Coelho Teresa, Ando Yukio, Benson Merrill D, Berk John L, Waddington-Cruz Márcia, Dyck Peter J, Gillmore Julian D, Khella Sami L, Litchy William J, Obici Laura, Monteiro Cecilia, Tai Li-Jung, Viney Nicholas J, Buchele Gustavo, Brambatti Michela, Jung Shiangtung W, St L O'Dea Louis, Tsimikas Sotirios, Schneider Eugene, Geary Richard S, Monia Brett P, Gertz Morie
Department of Neuroscience, Centro Hospitalar Universitário do Porto, Porto, Portugal.
Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Neurol Ther. 2021 Jun;10(1):375-389. doi: 10.1007/s40120-021-00235-6. Epub 2021 Feb 26.
AKCEA-TTR-L is a ligand-conjugated antisense (LICA) drug in development for the treatment of hereditary transthyretin amyloidosis (hATTR), a fatal disease caused by mutations in the transthyretin (TTR) gene. AKCEA-TTR-L shares the same nucleotide sequence as inotersen, an antisense medicine approved for use in hATTR polyneuropathy (hATTR-PN). Unlike inotersen, AKCEA-TTR-L is conjugated to a triantennary N-acetylgalactosamine moiety that supports receptor-mediated uptake by hepatocytes, the primary source of circulating TTR. This advanced design increases drug potency to allow for lower and less frequent dosing. The NEURO-TTRansform study will investigate whether AKCEA-TTR-L is safe and efficacious, with the aim of improving neurologic function and quality of life in hATTR-PN patients.
METHODS/DESIGN: Approximately 140 adults with stage 1 (independent ambulation) or 2 (requires ambulatory support) hATTR-PN are anticipated to enroll in this multicenter, open-label, randomized, phase 3 study. Patients will be assigned 6:1 to AKCEA-TTR-L 45 mg subcutaneously every 4 weeks or inotersen 300 mg once weekly until the prespecified week 35 interim efficacy analysis, after which patients receiving inotersen will receive AKCEA-TTR-L 45 mg subcutaneously every 4 weeks. All patients will then receive AKCEA-TTR-L through the remainder of the study treatment period. The final efficacy analysis at week 66 will compare the AKCEA-TTR-L arm with the historical placebo arm from the phase 3 trial of inotersen (NEURO-TTR). The primary outcome measures are between-group differences in the change from baseline in serum TTR, modified Neuropathy Impairment Score + 7, and Norfolk Quality of Life-Diabetic Neuropathy questionnaire.
NEURO-TTRansform is designed to determine whether targeted delivery of AKCEA-TTR-L to hepatocytes with lower and less frequent doses will translate into clinical and quality-of-life benefits for patients with hATTR-PN.
The study is registered at ClinicalTrials.gov (NCT04136184) and EudraCT (2019-001698-10).
AKCEA-TTR-L是一种正在研发的配体共轭反义（LICA）药物，用于治疗遗传性转甲状腺素蛋白淀粉样变性病（hATTR），这是一种由转甲状腺素蛋白（TTR）基因突变引起的致命疾病。AKCEA-TTR-L与已被批准用于治疗hATTR多发性神经病（hATTR-PN）的反义药物inotersen具有相同的核苷酸序列。与inotersen不同的是，AKCEA-TTR-L与一个三触角N-乙酰半乳糖胺部分结合，该部分支持受体介导的肝细胞摄取，而肝细胞是循环TTR的主要来源。这种先进的设计提高了药物效力，从而允许更低剂量和更少频率的给药。NEURO-TTRansform研究将调查AKCEA-TTR-L是否安全有效，目的是改善hATTR-PN患者的神经功能和生活质量。
方法/设计：预计约140名患有1期（独立行走）或2期（需要行走辅助）hATTR-PN的成年人将参加这项多中心、开放标签、随机3期研究。患者将按6:1的比例被分配接受每4周皮下注射一次45mg的AKCEA-TTR-L或每周一次300mg 的inotersen，直至预定的第35周中期疗效分析，之后接受inotersen的患者将改为每4周皮下注射一次45mg的AKCEA-TTR-L。在研究治疗期的剩余时间里，所有患者都将接受AKCEA-TTR-L治疗。第66周的最终疗效分析将把AKCEA-TTR-L组与inotersen 的3期试验（NEURO-TTR）中的历史安慰剂组进行比较。主要结局指标是血清TTR从基线变化、改良神经病变损害评分+7以及诺福克糖尿病神经病变生活质量问卷在组间的差异。
NEURO-TTRansform旨在确定以更低剂量和更少频率将AKCEA-TTR-L靶向递送至肝细胞是否会为hATTR-PN患者带来临床和生活质量方面益处。
该研究已在ClinicalTrials.gov（NCT04136184）和EudraCT（2019-001698-10）注册。
