like minded, willing doctors / patients try this in the meantime? I also found a report of an HIV positive person who also has Multiple Sclerosis who was on Tenofovir alafenamide as part of her HIV treatment, while she was taking it her MS symptoms were in remission and as soon as they stopped it and put her on Tenofovir disoproxil fumarate instead her MS was active again.
https://clinicaltrials.gov/ct2/show/NCT04880
577
https://pubmed.ncbi.nlm.nih.gov/33049462/
Geneuro is expected to report results of their anti-HERV-W monoclonal antibody temelimab in March (I'm guessing end of March). Results from an initial phase 2 were partially positive, albeit with no evident anti-inflammatory properties.
That being said, are neurologists tied up regarding prescribing HAART off label? How was Rituximab discovered to be efficient in MS?
Yes rituximab and other anti-CD20 are an anti-EBV agents. EBV resides in memory B cells.
Dr. G: I didn’t think Ocrelizumab nor Rituximab were able to deplete memory cells? That memory cells don’t present with CD19/20 cell surface protein. Could you please confirm for me?
I’m just coming out of AHSCT as I type. I had found this research EBV/HERV connection a few years ago and decided on a few drugs to pursue under supervision of my neuro who you know. My body didn’t tolerate them, yet at this stage I think I need to really ensure - moving forward - that I’ve got enough pharma under my belt to prevent disease reactivation. Please let me know your thoughts on specific anti-retroviral therapies….if you feel comfortable to? Thanks 🙏
I am really happy to volunteer as a participant for an anti retrovirus trial. Currently on Sizomus trial which is fascinating and very motivating. I gain so much knowledge from this and I would urge anyone who can travel confortably to Barts every 4 weeks, to take part. Once my engagement in this has ended, I would love to engage in an anti retrovirus trial. Prof G thankyou so much for all your ideas and for all the hard work you put in over many years, to bring these ideas to fruition.
Thank you.
I'd sign up for that trial, especially if I could stay on my DMT. I recently dropped out of ATA188 trial due to progression. Trying my third DMT now - Tysabri and it's definitely helping. But as I'm JC-positive, my time limit on the drug will sunset at some point because of the PML risk.
Are there significant differences between an antiviral like Valacyclovir and antiretrovirals? I'd read about that guy with HIV a while back, but never heard anything more.
Glad tysabri is working for you but that’s really disappointing on ATA 188
“Would you volunteer to participate in a clinical trial of an antiviral drug cocktail to suppress MS disease activity, in particular smouldering MS?”
Since you are asking this (it seems) in the context of any “stage” of MS, I’ll comment: I’m 64 and have made it this far, which means for many like me, we are concerned about not adding another thing to the mix of things we may have already added, that can contribute to things going wrong, when you are not a “spring chicken”. The immune system is the way it is; fine tuning has been happening by random luck I might add, over millions of years. The overall system has good reason to be exactly the way it is.
And you do a great job of trying to describe the outcome of all this in terms of MS, to us laypeople and/or others. I am reluctant to throw a wrench into the gears unless there is good evidence and reason to believe and trust that doing so, won’t screw things up even more. Not in MS terms, but in terms of other things that will eventually turn sour. And I say this in the context of us already seeing what happens when a new virus comes along and your B cell depleter med has wiped out sufficient parts of your immune system that would normally fight it. What also happens, socially, is that some of the people who manufacture the DMT just “blow through” the valid questions as if nothing were happening, leaving the consequences it seams, almost to random selection again- that is, who survives and why will be studied by someone else. B cells may do more than carry EBV, they may fight some types of cancer (I read), for example. So while I am a big believer in science I would be extremely hesitant to enroll in a study at this stage of my game, unless I was given some good reassurance. If I were 30, you’d get a different answer as things for me have already largely played out. Don’t get me wrong, I would like to hear and learn more. But, for “survival’s” sake, I am beyond the guinea pig stage.
I like the shade tree quote.