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— First Ever Trial in Pregnant Women at Higher Risk of Alloimmunization and FNAIT — — Screening in the Phase 2 Clinical Trial On Track to Initiate in 4Q 2024 — NEW HAVEN, CT, USA I October 29, 2024 I Rallybio Corporation (Nasdaq: RLYB), a clinical-stage biotechnology company translating scientific advances into transformative therapies for patients with devastating rare diseases, today announced the approval of its clinical trial applications (CTAs) for a Phase 2 clinical trial of RLYB212 in pregnant women at higher risk for HPA-1a alloimmunization and fetal and neonatal alloimmune thrombocytopenia (FNAIT). With these approvals from the European Medicines Agency (EMA) and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA), Rallybio will begin to activate Phase 2 clinical sites and expects to initiate screening of participants in the fourth quarter of 2024. “Securing these CTA approvals from European health authorities to advance RLYB212 into a Phase 2 trial is a significant achievement. These approvals are a testament to the dedication and innovation of our team and our partners as we advance this first ever program to prevent maternal alloimmunization and FNAIT,” said Stephen Uden, M.D., Chief Executive Officer of Rallybio. “We are activating clinical sites and expect to initiate screening this quarter, which will mark another important step toward achieving our mission to prevent FNAIT and its potentially devastating consequences.” The single-arm Phase 2 dose confirmation trial ( 2024-512651-20 / NCT06435845 ) will be conducted in Belgium, the Netherlands, Norway, Sweden, and the UK, and is designed to assess the pharmacokinetics (PK) and safety of RLYB212, a monoclonal anti-HPA-1a antibody, in a total of eight pregnant women at higher risk for HPA-1a alloimmunization and FNAIT. Secondary objectives include assessments of pregnancy and neonatal/infant outcomes, and the occurrence of emergent HPA-1a alloimmunization. Subcutaneous administration of RLYB212 will be initiated by Gestational Week 16 and will continue every 4 weeks through parturition. “These approvals recognize Rallybio’s commitment to safely and effectively progress a novel prophylactic approach for preventing alloimmunization in pregnant women at higher FNAIT risk,” said Steven Ryder, M.D., Chief Medical Officer at Rallybio. “We are proud to be leaders in bringing much needed innovation to this area of women’s health, which has gone unaddressed for far too long.” About FNAIT Fetal and Neonatal Alloimmune Thrombocytopenia (FNAIT) is a potentially life-threatening rare disease that can cause uncontrolled bleeding in fetuses and newborns. FNAIT can arise during pregnancy due to an immune incompatibility between an expectant mother and her fetus in a specific platelet antigen called human platelet antigen 1, or HPA-1. There are two predominant forms of HPA-1, known as HPA-1a and HPA-1b, which are expressed on the surface of platelets. Individuals who are homozygous for HPA-1b, meaning that they have two copies of the HPA-1b allele and no copies of the HPA-1a allele, are also known as HPA-1a negative. Upon exposure to the HPA-1a antigen, these individuals can develop antibodies to that antigen in a process known as alloimmunization. In HPA-1a-negative expectant mothers bearing a HPA-1a-positive fetus, alloimmunization can occur upon mixing of fetal blood with maternal blood. When alloimmunization occurs in an expectant mother, the anti-HPA-1a antibodies that develop in the mother can cross the placenta and destroy platelets in the fetus. The destruction of platelets in the fetus can result in severely low platelet counts, or thrombocytopenia, and potentially lead to devastating consequences including miscarriage, stillbirth, death of the newborn, or severe lifelong neurological disability in those babies who survive. There is currently no approved therapy for the prevention or prenatal treatment of FNAIT. About Rallybio Rallybio (NASDAQ: RLYB) is a clinical-stage biotechnology company with a mission to develop and commercialize life-transforming therapies for patients with severe and rare diseases. Rallybio has built a broad pipeline of promising product candidates aimed at addressing diseases with unmet medical need in areas of maternal fetal health, complement dysregulation, hematology, and metabolic disorders. The Company has two clinical stage programs: RLYB212, an anti-HPA-1a antibody for the prevention of fetal and neonatal alloimmune thrombocytopenia (FNAIT) and RLYB116, an inhibitor of complement component 5 (C5), with the potential to treat several diseases of complement dysregulation, as well as additional programs in preclinical development. Rallybio is headquartered in New Haven, Connecticut. For more information, please visit www.rallybio.com and follow us on LinkedIn and Twitter . SOURCE: Rallybio

There currently aren’t any approved therapies specifically targeting the prevention or prenatal treatment of fetal and neonatal alloimmune thrombocytopenia. A few weeks ago, Johnson & Johnson nabbed FDA fast-track status for nipocalimab in fetal and neonatal alloimmune thrombocytopenia (FNAIT). Now, the Big Pharma is making a combined cash and equity investment of over $7 million in Rallybio in order to get the biggest benefits from both companies' programs centered on this rare blood disorder. Under the deal, rare disease biotech Rallybio will receive an upfront $500,000 payment from J&J to raise awareness about the pharma's FNAIT therapy program as the biotech conducts a natural history study for RLYB212, a human monoclonal anti-HPA-1a antibody. RLYB212 is designed to prevent pregnant individuals from alloimmunizing—meaning it stops a pregnant person's immune system from attacking fetal platelets and therefore reduces the risk of severe bleeding complications for the baby. Rallybio will also be eligible to receive additional milestone payments of up to $3.7 million. Furthermore, J&J’s investment arm JJDC is putting down $6.6 million in equity for RallyBio. In return, Rallybio will share certain aggregated, anonymized natural history data from its FNAIT studies with J&J. The biotech will also "disseminate information to its FNAIT study sites related to J&J’s research and development of its complementary therapeutic approaches aimed at reducing the risk of FNAIT," the company told Fierce. Rallybio is running the FNAIT natural history study with the mission of providing a modern dataset for HPA-1a alloimmunization frequency that is intended to support a future registrational study of RLYB212. The biotech is slated to launch a phase 2 dose confirmation trial for RLYB212 among pregnant individuals with a higher risk of alloimmunization and FNAIT in the second half of this year. RLYB212 is the only known clinical-stage therapy designed for pregnant individuals at risk of FNAIT who haven’t alloimmunized, according to RallyBio. Meanwhile, J&J is currently running a phase 3 trial of nipocalimab—a monoclonal antibody designed to target FcRn—among pregnant individuals who are already alloimmunized. While RLYB212 is designed to be preventative, nipocalimab is aimed at individuals who already have the alloantibodies that cause FNAIT. There currently aren’t any approved therapies specifically targeting the prevention or prenatal treatment of FNAIT, Rallybio noted in an April 10 release.   “Our complementary approaches, if successful, would ensure that pregnant individuals at risk of developing FNAIT have a potential treatment option—regardless of their alloimmunization status,” Rallybio CEO Stephen Uden, M.D., said in the release. “Together, we can more effectively and expeditiously drive awareness of FNAIT, emphasize the importance of screening pregnant individuals for their risk of developing FNAIT and advance our complementary therapeutic approaches.”  The Big Pharma partnership comes a little more than two months after Rallybio sent 45% of its staff packing and zoomed in on two phase 2-ready programs—one of which is RLYB212—to extend its cash runway into the middle of 2026. The other program, RLYB116, is a C5 inhibitor that the biotech believes could potentially treat several diseases involving complement dysregulation.   Rallybio entered 2024 with cash, cash equivalents and marketable securities of $109.9 million.

引言血小板α-颗粒富含TGF-β1, TGF-β1与髓源性抑制细胞(myelloid -derived suppressor cell, MDSC)生物学有关。对血小板生成素受体激动剂(TPO-RAs)的应答者显示血小板和MDSCs的数量平行增加。2024年4月4日，山东大学侯宇团队在Blood（IF 20）在线发表题为“Platelet-derived TGF-β1 induces functional reprogramming of myeloid-derived suppressor cells in immune thrombocytopenia”的研究论文，该研究表明血小板来源的TGF-β1诱导免疫性血小板减少症中髓源性抑制细胞的功能性重编程。该研究将抗CD61免疫致敏的脾细胞转移到严重联合免疫缺陷小鼠体内，建立小鼠免疫性血小板减少 (ITP)的活性模型。随后，证明TPO-RAs通过抑制浆细胞分化、减少细胞毒性T细胞上Fas配体的表达和重新平衡T细胞亚群来增强MDSCs的抑制活性。在机制上，转录组分析证实TGF-β/Smad通路参与了TPO-RAs校正的MDSCs，这被Smad2/3敲除所抵消。在血小板TGF-β1缺陷小鼠中，TPO-RAs诱导的MDSCs扩增和抑制能力增强被取消。此外，回顾性数据显示，与仅达到部分缓解的ITP患者相比，达到完全血小板缓解的ITP患者具有更好的长期预后。总之，该研究证明血小板TGF-β1通过TGF-β/Smad途径诱导MDSCs的扩增和功能重编程。这些数据表明，血小板恢复不仅是治疗反应的终点，而且为免疫介导的血小板减少症的免疫稳态铺平了道路。血小板作为血栓形成和炎症的细胞介质具有双重生理作用。它们起源于巨核细胞，巨核细胞表达大量免疫传感器，并将抗原MHC I类复合物交叉呈现给CD8+ T细胞。这些免疫特性在血小板形成过程中扩散，构成血小板因子4 (PF4)、CD40L、白细胞介素-1 (IL-1)和转化生长因子-β1 (TGF-β1)等主要颗粒内容物。血小板中TGF-β1的含量是其他细胞的40-100倍，TGF-β1与肺动脉高压和宫颈癌的病理生理有关。TGF-β是免疫稳态的重要参与者，TGF-β信号的扰动是炎症和自身免疫性疾病的基础。作为TGF-β超家族的一员，TGF-β1是免疫细胞中的显性亚型，具有多效性免疫抑制作用，包括抑制T细胞活化、B细胞存活、增殖、免疫球蛋白(Ig)合成、促进外周调节性T细胞(Treg)和T辅助细胞(Th17)分化。Tgfb1基因的零突变可导致小鼠全身性炎症和过早死亡。在机制上，TGF-β1参与TGF-β受体(TGF-βR) II，然后募集和磷酸化TGF-βRI。受体复合物随后启动典型的Smad2和smad3依赖途径和/或非典型途径来调节免疫细胞中的靶基因的表达。髓源性抑制细胞(MDSCs)是一组异质性的未成熟髓细胞，具有强大的免疫抑制功能，包括抑制T细胞增殖/活化，促进Tregs募集/扩增。TGF-β1可以扩大MDSC群体，增强其免疫抑制功能。反过来，MDSCs通过诱导一氧化氮合酶(iNOS)、精氨酸酶-1(Arg-1)、活性氧(ROS)和多种分泌的细胞因子(包括TGF-β1)发挥功能。鉴于血小板中富含TGF-β1，血小板来源的TGF-β1对MDSCs细胞命运的影响有待进一步探讨。模式图（Credit: Blood）在多种自身免疫性疾病中已发现MDSCs受损。免疫性血小板减少症(ITP)是一种获得性出血性疾病，其特征是由于自身耐受性崩溃导致血小板破坏增加和血小板产生不足。之前的研究表明，ITP患者的MDSCs数量和功能受损，地塞米松通过Ets1，纠正MDSC功能障碍，地西他滨通过肝激酶B1增强MDSCs的氧化代谢。此外，MDSCs中有氧代谢受损有助于ITP中糖皮质激素抵抗的病理生理。在致死性血小板减少综合征和ITP活性中观察到TGF-β1的产生和血清水平显著降低，而TGF-β1升高与ITP的治疗反应相关。然而，血小板恢复是否能通过TGF-β1恢复免疫稳态尚不清楚。该研究表明，血小板来源的TGF-β1通过TGF-β1-Smad2/3通路增强了MDSCs的增殖和免疫抑制功能。此外，TPO-RAs可以间接和直接调节免疫稳态，这也解释了ITP患者在TPO-RA停药后的长期治疗反应。该研究结果表明，血小板恢复不仅是治疗反应的终点，而且还为免疫介导的血小板减少症的免疫稳态铺平了道路，这表明了ITP特异性治疗的共同机制。原文链接https://doi.org/10.1182/blood.2023022738责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述