Rocket Pharmaceuticals Announces Publication of Data from Phase 1/2 Trial of First-Generation RP-L102 for Fanconi Anemia in Nature Medicine

Rocket Pharma公布治疗范科尼贫血第一代RP-L102基因疗法试验数据

2019-09-11 16:30:30 BioSpace

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First Demonstration of Successful Engraftment of Gene Corrected Hematopoietic Stem Cells Without the Use of Conditioning Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT) (“Rocket”), a leading U.S.-based multi-platform clinical-stage gene therapy company, today announces the publication of long-term data from the ongoing Phase 1/2 trial of RP-L102, the Company’s lentiviral vector (LVV)-based gene therapy for Fanconi Anemia (FA) in the journal Nature Medicine. The data included in the manuscript are from the first four patients treated with RP-L102 in the Phase 1/2 FANCOLEN-I trial that utilized first-generation “Process A” without the use of any conditioning regimen. Follow-up for each of the initial four patients was 18-30 months from administration of RP-L102. “Data from our first trial of RP-L102 demonstrate increasing levels of bone marrow engraftment, leading to stabilization and restored bone marrow function. These data highlight the natural selective advantage that uniquely exists in FA for gene corrected stem cells over diseased stem cells, which potentially obviates the need for conditioning,” said Jonathan Schwartz, M.D., Chief Medical Officer and Senior Vice President of Rocket. “At the end of the year, we will have a first look at initial data from our Phase 1 trial of ‘Process B’ RP-L102, which utilizes fresh cells and incorporates a modified stem cell enrichment process, transduction enhancers, and commercial-grade vector and final drug product. We are also excited by the prospect of starting our global registrational trial incorporating recent alignment on endpoints from both the U.S. Food and Drug Administration and European Medicines Agency.” “There is an increased and urgent need for new therapies for patients and families suffering from FA as current treatments are limited to toxic and burdensome bone marrow transplant,” said Paula Río, Ph.D., Senior Scientist, División de Terapias Innovadoras en el Sistema Hematopoyético, CIEMAT/CIBERER Unidad Mixta de Terapias Avanzadas CIEMAT/IIS Fundación Jiménez Díaz, and co-first author of the manuscript. “We are very pleased to see long-term follow-up data that further support our thesis for RP-L102 gene therapy without any conditioning to serve as an innovative, low-toxicity treatment for the hematologic component of this devastating disease.” The data included in the manuscript are from four pediatric patients (ages 3-6 years) who received RP-L102 utilizing fresh or cryopreserved CD34+ cells that were collected and transduced. Patients 02002 and 02006 were treated with higher dose levels of RP-L102. Patients 02004 and 02005 received non-optimized and lower doses of RP-L102. Key highlights of the manuscript include: Follow-up data for the initial four patients 18-30 months post-infusion demonstrate progressively increased engraftment in peripheral blood leukocytes and in the bone marrow following administration of RP-L102 without the use of conditioning. In Patient 02002 at 30 months follow-up, approximately 44% of bone marrow CD34+ cells displayed gene marking, suggesting the engraftment of very primitive corrected hematopoietic stem cells (HSCs). Sequential increases in gene marking in peripheral blood and in the bone marrow for Patients 02004 and 02005 were also seen, but at more modest levels and after longer durations. Phenotypic correction of bone marrow cells was measured by resistance to mitomycin-C (MMC) in colony forming cells. The bone marrow resistance to MMC in Patient 02002 increased to 70% at 24 months, approaching the phenotype of a healthy donor. Patients 02004, 02005 and 02006 also displayed progressive increases in MMC resistance. Phenotypic correction of blood cells was measured by chromosomal stability of T-lymphocytes in the presence of diepoxybutane (DEB). DEB exposure resulted in a lower proportion of cells with aberrant chromosomes in Patients 02002, 02004 and 02006. Hematologic correction was measured by changes in previously declining pre-treatment blood count trajectories, which were evident in at least two peripheral blood lineages for each of the four patients. Patient 02002 demonstrated stabilized neutrophil counts and hemoglobin levels as early as six months post-administration of RP-L102. Similar trends were also seen in Patient 02006. Progressive increases in the total number of corrected leukocytes were observed shortly after the initial administration of RP-L102 in all treated patients. Favorable safety profile with no serious adverse events associated with infusion of the investigational product in these initial four patients. About Fanconi Anemia Fanconi Anemia (FA) is a rare pediatric disease characterized by bone marrow failure, malformations and cancer predisposition. The primary cause of death among patients with FA is bone marrow failure, which typically occurs during the first decade of life. Allogeneic hematopoietic stem cell transplantation (HSCT), when available, corrects the hematologic component of FA, but requires myeloablative conditioning. Graft-versus-host disease, a known complication of allogeneic HSCT, is associated with an increased risk of solid tumors, mainly squamous cell carcinomas of the head and neck region. Approximately 60-70% of patients with FA have a FANC-A gene mutation, which encodes for a protein essential for DNA repair. Mutation in the FANC-A gene leads to chromosomal breakage and increased sensitivity to oxidative and environmental stress. Chromosome fragility induced by DNA-alkylating agents such as mitomycin-C (MMC) or diepoxybutane (DEB) is the ‘gold standard’ test for FA diagnosis. Somatic mosaicism occurs when there is a spontaneous correction of the mutated gene that can lead to stabilization or correction of a FA patient’s blood counts in the absence of any administered therapy. Somatic mosaicism, often referred to as ‘nature’s gene therapy’ provides a strong rationale for the development of FA gene therapy because of the selective growth advantage of gene-corrected hematopoietic stem cells over FA cells1. 1Soulier, J.,et al. (2005) Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway. Blood 105: 1329-1336 About Rocket Pharmaceuticals, Inc. Rocket Pharmaceuticals, Inc. (NASDAQ: RCKT) (“Rocket”) is an emerging, clinical-stage biotechnology company focused on developing first-in-class gene therapy treatment options for rare, devastating diseases. Rocket’s multi-platform development approach applies the well-established lentiviral vector (LVV) and adeno-associated viral vector (AAV) gene therapy platforms. Rocket's first two clinical programs using LVV-based gene therapy are for the treatment of Fanconi Anemia (FA), a difficult to treat genetic disease that leads to bone marrow failure and potentially cancer, and Leukocyte Adhesion Deficiency-I (LAD-I), a severe pediatric genetic disorder that causes recurrent and life-threatening infections which are frequently fatal. Rocket’s first clinical program using AAV-based gene therapy is for Danon disease, a devastating, pediatric heart failure condition. Rocket’s pre-clinical pipeline programs for bone marrow-derived disorders are for Pyruvate Kinase Deficiency (PKD) and Infantile Malignant Osteopetrosis (IMO).
未经预处理的基因修饰造血干细胞成功植入的首次证明 美国领先的多平台临床阶段基因治疗公司Rocket Pharmaceuticals(纳斯达克:RCKT)(以下简称“Rocket”)今天宣布,该公司慢病毒载体基因疗法RP-L102的I/II期试验的长期数据已经公布。范科尼贫血(fa)的ed基因治疗发表在《自然医学》杂志上。手稿中包含的数据来自在1/2期fancolen-i试验中使用RP-L102治疗的前四名患者,该试验使用第一代“过程a”,而不使用任何条件治疗方案。最初4例患者的随访时间均为服用RP-L102后18-30个月。 “我们第一次RP-L102试验的数据显示,骨髓移植水平不断提高,导致骨髓功能的稳定和恢复。这些数据突出了fa对基因矫正干细胞的天然选择优势,这可能避免了对条件反射的需求,”rocket首席医疗官兼高级副总裁jonathan schwartz医学博士说。“在今年年底,我们将首先研究‘工艺B’RP-L102的第一阶段试验的初始数据,该试验利用新鲜细胞,并结合改良的干细胞富集工艺、转导促进剂、商业级载体和最终药物产品。我们还对开始我们的全球注册试验的前景感到兴奋,该试验纳入了美国食品和药物管理局(FDA)和欧洲药品管理局(European Medicines Agency)最近对终点的调整。” “由于目前的治疗仅限于毒性和繁重的骨髓移植,对患有fa的患者和家庭来说,对新的治疗方法的需求越来越迫切,”ciem的资深科学家paula río博士说。at/ciberer unidad mixta de terapias avanzadas ciemat/iis fundación jiménez díaz,手稿的共同第一作者。“我们很高兴看到长期的随访数据,这些数据进一步支持了我们关于RP-L102基因治疗的论文,而不需要任何条件,就可以作为这种毁灭性疾病血液学组成部分的创新性低毒治疗。” 手稿中包含的数据来自4名儿童患者(年龄3-6岁),他们使用新鲜或冷冻保存的cd34+细胞接受rp-l102,这些细胞被收集并导入。02002和02006患者接受了较高剂量的RP-L102治疗。02004和02005患者接受非优化和低剂量的RP-L102。手稿的要点包括: 最初4例患者在输注后18-30个月的随访数据显示,在不使用预处理的情况下给予RP-L102后,外周血白细胞和骨髓中的移植物逐渐增加。 在随访30个月的02002患者中,约44%的骨髓cd34+细胞显示出基因标记,表明移植了非常原始的校正造血干细胞(hscs)。 02004和02005患者的外周血和骨髓中的基因标记也出现了连续性的增加,但在更温和的水平和更长的持续时间后。 用集落形成细胞对丝裂霉素c(mmc)的抗性测定骨髓细胞的表型纠正。患者02002的骨髓对mmc的抵抗在24个月时增加到70%,接近健康供体的表型。患者02004、02005和02006也显示出mmc抵抗的逐渐增强。 用二羟丁烷(deb)存在下t淋巴细胞染色体稳定性测定血细胞表型校正。在02002、02004和02006患者中,DEB暴露导致染色体异常的细胞比例较低。 血液学校正是通过先前下降的治疗前血细胞计数轨迹的变化来测量的,这在四个患者中的每一个患者的至少两个外周血谱系中都是明显的。患者02002在给予RP-L102六个月后,中性粒细胞计数和血红蛋白水平稳定。同样的趋势也出现在02006病人身上。 在所有接受治疗的患者中,在初次服用RP-L102后不久,观察到校正白细胞总数的逐渐增加。 在最初的4名患者中,安全性良好,没有与试验药物的输注相关的严重不良事件。 关于范科尼贫血 范科尼贫血(fanconi anemia,fa)是一种罕见的儿童疾病,其特点是骨髓衰竭、畸形和癌症易感性。fa患者的主要死亡原因是骨髓衰竭,通常发生在生命的前十年。异基因造血干细胞移植(hsct)可纠正fa的血液学成分,但需要骨髓清除治疗。移植物抗宿主病是同种异体hsct的已知并发症,与实体瘤(主要是头颈部鳞状细胞癌)的风险增加有关。大约60-70%的fa患者有fanc-a基因突变,它编码一种dna修复所必需的蛋白质。FANC-A基因突变导致染色体断裂,增加了对氧化和环境胁迫的敏感性。dna烷基化剂如丝裂霉素c(mmc)或深度氧化丁烷(deb)诱导的染色体脆性是fa诊断的金标准。体细胞嵌合体发生在突变基因的自发纠正时,在没有任何治疗的情况下,该突变基因可导致fa患者血液计数的稳定或纠正。体细胞镶嵌,通常被称为“自然的基因疗法”,由于基因纠正造血干细胞比Fa细胞1具有选择性生长优势,为Fa基因疗法的发展提供了强有力的理论基础。 1苏利尔,J.等人(2005)fa/brca途径分析法检测fanconi贫血患者的体细胞嵌合体和分类。血液105:1329-1336 关于火箭制药公司。 Rocket Pharmaceuticals,Inc.(纳斯达克:RCKT)(Rocket)是一家新兴的、临床阶段的生物技术公司,专注于为罕见、毁灭性疾病开发一流的基因治疗方案。火箭的多平台开发方法应用了成熟的慢病毒载体(LVV)和腺相关病毒载体(AAV)基因治疗平台S。Rocket的前两个临床项目是使用基于LVV的基因疗法治疗Fanconi贫血(FA),Fanconi贫血是一种难以治疗的遗传病,可导致骨髓衰竭和潜在的癌症,而白细胞粘附缺陷I(LAD-I)是一种严重的儿童遗传病,可导致经常致命的复发性和危及生命的感染。火箭的第一个临床项目使用基于AAV的基因治疗是针对达农病,一种毁灭性的小儿心力衰竭。Rocket的骨髓源性疾病的临床前管道项目是针对丙酮酸激酶缺乏症(PKD)和婴儿恶性骨岩症(IMO)。

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