Clearing HPV infected Cells!
Are we already late introducing Inovio Pharmaceuticals (INO) after it announced positive results from Phase 2 VGX-3100 HPV therapeutic vaccine trial? For many reasons, it was difficult for specialists to believe that an effective therapeutic vaccine designed and developed by a development-stage firm would succeed when other drugs and vaccine developers, small and large, did not even attempt to embark on such a hard task. Needless to remind that current marketed vaccines are preventive, not therapeutics.
No. We do not believe we are late bringing Inovio’s positive news to our readers. On the contrary, we are introducing the clinical trial results at the right time, i.e., after discussing Inovio’s technology, its science and pipeline products, especially, the lead VGX-3100 HPV therapeutic vaccine. We waited for Inovio to announce the results of Phase 2 trial and took sometime to assess them when announced. As we felt good amassing enough information about the firm’s science and scientists and its management’s long-term strategy and of the announced phase 2 clinical trial results of VGX-3100, we decided to write this text that aims at explaining the importance of clearing up the infected cells before delineating VGX-3100 phase 2 results.
In order to appreciate Inovio’s accomplishments, investors must understand the virus behind the cancer that VGX-3100 therapeutic vaccine aim at eradicating.
HUMAN PAPILLOMA VIRUSES (HPVS)
Human papilloma viruses are a group of more than 150 related viruses. More than 40 of these groups can be easily spread through direct skin-to-skin contact during vaginal, anal, and oral sex. The sexually transmitted HPV types fall into two groups:
Low-risk HPVs, which do not cause cancers but can cause warts (condylomata acuminata) on or around the genitals or anus when subjected to the virus. In this group, HPV types 6 and 11 have been found to cause 90 percent of all genital warts.
High-risk HPVs, known also as oncogenic HPVs can cause cancer. Two types of the dozen of high-risk HPVs, type 16 and 18, are known now to cause most of HPV cancers. Having said that does not mean that all high-risk HPVs would end up causing cancers. Many high-risk HPV infections are symptomless and can disappear within one, or two years, without causing malignancies. They may, or may not cause cytologic abnormalities, or abnormal cell changes before they vanish.
Some HPV infections, however, can persist for many years. Persistent infections with high-risk HPV types can lead to serious cellular abnormal changes, or lesions, that if untreated, the cells may progress to cancer. In this case, once the high-risk HPV infects the cells in the skin, the throat, genital tract, and the anus. So, persistent infection is the most important risk factor for cervical cancer precursor lesions - cervical intraepithelial neoplasia, or CIN. A few years of infection, low-grade CIN—called CIN 1—may develop, which may spontaneously resolve and the infection clear, or may progress directly to high-grade CIN, called CIN2 or CIN3, etc., which If left undetected and untreated, CIN2 or 3 can progress to cervical cancer.
The virus starts making proteins – two of them interfere with normal functions in the cell, enabling the cell to grow in an uncontrolled manner. These cells are usually recognized by the immune system and eliminated. If the immune system fails to eradicate them, the infected cells will continue to grow, develop mutations, promoting cancer.
According to the CDC, HPV is the most common sexually transmitted infection (STI). HPV infection is so common that nearly all sexually active men and women get it at some point in their lives.
Inovio’s VGX-3100 Vaccine
Currently, the only available vaccines are preventive not therapeutic vaccines. Inovio’s VGX-3100 vaccine is a therapeutic vaccine meant to clear infected cells at various stages of the disease. VGX-3100 is an investigational SynCon® DNA therapeutic vaccine designed and used in a special process that enables it to treat cervical intraepithelial neoplasias (CIN) caused by HPV types 16 and 18 and other types. VGX-3100 includes plasmids that target the E6 and E7 proteins of HPV types 16 and 18, which causes the changes in chronically-infected cells. This plasmid DNA vaccine is injected intramuscularly followed by electroporation using Inovio’s CELLECTRA® delivery device.
Inovio’s therapeutic vaccine recognition: VGX-3100 was recognized as the most promising research at the 2011 Global Vaccine Congress, winning first prize in the Edward Jenner Award Competition. Also, the Vaccine received the Industry Excellence (ViE) Awards for “Best Therapeutic Vaccine” in 2013.
Previous results: A phase I study of VGX-3100 demonstrated that the vaccine has driven a robust immune responses against the antigens that are mainly present in the high risk types of human papillomavirus (HPV). The results have also demonstrated that the immune responses had a killing effect on cells changed by HPV into precancerous dysplasias (abnormal changes in the cells on the surface of the cervix (the lower part of the uterus (womb) that opens at the top of the vagina.)
The results of Phase 1 indicate that VGX-3100 has the potential to drive robust immune responses to antigens from high-risk types of HPV infection as well as generate an immune response powerful enough to initiate a killing effect on cells changed into precancerous dysplasias caused by HPV.
Announcing Phase 2 Trial Data
Phase 2 trial: Building on the positive outcomes of phase I dose escalation study that achieved best-in-class immune responses, Inovio initiated the phase 2 clinical trial evaluating VGX-3100 for the treatment of cervical dysplasias. This randomized, placebo-controlled, double blind study has enrolled adult females with CIN 2/3 or CIN 3 and biopsy-proven HPV 16 or 18.
Results: Inovio's HPV16/18-specific immunotherapy resulted in histopathological regression of CIN2/3 to CIN1 or no disease, meeting the study's primary endpoint. In addition, the trial demonstrated clearance of HPV in conjunction with regression of cervical lesions. Robust T-cell activity was detected in subjects who received Inovio’s vaccine compared to those who received placebo.
Mark Bagarazzi, MD, Chief Medical Officer, Inovio Pharmaceuticals stated: "This is a significant step toward providing women and their physicians a non-surgical approach to the treatment of precancerous lesions by stimulating their immune system to eliminate high risk HPV infection and induce regression of a cervical intraepithelial neoplastic process." Dr. Bagarazzi added, "This proof of concept trial will guide the advancement of VGX-3100 for precancerous dysplasias as well as HPV-associated cervical, head and neck, and anogenital cancers."
Treatment was randomized 3:1 between the VGX-3100 and placebo groups, and was stratified by age and severity of CIN.
The primary endpoint, which is histologic regression, was evaluated 36 weeks after the first treatment. In the per protocol analysis, CIN2/3 resolved to CIN1 or no disease in 53 of 107 (49.5%) women treated with VGX-3100 compared to 11 of 36 (30.6%) who received placebo. This difference was statistically significant (p<0.025).
The secondary endpoint of the trial, which is Virological clearance of HPV 16 or 18 from the cervix in conjunction with the regression of cervical dysplasia to CIN1 or no disease, was observed in 43 of 107 (40.2%) VGX-3100 recipients compared to 5 of 35 (14.3%) of placebo recipients (p<0.025).
As in the phase I study, VGX-3100 elicited robust HPV-specific T cell responses in the majority of treated subjects. A comprehensive analysis of T cell responses is ongoing.
The treatment was generally well tolerated, with only administration site redness occurring significantly more frequently in the VGX-3100 group compared to the placebo group in the 7- and 28-day periods following treatment.
An estimated 20 million Americans are currently infected with HPV; 6.2 million people become newly infected each year. Of the ~1.4 million CIN 1 dysplasias, 35 - 50% are caused by HPV types 16 and 18. HPV types 16 and 18 are responsible for ~70% of the 300,000 CIN 2/3 dysplasias and cases of cervical cancer. Cervical cancer currently affects 530,000 women worldwide and results in 275,000 deaths annually.
Prohost Observations: We agree with Dr. J. Joseph Kim, Inovio's President and CEO’s statement that the results from the phase 2 study represent a breakthrough in the field of immunotherapies. Indeed, the efficacy results and the T cell data provide evidence that SynCon® immunotherapy technology can activate the immune system to fight chronic infections, pre-cancers and, ultimately, cancers. Mr. Kim believes that the results of Phase 2 trial de-risk Inovio’s product and business development strategy not only regarding VGX-3100, but also the firm’s other pipeline SynCon® active immune therapeutics and vaccine products.
Read Our Upcoming Article On Inovio that will be soon posted on Prohost Website
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