Smouldering MS: the real MS becomes a tractable problem
Tolebrutinib, a second-generation BTK inhibitor, is the first to show a reduction in disability accumulation in non-relapsing secondary progressive MS or smouldering MS.
I suspect subscribers of MS-Selfie are tired of me banging on about smouldering MS. I have recently had some very vexatious emails and comments stating my newsletters are too downbeat and that I am destroying any hope that people with MS are living with. Is this true?
I have never wanted to pull my punches and provide a rose-tinted view of the world. My newsletters are designed to be as accurate as possible, to give you my worldview of MS, and to try and empower you to self-manage your MS as best you can and to ask the right questions when you see your MS HCPs (healthcare providers).
So, how do I tell you that one of the first trials designed to target smouldering MS in people with so-called non-relapsing secondary progressive MS is positive? How do I do this without creating false hope and unrealistic expectations? Let me give it a go.
Breaking news
Sanofi, the sponsor, has just released a press statement that Tolebrutinib, a second-generation BTK inhibitor, has met its primary endpoint in the HERCULES phase 3 study. This is the first trial to show a drug reduces disability accumulation in non-relapsing secondary progressive MS or smouldering MS.
I have to put out a disclaimer here that I am a member of the HERCULES steering committee, so anything positive needs to be taken with a pinch of salt.
Excerpts from Sanofi press release (02-Sep-2024)
“In the HERCULES study, tolebrutinib met the primary endpoint in delaying the time to onset of confirmed disability progression in people with nrSPMS, a population for which there are currently no approved therapies and significant unmet medical needs.
The GEMINI 1 and 2 studies evaluating tolebrutinib in people with relapsing MS (RMS) did not show significance in the primary endpoint of reducing annualized relapse rate over Aubagio (teriflunomide). Analysis of the key secondary endpoint of pooled 6-month confirmed disability worsening (CDW) data showed a considerable delay in time to onset.
Phase 3 study results will form the basis for future discussions with global regulatory authorities.
Study results will be presented at the ECTRIMS medical meeting on September 20, 2024.
Positive results from the HERCULES phase 3 study showed that tolebrutinib, Sanofi’s oral brain-penetrant BTK inhibitor, met the primary endpoint of improvement over placebo in delaying time to onset of confirmed disability progression (CDP) in people with non-relapsing secondary progressive MS (nrSPMS). In the HERCULES study, nrSPMS was defined at baseline as having a SPMS diagnosis with an expanded disability status scale (EDSS) score between 3.0 and 6.5, no clinical relapses for the previous 24 months and documented evidence of disability accumulation in the previous 12 months. Preliminary analysis of liver safety was consistent with previous tolebrutinib studies.
Results from the GEMINI 1 and 2 phase 3 studies evaluating tolebrutinib did not meet the primary endpoint of reducing annualised relapse rate (ARR), compared to teriflunomide, in people with relapsing forms of multiple sclerosis. However, analysis of the key secondary endpoint of pooled 6-month CDW data showed a considerable delay in time to onset, which supports the CDP data observed in HERCULES.”
My thoughts
After the failed evobrutinib phase 3 studies, I predicted the GEMINI 1 and 2 studies would not reach their primary outcome because teriflunomide is a much better anti-inflammatory DMT than we have previously appreciated and that trial populations have changed. In retrospect, the primary outcome for these studies should have been disability progression and not relapse rate. However, the fact that Tolebrutinb was positive on disability progression, or the real MS, in both relapsing and non-relapsing MS supports my claim that relapses and focal MRI activity are not MS. I sincerely hope the regulators come to their senses and allow people with smouldering MS, which includes pwMS across the disease spectrum, to access Tolebrutinb. What do you think?
These studies’ results support our claim that relapses are not MS and that the real MS is smouldering MS. We have been saying this for some time. I suggest you read the following MS-Selfie Newsletters and papers to learn about some of the issues these trial results raise and support.
If you use the search function on MS-Selfie and search for the term "smouldering", you will find many more newsletters, podcasts, and case studies on this topic, which becomes very pertinent now that we have emerging treatments that work on smouldering MS. I sincerely hope we have given the PPMS Tolebrutinib study enough power to deliver a positive result as well.
Papers of interest
Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the 'real MS' is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of 'no evident inflammatory disease activity' (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.
Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity." We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts.
Post-script
Thank you so much for your kind comments on my recent newsletter, “Farewell - no fanfare” (29-Aug-2024); some of the comments brought a tear to my eyes.
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General Disclaimer
Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
Good news Prof G - some level of hope for those of us that appear to be slipping into the SPMS stage with no relapses and stable MRI's but slow but gradual increases in levels of disability.
No, you are not overly negative and removing hope by your informative posts, just realistic and presenting your view, which is what anyone reading MS-Selfie should be aware of anyway. Unfortunately there are a lot of people who find it a release to vent and hurt others in an on-line platform without respect for others feelings - likely they wouldn't present such views person to person. Please keep up the good work in helping us find the best way through our lives with MS.
You do not spread doom. Unlike others you are honest. I respect honesty.