DNA-Based Immunotherapy Effective in Phase 3 Cervical Dysplasia Study

Mark Einstein, MD, MS, FACS, FACOG

The DNA-based HPV-specific immunotherapy VGX-3100 led to a 12.4% percentage point difference in regression of high-grade squamous intraepithelial lesions (HSIL) and HPV-16 and/or HPV-18 clearance at week 36 compared with matched placebo for women with cervical dysplasia, according to topline findings from the phase 3 REVEAL 1 trial.

These findings were from a protocol-defined modified intention to treat (mITT) cohort, which only included those with assessable end point data (n = 193). In this group, HSIL regression and virologic clearance was experienced by 23.7% of patients treated with VGX-3100 compared with 11.3% of those in the placebo group (P = .022; 12.4% difference; 95% CI, 0.4%-22.5%). In the full intent-to-treat population (ITT; n = 201), a non-statistically significant 11.4% percentage difference was observed between groups (P = .029; 95% CI, -0.4 to 21.2).

"These results are very encouraging and show that we are headed in the right direction," principal investigator Mark Einstein, MD, MS, FACS, FACOG, Professor and Chair, Department of OB/GYN & Women's Health, at Rutgers Health, said in a statement. "There is a very significant need for a non-surgical therapeutic for young women suffering from HPV-associated cervical dysplasia."

For the INOVIO DNA medicine, a computer algorithm designed by the company, called SynCon, first identifies how best to alter a DNA plasmid sequence to target a specific application. The plasmid is then genetically edited to encode the antigen and then the optimized plasmids are grown, manufactured, and delivered to the patient intramuscularly or intradermally. During plasmid administration, a hand-held device labeled Cellectra is used for electroporation. Once in the cells, the plasmids encode the antigen, which is recognized by the immune system and results in a T cell and antibody-mediated immune response. This allows for targeting of a broad set of diseases, from cancer to viruses.

The REVEAL study included 201 patients who were at least 18 years of age or older with histologically confirmed cervical HSIL associated with HPV-16 and/or HPV-18. The patients were randomized 2:1 to receive either VGX-3100 (n = 138) or placebo (n = 63) on weeks 0, 4, and 12. HPV-16 and HPV-18 were assessed in the trial using the cobas HPV test from ThinPrep samples.

INOVIO noted that differences between the ITT and mITT were related to a number of withdrawals from the study prior to assessment at week 36. Overall, 3 patients were lost to follow-up for undetermined reasons, 1 patient was randomized but not treated due to pregnancy, 1 withdrew due to an administration error, and 1 was lost to follow-up due to COVID-19 restrictions.

In the mITT, all secondary end points were also achieved, including regression of cervical HSIL to normal tissue alone and combined with HPV-16/18 viral clearance as well as virologic clearance alone. For the ITT group, the primary end point was met for 22.5% of patients compared with 11.1% in the placebo group. All secondary end points were significantly met in the ITT group, except for regression of cervical HSIL alone (12.8% difference in percentage; 95%CI, -0.6 to 24.5).

There were no treatment-related serious adverse events, according to the company, and most adverse events were mild to moderate and self-resolving. Full data from the study are being analyzed. INOVIO hopes to present the findings later this year at a scientific meeting.

"INOVIO is very proud to advance VGX-3100 as the first DNA medicine to achieve efficacy end points in a phase 3 clinical trial in all evaluable subjects," J. Joseph Kim, PhD, president and CEO of INOVIO, said in a release. "We expect VGX-3100, if approved, to be an important therapeutic option for those impacted by HPV-16-/18-related disease. The REVEAL 1 efficacy and safety data also represent an important proof-of-platform for INOVIO's DNA medicines."

INOVIO is working closely with QIAGEN to co-develop an RNA-based blood test to help guide treatment with VGX-3100. In a phase 2 study exploring the in vitro biomarker diagnostic, those identified as positive experienced an 85% regression of HPV-16- and/or HPV-18-associated cervical HSIL with VGX-3100. Targeting the immunotherapy will be an important next phase in the development, according to the company.

"Through our ongoing partnership with QIAGEN, we also plan to develop complementary a biomarker diagnostic test that would enable practitioners to more effectively identify women expected to respond to VGX-3100," Prakash Bhuyan, MD, PhD, senior vice president and Head of HPV Therapeutic Clinical Development at INOVIO, said in a statement. “"We thank the investigators, site personnel, and patients who made this research possible. We are excited to be developing a new therapeutic designed to advance women's health.”