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).

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.

Figure 1. Trial profile

*One patient had no viral clearance data and could not be included in the secondary endpoint analysis.

Figure 2. Clinical efficacy

Percentage of patients with histopathological regression or concomitant histopathological regression and viral clearance at week 36 in VGX-3100 and placebo groups in (A) the per-protocol analysis and (B) the modified intention-to-treat analysis. (C) Histopathological regression to normal for per-protocol and modified intention-to-treat analyses. (D) Effect of mixed infections including HPV-16 (left) compared with HPV-16 mono-infection (right) on rates of histopathological regression and viral clearance. HPV=human papillomavirus.

Figure 3. Immune responses to VGX-3100

(A) Interferon γ ELISpot responses to HPV-16 and HPV-18 E6 and E7 in VGX-3100 and placebo groups. (B) Change in T-cell responses to infecting genotype E6 in patients treated with VGX-3100 who had both histopathological regression and viral clearance versus those who did not at study week 14. Horizontal lines within boxes show median response. (C) Representative flow cytometric plot of HPV-specific upregulation of CD137 and perforin in CD8 T cells before and after VGX-3100 (left). Frequencies of CD137⁺ CD8⁺ T cells expressing perforin in patients treated with VGX-3100 who had both histopathological regression and viral clearance, versus those who did not, at study week 14 (right). Horizontal lines within boxes show median response. (D) Kinetics of antibody responses to HPV-16 and HPV-18 E7 in VGX-3100 and placebo groups; p values for the difference between treatment groups were calculated at each timepoint for both antigens, and the maximum p value is displayed at each timepoint. Arrows show timing of a dose. HPV=human papillomavirus. PBMC=peripheral blood mononuclear cells. SFU=spot-forming units.