A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled Study of Acoramidis for Transthyretin Amyloidosis Prevention in the Young (ACT-EARLY Trial)

Transthyretin amyloidosis (ATTR) is a disease where the normally occurring transthyretin (TTR) protein falls apart and forms amyloid, a sticky plaque- like substance that accumulates in different organs in the body and can cause damage to the organ. There are two ways that the TTR protein can fall apart. One way occurs as a person ages, where the normal TTR protein can fall apart and form amyloid that may no longer be sufficiently cleared by the body. This type of ATTR is known as wild-type ATTR (ATTRwt). The other way occurs when a person inherits a defective TTR gene that causes the TTR protein to spontaneously fall apart. This form of the disease is known as variant ATTR (ATTRv) and can be detected in adults by a genetic test of their TTR gene before they age.
Amyloid build-up in the heart causes the heart wall to become thick and stiff and can result in heart failure and even death. Accumulation of TTR amyloid in the heart is known as transthyretin amyloid cardiomyopathy or ATTR-CM. Amyloid can also deposit in the nerve tissues leading to nerve problems. Accumulation of TTR in the nerves is known as transthyretin amyloid polyneuropathy or ATTR-PN.
Acoramidis is an experimental drug designed to bind tightly to TTR in the blood and stabilize its structure, so it does not form the harmful amyloid plaques that can cause damage to organs.
This study is intended to determine if treatment with acoramidis in participants with ATTRv who have not yet developed any symptoms of disease can prevent or delay the development of ATTR-CM or ATTR-PN disease. If adults with an inherited defective TTR gene are treated early before any of the symptoms of disease have developed, it may be possible to delay the onset or prevent the disease entirely.

开始日期2024-10-01

申办/合作机构

Eidos Therapeutics, Inc.

CTIS2023-506130-67-00 / Recruiting

A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Infigratinib in Children 3 to <18 Years of Age with Achondroplasia: PROPEL 3 - QBGJ398-303

开始日期2024-08-22

申办/合作机构

QED Therapeutics, Inc.初创企业

[+1]

NCT06410976 / RecruitingN/A

Prospective Clinical Assessment Study in Children with Hypochondroplasia: ACCEL

This is a long-term, multicenter, non-interventional study of children ages 2.5 to <17 years with hypochondroplasia (HCH).

开始日期2024-06-05

申办/合作机构

QED Therapeutics, Inc.初创企业

100 项与 BridgeBio Pharma, Inc. 相关的临床结果

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0 项与 BridgeBio Pharma, Inc. 相关的专利（医药）

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项与 BridgeBio Pharma, Inc. 相关的文献（医药）

2024-04-05·Cancer Research

Abstract ND07: BBO-8520, a first-in-class, direct inhibitor of KRASG12C (ON), locks GTP-bound KRASG12C in the state 1 conformation resulting in rapid and complete blockade of effector binding

作者: Meynardie, Mary ; Mehdizadeh, Sadaf ; Esposito, Dom ; Lightstone, Felice C. ; Smith, Brian P. ; Stice, James ; Denson, John Paul ; Setoodeh, Saman ; Sharma, Alok ; Wang, Keshi ; Beltran, Pedro J. ; Larsen, Erik K. ; McCormick, Frank ; Yang, Yue ; Maciag, Anna E. ; Stephen, Andrew G. ; Wang, Bin ; Simanshu, Dhirendra ; Nissley, Dwight V. ; Xu, Rui ; Turner, David ; Ranieri, Michela ; Blanco, Maria Abreu ; Wallace, Eli ; Zhang, Zuhui ; Wong, Kwok Kin ; Lin, Ken ; Sinkevicius, Kerstin ; Dyba, Marcin ; Rabara, Dana ; Chan, Albert ; Alexander, Patrick ; Singh, Devansh

AbstractThe glycine to cysteine mutation on codon 12 of KRAS (KRASG12C) is found in ~15% of non-small cell lung cancers and in a low percentage of colorectal and pancreatic adenocarcinomas. This activating mutation pushes the balance of cellular KRAS towards its active, GTP-bound (ON) state that signals downstream and drives cellular proliferation. Recently approved inhibitors of KRASG12C that bind and sequester the oncogenic protein in its inactive GDP-bound (OFF) state, have demonstrated clinical efficacy; however, median duration of response has been < 9 months. Rapid tumor cell adaptation to KRASG12C (OFF)-only inhibitors like sotorasib and adagrasib has been attributed to reactivation of MAPK signaling through increased RTK flux and KRASG12C gene amplification that result in increased KRASG12C (ON) presence and activity. To block rapid KRASG12C (ON)-driven adaptation to KRASG12C (OFF) inhibitors, we have developed a first-in-class, direct, small molecule covalent inhibitor of both KRASG12C (ON) and (OFF) states. BBO-8520 binds in the switch II pocket and covalently modifies both the (ON) and (OFF) forms of KRASG12C independently of any other partner proteins. Mass spectrometry analysis of KRASG12C covalent engagement by BBO-8520 shows complete modification of both KRASG12C states within 15 minutes, while sotorasib and adagrasib, only modify the (OFF) state. 31P NMR studies demonstrate that BBO-8520 inhibits KRASG12C (ON) by locking the GTP-bound protein in state 1, a conformation where it is unable to bind effectors. The ability to directly bind KRASG12C (ON) leads to potent (~30 nM) inhibition in an effector (Raf1) binding assay where inactive (OFF) inhibitors demonstrate no measurable potency. BBO-8520 displays highly significant binding to KRASG12C in a global cysteine proteome analysis and is 100x more selective for KRASG12C than for WT KRAS and other mutant isoforms, with no measurable activity against N- or H-RAS. Cellular signaling and viability assays show that BBO-8520 has sub-nanomolar potency against KRASG12C mutant cell lines. In effector binding assays, BBO-8520 rapidly and completely blocks the RAS-RAF1 interaction, clearly differentiating it from inactive (OFF) inhibitors that require longer times to allow for cycling to the inactive (OFF) state. Additionally, long-term clonogenic assays that detect the emergence of resistance in the presence of inhibitors show that BBO-8520 is at least 30x more potent than sotorasib and adagrasib at preventing outgrowth. Importantly, the presence of growth factors (e.g., EGF) that push KRASG12C into its (ON) state, and significantly lower the potency of inactive (OFF) inhibitors (>20x), have only minor effects on BBO-8520’s potency. Drug-like pharmacokinetic properties allow BBO-8520 to achieve strong dose- and time-dependent pharmacodynamic effects (>80% inhibition of pERK) following a single, oral dose in KRASG12C mutant tumor bearing mice. In vivo target engagement and pERK inhibition in the MIAPaCa-2 and H358 KRASG12C mutant tumor models resulted in durable tumor regressions at 10 mg/kg. Similarly, daily dosing of 10 mg/kg of BBO-8520 in the KrasG12C-p53 driven GEMM model for 6 weeks resulted in better than 50% lung tumor volume regression. BBO-8520’s potent activity against KRASG12C (ON) presents, for the first time, the potential opportunity to directly target all mutant KRASG12C in cells, including the active form of KRASG12C, enabling efficacy following complete or near-complete target inhibition.Citation Format: Anna E. Maciag, James Stice, Bin Wang, Alok Sharma, Albert Chan, Ken Lin, Devansh Singh, Marcin Dyba, Yue Yang, Saman Setoodeh, Brian P. Smith, Dana Rabara, Zuhui Zhang, Erik K. Larsen, Dom Esposito, John Paul Denson, Michela Ranieri, Mary Meynardie, Sadaf Mehdizadeh, Patrick Alexander, Maria Abreu Blanco, David Turner, Rui Xu, Felice C. Lightstone, Kwok Kin Wong, Dhirendra Simanshu, Keshi Wang, Andrew G. Stephen, Kerstin Sinkevicius, Dwight V. Nissley, Eli Wallace, Frank McCormick, Pedro J. Beltran. BBO-8520, a first-in-class, direct inhibitor of KRASG12C (ON), locks GTP-bound KRASG12C in the state 1 conformation resulting in rapid and complete blockade of effector binding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND07.

2024-04-01·European Urology

Infigratinib Versus Placebo for Patients with High-risk Resected Urothelial Cancer Bearing an FGFR3 Genomic Alteration: Results from the PROOF302 Phase 3 Trial

Letter

作者: Davis, Kim ; Valderrama, Begona P ; Matin, Surena F ; Pal, Sumanta K ; Gupta, Shilpa ; Lerner, Seth P ; Bellmunt, Joaquim ; Fleming, Mark T ; van Veenhuyzen, David ; Grivas, Petros ; Sridhar, Srikala S ; Rodriguez-Vida, Alejo ; Sevillano Fernandez, Elena ; Sonpavde, Guru ; Daneshmand, Siamak ; Zengin, Zeynep ; Roghmann, Florian ; Loriot, Yohann ; Dizman, Nazli ; Master, Viraj ; Tripathi, Abhishek ; Weng, Richard

In the subset of patients with UC bearing alterations in the fibroblast growth factor 3 (FGFR3) gene, targeted therapies directed at this moiety have shown substantial antitumor effect in the metastatic setting.We examine infigratinib, a potent and selective inhibitor of FGFR3, as adjuvant therapy in patients with high-risk resected UC.In an international multicenter phase III clin. trial, we randomly assigned patients in a 1:1 ratio to receive either oral infigratinib (125 mg) or placebo daily for 21 days of a 28-day treatment cycle, for a maximum of 13 cycles or until disease recurrence.Eligible patients had confirmed invasive UC with susceptible FGFR3 alterations and had undergone radical surgery within 120 days of randomization.The primary endpoint of the study was centrally assessed disease-free survival (DFS), with secondary endpoints including investigator-assessed DFS, metastasis-free survival (MFS) and overall survival (OS).Despite intensive efforts to enroll approx. 218 patients (with 822 patients consented to mol. pre-screening), only 39 patients were enrolled with 20 and 19 patients randomized to receive infigratinib and placebo, resp.The frequency of FGFR3 alteration was significantly lower than anticipated, occurring in only 19% of patients overall; mutations were observed in 13% of patients with lower tract UC and 30% of patients with upper tract UC. No significant differences were observed in DFS, MFS or OS, and more frequent grade 3/4 adverse events were noted in the exptl. arm (35% vs. 16%).No fatal adverse events were observedOur failure to accrue sufficient patients to the current trial precludes any definitive conclusions around the role of infigratinib as adjuvant therapy for FGFR3-altered UC.In the process of study conduct, however, we garnered substantial insights that may aid in the development of future precision oncol. trials for adjuvant UC.

2024-02-01·Journal of Biological Chemistry

Revealing the mechanism of action of a first-in-class covalent inhibitor of KRASG12C (ON) and other functional properties of oncogenic KRAS by 31P NMR

Article

作者: Stephen, Andrew G ; Lightstone, Felice C ; Beltran, Pedro J ; Nissley, Dwight V ; Wang, Bin ; Sharma, Alok K ; Larsen, Erik K ; Yang, Yue ; Maciag, Anna E ; Rabara, Dana ; McCormick, Frank ; Wallace, Eli ; Pei, Jun ; Smith, Brian ; Dyba, Marcin ; Esposito, Dominic

Individual oncogenic KRAS mutants confer distinct differences in biochemical properties and signaling for reasons that are not well understood. KRAS activity is closely coupled to protein dynamics and is regulated through two interconverting conformations: state 1 (inactive, effector binding deficient) and state 2 (active, effector binding enabled). Here, we use ³¹P NMR to delineate the differences in state 1 and state 2 populations present in WT and common KRAS oncogenic mutants (G12C, G12D, G12V, G13D, and Q61L) bound to its natural substrate GTP or a commonly used nonhydrolyzable analog GppNHp (guanosine-5'-[(β,γ)-imido] triphosphate). Our results show that GppNHp-bound proteins exhibit significant state 1 population, whereas GTP-bound KRAS is primarily (90% or more) in state 2 conformation. This observation suggests that the predominance of state 1 shown here and in other studies is related to GppNHp and is most likely nonexistent in cells. We characterize the impact of this differential conformational equilibrium of oncogenic KRAS on RAF1 kinase effector RAS-binding domain and intrinsic hydrolysis. Through a KRAS G12C drug discovery, we have identified a novel small-molecule inhibitor, BBO-8956, which is effective against both GDP- and GTP-bound KRAS G12C. We show that binding of this inhibitor significantly perturbs state 1-state 2 equilibrium and induces an inactive state 1 conformation in GTP-bound KRAS G12C. In the presence of BBO-8956, RAF1-RAS-binding domain is unable to induce a signaling competent state 2 conformation within the ternary complex, demonstrating the mechanism of action for this novel and active-conformation inhibitor.

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项与 BridgeBio Pharma, Inc. 相关的新闻（医药）

2024-10-31

·PipelineReview

BridgeBio Oncology Therapeutics (BBOT) Announces First Patient Dosed with First-in-Class BBO-10203, a RAS:PI3Kα Breaker, in the Phase 1 BREAKER-101 Trial for Advanced Solid Tumors

SOUTH SAN FRANCISCO, CA, USA I October 30, 2024 I TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (“BBOT” or the “Company”), a clinical-stage biopharmaceutical company focused on RAS-pathway malignancies, has announced that the first patient has been dosed with BBO-10203 in the BREAKER-101 trial. BBO-10203 is a first-in-class orally bioavailable RAS:PI3Ka breaker that blocks the interaction between RAS and PI3Kα to inhibit PI3Kα-AKT signaling in tumors, without directly inhibiting the catalytic activity of PI3Kα. “I am thrilled to partner with BBOT to bring a potentially transformable new therapeutic to the clinic,” said Dr. Minal Barve, Chief Medical Officer and Principal Investigator at Mary Crowley Cancer Research, Dallas, TX. “BBO-10203 represents a first-in-class drug with potential to address high unmet medical needs and change the landscape of cancer care. We look forward to evaluating BBO-10203 in the BREAKER-101 trial.” BBO-10203 was designed to bind covalently and selectively to the RAS-binding domain (RBD) of PI3Kα. This selective inhibition is agnostic to the mutational status of PI3Kα and RAS, and in preclinical models, results in complete inhibition of RAS-driven pAKT signal at single digit nanomolar concentration. Additionally, no hyperglycemia was observed in preclinical species treated with BBO-10203. The discovery of BBO-10203 was the result of a collaboration between the RAS Initiative at Frederick National Laboratory, Lawrence Livermore National Laboratory, and BBOT. “BBO-10203 is a first-in-class program that inhibits the interaction of the two most mutated oncogenes in human cancer, and it will allow us to test, for the first time, the importance of RAS-coordinated activation of the MAPK and AKT signaling pathways,” said Pedro Beltran, PhD, Chief Scientific Officer of BBOT. “The discovery of BBO-10203 was made possible by the dedicated collaboration between academic, national laboratory, and industry experts that synergized to advance medicines for patients suffering from cancer.” The BREAKER-101 trial will enroll patients globally with locally advanced or metastatic HER2-positive breast cancer, HR-positive/HER2-negative breast cancer, KRAS mutant advanced colorectal cancer, and KRAS mutant advanced non-small cell lung cancer. “There is a tremendous opportunity to improve the standard of care in oncology by inhibiting oncogenic pAKT signaling without the metabolic side effects observed with kinase inhibitors, and the initiation of the Phase 1 study of BBO-10203 marks an important milestone in this regard,” said Yong (Ben) Ben, MD, Chief Medical and Development Officer of BBOT. “The second IND within six months of establishing BBOT clearly demonstrates our team’s capability in advancing our novel programs into the clinic. This novel mechanism and scientific rationale behind it will allow tremendous combination opportunities that optimally inhibit both pAKT and pERK – an approach we hope will bring unprecedented benefit to patients with RAS-driven cancers.” About TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (BBOT) BridgeBio Oncology Therapeutics (BBOT) is a clinical-stage biopharmaceutical company advancing a next generation pipeline of novel small molecule therapeutics targeting RAS and PI3K malignancies. Initially formed as a subsidiary of BridgeBio, BBOT completed a $200M private financing with external investors in 2024 with the goal of improving outcomes for patients with cancers driven by the two most prevalent oncogenes in human tumors. For more information visit bridgebiooncology.com . SOURCE: BridgeBio Oncology Therapeutics

临床1期

2024-10-26

·药明康德

使所有患者停止标准治疗的创新基因疗法；一针使病情发作减少超80%的基因编辑疗法…… | 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。用于治疗法布里病的在研基因疗法isaralgagene civaparvovec有望提前3年在美国获批上市。REGENXBIO公司与艾伯维（AbbVie）联合开发的ABBV-RGX-314有望成为首个治疗慢性视网膜疾病的基因疗法，在一项2期临床试验中使78%接受治疗的湿性年龄相关性黄斑变性（AMD）患者在治疗9个月后仍无需补充注射抗血管内皮生长因子（VEGF）抗体。基因编辑疗法NTLA-2002治疗遗传性血管水肿（HAE）患者的1/2期临床试验结果亮眼，单次给药使患者平均每月HAE发作率与安慰剂相比减少达81%。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 ———✦研发进展✦——— ◇ Sangamo Therapeutics宣布已与美国FDA就其在研基因疗法isaralgagene civaparvovec（ST-920）用于治疗法布里病的加速批准监管途径达成共识。FDA同意正在进行的1/2期STAAR研究的数据可以作为该疗法获得加速批准的主要依据，并将所有患者52周的估算肾小球滤过率（eGFR）斜率作为中间临床终点。Sangamo预计，支持加速批准的完整数据集将在2025年上半年完成，并计划于2025年下半年提交生物制品许可申请（BLA）。如果获批，将会比预期的批准时间提前三年，且无需进行额外的注册性研究。Sangamo已开始为isaralgagene civaparvovec的上市申请进行准备工作。 Isaralgagene civaparvovec是一种以重组腺相关病毒2/6（AAV2/6）为载体的基因疗法，将表达α-半乳糖苷酶A的GLA基因递送到肝脏，旨在通过一次性治疗获得持久疗效，减轻法布里病的标准治疗酶替代疗法（ERT）的输注负担。接受该疗法的患者不需要预处理。在STAAR研究中，在18名接受isaralgagene civaparvovec治疗并有超过一年随访数据的男女患者中，观察到平均和中位eGFR水平的显著改善，年化eGFR斜率呈现积极趋势。不仅如此，截至目前，所有18名患者均不再使用ERT。 ◇ REGENXBIO公司公布了其与艾伯维联合开发的在研基因疗法ABBV-RGX-314在双眼湿性年龄相关性黄斑变性患者中进行的2期研究的积极数据。数据显示，在接受ABBV-RGX-314治疗9个月后，患者的治疗负担减少了97%。100%的患者只需零次或一次补充抗VEGF抗体注射，78%的患者完全无需注射。根据公司网站，ABBV-RGX-314有望成为首个治疗慢性视网膜疾病的基因疗法。 ABBV-RGX-314使用AAV8载体携带表达抗VEGF抗体片段的转基因，在体内表达的蛋白通过阻断VEGF信号传导，抑制心血生成和视网膜液体聚集。在治疗湿性AMD之外，两家公司也在探索ABBV-RGX-314治疗糖尿病视网膜病变和其他慢性视网膜疾病的潜力。 ◇ Intellia Therapeutics公司公布了其在研体内CRISPR基因编辑疗法NTLA-2002用于治疗遗传性血管水肿患者的1/2期临床试验的2期部分积极数据。结果显示，在第5至16周期间，单次输注50 mg NTLA-2002可使患者平均每月HAE发作率与安慰剂相比减少达81%。目前该疗法的全球关键性3期HAELO研究正在进行中。 NTLA-2002通过脂质纳米颗粒（LNP）以mRNA形式递送CRISPR-Cas9基因编辑系统，靶向血浆前激肽释放酶（KLKB1）基因，使该蛋白失活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。根据新闻稿，NTLA-2002有望成为首个针对HAE的一次性治疗方案。 ◇ Spur Therapeutics公司公布了其用于治疗1型戈谢病的候选基因疗法FLT201的1/2期GALILEO-1试验的最新积极数据。结果显示，单次输注FLT201治疗的患者体内葡萄糖基神经酰胺（lyso-Gb1，戈谢病临床缓解的最佳预测指标之一）和骨髓负担持续降低，血细胞计数和器官容积得到改善或维持。在这项研究中接受治疗的所有患者中，FLT201继续表现出良好的安全性和耐受性。 FLT201是一种AAV基因疗法，用于治疗1型戈谢病成年患者。该疗法旨在提供一次性治疗，以持续增加患者体内GCase表达并减少有害底物的积累，阻止疾病进展，让患者不必终生接受治疗。FLT201采用Freeline的AAVS3衣壳，将新型基因引入肝细胞，生产经过理性设计的GCase变体。临床前和临床数据显示，FLT201的表达稳健而持久，并且由于酶缺乏而导致的底物毒性积累显著减少。 ◇ BridgeBio Pharma公司公布了其用于治疗卡纳万病（Canavan disease）的在研AAV9基因疗法BBP-812在CANaspire1/2期临床试验中的初步阳性数据。与该公司正在进行的CANinform自然史比较研究中观察到的疾病进程相比，接受BBP-812治疗后12个月时，患者运动功能的持续、渐进改善和运动里程碑的实现代表了重要的、具有统计学意义的变化。所有接受低剂量治疗患者的尿液、脑脊液和大脑中的N-乙酰天冬氨酸（NAA）水平显著、持续降低，接受高剂量BBP-812治疗患者尿液中的NAA水平呈进一步下降趋势。卡纳万病是一种由编码天冬氨酸酶的ASPA基因突变引起的超罕见、可致残或致命的疾病。BBP-812能够将ASPA基因的功能拷贝递送到全身并进入大脑，从而可能根治疾病。新闻稿指出，如果获得批准，BBP-812有望成为患有卡纳万病这种先天性致命神经发育障碍的患儿的首个治疗方案。 ◇ Interius BioTherapeutics公司宣布已在一项1期临床试验中为首例B细胞恶性肿瘤患者提供其在研基因疗法INT2104。INT2104是一种慢病毒载体基因疗法，设计靶向CD7阳性的T细胞和NK细胞，并递送嵌合抗原受体（CAR）转基因，以在体内生成效应CAR-T和CAR-NK细胞。这些CAR细胞靶向CD20阳性B细胞，用于治疗B细胞恶性肿瘤。与体外CAR-T疗法不同，INT2104是一种现货型的单剂量疗法，可通过静脉输注系统性给药，患者无需进行淋巴清除，治疗时不需要任何特殊设备或人员培训。根据行业媒体STAT报道，INT2104是首个进入人体临床试验的体内CAR-T疗法。 ◇ Precision BioSciences公司宣布，其主打在研体内基因编辑疗法PBGENE-HBV的临床试验申请（CTA）已获得摩尔多瓦（Moldova）的监管单位批准。PBGENE-HBV旨在通过消除乙型肝炎病毒（HBV）的共价闭合环状DNA（cccDNA），同时灭活整合在肝细胞中的HBV DNA，以达到功能性治愈慢性乙型肝炎的目的。该公司已启动1期临床项目，并准备进行患者给药。Precision公司预计向全球监管单位提交更多的CTA和IND申请。根据新闻稿，PBGENE-HBV是进入临床阶段的首个靶向HBV的体内基因编辑疗法。 ◇ 艾尔普再生医学宣布FDA批准了其自主研发的新一代细胞疗法“人诱导多能干细胞（iPSC）来源心肌细胞注射液”（HiCM-188）用于治疗终末期心力衰竭的IND申请。新闻稿指出，HiCM-188是首个在美国接受用于治疗终末期心力衰竭临床评估的iPSC衍生细胞创新药。该候选疗法此前已在中国获准临床试验，并取得安全性及有效性结果。 ◇ 中国国家药监局药品审评中心（CDE）官网公示，贝斯昂科生物1类新药NK510细胞注射液获批临床，拟开发用于经标准治疗失败的晚期恶性实体瘤。新闻稿指出，在产品研发过程中，NK510采用了零脱靶碱基编辑器AccuBase，对NK细胞中关键基因进行了精确修改，编辑效率超过90%。研究表明，NK510既能克服癌细胞的免疫逃逸，又能特异性地识别和杀伤癌细胞，在多项体外、体内实验中展现出强大的抗肿瘤能力。 ◇ CDE官网公示，原启生物自主研发的双靶点Claudin 18.2/MSLN自体CAR-T细胞疗法OriC613注射液获批临床，拟开发治疗晚期实体瘤。根据原启生物新闻稿介绍，OriC613采用“AND”逻辑门控设计，通过拆分二代CAR结构元件，使OriC613 CAR-T细胞表面并联表达针对MSLN和Claudin 18.2的嵌合抗原受体，且仅对同时表达两个抗原的肿瘤细胞产生应答，从而能在增加肿瘤靶向杀伤活性的同时降低非肿瘤靶向毒性（OTOT），提高临床安全性。 ———✦融资、合作、M&A✦——— 图片来源：123RF ◇ AvenCell Therapeutics公司宣布完成1.12亿美元的B轮融资，此次融资所获得的资金将用于继续验证AvenCell的专有可控通用CAR-T细胞疗法平台，该平台产生的CAR-T细胞即使在患者接受治疗后也可以快速“关闭”和“打开”。与传统细胞疗法相比，该通用平台旨在更安全、更有效地治疗多种血液系统恶性肿瘤。目前，AvenCell的临床管线包括一种高度差异化的自体CAR-T细胞疗法AVC-101，和一种通过CRISPR改造的异体CAR-T细胞疗法AVC-201，这两种管线均靶向急性髓系白血病（AML）细胞上常见的CD123抗原。这两款候选疗法已在早期临床试验中显示出令人鼓舞的安全性和疗效。此外，AvenCell有多个管线候选药物将在未来两年进入临床阶段。 ◇ 致力于开发B细胞疗法的Be Biopharma公司宣布完成8200万美元的融资，获得的资金将用于实现其用于治疗血友病B的主打项目BE-101的临床概念验证，并推进其用于治疗低磷酸酶症（HPP）的候选药物BE-102的开发。这两个项目均基于该公司强大且高效的B细胞药物（BCM）平台，该平台利用基因编辑技术改造B细胞，使其能够持续产生治疗性蛋白质，最终开发出具有持久性、可滴定且可重复给药的候选药物，无需预处理，具有成为潜在“best-in-class”基因疗法的潜力。 ◇ March Biosciences公司宣布成功完成超额认购的2840万美元A轮融资，获得资金将用于支持其主打在研自体CAR-T细胞疗法MB-105的2期临床开发，并进一步优化生产工艺。MB-105旨在治疗复发性和难治性CD5阳性T细胞淋巴瘤。MB-105专门设计用于克服与T细胞靶向相关的主要障碍，在解决T细胞同类相杀问题同时，保持对CD5阳性肿瘤细胞的高效杀伤力。MB-105在贝勒医学院（Baylor College of Medicine）进行的一项针对复发性T细胞淋巴瘤患者的1期临床试验中显示出良好的安全性和持久的缓解效果。该公司计划于2025年初开始2期临床试验。 ◇ 士泽生物宣布完成逾亿元B1轮市场化融资，至此，该公司近2年内已完成逾3亿元A轮/A+轮/B1轮融资。新闻稿指出，本轮融资将用于士泽生物临床级iPS衍生细胞药治疗神经系统疾病管线的完善、进一步开展临床研究以及推进多项注册临床试验。该公司自研设计并建立了底层技术平台，覆盖iPSC重编程与建库、基因编辑iPSC、iPSC分化为亚型特化的神经细胞及临床前疾病动物模型的构建及评价等关键技术平台，并与多家知名研究机构及医院开展技术研究及临床开发合作。目前，士泽生物的自研临床级iPS衍生细胞药已在渐冻症和帕金森病患者中取得进展。其中，用于治疗帕金森病的iPS衍生多巴胺能神经前体细胞在多个临床案例中显示出了良好的安全性和有效性，患者症状有显著改善趋势，且未出现细胞疗法相关不良事件。 ◇ 利用人工智能（AI）推动体内基因递送的生物技术公司Dyno Therapeutics宣布与罗氏（Roche）达成第二项研究合作，开发针对神经疾病的下一代AAV载体基因疗法。Dyno和罗氏此前于2020年10月宣布了一项针对神经疾病和肝脏定向疗法的研究合作与许可协议。根据此次新合作协议，Dyno将负责设计和发现具有改进功能特性的全新AAV衣壳。罗氏则负责进行衣壳验证研究，并推进多个神经基因疗法候选产品的临床前、临床期及商业化活动，这些产品均利用了Dyno开发的创新衣壳。罗氏将向Dyno支付5000万美元的预付款，此外在研究阶段还会进行额外付款，并有望根据临床前、临床期和销售里程碑支付总计超过10亿美元的款项。 ◇ Lyell Immunopharma公司宣布，已达成收购ImmPACT Bio公司的最终协议。ImmPACT公司的主打项目IMPT-314是一种CD19/20靶向CAR－T细胞候选产品，Lyell公司将继续开发该产品用于治疗血液恶性肿瘤，包括大B细胞淋巴瘤。新闻稿指出，收购ImmPACT公司预计将大大加强Lyell公司处于临床阶段的下一代CAR－T细胞疗法产品线，并补充其专有技术套件，这些技术旨在生成更持久的功能性T细胞，为实体瘤和血液系统恶性肿瘤患者带来更持久的疗效。 ▲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] Sangamo Therapeutics Announces Alignment With FDA on Accelerated Approval Pathway for ST-920 in Fabry Disease With BLA Submission Expected in 2025. Retrieved October 23, 2024, from https://investor.sangamo.com/news-releases/news-release-details/sangamo-therapeutics-announces-alignment-fda-accelerated [2] REGENXBIO Presents Positive Data from the Phase II Study of Subretinal ABBV-RGX-314 in Patients with Bilateral Wet AMD at AAO 2024. Retrieved October 21, 2024, from https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-presents-positive-data-phase-ii-study-subretinal-abbv [3] 世界首款碱基编辑NK细胞产品临床试验申请获得受理. Retrieved July 30, 2024, from https://mp.weixin.qq.com/s/_jnzmCZrRSi7pbSDHlUWSA [4] Spur Therapeutics Showcases Positive New Data from Phase 1/2 GALILEO-1 Trial of FLT201, Its Novel Gene Therapy Candidate for Gaucher Disease, in Oral Presentation at ESGCT 31st Annual Congress. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/23/2967469/0/en/Spur-Therapeutics-Showcases-Positive-New-Data-from-Phase-1-2-GALILEO-1-Trial-of-FLT201-Its-Novel-Gene-Therapy-Candidate-for-Gaucher-Disease-in-Oral-Presentation-at-ESGCT-31st-Annua.html [5] Interius BioTherapeutics Doses First Patient with in vivo Chimeric Antigen Receptor (CAR) Gene Therapy for B-cell Malignancies. Retrieved October 25, 2024, from https://interiusbio.com/2024/10/interius-biotherapeutics-doses-first-patient-with-in-vivo-chimeric-antigen-receptor-car-gene-therapy-for-b-cell-malignancies/ [6] 重大突破！艾尔普再生医学新一代细胞创新药临床IND获美国FDA批准. Retrieved October 25, 2024, from https://mp.weixin.qq.com/s/sNs5TT0emP4ns_CysiWNQw [7] 原启生物宣布双靶点MSLN/Claudin 18.2 OriC613注射液新药临床试验（IND）申请获中国NMPA批准. Retrieved October 17, 2024, from https://www.oricell.com/newsdetail/id/40.html [8] AvenCell Raises $112 Million in Series B; Funding Led by Novo Holdings. Retrieved October 22, 2024 from https://avencell.com/avencell-raises-112-million-in-series-b-funding-led-by-novo-holdings/ [9] Be Bio Announces $82 Million Financing and Transition to Clinical Stage Company. Retrieved October 22, 2024, from https://www.businesswire.com/news/home/20241022283327/en [10] March Biosciences Closes Oversubscribed $28.4 Million Series A Financing. Retrieved October 23, 2024, from https://www.globenewswire.com/news-release/2024/10/23/2967726/0/en/March-Biosciences-Closes-Oversubscribed-28-4-Million-Series-A-Financing.html [11] 士泽生物完成超亿元B1轮融资，推进临床级iPS衍生细胞药治疗神经系统疾病管线. Retrieved October 25, 2024, from https://mp.weixin.qq.com/s/R4wXpGtrxhwkVnRDbwV4ZA [12] BridgeBio Shares Positive Data from High Dose Cohort of Phase 1/2 CANaspire Study of Gene Therapy BBP-812 for Canavan Disease at ESGCT 2024. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/24/2968601/0/en/BridgeBio-Shares-Positive-Data-from-High-Dose-Cohort-of-Phase-1-2-CANaspire-Study-of-Gene-Therapy-BBP-812-for-Canavan-Disease-at-ESGCT-2024.html [13] Precision BioSciences Receives First Approval of Clinical Trial Application to Initiate PBGENE-HBV First-In-Human Study for the Treatment of Chronic Hepatitis B. Retrieved October 24, 2024, from https://investor.precisionbiosciences.com/news-releases/news-release-details/precision-biosciences-receives-first-approval-clinical-trial [14] Intellia Presents Positive Results from the Phase 2 Study of NTLA-2002, an Investigational In Vivo CRISPR Gene Editing Treatment for Hereditary Angioedema (HAE). Retrieved October 24, 2024 from https://ir.intelliatx.com/news-releases/news-release-details/intellia-presents-positive-results-phase-2-study-ntla-2002 [15] Dyno Therapeutics Forms New Strategic Partnership With Roche To Advance AAV Gene Therapy Vectors For Neurological Diseases. Retrieved October 24, 2024, from https://www.dynotx.com/dyno-therapeutics-forms-new-strategic-partnership-with-roche-to-advance-aav-gene-therapy-vectors-for-neurological-diseases/ [16] Lyell Immunopharma to Acquire ImmPACT Bio and Prioritizes its Pipeline to Focus on Next-Generation CAR T-cell Therapies. Retrieved October 24, 2024, from https://www.globenewswire.com/news-release/2024/10/24/2969054/0/en/Lyell-Immunopharma-to-Acquire-ImmPACT-Bio-and-Prioritizes-its-Pipeline-to-Focus-on-Next-Generation-CAR-T-cell-Therapies.html a-Therapeutics-and-Factor-Bioscience-Announce-Exclusive-License-and-Collaboration-Agreement-to-Accelerate-Cell-Therapy-Development-for-Oncology-Autoimmune-and-Rare-Diseases.html [12] 因诺惟康IVB103注射液获得CDE临床许可. Retrieved October 18, 2024, from https://mp.weixin.qq.com/s/OU_bxfT9u4a_-Cs6WreoDQ 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

基因疗法临床2期上市批准临床结果细胞疗法

2024-10-25

·药明康德

近80%患者癌细胞完全消失，新锐囊获新一代CAR-T疗法；潜在首款！基因疗法显著改善患者指标……

▎药明康德内容团队编辑聚焦下一代CAR-T疗法，Lyell Immunopharma收购ImmPACT Bio Lyell Immunopharma今日宣布已签订最终协议，将收购ImmPACT Bio。ImmPACT的主打在研疗法IMPT-314是一款靶向CD19/CD20的嵌合抗原受体（CAR）T细胞疗法，Lyell将继续推进该产品在血液恶性肿瘤（包括大B细胞淋巴瘤）中的开发。IMPT-314采用双靶向设计，旨在超越已获批的CD19靶向CAR-T细胞疗法的疗效，并通过在生产过程中富集初始和中心记忆T细胞来增强CAR-T细胞疗法的持久性。收购ImmPACT预计将显著增强Lyell的临床阶段新一代CAR-T细胞疗法管线，并补充其专有技术组合，以生成更持久的功能性T细胞，为实体瘤和血液恶性肿瘤患者提供更持久的疗效。在今年早些时候发布的临床试验数据显示，在13名接受IMPT-314治疗的复发/难治性（R/R）侵袭性非霍奇金淋巴瘤患者中，12名达到了完全或部分缓解（92%的客观缓解率），其中10名患者达到了确认的完全缓解（CR），完全缓解率为77%。中位随访时间为32个月时，中位无进展生存期为50.1个月，中位总生存期尚未达到。 BridgeBio Pharma基因疗法显著改善患者指标日前，BridgeBio Pharma公司公布了在研基因疗法BBP-812在治疗卡纳万病（Canavan disease）患者的1/2期临床试验CANaspire中的最新数据。试验结果显示，BBP-812显著改善患者的生物标志物指标。与自然病史数据相比，接受治疗患者的运动功能也获得渐进、持久的改善。新闻稿指出，如果获得批准，BBP-812可能成为卡纳万病患者的首个获批疗法。 CANaspire是一项1/2期开放标签研究，旨在评估BBP-812在患有卡纳万病的儿童患者中的安全性、耐受性和药效学活性。试验结果显示，在BBP-812给药后，参与者的尿液和脑中的N-乙酰天冬氨酸（NAA）水平迅速且持续降低。低剂量治疗后12个月NAA平均下降64%，高剂量治疗后3个月NAA平均下降73%。最早接受治疗的参与者在接近三年内维持了较低的尿液NAA水平。脑脊液（CSF）中的NAA在接受低剂量治疗后12个月平均减少70%。在T2加权核磁共振成像（MRI）中，观察到大多数接受BBP-812治疗的参与者的髓鞘形成获得改善。与自然病史相比，接受BBP-812治疗的患者运动功能逐渐改善（通过GMFM-88量表评估），并且达到运动功能里程碑（通过HINE-2量表评估）。卡纳万病是一种由编码天冬氨酸酶的ASPA基因突变引起的超罕见、可致残或致命的疾病。大多数儿童无法爬行、行走、坐着或说话，在婴幼儿时期就会面临死亡的威胁。天冬氨酸酶活性的缺乏会导致NAA的积累，并最终导致对髓鞘的毒性。目前，该病尚无获批的疗法。BBP-812利用腺相关病毒9载体将ASPA基因的功能拷贝递送到全身并进入大脑，从而可能根治疾病。它已获得美国FDA授予再生医学先进疗法（RMAT）认定、孤儿药资格、罕见儿科疾病资格和快速通道资格。治疗纤维化疾病，新锐完成8900万美元融资 Agomab Therapeutics今日宣布完成8900万美元的D轮融资，获得资金将用于进一步推进其核心候选药物AGMB-129的临床开发。 AGMB-129是一种针对纤维狭窄型克罗恩病（FSCD）患者的口服、肠道限制性ALK5小分子抑制剂。其2a期临床试验STENOVA的中期数据预计将于2025年第一季度发布。此外，这些资金还将用于推进AGMB-447的临床开发，这是一种针对肺部、吸入式的ALK5小分子抑制剂，目前正在1期临床试验中接受检验，用于治疗特发性肺纤维化（IPF）。该公司的研发管线中还有一款MET激动性抗体AGMB-101，目前处于支持IND申请的临床前研究的最后阶段，计划用于治疗肝硬化。 ▲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] Agomab Announces $89 Million Series D Financing to Support Broad Fibrosis-Focused Pipeline. Retrieved October 25, 2024, from https://www.businesswire.com/news/home/20241024624593/en [2] Lyell Immunopharma to Acquire ImmPACT Bio and Prioritizes its Pipeline to Focus on Next-Generation CAR T-cell Therapies. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/24/2969054/0/en/Lyell-Immunopharma-to-Acquire-ImmPACT-Bio-and-Prioritizes-its-Pipeline-to-Focus-on-Next-Generation-CAR-T-cell-Therapies.html [3] BridgeBio Shares Positive Data from High Dose Cohort of Phase 1/2 CANaspire Study of Gene Therapy BBP-812 for Canavan Disease at ESGCT 2024. Retrieved October 25, 2024, from https://investor.bridgebio.com/news-releases/news-release-details/bridgebio-shares-positive-data-high-dose-cohort-phase-12 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

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