CD38

PARIS, France I September 21, 2024 I The US Food and Drug Administration (FDA) has approved Sarclisa (isatuximab) in combination with bortezomib, lenalidomide, and dexamethasone (VRd) as a first line treatment option for adult patients with newly diagnosed multiple myeloma (NDMM) who are not eligible for autologous stem cell transplant (ASCT). Sarclisa is the first anti-CD38 therapy in combination with standard-of-care VRd to significantly reduce disease progression or death (by 40%) compared to VRd alone for patients with NDMM not eligible for transplant. Thomas Martin M.D. Helen Diller Family Comprehensive Cancer Center Clinical Professor of Medicine at the University of California San Francisco “Multiple myeloma is most frequently diagnosed in patients 65 years and older, yet the options for treatment in this population are limited due to a combination of age, frailty, and co-morbidities. This has resulted in a longstanding need for new treatment options that can potentially improve the standard-of-care. The significant clinical benefit and improvements in progression-free survival demonstrated by the IMROZ regimen of isatuximab plus VRd versus VRd alone make today’s approval an important moment for this vulnerable patient population and the larger multiple myeloma community.” This decision marks the third approved indication for Sarclisa in the US and the first approved indication in newly diagnosed patients. The FDA evaluated Sarclisa for this indication under Priority Review, which is reserved for medicines that represent potentially significant improvements in efficacy or safety in treating serious conditions. Sarclisa is also currently approved in more than 50 countries across two indications for the treatment of people with relapsed or refractory disease. Brian Foard Executive Vice President, Head of Specialty Care, Sanofi “Since first launching in 2020, we have made significant progress towards our ambition of establishing Sarclisa as a best-in-class therapy. The FDA’s decision marks another momentous milestone toward our goal and expands the reach of this potentially transformative therapy to a larger population. With today’s approval, doctors now have an important new option at their disposal that’s been shown to slow disease progression for longer compared to the current standard-of-care for adults living with newly diagnosed multiple myeloma who are not eligible for transplant in the US.” Results from the IMROZ phase 3 study supporting Sarclisa in NDMM not eligible for ASCT The FDA approval is based on data from the IMROZ phase 3 study recently presented at the American Society of Clinical Oncology (ASCO) 2024 annual meeting and published in The New England Journal of Medicine . IMROZ is the first global phase 3 study of an anti-CD38 monoclonal antibody in combination with standard-of-care VRd to significantly improve PFS versus VRd alone. In the IMROZ study, Sarclisa-VRd followed by Sarclisa-Rd met the primary endpoint of PFS, significantly reducing the risk of recurrence or death by 40%, compared to VRd followed by Rd, in patients with NDMM not eligible for ASCT (HR 0.60; 95% CI: 0.44 to 0.81, p=0.0009). At a median follow-up of 59.7 months, the median PFS with the Sarclisa-VRd combination was not reached versus 54.3 months with VRd. The estimated PFS-rate at 60 months was 63.2% for patients treated with Sarclisa-VRd versus 45.2% for VRd. Sarclisa-VRd also met several secondary endpoints which demonstrated deep responses in this patient population: The safety and tolerability of Sarclisa observed in this study was consistent with the established safety profile of Sarclisa and VRd with no new safety signals observed. The most common adverse reactions (≥20%) were upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19. The most common hematologic laboratory abnormalities (≥80%) were decreased hemoglobin, decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased neutrophils. Serious adverse reactions occurred in 71% of patients receiving Sarclisa combination therapy. The most frequent serious adverse reaction occurring in more than 5% of patients was pneumonia (30%). Permanent discontinuation of treatment due to an adverse reaction occurred in 22.8% of patients treated with Sarclisa combination therapy, compared to 26% in the comparator arm. Advancing Sarclisa in multiple myeloma Sanofi continues to advance Sarclisa as part of a patient-centric clinical development program, which includes several phase 2 and phase 3 studies across the MM treatment continuum spanning six potential indications. In addition, the company is evaluating a subcutaneous administration method for Sarclisa in clinical studies. The safety and efficacy of Sarclisa has not been evaluated by any regulatory authority outside of its approved indications and methods of delivery. In September, isatuximab-irfc (Sarclisa) was also added to the National Comprehensive Cancer Network (NCCN ® ) Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for MM non-transplant candidates as an NCCN Category 1 Preferred option in combination with VRd for patients <80 years old who are not frail. Category 1 is based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Preferred intervention are interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability. *NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. About Sarclisa Sarclisa (isatuximab) is a monoclonal antibody that binds to a specific epitope on the CD38 receptor on MM cells, inducing distinct antitumor activity. It is designed to work through multiple mechanisms of action including programmed tumor cell death (apoptosis) and immunomodulatory activity. CD38 is highly and uniformly expressed on the surface of MM cells, making it a target for antibody-based therapeutics such as Sarclisa. Based on the ICARIA-MM phase 3 study, Sarclisa is approved in more than 50 countries, including the US and the EU, in combination with pomalidomide and dexamethasone for the treatment of patients with relapsed refractory MM (RRMM) who have received ≥2 prior therapies, including lenalidomide and a proteasome inhibitor and who progressed on last therapy. Based on the IKEMA phase 3 study, Sarclisa is also approved in 50 countries in combination with carfilzomib and dexamethasone, including in the US for the treatment of patients with RRMM who have received 1–3 prior lines of therapy and in the EU for patients with MM who have received at least one prior therapy. In the US, the non-proprietary name for Sarclisa is isatuximab-irfc, with irfc as the suffix designated in accordance with nonproprietary naming of biological products guidance for industry issued by the US Food and Drug Administration. Sarclisa continues to be evaluated in multiple ongoing phase 3 clinical studies in combination with current standard treatments across the MM treatment continuum. It is also under investigation for the treatment of other hematologic malignancies, and its safety and efficacy have not been evaluated by any regulatory authority outside of its approved indication. Sanofi is committed to pursuing the advancement of Sarclisa through several investigational studies across the MM treatment continuum. Various patient-centric clinical development programs aim to bring Sarclisa to more patients, intercept the disease earlier in the treatment journey, explore potential new combinations and assess subcutaneous administration via a proprietary on body device system. The safety and efficacy of Sarclisa has not been evaluated by any regulatory authority outside of its approved indications and methods of delivery. In striving to become the number one immunoscience company globally, Sanofi remains committed to advancing oncology innovation. Through focused strategic decisions the company has reshaped and prioritized its pipeline, leveraging its expertise in immunoscience to drive progress. Efforts are centered on difficult-to-treat cancers such as select hematologic malignancies, and solid tumors with critical unmet needs, including multiple myeloma, acute myeloid leukemia, certain types of lymphomas, as well as gastrointestinal and lung cancers. For more information on Sarclisa clinical studies, please visit www.clinicaltrials.gov . About multiple myeloma MM is the second most common hematologic malignancy 1 , affecting more than 130,000 patients in the US; approximately 32,000 Americans are diagnosed with MM each year. 2 Despite available treatments, MM remains an incurable malignancy with an estimated 52% five-year survival rate for newly diagnosed patients. 3 According to physician-based surveys, the majority of NDMM patients are not considered eligible for transplant, creating a need for new frontline therapeutic options, particularly due to high attrition rates in subsequent lines of therapy. About Sanofi We are an innovative global healthcare company, driven by one purpose: we chase the miracles of science to improve people’s lives. Our team, across the world, is dedicated to transforming the practice of medicine by working to turn the impossible into the possible. We provide potentially life-changing treatment options and life-saving vaccine protection to millions of people globally, while putting sustainability and social responsibility at the center of our ambitions. Sanofi is listed on EURONEXT: SAN and NASDAQ: SNY 1 Kazandjian. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol. 2016;43(6):676-681. doi:10.1053/j/seminoncol.2016.11.004. 2 National Cancer Institute. Myeloma Cancer Stat Facts. Available at: www.seer.cancer.gov/statfacts/html/mulmy.html. Accessed on December 12, 2019. 3 Fonseca, R., Usmani, S.Z., Mehra, M. et al. Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma. BMC Cancer . 2020: 20(1087). https://doi-org.libproxy1.nus.edu.sg/10.1186/s12885-020-07503-y. SOURCE: Sanofi

印度仿制药公司Glenmark Pharmaceuticals似乎相中了业内潜在最佳的三抗。 Glenmark Pharmaceuticals是1977年成立的印度老牌仿制药企，近年来正在寻求转型，其瑞士盟友Ichnos Sciences之前就与Glenmark Pharmaceuticals达成了合作联盟，建立了一家合资公司Ichnos Glenmark Innovation。  近日，Ichnos Sciences宣布，已在Nature Cancer发表关于该公司CD3/BCMA/CD38三抗ISB 2001的临床前数据。结果显示，ISB 2001比强生的teclistamab（CD3xBCMA双抗）更有效地缩小了小鼠的多发性骨髓瘤肿瘤，并杀死了人体组织中的癌细胞，引起的T细胞因子分泌更少，因此比现有多发性骨髓瘤双抗更有优势的治疗窗口。 现有疗法的弊端 近年来，BCMA双抗和BCMA-CAR-T已经改变了多发性骨髓瘤（MM）的治疗格局，但是现有疗法仍然存在一些弊端。特别是治疗过后的复发问题仍待解决。 比如说，单药使用后就存在TAA表达下调，抗原丢失等问题，这类现象在CD38单抗daratumumab和BCMA-CAR-T中都能够观察到。 靶标达异质性可能是导致问题的原因之一，一些低CD38/BCMA表达的异质性肿瘤就会在杀伤后扩增。一些MM细胞甚至会在BCMA-CAR-T治疗后发生BCMA阴性突变导致耐药性逐渐增加。 另外，缓解深度似乎也是复发的关键因素。早先的荟萃性研究就表明，杀死微小残留病（MRD）阴性肿瘤是MM治疗成功的保障。为了解决这些问题，多靶点策略或许是这些问题的最佳解决方案，近年来CD3xBCMA双抗teclistamab+CD38单抗daratumumab的组合就被提上日程。CD38单抗无法清除的MRD就可能有赖于CD3xBCMA双抗teclistamab，反之亦然。 相似的策略还有同时靶向BCMA和CD38的CAR-T。 目前来看，多药联用已经展现出了较为优异的临床数据，联合方案可以获得较高的初始ORR，值得期待或许OS和PFS数据的读出。 虽然如此，CRS（细胞因子综合征）问题一直是TCEs在人体内应用时的阻碍，尤其是当teclistamab+daratumumab共同应用时，更加应该担忧治疗窗口。患有严重或危及生命的CRS的患者需要重症监护，需要采取安全缓解措施。 三抗ISB 2001的对应优势 ISB 2001运用了Ichnos Sciences的BEAT平台（基于T细胞受体的抗体的双特异性接合）能够将T细胞表面蛋白CD3的结合位点连接到抗体重链上，重链上同时兼有BCMA结合位点，Y型的另外一边重链则能够靶向CD38。 相较于teclistamab+daratumumab的组合，ISB 2001在临床前的体外和体内数据都更为优异。 相比于BMS已经放弃的alnuctamab以及强生的teclistamab，ISB 2001具有20-260倍的杀癌效力。 为了进一步测试ISB 2001的杀癌能力，研究人员将人类骨髓瘤细胞移植到小鼠身上，并用抗体治疗。在0.1mg/kg的剂量下，ISB 2001完全根除了所有八只小鼠的肿瘤；同时，接受teclistamab治疗的小鼠没有完全消退，只达到了30.8%的肿瘤生长抑制。 而在CRS问题上，ISB 2001也具有一定潜在优势，虽然细胞毒性上，ISB 2001比teclistamab高10-100倍，但ISB 2001在体外诱导了相似的细胞因子分泌。 这表明T细胞活化和细胞溶解活性所需的TCR刺激浓度远低于CRS发生的阈值。这解释了为什么ISB 2001尽管细胞毒性高，但并未显著增加CRS的风险。 因此理论上来说，ISB 2001有更大的治疗窗口。 目前这家公司已经招募了20人的ISB 2001的I期临床，预计相关数据将在今年晚些时候发布。 对于Glenmark来说，或许更值得担心的是市场和工艺，就在上个月BMS放弃了CD3xBCMA双抗alnuctamab，原因是市场竞争，疗效更优的ISB 2001是否能凭借性价比杀入未来市场值得一看。 参考来源： Carretero-Iglesia, L., Hall, O.J., Berret, J. et al. ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells. Nat Cancer (2024). https://doi-org.libproxy1.nus.edu.sg/10.1038/s43018-024-00821-1 https://iginnovate.com/2024/09/11/igi-announces-publication-in-nature-cancer-on-isb-2001-igis-innovative-trispecific-antibody-for-relapsed-refractory-multiple-myeloma/

▎药明康德内容团队报道 今日（9月21日），中国国家药监局药品审评中心（CDE）官网最新公示，石药集团达雷妥尤单抗注射液生物类似药的临床研究申请获得受理。公开资料显示，达雷妥尤单抗（daratumumab）是靶向CD38的抗体药物。 截图来源：CDE官网 作为一款CD38单抗，达雷妥尤单抗能以高亲和力的方式特异性识别在多发性骨髓瘤（MM）恶性浆细胞上高表达的CD38，之后该产品会触发人体自身的免疫系统来攻击癌细胞，除了直接导致癌细胞凋亡外，还通过多种免疫介导的机制和免疫调节作用快速杀死癌细胞。 公开资料显示，达雷妥尤单抗原研产品（商品名：DARZALEX）由强生（Johnson & Johnson）公司研发，自2015年首次获美国FDA批准上市以来，目前已经在全球范围内多个国家获批上市，与多个不同产品组成联合疗法，用于治疗不同治疗背景的多发性骨髓瘤患者。在中国，该产品最早于2019年获批上市，此后陆续获批多项新适应症，涵盖多种类型的多发性骨髓瘤。 参考资料： [1] 中国国家药监局药品审评中心（CDE）网站. Retrieved Sep 21，2024, from https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c 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。转载授权及其他合作需求，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。