A Randomized, Double Blind, Sham-controlled, Multi-center Phase I / II Clinical Study to Assess the Safety and Efficacy of IDCT in Patients With Lumbar Degenerative Disc Disease

The purpose of this study is to compare the safety and preliminary efficacy of intradiscal injections of two doses of IDCT (Discogenic Cells + Sodium Hyaluronate vehicle) and one sham control in subjects with chronic low back pain due to Degenerative Disc Disease (DDD) at one lumbar level from L3 to S1.

开始日期2019-05-23

申办/合作机构

DiscGenics, Inc.

NCT03347708 / Completed临床1期

A Prospective, Randomized, Double-Blinded, Vehicle- and Placebo-Controlled, Multicenter Study to Evaluate the Safety and Preliminary Efficacy of IDCT in Subjects With Single-Level, Symptomatic Lumbar Intervertebral Disc Degeneration

The purpose of this study is to compare the safety and preliminary efficacy of intradiscal injections of two doses of IDCT (Discogenic Cells + Sodium Hyaluronate vehicle) and two controls (saline, Sodium Hyaluronate vehicle) in subjects with chronic low back pain due to Degenerative Disc Disease (DDD) at one lumbar level from L3 to S1.

开始日期2018-02-26

申办/合作机构

DiscGenics, Inc.

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项与 DiscGenics, Inc. 相关的文献（医药）

2021-12-01·Stem cell research & therapy2区 · 医学

Transition from static culture to stirred tank bioreactor for the allogeneic production of therapeutic discogenic cell spheres

2区 · 医学

ArticleOA

作者: LeBaron, Cameron ; Bingham, Justin ; Erickson, Isaac ; Clark, Garrett ; Decaria, Paula ; Zurawski, Jeff ; Rodriguez-Granrose, Daniel ; Tandeski, Terry ; Loftus, Hannah ; Jones, Nephi ; Heaton, Will ; Dulatov, Galina ; Highsmith, Angelica Adrian ; Farhang, Niloo ; Scull, Erin ; Foley, Kevin T ; Jones, Amanda ; Conen, Mason ; Silverman, Lara

Abstract:

Background:

Culturing cells as cell spheres results in a tissue-like environment that drives unique cell phenotypes, making it useful for generating cell populations intended for therapeutic use. Unfortunately, common methods that utilize static suspension culture have limited scalability, making commercialization of such cell therapies challenging. Our team is developing an allogeneic cell therapy for the treatment of lumbar disc degeneration comprised of discogenic cells, which are progenitor cells expanded from human nucleus pulposus cells that are grown in a sphere configuration.

Methods:

We evaluate sphere production in Erlenmeyer, horizontal axis wheel, stirred tank bioreactor, and rocking bag format. We then explore the use of ramped agitation profiles and computational fluid dynamics to overcome obstacles related to cell settling and the undesired impact of mechanical forces on cell characteristics. Finally, we grow discogenic cells in stirred tank reactors (STRs) and test outcomes in vitro (potency via aggrecan production and identity) and in vivo (rabbit model of disc degeneration).

Results:

Computation fluid dynamics were used to model hydrodynamic conditions in STR systems and develop statistically significant correlations to cell attributes including potency (measured by aggrecan production), cell doublings, cell settling, and sphere size. Subsequent model-based optimization and testing resulted in growth of cells with comparable attributes to the original static process, as measured using both in vitro and in vivo models. Maximum shear rate (1/s) was maintained between scales to demonstrate feasibility in a 50 L STR (200-fold scale-up).

Conclusions:

Transition of discogenic cell production from static culture to a stirred-tank bioreactor enables cell sphere production in a scalable format. This work shows significant progress towards establishing a large-scale bioprocess methodology for this novel cell therapy that can be used for other, similar cell therapies.

2021-06-01·Bioprocess and biosystems engineering3区 · 工程技术

Design of experiment (DOE) applied to artificial neural network architecture enables rapid bioprocess improvement

3区 · 工程技术

Article

作者: Jones, Amanda ; Foley, Kevin T ; Heaton, Will ; Loftus, Hannah ; Rodriguez-Granrose, Daniel ; Tandeski, Terry ; Silverman, Lara

Abstract:

Modern bioprocess development employs statistically optimized design of experiments (DOE) and regression modeling to find optimal bioprocess set points. Using modeling software, such as JMP Pro, it is possible to leverage artificial neural networks (ANNs) to improve model accuracy beyond the capabilities of regression models. Herein, we bridge the gap between a DOE skill set and a machine learning skill set by demonstrating a novel use of DOE to systematically create and evaluate ANN architecture using JMP Pro software. Additionally, we run a mammalian cell culture process at historical, one factor at a time, standard least squares regression, and ANN-derived set points. This case study demonstrates the significant differences between one factor at a time bioprocess development, DOE bioprocess development and the relative power of linear regression versus an ANN-DOE hybrid modeling approach.

2020-01-01·The spine journal : official journal of the North American Spine Society2区 · 医学

In vitro and in vivo evaluation of discogenic cells, an investigational cell therapy for disc degeneration

2区 · 医学

Article

作者: Foley, Kevin T ; Toplon, David ; Lundell, Beverly ; Erickson, Isaac E ; Silverman, Lara Ionescu ; Howard, Antwain ; Tandeski, Terry ; Chintalacharuvu, Subba ; Wolff, Tricia ; Dulatova, Galina

BACKGROUND/CONTEXT:

Disc degeneration (DD) is a significant driver of low back pain and few treatments exist to treat the pain and disability associated with the disease.

PURPOSE:

Our group has developed a method to generate therapeutic discogenic cells as a potential treatment for symptomatic DD. These cells are derived and modified from adult nucleus pulposus cells. In this study, we evaluated the characteristics, mode of action, and in vivo efficacy and safety of these cells prior to human clinical testing.

STUDY DESIGN:

Privately funded in vitro studies and in vivo preclinical models were used in this study.

METHODS:

Discogenic cells generated from different adult human donors were evaluated for surface marker expression profile, matrix deposition and tumorigenic potential. Discogenic cells were then injected subcutaneously into nude mice to assess cell survival and possible extracellular matrix production in vivo. Finally, a rabbit model of DD was used to evaluate the therapeutic potential of discogenic cells after disc injury.

RESULTS:

We found that discogenic cells have a consistent surface marker profile, are multipotent for mesenchymal lineages, and produce extracellular matrix consisting of aggrecan, collagen 1 and collagen 2. Cells did not show abnormal karyotype after culturing and did not form tumor-like aggregates in soft agar. After subcutaneous implantation in a nude mouse model, the human discogenic cells were found to have generated regions rich with extracellular matrix over the course of 4 months, with no signs of tumorigenicity. Intradiscal injection of human discogenic cells in a rabbit model of DD caused an increase in disc height and improvement of tissue architecture relative to control discs or injection of vehicle alone (no cells) with no signs of toxicity.

CONCLUSIONS:

This study demonstrates that intradiscal injection of discogenic cells may be a viable treatment for human degenerative disc disease. The cells produce extracellular matrix that may rebuild the depleting tissue within degenerating discs. Also, the cells do not pose any significant safety concerns.

CLINICAL SIGNIFICANCE:

Human clinical testing of discogenic cells combined with a sodium hyaluronate carrier is ongoing in multiple randomized, controlled, double-blinded studies in the United States (clinicaltrials.gov identifier NCT03347708) and Japan (clinicaltrials.gov identifier NCT03955315).

项与 DiscGenics, Inc. 相关的新闻（医药）

2024-07-16

·PRNewswire

DiscGenics Announces US FDA Approval to Proceed with Phase III Clinical Evaluation of Allogeneic, Injectable Disc Progenitor Cell Therapy for Symptomatic Lumbar Degenerative Disc Disease

Receives FDA acceptance on Phase III clinical protocols for parallel pivotal and confirmatory trials Achieves alignment with FDA on Chemistry, Manufacturing, and Controls (CMC) aspects of Phase III program SALT LAKE CITY, July 16, 2024 /PRNewswire/ -- DiscGenics, Inc., a privately held, late-stage clinical, biopharmaceutical company developing allogeneic, cell-based, regenerative therapies for musculoskeletal degeneration, today announced it has gained acceptance from the U.S. Food and Drug Administration (FDA) for the clinical protocols and Chemistry, Manufacturing, and Controls (CMC) clinical development plan for Phase III clinical program of its allogeneic, injectable disc progenitor cell therapy (IDCT or rebonuputemcel) for painful lumbar degenerative disc disease (DDD), allowing the study to proceed. Continue Reading During treatment, a single dose of IDCT is injected into the painful disc percutaneously. "There are very few credible treatments on the market for mechanical back pain, and we believe early clinical evidence suggests DiscGenics' cell therapy has the potential to shift the paradigm of care from ablative / destructive procedures or fusion surgery to a revolutionary regenerative and minimally invasive treatment for patients suffering from painful degenerative disc disease," said Nagy Mekhail, MD, PhD, the Director of Evidence-Based Pain Medicine Research and Education, Department of Pain Management at the Cleveland Clinic. "We look forward to participating in the continued clinical evaluation of this long waited for, promising therapy." The Phase III clinical program agreed upon with the FDA will consist of two identical studies running in parallel: the pivotal study (DGX-A02 or PIVOT) and the confirmatory study (DGX-A03 or CONFIRM). Both studies are randomized, double-blinded, Sham-controlled, multicenter studies in subjects with single-level symptomatic lumbar intervertebral disc degeneration. "The Phase III clinical program builds on a strong foundation of clinical data from the combined Phase I/Phase II study of IDCT showing promising safety and efficacy results, recently published in the International Journal of Spine Surgery and is informed by several discussions with the FDA to ensure continued safe evaluation of IDCT in this patient population where the unmet clinical need is high," said Kevin T. Foley, MD, Chief Medical Officer of DiscGenics and Chairman of Semmes-Murphey Neurologic & Spine Institute. Each study will have a one-year primary endpoint with another one-year follow-up period (two-year total duration). The first subject in the pivotal study is estimated to be enrolled during Q4 2024. "To get to this point has been a long, but very exciting journey. From the early founding of this cell technology by the late Dr. Valery Kukekov to the successful first-in-human clinical evaluation of IDCT, we have become more confident not only around the safety of the cell, but also its regenerative potential," said Flagg Flanagan, Chief Executive Officer and Chairman of the Board for DiscGenics. "Our team has been passionately persistent in achieving this important regulatory milestone, which allows us to continue fulfilling our responsibility as stewards of this technology." Through this study, IDCT is being evaluated under an investigational new drug (IND) allowance by the U.S. Food and Drug Administration (FDA). If successful, this Phase III clinical program will support a biologics license application (BLA) to be filed with the FDA. About IDCT IDCT (injectable disc cell therapy, or rebonuputemcel) is a standalone, single-injection biologic treatment designed to halt progression of symptomatic lumbar disc degeneration and regenerate the disc from the inside out. The active ingredient (Drug Substance) in IDCT is a live, manufactured progenitor cell population derived from donated adult human intervertebral disc tissue. These cells are enriched and expanded into Discogenic Cells through a multistep manufacturing process in a highly controlled environment under current good manufacturing practices (cGMP) that results in significant proliferation and phenotypic changes to the cells. At the completion of the manufacturing process, the Discogenic Cells are subjected to extensive testing prior to use, including identity, purity, potency, and safety evaluations. The Discogenic Cells are then mixed with a viscous Sodium Hyaluronate Solution and excipients to generate IDCT, the Final Drug Product. IDCT is cryopreserved and maintained as individual "off-the-shelf" doses for administration via percutaneous injection into the intervertebral disc in an outpatient setting. IDCT has been granted regenerative medicine advanced therapy (RMAT) and Fast Track designations by the U.S. Food and Drug Administration. Disclaimer: IDCT is an investigational product that is under development by DiscGenics and has not been approved by the FDA or any other regulatory agency for human use. About Chronic Low Back Pain and Degenerative Disc Disease Chronic low back pain is a serious medical condition that represents a leading cause of disability worldwide and is the most common non-cancer reason for opioid prescription in the U.S. It affects 12-30% of U.S. adults at a given time and is estimated to cost the U.S. healthcare system over $100 billion each year, creating a significant burden on the economy and individual patients dealing with the condition. In nearly 40% of patients, low back pain is caused by DDD, a chronic and progressive condition where the intervertebral disc breaks down and causes pain. About DiscGenics DiscGenics is a privately held, late-stage clinical biopharmaceutical company developing allogeneic, cell-based regenerative therapies for musculoskeletal degeneration. It's lead product candidate, IDCT (injectable disc cell therapy, or rebonuputemcel), is a standalone, single-injection biologic treatment designed to halt progression of lumbar disc degeneration and regenerate the disc from the inside out. DiscGenics is also developing a follow-on allogeneic cell platform to enable new musculoskeletal indications. To further development of these unique therapies, and to maintain control over compliance, cost, and production timelines, DiscGenics has built and validated an in-house scalable, allogeneic cell manufacturing process and cGMP facility at its headquarters in Salt Lake City, Utah. For more information, visit discgenics.com. SOURCE DiscGenics, Inc.

细胞疗法临床3期快速通道加速审批

2024-07-14

·药明康德

令过半患者肿瘤完全消失的突破性细胞疗法；12周减重超13%的口服减肥疗法…… | 一周盘点

▎药明康德内容团队编辑本期看点 1. 治疗对CD19靶向CAR-T细胞疗法耐药的大B细胞淋巴瘤（LBCL）患者的CD22靶向CAR-T细胞疗法firi-cel公布积极1期临床试验数据，过半患者肿瘤完全消失。 2. 口服GLP-1和胰淀素的长效共激动剂amycretin在一项1期临床试验中使肥胖患者在用药12周后减重超过13.1%。 3. 治疗帕金森病的细胞疗法TED-A9在一项早期临床试验中使3名患者的运动能力获得显著改善。药明康德内容团队整理 Firicabtagene autoleucel（firi-cel）：公布1期临床试验数据 CARGO Therapeutics公司宣布，《柳叶刀》杂志发表了斯坦福大学医学院进行的一项单中心1期临床研究的积极数据，该研究评估了CARGO公司的CD22靶向CAR-T细胞疗法firicabtagene autoleucel（firi-cel）治疗对CD19靶向CAR-T细胞疗法耐药的大B细胞淋巴瘤患者。这款CAR-T疗法是由患者自体T细胞经慢病毒载体（m971-BBZ）转导而制造出来的，目前CARGO Therapeutics拥有它的研发权利。发布于《柳叶刀》的临床数据截至2023年5月22日，在中位随访时间23.3个月期间，所有接受治疗患者的总缓解率（ORR）和完全缓解（CR）率分别为68%和53%。CARGO在今年5月的欧洲血液学协会（EHA）大会上公布了该试验的更新数据。截至2024年2月1日，在中位随访31.4个月期间，所有接受治疗患者的ORR和CR率仍分别为68%和53%。其中，29例接受剂量水平1（DL1）治疗的患者在中位随访29.8个月时的中位总生存期（mOS）为25.7个月（95% CI：9.2-NE），预估的2年生存率为52%。对于达到CR的患者，其中位无进展生存期（PFS）、缓解持续时间和总生存期尚未达到。自2023年11月的最后一次数据截止以来，20名达到CR的患者中没有观察到新的复发。此外，在DL1中持续没有观察到3级或更高级别的细胞因子释放综合征（CRS）或免疫效应细胞相关神经毒性综合征（ICANS）的发生。新闻稿指出，美国FDA在检视试验初步数据后罕见地主动联系斯坦福医学中心，敦促其为该疗法申请突破性疗法认定（BTD）。 Amycretin：公布1期临床试验的新数据诺和诺德（Novo Nordisk）公布了其口服GLP-1和胰淀素的长效共激动剂amycretin的详细1期临床试验结果。分析显示，试验12周时，接受最高剂量amycretin的受试者的体重降幅高达13.1%，且受试者的体重下降尚未达到平台期。根据此积极结果，诺和诺德将对amycretin进行进一步开发。 ▲Amycretin在1期试验中的减重效果（图片来源：参考资料[6]）行业媒体Fierce Biotech在过去的报道中指出，已过STEP-1临床试验结果显示司美格鲁肽组患者在68周试验期间的体重降幅为14.9%。虽然不同临床试验之间的结果难以一同比较，但amycretin在1期试验早期结果中所展现的快速减重效果，体现了该药物的巨大潜力。目前诺和诺德正在计划进行更大规模和更长时间的研究以全面评估amycretin的疗效和安全性，其中，旨在评估该疗法皮下注射剂型的2期试验正在进行患者招募。 TED-A9：公布1/2a期临床试验数据 S.BIOMEDICS公司宣布了其细胞疗法TED-A9在治疗帕金森病的1/2期临床试验中的首批3名受试者的1年随访数据。TED-A9是一款通过对人类胚胎干细胞（hESC）进行小分子化合物处理而生成的高度纯化中脑多巴胺能祖细胞。此次公布的3名接受低剂量TED-A9治疗的患者的数据表明了TED-A9的安全性和有效性。患者在细胞植入一年后进行的核磁共振成像（MRI）和CT扫描显示，细胞移植或手术均未出现相关的不良反应；多巴胺转运蛋白（DAT）脑成像（FP-CIT-PET）显示多巴胺转运蛋白水平增加，意味着多巴胺神经元可能已定植并与患者的帕金森病症状改善相关；客观测量运动功能的MDS-帕金森病统一评定量表（MDS-UPDRS）第III部分评估显示，平均得分从基线的61.7分下降到一年后治疗后的49.0分，改善了12.7分，显示患者的运动能力得到了显著的改善。 INT2104：获得澳大利亚人类研究伦理委员会批准启动1期临床试验 Interius BioTherapeutics公司宣布，已获得澳大利亚治疗用品管理局（TGA）的人类研究伦理委员会（HREC）批准和临床试验通知（CTN）许可，以进行其在研体内CAR-T疗法INT2104的临床1期试验，用以治疗B细胞恶性肿瘤。INT2104是一种在研慢病毒载体基因疗法，设计靶向CD7阳性的T细胞和NK细胞，并传递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。该疗法在临床前实验中展现出积极的抗肿瘤作用。在系统性淋巴瘤小鼠模型中，单次静脉输注广泛剂量范围的INT2104可实现肿瘤完全消除。在未进行化疗预处理的非人灵长类动物中，单次载体输注后观察到显著的B细胞耗竭且没有观察到药物毒性，其中一只动物的B细胞耗竭效果已持续超过6个月。Interius计划在2024年第四季度开始试验，并有望在2025年第一季度实现关键里程碑。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。 Rebonuputemcel：公布1/2期临床试验数据 DiscGenics公司宣布在International Journal of Spine Surgery杂志上发表了同种异体椎间盘祖细胞疗法（IDCT）rebonuputemcel治疗疼痛性腰椎退行性椎间盘疾病（DDD）的1/2期联合临床研究的结果。IDCT是一种独立的单次注射生物疗法，旨在阻止有症状的腰椎间盘退行性病变的进展，并使椎间盘由内而外再生。IDCT中的活性成分是从捐赠的成人椎间盘组织中提取的活的祖细胞群。这些细胞经过多步骤的富集和扩增，导致细胞显著增殖和表型变化。随后，这些椎间盘源细胞会与粘性透明质酸钠溶液和辅料混合，成为最终的现货型细胞疗法IDCT。IDCT需要冷冻保存，可在门诊环境下经皮注射到椎间盘中使用。IDCT已获得美国FDA的再生医学先进疗法（RMAT）认定和快速通道资格。此次公布的结果显示，该研究达到了主要的安全性和有效性终点，单次椎间盘内注射高剂量IDCT可安全地增加椎间盘体积，并在腰椎间盘退行性病变患者注射后的2年内对患者的背痛、残疾和生活质量产生具有统计学意义和临床意义的改善。安全性方面，少数患者（18.3%）报告了严重不良事件，其中最高比例的报告来自安慰剂组。 AMT-130：公布1/2期临床试验的新数据 uniQure公司宣布其通过大脑直接注射的在研基因疗法AMT-130在治疗亨廷顿病（HD）的1/2期临床试验中获得积极中期结果。uniQure同时宣布AMT-130获得针对HD的首个RMAT认定。AMT-130是uniQure首个聚焦中枢神经系统的基因疗法，由AAV5载体携带专门沉默亨廷顿（HTT）基因表达的微RNA（microRNA），利用该公司专有的miQURE沉默技术，抑制突变亨廷顿蛋白的产生。在这项试验中，研究人员利用MRI成像引导，将基因疗法直接注射到大脑的壳核和尾状核中。此次公布的结果显示，在24个月时，接受高剂量AMT-130治疗的HD患者的疾病进展减缓达80%，且其脑脊液（CSF）中的神经丝蛋白轻链（NfL）水平显著低于基线水平。此外，与基线相比，在24个月的随访中，接受高剂量AMT-130治疗患者的运动和认知功能测量结果几乎保持稳定。根据迄今为止的数据，AMT-130在两种剂量下均显示出良好的耐受性和安全性。没有报告新的与AMT-130相关的严重不良事件。 SKY-0515：公布1期临床试验数据 Skyhawk Therapeutics公司公布了SKY-0515在1期临床试验A部分和B部分中的积极结果。SKY-0515正被开发为亨廷顿氏病的潜在治疗药物。SKY-0515是Skyhawk公司通过其新型RNA剪接平台开发的在研小分子RNA剪接修饰剂，旨在减少HTT蛋白和PMS1蛋白。PMS1蛋白是体细胞CAG重复扩增和HD病理学的一个关键驱动因素。 ▲多剂量递增研究的结果（图片来源：参考资料[9]）此次公布的结果显示，SKY-0515在健康受试者中显示出剂量依赖性的HTT mRNA降低，在多剂量递增研究中，最高剂量组的降低幅度为72%。SKY-0515在所有测试剂量下的耐受性均良好，鉴于这些积极的初步结果，该公司计划在2024年第三季度在患者组中进行剂量测试，并计划在明年年初启动2期研究。 STP122G：公布1期临床试验的中期数据圣诺制药（Sirnaomics）宣布在研RNAi疗法STP122G用于抗凝治疗的1期临床试验的第二患者队列圆满完成，并公布了中期数据。STP122G为第三代靶向凝血因子XI的抗凝血药物，适用于先前治疗不能完全防止出血情况的凝血障碍患者。因子XI是一种主要由肝脏内的肝细胞所产生的酶，其在人体凝血过程中发挥着重要作用。作为一种基于圣诺制药的GalAhead mxRNA递送平台的候选RNAi疗法，STP122G以肝细胞为靶点，抑制因子XI的产生，具有长期疗效及较小的出血风险。该临床试验的第二患者队列组由8名健康受试者组成。受试者通过皮下注射完成了50毫克剂量的注射，并接受了140天的随访。安全数据显示，没有发现剂量限制性毒性或严重不良事件，同时观察到了与剂量相关的靶点沉默活性。故此本次临床研究将推进至下一队列剂量组。 Danuglipron：公布1期临床试验数据辉瑞（Pfizer）宣布，基于进行中1期试验的药代动力学研究结果，公司已选择推进每日一次改良释放剂型danuglipron的临床开发用于治疗肥胖患者。Danuglipron（PF-06882961）是一款小分子口服胰高血糖素样肽-1（GLP-1）受体激动剂，与大分子GLP-1类似物不同的是，它们可通过更为简便的口服方式使用，并且不受食物或者服用时间的限制。此次公布的研究结果显示支持每日一次给药的药代动力学特征，其安全性与之前的danuglipron研究一致，在超过1400名研究受试者中未观察到肝酶升高。辉瑞计划在2024年下半年进行剂量优化研究，评估多种改良释放剂型的剂量，以为注册性试验提供信息。 RGT-61159：IND申请获得FDA许可 Rgenta Therapeutics公司宣布，其口服小分子RNA调节剂RGT-61159的IND申请获得FDA批准，可开展1a/1b期临床试验。RGT-61159旨在特异性调节转录因子MYB的RNA剪接，从而抑制致癌MYB蛋白的产生。RGT-61159有潜力抑制MYB蛋白过度表达的癌细胞的增殖或诱导细胞死亡。MYB是细胞增殖分化过程的主调节因子，它的异常表达已在多种人类癌症中得到证实，包括腺样囊性癌（ACC）、急性髓性白血病（AML）、T细胞急性淋巴细胞白血病（T-ALL）、结直肠癌（CRC）、小细胞肺癌（SCLC）和乳腺癌。RGT-61159正在开发用于治疗ACC、CRC和其他实体瘤，以及AML。 ▲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] uniQure Announces Positive Interim Data Update Demonstrating Slowing of Disease Progression in Phase I/II Trials of AMT-130 for Huntington’s Disease. Retrieved July 9, 2024, from https://www.globenewswire.com/news-release/2024/07/09/2910220/0/en/uniQure-Announces-Positive-Interim-Data-Update-Demonstrating-Slowing-of-Disease-Progression-in-Phase-I-II-Trials-of-AMT-130-for-Huntington-s-Disease.html [2] Interius BioTherapeutics Receives HREC Approval and CTN Clearance from the TGA to Commence a Phase 1 Clinical Trial for Its First-in-Class In Vivo CAR Therapeutic for B Cell Malignancies. Retrieved July 9, 2024, from https://interiusbio.com/2024/07/interius-biotherapeutics-receives-hrec-approval-and-ctn-clearance-from-the-tga-to-commence-a-phase-1-clinical-trial-for-its-first-in-class-in-vivo-car-therapeutic-for-b-cell-malignancies-will-initiate/ [3] Sirnaomics宣布基于GalNAc RNAi疗法药物STP122G用于抗凝治疗的I期临床试验第二序列圆满完成并公布了中期数据. Retrieved July 8, 2024, from https://www.prnasia.com/story/453316-1.shtml [4] S.BIOMEDICS Dopamine Cell Therapy for Parkinson’s Disease with TED-A9 Shows Promising Results at 12 months in Phase I/IIa Clinical Trial. Retrieved July 9, 2024, from https://www.businesswire.com/news/home/20240709317387/en [5] CARGO Therapeutics Announces Phase 1 Clinical Study of Firi-cel CAR T-Cell Therapy Published in The Lancet. Retrieved July 11, 2024, from https://investors.cargo-tx.com/news-releases/news-release-details/cargo-therapeutics-announces-phase-1-clinical-study-firi-cel-car [6] Safety, tolerability and weight reduction findings of oral amycretin: a novel amylin and glucagon-like peptide-1 receptor co-agonist, in a first-in-human study. Retrieved July 8, 2024 from https://cattendee.abstractsonline.com/meeting/20620/presentation/846 [7] Pfizer Advances Development of Once-Daily Formulation of Oral GLP-1 Receptor Agonist Danuglipron. Retrieved July 11, 2024, from https://www.businesswire.com/news/home/20240710971928/en/Pfizer-Advances-Development-of-Once-Daily-Formulation-of-Oral-GLP-1-Receptor-Agonist-Danuglipron [8] DiscGenics Announces the International Journal of Spine Surgery Has Published Results from an FDA-Approved Study of an Allogeneic Disc Progenitor Cell Therapy for the Treatment of Adults with Lumbar Disc Degeneration. Retrieved July 11, 2024, from https://www.prnewswire.com/news-releases/discgenics-announces-the-international-journal-of-spine-surgery-has-published-results-from-an-fda-approved-study-of-an-allogeneic-disc-progenitor-cell-therapy-for-the-treatment-of-adults-with-lumbar-disc-degeneration-302192071.html [9] Skyhawk Therapeutics Announces Positive Topline Results from Parts A and B of its Phase 1 Clinical Trial of SKY-0515 as a Treatment for Huntington’s Disease, Reaching 72% Huntingtin mRNA Reduction. Retrieved July 12, 2024, from https://www.globenewswire.com/news-release/2024/07/10/2911098/0/en/Skyhawk-Therapeutics-Announces-Positive-Topline-Results-from-Parts-A-and-B-of-its-Phase-1-Clinical-Trial-of-SKY-0515-as-a-Treatment-for-Huntington-s-Disease-Reaching-72-Huntingtin-.html# [10] Spur Therapeutics Completes Enrollment in Phase 1/2 GALILEO-1 Trial of FLT201 in Gaucher Disease and Selects Dose for Planned Phase 3 Trial. Retrieved July 12, 2024, from https://www.globenewswire.com/news-release/2024/07/08/2909533/0/en/Spur-Therapeutics-Completes-Enrollment-in-Phase-1-2-GALILEO-1-Trial-of-FLT201-in-Gaucher-Disease-and-Selects-Dose-for-Planned-Phase-3-Trial.html [11] MedPacto's vactosertib shows positive results in US osteosarcoma pre-clinical trial. Retrieved July 12, 2024, from https://www.koreabiomed.com/news/articleView.html?idxno=24495 [12] Immorna Biotherapeutics Receives U.S. FDA IND Clearance to Conduct Phase 1/2 Study of JCXH-211 IV as Monotherapy and in Combination with Checkpoint Inhibitor in Patients with Advanced Solid Tumors. Retrieved July 12, 2024, from https://www.prnewswire.com/news-releases/immorna-biotherapeutics-receives-us-fda-ind-clearance-to-conduct-phase-12-study-of-jcxh-211-iv-as-monotherapy-and-in-combination-with-checkpoint-inhibitor-in-patients-with-advanced-solid-tumors-302190627.html [13] Immix Biopharma Doses 1st Patient in U.S. AL Amyloidosis Trial with CAR-T NXC-201. Retrieved July 12, 2024, from https://www.globenewswire.com/news-release/2024/07/08/2909719/0/en/Immix-Biopharma-Doses-1st-Patient-in-U-S-AL-Amyloidosis-Trial-with-CAR-T-NXC-201.html [14] Epsilogen announces CTA approval for Phase Ib trial of MOv18 IgE in platinum-resistant ovarian cancer. Retrieved July 12, 2024, from https://www.businesswire.com/news/home/20240707808760/en/ [15] Abata Therapeutics Announces FDA Clearance of Investigational New Drug Application for Clinical Evaluation of ABA-101 in Progressive Multiple Sclerosis. Retrieved July 12, 2024, from https://www.globenewswire.com/news-release/2024/07/09/2910147/0/en/Abata-Therapeutics-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-Clinical-Evaluation-of-ABA-101-in-Progressive-Multiple-Sclerosis.html [16] Gain Therapeutics Announces the Completion of Dosing in the Multiple Ascending Dose (MAD) of the Phase 1 Study of GT-02287, a Novel Small Molecule Therapy for Parkinson’s Disease. Retrieved July 12, 2024, from https://www.globenewswire.com/news-release/2024/07/09/2910198/0/en/Gain-Therapeutics-Announces-the-Completion-of-Dosing-in-the-Multiple-Ascending-Dose-MAD-of-the-Phase-1-Study-of-GT-02287-a-Novel-Small-Molecule-Therapy-for-Parkinson-s-Disease.html [17] Monopar Announces First Patient Enrolled in First-in-Human Phase 1 Trial for Its Novel Radiopharmaceutical MNPR-101-Zr. Retrieved July 12, 2024, from https://www.globenewswire.com/news-release/2024/07/09/2910208/0/en/Monopar-Announces-First-Patient-Enrolled-in-First-in-Human-Phase-1-Trial-for-Its-Novel-Radiopharmaceutical-MNPR-101-Zr.html [18] Rgenta Therapeutics Announces FDA Clearance of IND Application for RGT-61159, an Oral Small Molecule RNA Modulator Designed to Halt Disease-Driver MYB Production in Adenoid Cystic Carcinoma (ACC) and Colorectal Cancer (CRC). Retrieved July 12, 2024, from https://www.prnewswire.com/news-releases/rgenta-therapeutics-announces-fda-clearance-of-ind-application-for-rgt-61159-an-oral-small-molecule-rna-modulator-designed-to-halt-disease-driver-myb-production-in-adenoid-cystic-carcinoma-acc-and-colorectal-cancer-crc-302192676.html [19] Tr1X Announces First Patient Dosed in Proof of Concept GvHD Trial Evaluating TRX103, a First-in-Class Type 1 Treg (Tr1) Cell Therapy. Retrieved July 12, 2024, from https://pipelinereview.com/tr1x-announces-first-patient-dosed-in-proof-of-concept-gvhd-trial-evaluating-trx103-a-first-in-class-type-1-treg-tr1-cell-therapy/ 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1期细胞疗法免疫疗法突破性疗法临床结果

2024-07-13

·药明康德

体内制造CAR-T疗法首次进入人体试验；现货型细胞疗法显著改善腰椎间盘疾病症状…… | 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。治疗对CD19靶向CAR-T细胞疗法耐药的大B细胞淋巴瘤（LBCL）患者的CD22靶向CAR-T细胞疗法firi-cel公布积极1期临床试验数据，过半患者肿瘤完全消失。治疗疼痛性腰椎退行性椎间盘疾病（DDD）的现货型细胞疗法rebonuputemcel达1/2期临床试验主要终点，高剂量组患者在治疗后的两年内背痛、残疾和生活质量有显著改善。INT2104获得澳大利亚人类研究伦理委员会批准启动1期临床试验，据行业媒体STAT报道是首个进入人体临床试验的体内CAR-T疗法。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✦——— ◇ CARGO Therapeutics公司宣布，《柳叶刀》杂志发表了斯坦福大学医学院进行的一项单中心1期临床研究的积极数据，该研究评估了CARGO公司的CD22靶向CAR-T细胞疗法firicabtagene autoleucel（firi-cel）治疗对CD19靶向CAR-T细胞疗法耐药的大B细胞淋巴瘤患者。这款CAR-T疗法是由患者自体T细胞经慢病毒载体（m971-BBZ）转导而制造出来的，目前CARGO Therapeutics拥有它的权利。发布于《柳叶刀》的临床数据截至2023年5月22日，在中位随访时间23.3个月期间，所有接受治疗患者的总缓解率（ORR）和完全缓解（CR）率分别为68%和53%。CARGO在今年5月的欧洲血液学协会（EHA）大会上公布了该试验的更新数据。截至2024年2月1日，在中位随访31.4个月期间，所有接受治疗患者的ORR和CR率仍分别为68%和53%。其中，29例接受剂量水平1（DL1）治疗的患者在中位随访29.8个月时的中位总生存期（mOS）为25.7个月（95% CI：9.2-NE），预估的2年生存率为52%。对于达到CR的患者，其中位无进展生存期（PFS）、缓解持续时间和总生存期尚未达到。自2023年11月的最后一次数据截止以来，20名达到CR的患者中没有观察到新的复发。此外，在DL1中持续没有观察到3级或更高级别的细胞因子释放综合征（CRS）或免疫效应细胞相关神经毒性综合征（ICANS）的发生。新闻稿指出，美国FDA在检视试验初步数据后罕见地主动联系斯坦福医学中心，敦促其为该疗法申请突破性疗法认定（BTD）。 ◇ DiscGenics公司宣布在International Journal of Spine Surgery杂志上发表了同种异体椎间盘祖细胞疗法（IDCT）rebonuputemcel治疗疼痛性腰椎退行性椎间盘疾病的1/2期联合临床研究的结果。此次公布的结果显示，该研究达到了主要的安全性和有效性终点，单次椎间盘内注射高剂量IDCT可安全地增加椎间盘体积，并在腰椎间盘退行性病变患者注射后的2年内对患者的背痛、残疾和生活质量产生具有统计学和临床意义的改善。安全性方面，少数患者（18.3%）报告了严重不良事件，其中最高比例的报告来自安慰剂组。 IDCT是一种独立的单次注射生物疗法，旨在阻止有症状的腰椎间盘退行性病变的进展，并使椎间盘由内而外再生。IDCT中的活性成分是从捐赠的成人椎间盘组织中提取的活祖细胞群。这些细胞经过多步骤的富集和扩增，导致细胞显著增殖和表型变化。随后，这些椎间盘源细胞会与粘性透明质酸钠溶液和辅料混合，成为最终的现货型细胞疗法IDCT。IDCT需要冷冻保存，可在门诊环境下经皮注射到椎间盘中使用。IDCT已获得美国FDA的再生医学先进疗法（RMAT）认定和快速通道资格。 ◇ S.BIOMEDICS公司宣布了其细胞疗法TED-A9在治疗帕金森病的1/2期临床试验中的首批3名受试者的1年随访数据。患者在细胞植入一年后进行的核磁共振成像（MRI）和CT扫描显示，细胞移植或手术均未出现相关的不良反应；多巴胺转运蛋白（DAT）脑成像（FP-CIT-PET）显示多巴胺转运蛋白水平增加，意味着多巴胺神经元可能已定植并与患者的帕金森病症状改善相关；客观测量运动功能的MDS-帕金森病统一评定量表（MDS-UPDRS）第III部分评估显示，平均得分从基线的61.7分下降到一年后治疗后的49.0分，改善了12.7分，显示患者的运动能力得到了显著的改善。 TED-A9是一款通过对人类胚胎干细胞（hESC）进行小分子化合物处理而生成的高度纯化中脑多巴胺能祖细胞。 ◇ Interius BioTherapeutics公司宣布，已获得澳大利亚治疗用品管理局（TGA）的人类研究伦理委员会（HREC）批准和临床试验通知（CTN）许可，以进行其在研体内CAR-T疗法INT2104的临床1期试验，用以治疗B细胞恶性肿瘤。INT2104是一种在研慢病毒载体基因疗法，设计靶向CD7阳性的T细胞和NK细胞，并传递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。该疗法在临床前实验中展现出积极的抗肿瘤作用。在系统性淋巴瘤小鼠模型中，单次静脉输注广泛剂量范围的INT2104可实现肿瘤完全消除。在未进行化疗预处理的非人灵长类动物中，单次载体输注后观察到显著的B细胞耗竭且没有观察到药物毒性，其中一只动物的B细胞耗竭效果已持续超过6个月。Interius计划在2024年第四季度开始试验，并有望在2025年第一季度实现关键里程碑。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。 ◇ uniQure公司宣布其通过大脑直接注射的在研基因疗法AMT-130在治疗亨廷顿病（HD）的1/2期临床试验中获得积极中期结果。在24个月时，接受高剂量AMT-130治疗的HD患者的疾病进展减缓达80%，且其脑脊液（CSF）中的神经丝蛋白轻链（NfL）水平显著低于基线水平。此外，与基线相比，在24个月的随访中，接受高剂量AMT-130治疗患者的运动和认知功能测量结果几乎保持稳定。根据迄今为止的数据，AMT-130在两种剂量下均显示出良好的耐受性和安全性。没有报告新的与AMT-130相关的严重不良事件。 AMT-130是uniQure首个聚焦中枢神经系统的基因疗法，由AAV5载体携带专门沉默亨廷顿蛋白（HTT）基因表达的微RNA（microRNA），利用该公司专有的miQURE沉默技术，抑制突变亨廷顿蛋白的产生。在这项试验中，研究人员利用MRI成像引导，将基因疗法直接注射到大脑的壳核和尾状核中。uniQure此次还同时宣布，AMT-130获得了针对HD的首个RMAT认定。 ◇ Abata Therapeutics公司宣布，美国FDA已经批准了该公司的IND申请，将在进展性多发性硬化患者中启动ABA-101的1期临床试验。通过对患者自身的Tregs细胞进行工程改造，ABA-101表达一种能特异性识别中枢神经系统中免疫原性髓鞘片段的T细胞受体（TCR）。这种方法具有很高的安全性，并能在发病部位产生高度局部抗炎作用。在体内临床前研究中，ABA-101的耐受性良好，并表现出抗原依赖性Treg功能、抗炎细胞因子生成、炎症细胞因子生成的抑制和治疗效果。 ◇ 尧唐生物宣布，其自主研发的体内基因编辑药物YOLT-201的1期临床试验成功招募了首例患者。YOLT-201采用体内基因编辑技术及脂质纳米颗粒（LNP）递送技术，可以在人肝脏中实现高效特异的转甲状腺素蛋白（TTR）靶基因敲除。该疗法旨在通过一次给药终身降低患者血液中的TTR蛋白水平，以实现终身治愈。该疗法拟定的适应症为转甲状腺素蛋白淀粉样变（ATTR），包括治疗转甲状腺素蛋白淀粉样变性多发性神经病（ATTR-PN）和转甲状腺素蛋白心脏淀粉样变（ATTR-CM）。 ◇ 明慧基因生物技术有限公司申报的1类创新药抗CD30CAR-T细胞注射液获中国国家药监局药品审评中心（CDE）批准可开展临床试验，拟开发用于霍奇金淋巴瘤和间变性大细胞淋巴瘤等CD30阳性肿瘤。 ———✦融资、合作、M&A✦——— 图片来源：123RF ◇ Pan Cancer T公司宣布获得了425万欧元的种子扩展轮融资，使其融资总额达到约1100万欧元。此轮融资获得的资金将用于完成该公司的TCR-T细胞产品PCT1：CO-STIM的临床前研究，并推进化学、生产和控制（CMC）活动。这笔资金还将支持其针对结直肠癌和卵巢癌的早期管线项目的推进，以及第二代工程化方法的开发。 PCT1：CO-STIM的TCR由该公司经过验证的TCR发现平台生成，对ROPN1具有高特异性。ROPN1是一种新型肿瘤限制性靶点，在90%以上的三阴性乳腺癌和黑色素瘤患者中都有强表达。此外，该候选疗法还整合了专有的肿瘤微环境（TME）解决方案，即使在恶劣的TME条件下也能为T细胞提供共刺激作用，在临床前模型中显著改善了治疗的缓解持续时间。 ◇ 跃赛生物宣布，自今年4月获得A轮超亿元融资后，公司再获数千万A+轮融资。本轮融资由知名投资机构国科创投参与，资金将主要用于推进公司在干细胞治疗领域的创新管线以及加速临床转化。自创立以来，跃赛生物一直致力于开发新一代基于人多能干细胞技术的细胞治疗药物，在研管线覆盖帕金森病和其他神经退行性疾病。公司拥有自主研发的人多能干细胞创新技术平台，包括神经分化技术，SISBAR谱系示踪技术，干细胞基因编辑技术、GMP级别的人诱导多能干细胞（iPSCs）构建。该公司的IND临床试验申请于2024年完成，计划于2025年年初入组。 ▲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] uniQure Announces Positive Interim Data Update Demonstrating Slowing of Disease Progression in Phase I/II Trials of AMT-130 for Huntington’s Disease. Retrieved July 9, 2024, from https://www.globenewswire.com/news-release/2024/07/09/2910220/0/en/uniQure-Announces-Positive-Interim-Data-Update-Demonstrating-Slowing-of-Disease-Progression-in-Phase-I-II-Trials-of-AMT-130-for-Huntington-s-Disease.html [2] Interius BioTherapeutics Receives HREC Approval and CTN Clearance from the TGA to Commence a Phase 1 Clinical Trial for Its First-in-Class In Vivo CAR Therapeutic for B Cell Malignancies. Retrieved July 9, 2024, from https://interiusbio.com/2024/07/interius-biotherapeutics-receives-hrec-approval-and-ctn-clearance-from-the-tga-to-commence-a-phase-1-clinical-trial-for-its-first-in-class-in-vivo-car-therapeutic-for-b-cell-malignancies-will-initiate/ [3] DiscGenics Announces the International Journal of Spine Surgery Has Published Results from an FDA-Approved Study of an Allogeneic Disc Progenitor Cell Therapy for the Treatment of Adults with Lumbar Disc Degeneration. Retrieved July 11, 2024, from https://www.prnewswire.com/news-releases/discgenics-announces-the-international-journal-of-spine-surgery-has-published-results-from-an-fda-approved-study-of-an-allogeneic-disc-progenitor-cell-therapy-for-the-treatment-of-adults-with-lumbar-disc-degeneration-302192071.html [4] S.BIOMEDICS Dopamine Cell Therapy for Parkinson’s Disease with TED-A9 Shows Promising Results at 12 months in Phase I/IIa Clinical Trial. Retrieved July 9, 2024, from https://www.businesswire.com/news/home/20240709317387/en [5] CARGO Therapeutics Announces Phase 1 Clinical Study of Firi-cel CAR T-Cell Therapy Published in The Lancet. Retrieved July 11, 2024, from https://investors.cargo-tx.com/news-releases/news-release-details/cargo-therapeutics-announces-phase-1-clinical-study-firi-cel-car [6] Abata Therapeutics Announces FDA Clearance of Investigational New Drug Application for Clinical Evaluation of ABA-101 in Progressive Multiple Sclerosis. Retrieved July 11, 2024, from https://www.globenewswire.com/news-release/2024/07/09/2910147/0/en/Abata-Therapeutics-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-Clinical-Evaluation-of-ABA-101-in-Progressive-Multiple-Sclerosis.html [7] First Patient Dosed in Phase I Clinical Trial of YOLT-201. Retrieved July 11, 2024, from https://www.prnewswire.com/news-releases/first-patient-dosed-in-phase-i-clinical-trial-of-yolt-201-302194779.html [8]中国国家药监局药品审评中心（CDE）官网.Retrieved July 10，2024, From https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [9] Pan Cancer T secures €4.25 Million in Seed Extension Round to advance next-generation T cell therapies. Retrieved July 11, 2024, from https://www.globenewswire.com/news-release/2024/07/11/2911561/0/en/Pan-Cancer-T-secures-4-25-Million-in-Seed-Extension-Round-to-advance-next-generation-T-cell-therapies.html [10] 跃赛生物再获数千万A+轮融资，干细胞治疗技术持续获得资本认可. Retrieved July 11，2024, from https://mp.weixin.qq.com/s/Tt1BpB3DZ87K3tANNmVayg 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

细胞疗法临床1期临床结果免疫疗法基因疗法

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药物(靶点)	适应症	全球最高研发状态

Rebonuputemcel	椎间盘疾病更多	临床1/2期
d-IDCT	椎间盘疾病更多	临床前
a-IDCT	脊柱融合更多	临床前
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