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更新于：2026-08-10
Tominersen
更新于：2026-08-10
概要
基本信息
最高研发阶段临床2期 |
首次获批日期- |
最高研发阶段(中国)终止 |
特殊审评孤儿药 (美国) |
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结构/序列
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Sequence Code 317419970
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关联
6
项与 Tominersen 相关的临床试验NCT05686551
A Phase II, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen in Individuals With Prodromal and Early Manifest Huntington's Disease
NCT04000594
An Open-Label Adaptive Multiple-Dose Study to Investigate the Pharmacokinetics and Pharmacodynamics of RO7234292 in CSF and Plasma, and Safety and Tolerability Following Intrathecal Administration in Patients With Huntington's Disease
NCT03842969
An Open-Label Extension Study to Evaluate the Long-Term Safety and Tolerability of Intrathecally Administered RO7234292 (RG6042) in Patients With Huntington's Disease
100 项与 Tominersen 相关的临床结果
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100 项与 Tominersen 相关的转化医学
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100 项与 Tominersen 相关的专利（医药）
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17
项与 Tominersen 相关的文献（医药）2026-04-01BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Quantitative relationship between tominersen concentrations in cerebrospinal fluid and biomarker changes in Huntington's disease patients
Article
作者: Sanwald Ducray, Patricia ; Hawellek, David J. ; Grimsey, Paul ; Björnsson, Marcus ; McColgan, Peter ; Tabrizi, Sarah ; Wild, Edward J. ; Silber Baumann, Hanna E. ; Anderson, Karen ; Leavitt, Blair R. ; Yamamoto, Yumi ; Landwehrmeyer, Bernhard G.
Aim:
Intrathecally administered antisense oligonucleotide tominersen aims to slow Huntington's disease progression by lowering mutant huntingtin (mHTT) protein levels. This study used non‐linear mixed effects population pharmacokinetic and pharmacodynamic (PKPD) modelling to characterize the relationship between tominersen concentration in cerebrospinal fluid (CSF) and CSF mHTT reduction. Additionally, the relationship between tominersen CSF exposure and changes in other CSF biomarkers was investigated to understand tominersen's pharmacodynamic profile. Finally, PKPD model simulations were conducted to inform the dose selection in the GENERATION HD2 study.
Methods:
Data from four clinical studies, including 915 participants receiving placebo or tominersen doses (30–120 mg) every 4, 8 or 16 weeks for up to 25 months, were used to develop the PKPD model. The model was utilized to predict tominersen CSF exposure metrics for individual patients in the GENERATION HD1 study for the exposure–response (ER) analysis and to simulate the PK and PD profiles for lower doses.
Results:
An indirect‐response model described the relationship between tominersen CSF concentration and mHTT reduction, estimating a half‐maximal inhibitory concentration (IC
50
) of 4.18 ng/mL. The ER analysis revealed that the highest exposure quartile showed a 54% mHTT reduction at steady state and transient elevations in biomarkers of neuroinjury and inflammation. In contrast, the lowest exposure quartile had a 24% mHTT reduction and a favourable biomarker profile.
Conclusions:
The PKPD model quantitatively confirms the relationship between tominersen exposure and CSF mHTT lowering. The ER analysis suggests that lower tominersen exposure levels may offer a better benefit–risk profile.
2025-12-01Molecular Therapy-Nucleic Acids
Molecular and imaging biomarker responses to brain mutant HTT lowering in a mouse model of Huntington disease
Article
作者: Bale, Kirsten ; Anderson, Christine ; Fan, Jianjia ; Ko, Seunghyun ; Wellington, Cheryl L ; Yung, Andrew ; Hayden, Michael R ; Kozlowski, Piotr ; Pouladi, Mahmoud A ; Caron, Nicholas S ; Ma, Da
Therapies targeting mutant huntingtin (mHTT) reduction in the brain hold promise as disease-modifying treatments for Huntington disease (HD), necessitating biomarkers that accurately reflect treatment response. We evaluated candidate molecular and imaging biomarkers after mHTT reduction in YAC128 HD mice, with equal numbers of males and females per group. At 6 months of age, YAC128 mice received unilateral intracerebroventricular injections of saline or mHTT-lowering antisense oligonucleotide (HTT ASO). Plasma neurofilament light chain (NEFL) and glial fibrillary acidic protein (GFAP) were measured longitudinally from 6 to 12 months. Structural MRI was performed at 6, 9, and 12 months. At study endpoint, we quantified mHTT target engagement in the brain and performed striatal RNA sequencing. Treatment with HTT ASO produced a sustained reduction of mHTT levels throughout the brain for up to 6 months, significantly slowed plasma NEFL increases, and moderately attenuated GFAP elevation. Although mHTT levels inversely correlated with gray and white matter volumes, treatment did not significantly stabilize regional brain atrophy, highlighting an association between mHTT load and neuroanatomical integrity. HTT ASO also partially reversed striatal transcriptome dysregulation and restored oligodendrocyte-specific gene expression. Plasma NEFL, but not brain imaging, emerges as a sensitive and dynamic response biomarker for mHTT-lowering therapies.
2024-09-01Molecular Therapy-Nucleic Acids
Preclinical evaluation of stereopure antisense oligonucleotides for allele-selective lowering of mutant HTT
Article
作者: Taborn, Kristin ; Prakasha, Priyanka Shiva ; Francis, Christopher ; Byrne, Mike ; Kandasamy, Pachamuthu ; Frank-Kamenetsky, Maria ; Upadhyay, Hansini ; Maguire, Abbie ; Jang, Hyun Gyung ; Purcell-Estabrook, Erin ; Dale, Elena ; Yang, Hailin ; Iwamoto, Naoki ; Meena ; Shimizu, Mamoru ; Hu, Xiao Shelley ; Shelke, Juili Dilip ; Yin, Yuan ; Tseng, Wei Chou ; Zhao, Anderson ; Liu, Yuanjing ; Verdine, Gregory L ; Longo, Ken ; Akhtar, Ali ; Metterville, Jake ; Looby, Richard ; Liu, Fangjun ; Kothari, Nayantara ; Lamattina, Anthony ; Pan, Qianli ; Bowman, Keith ; Vargeese, Chandra ; Standley, Stephany
Huntington's disease (HD) is an autosomal dominant disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in one copy of the HTT gene (mutant HTT, mHTT). The unaffected HTT gene encodes wild-type HTT (wtHTT) protein, which supports processes important for the health and function of the central nervous system. Selective lowering of mHTT for the treatment of HD may provide a benefit over nonselective HTT-lowering approaches, as it aims to preserve the beneficial activities of wtHTT. Targeting a heterozygous single-nucleotide polymorphism (SNP) where the targeted variant is on the mHTT gene is one strategy for achieving allele-selective activity. Herein, we investigated whether stereopure phosphorothioate (PS)- and phosphoryl guanidine (PN)-containing oligonucleotides can direct allele-selective mHTT lowering by targeting rs362273 (SNP3). We demonstrate that our SNP3-targeting molecules are potent, durable, and selective for mHTT in vitro and in vivo in mouse models. Through comparisons with a surrogate for the nonselective investigational compound tominersen, we also demonstrate that allele-selective molecules display equivalent potency toward mHTT with improved durability while sparing wtHTT. Our preclinical findings support the advancement of WVE-003, an investigational allele-selective compound currently in clinical testing (NCT05032196) for the treatment of patients with HD.
100 项与 Tominersen 相关的药物交易
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外链
| KEGG | Wiki | ATC | Drug Bank |
|---|---|---|---|
| D12013 | - | - | - |
研发状态
10 条进展最快的记录, 后查看更多信息
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 亨廷顿舞蹈病 | 临床3期 | 美国 | 2019-01-23 | |
| 亨廷顿舞蹈病 | 临床3期 | 日本 | 2019-01-23 | |
| 亨廷顿舞蹈病 | 临床3期 | 阿根廷 | 2019-01-23 | |
| 亨廷顿舞蹈病 | 临床3期 | 澳大利亚 | 2019-01-23 | |
| 亨廷顿舞蹈病 | 临床3期 | 奥地利 | 2019-01-23 | |
| 亨廷顿舞蹈病 | 临床3期 | 加拿大 | 2019-01-23 | |
| 亨廷顿舞蹈病 | 临床3期 | 智利 | 2019-01-23 | |
| 亨廷顿舞蹈病 | 临床3期 | 丹麦 | 2019-01-23 | |
| 亨廷顿舞蹈病 | 临床3期 | 法国 | 2019-01-23 | |
| 亨廷顿舞蹈病 | 临床3期 | 德国 | 2019-01-23 |
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临床结果
临床结果
适应症
分期
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临床1期 | 12 | (Dose Level 1 of RO7234292 (RG6042)) | 範糧鹽築餘構衊積積製(範鹹遞願鏇構範網醖獵) = 壓鹹積獵醖網積鏇網鑰 夢窪餘餘願壓艱窪顧餘 (衊構夢獵餘鏇觸製鑰獵, 71400) 更多 | - | 2024-10-03 | ||
(Dose Level 2 of RO7234292 (RG6042)) | 範糧鹽築餘構衊積積製(範鹹遞願鏇構範網醖獵) = 憲鹹齋製鏇鬱廠範醖淵 夢窪餘餘願壓艱窪顧餘 (衊構夢獵餘鏇觸製鑰獵, 132000) 更多 | ||||||
临床2期 | 46 | (RO7234292 Monthly) | 繭積醖積積築艱鏇膚衊 = 窪膚選衊淵壓繭衊築積 蓋觸遞積網糧遞網觸餘 (餘遞觸窪積窪窪顧鏇淵, 鬱鏇築廠鏇遞繭衊製構 ~ 鹹鏇醖襯艱廠衊蓋憲網) 更多 | - | 2021-01-19 | ||
(RO7234292 Bimonthly) | 繭積醖積積築艱鏇膚衊 = 餘壓構蓋膚願壓齋選憲 蓋觸遞積網糧遞網觸餘 (餘遞觸窪積窪窪顧鏇淵, 製鑰製齋醖糧鏇憲鹽願 ~ 餘網築餘齋繭鏇鏇鑰艱) 更多 | ||||||
临床1/2期 | 46 | Placebo (Placebo) | 遞製鬱衊構獵網選壓觸 = 鹹餘廠廠繭衊蓋選範廠 遞築簾鬱淵齋鹽糧衊築 (餘蓋網鹹積憲廠觸糧糧, 繭淵觸範蓋襯襯夢遞蓋 ~ 願顧鑰構選壓構鏇顧築) 更多 | - | 2019-05-31 | ||
(ISIS 443139 10 mg) | 遞製鬱衊構獵網選壓觸 = 鑰壓齋築夢壓醖鏇鏇選 遞築簾鬱淵齋鹽糧衊築 (餘蓋網鹹積憲廠觸糧糧, 網顧廠遞憲淵獵繭糧餘 ~ 範獵鏇遞齋鑰夢遞製製) 更多 |
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