Inovio's endpoint switcheroo backfires as phase 3 misses on new measure, hits on old

Inovio’s attempt to make its phase 3 trial better ended up making it worse. Eleven months after changing the primary endpoint of its late-phase cervical dysplasia study, the DNA medicine specialist has revealed the study failed against the new measure—but hit the mark on the old endpoint.

Here’s how things went down. In April, Inovio responded to the results of its first phase 3 clinical trial of VGX-3100—a DNA vaccine encoding human papilloma virus genes—and talks with the FDA by changing the primary endpoint of a second study, REVEAL2. The change narrowed the analysis to a biomarker-based subpopulation of women Inovio thought were more likely to respond to therapy, rather than all comers. 

Under the new design, the FDA no longer considered REVEAL2 to be pivotal, shutting down Inovio’s plans of filing for approval based on the data this year. Instead, the biotech would need to run one or two additional trials in the biomarker population. The REVEAL2 data suggest Inovio may have been wrong about the biomarker. 

VGX-3100 was no better than placebo at improving lesion regression and viral clearance in the biomarker-based subpopulation of women with high-grade squamous intraepithelial lesions, abnormal cells that form on the cervix and can turn cancerous. However, VGX-3100 did significantly improve lesion regression and viral clearance in the original all-participants primary endpoint population.

In the all-comers population, 27.6% of recipients of VGX-3100 met the primary endpoint, versus 8.7% of their counterparts in the placebo arm. The biomarker-selected population was much smaller—25 people versus 203 in the wider trial—and, while VGX-3100 beat placebo by 28.6% to 0%, it fell short of statistical significance with a p-value of 0.115. 

“We did expect a higher number of subjects to have the biomarker based on what we saw in REVEAL 1, Michael Sumner, Inovio’s chief medical officer, said on an analyst call. “But really, it wasn't a powering issue with the study. We genuinely saw a lower efficacy rate from the biomarker selective population. So that's what really makes us want to dig into the data and understand what went on. We're just not at the stage to do that at the moment.” 

After pooling the data with the results of the earlier phase 3 trial, Inovio reached statistical significance in both the biomarker-based and the all-comer populations. The biotech is now reviewing all of the data. Inovio CEO Jacqueline Shea, Ph.D., said the goal is to “really narrow down” and focus on the best opportunities. It is unclear whether VGX-3100 will make the cut. Inovio said the results “will be used as supportive data in any future regulatory interactions involving VGX-3100.”

The biotech ended last year with $253 million in the bank, a sum it expects to support its operations into the first quarter of 2025. Inovio’s pipeline also features a potential treatment for recurrent respiratory papillomatosis, another HPV-related disease, and a brain cancer candidate.