Day One

• Adapting preclinical findings to better mimic aging biology in human systems and organoids
• Identifying limitations of murine models and selecting higher-fidelity platforms for proof of concept
• Establishing predictive assays that correlate with human outcomes to enable more efficient translation

• Understanding and targeting the underlying molecular mechanisms that drive agerelated diseases and develop regenerative pharmacologic interventions for patients
• Restoring cell and tissue function by addressing age-related changes in cellular processes (e.g. mitochondrial health), cellular fate and state and cellular functions (e.g. energy expenditure)
• Understanding human aging processes (e.g. hallmarks of aging) contributing to disease and model aging physiology in preclinical rodent and complex human cellular assays and organoids (e.g. bio-artificial skeletal muscles)

• Unlock broader therapeutic impact by addressing the multiple interconnected pathways; immunity, metabolism, inflammation, and repair, that collectively drive aging
• Avoid costly trial failures by moving beyond single-pathway approaches and capturing critical crosstalk that shapes treatment outcomes
• Accelerate precision drug development through panomics, where integrating multiomics data reveals actionable insights to design more effective, aging-targeted therapies

• The overlap between cancer and biological models of aging
• Inelegant (but effective) problem solving bypassing the blood-brain barrier and treating the untreatable
• Coordinating diagnostic and therapeutic strategies to manage Leptomeningeal Metastases (LM)

• Mapping pathogenic cell states through integration of multi-modal single-cell and spatial data from thousands of human donors
• Uncovering precision surface markers that enable selective depletion of the harmful cell populations
• Restoring tissue balance by targeting chronic inflammation at its cellular source

• Targeting Senescent Cell Heterogeneity: Senescent cells are diverse, and distinct molecular pathways drive different subtypes. In skin aging and multiple chronic inflammatory skin diseases, specific senescent cell populations act as key pathological drivers
• Mechanism of Action: RLS-1496, a first-in-class GPX4 modulator discovered through the Alembic AI-enabled drug discovery platform, selectively induces ferroptosis in pathogenic senescent cell subtypes implicated in dermatological tissue aging and disease progression
• Clinical Translation: RLS-1496 has advanced into a Phase 1 basket trial, a randomized, double-blind, vehicle controlled study, evaluating safety, tolerability, and early efficacy signals in both chronic inflammatory skin diseases and aged skin

In this 45-minute discussion, we will examine pioneering strategies for redefining functional outcomes in aging interventions, emphasizing rapid, impactful markers of rejuvenation and aging. We will cover hurdles in integrating advanced technologies and standardized performance metrics into clinical trials, alongside navigating complex regulatory landscapes to validate QoL measures:

Using short-term recovery (i.e. post-surgery strength gains) as meaningful early indicators

Integrating wearables and physical performance tests into clinical trial design

Building regulatory acceptance for quality-of-life metrics over mortality

• Harnessing Genetic Resilience: Halia Therapeutics leverages insights from naturally occurring protective genetic variants to discover new therapeutic pathways that mimic resilience and prevent age-related disease
• The APOE4 Case Study: APOE4 is the strongest genetic risk factor for Alzheimer’s disease. Halia’s approach focuses on identifying resilience mechanisms that allow some APOE4 carriers to remain cognitively intact into old age
• HT-4253 as a Proof of Concept: Our drug, HT-4253, represents the first therapeutic candidate developed from this resilience framework, targeting innate immune dysfunction and neuroinflammation associated with APOE4 risk
• A Platform for Broader Impact: By systematizing resilience discovery, Halia is pioneering a new model for drug development, shifting from treating late-stage disease to intercepting pathology early in genetically high-risk populations

• Using composite health outcome endpoints combining cognition, mobility, and molecular readouts to capture the full spectrum of aging biology
• Leveraging circulating proteomics and future incidence of neurodegeneration to identify novel therapeutic targets that address root causes rather than downstream pathology
• From platform to pipeline: Case study of translation from target discovery to clinical program

• Protein quality control systems decline with age, increasing the likelihood that aberrant protein conformations will accumulate and promote cellular dysfunction
• With loss of proteostasis, endogenous mechanisms can opportunistically give rise to tau oligomers, which may be the most pathogenic species of tau protein
• In aged wild-type mice and tau transgenic models, pharmacological inhibition of cellular pathways that generate tau oligomers is accompanied by broad phenotypic amelioration
• Reduction of tau oligomer levels in the CNS is a promising therapeutic strategy for tauopathies, but may be generally relevant to diseases of aging