title: 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.
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).
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Inovio Pharmaceuticals.
authors.affiliation: Departments of Gynecology/Obstetrics, Oncology, and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: ctrimbl@jhmi.edu.
authors.forename: Cornelia L
authors.initials: CL
authors.lastname: Trimble
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Morrow
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kraynyak
authors.affiliation: Inovio Pharmaceuticals, Inc, San Diego, CA, USA.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Shen
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Dallas
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Suffolk Obstetrics & Gynecology, LLP, Port Jefferson, NY, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Edwards
authors.affiliation: Lyndhurst Gynecologic Associates, Winston-Salem, NC, USA.
authors.forename: R Lamar
authors.initials: RL
authors.lastname: Parker
authors.affiliation: Department of Obstetrics & Gynaecology, University of Cape Town, Groote Schuur Hospital, Observatory Cape Town, South Africa.
authors.forename: Lynette
authors.initials: L
authors.lastname: Denny
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Giffear
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Ami Shah
authors.initials: AS
authors.lastname: Brown
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Marcozzi-Pierce
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Shah
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Slager
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Sylvester
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Khan
authors.affiliation: Inovio Pharmaceuticals, Inc, San Diego, CA, USA.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Broderick
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Juba
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Herring
authors.affiliation: Inovio Pharmaceuticals, Inc, San Diego, CA, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Boyer
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lee
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Niranjan Y
authors.initials: NY
authors.lastname: Sardesai
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
authors.affiliation: Inovio Pharmaceuticals, Inc, Plymouth Meeting, PA, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Bagarazzi
mesh_terms: D000328:Adult; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology; D052161:Human papillomavirus 18 / Q000235:genetics / Q000276:immunology; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000821:virology; D053918:Papillomavirus Vaccines / Q000276:immunology / Q000627:therapeutic use*; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000821:virology; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use*; D055815:Young Adult; D002578:Uterine Cervical Dysplasia / Q000188:drug therapy* / Q000821:virology
chemical_list: D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D053918:Papillomavirus Vaccines; D012097:Repressor Proteins; C000604121:VGX-3100; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16