Clinical Trials

Date: 2015-09-17

Type of information: Publication of results in a medical journal

phase: 2b

Announcement: publication of results in The Lancet

Company: Inovio Pharmaceuticals (USA - PA)

Product: VGX-3100

Action mechanism: immunotherapy product. VGX-3100 is an immunotherapy containing two DNA plasmids targeting the E6 and E7 oncogenes of HPV types 16 and 18. The treatment is administered to patients by injection into muscle (typically in the arm), followed by electroporation using Inovio\'s Cellectra® device. VGX-3100 has been shown to induce a robust immune response against the E6 and E7 oncogenes associated with HPV types 16 and 18. These oncogenes are responsible for transforming HPV-infected cells into pre-cancerous and cancerous cells. Apart from this cervical dysplasia study, Inovio is also conducting studies using this immunotherapy against cervical as well as head and neck cancers caused by these HPV types.

Disease: cervical intraepithelial neoplasia 2/3 (CIN2/3) associated with human papillomavirus (HPV) types 16 or 18

Therapeutic area: Infectious diseases - Women health - Cancer - Oncology

Country: Australia, Canada, Estonia, Georgia, India, Republic of Korea, Puerto Rico, South Africa, USA

Trial details: immunotherapy product. HPV-003 is a phase II, randomized, placebo-controlled, double-blind study of women with CIN2 or CIN3 who were randomized 3:1 to the active and placebo groups. Women in the active group received three 6 mg doses of VGX-3100 in a 1 mL intramuscular injection followed by electroporation with Inovio\'s CELLECTRA® device at weeks 0, 4, and 12. Cervical tissue was examined before starting blinded treatment and 9 months later. (NCT01304524)  

Latest news:

• • On September 17, 2015, Inovio Pharmaceuticals announced that The Lancet published a peer-reviewed article detailing the successful results of its phase 2b trial with VGX-3100 in treating women with high grade cervical neoplasia. Previously, medical researchers have tried to stimulate therapeutic immune responses against the human papillomavirus (HPV) and cervical lesions with little success. This publication details that VGX-3100, a first-in-class product for treating high grade cervical neoplasia associated with HPV, is the first therapy to demonstrate that activated killer T cells induced in the body have the power to clear neoplastic lesions as well as the virus which caused the disease.
• Results of the trial were reported in the article entitled, “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 randomized, double-blind, placebo-controlled phase 2b trial,” by C. Trimble, et al. Dr. Cornelia Trimble, Professor of Gynecology and Obstetrics, Oncology, and Pathology at Johns Hopkins School of Medicine, was the principal investigator for the study. Specifically, the phase 2b trial showed that histopathological regression of high grade cervical neoplasia (CIN2/3) to low grade neoplasia (CIN 1) or no disease occurred in a significantly higher percentage of VGX-3100 recipients compared with placebo recipients. Furthermore, concomitant histopathological regression and clearance of HPV occurred in a significantly higher percentage of VGX-3100 recipients compared with placebo recipients. HPV-specific CD8+ “killer T cells” were also generated in the blood as well as a substantial infiltration of CD8+ cells in the cervical tissue of VGX-3100 recipients, underscoring the role played by Inovio’s best-in-class T-cell responses. VGX-3100 was safe and generally well-tolerated.
• In VGX-3100-treated women who regressed their lesion, most (43 out of 53) completely cleared their lesions to normal (complete response). Moreover, eighty percent of VGX-3100-treated women who regressed their lesion also eradicated the infecting HPV genotype (i.e. 16 or 18) in the cervix. This is an important outcome as persistence of the virus is associated with recurrence of the disease. All data analyzed per protocol or modified intent to treat were similar with equal statistical significance.
• Analyses of patient immune responses showed that overall antigen-specific T cell levels in women treated with VGX-3100 were greater than those treated by placebo at all observation periods. At week 14, T cell levels in women treated with VGX-3100 were ten times greater than those in the placebo group.
• Patients who regressed their lesions had higher frequencies of HPV-specific CD8+T cells which co-expressed key molecules important in T cell killing cascade and directly correlated with clinical efficacy. Specifically, we determined that higher levels of CD8+ killer T cells which co-expressed checkpoint molecule CD137 on their surface as well as the cytolytic protein perforin could be a predictive tool for efficacy. As a strong activation marker for CD8+ T cells, stimulation through CD137 has been shown in some systems to confer resistance of CD8+ T cells to the suppressive activity of regulatory T cells and its presence can identify tumor reactive T cells. Perforin is a pore-forming protein deployed by killer T cells to bore holes into the target cell\'s plasma membrane and destroy the cell. In fact, the difference in frequencies of CD8+ cells expressing CD137 and perforin was greatest in patients who had both regressed their lesions and cleared HPV compared to patients who did not.
• • On July 23, 2014, Inovio Pharmaceuticals announced successful results from its randomized, double-blind, placebo-controlled phase II trial of VGX-3100 in women with biopsy-proven cervical intraepithelial neoplasia 2/3 (CIN2/3) associated with human papillomavirus (HPV) types 16 or 18. Treatment with VGX-3100 resulted inhistopathological regression of CIN2/3 to CIN1 or no disease, meeting the study\'s primary endpoint. In addition, the trial demonstrated clearance of HPV in conjunction with regression of cervical lesions. Robust T-cell activity was detected in subjects who received VGX-3100 compared to those who received placebo. Treatment was randomized 3:1 between the VGX-3100 and placebo groups, and was stratified by age and severity of CIN. The primary endpoint, histologic regression, was evaluated 36 weeks after the first treatment. In the per protocol analysis, CIN2/3 resolved to CIN1 or no disease in 53 of 107 (49.5%) women treated with VGX-3100 compared to 11 of 36 (30.6%) who received placebo. This difference was statistically significant (p<0.025). Virological clearance of HPV 16 or 18 from the cervix in conjunction with histopathological regression of cervical dysplasia to CIN1 or no disease, a secondary endpoint of the trial, was observed in 43 of 107 (40.2%) VGX-3100 recipients compared to 5 of 35 (14.3%) placebo recipients (p<0.025). As in the phase I study, VGX-3100 elicited robust HPV-specific T cell responses in the majority of treated subjects. A comprehensive analysis of T cell responses is ongoing.
• The treatment was generally well-tolerated, with only administration site redness occurring significantly more frequently in the VGX-3100 group compared to the placebo group in the 7- and 28-day periods following treatment. Topline results will be presented at the 2014 International Society of DNA Vaccines Conference in San Diego, on July 23, 2014. Detailed study findings will be submitted for publication in a peer-reviewed scientific journal.

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