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Abstract：
BACKGROUND: Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs).
METHODS: This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations.
RESULTS: The study enrolled 49 HVs, with a median age of 39 (range 18-73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition.
CONCLUSIONS: RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy.
BACKGROUND: ISRCTN13175485.
METHODS: This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations.
RESULTS: The study enrolled 49 HVs, with a median age of 39 (range 18-73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition.
CONCLUSIONS: RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy.
BACKGROUND: ISRCTN13175485.
摘要：
背景：转化生长因子β（TGFβ）细胞因子（TGFβ1、TGFβ2和TGFβ3）在组织纤维化中起关键作用。然而,用全身性泛TGFβ抑制剂治疗已显示出不可接受的毒性。在这项研究中,我们评估了安全性，耐受性,药代动力学，和RO7303509的药效学，高亲和力，TGFβ3特异性，人源化免疫球蛋白G1单克隆抗体，在健康的成人志愿者（HVs）。
方法：此阶段1a，随机化，双盲试验包括六个队列进行评估，每个队列接受单剂量的安慰剂或RO7303509，静脉内给药（IV；50mg，150毫克，240毫克）或皮下（SC；240毫克，675毫克，1200毫克)。在整个研究中监测不良事件(AE)的频率和严重程度以及RO7303509血清浓度。我们还通过免疫测定法测量了血清骨膜素和软骨寡聚基质蛋白（COMP），并开发了群体药代动力学模型来表征RO7303509血清浓度。
结果：该研究招募了49辆HV，年龄中位数为39岁（18-73岁）。10名（27.8%）接受RO7303509治疗的受试者报告了24例不良事件，6名(30.8%)安慰剂治疗的受试者报告了6例AE。与研究药物相关的最常见的AE是注射部位反应和输注相关反应。RO7303509的最大血清浓度(Cmax)和从时间0到无穷大的浓度-时间曲线下面积(AUC0-inf)值似乎在所有测试剂量中剂量成比例地增加。队列中的血清浓度最好通过两室模型加上具有一级SC吸收动力学的储库室来表征。没有受试者在基线测试为阳性的抗药物抗体(ADAs);一名受试者(2.8%;50mgIV)在单个时间点(第15天)测试为阳性的ADAs。在TGFβ3抑制后，骨膜素或COMP未观察到明显的药效学作用。
结论：RO7303509在单SC剂量高达1200mg的HV中具有良好的耐受性，具有良好的药代动力学数据，似乎剂量成比例增加。TGFβ3特异性抑制可能适合发展为慢性抗纤维化疗法。
背景：ISRCTN13175485。
方法：此阶段1a，随机化，双盲试验包括六个队列进行评估，每个队列接受单剂量的安慰剂或RO7303509，静脉内给药（IV；50mg，150毫克，240毫克）或皮下（SC；240毫克，675毫克，1200毫克)。在整个研究中监测不良事件(AE)的频率和严重程度以及RO7303509血清浓度。我们还通过免疫测定法测量了血清骨膜素和软骨寡聚基质蛋白（COMP），并开发了群体药代动力学模型来表征RO7303509血清浓度。
结果：该研究招募了49辆HV，年龄中位数为39岁（18-73岁）。10名（27.8%）接受RO7303509治疗的受试者报告了24例不良事件，6名(30.8%)安慰剂治疗的受试者报告了6例AE。与研究药物相关的最常见的AE是注射部位反应和输注相关反应。RO7303509的最大血清浓度(Cmax)和从时间0到无穷大的浓度-时间曲线下面积(AUC0-inf)值似乎在所有测试剂量中剂量成比例地增加。队列中的血清浓度最好通过两室模型加上具有一级SC吸收动力学的储库室来表征。没有受试者在基线测试为阳性的抗药物抗体(ADAs);一名受试者(2.8%;50mgIV)在单个时间点(第15天)测试为阳性的ADAs。在TGFβ3抑制后，骨膜素或COMP未观察到明显的药效学作用。
结论：RO7303509在单SC剂量高达1200mg的HV中具有良好的耐受性，具有良好的药代动力学数据，似乎剂量成比例增加。TGFβ3特异性抑制可能适合发展为慢性抗纤维化疗法。
背景：ISRCTN13175485。
