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

• From expanding pipelines to next‑generation mechanisms: A cross‑disease view of how AD, PD, ALS and MSA pipelines are evolving, with biologics and advanced modalities reshaping the neuro drug landscape
• Clinical momentum accelerating across neurodegeneration: Key trends from 2025 trial activity, including the rise of early‑phase innovation, shifting global trial geographies, and pivotal readouts influencing development decisions
• Strategic forces driving the future of neuro R&D: How partnerships, licensing, investment shifts, and 2026 regulatory milestones are redefining opportunity across the neuro space from commercial strategy to AI‑enabled discovery

• 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

• Unlock a previously underexploited microglial pathway to help restore homeostatic, disease-resolving activity without relying solely on TREM2-centric strategies
• Enables a more direct and tractable mechanism for restoring microglial phagocytosis and immune balance, supporting clearer translation from biology to therapeutic design
• Strengthen the foundation for precision microglial therapeutics by broadening the set of actionable immune checkpoints that shape microglial behaviour across disease stages

• 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

• The involvement of peripheral B cells and T cells in propagating CNS inflammation and neurodegeneration, and the rationale for targeting these cells to reduce disease progression
• The novel concept of utilizing the regulatory properties of B cells in the context of CNS injury
• Leveraging a novel B cell–based immunomodulatory cell therapy to locally and systemically control inflammation, offering a targeted alternative to broad immunosuppression in neurotrauma and neurodegenerative disease
• Demonstrating therapeutic potential across multiple CNS indications, including traumatic brain injury, haemorrhagic stroke, and ALS, highlighting shared immune mechanisms that can be harnessed for neuroprotection
• Showcasing the full translational arc from mechanistic mouse studies to first-in-human clinical experience, illustrating how peripheral immune components can be developed into clinically viable CNS therapies