Thalidomide

2024年10月28日，Monte Rosa Therapeutics宣布与诺华达成全球独家开发和商业化许可协议，共同推进VAV1靶向分子胶降解剂（VAV1 MGD）的开发，主要包括MRT-6160。 根据协议条款，诺华将获得开发、制造和商业化MRT-6160和其他VAV1 MGD项目的全球独家权利，并将负责从2期临床研究开始的临床开发和商业化。Monte Rosa负责完成MRT-6160正在进行的1期临床研究。 诺华已经同意向Monte Rosa预付1.5亿美元。从2期研究启动开始，Monte Rosa有资格获得高达21亿美元的开发、监管和商业化里程碑付款，以及美国以外地区净销售额的分层版税。 Monte Rosa将共同资助任何3期临床开发，并将分享与MRT-6160在美国制造和商业化相关的任何利润和损失。 VAV1 MGD MRT-6160 VAV1长期以来一直被认为“不可成药”，VAV1是一种Rho家族的鸟嘌呤核苷酸交换因子，是T细胞和B细胞受体下游的关键信号蛋白。 细胞因子在自身免疫性疾病中起着至关重要的作用，通过VAV1 MGD可调节T细胞和B细胞受体介导的活性，降低细胞因子分泌，从而缓解自免疾病。 VAV1 MGD在自免疾病的临床前模型中心显示出有前景的活性，因此有可能为多种自免疾病（包括多发性硬化症、类风湿关节炎、炎症性肠炎和皮肤病等）提供潜在治疗。 MRT-6160有效的高选择性、口服生物可利用的VAV1靶向分子胶降解剂（VAV1 MGD）。MRT-6160的体内临床前研究表明，MRT-6160能够抑制自免模型的疾病进展。体外研究中，显示出对靶标的深度降解，导致于免疫介导条件相关的细胞因子显著减少，对其他蛋白质没有可检测的影响。 目前，MRT-6160正在进行一项在健康志愿者中进行的1期、单次给药剂量递增(SAD)/多次给药剂量递增（MAD）研究。 Monte Rosa首席执行官Markus Warmuth在一封邮件中写道，Monte Rosa和诺华看到了MRT-6160治疗多种全身和神经系统自身免疫性疾病的潜力。 与诺华达成协议，有望进一步加速MRT-6160的临床开发，并广泛探索多种适应症的治疗机会。 在一份声明中，诺华生物医学研究总裁Fiona Marshall表示，诺华一直对分子胶降解剂感兴趣，这种降解剂有可能解决具有挑战性的生物靶标。 事实上，诺华自己开发了一款WIZ分子胶和一种靶向CDO1的VHL分子胶，2024年7月，诺华的WIZ分子胶见刊于Science正刊，报道了首个WIZ分子胶结构dWIZ1与dWIZ2，并介绍了相关生物学机制；2024年1月，诺华在预印本网站bioRxiv上发表了一篇文章，介绍了一种靶向CDO1的VHL分子胶。 Monte Rosa Monte Rosa是一家明星分子胶降解剂开发公司，于2018年成立，于2021年登录纳斯达克上市。 Monte Rosa公司将人工智能、结构生物学和蛋白质组学相结合，开发了一种QuEEN™平台，能够系统地识别可降解的蛋白质靶点，并开创了一种可预测、可重复的分子胶设计方法。 Monte Rosa公司的工作也吸引了罗氏的关注。2023年10月，罗氏与Monte Rosa达成战略合作和授权合作，以针对之前被认为不可成药的癌症和神经系统疾病靶点发现和开发分子胶降解剂（MGD）。 MGD的魅力 许多疾病源于蛋白质功能异常。传统的小分子抑制剂药物无法满足要求，导致大约85%的蛋白质无法成药。 因此，能够针对那些传统上被认为不可成药的蛋白靶点的“靶向蛋白质降解”正在成为一种主流的药物开发策略，包括PROTACs（蛋白质水解靶向嵌合体），MGD（Molecular Glue Degraders，分子胶降解剂）。 PROTACs通常由3个部分组成（linker和两个配体分子），分子量较大，不满足类药五原则，因此生物利用度较低，药代动力学性质较差；而相对的，MGD分子量很小，理化性质便于优化。 相较于能够模块化设计的PROTACs，MGD也一度被认为是一种高度依赖运气的领域，从沙利度胺到CC-885，几乎所有重要的分子胶都是通过偶然发现而非理性设计得到的。 总而言之，MGD具有良好的应用前景，但是其设计难度大，目前还没有很好的药物开发策略。 MGD的应用潜力，也吸引了全球制药巨头的关注，除了与Monte Rosa达成合作的诺华、罗氏，还包括默沙东、百时美施贵宝、安斯泰来、赛诺菲等等。 参考资料： 1.https://www.biopharmadive.com/news/monte-rosa-novartis-molecular-glue-degraders/731185/ 2.https://www.monterosatx.com/pipeline/ 3.https://www.monterosatx.com/science/ 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

Phase 3 PERSEUS study of daratumumab subcutaneous (SC) formulation in combination with bortezomib, lenalidomide and dexamethasone induction and consolidation, followed by daratumumab SC and lenalidomide maintenance showed a 58 percent reduction in risk of disease progression or death 1 New regimen reinforces daratumumab SC as a foundational element for optimising frontline treatment of patients with newly diagnosed multiple myeloma, and significantly delaying disease progression 2 BEERSE, Belgium I October 23, 2024 I Janssen-Cilag International NV, a Johnson & Johnson company, today announced that the European Commission (EC) approved the indication extension for DARZALEX ® (daratumumab) subcutaneous (SC) formulation in combination with bortezomib, lenalidomide and dexamethasone (daratumumab-VRd) in patients with newly diagnosed multiple myeloma (NDMM) who are eligible for an autologous stem cell transplant (ASCT). 3 Patients will have the opportunity to receive this daratumumab SC-based quadruplet therapy at initial diagnosis, providing them with a new treatment shown to significantly improve outcomes. This approval is supported by data from the Phase 3 PERSEUS study, which evaluated daratumumab SC-based quadruplet regimen for induction and consolidation therapy, followed by daratumumab SC and lenalidomide (D-R) maintenance therapy, compared to bortezomib, lenalidomide and dexamethasone (VRd) during induction and consolidation, followed by lenalidomide (R) maintenance in 709 patients with NDMM eligible for ASCT. 4 “Multiple myeloma is a complex and highly varied disease, which reinforces the need for continuous innovation in first-line treatment strategies to deepen responses, reduce relapse and ultimately improve long-term outcomes,” said Dr. Paula Rodriguez-Otero, Department of Hematology, Cancer Center Clínica Universidad de Navarra, Pamplona, Navarra, Spain.* “The EC approval of this daratumumab SC-based quadruplet regimen offers a practice-changing new option, that has shown the potential to significantly improve progression-free survival, complete response rates, and MRD-negativity status compared to the current standard of care.” Findings from the PERSEUS study, after a median follow-up of 47.5 months, demonstrated a significant improvement in the primary endpoint of progression-free survival (PFS), with the daratumumab-VRd regimen reducing the risk of disease progression or death by 58 percent compared to VRd (hazard ratio [HR], 0.42; 95 percent confidence interval [CI], 0.30-0.59; p <0.0001). 1 Treatment with daratumumab-VRd resulted in deeper responses compared to VRd with overall minimal residual disease (MRD)-negativity rate assessed at 10 -5 of 75.2 percent vs 47.5 percent ( p <0.001), complete response or better of 87.9 percent vs 70.1 percent (p<0.001) and importantly, sustained MRD negativity for ≥12 months of 64.8 percent vs 29.7 percent, respectively. 1 “The European Commission’s approval of this daratumumab quadruplet regimen marks a pivotal step forward in the treatment of newly diagnosed multiple myeloma,” said Edmond Chan, MBChB, M.D. (Res), Senior Director, EMEA Therapeutic Area Lead Haematology, Innovative Medicine, Johnson & Johnson. “By incorporating daratumumab SC into this regimen we are further optimising frontline therapy for patients, building on our aim to transform outcomes, and establish new standards of care for eligible patients from induction through to maintenance.” The overall safety profile of daratumumab-VRd was consistent with the known safety profiles for daratumumab SC and VRd. 2 The most common haematologic adverse reactions (≥20 percent) in patients with multiple myeloma who received daratumumab-VRd vs VRd were neutropenia (69.2 percent vs 58.8 percent), thrombocytopenia (48.4 percent vs 34.3 percent) and anaemia (22.2 percent vs 20.7 percent). 2 The most common non-hematologic adverse reactions (≥20 percent) in patients with multiple myeloma who received daratumumab-VRd vs VRd were peripheral neuropathy (53.6 percent vs 51.6 percent), fatigue (23.9 percent vs 26.5 percent), peripheral oedema (20.5 percent vs 21.3 percent), pyrexia (31.6 percent vs 31.4 percent), upper respiratory infection (31.6 percent vs 25.1 percent), COVID-19 (35.0 percent vs 23.9 percent), constipation (33.9 percent vs 34.0 percent), diarrhoea (61.0 percent vs 54.2 percent), back pain (22.8 percent vs 19.0 percent), insomnia (27.1 percent vs 17.6 percent), asthenia (26.8 percent vs 25.6 percent) and rash (23.4 percent vs 27.1 percent). 2 “Since its first approval in 2016, over half a million patients worldwide have been treated with daratumumab, and today’s approval reinforces our commitment to bringing this transformative therapy to more patients as a first-line treatment, where it has the greatest potential for impact,” said Jordan Schecter, M.D., Vice President, Disease Area Leader, Multiple Myeloma, Innovative Medicine, Johnson & Johnson. “At Johnson & Johnson, we continually challenge ourselves to one day eliminate cancers like multiple myeloma, and today’s milestone marks a significant step toward achieving that goal.” About the PERSEUS study The PERSEUS study ( NCT03710603 ) is being conducted in collaboration with the European Myeloma Network as the sponsor. 4 PERSEUS is an ongoing, randomised, open-label, Phase 3 study comparing the efficacy and safety of daratumumab-VRd and autologous stem cell transplant (ASCT) followed by D-R maintenance vs VRd and ASCT followed by R maintenance in patients with TE NDMM (n=355). 2 The primary endpoint is PFS, and secondary endpoints include overall complete response or better rate, overall MRD-negativity (in patients with complete response or better), and OS. 2 Daratumumab SC was discontinued after at least 24 months of D-R maintenance therapy in patients who had a complete response or better and had sustained MRD-negative status for at least 12 months. 2 The median age is 61.0 (range, 32-70) years for patients in the daratumumab-VRd arm and 59.0 (range, 31-70) years for patients in the VRd arm. 2 The study is being conducted in 13 countries in Europe and Australia. 4 Data from the PERSEUS study were featured as a late-breaking oral presentation (LBA-1) at the 2023 American Society of Hematology (ASH) Annual Meeting and were simultaneously published in The New England Journal of Medicine in 2023. About Daratumumab and Daratumumab SC Johnson & Johnson is committed to exploring the potential of daratumumab for patients with multiple myeloma across the spectrum of the disease. In August 2012 , Janssen Biotech, Inc., a Johnson & Johnson company and Genmab A/S entered a worldwide agreement, which granted Johnson & Johnson an exclusive licence to develop, manufacture and commercialise daratumumab. Since launch, daratumumab has become a foundational therapy in the treatment of multiple myeloma, having been used in the treatment of more than 548,000 patients worldwide. 5 Daratumumab is the only CD38-directed antibody approved to be given subcutaneously to treat patients with multiple myeloma. 2 Daratumumab SC is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE ® drug delivery technology. 6 CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease. 3 Daratumumab binds to CD38 and inhibits tumour cell growth causing myeloma cell death. 3 Daratumumab may also have an effect on normal cells. 3 Data across ten Phase 3 clinical trials, in both the frontline and relapsed settings, have shown that daratumumab-based regimens resulted in significant improvement in progression-free survival and/or overall survival. 7,8,9,10,11,12,13,14,15,16 For further information on daratumumab, please see the Summary of Product Characteristics at: https://www.ema.europa.eu/en/documents/product-information/darzalex-epar-product-information_en.pdf . About Multiple Myeloma Multiple myeloma is currently an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow. 17,18 In multiple myeloma, these malignant plasma cells continue to proliferate, accumulating in the body and crowding out normal blood cells, as well as often causing bone destruction and other serious complications. 18 In the European Union, it is estimated that more than 35,000 people were diagnosed with multiple myeloma in 2022, and more than 22,700 patients died. 19 Whilst some patients with multiple myeloma initially have no symptoms, others can have common signs and symptoms of the disease, which can include bone fracture or pain, low red blood cell counts, fatigue, high calcium levels, infections, or kidney damage. 20 About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at www.innovativemedicine.jnj.com/emea. Follow us at www.linkedin.com/company/jnj-innovative-medicine-emea . Janssen-Cilag International NV, Janssen Pharmaceutica NV, Janssen-Cilag Limited, Janssen Biotech, Inc., and Janssen Research & Development, LLC are Johnson & Johnson companies. 1 Rodriguez-Otero P, et al., Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): Analysis of minimal residual disease (MRD) in the PERSEUS trial. ASCO 2024. Oral presentation. 7502. 2 Sonneveld P, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2024; 390:301-313. 3 European Medicines Agency. DARZALEX (daratumumab) Summary of Product Characteristics. October 2024. 4 ClinicalTrials.gov. Identifier NCT03710603. https://www.clinicaltrials.gov/study/NCT03710603 . Last accessed: October 2024. 5 Johnson & Johnson [data on file]. RF-430506. Number of patients treated with DARZALEX ® worldwide as of 30 June 2024. 6 Janssen EMEA. European Commission Grants Marketing Authorisation for DARZALEX ® (Daratumumab) Subcutaneous Formulation for All Currently Approved Daratumumab Intravenous Formulation Indications. Available at: www.businesswire.com/news/home/20200604005487/en/European-Commission-GrantsMarketingAuthorisation-for-DARZALEX%C2%AE%E2%96%BC-daratumumab-SubcutaneousFormulation-for-all-CurrentlyApproved-Daratumumab-Intravenous-Formulation-Indications . Last accessed: October 2024. 7 Moreau P, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, openlabel, phase 3 study. Lancet 2019;394(10192):29-38. 8 Facon T, et al. MAIA Trial Investigators. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med 2019;380(22):2104-2115. 9 Mateos MV, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. The Lancet 2020;395:P132-141. 10 Dimopoulos MA, et al. APOLLO Trial Investigators. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol 2021;22(6):801-812. 11 Palladini G, et al. Daratumumab plus CyBorD for patients with newly diagnosed AL amyloidosis: safety run-in results of ANDROMEDA. Blood 2020;2;136(1):71-80. 12 Chari A, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood 2017;130(8):974-981. 13 Bahlis NJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia 2020;34(7):1875-1884. 14 Mateos MV, et al. Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma: Three-year Follow-up of CASTOR. Clin Lymphoma Myeloma Leuk 2020;20(8):509-518. 15 Sonneveld, P. et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2024;390(4):301-313. DOI: 10.1056/NEJMoa23120 16 Usmani, S Z. et al. Daratumumab + Bortezomib/Lenalidomide/Dexamethasone in Patients With Transplant-ineligible or Transplant-deferred Newly Diagnosed Multiple Myeloma: Results of the Phase 3 CEPHEUS Study. Oral presentation. 21 st International Myeloma Society (IMS) Annual Meeting. September 25 – 28, 2024. 17 Abdi J, et al. Drug resistance in multiple myeloma: latest findings on molecular mechanisms. Oncotarget 2013;4(12):2186-2207. 18 American Society of Clinical Oncology. Multiple myeloma: introduction. Available at: https://www.cancer.net/cancer-types/multiple-myeloma/introduction. Last accessed: October 2024. 19 ECIS – European Cancer Information System. Estimates of cancer incidence and mortality in 2022, by country. Multiple myeloma. Available at: https://ecis.jrc.ec.europa.eu/explorer.php?$0-0$1-All$2-All$4-1,2$3-51$6-0,85$5-2022,2022$7-7$CEstByCountry$X0_8-3$X0_19-AE27$X0_20-No$CEstBySexByCountry$X1_8-3$X1_19-AE27$X1_-1-1$CEstByIndiByCountry$X2_8-3$X2_19-AE27$X2_20-No$CEstRelative$X3_8-3$X3_9-AE27$X3_19-AE27$CEstByCountryTable$X4_19-AE27 . Last accessed: October 2024. 20 American Cancer Society. Multiple myeloma: early detection, diagnosis and staging. Available at: https://www.cancer.org/content/dam/CRC/PDF/Public/8740.00.pdf . Last accessed: October 2024. SOURCE: Janssen