Ozekibart

No filing review issues identified by FDA with PDUFA goal date set for April 14, 2027 If Approved, Ozekibart Would Be the First and Only FDA-Approved Treatment for Unresectable or Metastatic Conventional Chondrosarcoma SAN DIEGO , June 15, 2026 /PRNewswire/ -- Inhibrx Biosciences, Inc. (Nasdaq: INBX) ("Inhibrx" or the "Company"), a clinical-stage biopharmaceutical company focused on developing novel biologic therapeutic candidates, today announced that the U.S. Food and Drug Administration (FDA) has accepted for filing its Biologics License Application (BLA) seeking approval of ozekibart (INBRX-109) for the treatment of patients with unresectable or metastatic conventional chondrosarcoma. The FDA has not identified any filing review issues at this time and has assigned a Prescription Drug User Fee Act (PDUFA) goal date of April 14, 2027. "The FDA's acceptance of our BLA for ozekibart is a monumental milestone for Inhibrx and, more importantly, for the chondrosarcoma community," said Mark Lappe, Chief Executive Officer of Inhibrx. "Chondrosarcoma is an aggressive and devastating bone cancer and there are currently no approved therapies for patients suffering from this disease. We look forward to working closely with the FDA during this review process to potentially bring this first-in-class targeted therapy to patients as quickly as possible." The BLA is supported by positive results from the ChonDRAgon study, a randomized, blinded, placebo-controlled, registrational trial of ozekibart in patients with metastatic or unresectable conventional chondrosarcoma, which met its primary endpoint of a statistically significant and clinically meaningful median progression-free survival (PFS) for patients treated with ozekibart compared to placebo. Ozekibart achieved a 52% reduction in the risk of disease progression or death compared to placebo (stratified Hazard Ratio [HR] 0.479; 95% CI: 0.33, 0.68; P<0.0001), more than doubling median PFS to 5.52 months versus 2.66 months for placebo. Importantly, ozekibart is the first investigational therapy to demonstrate a significant PFS benefit in a blinded, randomized trial for chondrosarcoma, a disease with no approved systemic options. If approved, ozekibart would become the first commercial product for Inhibrx and the first-ever approved systemic therapeutic for patients with unresectable or metastatic conventional chondrosarcoma. About Chondrosarcoma Chondrosarcoma is a rare type of cancer that primarily develops in the cartilage cells of bones, most commonly affecting the pelvis, hip, and shoulder. It stands as the second most common primary bone malignancy. When the disease becomes unresectable or metastatic, the prognosis is historically poor because the tumors are largely unresponsive to traditional oncology treatments, leaving surgical resection as the only effective management strategy for localized disease. About ozekibart (INBRX-109) Ozekibart is a precision-engineered, tetravalent death receptor 5 (DR5) agonist antibody designed to exploit the tumor-biased cell death induced by DR5 activation. In January 2021, the FDA granted Fast Track designation to ozekibart for the treatment of patients with metastatic or unresectable conventional chondrosarcoma, and, in November 2021, the FDA granted orphan drug designation to ozekibart for chondrosarcoma. In June 2021, Inhibrx initiated the ChonDRAgon study, a randomized, blinded, placebo-controlled, registrational trial of ozekibart in metastatic, unresectable conventional chondrosarcoma. The trial enrolled a total of 206 patients across 67 different sites worldwide. The primary objective of the trial was the evaluation of the efficacy of ozekibart as measured by median PFS, assessed by central real-time independent radiology review per RECIST 1.1. Secondary objectives were the evaluation of overall survival, median PFS by investigator assessment, quality of life, objective response rate, duration of response, disease control rate, safety and tolerability, pharmacokinetics and anti-drug antibodies to ozekibart. Key enrollment criteria in order for patients to qualify for inclusion in the trial were grade 2 or 3 unresectable or metastatic conventional chondrosarcoma. Patients received either ozekibart or placebo every three weeks at a randomization of 2:1, stratified by the line of therapy, grade and IDH1/2 mutation status. Patients randomized to the placebo arm were allowed to crossover to receive ozekibart upon confirmation of progression as reported by central independent radiology review. The ChonDRAgon study met its primary endpoint of a statistically significant and clinically meaningful median progression-free survival (PFS) for patients with advanced or metastatic chondrosarcoma treated with ozekibart compared to placebo. Ozekibart achieved a 52% reduction in the risk of disease progression or death compared to placebo (stratified Hazard Ratio [HR] 0.479; 95% CI: 0.33, 0.68); P<0.0001), more than doubling median PFS to 5.52 months versus 2.66 months for placebo. Importantly, ozekibart is the first investigational therapy to demonstrate a significant PFS benefit in a randomized trial for chondrosarcoma, a disease with no approved systemic options. The benefit of ozekibart was consistent across all pre-specified subgroups, including patients with IDH-wild-type and IDH-mutant tumors. Other key secondary endpoints, including disease control rate (54% vs 27.5%), and delay to deterioration in pain and physical function, further supported the clinical benefit observed with ozekibart. Ozekibart was generally well tolerated, with a manageable safety profile. The most common treatment-related adverse events were fatigue, constipation, and nausea. Hepatotoxicity, a known risk for this mechanism of action, occurs during the first treatment cycle and is in patients with underlying hepatic impairment. One hepatotoxicity-related fatal event occurred early in the study, prior to the implementation of mitigation measures. Over the course of the ChonDRAgon study, this risk was effectively mitigated by excluding patients with severe liver impairment and by implementing close monitoring during early treatment cycles, allowing for prompt management of liver enzyme elevations. This approach resulted in a low overall incidence of treatment-related hepatic adverse events, 11.8% compared to 4.5% in the placebo arm, the majority of which were Grade 1 or 2 in severity. In addition to the registrational trial in chondrosarcoma, Inhibrx is advancing ongoing expansion cohorts, evaluating ozekibart in combination with irinotecan-based regimens in Ewing sarcoma and colorectal cancer. Encouraging early signals support further exploration of ozekibart's potential in these difficult-to-treat tumor types with high unmet medical need. About Inhibrx Biosciences, Inc. Inhibrx Biosciences is a clinical-stage biopharmaceutical company focused on developing a broad pipeline of novel biologic therapeutic candidates. Inhibrx Biosciences utilizes diverse methods of protein engineering to address the specific requirements of complex target and disease biology, including its proprietary protein engineering platforms. Inhibrx Biosciences was incorporated in January 2024 as a direct, wholly-owned subsidiary of Inhibrx, Inc. Prior to the sale of Inhibrx, Inc. and the INBRX-101 program to Sanofi S.A., Inhibrx Biosciences acquired certain corporate infrastructure and other assets and liabilities through a series of internal restructuring transactions effected by Inhibrx, Inc. Inhibrx, Inc. also completed a distribution to holders of its shares of common stock of 92% of the issued and outstanding shares of Inhibrx Biosciences. Following such transactions, Inhibrx Biosciences' current clinical pipeline of therapeutic candidates includes ozekibart and INBRX-106, both of which utilize multivalent formats where the precise valency can be optimized in a target-centric way to mediate what we believe to be the most appropriate agonist function. For more information, please visit . Forward-Looking Statements Inhibrx cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on Inhibrx's current beliefs and expectations. These forward-looking statements include, but are not limited to, statements regarding: Inhibrx's judgments and beliefs regarding the strength of Inhibrx's pipeline; statements regarding the safety and efficacy of its therapeutic candidate, ozekibart, based on topline and interim results; the potential for ozekibart to be used for the treatment of colorectal cancer, Ewing sarcoma and solid tumor indications; the clinical development of ozekibart, including expected enrollment in the expansion cohort, data readouts, regulatory submissions and interactions, and the timing thereof; the potential commercial development of ozekibart, including becoming the first commercial product for Inhibrx; ozekibart becoming the first-ever FDA approved systemic therapeutic for patients with unresectable or metastatic conventional chondrosarcoma; and any presumption that topline, interim or preliminary data will be representative of final data or data in later clinical trials. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Inhibrx's business, including, without limitation, risks and uncertainties regarding: topline data may not accurately reflect the complete results of a particular study or trial and remain subject to audit, and final data may differ materially from topline data; the initiation, timing, progress and results of its preclinical studies and clinical trials, and its research and development programs; its ability to advance therapeutic candidates into, and successfully complete, clinical trials; its interpretation of topline, interim or preliminary data from its clinical trials, including interpretations regarding disease control and disease response; results from preclinical studies or early clinical trials not necessarily being predictive of future results; unexpected adverse side effects or inadequate efficacy of its therapeutic candidates that may limit their development, regulatory approval and/or commercialization; the potential for its programs and prospects to be negatively impacted by developments relating to its competitors, including the results of studies or regulatory determinations relating to its competitors; the timing or likelihood of regulatory filings and approvals and regulatory developments in the U.S. and foreign countries; the successful commercialization of its therapeutic candidates, if approved; an accelerated development or approval pathway may not be available for ozekibart or other therapeutic candidates and any such pathway may not lead to a faster development process; it may not realize the benefits associated with orphan drug designation, including that orphan drug exclusivity may not effectively protect a product from competition and that such exclusivity may not be maintained; the pricing, coverage and reimbursement of its therapeutic candidates, if approved; its ability to utilize its technology platform to generate and advance additional therapeutic candidates; and other risks described from time to time in the "Risk Factors" section of its filings with the U.S. Securities and Exchange Commission, including those described in its Annual Report on Form 10-K, its Quarterly Reports on Form 10-Q, and supplemented from time to time by its Current Reports on Form 8-K as filed from time to time. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Inhibrx undertakes no obligation to update these statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Investor and Media Contact: Kelly Deck, CFO ir@inhibrx.com 858-795-4260 View original content to download multimedia: SOURCE Inhibrx Biosciences, Inc.

引言：死亡受体——掌握细胞命运的“生死判官” 死亡受体5（DR5，也称TRAIL-R2）是肿瘤坏死因子受体（TNFR）超家族中的一员，一种横跨细胞膜的蛋白。它的生物学使命简单而决绝：一旦被激活，就立刻向细胞下达“自杀”指令——启动程序性细胞死亡，也就是凋亡。 在人体内，DR5的天然“钥匙”是配体TRAIL（肿瘤坏死因子相关凋亡诱导配体）。天然的TRAIL以三个分子聚在一起的三聚体形式存在。当这个三聚体与DR5结合时，会把多个DR5受体在细胞表面“拉拢”到一起。这种受体聚集会在细胞内形成死亡诱导信号复合物（DISC），接着招募FADD和pro-caspase-8（半胱天冬酶原-8），最终点燃细胞内的Caspase（半胱天冬酶）级联反应，对癌细胞执行“死刑”。 为什么DR5让制药界如此着迷？ 几十年来，凭借其独特的生物学特性，DR5一直是肿瘤药物研发中的热门靶点之一： 肿瘤高选择性：DR5在多种恶性肿瘤（包括肉瘤和胃肠道癌）表面高表达，而在健康组织中表达极低。这种理论上的表达差异，为药物提供了理想的治疗窗口。 不依赖p53的活性：绝大多数传统化疗需要正常的p53基因来触发细胞死亡。而晚期肿瘤经常发生p53突变，从而产生耐药性。DR5激动剂走的是“外源性凋亡通路”，完全绕过了p53，无论肿瘤的p53突变状态如何，都能主动杀伤癌细胞。 一击毙命：与许多激酶抑制剂仅仅抑制肿瘤增殖不同，DR5激动剂直接扣动Caspase这个“行刑酶”的扳机，直接杀死作用的癌细胞。 与标准疗法协同增效：化疗引起的细胞应激常常会上调肿瘤表面的DR5表达，相当于提前给癌细胞贴上了“靶标”，让它们对DR5激动剂格外敏感。 DR5药物研发：蛋白质工程改造的经典教科书案例 纵观DR5激动剂的临床开发史，堪称一部教科书级的案例，生动诠释了结构生物学和抗体工程的重要性。 第一代产品：双价抗体的失败与临床前“物种差异”的假阳性陷阱 2000年代中期，第一波DR5激动剂进入临床。它们都是第一代双价单克隆抗体，代表药物有Conatumumab（安进）、Tigatuzumab（第一三共）、Lexatumumab（人类基因组科学公司）。  这些药物在小鼠异种移植模型中表现得相当出色，然而这其实是小鼠模型制造的一场“骗局”：人类IgG骨架能高效结合小鼠免疫细胞表面的鼠源Fcγ受体，相当于给抗体提供了一个“锚”，将其交联成巨大的多价复合物，从而成功聚集DR5。但到了人体内，肿瘤微环境中的细胞无法提供同样强大的交联作用。失去了这种鼠源特异性的结构助力，双价抗体自身并没有足够能力有效聚集DR5受体，也就无法启动下游信号传导。尽管这些药物在I期试验中整体安全性良好，并顺利推进到II期，但无一例外，均未展现出有意义的临床疗效。根本原因在于结构设计：天然TRAIL是三聚体，而这些治疗性抗体只有两个结合臂，结构上太“弱”，无法将足够多的DR5分子拉拢在一起形成必需的聚集体，导致凋亡信号无法有效激活。双价DR5激活抗体的失败，暴露了临床前数据与临床现实之间的巨大鸿沟。 第二代产品：TAS266，被抗药抗体毁掉的结构创新 前一代药物的失败教训，促使整个领域开始转变研发思路。科学家们意识到，要想在人体内有效触发凋亡通路，治疗分子本身必须具备高阶价态（High-order valency，即包含多个结合位点）。 Ablynx 公司依托其灵活的单域纳米抗体（single domain antibody, sdAb）平台开发了 TAS266。通过将四个DR5识别单域抗体串联成一个紧凑的单分子，TAS266 成功构建了独立、强效聚集 DR5 所需的多价架构，理论上赋予了该分子强劲的肿瘤杀伤能力。然而，这一结构工程上的突破，却在临床阶段演变成了一场灾难。在 I 期临床试验中，100% 的受试患者均出现了严重的、剂量限制性的肝毒性，迫使项目被紧急叫停。后续机制研究揪出了元凶：患者体内天然存在针对外源纳米抗体骨架的预存抗药抗体（PE-ADA）。这些PE-ADA像渔网一样缠住TAS266，把本已是多价的药物交联成了巨大的分子聚集网。这种失控的“过度聚集”意外将健康肝细胞上低水平DR5受体激活，引发了灾难性的广泛肝细胞凋亡。 TAS266 的折戟沉沙为行业留下了极为深刻的教训：新药的临床前研究除了要做好常规的靶点毒性评估，还必须高度警惕“预存抗药抗体”这类在动物模型中极易被忽视、却在人体中足以致命的非常规转化风险。 INBRX-109（Ozekibart）：踏着前人的肩膀前行 Inhibrx公司汲取了TAS266的惨痛教训，在其专有的单域抗体平台上设计了四价DR5激动剂INBRX-109（Ozekibart）。通过严格的高通量筛选，Inhibrx在分子设计阶段就有意避开了那些会导致TAS266肝毒性的PE-ADA结合位点。 在药物开发过程中，对不同价态候选分子的系统探索进一步印证了DR5激动剂需要何等精细的调控：四价设计的INBRX-109在保持抗肿瘤活性的同时，成功规避了肝毒性；然而，一旦将DR5结合价态升级为六价，便会因过度激活正常肝细胞上本就低表达的DR5，导致肝毒性急剧飙升。由此可见，四价正是对于DR5靶点那个在安全性与疗效之间取得“恰到好处”平衡。 source: Inhibrx corporate deck INBRX-109的临床疗效与安全性 软骨肉瘤：在针对软骨肉瘤的注册性临床试验中，Ozekibart针对这一难治性疾病取得了突破性治疗效果：中位无进展生存期（mPFS）较对照近乎翻倍(5.52个月vs 2.66个月)。疾病进展或死亡风险大幅降低了52% (风险比（HR）0.479)。这一强劲数据支撑了其近期提交的生物制品许可申请（BLA）。 结直肠癌：在一项针对末线结直肠癌患者的I/II期中期分析中，INBRX-109联合FOLFIRI化疗方案，取得了20%的客观缓解率（ORR）和87%的疾病控制率（DCR）。显著优于历史标准疗法对照。 安全性：在上述试验中，未观察到显著且意料之外的肝毒性，成功排除了历史上这一靶点的安全隐患。 土猫碎碎念： 虽然Inhibrx的专利抗体骨架排除了与已知的预存抗药抗体结合，但并不能排除在持续的用药过程中，部分患者可能产生新发的抗药抗体，引起超聚肝毒反应。 为什么疗效依然受限？未来的路在何方？ 尽管攻克了肝毒性壁垒，DR5激动剂仍然面临巨大的生物学挑战，限制了它们在更广泛实体瘤人群中的疗效： 靶点表达不均一：靶点在实体瘤内部的表达极少是均匀的。这种斑驳的异质性导致药物覆盖不足，部分癌细胞得以逃逸。 诱饵受体陷阱：人类肿瘤常常会上调诱饵受体（DcR1和DcR2）。这些受体能结合DR5药物，却缺乏传递死亡信号所需的胞内结构域，像“生物海绵”一样稀释了药物的治疗效果。 抗凋亡信号干扰：重度经治的晚期肿瘤经常可能上调胞内抗凋亡蛋白（如c-FLIP、Bcl-2或Mcl-1）。即使DR5在细胞表面成功聚集、激活DR5下游信号通路转导，这些抗凋亡蛋白也会充当“挡箭牌”，在Caspase级联反应执行死刑之前，强行切断死亡信号。 未来方向：理性联用，克服耐药 DR5激动剂眼下最迫切的出路，是基于已知的机制，保证安全、减少耐药。主要有如下三种策略： 拆除“挡箭牌”——联合凋亡调节剂 将DR5激动剂与能够中和内部抗凋亡蛋白的药物联用，例如Bcl-2/Mcl-1抑制剂或SMAC模拟物。 土猫碎碎念：虽然中和这些抗凋亡蛋白可以加深已表达DR5的癌细胞的凋亡反应，但该策略根本上依然受限于肿瘤的异质性。如果某个癌细胞克隆群本身表面就缺乏DR5，那拆掉它的内部刹车也无济于事。因此，在更广泛的临床环境中，这种方法不太可能带来突破性改变。 激活免疫荒漠——联合免疫检查点抑制剂 DR5激动剂杀死细胞时，会引发免疫原性细胞死亡（ICD），将肿瘤抗原和危险信号释放到微环境中。将DR5激动剂与PD-1/PD-L1抑制剂联用，可利用具备的抗原释放激发全身性的T细胞反应，清扫残余的异质性肿瘤克隆。 土猫碎碎念：虽然在生物学逻辑上很诱人，但现实是——单靠DR5激动剂本身将“冷”肿瘤转变为“热”肿瘤，其能力可能微乎其微。如果没有额外的免疫激活剂，这种联用可能依然难以克服晚期实体瘤极度免疫抑制的微环境。 强制上调DR5——表观遗传调控 使用HDAC抑制剂或蛋白酶体抑制剂等药物，强制改变癌细胞处理蛋白质的方式，使肿瘤强制上调DR5的转录水平。 土猫碎碎念：虽然这不是解决所有耐药机制的方法，但颇具吸引力。一是因为很多上调DR5的表观遗传调控剂本身就是标准治疗药物，与标准治疗有机结合，普适性高；二是其直击了“肿瘤异质性”这个痛点。通过迫使那些原本隐藏靶蛋白的克隆把DR5推到表面，使其重新变得敏感。 Per Aspera Ad Astra (循此苦旅，以抵繁星) 正如但丁在《神曲》中历经地狱与炼狱才最终得见天堂，DR5激动剂的成药之路同样是一场艰难曲折的朝圣。近二十年来，研发先驱们曾在第一代双价抗体毫无活性的幽暗森林中迷失，也曾跌入过第二代TAS266严重肝毒性的深渊地狱。历经抗体工程反复优化与试错的“炼狱”淬炼，如今，INBRX-109终于撕开了暗夜的一角，让人们得以窥见漫天闪烁的繁星。它首次证明了：经过精巧设计的四价单域抗体，有望在激发抗肿瘤疗效的同时，守住安全底线。这一破局者的出现，为后续的理性联用提供了一个安全、稳固的基石，为未来全面释放这一“死亡受体”潜能的临床策略铺平了道路。 免责声明与风险提示：本文的分析与推演均基于已公开披露的行业信息、临床数据、公司财报及学术文献。笔者不对相关公开信息的准确性、完整性、及时性及适用性作出任何明示或暗示的保证。所载所有内容及观点仅代表笔者个人立场，与笔者现任职、曾任职的任何机构、雇主或关联方均无任何关联，亦绝不代表上述机构的官方立场、观点或意见。本文所包含的任何内容，均不构成任何实质性的投资建议、财务建议或临床医疗指导。 Headline cover artist: Studio After Cigs Inhibrx革了Agonist的命？ 从明星药物到濒临退市——为什么肝毒性难以预测？ 实体瘤TCE临床前疗效预测的天坑—从动物模型说起 实体瘤 TCE 开发的“冠上明珠”：为何 DLL3 的成功是个特例？ “超灵敏” HIT是拯救实体瘤CAR-T的希望吗？