Tuesday, February 19, 2013

Pexa-Vec Doubles Survival of Advanced Hepatocellular Carcinoma Patients

An oncolytic virus-based drug JX-594 (also called Pexa-Vec) is highly effective in patients with advanced hepatocellular carcinoma. According to the results of a Phase II clinical trial published online at Nature Medicine journal's website on February 10, 2013, the patients who were given higher (more effective) dose of JX-594 had a median survival of 14.1 months which was twice that seen in the low dose group (6.7 months).


The median survival of 6.7 months in the low dose group is similar to what is normally seen in untreated (or placebo) patients in similar trials.

Hepatocellular carcinoma: incidence and survival

Hepatocellular carcinoma is the third most leading cause of cancer deaths worldwide and ninth most in the US. About half-a-million people are diagnosed with hepatocellular carcinoma worldwide including 20,000 new cases diagnosed in the US every year. 

While 85% of all cases are in developing countries, countries in the sub-Saharan Africa, southeast Asia, and China (which together have 50% of all hepatitis B virus [HBV] infected people) also account for a larger much proportion of liver cancer cases worldwide.

In the US, the incidence of hepatocellular carcinoma has tripled over the last 2 decades, and parallels a rise in hepatitis C infection. Hispanics and Whites 40-60 years age group has seen a significant increase in hepatocellular carcinoma cases.

The 5-year survival remains less than 12%. Since this cancer rarely occurs before 40 years age and majority of the diagnoses are made between age 60 and 70, it is predominantly a cancer of the elderly. Elderly patients are unfortunately poor candidates for surgery and are more likely to show adverse effects or unable to tolerate nasty side-effects of chemotherapy.


(Hashem B. El-Serag, M.D., M.P.H., New England Journal of Medicine. 2011)

JX-594 Phase II trial in patients with advanced hepatocellular carcinoma

JX-594 trial enrolled 30 patients in Korea and North America (US and Canada) who were randomized to receive high dose (16 patients) or low dose (14 patients) of JX-594. All patients received three doses every two weeks (i.e., on days 1, 15 and 29) by an injection directly into the tumor.

In this trial, the median overall survival in the high dose arm (10^9 PFU) was 14.1 months compared to 6.7 months in the low dose arm (10^8 PFU). After one year, 66% of patients in the high dose group were alive compared to 23% who received the low dose of JX-594. And at 18 months, more than twice the number of patients on the high dose were alive, i.e. 35%, versus 11% in low dose group. This (i.e., 35%) is a significant increase in survival rate as the current survival rate in liver cancer patients is just 12-15%.


(Heo et al, Nat Med. 2013 Feb 10. doi: 10.1038/nm.3089)

This trial was designed and sponsored by Jennerex Biotherapeutics, Inc., San Francisco, Calif., and the data was first released in a November 2011 press release.
The final data from the HEP007 trial demonstrated that the risk of death for patients who received JX-594 at the high dose was markedly reduced (by more than 60 percent; hazard ratio = 0.39) 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)

Currently, JX-594 is in a TRAVERSE Phase 2b trial with 120 patients.



Pexa-Vec is an oncolytic poxvirus-based cancer-targeted drug

Pexa-Vec is a based on a strain of poxvirus commonly used for smallpox vaccination all over the world. To convert his humble virus into a cancer-fighting drug, scientists disrupt a viral gene called thymidine kinase (TK) required for its DNA replication. Lacking the viral TK gene, this modified virus can only replicate in human cells that are themselves multiplying (therefore, will have high cellular TK activity) and not in normal human cells that are slowly dividing, if at all. This is what makes this drug "targeted" to cancer.

Pexa-Vec is also engineered to express human granulocyte-macrophage colony stimulating factor (hGM-CSF). GM-CSF is a potent activator of dentritic cells. Dendritic cells are akin to police officers in patrol cars looking for trouble and as soon as they see one, they ask for backup via radio--here, dendritic cells are those police officers, and the trouble spots are the new antigens created by dying cancer cells. Those new cancer-specific antigens recognized and processed by dentritic cells activate the full fury of immune response against cancer cells. This is what makes drugs like Pexa-Vec "oncolytic".

Since drugs like Pexa-Vec rely on the basic biology of cancer and not a certain biomarker, they can be effective against a variety of cancers and can be used as off-the-shelf anti-cancer drug.


(Kirn et al, Nat Reviews Cancer. Jan 2009)

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REFERENCES:

ResearchBlogging.org






  • El-Serag HB (2011). Hepatocellular carcinoma. The New England journal of medicine, 365 (12), 1118-27 PMID: 21992124  
  • Centers for Disease Control and Prevention (CDC) (2010). Hepatocellular carcinoma - United States, 2001-2006. MMWR. Morbidity and mortality weekly report, 59 (17), 517-20 PMID: 20448528 
  • Heo J, Reid T, Ruo L, Breitbach CJ, Rose S, Bloomston M, Cho M, Lim HY, Chung HC, Kim CW, Burke J, Lencioni R, Hickman T, Moon A, Lee YS, Kim MK, Daneshmand M, Dubois K, Longpre L, Ngo M, Rooney C, Bell JC, Rhee BG, Patt R, Hwang TH, & Kirn DH (2013). Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nature medicine PMID: 23396206 

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