Day Two

• An overview of mechanistic biology underpinning microglial TREM2 activation and its potential role in modulating neuroinflammatory pathways
• New in vivo insights from studies that illuminate TREM2’s role in modulating neuroinflammation and downstream pathology
• How emerging biological understanding can guide the design and interpretation of future clinical strategies targeting the TREM2 axis

• Sanofi’s strategic acquisition of Vigil Neuroscience and the development of VG-3927, a novel oral TREM2 agonist designed to enhance microglial clearance of neurotoxic debris
• Recent clinical data from Phase 1 trials demonstrating safety, central nervous system penetration, and biomarker modulation supporting further clinical development
• The promise and challenges of TREM2-targeted therapies as potential disease modifying treatments that address neuroinflammation and microglial dysfunction beyond traditional protein-targeting approaches

CLINICAL UPDATE

• CD40L-CD40 interactions are instrumental in activating microglia and other immune cells in the CNS, contributing to the pathogenesis of neurodegenerative diseases. Inhibition of this pathway may reduce neuroinflammation and subsequent neuronal damage
• Sanofi’s investigational anti-CD40L monoclonal antibody, frexalimab, has demonstrated a 41% reduction in plasma neurofilament light chain (NfL) levels, a biomarker of nerve cell damage, in patients with relapsing MS after 48 weeks of treatment. These findings support its potential as a high-efficacy, diseasemodifying treatment for MS
• Studies have indicated that blocking CD40L is generally safe and well-tolerated. For instance, a phase I trial involving a humanized anti-CD40L monoclonal antibody in patients with relapsing-remitting MS reported no serious adverse events and an increase in anti-inflammatory cytokine profiles.
• While targeting CD40L shows promise, challenges remain, including potential risks of immunosuppression and the need for careful patient selection. Further studies are essential to establish long-term safety and efficacy profiles

• Deciphering Troculeucel’s mechanism of action in reducing CSF neuroinflammatory and protein biomarkers
• Ensuring auto-activated T cell targeting without affecting resting T cells to fundamentally address neuroinflammation
• Reviewing the early clinical efficacy of Troculeucel in AD and FTD patients

• The role of sigma-1 receptor as a broad anti-inflammatory mediator, impacting multiple cytokines beyond single targets like TNF-alpha
• Use of phenotypic screening approaches focusing on reversing disease-related impairments (e.g., cognitive deficits caused by amyloid-beta 1-42 in Alzheimer’s) rather than directly blocking pathogenic molecules
• Evidence that targeting impairments downstream of toxic proteins, rather than the proteins themselves, may offer more effective and practical therapeutic strategies
• Comparison with other inflammatory targets such as NF-kappa B, highlighting sigma-1 receptor’s broader and potentially safer anti-inflammatory profile
• The paradigm shift from target-centric to phenotype-driven drug discovery, where finding drugs that work precedes elucidating their precise mechanisms

• Combining neuroprotection and relapse prevention by targeting the neuroprotective factor Nurr1 and anti-inflammatory target DHODH
• Addressing neuronal function as a potential therapy for both relapsing and progressive forms of neurodegenerative diseases 
• Investigating Nurr1 as a relevant target to treat different neurodegenerative diseases

• How protective human genetic variants provide a blueprint for discovering genetically validated targets across ALS, FTD, PD, and Alzheimer’s disease
• Exploring the know and unknown roles of innate immune system in progression of age-related neurodegeneration
• Demonstrating therapeutic targeting of CD33 can be employed in several neurodegenerative diseases to rescue pathologic neuroinflammation
• The translational importance of genetically informed targets and biomarker-driven development for advancing next-generation therapies for neurodegeneration

• Unlocking the therapeutic promise of ADS024, a single-strain, orally delivered live biotherapeutic product, by demonstrating efficacy across Alzheimer’s and multiple neuroinflammatory and neurodegenerative disease models through LPAR3 agonism
• Exploring the gut–brain axis with a focus on ADS024’s impact on neuroinflammation, gut-derived signalling, and implications for disease progression
• Positioning LPAR3 as an underexplored GPCR target within the EDG/S1P receptor family, with genetic ties to Alzheimer’s biomarkers and strong potential for novel, accessible neuroinflammation therapies

• Discussions into the gut-brain-immune axis as a critical pathway where environmental insults and microbiome imbalances initiate peripheral immune responses that propagate inflammation to the brain
• Explore how microbiome imbalances and peripheral immune activation amplify gut-brain signalling and contribute to chronic neuroinflammation
• Discuss opportunities to leverage gut-brain axis research for biomarker discovery and precision strategies to prevent or slow neurodegenerative disease progression

• Exploring the role of microglia and astrocytes as central innate immune effectors driving neuroinflammation and contributing to disease pathology in disorders like Alzheimer’s and Parkinson’s, while examining how shared immune targets are uniquely regulated in CNS-resident cells
• The diverse functions of adaptive immune cells including effector T cells, regulatory T cells, and B cells in CNS infiltration, antigen-specific responses, and disease modulation
• Mechanisms of immune checkpoint regulation and antigen presentation that control lymphocyte trafficking and activation within the CNS, highlighting potential therapeutic targets
• Challenges and opportunities in developing therapies that modulate innate and adaptive immunity, including timing, CNS penetration, and avoiding detrimental immunosuppression
• The critical balance between pro-inflammatory and neuroprotective immune activities, emphasizing the need for precise immune modulation to promote CNS repair while limiting damage