At Sanofi, we are unlocking the science of neuroimmunology to develop treatments aimed to address the full spectrum of multiple sclerosis (MS). We’re exploring innovative strategies targeting a key driver of disability progression and accumulation: smoldering neuroinflammation.
This year marks the 40th anniversary of the annual European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting, signifying decades of progress in MS research and treatment development. However, it’s clear that there is still more work to do, as many people living with MS still experience disease worsening due to underlying smoldering neuroinflammation, which remains an unmet need despite currently available therapies.[1]
As we’ve also learned over these last 40 years, solving these challenges are best achieved together, and there is no better platform than this congress to connect with this diverse community of patients, advocates, healthcare providers and researchers. This year, we’re continuing to explore the pivotal role that smoldering neuroinflammation plays in driving disability accumulation and presenting our latest clinical research targeting this unaddressed process for people living with MS.
Our understanding of MS and the driver of disability accumulation has undergone a dramatic shift since the first MS therapy was approved over 30 years ago. It’s been understood that self-destructive inflammatory processes are central to MS progression, and our initial therapeutic efforts focused on targeting the inflammatory processes of peripheral adaptive immune cells, such as B cells and T cells, to address relapses and acute lesions.[2][3] However, despite current MS therapies effectively controlling relapse and acute lesion activity, many patients may continue to experience disease progression that results in disability accumulation.[1] Over time, this disability accumulation may involve cognitive decline, such as difficulties with memory, learning, and processing speed, as well as physical decline, such as functional loss in upper and lower extremities, strength, walking, vision, and speech – all aspects of a person’s self that impact their day-to-day to lives.[4][5][6][7] Sanofi is boldly leading the charge in actively investigating the science behind smoldering neuroinflammation to help protect this sense of self.
Historically, there have been two broad classifications of how an individual may experience worsening disease: relapse-associated worsening (RAW), which is the worsening of MS symptoms that occurs as a result of a clinical relapse, and progression independent of relapse activity (PIRA), which refers to the gradual and sustained worsening of MS symptoms without the presence of relapses. Rather than being driven by relapses, PIRA is thought to be driven by smoldering neuroinflammation, but given that PIRA is mainly related to motor impairment, the field has begun referring to symptoms independent of relapses as “smoldering-associated worsening (SAW)”. SAW is a broader umbrella concept, which encompasses PIRA, but also includes a wide range of gradually worsening symptoms that remain undetectable on standard assessments, especially in early disease stages, including subtle motor impairment, cognitive slowing, fatigue, neuropathic pain, bowel/bladder, and sexual dysfunction.[1]
Unlike acute neuroinflammation, which is primarily driven by B and T cells of the peripheral immune system, smoldering neuroinflammation is thought to be driven at least in part by microglia, immune cells that reside within the central nervous system.[1][8][9][10] Under healthy conditions, microglia play an important role in regulating brain health, including myelination, synaptic maintenance, blood-brain barrier permeability, and neurogenesis.[8] However, when pathologically active in MS, these microglia can trigger damage within the central nervous system (CNS) that exacerbates MS symptoms and disability accumulation. They do so through the development of chronic lesions, diffuse inflammation, increased demyelination, inhibited remyelination, increased blood-brain barrier permeability, axonal injury, and neurodegeneration.[9][10]
This persistent inflammatory process starts very early in the disease course, likely even before symptoms appear, and can continue even when patients’ scans show them to be free of new MRI activity.[1] This is because smoldering neuroinflammation is a subtle cellular process in the brain that early in disease course may not be detected within the current clinical metrics of MS disease progression, including imaging techniques and the Expanded Disability Status Scale (EDSS), which both reflect the damage buildup that has already occurred rather than the underlying neurodegenerative processes that are ongoing.[1][4][5]
While current MS treatments can successfully reduce the frequency and severity of acute relapses by modulating T and B cells from the periphery, they may fail to address an important mechanism of disease progression – smoldering neuroinflammation within the CNS. To effectively slow or halt disability accumulation in MS, research continues to not only address the B and T cells in the periphery but also the mechanisms behind the blood-brain barrier to target the pathogenic that are thought to drive these damaging neuroinflammatory pathways at its source.[1]
At Sanofi, we believe in taking an empathetic approach to neurology that is driven by a patient-centric philosophy born out of the idea that science can help people live for the moment, not the disease. In MS, our scientific and clinical development efforts are focused on developing targeted therapies that address both adaptive and innate immunity through novel pathways that span the entire MS disease continuum.
One promising target in MS is the Bruton’s Tyrosine Kinase (BTK) pathway, which plays a crucial role in the function of B cells and microglia, two primary drivers of both the acute and smoldering inflammatory pathways in MS, respectively. Therefore, BTK inhibitors that are capable of entering the CNS through the blood-brain barrier in bioactive concentrations may have the potential to simultaneously suppress both pathways, which could represent a more comprehensive disease-modifying treatment option that goes beyond relapse management. BTK inhibitors may introduce the possibility for disability targeting therapies, directly targeting the mechanisms driving chronic disability in MS.[3][11][12]
Sanofi is also exploring the costimulatory CD40/CD40L pathway in MS. CD40 and CD40L are proteins found on the cell surface of both adaptive (T and B cells) and innate (macrophages/microglia and dendritic cells) immune cells. These cell surface proteins can trigger the activation of these cells and, consequently, their self-damaging inflammatory pathways in MS. Targeting this upstream CD40/CD40L interaction potentially addresses both acute and chronic neuroinflammation in MS without depleting these crucial immune cells.[13]
At ECTRIMS 2024, we’re looking forward to presenting our latest research and engaging with the global MS community through a series of symposia and presentations that delve further into the role of neuroinflammation in MS, in addition to showcasing the latest clinical findings from our neurology portfolio. We invite all attendees to join our sessions, participate in discussions, and explore the potential of these emerging strategies to revolutionize managing MS.
Sanofi-hosted sessions at ECTRIMS 2024 will include the medical symposia: The Next Frontier: Diving Deep into the Underlying Drivers of Disability Accrual, on September 19 from 1:30 pm – 2:30 PM CEST.
We look forward to connecting with our colleagues across the MS research and treatment continuum to share knowledge, gain new perspectives, and accelerate progress in MS care.
References
[1] Giovannoni G, Popescu V, Wuerfel J, et al. Smouldering multiple sclerosis: the ‘real MS’. Ther Adv Neurol Disord. 2022;15:17562864211066751.
[2] Hernández-Pedro NY, Espinosa-Ramirez G, de la Cruz VP, Pineda B, Sotelo J. Initial immunopathogenesis of multiple sclerosis: innate immune response. Clin Dev Immunol. 2013;2013:413465.
[3] Häusser-Kinzel S, Weber MS. The role of B cells and antibodies in multiple sclerosis, neuromyelitis optica, and related disorders. Front Immunol. 2019;10:201.
[4] Lakin L, Davis BE, Binns CC, Currie KM, Rensel MR. Comprehensive approach to management of multiple sclerosis: addressing invisible symptoms—a narrative review. Neurol Ther. 2021;10(1):75-98.
[5] Ziemssen T, Derfuss T, de Stefano N, et al. Optimizing treatment success in multiple sclerosis. J Neurol. 2016;263(6):1053-1065.
[6] Dillenseger A, Weidemann ML, Trentzsch K, et al. Digital biomarkers in multiple sclerosis. Brain Sci. 2021;11(11):1519.
[7] Halper J, Kennedy P, Miller CM, Morgante L, Namey M, Ross AP. Rethinking cognitive function in multiple sclerosis: a nursing perspective. J Neurosci Nurs. 2003;35(2):70-81.
[8] Sierra A, Paolicelli RC, Kettenmann H. Cien años de microglía: milestones in a century of microglial research. Trends Neurosci. 2019;42(11):778-792.
[9] Guerrero BL, Sicotte NL. Microglia in multiple sclerosis: friend or foe? Front Immunol. 2020;11:374. doi:10.3389/fimmu.2020.00374
[10] Luo C, Jian C, Liao Y, et al. The role of microglia in multiple sclerosis. Neuropsychiatr Dis Treat. 2017;13:1661-1667. doi:10.2147/NDT.S140634.
[11] Hendriks RW. Drug discovery: new BTK inhibitor holds promise. Nat Chem Biol. 2011;7(1):4-5.
[12] Keaney J, Gasser J, Gillet G, Scholz D, Kadiu I. Inhibition of Bruton’s Tyrosine Kinase modulates microglial phagocytosis: therapeutic implications for Alzheimer’s disease. J Neuroimmune Pharmacol. 2019;14(3):448-461.
[13] Aarts S, Seijkens T, van Dorst K, et al. The CD40–CD40L Dyad in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis. Front Immunol. 2017; 8:1791.
MAT-GLB-2403516 v1.0 07/2024