| Author |
Juba, Robert J. Bagarazzi, Mark L. Parker, R. Lamar Yan, Jian Lee, Jessica Shah, Divya Trimble, Cornelia L. Giffear, Mary Boyer, Jean Sylvester, Albert J. Dallas, Michael Weiner, David B. Broderick, Kate E. Slager, Anna M. Herring, Timothy A. Marcozzi-pierce, Kathleen Sardesai, Niranjan Y. Denny, Lynette Morrow, Matthew P. Kraynyak, Kimberly A. Khan, Amir Shen, Xuefei Brown, Ami Shah Edwards, Lance |
| Description |
Author Affiliation: Trimble CL ( Departments of Gynecology/Obstetrics, Oncology, and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: ctrimbl@jhmi.edu.); Morrow MP ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Kraynyak KA ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Shen X ( Inovio Pharmaceuticals, Inc, San Diego, CA, USA.); Dallas M ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Yan J ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Edwards L ( Suffolk Obstetrics & Gynecology, LLP, Port Jefferson, NY, USA.); Parker RL ( Lyndhurst Gynecologic Associates, Winston-Salem, NC, USA.); Denny L ( Department of Obstetrics & Gynaecology, University of Cape Town, Groote Schuur Hospital, Observatory Cape Town, South Africa.); Giffear M ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Brown AS ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Marcozzi-Pierce K ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Shah D ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Slager AM ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Sylvester AJ ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Khan A ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Broderick KE ( Inovio Pharmaceuticals, Inc, San Diego, CA, USA.); Juba RJ ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Herring TA ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Boyer J ( Inovio Pharmaceuticals, Inc, San Diego, CA, USA.); Lee J ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Sardesai NY ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.); Weiner DB ( Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.); Bagarazzi ML ( Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.) |
| Abstract |
BACKGROUND: 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. METHODS: 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). FINDINGS: 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). INTERPRETATION: 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. FUNDING: Inovio Pharmaceuticals. |
