A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Adeno-Associated Virus Serotype 8-Mediated Gene Transfer of Glucose-6-Phosphatase in Patients With Glycogen Storage Disease Type Ia

The primary objectives of this study are to evaluate the efficacy of DTX401 to reduce or eliminate dependence on exogenous glucose replacement therapy to maintain euglycemia and to maintain or improve the quality of glucose control.

开始日期2021-11-08

申办/合作机构

Ultragenyx Pharmaceutical, Inc.

NCT03517085 / Completed临床1/2期

A Phase 1/2, Open-Label Safety and Dose-Finding Study of Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Glucose-6- Phosphatase (G6Pase) in Adults With Glycogen Storage Disease Type Ia (GSDIa)

The primary objective of the study is to determine the safety of single doses of DTX401, including the incidence of dose-limiting toxicities (DLTs) at each dose level.

开始日期2018-05-18

申办/合作机构

Ultragenyx Pharmaceutical, Inc.

100 项与 Pariglasgene brecaparvovec 相关的临床结果

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100 项与 Pariglasgene brecaparvovec 相关的转化医学

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100 项与 Pariglasgene brecaparvovec 相关的专利（医药）

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项与 Pariglasgene brecaparvovec 相关的文献（医药）

2011-12-01·Cancer gene therapy2区 · 医学

Inhibition and promotion of tumor growth with adeno-associated virus carcinoembryonic antigen vaccine and Toll-like receptor agonists

2区 · 医学

Article

作者: Selvarangan Ponnazhagan ; Wayne Aldrich ; Pierre L. Triozzi

Carcinoembryonic antigen (CEA) is a cancer vaccines' target. Several features of recombinant adeno-associated virus (rAAV) are attractive for vaccine applications. Combining other viral vector vaccines with Toll-like receptor (TLR) agonists enhances antitumor immunity. Wild-type and CEA transgenic (Tg) mice were immunized with rAAV-expressing CEA, the TLR9 agonist, oligodinucleotide (ODN)1826 and the TLR7 agonist, imiquimod. Mice were challenged with MC38 colon tumor cells and MC38 cells expressing CEA. rAAV-CEA immunization combined with ODN1826 or imiquimod enhanced CEA-specific T-helper 1 immunity and protected against tumor challenge in wild-type but not in CEA-Tg mice. In contrast, immunization with rAAV-CEA in CEA-Tg mice could abrogate the antitumor effects of ODN1826 and promote tumor growth. Compared to wild-type, CEA-Tg mice were characterized by a greater myeloid suppressor cell and T-helper 2 response to TLR agonists and to syngeneic tumors. Depleting PDCA1(+) plasmacytoid dendritic cells and Gr1(+) myeloid cells increased anti-CEA immune responses in CEA-Tg mice to rAAV-CEA-ODN1826 immunization, whereas depleting CD25(+) T cells did not. There are differences in the response of wild-type and CEA-Tg mice to rAAV-CEA, TLR agonists and syngeneic tumor. In CEA-Tg mice, tumor growth can be promoted with rAAV-CEA and TLR agonists. Dendritic and myeloid cells play a regulatory role.

项与 Pariglasgene brecaparvovec 相关的新闻（医药）

2024-06-13

·FierceBiotech

Ultragenyx wins surrogate endpoint debate, securing green light to seek FDA approval of gene therapy

Ultragenyx Pharmaceutical began a public offering of up to $350 million of its common stock after reporting a pipeline update. Ultragenyx Pharmaceutical's work to get the FDA to recognize a biomarker as a surrogate endpoint looks to have paid off. With the agency agreeing the biomarker is a reasonable surrogate endpoint, Ultragenyx is preparing to file for approval of its Sanfilippo syndrome gene therapy around the end of the year. A pivotal trial of the UX111 AAV gene therapy was already underway when Ultragenyx acquired global rights to the program from Abeona Therapeutics in 2022. Ultragenyx reported data from the study earlier this year but was unsure whether the FDA would accept a filing based on cerebral spinal fluid (CSF) heparan sulfate (HS). The biotech made its case at a Reagan-Udall Foundation event attended by FDA staff. Wednesday, Ultragenyx said it had reached an agreement with the agency on the use of the biomarker as a surrogate endpoint for accelerated approval. The biotech now plans to finalize the details of its filing at a meeting with the FDA and apply for approval either late in 2024 or early in 2025. Ultragenyx intends to base the submission on data from the ongoing pivotal study of UX111. In February, the rare disease specialist reported that levels of CSF HS fell within one month after treatment with the gene therapy. Ultragenyx reported declines in the biomarker in all 17 people with Sanfilippo, a fatal lysosomal storage disease also known as MPS IIIA, in its modified intention-to-treat group. The biotech correlated reductions in CSF HS exposure to changes in cognitive function. When looking at cognitive function, Ultragenyx said it saw “a positive rate of change indicating either stability or gains from baseline in 16 of the 17 patients during the expected window of plateau into decline.” Ultragenyx’s filing will show whether the FDA views the biomarker results and signs of clinical efficacy as enough for accelerated approval. But, while that big test is yet to come, securing the green light to file for approval is still another milestone in Ultragenyx’s push to quickly expand its portfolio of approved drugs. The biotech plans to file for approval of its DTX401 gene therapy in glycogen storage disease type Ia next year and is closing in on phase 3 data for its brittle bone disease drug setrusumab. Winning approval for the candidates, and securing the resulting revenues and priority review vouchers, is part of Ultragenyx’s plan for becoming profitable by 2026. Bringing UX111 to market will also increase Ultragenyx’s outgoings, though. The company will pay Abeona up to $30 million in commercial milestones following regulatory approval of the product. Abeona is also in line to receive tiered royalties of up to 10% on net sales. Ultragenyx began a public offering of up to $350 million of shares of its common stock after reporting the update on UX111.

临床3期基因疗法优先审批

2024-06-13

·Firstwordpharma

Ultragenyx preps US filing for Sanfilippo syndrome gene therapy

Ultragenyx Pharmaceutical announced plans to file for accelerated approval of its gene therapy UX111 for the rare, fatal lysosomal storage disease Sanfilippo syndrome type A (MPS IIIA). The decision follows the FDA agreeing that levels of the biomarker heparan sulfate in cerebral spinal fluid (CSF-HS) can serve as a reasonable surrogate endpoint to support the application.The biotech stated it will finalise details of the planned US regulatory filing with the FDA, and aims to submit before the end of 2024 or early 2025. It acquired exclusive global rights to the investigational AAV gene therapy, formerly known as ABO-102, through a $30-million deal with Abeona Therapeutics in 2022.Alignment with FDA"Gaining alignment with the FDA that CSF heparan sulfate is a relevant biomarker to enable accelerated approval in Sanfilippo syndrome is a pivotal moment for the community and paves the way for treatments for all fatal types of neuronopathic mucopolysaccharidoses," said Ultragenyx CEO Emil Kakkis.The announcement follows clinical data updates presented this past February from the pivotal TRANSPHER A study evaluating the one-time intravenous infusion. As of an August 2023 data cutoff, treatment with UX111 led to rapid and sustained reductions in CSF-HS that correlated with stabilisation or gains in cognitive function across 17 modified intent-to-treat patients."The data supported durable clinical benefit," Barclays analyst Geena Wang said in a note to clients at the time. Wang added she was "optimistic on the FDA's openness and flexibility for accelerated approval paths in rare disease" based on prior agency comments.Meanwhile, Ultragenyx is also preparing regulatory submissions for its DTX401 gene therapy in glycogen storage disease type 1a next year and recently reported longer-term Phase II data for its anti-sclerostin antibody setrusumab, partnered with Mereo BioPharma, in the rare inherited brittle bone disease osteogenesis imperfecta.

基因疗法临床结果临床2期

2024-06-09

·药明康德

一针免去上百次治疗的基因疗法获EMA批准；使超70%患者肿瘤细胞完全消失的CAR-T疗法…… | CGT周报

▎药明康德内容团队编辑近期，全球细胞和基因疗法（CGT）领域迎来系列进展。欧洲药品管理局（EMA）建议授予辉瑞（Pfizer）所开发用于治疗血友病B的一次性基因疗法Durveqtix有条件上市许可。百时美施贵宝（Bristol Myers Squibb）CD19靶向CAR-T细胞疗法Breyanzi治疗大B细胞淋巴瘤，在一项关键性3期临床试验中使74%的患者获得了完全缓解（CR）。多款治疗实体瘤的CAR-T细胞疗法临床数据亮眼，疾病控制率（DCR）超90%。本文将节选其中部分重要进展做简单介绍，仅供读者参阅。图片来源：123RF ◇ 5月31日，EMA建议授予辉瑞所开发的一次性基因疗法Durveqtix（fidanacogene elaparvovec）有条件上市许可，用于治疗重度和中重度血友病B成人患者，这些患者体内无凝血因子IX（FIX）抑制剂，且没有检测到针对腺相关病毒血清型Rh74变异体（AAVRh74var）的抗体。此次批准主要是基于一项开放标签临床3期试验的结果。与标准治疗相比，Durveqtix显著降低了患者的出血频率。Durveqtix组患者的年化出血率（ABR）为1.44，接受预防性疗法患者的ABR为4.50。此外，60%的Durveqtix组患者在个体观察期间（范围：2-4年）保持无出血事件，此数值在导入期接受常规预防治疗的患者中仅为29%。患者在接受Durveqtix治疗后，使得预防性FIX的消耗量降低了92.4%。 ▲在试验中，患者接受Durveqtix输注后，体内FIX活性稳定维持（图片来源：参考资料[2]） Durveqtix是一种新型的基因疗法，含有生物工程化的腺相关病毒衣壳和编码高活性FIX变体的转基因。对于血友病B患者来说，一年可能需要进行超过一百次以上的静脉输注FIX。Durveqtix的目标是使他们能通过一次性治疗产生自体的FIX蛋白，从而无需定期静脉输注FIX。辉瑞于2014年12月以2000万美元预付款从Spark Therapeutics获得该疗法。加拿大卫生部（Health Canada）于今年1月批准该疗法上市，美国FDA则在今年4月批准此基因疗法，商品名为Beqvez。 ◇ 百时美施贵宝公布了其CD19靶向CAR-T细胞疗法Breyanzi（lisocabtagene maraleucel）治疗接受初始治疗12个月内复发的大B细胞淋巴瘤成人患者的3期临床试验TRANSFORM的最新研究数据。分析显示，在中位随访33.9个月期间，Breyanzi显示出持续显著的临床益处。与标准疗法（SoC）相比，无事件生存期（EFS）的主要终点以及无进展生存期（PFS）、总缓解率（ORR）和缓解持续时间（DOR）的次要终点持续改善。Breyanzi组的ORR达87%，其中74%的患者获得CR，而SoC组的ORR为49%，CR率为43%。 Breyanzi是一种靶向CD19抗原的自体CAR-T细胞疗法，于2021年2月获美国FDA批准，用于治疗接受过两种或以上系统治疗的复发/难治性大B细胞淋巴瘤成人患者。这款疗法的独特之处在于CAR-T疗法中CD8阳性和CD4阳性T细胞的比例得到控制，从而可以更好地控制细胞疗法的毒副作用。 ◇ Ultragenyx Pharmaceutical公布了3期临床试验GlucoGene的积极顶线结果，该研究评估了在研基因疗法DTX401治疗8岁及以上Ia型糖原储积病（GSDIa）患者的疗效和安全性。这项研究达到主要终点，与安慰剂相比，在第48周，DTX401治疗显著且具有临床意义地减少了患者每日的玉米淀粉摄入量。 DTX401是一种在研AAV8基因疗法，目的是在天然启动子的控制下稳定表达具有活性的G6Pase-α，从而使接受治疗的肝细胞能够响应调节葡萄糖的正常激素信号，包括胰岛素、胰高血糖素和皮质醇。DTX401通过单次静脉输注给药，已在临床前研究中显示出改善G6Pase-α活性和减少肝糖原水平的效果，后者是疾病进展的已知生物标志物。DTX401已获得美国FDA授予的孤儿药资格、再生医学先进疗法（RMAT）认定和快速通道资格。 ◇ 阿斯利康（AstraZeneca）公布其GPC3靶向CAR-T疗法C-CAR031的最新临床试验结果。研究表明，超过90%的GPC3阳性晚期肝细胞癌（HCC）患者的肿瘤缩小，其中接受最高剂量C-CAR031治疗患者的ORR高达75%，且该疗法的安全性可控。阿斯利康的早期肿瘤学开发负责人Matt Hellmann博士在接受行业媒体STAT采访时表示：“这是首个在肝癌治疗上显示具疗效的CAR-T疗法。这也是GPC3靶点的首次临床验证。” GPC3是一种在肝癌中过表达的表面抗原，该蛋白在健康组织中几乎不存在。C-CAR031是一种GPC3靶向的自体CAR-T疗法，这款CAR-T疗法同时“装备”了TGFβ以抵抗免疫抑制微环境，以增强其效力。图片来源：123RF ◇ Intellia Therapeutics公司宣布了其用于治疗遗传性血管水肿（HAE）的在研疗法NTLA-2002的1期临床试验的长期数据。中位随访时间为20.1个月时，单次NTLA-2002治疗让患者的月均疾病发作率平均减少了98%，中度至重度发作平均减少了99%。在测试的每个剂量水平上，HAE发作率均显著减少。单次输注后，患者最长的无发作期超过26个月，并且仍在持续。此外，100%接受NTLA-2002治疗的患者在停止其他预防性治疗后无需再进行预防性治疗。 NTLA-2002是一种体内CRISPR基因编辑候选疗法，通过脂质纳米颗粒（LNP）以mRNA形式递送CRISPR-Cas9基因编辑系统，靶向敲除血浆前激肽释放酶基因（KLKB1），以永久性降低血浆中激肽释放酶活性，从而防止遗传性血管水肿的发作。 ◇ 传奇生物首次公布了西达基奥仑赛（Carvykti）针对多发性骨髓瘤患者的2期研究CARTITUDE-2队列D的结果。数据显示，在前线治疗自体干细胞移植后未达到CR的患者在单次输注西达基奥仑赛联合或不联合来那度胺维持治疗后，可获得深度持久的缓解，ORR达94%，16例患者均达到CR或更好。在15例微小残留病（MRD）可评估的患者中，80%的患者达到10-5 MRD阴性。西达基奥仑赛是一种靶向B细胞成熟抗原（BCMA）的CAR-T细胞疗法。该疗法的CAR蛋白具有两种靶向BCMA单域抗体，对表达BCMA的细胞具有高亲和力，在与表达BCMA的细胞结合后，CAR可促进T细胞活化、扩增，继而清除靶细胞。 ◇ 易慕峰生物公布了其靶向EpCAM的CAR-T细胞疗法IMC001治疗晚期胃癌的最新临床研究数据。11例接受了IMC001治疗的患者中有10人的疗效可评估。数据显示，DCR为90%，低剂量组中有1例患者（占1/3，33.3%）和中等剂量组中有2例患者（占2/5，40%）实现了PR。中等剂量组中有3/5的患者在研究截止时已存活超过10个月，其中有1例患者在第24周时确认达到了PR，并在第27周进行了根治性胃切除手术，至截止日期已存活超过22个月。 ◇ 科济药业公布了其靶向Claudin18.2的自体CAR-T细胞候选产品CT041（satricabtagene autoleucel，satri-cel）治疗Claudin18.2阳性晚期消化系统肿瘤的1期临床试验的最终结果。截至2024年1月26日的数据，中位随访时间为32.4个月，98例患者接受了CT041输注。其中51例存在靶病灶的胃癌/食管胃结合部腺癌患者中，ORR和DCR分别为54.9%（28/51）和96.1%（49/51），中位缓解持续时间为6.4个月。在所有胃癌/食管胃结合部腺癌患者（n=59）中，中位PFS为5.8个月，中位总生存期为9.0个月，12个月的生存率为37.3%。相关阅读：治疗实体瘤，这6款细胞疗法入选ASCO口头报告，来自西比曼/阿斯利康、科济药业等公司！ ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看） [1] New gene therapy treatment for haemophilia B. Retrieved May 31, 2024, from https://www.ema.europa.eu/en/news/new-gene-therapy-treatment-haemophilia-b [2] Efficacy and Safety of Fidanacogene Elaparvovec in Adults With Moderately Severe or Severe Hemophilia B: Results From the Phase 3 BENEGENE-2 Gene Therapy Trial. Retrieved January 4, 2024, from https://genetherapy.isth.org/efficacy-and-safety-of-fidanacogene-elaparvovec-in-adults-with-moderately-severe-or-severe-hemophilia-b-results-from-the-phase-3-benegene-2-gene-therapy-trial [3] Ultragenyx Announces Positive Top-Line Results from Phase 3 Study of DTX401 Gene Therapy for Glycogen Storage Disease Type Ia (GSDIa). Retrieved May 31, 2024, from https://ir.ultragenyx.com/news-releases/news-release-details/ultragenyx-announces-positive-top-line-results-phase-3-study [4] Bristol Myers Squibb’s Breyanzi Demonstrates Clinically Meaningful Outcomes Across Broad Range of B-Cell Malignancies in New Data Presented at 2024 ASCO® Annual Meeting. Retrieved June 3, 2024, from https://news.bms.com/news/corporate-financial/2024/Bristol-Myers-Squibbs-Breyanzi-Demonstrates-Clinically-Meaningful-Outcomes-Across-Broad-Range-of-B-Cell-Malignancies-in-New-Data-Presented-at-2024-ASCO-Annual-Meeting/default.aspx [5] Phase I study of C-CAR031, a GPC3-specific TGFβRIIDN armored autologous CAR-T, in patients with advanced hepatocellular carcinoma (HCC). Retrieved June 4, 2024, from https://meetings.asco.org/abstracts-presentations/234377 [6] Intellia Therapeutics Announces Positive Long-Term Data from Ongoing Phase 1 Study of NTLA-2002, an Investigational In Vivo CRISPR Gene Editing Treatment for Hereditary Angioedema (HAE). Retrieved June 3, 2024, from https://ir.intelliatx.com/news-releases/news-release-details/intellia-therapeutics-announces-positive-long-term-data-ongoing [7] 传奇生物在ASCO和EHA公布CARVYKTI®用于治疗多发性骨髓瘤迄今最早的数据及重要的亚组分析. Retrieved June 4, 2024, from https://mp.weixin.qq.com/s/EIVqa50eOpZCDAdVDD14Rg [8] Efficacy of EpCAM CAR-T IMC001 in advanced gastric cancers. Retrieved May 31，2024, from https://meetings.asco.org/abstracts-presentations/234259 [9] 科济药业CT041研究成果发布于《Nature Medicine》及2024 ASCO年会. Retrieved January 4, 2024, from https://www.prnasia.com/story/449450-1.shtml 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

细胞疗法基因疗法临床3期上市批准免疫疗法

100 项与 Pariglasgene brecaparvovec 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
I型糖原贮积病	临床3期	丹麦	Ultragenyx Pharmaceutical, Inc.	2021-10-09

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临床结果

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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


NCT03517085 (ASGCT2024) 人工标引	临床1/2期	I型糖原贮积病	12	DXT401	衊簾淵鑰觸構醖鬱網鬱(鬱範夢膚憲選願遞遞憲) = none 鏇顧膚觸鏇夢衊繭醖願 (廠鏇鏇衊淵蓋鏇選齋獵 ) 更多	积极	2024-04-23
NCT03517085 (CTgov)	临床1/2期	I型糖原贮积病	12	steroid regimen+DTX401 (DTX401 Cohort 1)	壓選膚積築壓鑰遞艱壓(網積願夢構遞齋衊蓋鏇) = 壓鹽範簾獵製餘積築選觸構獵憲網鑰淵鏇廠壓 (憲糧繭淵襯遞簾鹹窪鹹, 齋艱繭襯構獵夢鑰積廠 ~ 鹹夢網糧製觸繭積選鹽) 更多	-	2022-11-18
NCT03517085 (CTgov)	临床1/2期	I型糖原贮积病	12	steroid regimen+DTX401 (DTX401 Cohort 2)	壓選膚積築壓鑰遞艱壓(網積願夢構遞齋衊蓋鏇) = 遞遞觸觸餘壓餘艱範糧觸構獵憲網鑰淵鏇廠壓 (憲糧繭淵襯遞簾鹹窪鹹, 鬱衊鹹範醖醖簾膚廠艱 ~ 醖獵艱齋襯鬱夢壓積糧) 更多	-	2022-11-18
ASGCT2008	N/A	范可尼贫血	-	Adeno-Associated Virus Vector	鏇獵觸蓋獵獵築醖獵網(壓衊顧餘遞顧範廠衊膚) = 築膚築憲繭築艱廠網繭淵積艱蓋鑰顧鹽夢襯築 (築築壓鏇餘淵繭獵衊襯 )	-	2008-05-01
ASGCT2003	N/A	-	-	Adeno-Associated Virus Vector	製構窪鬱鏇鑰衊蓋憲遞(製簾艱鬱糧鏇襯膚選鏇) = 製繭鹹糧艱餘蓋醖襯構鹹膚淵壓艱構鬱糧襯製 (襯繭鹽鏇壓構淵衊獵顧, 3.5)	-	2003-05-01
ASGCT2003	N/A	-	-	Adeno-Associated Virus Vector	製構窪鬱鏇鑰衊蓋憲遞(製簾艱鬱糧鏇襯膚選鏇) = 壓窪範膚蓋夢獵齋廠繭鹹膚淵壓艱構鬱糧襯製 (襯繭鹽鏇壓構淵衊獵顧, 0.5)	-	2003-05-01