Yes, this is much better; with those changes and clarity around the story you want to tell using it. At the end of the day, the Hercules criteria is simple and practicable. This also neatly exposes the Siponimod contradiction (logic flaw?).
I agree that the licensing of siponimod for active SPMS changed the definition of active MS. We felt it was unethical to stop DMTs in patients with inactive-SPMS on DMT to wait for them to relapse or have MRI activity. The NHS and many healthcare systems agreed with us.
The entire history of BTK inhibitor development has been built around the idea that these drugs were claiming an exceptional role in the treatment of multiple sclerosis. The promise was the potential control of processes not associated with conventional inflammatory activity. In your blog, we have repeatedly seen posts about controlling “smoldering” inflammation, while senior colleagues urged us to get used to the idea (beautifully illustrated on slides) that these drugs work remarkably well behind the blood–brain barrier. Now the time has come to take stock - the most CNS-active BTK inhibitor has failed to find its niche. You previously noted, quite accurately, that the peripherally active fenebrutinib did, in fact, make a difference.
The conclusions are obvious. Inactivity has not been defeated.
The peaks of inflammatory activity control were reached in 2004, and since then no new therapy - whether given at two- or threefold doses, penetrating or not penetrating the barrier, selectively or non-selectively rebooting the immune system, acting on microglia or not - has made a meaningful difference. Yet instead of acknowledging this simple fact, we choose to look away.
First, we begin to talk about the need for some new composite endpoint, so that under a microscope, long and persistently, we can examine our Non-defeat. Then we awkwardly attempt to fit our inhibitor into an existing, essentially unsuccessful, artificial framework. You, incidentally, have always been opposed to this framework and for that, many thanks. These efforts were not in vain, your open stance has been enormously helpful for me, for many of my colleagues, and for my patients. But given the ambitious original concept behind BTK inhibitors, any practical value of such an algorithm evaporates. After all, if we follow your line of reasoning, any anti-inflammatory drug can be used for SPMS and everything should be registered at once (1); the choice of therapy for SPMS should be holistic and based on its real advantages (2) and on the recognition of the fact that SPMS - especially non-relapsing SPMS - does not, in principle, exist at all (3). We must stop restricting physicians and patients in their choice of treatment.
Since the MS community has chosen its path, our generation has a clear mission. Industrial propaganda dramatically simplifies Inactivity (as an entire constellation of processes) reducing it to smoldering inflammation. Unfortunately, the elegant industrial hypothesis, into which so much time and effort have been invested, has not worked so far. Without acknowledging these obvious disappointments, there will be no progress.
Yes, this is much better; with those changes and clarity around the story you want to tell using it. At the end of the day, the Hercules criteria is simple and practicable. This also neatly exposes the Siponimod contradiction (logic flaw?).
I agree that the licensing of siponimod for active SPMS changed the definition of active MS. We felt it was unethical to stop DMTs in patients with inactive-SPMS on DMT to wait for them to relapse or have MRI activity. The NHS and many healthcare systems agreed with us.
The second figure is much more complex, but describes better the many variables...
I, sincerely, got to the point and understood better the first figure. Could you submit both on the report?
Since options, yes or no, are already present after each box, I don't think you need a question mark.
You see, Gavin, here’s the thing.
The entire history of BTK inhibitor development has been built around the idea that these drugs were claiming an exceptional role in the treatment of multiple sclerosis. The promise was the potential control of processes not associated with conventional inflammatory activity. In your blog, we have repeatedly seen posts about controlling “smoldering” inflammation, while senior colleagues urged us to get used to the idea (beautifully illustrated on slides) that these drugs work remarkably well behind the blood–brain barrier. Now the time has come to take stock - the most CNS-active BTK inhibitor has failed to find its niche. You previously noted, quite accurately, that the peripherally active fenebrutinib did, in fact, make a difference.
The conclusions are obvious. Inactivity has not been defeated.
The peaks of inflammatory activity control were reached in 2004, and since then no new therapy - whether given at two- or threefold doses, penetrating or not penetrating the barrier, selectively or non-selectively rebooting the immune system, acting on microglia or not - has made a meaningful difference. Yet instead of acknowledging this simple fact, we choose to look away.
First, we begin to talk about the need for some new composite endpoint, so that under a microscope, long and persistently, we can examine our Non-defeat. Then we awkwardly attempt to fit our inhibitor into an existing, essentially unsuccessful, artificial framework. You, incidentally, have always been opposed to this framework and for that, many thanks. These efforts were not in vain, your open stance has been enormously helpful for me, for many of my colleagues, and for my patients. But given the ambitious original concept behind BTK inhibitors, any practical value of such an algorithm evaporates. After all, if we follow your line of reasoning, any anti-inflammatory drug can be used for SPMS and everything should be registered at once (1); the choice of therapy for SPMS should be holistic and based on its real advantages (2) and on the recognition of the fact that SPMS - especially non-relapsing SPMS - does not, in principle, exist at all (3). We must stop restricting physicians and patients in their choice of treatment.
Since the MS community has chosen its path, our generation has a clear mission. Industrial propaganda dramatically simplifies Inactivity (as an entire constellation of processes) reducing it to smoldering inflammation. Unfortunately, the elegant industrial hypothesis, into which so much time and effort have been invested, has not worked so far. Without acknowledging these obvious disappointments, there will be no progress.