An issue I did not discuss in the newsletter is medical altruism, i.e. many pwMS are prepared to put themselves at risk of a relapse or potentially getting worse to move the field along. We mustn't forget this! PwMS want action, i.e innovative trials to address the unmet need, rather than discussions about whether or not we should do the trials. One thing I have learnt by engaging with pwMS is that they don't like navel-gazing MS researchers who chirp (or tweet) from the side-lines; they like doers people and researchers who move the field forward.
Anything is better than nothing. I have been chatting with patients who have "non-active" SPMS who have been leaving the BTK inhibitor trial in their droves - the trial is against placebo and after 2 years they're showing significant worsening of symptoms (but it's not an episode / attack or whatever other gaslighting nonsense patients with SPMS are routinely fed).
Apparently for non-active SPMS there are no authorized treatments and therefore trials against placebo are perfectly ethical.
I think that teriflunomide is being chosen as a comparator because no one wants their drugs to go against the most efficacious treatments and lose. I think the most ‘ethical’ choice would be to use ocrelizumab as a comparator as it is one of the most effective and safe short-term agents.
But no pharmaceutical would want to do that. That’s just free pr for ocr in case their treatment isn’t proven more efficacious.
While teriflunomide might almost be as good as ocr in slowing disability I do think still relapses matter. Yes, there is PIRA and smouldering MS but relapses are not a ‘minor’ issue as they also drive progression.
All in all I think it’s a matter of $ than ‘what makes sense for the patients tbh
I know it's not your main point, but I'm glad that teriflunomide is (re)gaining some credit. I started it for many of the reasons you mention (impact on brain loss volume and progressing disability on the one hand, and lymphopeaenia and opportunistic infections I had using other DMTs on the other hand).
At that time, my neurologist was not happy with my decision;).
Exactly. Anything is better than nothing. If we use two drugs we can at least compare their effectiveness. And at least we can help to slow the progression. So its better to give anything instead of giving nothing. But is it all about the patient or rather about money? Cause I have a feeling that the patient matters the least.
Another point about ethical issues is that it is usually the minority view that is more important, particularly when ethical issues are usually raised.
You state that „teriflunomide has a remarkably robust effect on disability progression and slows the accelerated brain volume loss due to MS“. How do you explain the divergent results in this recently published analysis? Link: https://doi.org/10.57264/cer-2023-0016
Compared to other substances, the effect of teriflunomide on disability progression was rather weak here. However, it must certainly be noted that the statistical methods used with indirect comparison of the substances from different studies are quite problematic...
Gavin, your comments concerning teriflunomide strongly resonate with me, however it seems that all have forgotten about it's much better tolerated cousin, mycophenolate mofetil.
Surely the proprietary nature of the business was in favor of spending much to bring teriflunomide to market for MS, whereas mycophenolate moved off patent and has never been subjected to sufficiently sized, powered, etc trials to assess whether this purine base synthesis inhibitor (in contrast to the pyrimidine base synthesis inhibitor that teriflunomide is) would represent an effective, economical, and better tolerated agent from the base synthesis inhibition class of agents.
Yes, mycophenolate requires twice daily dosing, and doing so on an empty stomach (one hour before or two hours after a meal). The twice daily dosing, and requirement for empty stomach administration, are not trivial factors that impact upon the attractiveness of this agent.
However, I do recall a time when Roche (who owns Cellcept) had reported success with the production of a sustained-release, once daily formulation of mycophenolate mofetil, and one not requiring empty stomach dosing.
I will say that the use of this agent, whether in transplant recipients (still a blockbuster by the way), or in those with a wide diversity of autoimmune/inflammatory disorders, requires regularly underscoring the very important facts of drug-taking adherence. Defined by the World Health Organization, adherence is a combination of compliance (taking the medication correctly; as in twice daily, and on an empty stomach), with persistency over time.
Most of the breakthrough (in those who did achieve efficacy initially (not instantly mind you, but over time, as with other agents we've used in the past, such as azathioprine) that I've seen over the years with this agent (whether used in MS, NMOSD, sarcoid, etc) has been related to patients becoming nonchalant about the crucial nature of adherence, and especially when it comes to the requirement of empty stomach dosing. However, if you don't ask, you may not be able to truly define whether you're dealing with drug failure, or a patients with failed adherence.
Also tolerability is a core issue for these agents. Teriflunomide, and I've used much of it, not infrequently afflicts patients (particularly those who are age advanced) with GI symptoms, feeling poorly, and the hair loss, albeit secondary to telogen effluvium (cell cycle effects), that we also saw NOT uncommonly with interferons, can be an issue for a number of treated patients. Here again is plug for mycophenolate, which I've used much of across a spectrum of disorders, and rarely had patients complain of those side effects which I hear about often in my teriflunomide treated patients.
Finally, one can assess mycophenolate drug levels, and also we can assess for inosine monophosphate dehydrogenase (IMDH), enzyme over expression (the enzyme inhibited by mycophenolate in order to prevent purine base synthesis), a potentially useful measure of drug resistance, and prognostically to determine which patients are likely to develop 'chemoresistance' and insufficiently efficacy.
An issue I did not discuss in the newsletter is medical altruism, i.e. many pwMS are prepared to put themselves at risk of a relapse or potentially getting worse to move the field along. We mustn't forget this! PwMS want action, i.e innovative trials to address the unmet need, rather than discussions about whether or not we should do the trials. One thing I have learnt by engaging with pwMS is that they don't like navel-gazing MS researchers who chirp (or tweet) from the side-lines; they like doers people and researchers who move the field forward.
Anything is better than nothing. I have been chatting with patients who have "non-active" SPMS who have been leaving the BTK inhibitor trial in their droves - the trial is against placebo and after 2 years they're showing significant worsening of symptoms (but it's not an episode / attack or whatever other gaslighting nonsense patients with SPMS are routinely fed).
Apparently for non-active SPMS there are no authorized treatments and therefore trials against placebo are perfectly ethical.
Words fail.
I think that teriflunomide is being chosen as a comparator because no one wants their drugs to go against the most efficacious treatments and lose. I think the most ‘ethical’ choice would be to use ocrelizumab as a comparator as it is one of the most effective and safe short-term agents.
But no pharmaceutical would want to do that. That’s just free pr for ocr in case their treatment isn’t proven more efficacious.
While teriflunomide might almost be as good as ocr in slowing disability I do think still relapses matter. Yes, there is PIRA and smouldering MS but relapses are not a ‘minor’ issue as they also drive progression.
All in all I think it’s a matter of $ than ‘what makes sense for the patients tbh
Thank you for addressing this topic. I have been wondering about this myself for years.
I know it's not your main point, but I'm glad that teriflunomide is (re)gaining some credit. I started it for many of the reasons you mention (impact on brain loss volume and progressing disability on the one hand, and lymphopeaenia and opportunistic infections I had using other DMTs on the other hand).
At that time, my neurologist was not happy with my decision;).
Exactly. Anything is better than nothing. If we use two drugs we can at least compare their effectiveness. And at least we can help to slow the progression. So its better to give anything instead of giving nothing. But is it all about the patient or rather about money? Cause I have a feeling that the patient matters the least.
I believe that any subjects willing to go on a trial which be ethical if it means that the closure of multiple sclerosis comes.
Is teriflunomide any good for non-relapsing SPMS? How would it fare against siponimod do you think?
Extremely interesting!
Another point about ethical issues is that it is usually the minority view that is more important, particularly when ethical issues are usually raised.
You state that „teriflunomide has a remarkably robust effect on disability progression and slows the accelerated brain volume loss due to MS“. How do you explain the divergent results in this recently published analysis? Link: https://doi.org/10.57264/cer-2023-0016
Compared to other substances, the effect of teriflunomide on disability progression was rather weak here. However, it must certainly be noted that the statistical methods used with indirect comparison of the substances from different studies are quite problematic...
Gavin, your comments concerning teriflunomide strongly resonate with me, however it seems that all have forgotten about it's much better tolerated cousin, mycophenolate mofetil.
Surely the proprietary nature of the business was in favor of spending much to bring teriflunomide to market for MS, whereas mycophenolate moved off patent and has never been subjected to sufficiently sized, powered, etc trials to assess whether this purine base synthesis inhibitor (in contrast to the pyrimidine base synthesis inhibitor that teriflunomide is) would represent an effective, economical, and better tolerated agent from the base synthesis inhibition class of agents.
Yes, mycophenolate requires twice daily dosing, and doing so on an empty stomach (one hour before or two hours after a meal). The twice daily dosing, and requirement for empty stomach administration, are not trivial factors that impact upon the attractiveness of this agent.
However, I do recall a time when Roche (who owns Cellcept) had reported success with the production of a sustained-release, once daily formulation of mycophenolate mofetil, and one not requiring empty stomach dosing.
I will say that the use of this agent, whether in transplant recipients (still a blockbuster by the way), or in those with a wide diversity of autoimmune/inflammatory disorders, requires regularly underscoring the very important facts of drug-taking adherence. Defined by the World Health Organization, adherence is a combination of compliance (taking the medication correctly; as in twice daily, and on an empty stomach), with persistency over time.
Most of the breakthrough (in those who did achieve efficacy initially (not instantly mind you, but over time, as with other agents we've used in the past, such as azathioprine) that I've seen over the years with this agent (whether used in MS, NMOSD, sarcoid, etc) has been related to patients becoming nonchalant about the crucial nature of adherence, and especially when it comes to the requirement of empty stomach dosing. However, if you don't ask, you may not be able to truly define whether you're dealing with drug failure, or a patients with failed adherence.
Also tolerability is a core issue for these agents. Teriflunomide, and I've used much of it, not infrequently afflicts patients (particularly those who are age advanced) with GI symptoms, feeling poorly, and the hair loss, albeit secondary to telogen effluvium (cell cycle effects), that we also saw NOT uncommonly with interferons, can be an issue for a number of treated patients. Here again is plug for mycophenolate, which I've used much of across a spectrum of disorders, and rarely had patients complain of those side effects which I hear about often in my teriflunomide treated patients.
Finally, one can assess mycophenolate drug levels, and also we can assess for inosine monophosphate dehydrogenase (IMDH), enzyme over expression (the enzyme inhibited by mycophenolate in order to prevent purine base synthesis), a potentially useful measure of drug resistance, and prognostically to determine which patients are likely to develop 'chemoresistance' and insufficiently efficacy.
Just a few thoughts. EMF