Barzolvolimab

– EMBARQ-CSU1 and EMBARQ-CSU 2 will enroll more than 1800 patients suffering from CSU – – Studies include both biologic naïve and experienced patients – HAMPTON, NJ, USA I July 16, 2024 I Celldex Therapeutics, Inc. (NASDAQ:CLDX) announced today the initiation of its global Phase 3 program, consisting of two Phase 3 trials (EMBARQ-CSU1 and EMBARQ-CSU2) designed to establish the efficacy and safety of barzolvolimab in adult patients with CSU who remain symptomatic despite H1 antihistamine treatment. The studies will also include patients who remain symptomatic after treatment with biologics. For patients with CSU, the activation of mast cells in the skin results in episodes of itchy hives, swelling and inflammation of the skin that can severely impact their daily lives for years or even decades. Treatment options are limited, particularly for patients not adequately controlled by omalizumab. Barzolvolimab, a novel monoclonal antibody, works upstream of other treatment approaches for CSU, targeting the root driver of the disease—mast cells—by blocking the receptor tyrosine kinase KIT, which is required for mast cell function and survival. “Across multiple studies in CSU, barzolvolimab has demonstrated a unique and profound ability to offer rapid, durable and complete disease control, regardless of prior treatment history, to patients suffering from this often severe and debilitating disease,” said Marcus Maurer, MD, Professor of Dermatology and Allergy at Charité – Universitätsmedizin in Berlin and a Principal Investigator in the Phase 3 studies of barzolvolimab. “Advancing a promising agent that addresses the root driver of the disease—the mast cell—into late stage studies is a significant and hopeful step forward for patients and physicians who desperately need better treatment options.” EMBARQ-CSU1 and EMBARQ-CSU2 are designed to establish the efficacy and safety of barzolvolimab in adult patients with CSU who remain symptomatic despite H1 antihistamine treatment. Both Phase 3 trials are randomized, double-blind, placebo-controlled, parallel group, global studies where approximately 915 patients will be randomized evenly to barzolvolimab 150 mg every 4 weeks (following 300 mg loading dose), barzolvolimab 300 mg every 8 weeks (following 450 mg loading dose) or placebo for 52 weeks. At 24 weeks, patients on placebo will be re-randomized to active treatment across both dosing groups. The primary endpoint of the study will evaluate the clinical effect of barzolvolimab in reducing urticaria activity (weekly urticaria activity score; UAS7) at Week 12. The study is designed to detect a clinically meaningful difference between each of the active arms vs placebo in the overall population as well as in the subpopulation of omalizumab refractory participants. “Treatment options that deliver complete disease control for more patients are sorely needed in CSU and advancing barzolvolimab into registrational studies is an important step forward for patients,” said Anthony Marucci, Co-founder, President and Chief Executive Officer of Celldex Therapeutics. “We are focused on executing these trials seamlessly and achieving our goal of making barzolvolimab available to meet the needs of patients with CSU, while also advancing barzolvolimab across additional indications.” Results from a placebo controlled Phase 2 study in CSU demonstrated that barzolvolimab met the primary endpoint of the study, a statistically significant mean change from baseline to week 12 in UAS7, across all dose levels. Secondary and exploratory endpoints in the study were also achieved at week 12 and strongly support the primary endpoint results, including changes in ISS7 (weekly itch severity score) and HSS7 (weekly hives severity score) and responder analyses (UAS7<=6 or UAS7=0). Importantly, barzolvolimab demonstrated rapid, durable and clinically meaningful responses in patients with moderate to severe CSU refractory to antihistamines, including patients with prior omalizumab treatment and was well tolerated with a favorable safety profile. For additional information on EMBARQ-CSU1 and EMBARQ-CSU2 (NCT06455202 and NCT06445023), please visit www.clinicaltrials.gov About Chronic Spontaneous Urticaria (CSU) CSU is characterized by the occurrence of hives or wheals for 6 weeks or longer without identifiable specific triggers or causes. The activation of the mast cells in the skin (release of histamines, leukotrienes, chemokines) results in episodes of itchy hives, swelling and inflammation of the skin that can go on for years or even decades. Current therapies provide symptomatic relief only in some patients. About Barzolvolimab Barzolvolimab is a humanized monoclonal antibody that binds the receptor tyrosine kinase KIT with high specificity and potently inhibits its activity. KIT is expressed in a variety of cells, including mast cells, which mediate inflammatory responses such as hypersensitivity and allergic reactions. KIT signaling controls the differentiation, tissue recruitment, survival and activity of mast cells. In certain inflammatory diseases, such as chronic urticaria, mast cell activation plays a central role in the onset and progression of the disease. Barzolvolimab is currently being studied in chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU), prurigo nodularis (PN) and eosinophilic esophagitis (EOE) with additional indications planned for the future, including atopic dermatitis (AD). About Celldex Therapeutics, Inc. Celldex is a clinical stage biotechnology company leading the science at the intersection of mast cell biology and the development of transformative therapeutics for patients. Our pipeline includes antibody-based therapeutics which have the ability to engage the human immune system and/or directly affect critical pathways to improve the lives of patients with severe inflammatory, allergic, autoimmune and other devastating diseases. Visit www.celldex.com. SOURCE: Celldex Therapeutics

01 c-Kit激酶 c-Kit激酶是人体中众多酪氨酸激酶中的一种，其本质是一种跨膜蛋白。c-Kit蛋白通过激活各种信号通路，对细胞的增值，分化，存活，以及迁移起着重要的作用。 c-Kit蛋白由胞外区，跨膜区和胞内区三部分组成。其中,胞外区由5个免疫球蛋白样结构域组成，跨膜区为一次跨膜α螺旋，胞内区为受体催化域，具体分为近膜（juxtamembrane (JM)域，酪氨酸激酶1域，酪氨酸激酶插入域，酪氨酸激酶2域。在正常的状态下，失活时c-Kit以单体形式存在；一旦与配体干细胞因子结合，c-Kit就会二聚化。二聚化的单体相互在Y568，Y570和（或）Y823发生自身磷酸化，从而激活下游信号通路，引起细胞生长和分化。一些含有SH2和蛋白酪氨酸结合域的蛋白，如蛋白酪氨酸磷酸酶 SHP-1，细胞因子抑制剂6（suppressor of cytokine signaling 6 ，SOCS6）等，是c-Kit活性的负调控蛋白。 已有研究表明，c-Kit的丧失功能突变会导致耳聋，便秘等疾病；而获得功能的突变则与胃肠基质瘤（GIST），肥大细胞白血病（MCL），急性髓系白血病（AML）等疾病有关。临床上针对酪氨酸激酶的小分子抑制剂用来治疗各种癌症，并且，对于不同的癌症病人都已经有了很多可选择的治疗方案，这些特异的对激酶信号通路的抑制能够导致肿瘤的生长大小，生长速度，延缓病情恶化。 02 c-Kit在研格局 根据新药情报库所披露信息 ，目前c-kit靶点共有在研药物112个，包含的适应症有557种，在研机构211家，涉及相关的临床试验4892件，专利多达21701件…… 多款特异性c-KIT抑制剂已进入临床研究阶段，如Bezuclastinib（PLX-9486）、KTN-0158、JSP-191、BLU-263、CDX-0159，等十几项临床研究在海外进行中，其中除Bezuclastinib、BLU-263 进展较快已进入Ⅲ期阶段外，大多为I期临床研究。 6月12日，Celldex Therapeutics在Clinicaltrials.gov网站上注册了Barzolvolimab治疗慢性自发性荨麻疹（CSU）的三期临床试验。Barzolvolimab为一款KIT抗体，是Celldex的首发管线，正在探索多种自免适应症，此前的二期临床在表现出优异的疗效。 国内来看，聚焦自免的荃信生物，今年2月申报了一款针对c-kit靶点的人源化IgG1单克隆抗体QX013N，今年5月获批临床，拟开发用于治疗慢性自发性荨麻疹（CSU）。 03 展望 过去十年，KIT抑制剂在GIST等肿瘤领域的应用为患者治疗带来新的选择和方向。然而,仍有相当部分患者初始治疗无效, 或出现继发耐药。临床实践中, 可以考虑与其它治疗策略进行联用, 包括化疗、放疗、各种分子靶向药物、免疫抑制剂、细胞因子抑制剂、病毒疗法及肿瘤疫苗等。相信随着恶性肿瘤的治疗及耐药机制探索的不断深入, 未来越来越多的患者将会从治疗中获益。 吉满生物特色产品 为满足c-Kit相关药物研发需求，吉满生物分别开发出高质量的稳定过表达细胞株和抗体，可用于抗体筛选、表征、一致性评价, 充分满足药物研发的需求，助力抗体药物临床申报。除此之外，吉满生物还可提供高活性c-Kit重组蛋白，可满足客户在动物免疫、抗体筛选以及表位鉴定等不同场景中的需求，所有产品均已通过严格的质量监测。(咨询吉满客服联系同微信:18916119826）。 产品列表 数据展示（部分）： GM-C36580 H_c-Kit(CD117) GNNK(-) CHO-K1 Cell Line使用Anti-c-Kit(CD117) hIgG1 Antibody(barzolvolimab)流式验证 GM-C36717 H_c-Kit(CD117) GNNK(+) CHO-K1 Cell Line使用Anti-c-Kit(CD117) hIgG1 Antibody(barzolvolimab)流式验证结果 GM-C36581 Cynomolgus_c-Kit(CD117) GNNK(-) CHO-K1 Cell Line使用Anti-c-Kit(CD117) hIgG1 Antibody(barzolvolimab)流式验证结果 蛋白数据展示 GM-87117RP   Human c-Kit(CD117) Protein His Tag SDS-PAGE On SDS-PAGE under reducing (R) condition. The gel was stained overnight with Coomassie Blue. The purity of the protein is greater than 95%. ★ His Tag ELISA验证  His Tag (Catalog # GM-87117RP) was immobilized at 2 μg/ml (100 μL/well). Increasing concentrations of Human SCF Protein; mFc Tag (Catalog # GM-87653RP) were added. ★  His Tag ELISA验证 His Tag (Catalog # GM-87117RP) was immobilized at 2 μg/ml (100 μL/well). Increasing concentrations of Anti-c-Kit(CD117) hIgG1 Antibody(barzolvolimab) (Catalog # GM-86542AB) were added. ★ GM-87120RP   Cynomolgus c-Kit(CD117) Protein  His Tag SDS-PAGE On SDS-PAGE under reducing (R) condition. The gel was stained overnight with Coomassie Blue. The purity of the protein is greater than 95%. ★ His Tag ELISA验证 Cynomolgus c-Kit(CD117) Protein; His Tag (Catalog # GM-87120RP) was immobilized at 2 μg/ml (100 μL/well). Increasing concentrations of Anti-c-Kit(CD117) hIgG1 Antibody(barzolvolimab) (Catalog # GM-86542AB) were added. ★ GM-87119RP   Human c-Kit(CD117) Protein hFc Tag SDS-PAGE On SDS-PAGE under nun-reducing (NR) condition and reducing (R) condition. The gel was stained overnight with Coomassie Blue. The purity of the protein is greater than 95%. ★  hFc Tag ELISA验证 Human SCF Protein; His Tag (Catalog # GM-87651RP) was immobilized at 2 μg/ml (100 μL/well). Increasing concentrations of Human c-Kit(CD117) Protein; hFc Tag (Catalog # GM-87119RP) were added. 联系我们 吉满生物助力药物研发，紧随前沿靶点资讯，储备几百株现货细胞，覆盖GPCR、细胞因子、免疫检查点、TAA等多领域，截止当前已布局近300个热门靶向药靶点，1000余株细胞系，旨在助力、加速大分子早期研发，做到进口细胞的国产替代。同时可根据客户需求提供细胞系服务。 扫码咨询 扫码找现货