VGX-3100 SynCon® immunotherapy for cervical dysplasia
MilestoneExpect to initiate a phase III clinical trial 2016
VGX-3100 is an investigational DNA immunotherapy candidate designed to treat precancers and cancers caused by human papillomavirus (HPV). VGX-3100 includes plasmids targeting the E6 and E7 proteins of HPV types 16 and 18. Intramuscular injection of the plasmid DNA immunotherapy is followed by electroporation using our CELLECTRA® delivery device.
In a phase II trial, VGX-3100 induced regression of precancerous cervical disease and cleared HPV infection with robust T cell responses.
In July, 2014, Inovio completed a randomized, double-blind, placebo-controlled phase II trial of VGX-3100 in women with biopsy-proven cervical intraepithelial neoplasia 2/3 (CIN2/3) associated with HPV types 16 or 18. Meeting its efficacy endpoints, the results of this study represent a significant step toward providing women and physicians a non-surgical treatment for precancerous lesions. VGX-3100 induced regression of a cervical intraepithelial neoplastic process and eliminated high risk HPV infection. Inovio intends to advance VGX-3100 into a phase III clinical trial early 2016.
Human papillomavirus (HPV) is the most common sexually transmitted disease. At any given time, approximately 11% percent of the world population is infected with HPV. Roughly 90% of HPV infections are cleared by naturally occurring immune responses within two years.
Persistent HPV infection can lead to dysplasia, or premalignant changes, in cervical cells. HPV types 16 and 18 cause 70% of cervical dysplasia and cervical cancer cases. In just the US and EU5 countries alone, there are approximately 3.4 million incidences of low grade and high grade cervical precancers. All cervical cancers arise from untreated CIN 2/3.
VGX-3100 cervical dysplasia immunotherapy
In July, 2014, Inovio completed a phase II clinical trial for VGX-3100, its investigational synthetic DNA immunotherapy for precancers and cancers caused by human papillomavirus (HPV).
The study, designated HPV-003, assessed adult females with CIN 2 or CIN 3 and biopsy-proven HPV 16 or 18. The randomized, placebo-controlled, double-blind study in women evaluated cervical tissue changes after three 6 mg doses of VGX-3100 in a 1 mL intramuscular injection followed by electroporation with Inovio’s CELLECTRA® device at weeks 0, 4, and 12. Cervical tissue was examined before starting blinded treatment and 9 months later.
The primary endpoint of this study was to assess regression of cervical lesions from CIN 2 or CIN 3 to CIN 1 or no disease. A secondary endpoint was to clear HPV 16 or 18 in conjunction with regression of CIN 2/3 to CIN or no disease. The study evaluated the efficacy of the immune therapy in patients who received VGX-3100 at 0, 4 and 12 weeks compared to placebo recipients, based on biopsies performed before the blinded treatments and six months after the final treatment.
The study also explored humoral and cell mediated immune responses to VGX-3100 in blood samples taken prior to the first immune therapy dose and periodically thereafter. Cervical samples were analyzed for evidence of immune responses in the cervix at the beginning of the trial and subsequent intervals. Subjects were also monitored for tolerability and safety.
We intend to independently advance VGX-3100 into a phase III registration study with target patient characteristics and a treatment regimen similar to the phase II study. The Company expects to complete its end-of-phase-II meeting with the FDA in 2015 and begin treating women in this phase III study in early 2016.
VGX-3100 SynCon® cervical dysplasia immunotherapy
Phase II results: Inovio achieved primary and secondary endpoints
Inovio’s phase II VGX-3100 trial showed that histopathological regression of high grade cervical neoplasia (CIN2/3) to low grade neoplasia (CIN 1) or no disease occurred in a significantly higher percentage of VGX-3100 recipients compared with placebo recipients. Furthermore, concomitant histopathological regression and clearance of HPV occurred in a significantly higher percentage of VGX-3100 recipients compared with placebo recipients. HPV-specific CD8+ "killer T cells" were also generated in the blood as well as a substantial infiltration of CD8+ cells in the cervical tissue of VGX-3100 recipients, underscoring the role played by Inovio's best-in-class T-cell responses.
In VGX-3100-treated women who regressed their lesion, most (43 out of 53) completely cleared their lesions to normal (complete response). Moreover, eighty percent of VGX-3100-treated women who regressed their lesion also eradicated the infecting HPV genotype (i.e. 16 or 18) in the cervix. This is an important outcome as persistence of the virus is associated with recurrence of the disease.
Analyses of patient immune responses showed that overall antigen-specific T cell levels in women treated with VGX-3100 were greater than those treated by placebo at all observation periods. At week 14, T cell levels in women treated with VGX-3100 were ten times greater than those in the placebo group.
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.
Detailed study findings have been published in The Lancet in the article entitled, "Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomized, double-blind, placebo-controlled phase 2b trial," by C. Trimble, et al.
This is the first publication to our knowledge that demonstrates the correlation of antigen-specific CD8 T cells directly to clinical efficacy.
Phase I results
In 2010, Inovio completed a phase I dose escalation study of VGX-3100 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."
Response rate and magnitude
The paper reported that 78% (14 of 18) of the patients showed antigen-specific cytotoxic T-lymphocyte (CTL, or killer T-cell) responses against at least one of the four antigens (E6 and E7 proteins for HPV types 16 and 18) in the ELISpot assay. At month four, 14 of 18 vaccinated subjects (78%) had developed significant T-cell responses, with positive responses ranging from 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 an extension of this phase I study, T-cell immune data 24 weeks after the last immunization was analyzed among responders. Immune data showed that the responses were still detectable in 86% of evaluable patients, indicating that T-cell responses persisted for at least six months after the final immunization. At the latest time measured, Inovio reported durability of T-cell immune responses over two years in 7 of 8 evaluated patients following a fourth immunization of VGX-3100.
Further tests of T-cell immunity among responders measured the ability of CD8+ T-cells from vaccinated patients to kill cells displaying HPV antigens on their surface: 91% of patients (10/11) who developed T-cell responses showed the presence of CD8+ T-cells capable of this type of killing activity (so-called "killer T-cells"), which is believed to be critical for the treatment of cervical dysplasia and ultimately cancer caused by HPV.
Overall, 100% of the study participants (18 of 18) reported antibody positivity to at least two vaccine antigens. 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 immunization 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 immunizations without safety concerns or unwanted immune responses is a notable advantage of Inovio's DNA immunotherapy technology.
Cervical dysplasia caused by HPV
An estimated 79 million Americans are currently infected with HPV; 14 million people become newly infected each year. Many people who have HPV are asymptomatic and can pass the virus to others without knowing it.
While 90% of HPV infections clear naturally within two years, 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 in the US, 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.
Patients with early dysplasias must typically endure a stressful “watch-and-wait” period to see if the disease naturally clears 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.
There is a significant unmet need for an immunotherapy for high grade cervical dysplasias that, unlike current surgical procedures, does not pose risk of causing pre-term births, and may also eliminate HPV throughout the body (not just at the surgical treatment site) and reduce the risk of new or recurrent precancers. Such a non-surgical treatment would provide an appealing alternative to caregivers and their patients.
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