Inovio Pharmaceuticals Achieves Unprecedented T-Cell Immune Responses in Human Trial of DNA Vaccine for Cervical Dysplasia and Cancer Caused by HPV
DNA Vaccine Delivered Using Electroporation Shows Potential to Treat Cervical Cancer and Precursor Dysplasias; Vaccine to Start Phase II in Early 2011
BLUE BELL, Pa., Sep 13, 2010 (BUSINESS WIRE) -- Inovio Pharmaceuticals, Inc., a leader in the development of therapeutic and preventive vaccines against cancers and infectious diseases, announced today that it has achieved best-in-class immune responses in its Phase I dose escalation study of VGX-3100, its DNA vaccine to treat pre-cancerous cervical dysplasias and cervical cancers caused by human papillomavirus (HPV) types 16 and 18. This vaccine targets HPV E6 and E7 proteins and is delivered via in vivo electroporation. All dose groups developed significant antibody and T-cell immune responses; however, more notably, in the third and final dose group, five of six (83%) patients developed unprecedented T-cell responses not achieved by any other non-replicating vaccine platform in humans. Inovio is planning to start a Phase II clinical study in the first quarter of 2011.
Preliminary data from the trial indicate:
-- Antigen-specific, dose-related T-cell responses across the three dose groups, averaging 1362 SFU per million cells in the high dose group responders
-- Strong antigen-specific antibody responses in all three dose groups
-- VGX-3100 delivered using Inovio's proprietary CELLECTRA(R) 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.
Stanley A. Plotkin, M.D., Emeritus Professor, Wistar Institute and University of Pennsylvania, stated: "Considering that cellular (T-cell) immune responses are known to correlate with suppression of oncogenic transformation (i.e. cell changes that lead to cancer) by HPVs, this study shows the potential for a new therapeutic vaccine to treat cervical dysplasias and cancers caused by those viruses. These are diseases with great unmet medical needs affecting millions of women around the world. The results include some of the best-ever T-cell immune responses induced by a non-replicating vaccine in humans. Therefore, Inovio's DNA vaccine platform could have significant implications and promise for the advancement of DNA vaccines against cancers and other infectious diseases globally." Dr. Plotkin, a member of Inovio's scientific advisory board, is a vaccine pioneer who developed the rubella and rabies vaccines still being used today.
Dr. J. Joseph Kim, Inovio's President and CEO, said: "We have raised the bar in terms of T-cell immune responses achieved by any DNA vaccine platform in humans. We are pleased that the results of this Phase I study strongly support advancing this vaccine candidate to Phase II clinical studies. An important goal for us was to also validate our DNA vaccine platform in the clinic to support the development of our other vaccine candidates: we have definitively accomplished this goal."
This dose escalation study tested the safety and immunogenicity of VGX-3100 in women previously treated for moderate or severe cervical intraepithelial neoplasia (CIN 2/3), a high grade premalignant lesion that may lead to cervical cancer. The trial enrolled patients in three cohorts of six subjects each with DNA vaccine doses of 0.6 mg (0.3 mg each of two DNA plasmids), 2.0 mg, and 6.0 mg. Each subject received the respective dose at day 0, month 1 and month 3. All subjects in the first and second dose groups have completed the nine month follow-up period. Patients in the third dose group will complete their follow-up in the first quarter of 2011.
Immunological analyses of blood samples collected before and after vaccination indicate that antigen-specific immune responses were induced against the target proteins produced by Inovio's vaccine. 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). In this third cohort, five of six vaccinated subjects (83%) developed significant CTL responses, with average responses of 1362 SFU per million cells after three immunizations. This was a 118% increase compared to the intermediate dose cohort average of 626 SFU per million cells (four responders out of six) and a 174% increase compared to the low dose cohort average of 497 SFU per million cells (four responders out of six).
Antibody responses to E6 and E7 antigens were also measured. 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. Antibodies were generated against all four antigens, as tested by the enzyme-linked immunosorbent assay (ELISA). In the third cohort, antibody responses were observed in five of six subjects (83%).
Overall, in all three doses combined, 13 out of 18 vaccinated subjects (72%) developed significant CTL responses, with positive responses ranging from under 100 to over 5000 SFU per million cells. Fifteen out of 18 vaccinated subjects (83%) developed antibody responses to at least one antigen with most subjects developing responses to two or more antigens.
While the study targeted only safety and immunogenicity as endpoints and did not address clinical efficacy, several literature reports support the hypothesis that induction of tumor antigen specific T-cell responses is important in controlling cancer. Furthermore, there are examples of cancer vaccine candidates targeting the E6 and/or E7 proteins achieving significant clinical efficacy in patients with cervical or vulvar intraepithelial neoplasia, yet the CTL responses achieved in such studies were lower than those observed in the current VGX-3100 study.
Inovio is now planning a randomized, blinded Phase II study of VGX-3100 delivered using its CELLECTRA(R) intramuscular electroporation device in women with HPV Type 16 or 18 and diagnosed with, but not yet treated for, cervical intraepithelial neoplasia (CIN) 2/3. CIN 2/3s are precancerous lesions that may progress to cervical cancer. Patients in the control group will not receive the therapy. Inovio intends to launch this clinical study in the first quarter of 2011.
About HPV, Cervical Cancer and Inovio's Therapeutic DNA Vaccine
Human papillomavirus (HPV) is the causative agent responsible for most cases of cervical cancer. At any given time, approximately 10% of women worldwide are infected with HPV. While roughly 70% of HPV infections are cleared by the body on its own, persistent HPV can lead to dysplasia, or premalignant changes in cells, of the cervix. Researchers have estimated the global prevalence of clinically pre-cancerous HPV infections at between 28 and 40 million. Persistent dysplasias may then progress to cancer. Every year, 470,000 cases of cervical cancer are diagnosed worldwide, and about half of the afflicted women, primarily in developing countries, die.
Preventive vaccines such as GARDASIL(R) and CERVARIX(R) are playing an important role in limiting new HPV infections. However, preventive vaccines cannot provide protection for those already infected with HPV, which is a large population. In addition, not all girls and women eligible to be vaccinated are receiving these vaccines. There is no viable therapeutic vaccine or drug to fight HPV, nor dysplasias and cancers caused by HPV. Current ablative or surgical procedures to remove cervical dysplasias and cancers are unappealing due to the potential for disfigurement and the psychological stress with perceived negative impacts on childbirth.
HPV types 16 and 18 are responsible for about 70% of cervical cancer incidence. Inovio's VGX-3100 is designed to raise immune responses against the E6 and E7 genes common to HPV types 16 and 18 that are present in both pre-cancerous and cancerous cells transformed by these HPV types. E6 and E7 are oncogenes that play an integral role in transforming HPV-infected cells into cancerous cells. The goal is to stimulate the body's immune system to mount a T-cell response strong enough to cause the rejection of these infected or transformed cells from the body. The potential of such a vaccine would be to treat cervical cancers, pre-cancerous dysplasias (CINs), as well as persistent HPV infections and other cancers caused by these HPV types.
About Inovio Pharmaceuticals, Inc.
Inovio is developing a new generation of vaccines, called DNA vaccines, to treat and prevent cancers and infectious diseases. These SynCon(TM) vaccines are designed to provide broad cross-strain protection against known as well as newly emergent strains of pathogens such as influenza. These vaccines, in combination with Inovio's proprietary electroporation delivery devices, have been shown to be safe and generate significant immune responses. Inovio's clinical programs include HPV/cervical dysplasia and cancer (therapeutic), avian flu (preventive), and HIV vaccines (both preventive and therapeutic). Inovio is developing universal influenza and other vaccines in collaboration with scientists from the University of Pennsylvania. Other partners and collaborators include Merck, National Cancer Institute, HIV Vaccines Trial Network, National Microbiology Laboratory of the Public Health Agency of Canada, and PATH Malaria Vaccine Initiative. More information is available at www.inovio.com.
This press release contains certain forward-looking statements relating to our business, including our plans to develop electroporation-based drug and gene delivery technologies and DNA vaccines and our capital resources. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in pre-clinical studies, clinical trials and product development programs (including, but not limited to, the fact that pre-clinical and clinical results referenced in this release may not be indicative of results achievable in other trials or for other indications, that the studies or trials may not be successful or achieve the results desired, that results from one study may not necessarily be reflected or supported by the results of other similar studies and that results from an animal study may not be indicative of results achievable in human studies), the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA vaccines, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by the company or its collaborators, including alternatives that may be more efficacious or cost-effective than any therapy or treatment that the company and its collaborators hope to develop, evaluation of potential opportunities, issues involving product liability, issues involving patents and whether they or licenses to them will provide the company with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether the company can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of the company's technology by potential corporate or other partners or collaborators, capital market conditions, our ability to successfully integrate Inovio and VGX Pharmaceuticals, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2009, our Form 10-Q for the six months ended June 30, 2010, and other regulatory filings from time to time. There can be no assurance that any product in Inovio's pipeline will be successfully developed or manufactured, that final results of clinical studies will be supportive of regulatory approvals required to market licensed products, or that any of the forward-looking information provided herein will be proven accurate.
SOURCE: Inovio Pharmaceuticals, Inc.