LRP4

SHANGHAI, NANJING, China and SAN JOSE, Calif., April 4, 2024 /PRNewswire/ -- IASO Biotechnology ("IASO Bio"), a biopharmaceutical company dedicated to discovering, developing, manufacturing and commercialising innovative cell therapy and antibody products, is pleased to announce that the Investigational New Drug (IND) application for its BCMA CAR-T (Equecabtagene Autoleucel) has been approved by the U.S. Food and Drug Administration (FDA) for use in U.S. clinical trials for generalised myasthenia gravis (gMG). The Chinese IND for this indication of Equecabtagene Autoleucel was approved by the NMPA in January this year. Two subjects with refractory MG were enrolled in an investigator-initiated open-label study to evaluate the safety and efficacy of Eque-cel for the treatment of relapsed/refractory antibody-mediated idiopathic inflammatory disorders of the nervous system (NCT04561557 One was a 33-year-old female, AChR-IgG and Titin-IgG positive, who had been treated with thymectomy 21 months prior to enrollment and had not achieved clinical remission after treatment with cholinesterase inhibitors, glucocorticoids, immunosuppressants, and anti-CD20 monoclonal antibody. The other subject was a 60-year-old female, MuSK-IgG4 positive, with a 20-year history of the disease and failed the previous treatment with hormones, immunosuppressants, and anti-CD20 monoclonal antibody. The 2 subjects were treated with a single infusion of Eque-cel at the doses of 1.0×106 CAR-T/Kg, respectively. Safety: Of the 2 subjects, only 1 subject developed grade 1 Cytokine Release Syndrome (CRS), and no Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS). All grade ≥3 hemocytopenia recovered within 4 weeks post infusion. No new safety risk was identified, and the safety profile was superior compared to that in multiple myeloma indication. Eff icacy : Clinical symptoms continued to improve over 18 months in the 2 subjects. From 3 months after the infusion, patients showed significant improvement in limb strength and vital capacity, and sustained improvement in Myasthenia Gravis-Activities of Daily Living Score (MG-ADL), Quantitative Myasthenia Gravis Score (QMG), Myasthenia Gravis-Quality of Life Score (MG-QOL), and Modified Rankin Score (mRS). No immunomodulatory therapy other than low dose pyridostigmine (90 mg/day and 60 mg/day, respectively) was used during the follow-up period. PK/PD: Eque-cel expanded well after infusion. Anti-AChR antibodies, anti-Titin antibodies, and anti-MuSK antibodies decreased rapidly and maintained at very low levels in both subjects after infusion. B cells and plasma cells decreased to undetectable levels in both subjects within 2 months after infusion and then recovered gradually. At 18 months post-infusion, the B cells of both subjects had returned to normal levels, with approximately 80% of them being naïve B cells, while plasma cells remained at low levels. This result suggests that the long-term efficacy of CAR-T cell therapy may be related to the reconstitution of B cells with a predominantly naïve phenotype and the continued clearance of plasma cells. About MG Myasthenia gravis (MG) is an autoantibody-mediated neuromuscular junction disorder. The main clinical manifestation of MG is a decrease in muscle strength in local or systemic muscles, which can affect eye, respiratory and limb muscles and other important muscle groups, which has a huge negative impact on the patient's quality of life, and dysphagia or breathing difficulty caused by a myasthenic crisis can be life-threatening. The main pathogenic antibodies in MG include AChR, MuSK and LRP4 antibodies. A very small number of patients have no detectable antibodies in their serum1. MG can occur at any age and is slightly more common in women than in men 2. According to relevant studies, the incidence rate of MG in the United States is 3.1/100,000 people and the prevalence rate is 37.0/100,000 people3. It is estimated that the number of people with MG incidence in the United States in 2023 was more than 10,000, and the number of patients with MG was about 124,000. Ms. Jinhua Zhang, Founder, Chairman, and Chief Executive Officer of IASO Bio, stated, "We are very pleased that Equecabtagene Autoleucel has been approved for clinical trial for myasthenia gravis in the United States. This is the result of the unremitting efforts of our team and is an important milestone in our efforts to improve the quality of life of patients with autoimmune diseases around the world. We will actively obtain more data on the safety and efficacy of Equecabtagene Autoleucel in the treatment of MG patients, and better explore and define the significance of this innovative cell therapy in the treatment of immune diseases. We hope Equecabtagene Autoleucel will provide a more efficient and long-lasting therapeutic option for myasthenia gravis and potentially other autoimmune diseases." About IASO Bio IASO Bio is a biopharmaceutical company engaged in the discovery and development of novel cell therapies and biologics for oncology and autoimmune diseases. IASO Bio possesses comprehensive capabilities spanning the entire drug development process, from early discovery to clinical development, regulatory approval, and commercial production. The pipeline in the company includes a diversified portfolio of over 10 novel products, including Equecabtagene Autoleucel (a fully human BCMA CAR-T injection). Equecabtagene Autoleucel received New Drug Application (NDA) approval from China's National Medical Products Administration (NMPA) and U.S. FDA IND approval for the treatment of R/RMM. Leveraging its strong management team, innovative product pipeline, GMP production, as well as integrated manufactural and clinical capabilities, IASO aims to deliver transformative, curable, and affordable therapies that fulfil unmet medical needs to patients in China as well as around the world. For more information, please visit or . SOURCE IASO Bio

▎药明康德内容团队编辑近期，驯鹿生物宣布其开发的全人源靶向BCMA的CAR-T细胞产品伊基奥仑赛注射液（研发代号CT103A）治疗自身免疫性疾病的两项研究者发起的临床试验数据分别在国际权威学术期刊EMBO Molecular Medicine、《美国国家科学院院刊》（The Proceedings of the National Academy of Sciences，PNAS）上发表。这两项研究数据分别初步展现了伊基奥仑赛注射液治疗难治性重症肌无力、免疫介导坏死性肌病的潜力。在中国，伊基奥仑赛已于2023年6月获批治疗复发/难治多发性骨髓瘤成人患者。伊基奥仑赛治疗难治性重症肌无力的研究数据2月26日，EMBO Molecular Medicine正式发表了伊基奥仑赛注射液治疗2例难治性重症肌无力（MG）受试者的临床研究论文——B cell lineage reconstitution underlies CAR-T cell therapeutic efficacy in patients with refractory myasthenia gravis。该研究初步展现了靶向BCMA的CAR-T疗法在MG治疗中的良好耐受性和安全性以及持久的临床疗效。MG是由自身抗体介导的获得性神经-肌肉接头（NMJ）传递障碍的自身免疫性疾病。乙酰胆碱受体（AChR）抗体是最常见的致病性抗体。此外，针对突触后膜其他组分，包括肌肉特异性受体酪氨酸激酶（MuSK）、低密度脂蛋白受体相关蛋白4（LRP4）及兰尼碱受体（RyR）等抗体陆续被发现参与MG发病。目前，MG的治疗仍以胆碱酯酶抑制剂、糖皮质激素、免疫抑制剂、静脉注射免疫球蛋白、血浆置换以及胸腺切除为主。患者主要的死亡原因包括呼吸衰竭、肺部感染等。本次在EMBO Molecular Medicine上发表的是一项研究者发起的开放评价输注伊基奥仑赛注射液治疗复发/难治性抗体介导的神经系统特发性炎症性疾病的安全性和有效性的探索性临床研究，该试验的研究者为华中科技大学同济医学院附属同济医院王伟教授团队。该研究中入组了2例难治性MG受试者，其中1例受试者为33岁女性，AChR-IgG和Titin-IgG阳性，入组前21个月接受了胸腺切除术治疗，经胆碱酯酶抑制剂、糖皮质激素、免疫抑制剂及靶向CD20单抗治疗仍未达到临床缓解；另1例受试者为60岁女性，MuSK-IgG4阳性，20年病史，既往接受过激素、免疫抑制剂、靶向CD20单抗等多种治疗无效。2例受试者分别接受了1.01×106CAR-T/Kg和0.96×106CAR-T/Kg的伊基奥仑赛注射液单次回输治疗。安全性数据显示：2例受试者中，仅1例受试者发生了1级的细胞因子释放综合征（CRS），未发生免疫效应细胞相关神经毒性综合征（ICANS），≥3级的血细胞减少均在回输后4周内恢复；相较于在多发性骨髓瘤适应症研究中的安全性谱，未发现新的安全性风险，且安全性更优。有效性数据显示：2例受试者的临床症状持续改善超过18个月；伊基奥仑赛注射液回输后3个月开始，患者肢力和肺活量明显改善，重症肌无力-日常生活活动评分（MG-ADL）、重症肌无力定量评分（QMG）、重症肌无力-生活质量评分（MG-QOL）和改良Rankin评分（mRS）持续改善；随访期间除外低剂量新斯的明（分别为90mg/天和60mg/天），未合并使用其他免疫调节治疗。PK/PD数据显示：伊基奥仑赛注射液回输后在受试者体内扩增良好，持续时间较短；2例受试者的抗AChR和抗Titin抗体、抗MuSK抗体在回输后均迅速降低并长期维持在极低水平；2例受试者的B细胞和浆细胞在回输后2个月内降低至无法检测，而后逐渐恢复；两例受试者的B细胞在回输后18个月均已恢复至正常水平，其中约80%为幼稚B细胞，而浆细胞仍维持较低水平。该结果显示CAR-T细胞治疗的长期疗效，可能与幼稚表型为主的B细胞重建而浆细胞持续清除有关。此项研究主要研究者、华中科技大学同济医学院附属同济医院王伟教授表示：“重症肌无力病程长、难治愈、易复发，当前传统药物的治疗虽在一定程度上能改善肌无力症状，但在疾病控制、长期安全性等方面均存在不足，患者对更好的临床结局和治疗方式有迫切需求。在我们此次的IIT研究中，很高兴地看到BCMA CAR-T细胞疗法可以阻止MG疾病进展，并表现出逆转疾病征象，有望改变MG治疗格局，为患者带来治愈的希望。”伊基奥仑赛治疗免疫介导坏死性肌病的研究数据1月30日，《美国国家科学院院刊》正式发表了驯鹿生物伊基奥仑赛注射液治疗免疫介导坏死性肌病（IMNM）的研究论文“Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR T-cell therapy”。该研究数据初步展现了靶向BCMA的CAR-T疗法在IMNM中的良好耐受性和安全性、持久的致病性抗体清除作用以及潜在的持久性临床疗效，为抗体介导的自身免疫性疾病提供了一种新的治疗思路。IMNM是自身免疫介导的骨骼肌疾病，属特发性炎性疾病。人类抗信号识别颗粒（SRP）抗体属于IMNM特异性自身抗体，SRP抗体介导的IMNM主要表现为四肢近端肌对称无力、吞咽困难表现突出、血清肌酸激酶显著升高，有起病急、病情重、进展快的特点，对常规药物的治疗反应性差，复发率高。本次在《美国国家科学院院刊》上发表的是一项研究者发起的开放评价输注伊基奥仑赛注射液治疗复发/难治性抗体介导的神经系统特发性炎症性疾病的安全性和有效性的探索性临床研究，该试验的研究者为华中科技大学同济医学院附属同济医院王伟教授团队。该研究中入组的一例25岁SRP抗体阳性的难治性IMNM男性受试者，7年病史，既往接受过激素、钙调磷酸酶抑制剂、叶酸拮抗剂、CD20单抗、白介素6（IL-6）受体拮抗剂、次黄嘌呤核苷磷酸脱氢酶（IMPDH）抑制剂、烷化剂、血浆置换、静脉注射免疫球蛋白和间充质干细胞输注等多种治疗，但仍遭受多次复发和持续损伤。入组前在规律使用激素、IL-6受体拮抗剂、叶酸拮抗剂和静脉注射免疫球蛋白的联合治疗下，患者仍瘫痪卧床，手臂不能举过头顶，血清肌酸激酶高达4806 IU/L（参考值≤190 U/L）。安全性数据显示：该受试者仅发生了1级的细胞因子释放综合征（CRS），未发生免疫效应细胞相关神经毒性综合征（ICANS），仅经历了短暂的血细胞减少；相较于在多发性骨髓瘤适应症研究中的安全性谱，未发现新的安全性风险。有效性数据显示：在伊基奥仑赛注射液回输后18个月的随访中，患者的临床症状和影像学特征均得到了持续的改善，伊基奥仑赛注射液回输后3个月，患者四肢力量明显改善，抬臂没有限制，并恢复了行走能力；徒手肌力检查（Manual Muscle Testing-8，MMT-8）评分从基线的96分，改善至末次访视（回输后18个月）的137分；血清肌酸激酶水平从回输前的4778 IU/L降至末次访视的260 IU/L，肌红蛋白水平从回输前的837 ng/mL降至末次访视的66.2 ng/mL；在其它生活质量表方面也观察到了明显的改善。随访期间未合并使用其他免疫调节治疗。PK/PD数据显示：伊基奥仑赛注射液回输后CAR-T细胞在受试者体内扩增良好，血清SRP抗体水平迅速下降并持续维持在极低水平。此项研究主要研究者、华中科技大学同济医学院附属同济医院王伟教授表示，这是该产品继成功治疗视神经脊髓炎后在自身免疫病领域中的又一重要突破，期待CAR-T疗法在自免领域的进一步发展，为患者带来治愈的希望。”除本次发表的两项研究结果外，驯鹿生物和研究者团队仍在持续探索伊基奥仑赛注射液在治疗其它抗体介导的自身免疫性疾病的安全性和有效性，包括视神经脊髓炎谱系疾病（NMOSD）、慢性炎性脱髓鞘性多发性神经病（CIDP），希望为更多的自免疾病带来新的治疗选择。参考资料：[1] 驯鹿生物伊基奥仑赛注射液治疗难治性重症肌无力(MG)病例报告在《EMBO Molecular Medicine》发表. Retrieved Feb 28, 2024,  from https://mp.weixin.qq.com/s/O1tUmBLLeN8jC9B3gkmoSw[2] 驯鹿生物伊基奥仑赛注射液全球首次用于治疗免疫介导坏死性肌病（IMNM）的研究成果在《美国国家科学院院刊》（PNAS）发表. Retrieved Jan 30, 2024,   from https://mp.weixin.qq.com/s/c1tpfhH5uNu2pMoqSp93lA本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。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。

SHANGHAI and NANJING, China and SAN JOSE, Calif., Feb. 29, 2024 /PRNewswire/ -- On February 26, 2024, the impactful international academic journal, EMBO Molecular Medicine, published the clinical data of the fully human BCMA targeting autologous CAR-T cell injection (Equecabtagene Autoleucel, Eque-cel, CT103A) for the treatment of two refractory myasthenia gravis (MG) subjects. B cell lineage reconstitution underlies CAR-T cell therapeutic efficacy in patients with refractory myasthenia gravis, initially demonstrated the good tolerability and safety of Eque-cel in the treatment of MG, as well as the durable clinical efficacy. MG is an autoimmune disease with acquired neuromuscular junction (NMJ) transmission disorders mediated by antibodies. Antibodies to the Acetylcholine Receptor (AChR) are the most common pathogenic antibodies; in addition, antibodies such as Muscle-Specific receptor tyrosine Kinase (MuSK), low-density Lipoprotein Receptor-related Protein 4 (LRP4), and Ryanodine Receptor (RyR), have also been found to be involved in the pathogenesis of MG. Currently, the treatment of MG is still based on cholinesterase inhibitors, glucocorticoids, immunosuppressants, intravenous immunoglobulin, plasma exchange, and thymectomy. The main causes of death in MG patients include respiratory failure and pulmonary infections. This is an investigator-initiated open-label study to evaluate the safety and efficacy of Eque-cel for the treatment of relapsed/refractory antibody-mediated idiopathic inflammatory disorders of the nervous system (NCT04561557). It was conducted by Prof. Wei Wang's team at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Two subjects with refractory MG were enrolled in this study. One was a 33-year-old female, AChR-IgG and Titin-IgG positive, who had been treated with thymectomy 21 months prior to enrollment and had not achieved clinical remission after treatment with cholinesterase inhibitors, glucocorticoids, immunosuppressants, and anti-CD20 monoclonal antibody. The other subject was a 60-year-old female, MuSK- IgG4 positive, with a 20-year history of the disease and failed the previous treatment with hormones, immunosuppressants, and anti-CD20 monoclonal antibody. The 2 subjects were treated with a single infusion of Eque-cel at the doses of 1.01×106 CAR-T/Kg and 0.96×106 CAR-T/Kg， respectively. Safety: Of the 2 subjects, only 1 subject developed grade 1 Cytokine Release Syndrome (CRS), and no Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS). All grade ≥3 hemocytopenia recovered within 4 weeks post infusion. No new safety risk was identified, and the safety profile was superior compared to that in multiple myeloma indication. Effectiveness: Clinical symptoms continued to improve over 18 months in the 2 subjects. From 3 months after the infusion, patients showed significant improvement in limb strength and vital capacity, and sustained improvement in Myasthenia Gravis-Activities of Daily Living Score (MG-ADL), Quantitative Myasthenia Gravis Score (QMG), Myasthenia Gravis-Quality of Life Score (MG-QOL), and Modified Rankin Score (mRS). No immunomodulatory therapy other than low dose pyridostigmine (90 mg/day and 60 mg/day, respectively) was used during the follow-up period. PK/PD: Eque-cel expanded well after infusion and persisted for a shorter period than that in multiple myeloma patients. Anti-AChR antibodies, anti-Titin antibodies, and anti-MuSK antibodies decreased rapidly and maintained at very low levels in both subjects after infusion. B cells and plasma cells decreased to undetectable levels in both subjects within 2 months after infusion and then recovered gradually. At 18 months post-infusion, the B cells of both subjects had returned to normal levels, with approximately 80% of them being naïve B cells, while plasma cells remained at low levels. This result suggests that the long-term efficacy of CAR-T cell therapy may be related to the reconstitution of B cells with a predominantly naïve phenotype and the continued clearance of plasma cells. The principal investigator of this study, Prof. Wei Wang of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, said "Myasthenia Gravis has a long course, is difficult to cure, and is prone to recurrence. Current treatment with traditional medications, although is able to improve symptoms of Myasthenia Gravis to a certain extent, is deficient in terms of disease control and long-term safety, and there is an urgent need for patients to have a better clinical outcome and treatment modality. In our study, it is gratifying to see that BCMA CAR-T cell therapy can prevent MG disease progression and show signs of reversal of the disease, which is expected to change the MG treatment landscape and bring hope for a cure to patients." In addition to the results of this published study, IASO Bio and a team of investigators continue to explore the safety and efficacy of Equecabtagene Autoleucel in the treatment of other antibody-mediated autoimmune diseases, including optic neuromyelitis optica spectrum disorders (NMOSD), Immune-Mediated Necrotizing Myelopathy (IMNM), and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), with an aim to change the landscape of treatment for autoimmune diseases. About IASO Bio IASO Bio is a biopharmaceutical company engaged in the discovery and development of novel cell therapies and biologics for oncology and autoimmune diseases. IASO Bio possesses comprehensive capabilities spanning the entire drug development process, from early discovery to clinical development, regulatory approval, and commercial production. The pipeline in the company includes a diversified portfolio of over 10 novel products, including Equecabtagene Autoleucel (a fully human BCMA CAR-T injection). Equecabtagene Autoleucel received New Drug Application (NDA) approval from China's National Medical Products Administration (NMPA) and U.S. FDA IND approval for the treatment of RRMM. Leveraging its strong management team, innovative product pipeline, GMP production, as well as integrated manufactural and clinical capabilities, IASO aims to deliver transformative, curable, and affordable therapies that fulfil unmet medical needs to patients in China as well as around the world. For more information, please visit or . SOURCE IASO Bio