National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China.
Phase I Clinical Trial Center and Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.
Front Endocrinol (Lausanne). 2023 Apr 5;14:1168757. doi: 10.3389/fendo.2023.1168757. eCollection 2023.
SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50-400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned. Twenty-one received placebo and eighty-four received SHR-1222 sequentially (100 mg QM, n=4; 200 or 300 mg QM, n=20; and 400 or 600 mg Q2M, n=20). The most common adverse events included increased blood parathyroid hormone, increased low-density lipoprotein, increased blood alkaline phosphatase, increased blood cholesterol, back pain, and arthralgia, the majority of which were mild in severity without noticeable safety concerns. Serum SHR-1222 exposure (C and AUC) increased in a greater than dose-proportional manner. Following multiple doses of SHR-1222, the bone formation markers (terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and osteocalcin) increased in a dose-dependent manner, whereas the bone resorption marker (β-C-telopeptide) was downregulated. Accordingly, BMD gains in the lumbar spine, total hip, and femoral neck were observed. The maximum BMD increase from baseline at the lumbar spine was detected in the 300 mg QM cohort (14.6% vs. 0.6% in the placebo group on day 169). Six (6/83; 7.2%) subjects developed anti-SHR-1222 antibodies with no discernible effects on PKs, PDs, and safety. Thus, multiple doses of SHR-1222 showed an acceptable safety profile and dose-dependent plasma exposure in women with POP, and could improve their BMD rapidly and prominently by promoting bone formation and inhibiting bone resorption. These findings further support SHR-1222 as a potential alternative agent for the treatment of POP.
SHR-1222 是一种新型人源化单克隆抗体，针对硬骨素。在我们之前的 I 期临床试验中，单次给药范围在 50-400mg 时，已显示出诱导骨形成和减少骨吸收的作用。这项研究是一项随机、双盲、安慰剂对照、剂量递增的 I 期临床试验，进一步研究了 SHR-1222 在绝经后骨质疏松症（POP）女性中的安全性、耐受性、药代动力学（PK）、药效学（PD）和免疫原性。共纳入 105 名 POP 女性患者，并进行了随机分组。21 名患者接受安慰剂，84 名患者接受 SHR-1222 序贯治疗（100mg QM，n=4；200 或 300mg QM，n=20；400 或 600mg Q2M，n=20）。最常见的不良事件包括甲状旁腺激素升高、低密度脂蛋白升高、碱性磷酸酶升高、胆固醇升高、背痛和关节痛，大多数不良事件的严重程度为轻度，无明显安全性问题。血清 SHR-1222 暴露（C 和 AUC）呈大于剂量比例的增加。接受 SHR-1222 多次给药后，骨形成标志物（I 型前胶原羧基端肽、骨特异性碱性磷酸酶和骨钙素）呈剂量依赖性增加，而骨吸收标志物（β-C-端肽）则被下调。因此，观察到腰椎、全髋和股骨颈的骨密度增加。腰椎骨密度从基线的最大增加在 300mg QM 组中检测到（第 169 天安慰剂组为 0.6%，而 14.6%）。6 名（6/83；7.2%）受试者产生抗 SHR-1222 抗体，对 PK、PD 和安全性无明显影响。因此，在 POP 女性中，多次 SHR-1222 给药显示出可接受的安全性和剂量依赖性的血浆暴露，并可通过促进骨形成和抑制骨吸收快速显著地改善骨密度。这些发现进一步支持 SHR-1222 作为治疗 POP 的潜在替代药物。
