Pexastimogene devacirepvec
JX-594 is an oncolytic virus is designed to target and destroy cancer cells. It is also known as Pexa-Vec, INN pexastimogene devacirepvec) and was constructed in Dr. Edmund Lattime's lab at Thomas Jefferson University, tested in clinical trials on melanoma patients, and licensed and further developed by SillaJen.
JX-594 is a modified Copenhagen strain vaccinia poxvirus engineered by addition of the GM-CSF gene and deletion of the thymidine kinase gene which limits viral replication to cells with high levels of thymidine kinase, typically seen in cancer cells with a mutated RAS or p53 gene. The virus also has the LacZ gene insertion under control of the p7.5 promoter. The virus kills the infected/cancer cells by lysis and also expresses GM-CSF which may help initiate an anti-tumour immune response.
It has orphan drug designation from US Food and Drug Administration and EUMA for the treatment of hepatocellular carcinoma.
In clinical trials doses have been administered by intratumoral or intravenous injection.
Technology
Pexa-Vec is the most advanced product candidate from SillaJen's proprietary SOLVE™ platform. SOLVE is used to optimize virus targeting to specific cancer types, to select transgenes to include into the viral genome, and to optimize viral infection and/or replication selectively through targeted mutations.Oncolytic viruses could have 3-prolonged attack on cancer: direct cell lysis with replication and spread, immune activation, and antivascular
- Tumor selective intratumoral replication of the virus leads to lysis of the infected cancer cell and spread to adjacent cancer cells
- Induction of tumor-specific cytotoxic T-lymphocytes and “arming” for expression of therapeutic transgene products enhance immune response to the tumor
- Blood flow to tumors can be blocked following intratumoral replication and spreadJX-900 : VVDD Platform: Next-gen enhanced oncolytic immunotherapy.
- JX-900 is a series of modified vaccinia vaccine with enhanced oncolytic potency
- Attenuation via “Double-Deletion” : thymidine kinase and vaccinia growth factor gene inactivation
- JX-929 experience in solid tumors
- JX-970 next generation of the VVDD series
Clinical trials
A phase 3 randomized, open-label, clinical trial of Pexa-Vec plus sorafenib versus sorafenib is being conducted on patients with advanced hepatocellular carcinoma who have not previously received any systemic therapy. The study is being done to determine and compare overall survival for patients in the two treatment arms. The study is Sponsored by SillaJen, Inc.Mechanism of Action of Pexa-Vec (Jx-594)
The experimental therapy, Pexa-Vec, is an attenuated vaccinia virus engineered to stimulate anti-tumor immunity and directly lyse tumor cells. Pexa-Vec has cancer selectivity through the deactivation of its thymidine kinase gene, and it has been engineered to express the granulocyte-macrophage colony-stimulating factor gene to stimulate a systemic anti-tumor immune response. Researchers believe that Pexa-Vec may be a systemic treatment of hepatocellular carcinoma by inducing tumor necrosis and shrinkage of both injected and non-injected tumors after direct intratumoral delivery. Final data from a randomized dose-ranging phase 2 study of Pexa-Vec in mainly sorafenib naïve patients with advanced hepatocellular carcinoma demonstrated that the risk of death for patients who received Pexa-Vec at the high dose was markedly reduced when compared to patients randomized to a low dose control. The median overall survival for high and low dose groups was 14.1 months versus 6.7 months, respectively. Pexa-Vec was well tolerated, with patients experiencing transient flu-like symptoms that generally resolved within 24 hours.these are the clinical trials investigating Pexa-Vec.
| Indication | Phase | Status | Notes | Sponsor | Ref |
| Hepatocellular carcinoma | III | Recruiting | Combined with sorafenib | SillaJen | NCT02562755 |
| Solid Tumors | II | Recruiting | Combined with metronomic cyclophosphamide | Investigator | NCT02630368 |
| Renal Cell Carcinoma 2L | I | Recruiting | Combined with REGN2810 | SillaJen | NCT03294083 |
| Colorectal Cancer 2L/3L | I | Recruiting | Combined with PD-L1 and CTLA4 | Investigator | |
| Liver Cancer | I | Recruiting | Combined with Nivolumab | Transgene | NCT03071094 |
| Solid Tumors | I | Recruiting | Combined with Ipilimumab | Investigator | NCT02977156 |
Study Design
Participants will be randomly assigned to one of two treatment arms, having an equal chance of receiving either Pexa-Vec followed by sorafenib, or sorafenib alone.Arm A: Pexa-Vec followed by sorafenib
- Participants will visit the study center approximately 14 times over 18 weeks.
- All Pexa-Vec treatments will be given by intratumoral injections into liver tumors.
- Following Pexa-Vec injection series completion, patients will receive sorafenib starting at week 6 of the study
Arm B: sorafenib
- Participants will visit the study center approximately 12 times over 18 weeks and receive sorafenib as per standard of care.