Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial.
Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial.
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DOI：
10.1016/s0140-6736(15)00239-1
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发表时间：
2015-11-21
期刊：
影响因子：
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通讯作者：
Bagarazzi ML
中科院分区：
文献类型：
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作者：
Trimble CL;Morrow MP;Kraynyak KA;Shen X;Dallas M;Yan J;Edwards L;Parker RL;Denny L;Giffear M;Brown AS;Marcozzi-Pierce K;Shah D;Slager AM;Sylvester AJ;Khan A;Broderick KE;Juba RJ;Herring TA;Boyer J;Lee J;Sardesai NY;Weiner DB;Bagarazzi ML
尽管有致癌性人乳头瘤病毒（HPV）的预防性疫苗，但宫颈上皮内瘤变（CIN）仍很常见，目前的治疗方法是消融性的，可导致长期生殖疾病。我们评估了VGX-3100，靶向HPV-16和HPV-18 E6和E7蛋白的合成质粒，通过电穿孔递送，是否会导致CIN 2/3女性的组织病理学消退。在一项随机、双盲、安慰剂对照的IIb期研究中，评估了VGX-3100在与HPV-16和HPV-18相关的CIN 2/3中的疗效、安全性和免疫原性。来自7个国家的36个学术和私人妇科诊所的患者随机（3：1）接受6 mg VGX-3100或安慰剂（1 mL），在第0、4和12周肌内给药。根据年龄（<25岁vs ≥25岁）和计算机生成的分配序列（区组大小4）对CIN 2 vs CIN 3进行随机分层。Funder和研究中心工作人员、受试者和病理学家对治疗设盲。主要疗效终点为首次给药后36周消退至CIN 1或正常病理学。符合方案分析和改良的意向治疗分析分别基于接受三次剂量且未违反方案的患者和至少接受一次剂量的患者。安全性人群包括至少接受1剂给药的所有患者。该试验在ClinicalTrials.gov（编号NCT 01304524）和EudraCT（编号2012-001334-33）上注册。2011年10月19日至2013年7月30日期间，167例患者接受VGX-3100（n=125）或安慰剂（n=42）。在符合方案分析中，107例VGX-3100接受者中有53例（49.5%）和36例安慰剂接受者中有11例（30.6%）出现组织病理学消退（百分点差异19.0 [95% CI 1.4-36.6]; p=0.034）。在改良的意向治疗分析中，114例VGX-3100接受者中有55例（48.2%）和40例安慰剂接受者中有12例（30.0%）出现组织病理学消退（百分点差异18.2 [95% CI 1.3-34.4]; p=0.034）。大多数患者发生注射部位反应，但VGX-3100组（98/125，78.4%）仅红斑显著高于安慰剂组（24/42，57.1%;百分点差异21.3 [95% CI 5.3-37.8]; p=0.007）。VGX-3100是第一个对HPV-16和HPV-18相关的CIN 2/3显示有效性的治疗性疫苗。VGX-3100可以为CIN 2/3提供非手术治疗选择，改变这种常见疾病的治疗前景。Inovio制药
Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524) and EudraCT (number 2012-001334-33). Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49.5%) of 107 VGX-3100 recipients and 11 (30.6%) of 36 placebo recipients had histopathological regression (percentage point difference 19.0 [95% CI 1.4–36.6]; p=0.034). In the modified intention-to-treat analysis 55 (48.2%) of 114 VGX-3100 recipients and 12 (30.0%) of 40 placebo recipients had histopathological regression (percentage point difference 18.2 [95% CI 1.3–34.4]; p=0.034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78.4%) than in the placebo group (24/42, 57.1%; percentage point difference 21.3 [95% CI 5.3–37.8]; p=0.007). VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Inovio Pharmaceuticals.