Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)

Objective: Multiple pathogenic mechanisms drive progression of disability in fully established multiple sclerosis (MS); therefore, it is unlikely that a single therapeutic agent will be curative. Analogous to cardiovascular diseases, effective treatments for evolved MS will likely require individualized combination therapies that target pathogenic processes active in the particular patient. Ability to reliably measure such pathogenic mechanisms in living subjects is a prerequisite for a precisionmedicine approach to MS. We have already demonstrated the clinical utility of combinatorial cerebrospinal fluid (CSF) biomarkers for diagnosing, staging and prognosticating MS. In an external validation study by the multicenter SPINal fluid COnsortium for Multiple Sclerosis (SPINCOMS), these proteomic molecular tests outperformed traditional phenomenological approaches in diagnostic and staging accuracy and also predicted future disability. These proteomic tests revealed substantial intra-individual heterogeneity in the candidate mechanisms of MS progression, which are largely distinct from those underlying MS susceptibility. Identified progression-related processes include compartmentalized inflammation; activation of innate immunity (e.g., myeloid lineage, complement, and coagulation cascades); continuous damage to CNS epithelial barriers; toxic astrogliosis; fibrotic remodeling of the extracellular matrix; and altered expression of pathways involved in synaptogenesis, neurogenesis, and remyelination. These mechanisms are largely unaffected by current FDA-approved DMTs, consistent with their declining efficacy as patients age-ultimately providing no measurable group benefit on disability progression beyond approximately 55 years of age. Accordingly, the objectives of this protocol are to: * Develop clinical trial methodology for economical screening of therapeutic agents targeting candidate pathogenic mechanisms of MS using CSF biomarkers. * Build a knowledge base on the intrathecal effects of current DMTs and emerging treatments on candidate pathogenic (and reparative) mechanisms of MS. * Establish and validate framework for designing effective and safe combination therapies for MS within a precision medicine paradigm. Study population: * Progressive MS (ProgMS): People with MS (pwMS) who exhibit ongoing clinical disability progression despite treatment with FDA-approved DMTs, or while untreated, either due to age over 55y, prior DMT failure, or personal choice to forgo treatment. The therapeutic goal in this cohort is to slow the rate of disability progression. * Non-progressing MS with residual disability: pwMS with no/very low measurable disease progression while on FDA-approved DMTs (or untreated), but who continue to experience residual disability. The therapeutic goal in this cohort is to improve existing disability. Design: The protocol employs an adaptable workflow that enables simultaneous evaluation of multiple therapeutic agents, maximizing potential benefit to participants while generating knowledge essential for the rational development of future combination therapies for MS. It focuses on drugs with mechanisms of action (MOAs) targeting biological processes that underlie MS severity. Participants will be assigned to therapies based on individual therapeutic targets and comorbidities. Longitudinal CSF biomarker measurements will assess whether assigned treatments elicit the desired pharmacodynamic (PD) effects within the intrathecal compartment. Agents that fail to reproducibly modulate their intended CSF targets will be discontinued (or tested at higher doses, if feasible) and replaced under protocol amendments. Agents that demonstrate measurable and desired intrathecal PD activity will be evaluated in combination to assess additive or synergistic effects. Participants receiving discontinued/ineffective agents or not tolerating assigned treatment will be transitioned to alternative treatments, restarting their monotherapy or combination therapy periods, with the aim of each subject completing 18 months of monotherapy followed by either continued monotherapy or 18 months of combination therapy using only effective agents. Participants who complete 36 months of treatment may be re-enrolled to evaluate new therapeutic agents as they become available. Safety, tolerability, and preliminary clinical/imaging outcomes will inform the surrogacy of CSF biomarkers and guide power calculations for future definitive trials. In parallel, enhanced understanding of biomarker biology will support the development of process-specific combinatorial biomarkers and signatures predictive of clinical efficacy. Outcome measures: Primary outcome will be the change in Combinatorial Weight adjusted disability Scale (CombiWISE) progression at the end of monotherapy + combination therapy period in comparison to projected baseline disability progression. The acquired longitudinal data will be used for assessment of biomarker surrogacy, for identification and validation of PD markers for development of new therapeutic entities and for power analysis of future/definitive clinical trials.