Luana, Marano (2021) DEVELOPMENT OF THE FIRST-IN-CLASS ORAL FACTOR D INHIBITOR DANICOPAN FOR THE TREATMENT OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA. [Tesi di dottorato]
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| Tipologia del documento: | Tesi di dottorato |
|---|---|
| Lingua: | English |
| Titolo: | DEVELOPMENT OF THE FIRST-IN-CLASS ORAL FACTOR D INHIBITOR DANICOPAN FOR THE TREATMENT OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA |
| Autori: | Autore Email Luana, Marano luanamarano@libero.it |
| Data: | 7 Febbraio 2021 |
| Numero di pagine: | 62 |
| Istituzione: | Università degli Studi di Napoli Federico II |
| Dipartimento: | Medicina Clinica e Chirurgia |
| Dottorato: | Terapie avanzate biomediche e chirurgiche |
| Ciclo di dottorato: | 33 |
| Coordinatore del Corso di dottorato: | nome email Di Minno, Giovanni diminno@unina.it |
| Tutor: | nome email Risitano, Antonio Maria [non definito] |
| Data: | 7 Febbraio 2021 |
| Numero di pagine: | 62 |
| Parole chiave: | Paroxysmal nocturnal hemoglobinuria, complement-mediated intravascular hemolysis, Danicopan, complement alternative pathway, factor D inhibitor, extravascular hemolysis, LDH, hemoglobin, GPI-deficient erythrocytes |
| Settori scientifico-disciplinari del MIUR: | Area 06 - Scienze mediche > MED/15 - Malattie del sangue |
| Depositato il: | 24 Feb 2021 09:41 |
| Ultima modifica: | 07 Giu 2023 10:25 |
| URI: | http://www.fedoa.unina.it/id/eprint/14010 |
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematological disorder of the hematopoietic stem cells, characterized by chronic complement-mediated intravascular hemolysis (IVH) due to absence of complement regulators CD55 and CD59 on affected erythrocytes, thromboembolic events affecting mostly venous vessels and bone marrow failure of different degrees. Danicopan is a, first-in-class proximal, complement alternative pathway (AP) factor D (FD) inhibitor, proximal AP inhibition may disable both terminal complement activation (inhibiting MAC–mediated IVH) and C3 fragment opsonization (preventing extravascular hemolysis (EVH)), with additional convenience of oral administration. Untreated hemolytic PNH patients received danicopan monotherapy (100-200 mg thrice daily). Endpoints included change in lactate dehydrogenase (LDH) and hemoglobin. Safety, pharmacokinetics/pharmacodynamics, and patient-reported outcomes were measured. Danicopan used in monotherapy resulted in inhibition of IVH, with significant LDH reduction at day 28 (primary endpoint), it also prevented C3 deposition on surviving GPI-deficient erythrocytes, preventing EVH (confirmed by reduction of bilirubin and reticulocytes). Concomitant inhibition of IVH and prevention of C3-mediated EVH resulted in improvement of anemia, with a mean hemoglobin gain of 1.7 g/dL after 12 weeks of treatment. Consistent with these findings, all patients exhibited significant increases in the percentage of GPI-deficient erythrocytes, confirming their extended half-life in vivo, and improvement in FACIT-Fatigue quality-of-life measurements.
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