FDA Endorses Phase 3 Design for Oncolytic Virus in Metastatic PDAC

Theriva Biologics has received FDA agreement on the core design elements of a pivotal phase 3 trial evaluating zabilugene almadenorepvec (VCN-01) in combination with standard gemcitabine/nab-paclitaxel for the first-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). The Type B End-of-Phase 2 meeting outcome, combined with earlier guidance from the European Medicines Agency (EMA), clears a regulatory path for Theriva to finalize a confirmatory trial protocol.¹

Overall the FDA was aligned with the company’s proposed phase 3 design, which closely mirrors the phase 2b VIRAGE trial (NCT05673811). Previously reported results from the VIRAGE trial showed that zabilugene almadenorepvec plus gemcitabine/nab-paclitaxel met its primary efficacy and safety end points in 96 patients with newly diagnosed metastatic PDAC.²

The median overall survival (OS) 10.8 months in the combination arm versus 8.6 months in the control arm (HR, 0.57; 95% CI, 0.34-0.96; P = .0546). Progression-free survival (PFS) was also improved, with a median of 7.0 months versus 4.6 months (HR, 0.55; 95% CI, 0.34-0.88; P = .0105), and median duration of response (DoR) was doubled from 5.4 months to 11.2 months in the experimental arm (HR, 0.22; 95% CI, 0.08-0.62; P = .0035).²

The proposed phase 3 trial will be a single, randomized, double-blinded study comparing zabilugene almadenorepvec plus gemcitabine/nab-paclitaxel against gemcitabine/nab-paclitaxel plus placebo. The FDA expressed agreement on proposed dosing, inclusion and exclusion criteria, the primary endpoint of OS, key secondary endpoints including PFS, and use of an adaptive design. Regulators also clarified statistical expectations for planned interim analyses and data quality requirements that could support a sample size re-estimation or an early efficacy determination.¹

A notable feature of the phase 3 design is the incorporation of repeated "macrocycles" - scheduled dosing intervals that allow more than two administrations of zabilugene almadenorepvec. This approach was motivated by a subgroup observation from VIRAGE, in which treatment outcomes were highly favorable in patients who received 2 doses of the agent and at least 4 cycles of gemcitabine/nab-paclitaxel. These patients received the second dose of zabilugene almadenorepvec approximately 92 days after the first.

Mechanism of Action

Zabilugene almadenorepvec is a systemically administered, tumor-selective oncolytic adenovirus engineered to replicate preferentially within tumor cells and to degrade hyaluronan-rich tumor stroma—a physical and immunosuppressive barrier that limits chemotherapy penetration in PDAC. The compound's proposed antitumor effects include selective lysis of malignant cells, enhancement of co-administered chemotherapy perfusion into the tumor microenvironment, and augmentation of tumor immunogenicity.

Systemic delivery is intended to allow the agent to act on both the primary tumor and distant metastatic sites.¹

Safety Profile

In VIRAGE, the adverse event (AE) profile of zabilugene almadenorepvec was consistent with that observed in prior clinical trials. The most frequently reported agent-related AEs - pyrexia, flu-like illness, vomiting, nausea, and elevated transaminases - were transient and reversible. Notably, these events appeared to be less frequent and of lower Common Terminology Criteria for Adverse Events (CTCAE) grade after the second dose compared with the first. An Independent Data Monitoring Committee review concluded that the overall type and number of AEs in the experimental group were consistent with expectations for the pancreatic cancer population, the duration of treatment, and the administration of an oncolytic virus. The trial met its primary safety endpoint.

Regulatory and Development Pathway

The FDA's guidance is consistent with scientific advice previously received from the Committee for Medicinal Products for Human Use of the EMA. Both agencies have indicated that a biologics license application in metastatic PDAC could be supported by a single, high-quality, randomized, double-blinded, controlled trial, provided it meets the agreed-upon standards for data quality and statistical rigor. No Phase 3 start date or NCT number has been assigned as of this writing.

The FDA previously granted zabilugene almadenorepvec both Orphan Drug Designation and Fast Track Designation for pancreatic cancer.

REFERENCES

1. Theriva Biologics. Theriva Biologics announces positive End-of-Phase 2 meeting with U.S. FDA regarding the design of a Phase 3 trial of VCN-01 in metastatic pancreatic ductal adenocarcinoma. Press release. March 23, 2026. https://tinyurl.com/ytsx3x38

2. Theriva Biologics. Theriva Biologics announces primary endpoints for efficacy and safety achieved in VIRAGE Phase 2b clinical trial of VCN-01 with gemcitabine/nab-paclitaxel in newly diagnosed metastatic pancreatic cancer patients (NCT05673811). Press release. May 7, 2025. https://tinyurl.com/3fwa72u6