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

This study will evaluate the safety, biomarkers, and efficacy of tominersen compared with placebo in participants with prodromal and early manifest Huntington's Disease (HD).

开始日期2023-02-03

申办/合作机构

F. Hoffmann-La Roche Ltd.

NCT04000594

/ Completed临床1期

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

Study BP40410 is an open-label, adaptive multiple-dose clinical study designed to characterize the PK of RO7234292 (RG6042) in plasma and CSF as well as the acute time course and recovery profile of CSF mHTT lowering in response to RO7234292 (RG6042) treatment after intrathecal (IT) administration of RO7234292 (RG6042) to patients with manifest Hungtington's disease (HD).

开始日期2019-09-02

申办/合作机构

Hoffmann-La Roche, Inc.

NCT03842969

/ Completed临床3期

An Open-Label Extension Study to Evaluate the Long-Term Safety and Tolerability of Intrathecally Administered RO7234292 (RG6042) in Patients With Huntington's Disease

This study will evaluate the long-term safety and tolerability of RO7234292 (RG6042) in participants who have completed other F. Hoffmann-La Roche, Ltd.-sponsored and/or Genentech-sponsored studies in the Huntington's disease (HD) in the development program for RG6042.

开始日期2019-04-23

申办/合作机构

Hoffmann-La Roche, Inc.

100 项与 HTT抑制剂(罗氏制药) 相关的临床结果

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100 项与 HTT抑制剂(罗氏制药) 相关的转化医学

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100 项与 HTT抑制剂(罗氏制药) 相关的专利（医药）

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项与 HTT抑制剂(罗氏制药) 相关的文献（医药）

2024-09-01·Molecular 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 ; Yang, Hailin ; Dale, Elena ; Iwamoto, Naoki ; Meena ; Shimizu, Mamoru ; Hu, Xiao Shelley ; Shelke, Juili Dilip ; Yin, Yuan ; Tseng, Wei Chou ; Zhao, Anderson ; Liu, Yuanjing ; Akhtar, Ali ; Metterville, Jake ; Verdine, Gregory L ; Longo, Ken ; Looby, Richard ; Liu, Fangjun ; Kothari, Nayantara ; Lamattina, Anthony ; Pan, Qianli ; Bowman, Keith ; Standley, Stephany ; Vargeese, Chandra

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.

2024-03-14·The New England journal of medicine1区 · 医学

Concern about Tominersen in Patients with Huntington’s Disease

1区 · 医学

Letter

作者: McColgan, Peter ; Tabrizi, Sarah J ; Doody, Rachelle S

2024-03-01·Journal of controlled release : official journal of the Controlled Release Society

Systemic delivery of mutant huntingtin lowering antisense oligonucleotides to the brain using apolipoprotein A-I nanodisks for Huntington disease

Article

作者: Reid, Gregor S D ; Martin, Dale D O ; Anderson, Christine ; Ko, Seunghyun ; Rahavi, Seyed M R ; Stanimirovic, Danica ; Anderson, Lisa M ; Schmidt, Mandi E ; McBride, Jodi L ; Abulrob, Abedelnasser ; Leavitt, Blair R ; Oda, Michael N ; Aly, Amirah E-E ; Findlay Black, Hailey ; Casal, Lorenzo L ; Caron, Nicholas S ; Hayden, Michael R ; Harvey, Emily M

Efficient delivery of therapeutics to the central nervous system (CNS) remains a major challenge for the treatment of neurological diseases. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion mutation in the HTT gene which codes for a toxic mutant huntingtin (mHTT) protein. Pharmacological reduction of mHTT in the CNS using antisense oligonucleotides (ASO) ameliorates HD-like phenotypes in rodent models of HD, with such therapies being investigated in clinical trials for HD. In this study, we report the optimization of apolipoprotein A-I nanodisks (apoA-I NDs) as vehicles for delivery of a HTT-targeted ASO (HTT ASO) to the brain and peripheral organs for HD. We demonstrate that apoA-I wild type (WT) and the apoA-I K133C mutant incubated with a synthetic lipid, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, can self-assemble into monodisperse discoidal particles with diameters <20 nm that transmigrate across an in vitro blood-brain barrier model of HD. We demonstrate that apoA-I NDs are well tolerated in vivo, and that apoA-I K133C NDs show enhanced distribution to the CNS and peripheral organs compared to apoA-I WT NDs following systemic administration. ApoA-I K133C conjugated with HTT ASO forms NDs (HTT ASO NDs) that induce significant mHTT lowering in the liver, skeletal muscle and heart as well as in the brain when delivered intravenously in the BACHD mouse model of HD. Furthermore, HTT ASO NDs increase the magnitude of mHTT lowering in the striatum and cortex compared to HTT ASO alone following intracerebroventricular administration. These findings demonstrate the potential utility of apoA-I NDs as biocompatible vehicles for enhancing delivery of mutant HTT lowering ASOs to the CNS and peripheral organs for HD.

项与 HTT抑制剂(罗氏制药) 相关的新闻（医药）

2025-06-05

·CPHI制药在线

收藏 | 现有管线与上市RNA疗法汇总

关注并星标CPHI制药在线RNA疗法正迅速成为现代医学中最具变革性的治疗策略之一。从反义寡核苷酸（ASO）和小干扰RNA（siRNA）等精准调控基因表达的工具，到mRNA疫苗和肿瘤免疫疗法等前沿应用，RNA技术已在多个疾病领域展现出巨大潜力。近年来，随着递送系统、生物偶联技术和修饰化学的不断进步，RNA疗法的临床管线迅速扩展，涵盖了罕见病、神经系统疾病、代谢性疾病以及肿瘤等多个领域。目前，RNA疗法的临床开发全景涵盖了ASO、siRNA、mRNA、核酸适体（aptamer）等主要技术路径，在不同适应症中布局广泛，关键企业的研发动态频繁，已获批上市的代表性药物不断涌现。本文总结了现有管线和上市的 RNA疗法，将这一新兴领域的开发全景呈现出来。1. ASO类 RNA资产梳理 1.1 I期ASO资产 • Praxis ASO资产：Elsunersen（PRAX-222）靶点：SCN2A基因适应症：由SCN2A基因的功能获得性突变引起的早发性SCN2A发育性和癫痫性脑病。 • PYC Therapeutics ASO资产：VP-001 靶点：PRPF31基因适应症：由PRPF31基因突变引起的视网膜色素变性11型 ASO资产：PYC-001 靶点：OPA1基因适应症：由OPA1基因突变引起的常染色体显性视神经萎缩（ADOA） ASO资产：PYC-003 靶点：PKD1基因适应症：常染色体显性多囊肾病（ADPKD） • Bio-Path Holdings ASO资产：BP1002（Liposomal Grb2 ASO）适应症：急性髓性白血病（AML）、B细胞淋巴瘤（B-cell lymphoma）技术特点：使用独特的中性脂质体递送系统（DNAbilize® Platform）递送ASO。1.2 II期ASO资产 • Stoke Therapeutics ASO资产：Zorevunersen（STK-001）靶点：SCN1A基因适应症：Dravet综合征（一种严重癫痫） ASO资产：STK-002 靶点：OPA1基因适应症：常染色体显性视神经萎缩（ADOA） • Entrada Therapeutics ASO资产：ENTR-601-44 适应症：Duchenne肌营养不良（DMD）靶点：DMD中的Exon 44跳跃技术特点：使用Entrada独有的分子穿透技术（Endosomal Escape Vehicle, EEV）提高细胞内递送效率。 ASO资产：ENTR-601-45 靶点：DMD基因的外显子45（Exon 45）适应症：适用于外显子45跳跃的杜氏肌营养不良症（DMD）患者 • Dyne Therapeutics ASO资产：DYNE-251 适应症：Duchenne肌营养不良（DMD），针对DMD中的Exon 51跳跃。技术特点：使用抗体-寡核苷酸结合平台（FORCE platform）进行肌肉组织特异性递送。 ASO资产：DYNE-101 适应症：肌强直性营养不良症1型（DM1）靶点：DMPK基因的异常CTG重复序列 • Ribomic ASO资产：Umedaptanib Pegol（原RBM-007，严格来说是核酸适体aptamer，而不是典型ASO) 靶点：FGF2（成纤维细胞生长因子2）。适应症：湿性年龄相关性黄斑变性（wAMD），软骨发育不全症 • Wave Life Sciences ASO资产： WVE-N531：DMD（杜氏肌营养不良症）治疗，靶向Exon 53跳跃 WVE-003：亨廷顿舞蹈症（Huntington's Disease, HD），靶向HTT基因突变 • PepGen ASO资产：PGN-EDO51 适应症：Duchenne肌营养不良（DMD）技术特点：结合增强型细胞穿透肽（Enhanced Delivery Oligonucleotide, EDO）技术，提高ASO进入肌肉细胞的效率。 ASO资产：PGN-EDODM1 靶点：DMPK基因的异常CUG重复序列适应症：肌强直性营养不良症1型（DM1） • 罗氏 ASO资产：Tominersen（RG6042）靶点：Huntingtin（HTT）基因适应症：亨廷顿病（Huntington's Disease, HD） ASO资产：IONIS-FB-LRx（RO7434656 / RG6299）靶点：补体因子B（Factor B）适应症：IgA肾病（IgAN） • Ultragenyx ASO资产：GTX-102 靶点：UBE3A-AS（UBE3A反义转录本）适应症：天使综合征（Angelman Syndrome）1.3 ASO类3期资产 • Oncotelic Therapeutics ASO资产：OT-101（也叫Trabedersen）靶点：转化生长因子β2（TGF-β2）适应症：胶质母细胞瘤（GBM）、胰腺癌、恶性黑色素瘤机制：抑制TGF-β2，有望减轻肿瘤免疫抑制，增强抗肿瘤免疫反应 • 阿斯利康 ASO资产：ION449（亦称AZD8233），与Ionis合作开发的ASO疗法靶点：PCSK9（一种影响低密度脂蛋白胆固醇LDL-C水平的蛋白质）适应症：高胆固醇血症（hypercholesterolemia）备注：主要竞争对手包括小分子抑制剂和PCSK9单抗（如Repatha、Praluent） • GSK ASO资产：bepirovirsen 靶点：乙型肝炎病毒（HBV）的前基因组RNA和mRNA 适应症：慢性乙型肝炎（chronic hepatitis B, CHB），通过抑制HBV基因表达，帮助病毒清除或实现功能性治愈（functional cure）。 • 诺华 ASO资产：Pelacarsen 靶点：LPA基因（编码脂蛋白(a)）作用机制：Pelacarsen通过抑制LPA基因的mRNA，降低血液中脂蛋白(a)(Lp(a))水平，从而降低心血管疾病风险。Lp(a)是目前被认为的重要但尚无针对性治疗手段的心血管风险因子。适应症：主要用于治疗动脉粥样硬化性心血管疾病高危患者中，血脂异常（特别是Lp(a)升高）的情况。临床阶段：正在进行III期临床试验（Lp(a)HORIZON）。Pelacarsen可能成为首个专门针对Lp(a)升高治疗获批的药物。1.4 ASO类上市药物 • 渤健 Spinraza（nusinersen）靶点：SMN2前体mRNA（促进功能性SMN蛋白表达）适应症：脊髓性肌萎缩症（SMA）获批时间：2016年12月（美国FDA批准）备注：全球首个获批的SMA治疗药物。由Ionis开发，Biogen负责商业化。 • Sarepta Therapeutics Exondys 51（eteplirsen）靶点：DMD基因的Exon 51 适应症：Duchenne肌营养不良（DMD）获批时间：2016年9月（FDA加速批准） Vyondys 53（golodirsen）靶点：DMD基因的Exon 53 适应症：DMD 获批时间：2019年12月 Amondys 45（casimersen）靶点：DMD基因的Exon 45 适应症：DMD 获批时间：2021年2月（FDA加速批准） • Ionis Pharmaceuticals Tegsedi（inotersen）靶点：TTR（转甲状腺素蛋白）适应症：遗传性转甲状腺素蛋白淀粉样变性多发性神经病（hATTR-PN）获批时间：2018年10月（FDA，EMA批准） Waylivra（volanesorsen）靶点：APOC3（载脂蛋白C-III）适应症：家族性乳糜微粒血症综合征（FCS）获批时间：2019年5月（欧洲EMA批准；未获美国FDA批准） • NS Pharma Viltepso（viltolarsen）靶点：DMD基因的Exon 53 适应症：Duchenne肌营养不良（DMD）获批时间：2020年8月（FDA加速批准）2.RNAi类 RNA资产2.1 I期RNAi资产 • Aligos Therapeutics RNAi资产：ALG-125755 靶点：乙型肝炎病毒（HBV）RNA 适应症：慢性乙型肝炎（CHB） • Regulus Therapeutics RNAi资产：RGLS8429 靶点：microRNA-17（miR-17家族）适应症：常染色体显性多囊肾病（ADPKD） • Phio Pharmaceuticals RNAi资产：PH-762 靶点：程序性死亡受体1（PD-1）适应症：癌症免疫疗法（通过下调T细胞表面PD-1，增强免疫杀伤）技术特点：采用其自有的INTASYL✓平台，优化了siRNA的稳定性和局部递送。 • TransCode Therapeutics RNAi资产：VIR-2218 TTX-MC138 靶点：microRNA-10b（miR-10b）适应症：针对转移性实体肿瘤（如乳腺癌、胰腺癌、脑肿瘤等）技术特点：使用纳米颗粒系统高效递送siRNA药物，特别适合针对深部转移灶。2.2 II期RNAi资产 • Arbutus Biopharma RNAi资产：AB-729 靶点：乙型肝炎病毒（HBV）表面抗原（HBsAg）适应症：慢性乙型肝炎（CHB）备注：AB-729是Arbutus当前最重要的核心资产之一。 • OliX Pharmaceuticals RNAi资产：OLX703A 靶点：HBV病毒相关RNA 适应症：慢性乙型肝炎（CHB）机制：抑制HBV病毒蛋白表达 • Silence Therapeutics RNAi资产：SLN360 靶点：LPA基因（编码脂蛋白Lp(a)）适应症：高脂蛋白(a)血症（Lp(a)过高相关的心血管疾病）机制：通过降低血液中Lp(a)水平，减少动脉粥样硬化风险。备注：SLN360是Silence在心血管RNA疗法领域的主力项目。 • Sirnaomics RNAi资产：STP705 靶点：双靶点siRNA药物，靶向TGF-β1和COX-2。适应症：瘢痕治疗（皮肤纤维化）、非黑色素瘤皮肤癌（如基底细胞癌、鳞状细胞癌）机制：抑制纤维化、降低肿瘤微环境免疫抑制。备注：Sirnaomics的特点是双靶点siRNA联合递送。 • GSK RNAi资产：GSK4532990 靶点：靶向HSD17B13基因适应症：代谢功能障碍相关脂肪性肝炎（MASH） • 礼来 RNAi项目：LY3561774 靶点：SERPINA1基因适应症：α1-抗胰蛋白酶缺乏症（AATD）机制：降低异常α1-抗胰蛋白酶（AAT）积聚 • VIR Biotechnology RNAi项目：VIR-2218 靶点： HBV RNA 适应症：慢性乙型肝炎（CHB）。机制：抑制HBV表面抗原表达 • 罗氏 RNAi资产：Zilebesiran 靶点：肝脏表达的血管紧张素原（AGT）基因。适应症：高血压，特别是高心血管风险患者。2.3 III期RNAi资产 • Arrowhead Pharmaceuticals RNAi资产：ARO-APOC3 靶点：APOC3（载脂蛋白C-III），适应症：高甘油三酯血症和罕见脂代谢异常 • 武田 RNAi资产：Fazirsiran 靶点：SERPINA1（编码α1-抗胰蛋白酶）适应症：α1-抗胰蛋白酶缺乏症（AATD）引起的肝病 • 安进 RNAi资产：Olpasiran 靶点：LPA基因（脂蛋白(a)）适应症：高脂蛋白(a)血症及其引发的心血管疾病风险备注：这是一款非常重磅的RNAi项目，对心血管领域意义重大。 • Avidity Biosciences RNAi资产：AOC 1001 靶点：DMPK基因（导致肌强直性营养不良症1型DM1）适应症：肌强直性营养不良症1型（DM1）技术特点：AOC（Antibody Oligonucleotide Conjugate，抗体-寡核苷酸偶联体），用于肌肉靶向递送siRNA。 • 赛诺菲 RNAi资产：Fitusiran 靶点：AT（抗凝血酶）适应症：血友病A或B患者的出血预防 • VIR Biotechnology RNAi资产：VIR-2218 靶点：HBV RNA 适应症：慢性乙型肝炎（CHB）2.4 上市RNAi资产 • Alnylam Pharmaceuticals Alnylam是全球RNAi疗法先锋，拥有最多已上市RNAi药物。 Onpattro（Patisiran）靶点：TTR 适应症：遗传性转甲状腺素蛋白淀粉样变性引起的多发性神经病（hATTR-PN）批准情况：2018年FDA/EMA批准 Givlaari（Givosiran）靶点：ALAS1 适应症：急性肝卟啉症（AHP）批准情况：2019年FDA/EMA批准 Oxlumo（Lumasiran）靶点：HAO1 适应症：原发性高草酸尿症1型（PH1）批准情况：2020年FDA/EMA批准 Amvuttra（Vutrisiran）靶点：TTR 适应症：遗传性转甲状腺素蛋白淀粉样变性引起的多发性神经病（hATTR-PN）（长效皮下注射版）批准情况：2022年FDA批准 • 诺华 RNAi资产：Leqvio（Inclisiran）靶点：PCSK9 适应症：高胆固醇血症，动脉粥样硬化性心血管疾病风险降低批准情况：2020年欧洲EMA批准；2021年底美国FDA批准 • 诺和诺德 RNAi资产：Rivfloza (nedosiran) 靶点：肝脏中乳酸脱氢酶（LDH）mRNA 适应症：治疗9岁及以上、肾功能相对良好的原发性高草酸尿症1型（PH1）患者。作用机制：抑制LDH蛋白表达，减少草酸过度生成，缓解PH1疾病过程，减少肾脏损害风险。批准情况：2023年9月29日FDA正式批准Rivfloza上市。成为继Alnylam的Oxlumo（Lumasiran）之后，全球第二款获批用于PH1治疗的RNAi药物。3.mRNA类 RNA药物资产3.1 1期mRNA资产 • 赛诺菲 SP0237: 季节性流感 mRNA 疫苗适应症：针对 A/H3N2 毒株的季节性流感。 SP0256 – RSV mRNA 疫苗（老年人群）适应症：用于预防老年人群中的呼吸道合胞病毒（RSV）感染。 SP0268 – mRNA 痤疮疫苗适应症：针对痤疮（Acne）的 mRNA 疫苗。 SP0291 – 多价呼吸道病毒 mRNA 疫苗适应症：针对 RSV、人类偏肺病毒（hMPV）和副流感病毒 3 型（PIV3）的组合疫苗，主要用于老年人群。沙眼衣原体（Chlamydia）mRNA 疫苗候选适应症：预防沙眼衣原体感染，主要针对 18 至 29 岁的成人。 • Vertex mRNA资产：VX-522：用于囊性纤维化（CF）的mRNA疗法靶点：CFTR基因（囊性纤维化跨膜电导调节因子）。适应症：无法通过CFTR调节剂治疗的CF（囊性纤维化）患者，尤其是那些由于CFTR基因突变导致CFTR蛋白缺失的患者。作用机制：VX-522是一种mRNA疗法，通过脂质纳米颗粒（LNP）递送CFTR mRNA至肺部细胞，促使其合成功能性CFTR蛋白，从而恢复氯离子通道的功能。3.2 II期mRNA资产 • Gritstone Bio GRANITE（GRT-C901/GRT-R902）个体化肿瘤新抗原疫苗，采用腺病毒（ChAd68）和自扩增mRNA（samRNA）组成的异源prime-boost策略。适应症：用于治疗转移性微卫星稳定型结直肠癌（MSS-CRC）。 CORAL 基于自扩增mRNA（samRNA）的COVID-19疫苗，诱导广泛且持久的中和抗体和T细胞免疫反应。 • CureVac/GSK 季节性流感mRNA疫苗候选该疫苗候选基于CureVac的第二代mRNA平台，针对流感病毒株，包括A型和B型毒株。 COVID-19 mRNA疫苗候选CV0601和CV0701 CV0601为单价疫苗，编码Omicron BA.4/5变异株的刺突蛋白；CV0701为二价疫苗，编码Omicron BA.4/5变异株和原始SARS-CoV-2毒株的刺突蛋白。3.3 III期mRNA资产 • 第一三共 DS-5670a（原始毒株单价疫苗）适应症：Covid-19疫苗，作为加强针用于已完成初始疫苗接种的成人和老年人。 DS-5670a/b（原始毒株与Omicron BA.4/5二价疫苗）适应症：Covid-19疫苗，作为加强针用于12岁及以上已完成初始疫苗接种的人群。 DS-5670d（Omicron XBB.1.5单价疫苗）适应症：Covid-19疫苗，作为季节性加强针用于12岁及以上人群，包括未接种疫苗者。 • 默沙东 mRNA资产：V940（mRNA-4157）类型：肿瘤疫苗（个体化mRNA疫苗）适应症：手术切除后的高风险黑色素瘤患者辅助治疗靶点：个体化新抗原（根据患者肿瘤突变特异设计）3.4上市mRNA资产 • Arcturus Therapeutics mRNA资产：KOSTAIVE（ARCT-154 / Zapomeran）类型：自扩增mRNA（sa-mRNA）疫苗适应症：用于预防COVID-19，适用于18岁及以上人群靶点：SARS-CoV-2病毒刺突蛋白（Spike protein） • BioNTech/辉瑞 Comirnaty 类型：mRNA疫苗适应症：用于预防COVID-19，适用于6个月及以上人群靶点：SARS-CoV-2病毒刺突蛋白（Spike protein）获批时间：✓2020年12月获得FDA紧急使用授权，2021年8月获得美国FDA完全批准 • 莫德纳 Spikevax 类型：mRNA疫苗适应症：用于预防COVID-19，适用于6个月及以上人群靶点：SARS-CoV-2病毒刺突蛋白（Spike protein）获批时间：2020年12月18日，美国FDA授予紧急使用授权；2022年1月31日，获得FDA完全批准Ref. TD Cowen. Pharmaceuticals’ websitesEND【企业推荐】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床2期寡核苷酸上市批准信使RNA临床1期

2025-06-05

·BioSpace

uniQure’s Regulatory Progress Sparks Optimism for ‘Desperate’ Huntington’s Space

iStock, wildpixel Analysts reacted positively to the news that uniQure is in alignment with the FDA on an accelerated approval pathway and on target for a Q1 2026 submission for its one-time gene therapy for Huntington’s disease—but patients have been here before. When uniQure CEO Matt Kapusta speaks to patients with Huntington’s disease, he hears a sense of “deep desperation.” Currently, people with Huntington’s—who number around 30,000 in the U.S.—are only offered drugs that can manage symptoms, which include movement abnormalities and cognitive impairment, “and those drugs really don’t work very well,” Kapusta told BioSpace . “There’s no disease-modifying treatments for them.” uniQure is hoping to change that. Last fall, the Massachusetts-based biotech announced alignment with the FDA on “key elements” of an accelerated approval pathway for AMT-130, a one-time gene therapy for Huntington’s. These elements include the use of natural history external controls as a comparator and change in the composite Unified Huntington’s Disease Rating Scale (cUHDRS) as an intermediate clinical endpoint. The cUHDRS measures the cognitive, motorial, psychiatric and behavioral symptoms of Huntington’s disease, Kapusta explained. For AMT-130, which is currently in Phase I/II studies, this would negate the need for another trial before uniQue can approval, and Stifel analysts at the time called the alignment “a best case scenario” for the company. On Monday, uniQure shared another regulatory update , communicating that it has “reached alignment with the FDA on several key components of the statistical analysis plan and chemistry, manufacturing and controls [CMC] information that will support” a biologics license application (BLA) in the first quarter of 2026. If successful, uniQure plans to launch the product before the end of next year. AMT 130 represents “the first potentially disease modifying treatment that could be available for [patients],” Kapusta said. Much of this, however, could hinge on three-year topline data which Kapusta expects to read out in September. At 24-months, a higher dose of AMT 130 slowed disease progression by 80% versus external controls, uniQure reported last July. The BLA will be based on this higher dose cohort, and the company will also analyze changes in neurofilament light—an accepted neurodegenerative biomarker—as supporting evidence. In September, Kapusta said the company will be seeking “consistency” with the two-year data. “If we’re able to demonstrate in treated patients at three years after a one-time administration of AMT 130 that there’s meaningful slowing of disease progression compared to this very closely matched external control cohort, I think that would be immensely powerful, and I think potentially supportive of a conditional approval,” he said. Typically, Kapusta said, early manifest patients—like those enrolled in uniQure’s study—lose around half a point on the cUHDRS scale per year. At two years, external controls in uniQure’s Phase I/II study had lost around one point, while patients treated with AMT 130 lost only 0.2 points. “If you extrapolate these things, what you’re really doing is you’re giving back to patients potentially years of their life, years of career development, years of weddings with their children, or birth of grandchildren, bar mitzvahs, sweet sixteens,” he said, “That’s what we’re hoping we can demonstrate in the third quarter.” uniQure’s news generated some buzz on Wall Street, with H.C. Wainwright assigning AMT-130 a 75% probability of success, “with anticipated approval in 2026E.” William Blair, meanwhile, called the regulatory update “favorable” both for uniQure and the broader gene therapy space, “as it demonstrates the FDA’s continued flexibility regarding registrational pathways for transformative therapies for rare diseases with a high unmet need.” Kapusta echoed this sentiment, saying that uniQure has not noticed a difference in terms of the company’s FDA interactions occurring before and after the administration turnover this year. “There’s still senior people that are attending our meetings from [CBER’s] office of therapeutic products . . . and we continue to see significant engagement and productive, constructive interactions with the FDA,” he added. While Kapusta said there has been a “knee jerk” reaction to past comments made by new Center for Biologics Evaluation and Research director Vinay Prasad regarding accelerated approvals, “It definitely seems that in comments he’s made to his own FDA staff, and comments that he’s made in other interactions, that he appears to be making it clear that he supports regulatory flexibility as it relates to innovative medicines in very high needs in rare diseases.” Indeed, on Tuesday, Prasad said the FDA plans to “rapidly make available” rare disease drugs, making use of surrogate endpoints to get promising medicines to patients before they clear the traditional efficacy bar for authorization. He made these remarks during a keynote speech organized by the National Organization for Rare Disorders. Prasad’s comments largely echo those of his boss. In April, during an interview with former Fox News journalist Megyn Kelly, FDA Commissioner Marty Makary introduced plans for a “conditional pathway” that would potentially allow for the approval of rare disease drugs based on a “plausible mechanism.” A Precedent of Disappointment As uniQure and analysts express optimism—albeit gaurded—the Huntington’s space has been here before, with myriad late-stage assets nearing the regulatory finish line only to falter. Five years ago, the community pinned its hopes on Roche’s antisense oligonucleotide tominersen . The ASO was designed to lower levels of the huntingtin ( HTT ) gene, particularly mutant HTT, which plays a crucial role in the development of the disease. Tominersen had shown great promise in Phase II, but in March 2021, Roche discontinued a Phase III trial of the drug after it ultimately failed to elicit higher efficacy than placebo, and actually led to worse outcomes when given more frequently. 2021 was a particularly bad year for the Huntington’s space, as Wave Life Sciences likewise shelved its two lead ASOs after they failed to elicit a therapeutic effect. But Huntington’s-focused companies aren’t giving up. Wave is back with a next-gen ASO, WVE-003, that targets a single-nucleotide polymorphism found on mutant HTT mRNA. Like uniQure, Wave is targeting accelerated approval for its candidate, having “initiated engagement” with regulators regarding a clinical development path, CEO Paul Bolno told BioSpace in November 2024. And at least on a global scale, uniQure has some competition to bring the first disease-modifying drug for Huntington’s to the market. In September 2024, Prilenia Therapeutics announced that the European Medicines Agency had accepted its marketing authorization application for pridopidine, a “highly selective and potent” agonist of the sigma-1 receptor, which is highly expressed in the brain and spinal cord and regulates several key processes that are commonly impaired in neurodegenerative diseases. Prilenia expects an opinion from the European regulator in the second half of this year, a company spokesperson told BioSpace in November 2024. A breakthrough can’t come soon enough for patients. Huntington’s is a dominantly transmitted neurodegenerative disorder and children of HD gene carriers have a 50% chance of inheriting the disease. Kapusta described a situation in which an individual has watched the degeneration of their parent—and possibly even acted as a caregiver. “If this is a patient that has been genetically confirmed, they know it’s 100% penetrative; they’re going to develop the disease, and they’re going to have to relive that movie as the main actor,” he said. “So right now, anything for them would give them hope.”

临床3期上市批准寡核苷酸临床结果临床2期

2025-04-17

·Endpoints

Roche discontinues low dose in Huntington’s trial, will switch patients to high dose

Roche is stopping patients on the low dose of its experimental Huntington’s drug tominersen, and will be transitioning them to the high dose following recommendations by an independent data monitoring committee. The Swiss pharma is studying tominersen, an antisense oligonucleotide, in a Phase 2 study of Huntington’s disease patients in the initial stages of the disease. The study is fully enrolled, and patients were receiving a 60 mg dose, 100 mg dose or placebo. Roche said the independent data monitoring committee did not raise concerns around safety or signs of symptom worsening with either dose in the Phase 2 study. That’s notable, because Roche stopped a previous Phase 3 study when tominersen appeared to make patients with later-stage disease worse off compared to those who got placebo. “The 100mg dose was found to be more likely than the 60mg dose to result in clinical benefit. Therefore for the remainder of the study only the 100mg dose will be tested against placebo, and the 60mg dose will be discontinued,” Roche’s neuroscience patient partnership leader Mai-Lise Nguyen wrote in a letter to patient advocates Thursday. The letter was shared publicly by Huntington’s Disease Youth Organization. Roche will switch patients assigned the 60 mg dose to the 100 mg dose, according to the letter. Patients receive one dose of tominersen every four months via spinal injection. The Phase 2 study was designed as a dose-finding study. However, this change does not mean Roche is bringing the high dose into next stages of development. The study remains blinded and is expected to complete in early 2026. Known as GENERATION HD2, the study includes patients before or at early-stage disease. The study was designed with a narrower patient population compared to the stopped Phase 3 study after Roche conducted a post-hoc analysis and identified a possible efficacy signal in the earlier population. Ionis Pharmaceuticals discovered tominersen, then partnered with Roche on the drug. Tominersen is meant to destroy the mRNA encoding the instructions for the huntingtin protein, in hopes of lowering levels of the mutant protein. In people with Huntington’s disease, the gene for that protein is mutated.

临床2期寡核苷酸临床3期临床失败

100 项与 HTT抑制剂(罗氏制药) 相关的药物交易

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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	Ionis Pharmaceuticals, Inc.	2019-04-23

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04000594 (CTgov)	临床1期	亨廷顿舞蹈病	12	RO7234292 (RG6042) (Dose Level 1 of RO7234292 (RG6042))	鹹網鏇獵構窪觸構繭艱(膚積衊遞壓醖窪繭構廠) = 鬱製繭鏇鹽選鹹膚壓遞鹹網範餘襯鏇壓築鹹範 (遞觸艱鏇憲衊製選繭憲, 71400) 更多	-	2024-10-03
				RO7234292 (RG6042) (Dose Level 2 of RO7234292 (RG6042))	鹹網鏇獵構窪觸構繭艱(膚積衊遞壓醖窪繭構廠) = 遞鬱糧廠鹽鹽醖選糧遞鹹網範餘襯鏇壓築鹹範 (遞觸艱鏇憲衊製選繭憲, 132000) 更多
NCT03342053 (CTgov)	临床2期	亨廷顿舞蹈病	46	RO7234292 (RG6042) (RO7234292 Monthly)	廠鑰廠獵願繭壓膚餘網 = 餘憲構鹽鏇憲範鏇醖襯鏇製淵觸積製襯願鬱鏇 (壓襯糧製糧糧壓鹹鹽醖, 齋顧網餘觸簾範窪鹹糧 ~ 夢齋廠範顧鑰築遞壓衊) 更多	-	2021-01-19
				RO7234292 (RG6042) (RO7234292 Bimonthly)	廠鑰廠獵願繭壓膚餘網 = 衊廠築鑰襯糧繭夢鑰艱鏇製淵觸積製襯願鬱鏇 (壓襯糧製糧糧壓鹹鹽醖, 憲鹽襯膚蓋顧簾艱齋觸 ~ 餘築壓觸淵憲願壓觸醖) 更多
NCT02519036 (CTgov)	临床1/2期	亨廷顿舞蹈病	46	Placebo (Placebo)	鑰衊憲遞齋獵築範鹽願 = 糧壓製淵獵餘積齋艱鹽餘衊糧積繭築餘廠積遞 (膚艱簾鹹願廠廠廠鹽鹽, 鹽簾顧鬱夢築糧鑰鹹齋 ~ 醖構廠醖鑰願顧築遞襯) 更多	-	2019-05-31
				ISIS 443139 10 mg (ISIS 443139 10 mg)	鑰衊憲遞齋獵築範鹽願 = 艱鹽壓鹹鑰餘鹹壓遞鏇餘衊糧積繭築餘廠積遞 (膚艱簾鹹願廠廠廠鹽鹽, 願壓醖獵壓鹽積衊糧鬱 ~ 簾願窪襯築憲膚鬱襯廠) 更多