MYO7A

▎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。多款嵌合抗原受体（CAR）T细胞疗法在早期临床研究中表现亮眼，总缓解率（ORR）/客观缓解率超90%。源于人类多能干细胞的再生细胞候选疗法NRTX-1001用于治疗耐药性内侧颞叶癫痫（MTLE）患者，接受低剂量治疗的前两名患者在单次治疗两年后仍报告癫痫发作减少>97%。现货型γδ T细胞疗法INB-100用于接受减低强度预处理（RIC）后进行半相合造血干细胞移植（HSCT）的老年血液系统恶性肿瘤患者，在一项1期临床试验中使所有（100%）急性髓系白血病（AML）患者在中位随访时间为19.7个月时仍处于完全缓解（CR）状态，包括3名具有高风险细胞遗传学特征的AML患者。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✦——— ◇ 强生（Johnson & Johnson）公司公布了3期临床试验CARTITUDE-4的最新研究结果。结果显示，在接受过1至3种治疗方案（包括蛋白酶体抑制剂），且对来那度胺耐药的复发或难治性多发性骨髓瘤（RRMM）患者中，单次输注与传奇生物联合开发的B细胞成熟抗原（BCMA）靶向CAR-T细胞疗法Carvykit（cilta-cel），与标准治疗方案相比，显著提高了患者的微量残留病（MRD）阴性率。在中位随访期为34个月时，可评估患者的MRD阴性率在cilta-cel治疗组中是标准治疗组的两倍以上（89%比38%；p<0.0001）。在接受治疗后30个月时，cilta-cel治疗组中持续（12个月或更长时间）达到MRD阴性完全缓解或更好的可评估患者比例是标准治疗组的五倍（52%比10%；p<0.0001）。 ◇ Protara Therapeutics公司公布了开放标签2期临床试验ADVANCED-2的最新结果。该试验评估了其基于一种失活的化脓性链球菌（Streptococcus pyogenes）菌株的在研细胞疗法TARA-002对携带高风险原位癌的非肌层浸润性膀胱癌（NMIBC）患者的疗效，包括对卡介苗（BCG）无应答或为BCG初治患者。结果显示，在所有患者中，接受治疗后6个月时的CR率为72%（13/18），任意时间点的CR率为70%（14/20）。在3位随访时间达到9个月的可评估患者中，有2位在9个月时仍保持CR。此外，在对BCG无应答的患者队列中，接受治疗6个月时的CR率为100%（4/4），任意时间点的CR率为80%（4/5）。 ◇ Beacon Therapeutics公司公布了在研基因疗法laru-zova（AGTC-501），在治疗X连锁视网膜色素变性（XLRP）患者的2期临床试验DAWN中获得的3个月中期数据。数据显示在低亮度视力（LLVA）这一关键视觉功能指标上，接受laru-zova治疗3个月的患者有早期改善的良好迹象。Laru-zova是一款基于腺相关病毒载体（AAV）的基因疗法，表达全长RPGR蛋白，因此有望解决XLRP导致的所有感光细胞的损伤，包括杆状细胞和锥状细胞的丧失，代表了针对XLRP患者渐进性视力丧失的潜在“best-in-class”治疗方案。 ◇ Arcellx公司公布了其BCMA靶向CAR-T细胞疗法anitocabtagene autoleucel（anito-cel）用于治疗RRMM的关键性2期研究iMMagine-1的积极数据。截至2024年10月31日的数据，中位随访时间为9.5个月，86例疗效可评估患者的ORR为97%（83/86），CR/严格CR（sCR）率为62%（53/86），非常好的部分缓解或更佳（≥VGPR）率为81%（70/86）。6个月时的无进展生存率和总生存率分别为93.3%和96.5%，12个月时的无进展生存率和总生存率分别为78.5%和96.5%。在此前的1期研究中，中位随访时间为38.1个月时，RRMM患者的中位无进展生存期为30.2个月。迄今为止，在此前的1期研究和iMMagine-1研究中给药的150多名患者中未观察到anito-cel导致的迟发性神经毒性。 ◇ Poseida Therapeutics公司公布了其BCMA靶向同种异体CAR-T疗法P-BCMA-ALLO1用于治疗RRMM患者的1期试验的中期数据。结果显示，优化淋巴细胞清除组（C组）患者的ORR为91%，既往未接受过BCMA靶向治疗患者的ORR为100%，而既往接受过至少一种BCMA和/或GPRC5D靶向治疗患者的ORR为86%。此外，该研究还取得了显著的安全性成果，无剂量限制性毒性反应（DLT），细胞因子释放综合征（CRS）和免疫效应细胞神经毒性综合征（ICANS）发生率低（均≤2级），无移植物抗宿主病（GVHD）或帕金森病。 ◇ Lyell Immunopharma公司公布了其CD19/CD20双靶向自体CAR-T细胞疗法IMPT-314治疗大B细胞淋巴瘤患者的多中心1/2期研究的初步数据。截至2024年10月22日的数据，17例疗效可评估患者的客观缓解率为94%，CR率为72%，这些患者既往接受过至少2线治疗，但未接受过CAR-T细胞疗法治疗。IMPT-314的安全性可控，无高级别CRS且3级ICANS发生率低，这些不良事件可通过标准治疗方案得到解决。 ◇ Synthekine公司公布了其CD19靶向自体CAR-T细胞疗法SYNCAR-001联用工程化改造的聚乙二醇化IL-2细胞因子STK-009治疗复发或难治性CD19阳性血液系统恶性肿瘤的1期研究的初步结果。截至2024年10月8日的数据，该组合疗法展现良好的安全性，未观察到DLT或IL-2相关毒性，无>2级的CRS或>1级的ICANS。所有（100%）接受该组合疗法治疗的非霍奇金淋巴瘤（NHL）患者均达到了CR并在数据截止时保持CR，最长的CR持续时间超过480天。 ◇ Neurona Therapeutics公司公布了其源于人类多能干细胞的再生细胞候选疗法NRTX-1001用于治疗耐药性内侧颞叶癫痫的1/2期临床试验结果。结果显示，低剂量组患者的中位失能性癫痫发作次数比基线减少92%，80%的患者在用药后7-12个月的主要疗效评估期间报告癫痫发作减少>75%。接受低剂量细胞疗法的前两名患者在单次治疗两年后仍报告癫痫发作减少>97%。高剂量组患者的中位失能性癫痫发作次数比基线减少78%，60%的患者在用药后4-6个月的中期评估期间报告癫痫发作减少>75%。在两个剂量组中，均未发现临床上显著的认知和生活质量损害，部分受试者的测试成绩显著提高。此外，迄今为止，高剂量和低剂量的NRTX-1001均耐受性良好。 ◇ AAVantgarde Bio公司公布了1/2期开放标签临床试验LUCE-1中前两名受试者的安全性数据。该研究旨在评估以AAV8为载体的视网膜内基因疗法AAVB-081用于治疗Usher综合征1B型（USH1B）相关的视网膜色素变性患者的安全性和耐受性。AAVB-081使用两个AAV8载体，每个载体都携带目标基因的一半信息，两个基因片段在细胞核内重新组合为一个完整的基因，从而能够生成治疗水平的MYO7A蛋白。此次公布的结果显示，两名接受低剂量治疗的受试者的最佳矫正视力（BCVA）在2周内恢复到治疗前的水平。所有不良事件都是轻微的，无需进一步干预即可解决。迄今为止，尚未观察到DLT。 ◇ CRISPR Therapeutics公司公布了其下一代CD19靶向同种异体CAR-T细胞疗法CTX112用于治疗复发或难治性CD19阳性B细胞恶性肿瘤的1/2期临床试验数据。结果显示，CTX112在所有剂量水平上均具有良好的耐受性，并在所有剂量水平下均产生了缓解。12名接受治疗的患者中有5名患者的缓解持续了超过6个月。1名接受剂量1治疗的患者在初始输注后的一年内仍保持CR。 ▲CTX112的临床疗效结果（图片来源：参考资料[12]） ◇ IN8bio公司公布了其在研现货型γδ T细胞疗法INB-100用于接受减低强度预处理后进行半相合造血干细胞移植的老年血液系统恶性肿瘤患者的1期试验的最新数据。历史数据显示，大约25%接受HSCT的AML患者预计在移植后的100天内会出现复发，其中高达50%的患者会在一年内复发。此次公布的结果显示，中位随访时间为19.7个月时，接受INB-100治疗的所有（100%）AML患者仍处于CR状态，包括3名具有高风险细胞遗传学特征的AML患者，他们在未接受维持治疗的情况下，仍然保持CR超过三年。 ———✦融资、合作、M&A✦——— 图片来源：123RF ◇ Chroma Medicine公司和Nvelop Therapeutics公司宣布合并，将表观遗传编辑技术和下一代体内递送技术相结合，以成立一家名为nChroma Bio的公司重新定义基因药物的未来。在合并的同时，nChroma公司还完成了7500万美元的超额认购融资，为公司提供额外的资金，以推动其主导项目获得有意义的临床数据，并建立强大的下一代肝脏和肝外靶向治疗管线。该公司的主导项目CRMA-1001是一种肝脏靶向表观遗传编辑疗法，具有潜在“best-in-class”的效力和推动慢性乙型肝炎和丁型肝炎功能性治愈的潜力。 ▲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] CARVYKTI®▼ (ciltacabtagene autoleucel; cilta-cel) demonstrated significantly higher rates of minimal residual disease negativity compared to standard therapies in the CARTITUDE-4 study. Retrieved December 11, 2024, from https://www.globenewswire.com/news-release/2024/12/10/2994233/0/en/CARVYKTI-ciltacabtagene-autoleucel-cilta-cel-demonstrated-significantly-higher-rates-of-minimal-residual-disease-negativity-compared-to-standard-therapies-in-the-CARTITUDE-4-study.html [2] Beacon Therapeutics Announces Positive 3-Month Data from Phase 2 DAWN Trial of laru-zova (AGTC-501) in Patients with X-Linked Retinitis Pigmentosa (XLRP). Retrieved December 6, 2024, from https://www.prnewswire.com/news-releases/beacon-therapeutics-announces-positive-3-month-data-from-phase-2-dawn-trial-of-laru-zova-agtc-501-in-patients-with-x-linked-retinitis-pigmentosa-xlrp-302324627.html [3] Protara Announces Positive Results from the Ongoing Phase 2 ADVANCED-2 Trial of TARA-002 in Patients with NMIBC. Retrieved December 5, 2024, from https://www.globenewswire.com/news-release/2024/12/05/2992222/0/en/Protara-Announces-Positive-Results-from-the-Ongoing-Phase-2-ADVANCED-2-Trial-of-TARA-002-in-Patients-with-NMIBC.html [4] Arcellx Announces New Positive Data for Its iMMagine-1 Study in Patients With Relapsed or Refractory Multiple Myeloma to be Presented During an Oral Presentation at the 66th ASH Annual Meeting and Exposition. Retrieved December 12, 2024, from https://ir.arcellx.com/news/news-details/2024/Arcellx-Announces-New-Positive-Data-for-Its-iMMagine-1-Study-in-Patients-With-Relapsed-or-Refractory-Multiple-Myeloma-to-be-Presented-During-an-Oral-Presentation-at-the-66th-ASH-Annual-Meeting-and-Exposition/default.aspx [5] Poseida Therapeutics Highlights Positive Interim Phase 1 Results for P-BCMA-ALLO1 and Preclinical Data for Dual CAR-T P-CD19CD20-ALLO1 at the 66th American Society of Hematology (ASH) Annual Meeting. Retrieved December 12, 2024, from https://www.prnewswire.com/news-releases/poseida-therapeutics-highlights-positive-interim-phase-1-results-for-p-bcma-allo1-and-preclinical-data-for-dual-car-t-p-cd19cd20-allo1-at-the-66th-american-society-of-hematology-ash-annual-meeting-302325606.html [6] Lyell Presents Positive Initial Clinical Data from the Phase 1-2 Clinical Trial of IMPT-314 for the Treatment of B-cell Lymphoma at the 2024 ASH Annual Meeting. Retrieved December 12, 2024, from https://www.globenewswire.com/news-release/2024/12/10/2994158/0/en/Lyell-Presents-Positive-Initial-Clinical-Data-from-the-Phase-1-2-Clinical-Trial-of-IMPT-314-for-the-Treatment-of-B-cell-Lymphoma-at-the-2024-ASH-Annual-Meeting.html [7] Synthekine Presents Positive Initial Results from Phase 1 Clinical Trial of CD19 CAR-T (SYNCAR-001) and Orthogonal IL-2 (STK-009) Combination Therapy for Treatment of Hematologic Malignancies at ASH 2024 Annual Meeting. Retrieved December 12, 2024, from https://www.synthekine.com/news/synthekine-presents-positive-initial-results-from-phase-1-clinical-trial-of-cd19-car-t-syncar-001-and-orthogonal-il-2-stk-009-combination-therapy-for-treatment-of-hematologic-malignancies-at-ash-2/ [8] AAVantgarde presents safety data of the LUCE-1 study of AAVB-081 for RP related to Usher 1B. Retrieved December 12, 2024, from https://www.aavantgarde.com/en/news/aavantgarde-presents-safety-data-of-the-luce-1-study-of-aavb-081-for-rp-related-to-usher-1b/ [9] Neurona Therapeutics Presents Positive Clinical Update: New Data from NRTX-1001 Cell Therapy Trial in Drug-resistant Epilepsy Announced at 2024 Annual Meeting of the American Epilepsy Society. Retrieved December 12, 2024, from https://www.neuronatherapeutics.com/news/press-releases/120624/ [10] IN8bio Reports Continued Progression-Free Survival in Phase 1 Investigator-Sponsored Trial of INB-100 Allogeneic Gamma-Delta T Cells for Leukemias at the 2024 American Society of Hematology Annual Meeting. Retrieved December 12, 2024, from https://www.globenewswire.com/news-release/2024/12/10/2994365/0/en/IN8bio-Reports-Continued-Progression-Free-Survival-in-Phase-1-Investigator-Sponsored-Trial-of-INB-100-Allogeneic-Gamma-Delta-T-Cells-for-Leukemias-at-the-2024-American-Society-of-H.html [11] CRISPR Therapeutics Presents Data at the 2024 American Society of Hematology (ASH) Annual Meeting. Retrieved December 12, 2024, from https://www.globenewswire.com/news-release/2024/12/09/2993974/0/en/CRISPR-Therapeutics-Presents-Data-at-the-2024-American-Society-of-Hematology-ASH-Annual-Meeting.html [12] Chroma Medicine and Nvelop Therapeutics Unite to Form nChroma Bio, Securing $75 Million to Accelerate Genetic Medicines. Retrieved December 12, 2024, from https://chromamedicine.com/2024/12/10/chroma-medicine-and-nvelop-therapeutics-unite-to-form-nchroma-bio-securing-75-million-to-accelerate-genetic-medicines/ 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

Dec. 02, 2024 -- AAVantgarde Bio (AAVantgarde), a clinical-stage, Italian-based international biotechnology company with two proprietary Adeno-Associated Viral (AAV) vector platforms for large gene delivery, today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to its lead program, AAVB-081 for the treatment of Usher Syndrome Type 1B (USH1B) retinitis pigmentosa. “People living with USH1B are in urgent need of a therapy to prevent their progressive loss of vision leading to eventual blindness. Receiving FDA Orphan Drug Designation reinforces the unmet need of this indication and is an important milestone in the development of this program,” said Dr. Natalia Misciattelli, Chief Executive Officer of AAVantgarde. The FDA’s Orphan Drug Designation program provides orphan status to drugs and biologics for rare diseases that meet certain criteria. Orphan Drug Designation provides various incentives including tax credits for qualified clinical trials, exemption from user fees, and the potential for seven years of market exclusivity after approval. AAVB-081 is an intra-retinal AAV8-based dual hybrid product targeting MYO7A-associated Usher syndrome (USH1B). AAVantgarde’s dual hybrid platform uses two AAV8 vectors, each containing one half of an expression cassette encoding for the Myo7A gene and works at the cell nucleus level, recombining the two halves of the transgene back into a single one within the cell. This technology translates into an efficient recombination that generates therapeutically meaningful protein levels in animal models. Usher syndrome type 1B (Usher1B) is an inherited disease that affects the retina and the inner ear. Usher1B is caused by mutations in the MYO7A gene. The therapeutic gene to treat Usher1B is 6.7 kb long and is therefore too large to fit inside a standard AAV vector. Approximately 20,000 patients in the U.S. and E.U. have Usher1B. These children are born deaf, have vestibular dysfunction, and begin to progressively lose vision in their first decade of life. Although there are surgical treatments available to treat deafness in these patients, there are no treatments available to treat progressive vision loss and blindness in these patients. AAVantgarde Bio is a clinical stage, international biotechnology company that has developed two proprietary Adeno-Associated Viral (AAV) vector platforms to address the gene therapy cargo capacity limitations of AAV vectors. The AAVantgarde platforms could be used to deliver large genes to ocular and non-ocular tissues. AAVantgarde is initially validating its platforms in two inherited retinal diseases with clear unmet need, with its lead program in Usher syndrome type 1B already in the clinic. For more information, please visit: www.aavantgarde.com The content above comes from the network. if any infringement, please contact us to modify.

MILAN, Dec. 03, 2024 (GLOBE NEWSWIRE) -- AAVantgarde Bio (AAVantgarde), a clinical-stage, Italian-based international biotechnology company with two proprietary Adeno-Associated Viral (AAV) vector platforms for large gene delivery, today announces an oral presentation at the FLORetina Annual Meeting, to be held December 5-8 in Florence (Italy). At this conference, safety results at 60 days for the two first subjects with advanced retinitis pigmentosa due to Usher syndrome 1B dosed in the LUCE-1 study will be presented by Prof. Francesca Simonelli, Principal Investigator for this study. This is the first administration of a dual AAV gene therapy in Ophthalmology. Oral Presentations details: Presentation Date/Time: 7 December 2024, 10.50-10.54 h CETPresenter: Prof. Francesca SimonelliSession title: Multicentric longitudinal study in Usher Syndrome IB: disease course and implication for gene therapySession: Inherited retinal diseases treatments About the AAVB-081 programAAVB-081 is an intra-retinal AAV8-based dual hybrid product targeting MYO7A-associated Usher syndrome (USH1B). AAVantgarde’s dual hybrid platform uses two AAV8 vectors, each containing one half of an expression cassette encoding for the Myo7A gene and works at the cell nucleus level, recombining the two halves of the transgene back into a single one within the cell. This technology translates into an efficient recombination that generates therapeutically meaningful protein levels in animal models. About the LUCE-1 TrialLUCE-1 is a Phase 1/2 multicenter, open-label, dose escalation study investigating safety, tolerability and preliminary efficacy of 3 dose levels of dual AAV8.MYO7A (AAVB-081) administered subretinally in subjects with retinitis pigmentosa associated with Usher Syndrome Type 1B. For further information, please refer to: https://clinicaltrials.gov/study/NCT06591793?term=AAvantgarde&rank=2 About Usher syndrome type 1BUsher syndrome type 1B (Usher1B) is an inherited disease that affects the retina and the inner ear. Usher1B is caused by mutations in the MYO7A gene. The therapeutic gene to treat Usher1B is 6.7 kb long and is therefore too large to fit inside a standard AAV vector. Approximately 20,000 patients in the U.S. and E.U. have Usher1B. These children are born deaf, have vestibular dysfunction, and begin to progressively lose vision in their first decade of life. Although there are surgical treatments available to treat deafness in these patients, there are no treatments available to treat progressive vision loss and blindness in these patients. About AAVantgarde BioAAVantgarde Bio is a clinical stage, Italian headquartered, international biotechnology company that has developed two proprietary Adeno-Associated Viral (AAV) vector platforms to address the gene therapy cargo capacity limitations of AAV vectors. The AAVantgarde platforms could be used to deliver large genes to ocular and non-ocular tissues. Co-founded by Professor Alberto Auricchio at TIGEM (Telethon Institute of Genetics and Medicine) in Naples, Italy, and Telethon Foundation, AAVantgarde will initially validate the platform in the clinic in two inherited retinal diseases with clear unmet need. For more information, please visit: www.aavantgarde.com Contact:Magda Blanco – Head of Corporate Development AAVantgardeEmail: info@avvantgarde.com