Offman Elliot, Singh Noopur, Julian Mark W, Locke Landon W, Bicer Sabahattin, Mitchell Jonah, Matthews Thomas, Anderson Kirsten, Crouser Elliott D
Certara, Princeton, NJ, United States.
Xentria, Inc., Chicago, IL, United States.
Front Pharmacol. 2023 Mar 20;14:1066454. doi: 10.3389/fphar.2023.1066454. eCollection 2023.
Sarcoidosis is a chronic, multisystem inflammatory disorder characterized by non-caseating epithelioid granulomas; infiltration of mononuclear cells; and destruction of microarchitecture in the skin, eye, heart, and central nervous system, and the lung in >90% of cases. XTMAB-16 is a chimeric anti-tumor necrosis factor alpha (TNFα) antibody, distinct from other anti-TNF antibodies based on its molecular structure. The efficacy of XTMAB-16 has not been clinically demonstrated, and it is still undergoing clinical development as a potential treatment for sarcoidosis. The current study demonstrates the activity of XTMAB-16 in a well-established sarcoidosis granuloma model, although XTMAB-16 is not yet approved by the United States Food and Drug Administration (FDA) for treatment of sarcoidosis, or any other disease. To provide data to guide safe and efficacious dose selection for the ongoing clinical development of XTMAB-16 as a potential treatment for sarcoidosis. First, XTMAB-16 activity was evaluated in an established model of granuloma formation using peripheral blood mononuclear cells from patients with active pulmonary sarcoidosis to determine a potentially efficacious dose range. Second, data obtained from the first-in-human study of XTMAB-16 (NCT04971395) were used to develop a population pharmacokinetic (PPK) model to characterize the pharmacokinetics (PK) of XTMAB-16. Model simulations were performed to evaluate the sources of PK variability and to predict interstitial lung exposure based on concentrations in the granuloma model. XTMAB-16 dose levels of 2 and 4 mg/kg, once every 2 weeks (Q2W) or once every 4 weeks (Q4W) for up to 12 weeks, were supported by data from the non-clinical, secondary pharmacology; the Phase 1 clinical study; and the PPK model developed to guide dose level and frequency assumptions. XTMAB-16 inhibited granuloma formation and suppressed interleukin-1β (IL-1β) secretion in the granuloma model with a half maximal inhibitory concentration (IC) of 5.2 and 3.5 μg/mL, respectively. Interstitial lung concentrations on average, following 2 or 4 mg/kg administered Q2W or Q4W, are anticipated to exceed the IC concentrations. The data presented in this report provide a rationale for dose selection and support the continued clinical development of XTMAB-16 for patients with pulmonary sarcoidosis.
结节病是一种慢性多系统炎症性疾病，其特征为非干酪样上皮样肉芽肿、单核细胞浸润以及皮肤、眼睛、心脏、中枢神经系统和肺部（超过90%的病例）的微结构破坏。XTMAB - 16是一种嵌合型抗肿瘤坏死因子α（TNFα）抗体，基于其分子结构与其他抗TNF抗体不同。XTMAB - 16的疗效尚未在临床上得到证实，它仍在作为结节病的潜在治疗方法进行临床开发。目前的研究证明了XTMAB - 16在一个成熟的结节病肉芽肿模型中的活性，尽管XTMAB - 16尚未获得美国食品药品监督管理局（FDA）批准用于治疗结节病或任何其他疾病。为正在进行的将XTMAB - 16作为结节病潜在治疗方法的临床开发提供数据，以指导安全有效的剂量选择。首先，使用活动性肺结节病患者的外周血单核细胞，在一个已建立的肉芽肿形成模型中评估XTMAB - 16的活性，以确定一个潜在有效的剂量范围。其次，从XTMAB - 16的首次人体研究（NCT04971395）中获得的数据用于建立一个群体药代动力学（PPK）模型，以表征XTMAB - 16的药代动力学（PK）。进行模型模拟以评估PK变异性的来源，并根据肉芽肿模型中的浓度预测肺间质暴露情况。非临床、二级药理学研究、1期临床研究以及为指导剂量水平和频率假设而建立的PPK模型的数据支持了每2周（Q2W）或每4周（Q4W）一次给予2和4mg/kg的XTMAB - 16剂量水平，持续12周。在肉芽肿模型中，XTMAB - 16抑制肉芽肿形成并抑制白细胞介素 - 1β（IL - 1β）分泌，其半数最大抑制浓度（IC）分别为5.2和3.5μg/mL。预计每2周或每4周给予2或4mg/kg后，肺间质平均浓度将超过IC浓度。本报告中呈现的数据为剂量选择提供了理论依据，并支持XTMAB - 16继续用于肺结节病患者的临床开发。
