背景:3期NEURO-TTRansform试验显示,eplontersen治疗65周降低了甲状腺素运载蛋白(TTR),神经病变的进展停止,遗传性TTR介导的淀粉样变性伴多发性神经病(ATTRv-PN)的成年患者的生活质量(QoL)得到改善,vs.历史安慰剂。
方法:NEURO-TTRansform纳入ATTRv-PN患者。一部分患者被随机分配接受每周300mg的皮下inotersen(第1-34周),随后改用每4周45mg的皮下eplontersen(第37-81周)。通过第85周评估血清TTR的变化和治疗引起的不良事件(TEAE)。对神经病变损害的影响,QoL,和营养状况也进行了评估。
结果:在随机分配给inotersen的24名患者中,20(83%)在第37周改用eplontersen,第4周由于AE/研究者决定而中止。在从inotersen(-74.3%;第35周)切换到eplontersen(-80.6%;第85周)后,血清TTR的绝对变化更大。从伊诺特森治疗结束后,神经病变受损和QoL稳定(即,没有进展)在eplontersen上,营养状况没有恶化。与inotersen相比,eplontersen(第37-85周;19/20[95%]患者)的TEAE较少(直到第35周;24/24[100%]患者)。Inotersen治疗期间平均血小板计数下降(平均最低点下降40.7%),并在eplontersen治疗期间恢复至基线(平均最低点下降,3.2%)。
结论:从inotersen转换为eplontersen进一步降低了血清TTR,停止疾病进展,稳定的QoL,血小板计数恢复,和提高耐受性,没有恶化的营养状况。这支持了从inotersen转换为eplontersen的ATTRv-PN患者的积极获益-风险状况。
BACKGROUND: The phase 3 NEURO-TTRansform trial showed eplontersen treatment for 65 weeks reduced transthyretin (TTR), halted progression of neuropathy impairment, and improved quality of life (QoL) in adult patients with hereditary TTR-mediated amyloidosis with polyneuropathy (ATTRv-PN), vs. historical placebo.
METHODS: NEURO-TTRansform enrolled patients with ATTRv-PN. A subset of patients were randomized to receive subcutaneous inotersen 300 mg weekly (Weeks 1-34) and subsequently switched to subcutaneous eplontersen 45 mg every 4 weeks (Weeks 37-81). Change in serum TTR and treatment-emergent adverse events (TEAEs) were evaluated through Week 85. Effects on neuropathy impairment, QoL, and nutritional status were also evaluated.
RESULTS: Of 24 patients randomized to inotersen, 20 (83%) switched to eplontersen at Week 37 and four discontinued due to AEs/investigator decision. Absolute change in serum TTR was greater after switching from inotersen (-74.3%; Week 35) to eplontersen (-80.6%; Week 85). From the end of inotersen treatment, neuropathy impairment and QoL were stable (i.e., did not progress) while on eplontersen, and there was no deterioration in nutritional status. TEAEs were fewer with eplontersen (Weeks 37-85; 19/20 [95%] patients) compared with inotersen (up to Week 35; 24/24 [100%] patients). Mean platelet counts decreased during inotersen treatment (mean nadir reduction ‒40.7%) and returned to baseline during eplontersen treatment (mean nadir reduction, ‒3.2%).
CONCLUSIONS: Switching from inotersen to eplontersen further reduced serum TTR, halted disease progression, stabilized QoL, restored platelet count, and improved tolerability, without deterioration in nutritional status. This supports a positive benefit-risk profile for patients with ATTRv-PN who switch from inotersen to eplontersen.