| Autor: |
Narayanan P; Ionis Pharmaceuticals, Carlsbad, California., Curtis BR; Platelet and Neutrophil Immunology Laboratory, Versiti Wisconsin, Inc., Milwaukee, Wisconsin., Shen L; Ionis Pharmaceuticals, Carlsbad, California., Schneider E; Ionis Pharmaceuticals, Carlsbad, California., Tami JA; Ionis Pharmaceuticals, Carlsbad, California., Paz S; Ionis Pharmaceuticals, Carlsbad, California.; aTyr Pharma, San Diego California., Burel SA; Ionis Pharmaceuticals, Carlsbad, California., Tai LJ; Ionis Pharmaceuticals, Carlsbad, California., Machemer T; Ionis Pharmaceuticals, Carlsbad, California., Kwoh TJ; Ionis Pharmaceuticals, Carlsbad, California., Xia S; Ionis Pharmaceuticals, Carlsbad, California., Shattil SJ; Department of Medicine, University of California, San Diego, La Jolla, California., Witztum JL; Department of Medicine, University of California, San Diego, La Jolla, California., Engelhardt JA; Ionis Pharmaceuticals, Carlsbad, California., Henry SP; Ionis Pharmaceuticals, Carlsbad, California., Monia BP; Ionis Pharmaceuticals, Carlsbad, California., Hughes SG; Ionis Pharmaceuticals, Carlsbad, California. |
| Abstrakt: |
Inotersen, a 2'-O-methoxyethyl (2'-MOE) phosphorothioate antisense oligonucleotide, reduced disease progression and improved quality of life in patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) in the NEURO-TTR and NEURO-TTR open-label extension (OLE) trials. However, 300 mg/week inotersen treatment was associated with platelet count reductions in several patients. Mean platelet counts in patients in the NEURO-TTR-inotersen group remained ≥140 × 10 9 /L in 50% and ≥100 × 10 9 /L in 80% of the subjects. However, grade 4 thrombocytopenia (<25 × 10 9 /L) occurred in three subjects in NEURO-TTR trial, and one of these suffered a fatal intracranial hemorrhage. The two others were treated successfully with corticosteroids and discontinuation of inotersen. Investigations in a subset of subjects in NEURO-TTR ( n = 17 placebo; n = 31 inotersen) and OLE ( n = 33) trials ruled out direct myelotoxicity, consumptive coagulopathy, and heparin-induced thrombocytopenia. Antiplatelet immunoglobulin G (IgG) antibodies were detected at baseline in 5 of 31 (16%) inotersen-treated subjects in NEURO-TTR, 4 of whom eventually developed grade 1 or 2 thrombocytopenia while on the drug. In addition, 24 subjects in the same group developed treatment-emergent antiplatelet IgG antibodies, of which 2 developed grade 2, and 3 developed grade 4 thrombocytopenia. Antiplatelet IgG antibodies in two of the three grade 4 thrombocytopenia subjects targeted GPIIb/IIIa. Plasma cytokines previously implicated in immune dysregulation, such as interleukin (IL)-23 and a proliferation-inducing ligand (APRIL) were often above the normal range at baseline. Collectively, these findings suggest an underlying immunologic dysregulation predisposing some individuals to immune-mediated thrombocytopenia during inotersen treatment. |
