Zabilugene Almadenorepvec Plus Chemo Shows Survival Gains in Metastatic PDAC

According to findings from the phase 2b VIRAGE trial (NCT05673811) published in Nature Medicine, the addition of zabilugene almadenorepvec to gemcitabine and nab-paclitaxel (GnP) was associated with longer overall survival (OS), progression-free survival (PFS), and duration of response compared with GnP alone in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC).^1,2

In the full analysis set, which included 48 patients in each treatment group, median OS was 10.8 months with zabilugene almadenorepvec plus GnP compared with 8.6 months with GnP alone (HR, 0.57; 95% CI, 0.34-0.96; P =.055). Median PFS was 7.0 months and 4.6 months, respectively (HR, 0.55; 95% CI, 0.34-0.88; P =.011). The primary efficacy end point for OS was met in the full analysis set population.

In addition to the OS and PFS findings, duration of response was 11.2 months with the combination vs 5.4 months with GnP alone (HR, 0.22; 95% CI, 0.08-0.63; P =.004). Survival rates were 35.5% vs 12.8% at 15 months and 31.1% vs 8.5% at 18 months.

Regarding safety, the most frequent zabilugene almadenorepvec-related adverse events included pyrexia, flu-like symptoms, elevated liver enzymes, and decreased platelet counts. Serious adverse events occurred in 22.6% of patients. Toxicity was generally milder after the second administration. Two fatal events occurred, 1 in each treatment group, and neither was considered related to study treatment.

“As elaborated in the publication, improved [OS, PFS], and duration of response were observed in [patients with] metastatic pancreatic cancer treated with [zabilugene almadenorepvec] combined with standard-of-care (SOC) gemcitabine/nab-paclitaxel chemotherapy compared to patients receiving SOC chemotherapy alone. Moreover, the Kaplan-Meier survival analysis and the timing of responses in [zabilugene almadenorepvec]-treated patients suggest an immune mediated mechanism of action for [zabilugene almadenorepvec] in addition to its stroma degrading effects,” Manel Cascalló, PhD, general director of Theriva Biologics and study co-author, stated in a news release. “We are excited about the potential for [zabilugene almadenorepvec] in different cancer therapy combinations, and we are extremely grateful to the patients who participated in VIRAGE, their families, our clinical investigators and their teams, and our co-authors for their commitment, dedication and diligence.”

About Zabilugene Almadenorepvec

Zabilugene almadenorepvec is a systemically administered, tumor-selective oncolytic adenovirus designed to replicate in tumor cells and degrade hyaluronan-rich tumor stroma. This mechanism is intended to facilitate chemotherapy access to the tumor microenvironment and increase tumor immunogenicity.

About VIRAGE and Prior Data

VIRAGE was a randomized, open-label phase 2b trial evaluating first-line zabilugene almadenorepvec plus GnP vs GnP alone in newly diagnosed metastatic PDAC.³ Patients received intravenous zabilugene almadenorepvec 7 days before the first and fourth cycles of GnP, approximately 14 weeks apart.

Prior VIRAGE data presented at the 2025 European Society for Medical Oncology (ESMO) Congress showed greater survival outcomes among patients who received both planned doses. In a subgroup of patients who started cycle 4, median OS was 14.8 months with zabilugene almadenorepvec plus GnP vs 11.6 months with GnP alone (HR, 0.44; 95% CI, 0.21-0.92; P =.046).

Next Steps in Development

Earlier this year, the FDA aligned with the sponsor on core elements of a potential phase 3 design during a type B end-of-phase 2 meeting. The design, closely mirroring VIRAGE, includes a randomized, double-blind comparison of zabilugene almadenorepvec plus GnP vs GnP plus placebo, with OS as the primary end point and PFS as a key secondary end point.

The ongoing phase 2a VIRAGE2 trial (NCT07701486), launched after the FDA’s feedback, is evaluating more frequent repeat dosing of zabilugene almadenorepvec with GnP, with at least 3 doses administered approximately 2 months apart. Findings from VIRAGE2 are intended to inform the dosing regimen for subsequent phase 3 clinical development.

REFERENCES

1. Garcia-Carbonero R, Pazo Cid R, Macarulla T, et al. Intravenous hyaluronidase-expressing oncolytic adenovirus with chemotherapy in metastatic pancreatic cancer: a randomized phase 2b trial. Nature Med. Published online September 30, 2026. doi:10.1038/s41591-026-04705-y

2. Theriva™ Biologics Announces Publication of the Results from the VIRAGE Phase 2b Clinical Trial of VCN-01 in Metastatic Pancreatic Cancer Published in Nature Medicine. News release. Theriva Biologics. September 30, 2026. Accessed October 1, 2026. https://tinyurl.com/36rwdszf

3. Study of Nab-Paclitaxel and Gemcitabine and Plus/​Minus VCN-01 in Patients With Metastatic Pancreatic Cancer (VIRAGE). ClinicalTrials.gov. Updated April 16, 2026. Accessed October 1, 2026. https://clinicaltrials.gov/study/NCT05673811