Bortezomib

作为MM领域的资深玩家，强生已经有4款药物获批上市，小分子药物Bortezomib，靶向CD38的单克隆抗体Daratumumab，靶向BCMA的CAR-T药物Carvykti和靶向BCMA/CD3的双特异抗体Tecvayli《第7款双抗!强生BCMA/CD3双抗获批上市》，靶向GPRC5D/CD3的双抗《第11款双抗：强生GPRC5D/CD3双抗获批上市》。然而强生的布局并不限于这些，目前在临床中，其已经在开发多种联合疗法，包括两款双抗的联合，双抗与单抗联合，甚至开发了三抗和单抗的联合。关于双抗联合疗法，在去年的ASCO会议上，强生已经公布初步疗效《不服不行啊！》，而最近，其在《新英格兰》上发表了一期临床的最终疗效。 其Ⅰ期临床设计如下图所示，116患者经过筛查后最终94位患者入组临床介绍不同剂量的双抗联合治疗。在GPRC5D/CD3的双特异抗体Talquetamab的剂量选择上，总共有三个剂量，0.2 mg/kg，0.4和0.8mg/kg，而在BCMA/CD3的双特异抗体teclistamab的剂量选择上，同样有三个剂量0.75 mg/kg，1.5和3 mg/kg. 入组患者如下：来自加拿大、以色列、韩国和西班牙的合格患者根据国际骨髓瘤工作组标准26存在可测量的骨髓瘤，并且疾病复发或对既往治疗耐药，或者在既往治疗（包括最后一线治疗）中出现了不可接受的不良事件水平。患者必须既往接受过蛋白酶体抑制剂、免疫调节药物和抗CD38单克隆抗体（即至少三类药物暴露）治疗，并且东部肿瘤协作组体能状态评分为0或1（评分范围为0 - 5，数值越高表示残疾程度越高）。存在至少一个未接受过放疗、不依赖骨骼的病灶（最大径≥2厘米）的髓外疾病患者被纳入研究。 安全性方面：在基线时，94名患者中有53名（56%）患有非IgG型骨髓瘤。这53名非IgG型骨髓瘤患者中有37名（70%）在基线时存在低丙种球蛋白血症（定义为IgG值<400毫克/分升），30名（57%）在治疗后出现低丙种球蛋白血症。评估排除了IgG型骨髓瘤患者以及接受静脉免疫球蛋白替代治疗的患者。共有30名（57%）非IgG型骨髓瘤患者接受了静脉免疫球蛋白治疗。细胞因子释放综合征发生在74名患者（79%）中。大多数事件为1级或2级，发生在治疗给药的剂量逐步增加阶段和早期；3级细胞因子释放综合征发生在2名患者（2%）中。细胞因子释放综合征导致14名患者（15%）出现周期延迟或剂量调整。细胞因子释放综合征的中位发病时间和持续时间均为2天。共有61名患者（65%）接受了支持性措施，其中包括24名（26%）接受了托珠单抗治疗。总体而言，患者中观察到的事件中有98%出现了恢复，1%出现了有后遗症的恢复，1%出现了不完全恢复。ICANS发生在3名患者（3%）中，报告了1例3级事件；1名患者出现了两次事件。 疗效方面：在RP2R（推荐2期方案）中，44名患者中有35位患者（80%）达到PR及以上缓解），首次反应的中位时间为1.4个月（范围0.3 - 5.1个月）。共有34名患者（77%）达到VGPR或者更好，23名患者（52%）达到CR或者更好。在具有临床相关亚组的患者中，包括国际分期系统III期骨髓瘤患者（8名患者中的7名[88%]）、既往接受过三种或以上治疗方案的患者（38名患者中的29名[76%]）、具有高危细胞遗传学特征的患者（8名患者中的6名[75%]）以及存在髓外疾病的患者（18名患者中的11名[61%]），采用推荐的2期方案后有高比例的患者出现了反应（见图S2A）。在所有剂量水平下，94名患者中有73名（78%）出现了反应，首次反应的中位时间为1.8个月（范围0.3 - 7.7个月）。共有70名患者（74%）达到VGPR或者更好，45名（48%）达到CR或者更好。 采用推荐的2期方案，患者在12个月和18个月时继续维持反应的可能性分别为91%（95%置信区间[CI]为75% - 97%）和86%（95% CI为66% - 95%），在所有剂量水平下，这一可能性分别为86%（95% CI为75% - 92%）和77%（95% CI为64% - 85%）。在存在髓外疾病的患者中，采用推荐的2期方案，在12个月和18个月时继续维持反应的可能性在两个时间点均为82%（95% CI为45% - 95%），而在所有剂量水平下，这一可能性在12个月时为70%（95% CI为45% - 85%），在18个月时为52%（95% CI为25% - 74%）。在所有28名从每两周给药一次转变为每月给药一次的患者中，采用推荐的2期方案，反应得以维持或加深。 采用推荐的2期方案，无进展生存率在12个月时估计为74%（95%置信区间[CI]为57% - 84%），在18个月时为70%（95% CI为52% - 82%）。在存在髓外疾病的患者中，无进展生存率在两个时间点均为53%（95% CI为28% - 73%）。在所有剂量水平下，无进展生存率在12个月时估计为71%（95% CI为60% - 79%），在18个月时为62%（95% CI为51% - 72%）。 总结 在接受每周0.4mg/kg剂量talquetamab治疗的患者中观察到反应的比例为74%，在接受每两周0.8mg/kg剂量talquetamab治疗的患者中为72%，在接受teclistamab治疗的患者中为63%，在接受elranatamab治疗的患者中为61%，在接受ciltacabtagene（CAR-T）治疗的患者中为83%，在接受idecabtagene vicleucel（CAR-T）治疗的患者中为67%。而在talquetamab联合teclistamab治疗中观察到深度反应，采用推荐的2期方案治疗的患者中有52%出现完全反应或更好，而在所有剂量水平下有48%的患者出现完全反应或更好。在之前talquetamab单药治疗的研究中，每周接受0.4mg/kg剂量治疗的患者中有34%出现完全反应或更好，每两周接受0.8mg/kg剂量治疗的患者中有39%出现完全反应或更；在之前teclistamab单药治疗的研究中，每周接受1.5mg/kg剂量治疗的患者中有45%出现完全反应或更。采用推荐的2期方案，中位随访时间为18.2个月，反应高度持久，患者在18个月时继续维持反应的可能性为86%。在接受每周0.4mg/kg剂量talquetamab单药治疗的患者中，18个月时继续维持反应的可能性为37%，在接受每两周0.8mg/kg剂量talquetamab单药治疗的患者中为49%，在接受每周1.5mg/kg剂量teclistamab单药治疗的患者中为57%。 安全性方面，talquetamab联合teclistamab的安全性特征与每种药物单药治疗时相似，尽管观察到3级或4级感染的发生率在联合治疗中高于talquetamab或teclistamab单药治疗。 我们已经建立抗体密码读者交流群，有兴趣的可以扫描下方二维码添加微信进群，请主动备注姓名-公司-职位（高校-专业），非诚勿扰！ 往期精彩回顾 抗体密码文章合集 双特异抗体平台 靶点相关 双特异抗体作用机制 综述，行业概览 抗体筛选技术 相关公司技术汇总 医药资讯 因为你的分享、点赞、在看 我足足的精气神儿！ 声明 本公众号所发表文章以宣传知识为目的，因此不构成投资，病人用药等建议。如果文章侵您的权益及时联系小编进行删除！ 欢迎扫码交流/咨询/合作= 参考文献： DOI: 10.1056/NEJMoa2406536

Sarclisa obtains first approval in China for the treatment of adult patients with relapsed or refractory multiple myeloma Approval based on positive pivotal ICARIA-MM phase 3 study using the China-based IsaFiRsT real-world study as bridging data, which demonstrated Sarclisa and the standard treatment Pd, improved responses and long-term outcomes compared to Pd alone in R/R MM patients Sarclisa-Pd is currently recommended by the Chinese Society of Clinical Oncology (CCSCO) and Chinese Anti-Cancer Association (CACA) treatment guidelines for this patient population Paris, January 13, 2025. The National Medical Products Administration (NMPA) in China has approved Sarclisa, an anti-CD38 medicine, in combination with pomalidomide and dexamethasone (Pd) for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior line of therapy, including lenalidomide and a proteasome inhibitor. This approval is based on results from the pivotal ICARIA-MM phase 3 study, using the China-based IsaFiRsT real-world study as bridging data. The ICARIA-MM study demonstrated Sarclisa in combination with Pd significantly reduced the risk of disease progression or death by 40% (HR 0.596, 95% CI 0.44-0.81, p=0.001), and resulted in a clinically meaningful, 6.9-month improvement in overall survival (OS) (HR=0.78; log-rank 1-sided P=0.0319), compared to Pd alone. Additionally, the IsaFiRsT study, which is the first real-world study for the registration of an anti-CD38 therapy in combination with Pd in China, showed an overall response rate (ORR) of 82.6% among relapsed or refractory multiple myeloma (R/R MM) adult patients. Olivier NatafGlobal Head, Oncology “This approval marks an important milestone for Sanofi in China. The results of the ICARIA-MM phase 3 study, coupled with the real-world IsaFiRsT study, highlight the benefit of Sarclisa for patients living with multiple myeloma and the importance of innovative regulatory pathways for timely access to different treatments. We look forward to continuing to build strong partnerships with the medical community, local companies, and authorities in China as we work to bring more innovative treatments to patients.” Through the Lecheng Pilot for real-world data application, the NMPA has increasingly used real-world evidence (RWE) to help accelerate the review and approval of innovative therapies and medical devices in China. Sarclisa was one of the first three treatments authorized for real-world studies as part of the pilot program and is the first blood cancer treatment approved based on RWE, in addition to clinical data. In addition to the NMPA approval, the Chinese Society of Clinical Oncology (CSCO) and Chinese Anti-Cancer Association (CACA) guidelines include Sarclisa-Pd as a "Category I Recommendation" and the "Preferred Option" for the treatment of patients with first-relapsed MM. Beyond R/R MM, a regulatory submission for Sarclisa in combination with bortezomib, lenalidomide and dexamethasone (VRd) for newly diagnosed multiple myeloma (NDMM) in adult patients not eligible for autologous stem cell transplant, is also under review in China with a final decision expected in the coming months. As one of the first multinational companies to enter China in 1982, Sanofi is committed to accelerating the introduction of innovative medicines and vaccines into China, aiming to transform the practice of medicine for the benefit of more Chinese people. About the ICARIA-MM studyICARIA-MM was a pivotal phase 3 randomized, open-label, multi-center trial evaluating Sarclisa in combination with Pd versus Pd alone in patients with R/R MM. The study enrolled 307 patients with R/R MM across 96 centers spanning 24 countries. Overall, patients had received a median of three prior lines of anti-myeloma therapies, including at least two consecutive cycles of lenalidomide and a proteasome inhibitor given alone or in combination. During the trial, Sarclisa was administered by intravenous infusion at a dose of 10mg/kg once weekly for four weeks, then every other week for 28-day cycles in combination with standard doses of Pd for the duration of treatment. The primary endpoint of ICARIA-MM was progression-free survival (PFS). Key secondary endpoints included ORR and OS. About the IsaFiRsT studyThe IsaFiRsT study was a single-arm, observational, prospective, real-world study evaluating Sarclisa in combination with Pd in patients with R/R MM. The study enrolled 24 patients with R/R MM at one site in China. Overall, patients received a median of three prior lines of therapy, including lenalidomide and a proteasome inhibitor, and had measurable serum or urine M-protein. During the trial, Sarclisa was administered through an intravenous infusion at a dose of 10mg/kg once weekly for four weeks, then every other week for 28-day cycles in combination with standard doses of Pd for the duration of treatment. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint of IsaFiRsT was ORR. Key secondary endpoints included PFS, OS, duration of response (DOR) and safety. About SarclisaSarclisa (isatuximab) is a CD38 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. 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 FDA. Currently, Sarclisa is approved in more than 50 countries, including the US and EU, across two indications; Sarclisa is approved under an additional indication in the US. Based on the ICARIA-MM phase 3 study, Sarclisa is approved in combination with Pd for the treatment of patients with R/R MM 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 R/R MM who have received 1–3 prior lines of therapy and in the EU for patients with MM who have received at least 1 prior therapy. In the US, Sarclisa is approved in combination with VRd as a front-line treatment option for adult patients with NDMM not eligible for transplant based on the IMROZ phase 3 study. On November 14, 2024, the European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending the approval of Sarclisa-VRd in this patient population. A final decision is expected in the coming months. 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 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 often rare 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 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 Media RelationsSandrine Guendoul | +33 6 25 09 14 25 | sandrine.guendoul@sanofi.com Evan Berland | +1 215 432 0234 | evan.berland@sanofi.com Nicolas Obrist | +33 6 77 21 27 55 | nicolas.obrist@sanofi.com Léo Le Bourhis | +33 6 75 06 43 81 | leo.lebourhis@sanofi.com Victor Rouault | +33 6 70 93 71 40 | victor.rouault@sanofi.comTimothy Gilbert | +1 516 521 2929 | timothy.gilbert@sanofi.com Investor RelationsThomas Kudsk Larsen |+44 7545 513 693 | thomas.larsen@sanofi.com Alizé Kaisserian | +33 6 47 04 12 11 | alize.kaisserian@sanofi.comFelix Lauscher | +1 908 612 7239 | felix.lauscher@sanofi.com Keita Browne | +1 781 249 1766 | keita.browne@sanofi.comNathalie Pham | +33 7 85 93 30 17 | nathalie.pham@sanofi.comTarik Elgoutni | +1 617 710 3587 | tarik.elgoutni@sanofi.com Thibaud Châtelet | +33 6 80 80 89 90 | thibaud.chatelet@sanofi.com Sanofi forward-looking statementsThis press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. 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