Pexastimogene devacirepvec

JX-594 is an oncolytic virus (also known as Pexa-Vec,[1] INN pexastimogene devacirepvec[2]) originally constructed in Dr. Edmund Lattime's lab at Thomas Jefferson University and tested in clinical trials in melanoma patients; later licensed and further developed by SillaJen, Inc. Pexa-Vec is designed to target and destroy cancer cells.[3]

JX-594 is a modified Copenhagen[4] strain (or Wyeth strain[2]) 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.[5] The virus also has the LacZ gene insertion under control of the p7.5 promoter.[2] The virus kills the infected/cancer cells by lysis and also expresses GM-CSF which may help initiate an anti-tumour immune response.[6][7] [8]

It has orphan drug designation from US FDA and EUMA for the treatment of hepatocellular carcinoma (HCC).[1]

In clinical trials doses have been administered by intratumoral or intravenous injection.[2]

Technology

Pexa-Vec (JX-594) is the most advanced product candidate from SillaJen's proprietary SOLVE™ (Selective Oncolytic Vaccinia Engineering) platform.[9]

SOLVE™ (Selective Oncolytic Vaccinia Engineering) platform:[9] This platform 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 Virus could have 3-prolonged attack on cancer : direct cell lysis with replication and spread, immune activation, and antivascular[10][11][12][13]

  • Tumor selective intratumoral replication of the virus leads to lysis of the infected cancer cell and spread to adjacent cancer cells[14]
  • Induction of tumor-specific cytotoxic T-lymphocytes and “arming” for expression of therapeutic transgene products (e.g. GM-CSF) enhance immune response to the tumor[14]
  • Blood flow to tumors can be blocked following intratumoral replication and spread[14]JX-900 (VVDD):[15] VVDD Platform: Next-gen enhanced oncolytic immunotherapy.[16]

JX-900 (VVDD):[15] VVDD Platform: Next-gen enhanced oncolytic immunotherapy.[16]

  • JX-900 is a series of modified vaccinia vaccine (Western Reserve strain) with enhanced oncolytic potency
  • Attenuation via “Double-Deletion” : TK (thymidine kinase) & VGF (vaccinia growth factor) gene inactivation
  • JX-929 (vvDD expressing CD for 5-FU pro-drug) experience in solid tumors (CRC and melanoma)
  • JX-970 (vvDD expressing GM-CSF) next generation of the VVDD series

Clinical trials

The PHOCUS Study is a phase 3 randomized, open-label, trial of Pexa-Vec plus sorafenib versus sorafenib in patients with advanced HCC who are systemic therapy naive. The study is being conducted to determine and compare overall survival for patients in the two treatment arms. The PHOCUS Study may provide another potential treatment option to patients.[17] The PHOCUS trial is Sponsored by SillaJen, Inc.[18]

Mechanism of Action of Pexa-Vec (Jx-594)

The investigational therapy, Pexa-Vec, is an attenuated vaccinia virus engineered to stimulate anti-tumor immunity and directly lyse tumor cells. Pexa-Vec has enhanced cancer selectivity through the deactivation of its thymidine kinase (TK) gene, and it has been engineered to express the granulocyte-macrophage colony stimulating factor (GM-CSF) gene to stimulate a systemic anti-tumor immune response. Researchers believe that Pexa-Vec may be a systemic treatment of HCC 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[19] in mainly sorafenib naïve patients with advanced HCC demonstrated that the risk of death for patients who received Pexa-Vec at the high dose was markedly reduced (by nearly 60 percent; hazard ratio = 0.41) when compared to patients randomized to a low dose control (one-tenth of the high dose). The median overall survival for high and low dose groups was 14.1 months versus 6.7 months, respectively (p = 0.020 for superiority of the high dose). Pexa-Vec was well tolerated, with patients experiencing transient flu-like symptoms that generally resolved within 24 hours.[17]

As of June 2018, these are the clinical trials investigating Pexa-Vec.[20][21][22][23]

<tbody></tbody>

IndicationPhaseStatusNotesSponsorRef
Hepatocellular carcinomaIIIRecruitingCombined with sorafenibSillaJenNCT02562755
Solid TumorsIIRecruitingCombined with metronomic cyclophosphamideInvestigatorNCT02630368
Renal Cell Carcinoma 2LIRecruitingCombined with REGN2810SillaJenNCT03294083
Colorectal Cancer 2L/3LIRecruitingCombined with PD-L1 and CTLA4Investigator
Liver CancerIRecruitingCombined with NivolumabTransgeneNCT03071094
Solid TumorsIRecruitingCombined with IpilimumabInvestigatorNCT02977156

Study Design

Participants will be randomly assigned to one of two treatment arms, having an equal chance of receiving 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.[17]
  • All Pexa-Vec treatments (3) 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.[17]

Pipeline Candidate

JX-Next Generation[24]

Novel oncolytic viruses in SillaJen pipeline are engineered through the Selective Oncolytic Vaccinia Engineering (SOLVE) platform.

JX-929

JX-929 is derived from Western Reserve strain vaccinia virus. JX-929's tumor selectivity has been optimized through deletion of thymidine kinse (TK) and vaccinia growth factor (VGF). JX-929 has been administered as a monotherapy to patients with breast, colorectal, and pancreatic cancer via intratumoral & intravenous injections in a Phase 1, dose escalation clinical trial. This Phase 1 study showed delivery to and replication within tumors [25] both IT[26] and IV.[27]

JX-970

JX-970 is also derived from a Western Reserve strain vaccinia virus and utilizes the same tumor selectivity mechanisms as JX-929. In addition, it expresses GM-CSF to stimulate immune responses. In nonclinical studies, the JX-970 backbone exerted a tumor debulking effect and at the same time demonstrated a selective preference for tumor tissues.[26] The precursor of JX-970 is JX-963 which demonstrated efficacy in pre-clinical studies.

References
  1. Jennerex Granted FDA Orphan Drug Designation for Pexa-Vec in Hepatocellular Carcinoma (HCC)
  2. Phase 1 Study of Intratumoral Pexa-Vec (JX-594), an Oncolytic and Immunotherapeutic Vaccinia Virus, in Pediatric Cancer Patients
  3. Un virus contre le cancer 25 March 2012, Radio Canada (in French)
  4. Transgene Presents Data on Improved Cytotoxic Activity of Oncolytic Viruses Expressing Intrabodies in Resistant Tumor Cell Lines. October 2016
  5. Bos, JL (September 1, 1989). "ras oncogenes in human cancer: a review". Cancer Research. 49 (17): 4682–9. PMID 2547513.
  6. "NCI Drug Dictionary". National Cancer Institute. 2011-02-02. Retrieved 25 March 2013.
  7. "Novel Cancer-Targeting Virus Therapy Shows Efficacy in Early-Stage Trial". 31 August 2011.
  8. Breitbach at al. (2011). "Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans". Nature. 477 (7362): 99–102. Bibcode:2011Natur.477...99B. doi:10.1038/nature10358. PMID 21886163.
  9. INTERNET, CENTUM. "SOLVE® > TECHNOLOGY > Sillajen". www.sillajen.com (in Korean). Retrieved 2018-06-17.
  10. Breitbach, Caroline J.; Burke, James; Jonker, Derek; Stephenson, Joe; Haas, Andrew R.; Chow, Laura Q. M.; Nieva, Jorge; Hwang, Tae-Ho; Moon, Anne (2011-08-31). "Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans". Nature. 477 (7362): 99–102. Bibcode:2011Natur.477...99B. doi:10.1038/nature10358. ISSN 1476-4687. PMID 21886163.
  11. Kirn, David H.; Thorne, Steve H. (January 2009). "Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer". Nature Reviews. Cancer. 9 (1): 64–71. doi:10.1038/nrc2545. ISSN 1474-1768. PMID 19104515.
  12. Breitbach, Caroline J.; Arulanandam, Rozanne; De Silva, Naomi; Thorne, Steve H.; Patt, Richard; Daneshmand, Manijeh; Moon, Anne; Ilkow, Carolina; Burke, James (2013-02-15). "Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans". Cancer Research. 73 (4): 1265–1275. doi:10.1158/0008-5472.CAN-12-2687. ISSN 1538-7445. PMID 23393196.
  13. Parker, Charles Thomas; Garrity, George M (2003-01-01). Parker, Charles Thomas; Garrity, George M (eds.). "Exemplar Abstract for Mycobacterium yongonense Kim et al. 2013 and Mycobacterium intracellulare yongonense (Kim et al. 2013) Castejon et al. 2018". doi:10.1601/ex.23701. Cite journal requires |journal= (help)
  14. INTERNET, CENTUM. "SOLVE® > TECHNOLOGY > Sillajen". www.sillajen.com (in Korean). Retrieved 2018-06-16.
  15. INTERNET, CENTUM. "JX-900 Series > PIPELINE > Sillajen". www.sillajen.com (in Korean). Retrieved 2018-06-17.
  16. Zeh, Herbert J; Downs-Canner, Stephanie; McCart, J Andrea; Guo, Zong Sheng; Rao, Uma N M; Ramalingam, Lekshmi; Thorne, Stephen H; Jones, Heather L; Kalinski, Pawel (January 2015). "First-in-man Study of Western Reserve Strain Oncolytic Vaccinia Virus: Safety, Systemic Spread, and Antitumor Activity". Molecular Therapy. 23 (1): 202–214. doi:10.1038/mt.2014.194. ISSN 1525-0016. PMC 4426804. PMID 25292189.
  17. "General Information | PHOCUS". SillaJen. Retrieved 2018-06-27.
  18. "Hepatocellular Carcinoma Study Comparing Vaccinia Virus Based Immunotherapy Plus Sorafenib vs Sorafenib Alone - Full Text View - ClinicalTrials.gov". Retrieved 2018-06-27.
  19. Heo, Jeong; Breitbach, Caroline; Cho, Mong; Hwang, Tae-Ho; Kim, Chang Won; Jeon, Ung Bae; Woo, Hyun Young; Yoon, Ki Tae; Lee, Jun Woo; Burke, James; Hickman, Theresa; Longpre, Lara; Patt, Richard H.; Kirn, David H. (2013-05-20). "Phase II trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC)". Journal of Clinical Oncology. 31 (15_suppl): 4122. doi:10.1200/jco.2013.31.15_suppl.4122.
  20. "Hepatocellular Carcinoma Study Comparing Vaccinia Virus Based Immunotherapy Plus Sorafenib vs Sorafenib Alone - Full Text View - ClinicalTrials.gov". Retrieved 2018-06-16.
  21. "A Study of Metronomic CP and JX-594 in Patients With Advanced Breast Cancer and Advanced Soft-tissue Sarcoma (METROmaJX) - Full Text View - ClinicalTrials.gov". Retrieved 2018-06-16.
  22. "A Trial to Evaluate the Safety and Efficacy of the Combination of the Oncolytic Immunotherapy Pexa-Vec With the PD-1 Receptor Blocking Antibody Nivolumab in the First-line Treatment of Advanced Hepatocellular Carcinoma (HCC) - Full Text View - ClinicalTrials.gov". Retrieved 2018-06-16.
  23. "Immunization Strategy With Intra-tumoral Injections of Pexa-Vec With Ipilimumab in Metastatic / Advanced Solid Tumors. - Full Text View - ClinicalTrials.gov". Retrieved 2018-06-16.
  24. INTERNET, CENTUM. "JX-900 Series > PIPELINE > Sillajen". www.sillajen.com (in Korean). Retrieved 2018-06-16.
  25. Thorne, R. M.; Horne, R. B. (December 2007). "Comment onKhazanov et al.[2002] andKhazanov et al.[2006]". Journal of Geophysical Research: Space Physics. 112 (A12): n/a. Bibcode:2007JGRA..11212214T. doi:10.1029/2007ja012268. ISSN 0148-0227.
  26. Zeh, Herbert J.; Downs-Canner, Stephanie; McCart, J. Andrea; Guo, Zong Sheng; Rao, Uma N. M.; Ramalingam, Lekshmi; Thorne, Stephen H.; Jones, Heather L.; Kalinski, Pawel (January 2015). "First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity". Molecular Therapy. 23 (1): 202–214. doi:10.1038/mt.2014.194. ISSN 1525-0024. PMC 4426804. PMID 25292189.
  27. Downs-Canner, Stephanie; Guo, Zong Sheng; Ravindranathan, Roshni; Breitbach, Caroline J; O'Malley, Mark E; Jones, Heather L; Moon, Anne; McCart, Judith Andrea; Shuai, Yongli (August 2016). "Phase 1 Study of Intravenous Oncolytic Poxvirus (vvDD) in Patients With Advanced Solid Cancers". Molecular Therapy. 24 (8): 1492–1501. doi:10.1038/mt.2016.101. ISSN 1525-0016. PMC 5023393. PMID 27203445.
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