VGX-3100 SynCon® vaccine for cervical dysplasia/cancer
MilestonePhase II study enrollment completed; top-line data expected in mid-2014.
VGX-3100 is an investigational SynCon® therapeutic DNA vaccine candidate designed to treat cervical intraepithelial neoplasias (CIN) that are caused by human papillomavirus (HPV) types 16 and 18 and others. VGX-3100 includes plasmids that target the E6 and E7 proteins of HPV types 16 and 18. Intramuscular injection of the plasmid DNA vaccine is followed by electroporation using our CELLECTRA® delivery device.
A phase I study of VGX-3100 demonstrated that the vaccine is capable not only of driving robust immune responses to antigens from high risk types of human papillomavirus (HPV) infection but that these immune responses displayed a powerful killing effect on cells changed by HPV into precancerous dysplasias. This T-cell effect may ultimately contribute to the regression or elimination of cervical dysplasia and cervical cancer.
VGX-3100 was recognized as the most promising research at the 2011 Global Vaccine Congress, winning first prize in the Edward Jenner Award Competition. It was also recognized by the Vaccine Industry Excellence (ViE) Awards for "Best Therapeutic Vaccine" in 2013.
In 2010, Inovio completed a phase I dose escalation study of VGX-3100, its investigational therapeutic cervical dysplasia synthetic DNA vaccine designed to treat pre-cancerous cervical dysplasias and cervical cancers, delivered with its CELLECTRA® electroporation device. Of all phase I trial subjects evaluated to date, 100% of study participants reported antibody positivity to at least two vaccine antigens and 78% of the subjects showed T-cell responses to at least one vaccine antigen. These results 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 by HPV. Building on positive outcomes of an 18-subject phase I dose escalation study that achieved best-in-class immune responses, a phase II clinical trial evaluating VGX-3100 for the treatment of cervical dysplasias is ongoing. 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. Inovio expects to report unblinded, top-line data from this trial in mid-2014.
There is a great need for an effective therapeutic vaccine to treat cervical dysplasias and cancers caused by HPV. Cervical cancer is unique among all cancers in that there is an identifiable, slow-progressing precancerous stage. While 70% of HPV infections clear naturally, persistent infections may lead to benign atypical squamous cells of undetermined significance (ASCUS) and then further progress to the CIN stage.
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.
VGX-3100 Therapeutic Cervical Dysplasia Vaccine
In March, 2011, Inovio initiated a phase II clinical trial for its investigational VGX-3100 synthetic DNA vaccine for cervical dysplasia caused by human papillomavirus (HPV).
The study, designated HPV-003, is assessing adult females with CIN 2/3 or CIN 3 and biopsy-proven HPV 16 or 18. Cervical intraepithelial neoplasias (CIN) are pre-cancerous stages of abnormal cells that precede cervical cancer. The randomized, placebo-controlled, double-blind study in a minimum of 148 women will evaluate cervical tissue changes after three 6 mg doses of VGX-3100 are administered by injection in combination with Inovio's CELLECTRA® electroporation delivery device. Enrollment has been completed for this study.
The primary endpoints of this study are to assess regression of cervical lesions to CIN 1 or less and clearance of HPV 16 or 18. The study will evaluate the efficacy of the vaccine in patients who receive VGX-3100 at 0, 4 and 12 weeks compared to placebo recipients, based on a biopsy performed six months after the final vaccine dose.
The study will also explore humoral and cell mediated immune responses to VGX-3100 in blood samples taken prior to the first vaccine dose and periodically thereafter. Cervical samples will be analyzed for evidence of immune responses in the cervix at the beginning of the trial and subsequent intervals. Subjects will also be monitored for tolerability and safety.
VGX-3100 SynCon® Therapeutic Cervical Dysplasia Vaccine
Phase I Results
In 2010, Inovio completed a phase I dose escalation study of VGX-3100, its investigational therapeutic cervical dysplasia synthetic DNA vaccine designed to treat pre-cancerous cervical dysplasias and cervical cancers, delivered with its CELLECTRA® electroporation device. The study treated 18 women who had previously been diagnosed with and surgically treated for high grade cervical intraepithelial neoplasia (CIN 2/3), a premalignant lesion that may lead to cervical cancer, caused by human papillomavirus (HPV) types 16 and 18.
Data from the phase I trial indicate:
- Antigen-specific, dose-related T-cell responses across the three dose groups.
- Unprecedented T-cell responses not achieved by a DNA vaccine or any other non-replicating vaccine platform in humans.
- Strong antigen-specific antibody responses in all three dose groups.
- VGX-3100 delivered using Inovio's proprietary CELLECTRA® intramuscular electroporation delivery device was generally safe and well tolerated at all dose levels.
- There were no vaccine-related serious adverse events. Reported adverse events and injection site reactions were mild to moderate and required no treatment.
These results were published in the peer-reviewed journal, Science-Translational Medicine, in a paper entitled, "Immunotherapy against HPV 16/18 generates potent Th1 and cytotoxic cellular immune responses."
This study treated subjects with a history of surgically treated cervical intraepithelial neoplasias (CIN2 or CIN2/3) who also had HPV type 16 or 18. Using a validated, standard ELISPOT assay, antigen-specific cytotoxic T-lymphocyte (CTL, or killer T-cell) responses were observed against all four antigens (E6 and E7 proteins for HPV types 16 and 18). At month four, 13 of 18 vaccinated subjects (72%) had developed significant T-cell responses, with positive responses ranging from under 100 to over 5000 SFU per million cells. In the third and highest dose group, 83% (5 of 6) had strong T-cell responses, with average responses of 1458 SFU per million cells after three immunizations. This was a 114% increase compared to the intermediate dose cohort average of 683 SFU per million cells (four responders out of six) and a 125% increase compared to the low dose cohort average of 648 SFU per million cells (four responders out of six).
As indicated by the chart and table below, the T-cell levels generated by VGX-3100 far exceed those generated by competitive technologies.
In addition, 15 of 18 vaccinated subjects (83%) developed antibody responses to at least one antigen with most subjects developing responses to two or more antigens. No one has previously achieved this rate of response. Specific antibody responses to tumor antigens can function as an important surrogate potency marker for determining the immunogenicity of a vaccine, i.e. the ability of a vaccine to induce an immune response.
In an extension of this phase I study, Inovio reported durability of T-cell immune responses over two years (at the latest time measured) in 7 of 8 evaluated patients following a fourth vaccination of VGX-3100.
In general, the durability of these T-cell responses places Inovio's DNA vaccine technology on par with live virus vaccines, but without their various safety and other issues, and substantially exceeds current data from alternative non-replicating vaccine technologies. Furthermore, being able to use multiple vaccinations without safety concerns or unwanted immune responses is a notable advantage of Inovio's DNA vaccine technology.
Cervical Dysplasia and Cancer Caused by HPV
Each day in the United States, 30 women are diagnosed with cervical cancer (about 11,000 women per year) and 11 women die from it. Cervical cancer is primarily caused by various types of human papillomavirus (HPV). An estimated 20 million Americans are currently infected with HPV; 6.2 million people become newly infected each year. Many people who have HPV are asymptomatic, and can pass the virus to others without knowing it.
Cervical cancer is unique among all cancers in that it there is an identifiable, slow-progressing precancerous stage. The purpose of a Pap smear is to identify these abnormal cells in the cervix, which is the lower, narrow part of the uterus where it joins with the top end of the vagina.
FDA-approved preventive vaccines like GARDASIL® and Cervarix® are designed to generate immunity and protect against HPV infection in non-infected individuals. However, once a person has an established HPV infection these vaccines are not able to prevent the development of cervical dysplasias and cancer. There is a great need for an effective therapeutic vaccine to treat cervical dysplasias and cancers caused by HPV.
While 70% of HPV infections clear naturally, persistent infections may lead to benign atypical squamous cells of undetermined significance (ASCUS). This condition may possibly progress to the abnormal cells referred to as cervical intraepithelial neoplasia (CIN).
CIN is classified in three grades based on what part of the cervical epithelium is affected by the abnormal cell growth. CIN 1, the least risky type, represents only mild dysplasia and is confined to the basal 1/3 of the epithelium. Of the estimated 1.4 million CIN 1 dysplasias, 35 - 50% are caused by HPV types 6, 11, 16 and 18. CIN 2 is moderate dysplasia confined to the basal 2/3 of the epithelium, while CIN 3 is severe dysplasia spanning more than 2/3 of the epithelium, and may involve the full thickness. Up to 70% of CIN 2/3 dysplasias and cervical cancers are caused by two high-risk HPV types, HPV 16 or 18.
Most low-grade cervical lesions go away in 18 to 24 months without treatment. More severe or “high-grade” cervical lesions usually don’t fix themselves without treatment. High-grade cervical dysplasia is more dangerous because it’s more likely to lead to cervical cancer.
Early dysplasias are first preceded by a stressful watch-and-wait period to see if the disease may naturally clear on its own. In the case of high-grade dysplasias designated as CIN 2/3 or CIN 3, ablative or surgical procedures are used to remove the precancerous lesions. These same procedures are used to remove cervical cancer. These procedures may be unappealing due to their invasiveness and possible negative impact on childbirthing. Doctors are now researching new potential treatments that someday may help avoid surgery.
Inovio Pharmaceuticals’ investigational therapeutic synthetic vaccine candidate, VGX-3100, is designed to stimulate the body’s immune system to clear HPV 16 and 18 and precancerous cells of the cervix in women with CIN 2/3 or CIN 3 and biopsy-proven HPV 16 or 18. The objective is for this vaccine to place into patients' cells DNA code that instructs these cells to produce the E6 and E7 antigenic proteins that are part of HPV types 16 and 18. The DNA code cannot create HPV or cause detrimental cell changes of the cervix. However, production of these two proteins can enhance the immune system’s recognition of cells infected by HPV and may strengthen the body’s ability to clear cells of the cervix that have undergone detrimental cell changes.
VGX-3100 is injected into a patient’s shoulder muscle. This is followed by the application of controlled electrical pulses using Inovio’s CELLECTRA®-5P system. The electrical pulses enhance the body’s immune response to the vaccine. This treatment method does not involve ablation or a surgical procedure.
Looking to the future, Inovio aims to apply this therapeutic vaccine to cervical cancers and to earlier stage CIN 1 lesions that today may be unnecessarily treated with a surgical or ablation procedure or are simply left to a watch-and-wait process to assess progress of the disease – a process that may be quite stressful for the patient.
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