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 × 109/L in 50% and ≥100 × 109/L in 80% of the subjects. However, grade 4 thrombocytopenia (<25 × 109/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.

中文翻译：

---

潜在的免疫障碍可能会使某些转甲状腺素蛋白淀粉样变性患者易患 Inotersen 介导的血小板减少症。

Inotersen 是一种 2'-O-甲氧基乙基 (2'-MOE) 硫代磷酸酯反义寡核苷酸，可在 NEURO-TTR 和 NEURO-TTR 开放中减少遗传性转甲状腺素蛋白淀粉样变性伴多发性神经病 (hATTR-PN) 患者的疾病进展和改善生活质量-标签扩展 (OLE) 试验。然而，300 毫克/周的 inotersen 治疗与几名患者的血小板计数减少有关。NEURO-TTR-inotersen 组患者的平均血小板计数在 50% 中保持 ≥ 140 × 109/L，在 80% 受试者中保持 ≥ 100 × 109/L。然而，在 NEURO-TTR 试验中，三名受试者发生了 4 级血小板减少症 (<25 × 109/L)，其中一名受试者出现了致命的颅内出血。其他两人用皮质类固醇成功治疗并停止使用 inotersen。在 NEURO-TTR（n = 17 安慰剂；n = 31 inotersen）和 OLE（n = 33）试验中对一部分受试者进行的调查排除了直接骨髓毒性、消耗性凝血病和肝素诱导的血小板减少症。在 NEURO-TTR 中，31 名接受本品治疗的受试者中有 5 名 (16%) 在基线时检测到抗血小板免疫球蛋白 G (IgG) 抗体，其中 4 名最终在服药期间出现 1 级或 2 级血小板减少症。此外，同一组的 24 名受试者出现了治疗中出现的抗血小板 IgG 抗体，其中 2 名出现了 2 级，3 名出现了 4 级血小板减少症。三名 4 级血小板减少症受试者中有两名的抗血小板 IgG 抗体靶向 GPIIb/IIIa。先前与免疫失调有关的血浆细胞因子，例如白细胞介素 (IL)-23 和增殖诱导配体 (APRIL) 在基线时通常高于正常范围。总的来说，这些发现表明潜在的免疫失调使一些个体在 inotersen 治疗期间易患免疫介导的血小板减少症。