Assessment of Multiple-Dose Pharmacokinetics and Safety of the Co-administration of Galicaftor, Navocaftor and ABBV-576 and Potential of ABBV-576 for CYP3A Induction in Healthy Volunteers

开始日期2022-09-20

申办/合作机构

AbbVie, Inc.

NCT04853368

/ Terminated临床2期

A Phase 2 Study of Galicaftor/Navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 Combination Therapies in Subjects With Cystic Fibrosis Who Are Homozygous or Heterozygous for the F508del Mutation

Cystic Fibrosis (CF) is a rare, life-threatening, genetic disease that affects the lungs and digestive system, significantly impairing the quality of life, with those affected having a median age of death at 40. The main objective of this study is to assess how safe and effective is the combination therapy of galicaftor/navocaftor/ABBV-119 or Galicaftor/Navocaftor/ABBV-576 in adult participants with CF who are homozygous or heterozygous for the F508del mutation in each arm.
Galicaftor/Navocaftor/ABBV-119 combination therapy and Galicaftor/Navocaftor/ABBV-576 is being developed as an investigational drug for the treatment of CF. Study doctors place participants in 1 of the 4 groups, called treatment arms. Each group receives a different treatment. Around 90 adult participants with a diagnosis of CF will be enrolled in the study around approximately 35 sites worldwide.
Participants in arm 1 will receive oral capsules of galicaftor/navocaftor dual combination for 28 days followed by galicaftor/navocaftor/ABBV-119 triple combination for 28 days. Participants in arms 2 and 3 will receive the galicaftor/navocaftor/ABBV-119 triple combination or placebo for 28 days. Participants in arm 4 will receive galicaftor/navocaftor/ABBV-576 triple combination therapy for 28 days. For all study arms, ABBV-576, galicaftor, navocaftor, will be given once daily and ABBV-119 twice a day.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a hospital or clinic. The effect of the treatment will be checked by medical assessments, blood tests, checking for side effects and completing questionnaires.

开始日期2021-09-20

申办/合作机构

AbbVie, Inc.

100 项与 Galicaftor 相关的临床结果

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100 项与 Galicaftor 相关的转化医学

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100 项与 Galicaftor 相关的专利（医药）

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项与 Galicaftor 相关的文献（医药）

2024-03-01·European Journal of Pharmacology

PTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR

Article

作者: Ferreira, Filipa C ; Lopes-Pacheco, Miquéias ; Bacalhau, Mafalda ; Amaral, Margarida D

The deletion of a phenylalanine at position 508 (p.Phe508del) in the CFTR anion channel is the most prevalent variant in people with Cystic Fibrosis (CF). This variant impairs folding and stability of the CF transmembrane conductance regulator (CFTR) protein, resulting in its defective trafficking and premature degradation. Over the last years, therapeutic accomplishments have been attained in developing small molecules that partially correct p.Phe508del-CFTR defects; however, the mechanism of action (MoA) of these compounds has only started to be uncovered. In this study, we employed biochemical, fluorescence microscopy, and functional assays to examine the efficacy and properties of PTI-801, a newly developed p.Phe508del-CFTR corrector. To exploit its MoA, we assessed PTI-801 effects in combination with low temperature, genetic revertants of p.Phe508del-CFTR (the in cis p.Val510Asp, p.Gly550Glu, p.Arg1070Trp, and 4RK) and other correctors. Our results demonstrated that PTI-801 rescues p.Phe508del-CFTR processing, PM trafficking, and channel function (upon agonist stimulation) with greater correction effects in combination with ABBV-2222, FDL-169, VX-661, or VX-809, but not with VX-445. Although PTI-801 exhibited no potentiator activity on low temperature- and corrector-rescued p.Phe508del-CFTR, this compound displayed similar behavior to that of VX-445 on genetic revertants. Such evidence associated with the lack of additivity when PTI-801 and VX-445 were combined indicates that they share a common binding site to correct p.Phe508del-CFTR defects. Despite the high efficacy of PTI-801 in combination with ABBV-2222, FDL-169, VX-661, or VX-809, these dual corrector combinations only partially restored p.Phe508del-CFTR conformational stability, as shown by the lower half-life of the mutant protein compared to that of WT-CFTR. In summary, PTI-801 likely shares a common MoA with VX-445 in rescuing p.Phe508del-CFTR, thus being a feasible alternative for the development of novel corrector combinations with greater capacity to rescue mutant CFTR folding and stability.

2023-08-15·Biochemistry

Computational Exploration of Potential CFTR Binding Sites for Type I Corrector Drugs.

Article

作者: Mitchell, Alexis ; Dixon, Brandon ; Sandman, Madeline ; Girard, Christian ; Poulos, Jack ; Spinney, Allison ; Reber, Callista ; Lester, Anna ; Herring, Caitlin ; Turlington, Mark ; Evans, Claudia N ; Ramsdell, Havanna ; Henager, Marissa E ; Johnson, Quentin R

Cystic fibrosis (CF) is a recessive genetic disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The recent development of a class of drugs called "correctors", which repair the structure and function of mutant CFTR, has greatly enhanced the life expectancy of CF patients. These correctors target the most common disease causing CFTR mutant F508del and are exemplified by the FDA-approved VX-809. While one binding site of VX-809 to CFTR was recently elucidated by cryo-electron microscopy, four additional binding sites have been proposed in the literature and it has been theorized that VX-809 and structurally similar correctors may engage multiple CFTR binding sites. To explore these five binding sites, ensemble docking was performed on wild-type CFTR and the F508del mutant using a large library of structurally similar corrector drugs, including VX-809 (lumacaftor), VX-661 (tezacaftor), ABBV-2222 (galicaftor), and a host of other structurally related molecules. For wild-type CFTR, we find that only one site, located in membrane spanning domain 1 (MSD1), binds favorably to our ligand library. While this MSD1 site also binds our ligand library for F508del-CFTR, the F508del mutation also opens a binding site in nucleotide binding domain 1 (NBD1), which enables strong binding of our ligand library to this site. This NBD1 site in F508del-CFTR exhibits the strongest overall binding affinity for our library of corrector drugs. This data may serve to better understand the structural changes induced by mutation of CFTR and how correctors bind to the protein. Additionally, it may aid in the design of new, more effective CFTR corrector drugs.

2021-05-01·American Journal of Respiratory Cell and Molecular Biology

Novel Correctors and Potentiators Enhance Translational Readthrough in CFTR Nonsense Mutations

Article

作者: Rowe, Steven M. ; Sharma, Jyoti ; Mutyam, Venkateshwar ; Peng, Ning ; Falk Libby, Emily ; Li, Yao ; Chen, Jianguo ; Tang, Li Ping ; Singh, Ashvani K. ; Conrath, Katja

Premature-termination codons (PTCs) in CFTR (cystic fibrosis [CF] transmembrane conductance regulator) result in nonfunctional CFTR protein and are the proximate cause of ∼11% of CF-causing alleles, for which no treatments exist. The CFTR corrector lumacaftor and the potentiator ivacaftor improve CFTR function with terminal PTC mutations and enhance the effect of readthrough agents. Novel correctors GLPG2222 (corrector 1 [C1]), GLPG3221 (corrector 2 [C2]), and potentiator GLPG1837 compare favorably with lumacaftor and ivacaftor in vitro. Here, we evaluated the effect of correctors C1a and C2a (derivatives of C1 and C2) and GLPG1837 alone or in combination with the readthrough compound G418 on CFTR function using heterologous Fischer rat thyroid (FRT) cells, the genetically engineered human bronchial epithelial (HBE) 16HBE14o^- cell lines, and primary human cells with PTC mutations. In FRT lines pretreated with G418, GLPG1837 elicited dose-dependent increases in CFTR activity that exceeded those from ivacaftor in FRT-W1282X and FRT-R1162X cells. A three-mechanism strategy consisting of G418, GLPG1837, and two correctors (C1a + C2a) yielded the greatest functional improvements in FRT and 16HBE14o^- PTC variants, noting that correction and potentiation without readthrough was sufficient to stimulate CFTR activity for W1282X cells. GLPG1837 + C1a + C2a restored substantial function in G542X/F508del HBE cells and restored even more function for W1282X/F508del cells, largely because of the corrector/potentiator effect, with no additional benefit from G418. In G542X/R553X or R1162X/R1162X organoids, enhanced forskolin-induced swelling was observed with G418 + GLPG1837 + C1a + C2a, although GLPG1837 + C1a + C2a alone was sufficient to improve forskolin-induced swelling in W1282X/W1282X organoids. Combination of CFTR correctors, potentiators, and readthrough compounds augments the functional repair of CFTR nonsense mutations, indicating the potential for novel correctors and potentiators to restore function to truncated W1282X CFTR.

项与 Galicaftor 相关的新闻（医药）

2024-07-16

·药明康德

2.6亿美元助力开发潜在“first-in-class”心衰疗法；1.5亿美元推进新一代精准抗癌小分子开发……

▎药明康德内容团队编辑开发潜在“first-in-class”心衰疗法，新锐完成2.6亿美元B轮融资 Cardurion Pharmaceuticals公司今日宣布已完成2.6亿美元的B轮融资。获得资金将用于支持该公司两款主要候选药物的后期临床试验，这两款药物分别是治疗心力衰竭的潜在“first-in-class”磷酸二酯酶-9（PDE9）抑制剂和具有广泛治疗潜力的钙/钙调蛋白依赖性蛋白激酶II（CaMKII）抑制剂。此外，这些资金还将用于扩大Cardurion的候选药物管线在心血管适应症方面的应用、扩展研发管线等用途。该公司目前正在对其主打PDE9抑制剂CRD-750进行两项包含总计640名心力衰竭患者的2期临床试验。此外，公司还在进行其主打CaMKII抑制剂CRD-4730用于治疗儿茶酚胺多态性室性心动过速（CPVT）的2期临床试验。 1.5亿美元助力推进新一代精准抗癌小分子药物临床开发 Scorpion Therapeutics公司今日宣布已完成1.5亿美元的C轮融资。获得资金将用于推进其差异化小分子肿瘤学项目的研发，特别是扩展其别构、差异化、突变选择性PI3Kα抑制剂STX-478的临床试验。此外，该公司将继续推进其临床阶段的EGFR抑制剂系列，包括STX-721和STX-241，以及下一代精准癌症治疗的发现管线。 STX-478旨在改善携带PI3Kα突变患者的治疗效果，PI3Kα突变是癌症最常见的驱动因素之一。在临床前模型中，STX-478针对多种PI3Kα突变表现出强大的活性，同时在正常组织中避免了对野生型PI3Kα的抑制。非选择性PI3Kα抑制剂由于靶向毒性而对患者的益处有限。Scorpion的1/2期临床试验是一项多中心、全球性、开放标签研究，旨在评估STX-478治疗局部晚期或转移性HR+/HER2-乳腺癌和由PI3Kα突变驱动的其他实体肿瘤患者的安全性和疗效。该公司计划在未来的学术会议上披露初步的安全性、药代动力学和药效学数据以及初步疗效数据。针对免疫检查点抑制剂耐药性，1.5亿美元助力开发抗癌疗法 CatalYm公司今日宣布已完成1.5亿美元的D轮融资。获得资金将用于扩展公司主打疗法visugromab的2b期开发。Visugromab已经在与免疫检查点抑制剂联用的临床试验中展示了出色的抗肿瘤活性。 Visugromab是一种人源化单克隆抗体，旨在中和肿瘤产生的生长分化因子-15（GDF-15），GDF-15是肿瘤产生免疫抵抗的关键调节因子。CatalYm最近在2024年美国临床肿瘤学会（ASCO）年会上以口头报告形式发布了其正在进行1/2a期临床试验GDFATHER的积极数据。数据显示，visugromab与抗PD-1抗体nivolumab联用，在抗PD-1/PD-L1药物复发/难治性非小细胞肺癌（NSCLC）、尿路上皮癌（UC）或肝细胞癌（HCC）患者中实现了深度和持久的抗肿瘤活性，包括几例完全缓解。开发囊性纤维化创新组合疗法，新锐与艾伯维达成授权协议 Sionna Therapeutics公司今日宣布与艾伯维（AbbVie）达成授权协议，获得了多个临床阶段化合物的全球独家开发和商业化权利。根据协议条款，Sionna将承担galicaftor（ABBV-2222），一种靶向跨膜蛋白域1（TMD1）的囊性纤维化跨膜电导调节因子（CFTR）矫正剂，以及navocaftor（ABBV-3067），一种CFTR增强剂的所有开发责任，这两种药物均已完成2期研究。此外，Sionna还囊获处于1期临床开发阶段的TMD1靶向矫正剂ABBV-2851。艾伯维将收到一笔预付款、对Sionna的股权投资，并有资格获得后期开发和商业里程碑付款。在艾伯维进行的临床研究中，ABBV-2222和ABBV-3067安全和耐受性良好。在2期临床试验中，ABBV-2222与ABBV-3067联用展示了临床疗效，包括增加1秒用力呼气量百分比（ppFEV1）和降低汗液中氯离子（SwCl）水平，其效果与已批准的双调节剂组合相当。在由Sionna进行的包括囊性纤维化人体支气管上皮（CFHBE）在内的临床前实验中，Sionna靶向CFTR核苷酸结合域1（NBD1）的稳定剂与艾伯维的互补调节剂构成的双药组合显示出优于当前标准治疗的潜在疗效，并且一些组合有可能完全矫正ΔF508 CFTR突变体，达到野生型CFTR功能水平。 ▲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： [1] Cardurion Pharmaceuticals Announces $260 Million Series B Financing to Advance Its Pipeline of Innovative Medicines for Cardiovascular Diseases. Retrieved July 16, 2024, from https://cardurion.com/cardurion-pharmaceuticals-announces-260-million-series-b-financing-to-advance-its-pipeline-of-innovative-medicines-for-cardiovascular-diseases/ [2] Scorpion Therapeutics Announces $150 Million Series C Financing to Advance Leading Clinical-stage Precision Oncology Pipeline. Retrieved July 16, 2024, from https://www.scorpiontx.com/press-release/scorpion-therapeutics-announces-150-million-series-c-financing/ [3] CatalYm Announces New Financing of $150M to Support Broad Phase 2b Development Program for Visugromab. Retrieved July 16, 2024, from https://www.catalym.com/catalym-announces-new-financing-of-150m-to-support-broad-phase-2b-development-program-for-visugromab/ [4] SIONNA THERAPEUTICS EXPANDS PIPELINE WITH MULTIPLE CLINICAL STAGE CYSTIC FIBROSIS COMPOUNDS THROUGH A LICENSE AGREEMENT WITH ABBVIE. Retrieved July 16, 2024, from https://www.sionnatx.com/press-releases/sionna-therapeutics-expands-pipeline-with-multiple-clinical-stage-cystic-fibrosis-compounds-through-a-license-agreement-with-abbvie/ 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

临床2期ASCO会议临床结果临床1期

2024-07-16

·FierceBiotech

Sionna salvages AbbVie assets, teeing up dual combo assault on cystic fibrosis

The expansion of the pipeline gives Sionna a choice to make. Sionna Therapeutics has quickly found a use for some of its $182 million series C haul, inking a deal with AbbVie to add three clinical-phase candidates to its burgeoning pipeline of cystic fibrosis prospects. Boston-based Sionna has established itself as a potential threat to Vertex’s iron-grip on the cystic fibrosis market by advancing programs directly targeting correction of NBD1. The biotech has identified NBD1 correction as a way to fully restore CFTR function in patients with the most common mutation of the key cystic fibrosis protein. But it has also recognized combinations may be the route to the best results. Sionna fast tracked its combination ambitions Tuesday by picking up a trio of molecules from AbbVie. The acquired portfolio includes two midphase compounds, the CFTR corrector ABBV-2222 and the CFTR potentiator ABBV-3067. AbbVie studied ABBV-2222 and ABBV-3067, molecules respectively also called galicaftor and navocaftor, in combination with a C1 or C2 inhibitor in a midphase clinical trial. However, neither combination lived up to AbbVie’s expectations, prompting the company to stop the study and ax its cystic fibrosis program. AbbVie expanded in cystic fibrosis by paying Galapagos $45 million upfront in 2018. Sionna has also picked up the rights to a phase 1 corrector, ABBV-2851. The biotech said ABBV-2222 and ABBV-2851 are correctors directed at TMD1, one of the CTFR protein function domains. Sionna has its own TMD1-directed corrector, SION-676, in preclinical development, plus an ICL4-targeted candidate, SION-109, in phase 1. The expansion of the pipeline gives Sionna a choice to make. Pairing Sionna’s NBD1 stabilizers with any one of SION-109 and the three ex-AbbVie assets delivered better efficacy than the standard of care in a cystic fibrosis assay, the biotech said. Sionna will prioritize advancing one of the four compounds in a dual combination with its most advanced NBD1 stabilizer. AbbVie parted company with the assets in return for an upfront payment, an equity investment in Sionna and a chance to receive late-stage development and commercial milestones and royalties. Neither party has disclosed the size of the deal.

临床1期并购引进/卖出蛋白降解靶向嵌合体上市后研究

2024-07-16

·Firstwordpharma

Sionna breathes new life into AbbVie's abandoned CF compounds

A little over a year after AbbVie exited the cystic fibrosis (CF) space due to disappointing clinical results, Sionna Therapeutics is reviving the abandoned compounds, bagging exclusive worldwide rights to develop and commercialise multiple assets from the pharma.Financial specifics were not disclosed, but the deal includes an upfront payment to AbbVie along with potential late-stage development and commercial milestones and royalties. AbbVie has also made an equity investment in Sionna, which raised $182 million in an oversubscribed series C round earlier this year.The agreement encompasses ABBV-2222 (galicaftor) and ABBV-3067 (navocaftor), both of which have completed Phase II, and ABBV-2851, which is in Phase I development. ABBV-2222 and ABBV-2851 are both TMD1-directed correctors, while ABBV-3067 functions as a CFTR potentiator.AbbVie had discontinued its CF programme after a triple combination therapy that included the C2 corrector ABBV-576 added to a backbone of ABBV-2222 plus ABBV-3067 failed to meet efficacy criteria in a proof-of-concept study.Dual combinationsSionna, however, sees untapped potential in the compounds when combined with its proprietary NBD1 stabilisers, pointing to preclinical assays that have shown promising results. "Our strategy is to build a CF franchise anchored on our novel correctors that stabilise the NBD1 of the CFTR protein," said CEO Mike Cloonan.Sionna is looking to pair one of its NBD1 stabilisers with either an AbbVie compound or its own ICL4-directed corrector, SION-109, to create more effective dual combinations. The company reports that some pairings have shown promise in preclinical studies, with "potential for superior efficacy" over current treatments, while some combos have shown the ability "to fully correct ΔF508 CFTR and achieve wild type levels of CFTR function."Sionna has said it expects to complete a Phase I trial of SION-109 in the second half. Phase I studies of two NBD1 stabilisers, SION-451 and SION-719, are also due to start this year.Its most advanced NBD1 corrector is SION-638, which is poised to enter Phase II, while the company is also developing the TMD1-directed corrector SION-676.

临床1期引进/卖出临床2期蛋白降解靶向嵌合体

100 项与 Galicaftor 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11724	-	-	DB14894

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适应症	最高研发状态	国家/地区	公司	日期
囊性纤维化	临床2期	美国	Sionna Therapeutics, Inc.初创企业	-

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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


NCT04853368 (CTgov)	临床2期	囊性纤维化	48	ABBV-119+Galicaftor+Navocaftor (Cohort 1(Day 1 - 29) Triple Combination Galicaftor + Navocaftor + ABBV-119 for F508del Homozygous)	顧觸選獵築廠餘淵膚遞(壓築簾範鬱積艱糧糧夢) = 鬱膚襯艱夢糧衊夢夢廠觸積襯繭膚積艱糧鏇齋 (壓夢壓觸窪網齋繭鬱憲, 鏇網築範範遞鑰襯淵範 ~ 積窪夢鑰觸繭醖獵衊選) 更多	-	2024-07-16
				ABBV-119+Galicaftor+Navocaftor (Cohort 2(Day 1 - 29) Triple Combination Galicaftor+ Navocaftor + ABBV-119 for F508del Heterozygous)	顧觸選獵築廠餘淵膚遞(壓築簾範鬱積艱糧糧夢) = 夢築鬱齋衊餘壓鹹艱鹽觸積襯繭膚積艱糧鏇齋 (壓夢壓觸窪網齋繭鬱憲, 壓簾範醖範醖憲製醖製 ~ 積齋鬱鬱窪襯製遞鑰糧) 更多
NCT03969888 (CTgov)	临床2期	囊性纤维化	78	Placebo ABBV-2222+ABBV-3067 (ABBV-3067 50 mg + Placebo for ABBV-2222)	醖鏇獵餘鏇顧糧簾鑰齋(糧獵憲夢糧廠鬱築製壓) = 醖糧築襯鏇築遞淵壓網繭獵襯選醖獵糧齋獵淵 (襯鏇餘淵製餘觸蓋窪餘, 淵繭願憲獵積衊膚糧選 ~ 蓋製膚淵選願顧鏇蓋廠) 更多	-	2023-06-28
				Placebo ABBV-2222+ABBV-3067 (ABBV-3067 150 mg + Placebo for ABBV-2222)	醖鏇獵餘鏇顧糧簾鑰齋(糧獵憲夢糧廠鬱築製壓) = 齋積製鬱築簾鏇壓蓋窪繭獵襯選醖獵糧齋獵淵 (襯鏇餘淵製餘觸蓋窪餘, 簾壓齋製壓遞範築襯鏇 ~ 淵顧蓋鬱糧範鏇築繭齋) 更多
NCT03119649 (FLAMINGO, Pubmed \| J Cyst Fibros) 人工标引	临床2期	囊性纤维化	59	GLPG2222	(願淵網網糧餘憲鹹艱夢) = 繭鬱糧遞鬱範遞淵顧範醖鏇醖繭遞襯夢製壓築 (願鏇選製壓鹹鏇顧蓋觸 )	不佳	2019-09-01
NCT03119649 (FLAMINGO, CTgov)	临床2期	囊性纤维化	59	Placebo+GLPG2222 100 mg (Cohort A: GLPG2222 100 mg QD)	鹽淵製構積鹹齋齋襯願(繭範鏇鏇觸蓋蓋積鏇鹹) = 淵鏇顧淵製獵糧鏇糧鑰構繭積鏇襯壓廠構憲顧 (廠繭顧顧鬱窪遞糧衊選, 網觸網製構鑰糧鏇鑰廠 ~ 製觸顧願範艱夢願鏇網) 更多	-	2018-11-16
				Placebo+GLPG2222 200 mg (Cohort B: GLPG2222 200 mg QD)	鹽淵製構積鹹齋齋襯願(繭範鏇鏇觸蓋蓋積鏇鹹) = 艱衊夢簾鑰構繭窪選窪構繭積鏇襯壓廠構憲顧 (廠繭顧顧鬱窪遞糧衊選, 糧淵餘淵築範糧鹹鏇餘 ~ 齋艱獵齋衊網餘選齋夢) 更多