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Inovio Pharmaceuticals’ novel DNA vaccine technology is churning out multiple vaccine candidates

Inovio is focused on the development of a novel DNA vaccine technology, a leap forward over current vaccines that use live or attenuated viruses. Its platform technology has given the company a pipeline of vaccine candidates ranging from influenza to hepatitis to cancer. Vaccines are currently one of the fastest growing segments of the drug market, putting Inovio in an enviable position.

There are multiple advantages to DNA vaccines. Unlike vaccines using live or attenuated viruses, DNA vaccines do not have the capacity to cause disease. There would be no need to restrict them from use in  individuals with weakened immune systems.

While safety advantages are important, what really sets DNA vaccines apart is their ability to extend the benefits of immune system stimulation to challenging diseases such as HIV and cancers, and to provide not only preventive but therapeutic capabilities. This new generation of vaccines is also highly cost-effective. The vaccine is comprised of DNA plasmids that are easily reproduced by bacteria whereas traditional vaccines require either mammalian cell cultures or even whole chicken eggs.

There are two features that distinguish Inovio’s DNA vaccines. The first involves the ability to create vaccines that can provide universal protection against multiple strains of a virus. As was highlighted by 2009’s H1N1 outbreak, if a virus strain against which a vaccine was developed (which is today’s paradigm) mutates enough, the vaccine can no longer provide protection against the virus.

Whereas today’s vaccines are designed to provide protection against known strains, and are matched to the genetic makeup of the virus, Inovio’s novel SynConTM technology is used to design vaccines with the potential to protect against both known and newly emergent, unmatched strains. Inovio uses proprietary algorithms to design a synthetic strain of an antigen: it is derived from a consensus of amino acids making up multiple different strains of the targeted antigen.

Inovio’s DNA plasmids, which contain the code to produce the targeted antigen, is optimized for high expression in human cells. When these plasmids are placed inside a cell, the cell’s own machinery produces the desired antigen in order to then induce the intended immune response. By taking this approach, Inovio’s SynConTM universal vaccines have the potential to provide effective, broad protection against viruses that rapidly and regularly mutate such as influenza, and hepatitis C virus, and HIV. Inovio has shown in animal studies that a single vaccine is able to protect against divergent strains of a virus.

The second key distinguishing component of its DNA vaccine technology is vaccine delivery. The DNA plasmid must be placed into cells; however, delivering genetic material into cells has always been a challenge for the medical field and still remains so. Due to the negatively charged nature of DNA, it is excluded by cell membranes. To counteract this, scientists have used a range of methods including:

•    Viral- Harmless virus infects cells with the target gene
•    Gene Gun- DNA coated gold beads are bombarded into cells
•    Liposomes- DNA is carried into cells in lipid spheres

Each of these methods has weaknesses. The most researched alternative, viral vectors, can actually induce unwanted immune responses against itself, potentially neutralizing any possible benefit from the vaccine.

Inovio has developed a safer alternative with its proprietary electroporation technology. Discovered in the ‘70s, electroporation has been widely used in research labs and its utility and safety is widely documented. Electroporation involves the application of milliseconds electrical pulses for just a second to create pores in the cell membrane.

After the injection of a DNA vaccine, the pores created by electroporation permit the DNA to be transported into the cell, enhancing uptake by a 1000 times or more. According to the company, its technology improves gene expression of DNA plasmids by 100 times compared to simply injecting “naked” DNA. Inovio has multiple electroporation devices with needles that deliver the electrical pulses into skin or muscle. Some devices deliver both the vaccines and electroporation. Its newest devices include ever-smaller, rechargeable devices that could be ideal for mass vaccination purposes.

With its synthetic consensus approach to developing universal vaccines and its to-date safe and efficient delivery technology, Inovio’s DNA vaccine technology platform is positioned to potentially produce vaccines for an array of diseases.

The company has a strong pipeline of vaccine candidates. Its most advanced product is VGX-3100, a therapeutic vaccine for cervical cancer. VGX-3100 targets the E6 and E7 proteins of human papillomavirus (HPV) types 16 and 18; HPV is the most common cause of cervical cancer.

In results of a dose-escalating Phase I trial released in September 2010, VGX-3100 demonstrated best-in-class immune responses and good safety at the highest dose levels. VGX-3100 was administered at doses of 0.6 mg, 2.0 mg and 6.0 mg across three cohorts at day 0, month 1, and month 3. It was observed that 83% developed significant antigen-specific cytotoxic T-lymphocyte (CTL) responses at the highest dose of 1362 spot forming units (SFU) (T-cell responses), 626 SFU at the middle dose and 497 at the low dose. SFU T-cell responses are hypothesized as an important measure to control cancer. 

Inovio is now planning a randomized, blinded, placebo controlled study of VGX-3100 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.

The study is expected to begin the first quarter of this year. In the US alone there are 250, 000 women diagnosed annually with CIN 2/3. While current ablation treatments can be effective, it is typically younger women diagnosed with this condition and there is some concern about this treatment approach’s potential effects on child-bearing. Earlier stage CINs (CIN 1) amount to about 1 million annually in the US. Because a high percentage will regress naturally, they are often “treated” on a watch-and-wait basis but being afflicted with a pre-cancerous condition can create tremendous anxiety. Having a therapeutic vaccine would therefore be an attractive alternative for treating all CIN stages. Inovio would also aim to move “downstream” to cervical cancers given success in the currently planned Phase II.

Multiple HIV projects are ongoing under the PENNVAX umbrella. The company is working with the University of Pennsylvania to develop an HIV vaccine for prevention and therapeutic use. In November 2010, positive interim data, including best-in-class immune responses, was announced from its ongoing Phase I study of 48 healthy volunteers. Subjects either received placebo, PENNVAX-B, or PENNVAX-B plus IL-12 DNA as a booster. After three vaccinations:

•    67% (6 out of 9) of evaluated subjects receiving PENNVAX-B and 91% (20 of 22) of evaluated subjects receiving PENNVAX-B + IL-12 were observed to have generated antigen-specific T-cell responses (either CD4+ or CD8+).

•    Antigen-specific CD4+ T-cell responses were generated by the vaccine in 70% of evaluated vaccine recipients (21 out of 30).

•    Significantly strong antigen-specific, CD8+ T-cell responses were also generated by the vaccine in 55% of evaluated vaccine recipients (17 out of 31).

•    Samples from eight placebo recipients and pre-vaccine samples from vaccine recipients were also tested and were negative for both CD4+ T-cell responses and CD8+ T-cell responses.

•    PENNVAX-B delivery with or without IL-12 was generally safe and well tolerated. There were no vaccine-related serious adverse events. Reported adverse events and injection site reactions were mild to moderate and required no treatment.

Seeing as there are no available HIV vaccines, successful development of PENNVAX would be of enormous value.
In addition, Inovio is developing DNA vaccines for HCV and influenza, both very large markets. Early, interim data from a Phase I/II HCV study run by Inovio’s partner, Chrontech, has shown Chrontech’s vaccine, ChronVac-C, to be safe and well tolerated, with significant T-cell immune responses and viral load reductions of 93% and 99.7% at the highest doses. Post-study observations made on seven subjects that completed the protocol and then entered into standard of care treatment using interferon and ribavirin showed a complete and rapid early viral response in five individuals (71%); that is, the virus was undetectable after 12 weeks of standard care. With standard of care (SOC) alone, about 45% of patients achieve a sustained virologic response.

In addition, SOC has side effects with similarities to chemotherapy. Any improvement to HCV SOC response rates and harsh side effects would be well-received by HCV patients and practitioners. These positive outcomes of CHRONVAC-C may warrant further investigation with additional clinical studies and have provided encouragement to the ongoing development of its proprietary DNA vaccine for HCV. In April 2010, Inovio and its collaborators were awarded a $2.8 million grant by the State of Pennsylvania to advance their research on a DNA vaccine against HCV.

Influenza vaccine candidate VGX-3400, now in Phase I, appears promising. Pre-clinical animal data looked good - strong immune responses were seen in five animal species and complete protection from H5N1 virus was seen in both mice and ferrets, the only ones tested.

While VGX-3400 may not be integral to a seasonal influenza vaccine strategy, if it is able to generate significant antigen-specific immune responses in humans it will have the potential to be considered by the Biomedical Advanced Research and Development Authority (BARDA) for a stockpiling contract. While this would not be the core focus of any biotech’s business strategy, these contracts to manufacture agents to protect against mass pandemic threats and emergencies are often valued in hundreds of millions of dollars.

On the seasonal front, Inovio has shown that its H1N1 vaccine was able to protect against multiple strains of this influenza virus, including the 1918 strain that killed over 40 million people and 2009’s “swine flu.” The vaccine provided 100% protection against challenges with the virus in the tested species, which were mice and ferrets. H1N1 is one of the predominant influenza sub-types affecting humans at this time, along with H2N2 and H3N2.  Inovio is advancing its H1N1 SynConTM into a Phase I clinical study in Q2.

The potential for Inovio’s influenza vaccines to provide protection against known and unknown strains within a sub-type and the ability to mix and match vaccines against different sub-types creates a powerful potential strategy against influenza. Combined with the ease of production, this approach, given clinical success, would have potential for significant sales.

Inovio is still in phase I clinical development in three diseases and expects the launch of its first phase II in the first quarter of 2011 with its cervical dysplasia/cancer DNA vaccine. Initial proof of concept has already been shown in two human studies.

Inovio’s broader efforts and R&D success have been reflected by the publishing in scientific journals of research in a multitude of disease areas, including dengue fever, Chikungunya virus, and smallpox.  In 2011, we would expect to see further visibility into Inovio’s broadening preclinical pipeline encompassing additional disease areas and to see the company’s further steps forward into the clinic.