Multiple sclerosis (MS) is a chronic inflammatory, autoimmune, and neurodegenerative disease of the central nervous system (CNS), characterized by marked heterogeneity and a highly variable clinical course. In recent years, a deeper understanding of the immunopathogenic mechanisms underlying MS has transformed the therapeutic approach, promoting the development of numerous disease-modifying therapies (DMTs) capable of reducing inflammatory activity, limiting the formation of new lesions, and slowing disability progression. The aim of this thesis is to provide a critical analysis of the main disease-modifying therapies, comparing small molecules and biologic agents from pharmacological, clinical, and regulatory perspectives. Following an overview of the disease pathophysiology and the immune processes driving its progression, the rationale underlying the development of modern disease-modifying therapies (DMTs) is discussed, highlighting how the identification of specific immunological targets has enabled the introduction of increasingly selective and personalized treatment strategies. Among the small molecules, an overview is provided of the main classes currently available for relapsing-remitting multiple sclerosis, including fumarates, sphingosine-1-phosphate receptor modulators, teriflunomide, and cladribine, with emphasis on their different mechanisms of action and therapeutic characteristics. Within the fumarate class, particular attention is devoted to dimethyl fumarate, focusing on its mechanism of action, efficacy demonstrated in pivotal clinical trials and real-world studies, safety profile, major adverse reactions, and monitoring strategies. Special consideration is also given to diroximel fumarate, which was developed to improve gastrointestinal tolerability. The thesis then focuses on biologic therapies, describing the main monoclonal antibodies used in relapsing-remitting multiple sclerosis, including ocrelizumab, ofatumumab, alemtuzumab, and natalizumab, illustrating their different therapeutic targets and mechanisms of immune modulation. Among these agents, natalizumab is examined in greater detail as a model of high-efficacy biologic therapy, with particular emphasis on its mechanism of action, clinical evidence, safety profile, and strategies adopted to prevent and manage the risk of progressive multifocal leukoencephalopathy. A dedicated chapter is also devoted to the regulatory aspects associated with the development and commercialization of disease-modifying therapies, describing the role of the major regulatory authorities, marketing authorization pathways, pharmacovigilance procedures, and risk management tools, with particular attention to Risk Management Plans (RMPs), which are essential to ensure the appropriate and safe use of these medicines. The literature reviewed demonstrates that the treatment of relapsing-remitting multiple sclerosis has undergone profound evolution, shifting from therapeutic strategies primarily aimed at controlling relapses to an increasingly personalized approach based on selecting the most appropriate therapy according to the patient's clinical characteristics, disease activity, benefit-risk profile, and individual preferences. In this context, the availability of both small molecules and biologic therapies represents one of the most important advances in improving disease control, preserving neurological function, and enhancing patients' quality of life.
La sclerosi multipla (SM) è una patologia infiammatoria cronica, autoimmune e neurodegenerativa del SNC, caratterizzata da un’elevata eterogeneità e da un decorso evolutivo variabile. Negli ultimi anni la crescente comprensione dei meccanismi immunopatogenetici coinvolti nella SM ha modificato l’approccio terapeutico, favorendo lo sviluppo di numerose terapie modificanti il decorso della malattia, in grado di ridurre l’attività infiammatoria, limitare la comparsa di nuove lesioni e rallentare l’accumulo della disabilità. L’obiettivo del seguente elaborato è analizzare criticamente le principali terapie modificanti il decorso della malattia, confrontando small molecules e farmaci biologici dal punto di vista farmacologico, clinico e regolatorio. Dopo una descrizione della fisiopatologia della malattia e dei processi immunitari che ne sostengono la progressione, viene illustrato il razionale che ha guidato lo sviluppo delle moderne terapie modificanti la malattia (DMT), evidenziando come l’identificazione di specifici bersagli immunologici abbia consentito l’introduzione di trattamenti sempre più selettivi e personalizzabili. Nell’ambito delle small molecules viene presentata una panoramica delle principali classi oggi disponibili per la forma recidivante-remittente, tra cui i fumarati, i modulatori del recettore della sfingosina-1-fosfato, la teriflunomide e la cladribina, mettendo in evidenza i differenti meccanismi d’azione e le rispettive caratteristiche terapeutiche. Nell’ambito dei fumarati, un focus specifico è dedicato al dimetilfumarato, analizzandone il meccanismo d’azione, il profilo di efficacia documentata dagli studi clinici registrativi e dalle evidenze di real-world, gli aspetti di sicurezza, le principali reazioni avverse e le strategie di monitoraggio; particolare attenzione è inoltre dedicata al diroximel fumarato, sviluppato per migliorare la tollerabilità gastrointestinale. Successivamente la trattazione si concentra sui farmaci biologici, con una descrizione dei principali anticorpi monoclonali impiegati nella SM recidivante-remittente, tra cui ocrelizumab, ofatumumab, alemtuzumab e natalizumab, illustrando i differenti bersagli terapeutici e i meccanismi attraverso cui modulano la risposta immunitaria. Tra questi, il natalizumab, viene approfondito come modello di terapia biologica ad alta efficacia, analizzandone il meccanismo d’azione, le evidenze cliniche, gli aspetti legati alla sicurezza e le strategie adottate per la prevenzione e la gestione del rischio di leucoencefalopatia multifocale progressiva. L’elaborato dedica inoltre un capitolo agli aspetti regolatori che accompagnano lo sviluppo e la commercializzazione dei farmaci modificanti il decorso della malattia, descrivendo il ruolo delle principali autorità regolatorie, i percorsi autorizzativi, le procedure di farmacovigilanza e gli strumenti di gestione del rischio, con particolare attenzione ai risk management plans, elementi fondamentali per garantire un impiego appropriato e sicuro dei medicinali. Dall’analisi della letteratura emerge come il trattamento della SM recidivante-remittente abbia subito una profonda evoluzione, passando da strategie terapeutiche prevalentemente orientate al controllo delle ricadute a un approccio sempre più personalizzato, fondato sulla scelta della terapia più idonea in funzione delle caratteristiche cliniche del paziente, dell’attività di malattia, del profilo beneficio-rischio e delle preferenze individuali. In tale contesto, la disponibilità di small molecules e farmaci biologici rappresenta oggi uno dei principali strumenti per migliorare il controllo della malattia, preservare la funzionalità neurologica e migliorare la qualità della vita dei pazienti.
SMALL MOLECULES E FARMACI BIOLOGICI NELLA SCLEROSI MULTIPLA RECIDIVANTE-REMITTENTE: BASI FARMACOLOGICHE ED EVOLUZIONE DELLE TERAPIE IMMUNOMODULANTI
DA PIAN, SARA
2025/2026
Abstract
Multiple sclerosis (MS) is a chronic inflammatory, autoimmune, and neurodegenerative disease of the central nervous system (CNS), characterized by marked heterogeneity and a highly variable clinical course. In recent years, a deeper understanding of the immunopathogenic mechanisms underlying MS has transformed the therapeutic approach, promoting the development of numerous disease-modifying therapies (DMTs) capable of reducing inflammatory activity, limiting the formation of new lesions, and slowing disability progression. The aim of this thesis is to provide a critical analysis of the main disease-modifying therapies, comparing small molecules and biologic agents from pharmacological, clinical, and regulatory perspectives. Following an overview of the disease pathophysiology and the immune processes driving its progression, the rationale underlying the development of modern disease-modifying therapies (DMTs) is discussed, highlighting how the identification of specific immunological targets has enabled the introduction of increasingly selective and personalized treatment strategies. Among the small molecules, an overview is provided of the main classes currently available for relapsing-remitting multiple sclerosis, including fumarates, sphingosine-1-phosphate receptor modulators, teriflunomide, and cladribine, with emphasis on their different mechanisms of action and therapeutic characteristics. Within the fumarate class, particular attention is devoted to dimethyl fumarate, focusing on its mechanism of action, efficacy demonstrated in pivotal clinical trials and real-world studies, safety profile, major adverse reactions, and monitoring strategies. Special consideration is also given to diroximel fumarate, which was developed to improve gastrointestinal tolerability. The thesis then focuses on biologic therapies, describing the main monoclonal antibodies used in relapsing-remitting multiple sclerosis, including ocrelizumab, ofatumumab, alemtuzumab, and natalizumab, illustrating their different therapeutic targets and mechanisms of immune modulation. Among these agents, natalizumab is examined in greater detail as a model of high-efficacy biologic therapy, with particular emphasis on its mechanism of action, clinical evidence, safety profile, and strategies adopted to prevent and manage the risk of progressive multifocal leukoencephalopathy. A dedicated chapter is also devoted to the regulatory aspects associated with the development and commercialization of disease-modifying therapies, describing the role of the major regulatory authorities, marketing authorization pathways, pharmacovigilance procedures, and risk management tools, with particular attention to Risk Management Plans (RMPs), which are essential to ensure the appropriate and safe use of these medicines. The literature reviewed demonstrates that the treatment of relapsing-remitting multiple sclerosis has undergone profound evolution, shifting from therapeutic strategies primarily aimed at controlling relapses to an increasingly personalized approach based on selecting the most appropriate therapy according to the patient's clinical characteristics, disease activity, benefit-risk profile, and individual preferences. In this context, the availability of both small molecules and biologic therapies represents one of the most important advances in improving disease control, preserving neurological function, and enhancing patients' quality of life.| File | Dimensione | Formato | |
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https://hdl.handle.net/20.500.14239/36206