Vulvar HSIL remains a condition with no licensed alternatives to surgery. The recurrence rate under current surgical and medical approaches is extremely high. There is a high psychological and physical negative impact of surgery. Vulvar HSIL is symptomatic and impacts activities of daily living. Prophylactic HPV vaccines have no therapeutic activity against vulvar HSIL and have not achieved universal uptake, leaving a population of susceptible and impacted women. The early diagnosis of vulvar HSIL is limited to visual inspection with biopsy. We now present the final data for a Phase 2b study showing proof of concept against cervical HSIL of VGX-3100 an investigational DNA-based immunotherapy and present our trial design approach to studying efficacy against VIN.
For the cervical HSIL study 169 subjects were randomized: 127 subjects in the VGX 3100+EP arm and 42 in the placebo+EP arm. Female subjects aged 18 to 55 years with histologically confirmed HPV-16 or HPV-18-associated high grade CIN from tissue collected less than 10 weeks prior to the first injection/EP with no evidence of invasive cancer in any specimen were eligible. One mL of VGX-3100 (designed to enable the immunologic targeting of HPV-16 E6 and E7, and HPV-18 E6 and E7) was administered IM, followed by EP using the CELLECTRA 2000 EP system three times during the study (Day 0, Week 4, and Week 12).
The study met its primary efficacy endpoint; treatment with VGX-3100 significantly improved histologic regression of CIN2/3 to CIN1 or normal pathology during the Week 36 primary analysis period. In the mITT population, histopathological regression occurred in 48% (55/114) of the VGX-3100 recipients compared with 30% (12/40) of the placebo recipients (strata adjusted percentage point difference, 17.8; 95% CI, 1.3‑34.4; p=0.034). The secondary endpoint of concomitant histopathological regression to CIN1 or normal pathology and clearance of HPV-16 or HPV-18, or both HPV-16 and HPV-18 (virologic clearance) during the Week 36 primary analysis period after immunization with VGX-3100 was also met. In the mITT population, concomitant histopathological regression and virologic clearance occurred in 41% (46/112) of the VGX‑3100 recipients and 15% (6/40) of the placebo recipients (strata adjusted percentage point difference, 23.9; 95% CI, 9.3–38.5; p=0.001). mITT results were similar to PP.
Proof of concept was demonstrated for VGX-3100 against HPV-16 and HPV-18 associated cervical HSIL, We now propose an approach to study VGX-3100 as a treatment for HPV-16 and/or HPV-18 associated vulvar HSIL, which is an area of significant undermet medical need.
Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. 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. Lancet 2015,386:2078-2088.