$INO - The Disruptive Potential Of Inovio's SynCon DNA Vaccines
http://seekingalpha.com/article/1652522-the-disruptive-potential-of-inovios-syncon-dna-vaccines
The purpose of this report is to highlight the disruptive potential of Inovio's (INO) SynCon DNA vaccines, and Inovio's increasing leadership role in revolutionizing vaccines.
The key takeaways from this article are:
Inovio's Synthetic Consensus (SynCon) vaccines have the potential to disrupt the vaccine industry - e.g. broadened immunological impact, speedier design, cheaper production costs, more stable and easier to transport than alternatives, superior safety profiles, higher efficacy profiles, leverages the power of the human immune system, etc. Inovio's electroporation provides a superior method of delivering and invoking a targeted human immune system response.
The safety and efficacy studies of DNA vaccines have now matured to the point that there is a clear implication that DNA-based vaccines are likely to play an increasingly important role in preventative and therapeutic solutions in the near future.
Inovio Pharmaceuticals Inc. is positioned to lead the 21st century vaccine industry based on its increasingly broad & maturing pipeline, formidable IP patent estate, significant non-dilutive funding of its research through government (GO) and non-government organizations (NGO), eminent management and advisory teams with years of vaccines & immunology experience.
Inovio's share price is currently in an oversold position in comparison with the recent 52 week high of $3.03 due to significant uptick in short-seller interest (10.12M shares as of July 31, expectedly much higher as of August 20), presenting an opportunity for investors to establish a position prior to 2014 Ph II. HPV Therapeutic Clinical Study Results, and future partnership announcements.
Inovio's increasingly broad & maturing pipeline, its expanding GO & NGO agreements, are tangible catalysts for significant stock appreciation in 2013 and beyond. This report provides a detailed view of the pre- and clinical vaccines & candidates to demonstrate that Inovio is the real deal…with vaccines to combat some of the toughest infectious diseases, viruses, cancers, etc.
I. Reflections on the 2013 McKinsey Global Institute Report: "Disruptive technologies: Advances that will transform life, business, and the global economy"
McKinsey & Company is a premier global management consulting firms that advises Fortune 500 firms & governments on business & technology strategy, enabling transformational change.
In the opening section of the report, McKinsey states "….we believe these technologies will have large and disruptive impact. More importantly, the results of our research show that business leaders and policy makers-and society at large-will confront change on many fronts: in the way businesses organize themselves, how jobs are defined, how we use technology to interact with the world (and with each other), and, in the case of next-generation genomics, how we understand and manipulate living things. There will be disruptions to established norms, and there will be broad societal challenges. Nevertheless, we see considerable reason for optimism. Many technologies on the horizon offer immense opportunities. We believe that leaders can seize the opportunities, if they start preparing now."
The McKinsey article also states: "The science of genomics is at the beginning of a new era of innovation. The rapidly declining cost of gene sequencing is making huge amounts of genetic data available, and the full power of information technology is being applied to vastly speed up the process of analyzing these data to discover how genes determine traits or mutate to cause disease. Armed with this information, scientists and companies are developing new techniques to directly write DNA and insert it into cells, building custom organisms and developing new drugs to treat cancer and other diseases. Over the coming decade, next-generation genomics technology could power rapid acceleration in the field of biology and further alter healthcare…."
The criteria McKinsey used for identifying disruptive technology were:
The technology is rapidly advancing or experiencing breakthroughs
The potential scope of impact is broad
Significant economic value could be affected
Economic impact is potentially disruptive
The McKinsey report defined Next-generation genomics as: "Next-generation genomics marries advances in the science of sequencing and modifying genetic material with the latest big data analytics capabilities…. The next step is synthetic biology-the ability to precisely customize organisms by "writing" DNA. These advances in the power and availability of genetic science could have profound impact on medicine, agriculture, and even the production of high-value substances such as biofuels-as well as speed up the process of drug discovery."
Inovio plays an important role in this transformational field by a.) Effectively harnessing the power & insights of genomic sequencing and b.) Combining patented & novel processes to create synthetic DNA (SynCon) vaccines that equip the human immune system with the means to prevent & fight life-threatening infectious diseases, cancers, autoimmune disorders. These vaccines are effectively delivered to the human immune system via electroporation.
II. Inovio's SynCon DNA Vaccines - Innovative & Disruptive
In the book "The Innovator's Dilemma", the author Christenson describes the following characteristics of disruptive innovations:
Disruptive technology is "simpler, cheaper, and lower performing"
Incumbent firms "most profitable customers generally can't use and don't want" disruptive technology
Disruptive technology is "first commercialized in emerging or insignificant markets"
Disruptive technology promises "lower margins, not higher profits"
Advantages: DNA immunization offers many advantages over the traditional forms of vaccination
It is able to induce the expression of antigens that resemble native viral epitopes more closely than standard vaccines do since live attenuated and killed vaccines are often altered in their protein structure and antigenicity.
Plasmid vectors can be constructed and produced quickly and the coding sequence can be manipulated in many ways. DNA vaccines encoding several antigens or proteins can be delivered to the host in a single dose, only requiring a microgram of plasmids to induce immune responses.
Rapid and large-scale production are available at costs considerably lower than traditional vaccines, and they are also very temperature stable making storage and transport much easier.
Another important advantage of genetic vaccines is their therapeutic potential for ongoing chronic viral infections. DNA vaccination may provide an important tool for stimulating an immune response in HBV, HCV and HIV patients. The continuous expression of the viral antigen caused by gene vaccination in an environment containing many APCs may promote successful therapeutic immune response which cannot be obtained by other traditional vaccines"
Inovio SynCon DNA Vaccines: the future of vaccines
Inovio has leveraged the valuable body of genomics, immunology, epidemiology, and bio-engineering research to dramatically improve on the effectiveness of its SynCon vaccines: (the following sections of this report are based on information available on Inovio's website: inovio.com)
Design and selection of appropriate antigen targets for a particular disease. These include targets associated with the induction of antibody or T-cell or both immune responses observed during natural infection.
SynCon vaccines use a DNA fragment with instructions that enable cells in the body to produce ONLY the targeted antigen relating to a pathogen or cancer. The fragment cannot replicate and is not able to cause the disease.
Rather than being constrained by the paradigm of matching a preventive or therapeutic vaccine to a single pathogen strain, [Inovio's] SynCon vaccines are based on genetic code for a specific antigen from multiple strains of the target pathogen.Thus, while the SynCon antigens may not be perfectly (100%) matched to the pathogenic strains, they are designed to protect against multiple existing strains as well as changing strains of a virus. Extensive preclinical data has validated their ability to protect against many strains of a disease; initial human data for [Inovio's] influenza vaccine has also provided evidence of this capability.
With respect to cancers, preclinical data has shown that these "unmatched" gene sequences aid the immune system's recognition of "self-made" cells that are cancerous. Whereas normally it might tolerate these cells made in the body, antigens produced by SynCon therapeutic vaccines are able to induce strong immune responses against the cancer cells.
SynCon vaccines can produce strong T-cell responses (both CD4+ and CD8+): T-cell immune responses are considered vital to fighting cancerous cells and chronic infections. While live virus vaccines are able to generate T-cells, this approach is not viable for many diseases, such as HIV. Other "conventional" vaccine technologies (such as recombinant proteins, virus-like particles, subunit vaccines, and peptides) can at best produce only weak T-cell responses. Experimental approaches such as viral vectors have achieved strong T-cell responses, but have limiting factors such as their inability to boost with repeated vaccination due to immune responses to the viral vector itself (which can be based on a virus, such as a cold virus, to which we have been previously exposed).
However, Inovio's SynCon vaccines have, in human studies for cervical dysplasia and HIV, generated best-in-class T-cell responses that exceed all these approaches. What is particularly exciting is that these responses include strong CD8+ T-cell responses which are able to kill targeted infected cells. In a recent human study, Inovio's vaccine for cervical dysplasia demonstrated for the first time that a DNA-based therapeutic vaccine can produce immune responses with a killing effect on target cells and potentially reverse disease progression to cervical cancer.
Inovio's synthetic DNA vaccines can be designed in weeks instead of months or years. They are manufactured by a fast and efficient fermentation process. They have a better stability profile and do not require maintenance of cold-chain requirements for storage and transport. These important advantages yield more timely vaccine development and can improve accessibility in nations with less developed infrastructure.
The novel SynCon genetic sequences, which do not exist in nature, are patentable.
The elegance of Inovio's SynCon vaccines is that [Inovio] is not creating an immunogen that would then be placed into the body to induce a desired immune response. Instead, [Inovio] creates a fragment of DNA to produce one or more targeted antigens and place that DNA into cells of the body (with the assistance of our proprietary electroporation systems) where it does nothing other than give instructions to the cells to produce the desired antigen. This approach results in the body creating an immunogen capable of inducing strong, multi-faceted immune responses similar to immune responses to actual pathogens. Human data to date has shown our approach has a positive safety profile."
III. Further Information
Company History:
Inovio Pharmaceuticals, founded in 1983, engages in DNA vaccine research through subsidiaries VGX Pharmaceuticals and VGX Animal Health. The company became incorporated in 2001, in Delaware, and is currently headquartered in Blue Bell, PA, USA. The three companies focus on the discovery and development of DNA vaccines for the treatment of cancer and infectious diseases. The CEO of Inovio, Dr. Joseph Kim, co-founded VGX Pharmaceuticals with DNA vaccine pioneer Professor David Wyner (University of Pennsylvania), in December 2000. In June 2009, his company merged with Inovio Pharma.
Cash Position & Runway:
As of June 30, 2013, cash and cash equivalents plus short-term investments were $23.6 million compared with $13.8 million as of December 31, 2012.
Based on management's projections and analysis, the Company believes that cash and cash equivalents are sufficient to meet its planned working capital requirements through the first quarter of 2015.
Corporate Development:
Inovio continues to advance discussions with large pharmaceutical companies with the goal of securing strategic partnerships to advance the development of SynCon vaccines.
Inovio and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) received a $3.5 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) to advance the development of Inovio's next generation DNA vaccine delivery device capable of simultaneously administering multiple synthetic vaccines via skin surface electroporation.
Inovio was recognized with Vaccine Industry Excellence (ViE) Awards for "Best Early Stage Biotech" and "Best Therapeutic Vaccine," for its HPV vaccine, VGX-3100, at the World Vaccine Congress. The ViE Awards recognize outstanding vaccine advancements and achievements of vaccine developers across the global industry as judged by a panel of global biotech industry stakeholders.
Due Diligence:
Prospective investors should research the potential risks and rewards associated with investing in Inovio, as well as any publicly held company. Inovio is a clinical-stage company, has been unprofitable thus far, and will likely require additional capital to further the research and development of vaccines. Investors may obtain access to the company's SEC reports at: http://ir.inovio.com/secfilings
IV. Inovio's Pipeline
Inovio has a growing and maturing pipeline of vaccines covering major infectious diseases, cancers, and autoimmune disorders:
Table I. Inovio's Pipeline: Clinical & Pre-clinical Test Results
Disease / Vaccine / Antigen / Clinical Study Results:
Cervical dysplasia HPV Type 16/18
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 510,000 women worldwide and results in 288,000 deaths annually.
Vaccine: VGX-3100 Therapeutic
Antigens: E6,E7
Phase II.
PhII results expected Mid-2014. (internally funded) 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.
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.
Clinical Study 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. 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.
Prostate Cancer
In 2010, more than 218,000 new cases were diagnosed and over 32,000 men died from prostate cancer in the U.S. alone.
Vaccine: INO-5150 Therapeutic
Antigens: PSA,PSMA
Phase: Pre-clinical
PhI. Study launch by Q4-2013. (internally funded) INO-5150 is Inovio's dual-antigen SynCon vaccine targeting prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA). INO-5150 was generated by the creation of PSA and PSMA synthetic consensus antigens based on human and primate antigen gene sequences. By creating synthetic consensus gene sequences for the antigens coded by the vaccine that slightly differ from native proteins, the intent of this vaccine design is to help break the body's tolerance of self-made prostate cancer cells.
Pre-clinical Study Results:
Inovio is advancing INO-5150 into human trials based on strong positive preclinical data, including a simian study in which vaccination with INO-5150 generated strong and robust T-cell immune responses, and a murine study in which treatment with INO-5150 induced potent antibody and T-cell responses. Inovio intends to initiate a phase I clinical study in 2013.
Hepatitis C Genotype 1a & 1b
Hepatitis C virus is a disease characterized by inflammation of the liver. HCV is spread primarily by direct contact with human blood; the major causes worldwide are the use of unscreened blood transfusions and re-use of inadequately sterilized needles and syringes. About 5% of infected persons may die from the consequences of long term infection that leads to liver cancer or cirrhosis. The disease has been notoriously difficult to treat, with a prevalence exceeding 170 million worldwide. An estimated 5 million people are living with chronic HCV in the U.S.
Vaccine: INO-8000 Therapeutic
Antigens: NS3/4A, NS4B, NS5A
Phase: Pre-clinical
Phase I/IIa clinical trial in HCV infected individuals (4Q 2013) (funded by VGX INTL Inc.) Inovio is developing a synthetic multi-antigen DNA vaccine covering hepatitis C virus (HCV) genotypes 1a and 1b and targeting the antigens NS3/4A, which includes HCV nonstructural proteins 3 (NS3) and 4A (NS4A), as well as NS4B and NS5A proteins. The vaccine will be delivered with Inovio's CELLECTRA delivery device.
Pre-clinical Study Results:
Supporting this product development advancement are positive preclinical results, which were published in Molecular Therapy. Following immunization, rhesus macaques mounted strong HCV-specific T cell immune responses strikingly similar to those reported in patients who have cleared the virus on their own. The responses included strong NS3-specific interferon-? (IFN-?) induction, robust CD4 and CD8 T cell proliferation, and induction of polyfunctional T cells. The study was funded in part by a $2.8 million PA CURE grant received by Inovio and its collaborators in 2010.
HIV Clade B
Nearly 30 million people have died from HIV-related causes and 34 million are living with HIV1. Although a highly active antiretroviral therapy regimen has dramatically transformed the treatment of the disease in developed countries, effective HIV vaccines are needed to stop the spread of disease and reduce the need for antiretroviral treatments, which can have harsh side effects and lose their efficacy over time.
Vaccine: PENNVAX-B Preventative & Therapeutic
Antigens: gag,pol,env
Phase I. completed
Inovio is focusing future development on the HIV PENN-VAX GP (HIV Clade B Ph I. study funded by HIV Vaccine Trials Network)
PENNVAX-B is a DNA vaccine that was designed for the prevention and treatment of the HIV subtype prevalent in North America and Europe. The vaccine consists of SynCon immunogens targeting HIV gag, pol, and env proteins from HIV subtype, or clade, B. It is delivered with Inovio's CELLECTRA electroporation device.
Clinical Study Results:
In March 2012, Inovio reported that in an open label, phase I clinical trial (HIV-001) of PENNVAX-B in 12 adult HIV-positive volunteers, the vaccine generated significant T-cell immune responses. These responses were predominately antigen-specific CD8+ T-cells, which are considered to be paramount in clearing chronic viral infections and an important performance measure. There were no significant adverse events. In this study, four doses of PENNVAX-B were delivered with the CELLECTRA electroporation device. The study was conducted at the University of Pennsylvania Medical Center.
In a prior phase I study (HVTN-080) of 48 healthy patients, PENNVAX-B demonstrated best-in-class immune responses. These results indicated the potency of Inovio's synthetic vaccine technology platform, raising the potential for the development of therapeutic vaccines against HIV.
Knowledge from the PENNVAX-B HIV program has been incorporated into the design of our multi-clade, globally oriented PENNVAX-GP vaccine, which is now our lead preventive and therapeutic vaccine that broadly targets global HIV strains. Inovio will not further develop PENNVAX-B.
HIV Clades A,C,D
Vaccine: PENNVAX-G Preventative & Therapeutic
Antigens: env,gag
Phase I. Completed enrollment.
(funded by USMHRP/NIAID) PENNVAX-G is a developmental vaccine for the prevention and treatment of HIV strains present in Africa and Asia. It is intended to induce broad antibody and T-cell immune responses. This multi-subtype vaccine is based on optimized synthetic immunogens targeting the env and gag antigens of HIV-1 global subtypes A, C, and D. It is delivered via Inovio's CELLECTRA electroporation device.
Clinical Study Results:
A phase I study is evaluating administration of Inovio's PENNVAX-G global HIV vaccine plus a viral vector vaccine, Modified Vaccinia Ankara-Chiang Mai Double Recombinant (MVA-CMDR), as a unique prime-boost preventive HIV vaccination strategy. Together, PENNVAX-G and MVA-CMDR target a mixture of antigens for HIV-1 subtypes A, B, C, D and E to potentially provide global coverage.
This study, designed to assess safety and immune responses, is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health (NIH), and is being conducted by the U.S. Military HIV Research Program (MHRP) through its clinical research network in the U.S. and East Africa.
Positive interim data was presented in September 2011. In the cohort of 11 healthy subjects enrolled in the U.S., administration of PENNVAX-G plus MVA-CBMR was associated with strong immune responses and safety. Early analysis of this initial data revealed a strong cell-mediated immune response, with CD4+ and CD8+ T-cells specific for both the gag and env antigens encoded by the prime and boost agents. The study was then expanded to three global MHRP sites, at which a total of 80 healthy, HIV-uninfected international participants have been enrolled.
HIV Clades A,C (B)
Vaccine: PENNVAX-GP Preventative & Therapeutic
Antigens: gag,pol,env
Phase: Pre-clinical
PhI. Study launch by Q4-2013 (funded by NIH/NIAID/HVTN)
PENNVAX-GP is a developmental vaccine to prevent and treat HIV strains primarily present in Africa, Asia, Europe, and North America. It is intended to induce broad antibody and T-cell immune responses. This multi-subtype vaccine is based on optimized synthetic immunogens targeting the env, gag and pol antigens of HIV-1 global subtypes A, C, and B. It is delivered using Inovio's CELLECTRA electroporation device. PENNVAX-GP is our lead preventive and therapeutic HIV DNA vaccine candidate.
Influenza - Universal Pandemic
Despite efforts to control the avian flu following outbreaks in 2004, the H5N1 influenza strain has spread from Asia. H5N1 was reported in wild birds in Europe in 2005, and in wild birds and poultry in both Africa and Asia in 2006. Nearly 600 human cases of H5N1 have been reported to the World Health Organization (WHO) from 15 countries with an alarmingly high mortality rate of about 60%. No occurrences of man-to-man transmission of H5N1 have been identified. The concern, however, is that through potential re-assortment with influenza subtypes that do transfer from man to man, highly pathogenic new strains may emerge.
Since the first-ever infection of a human with the new influenza subtype, H7N9, in early 2013, the very rapid spread of this subtype caused a total of 133 confirmed human infections in Asia, with 43 deaths. No occurrences of man-to-man transmission of H7N9 have been identified, however, experts remain fearful of the possibility of the virus mutating into a form easily transmissible between humans, with the potential to trigger a pandemic. In addition, laboratory tests showed that the H7N9 virus was resistant to treatment drugs in some patients.
Vaccine: VGX-3400X Preventative
Antigens: HA,NA,NP
Phase I. completed
(internally funded)
VGX-3400X is Inovio's proprietary, preventive DNA vaccine candidate to prevent infection by avian influenza (H5N1). In a completed phase I study this plasmid vaccine was initially delivered into muscle tissue using Inovio's CELLECTRA DNA Delivery System and followed by a booster vaccination in skin. In the future it would be exclusively delivered using intradermal electroporation to facilitate expression of the plasmid to produce the H5N1consensus antigen.
Clinical Study Results:
In this open-label phase I dose escalation study, a single intradermal electroporation boost of VGX-3400X generated hemagglutination inhibition (HAI) titers against six different, unmatched strains of H5N1; was associated with a four-fold or greater rise in HAI titers in 50% of boosted subjects; and generated antigen-specific antibody and cytotoxic T-lymphocyte responses against all three antigens that it was encoded to produce: HA, NA and NP.
The 17 patients boosted with the minimally invasive intradermal electroporation vaccination were given a second booster vaccination intradermally. 47% of immunized subjects generated an HAI titer of 1:40 or higher against at least one of the tested H5N1 viruses, and 71% had an HAI titer of 1:20 or higher against at least one H5N1 strain. This data indicates the potential of VGX-3400X to provide protection across influenza subtypes and strains.
More recently, positive results from a preclinical study of Inovio's influenza DNA vaccine against the newly emergent H7N9 flu showed protection against sickness and death in 100% of the vaccinated animals when they were challenged with a lethal dose of H7N9 virus. In addition to generating a strong immune response, the vaccine was designed, optimized, and manufactured within two weeks, proving Inovio's ability to not only rapidly create a DNA vaccine construct that can address a new global threat, but the ability of the SynCon vaccines to mount robust defenses against newly emerging viral threats with pandemic potential.
Influenza - Universal Seasonal (18 - 55 yrs.)
Influenza is one of the most communicable diseases, and is typically most severe in young children and the elderly. An influenza season usually strikes both hemispheres each year, resulting in three to five million cases of severe illness and up to 500,000 deaths annually.
The protective capability of currently available influenza vaccines is substantially limited: the vaccine can only protect against the influenza strains it contains; if the selected strains continue to mutate, the vaccine may not be effective. By encompassing multiple strains, Inovio's universal influenza vaccine strategy circumvents the traditional model and may potentially protect against changing strains within the targeted subtypes across many seasons.
Vaccine: H1 + H5 Preventative
Antigen: HA
Phase I. data reported
(funded by NIH Director's Office Transformative Research Award) Inovio is advancing the development of a synthetically created, prophylactic DNA vaccine against seasonal influenza based on multiple flu strains within different subtypes. Rather than specifically matching a single targeted influenza strain within a subtype, like today's conventional influenza vaccines, Inovio designs individual "constructs" based on a genetic consensus of multiple existing strains within each selected subtype. By combining multiple constructs, we created a vaccine to potentially protect against newly emergent strains and achieve "universality" within and across selected subtypes. Inovio has created subtype constructs for Type A H1N1, H2N2, H3N2 as well as Type B influenza, which are all strains that have caused seasonal influenza outbreaks.
Clinical Study Results:
Inovio has reported data from two phase I open label studies to evaluate safety, tolerability and immune responses generated by multiple combinations of Type A influenza subtypes.
In a phase I study assessing immune responses generated by a vaccine targeting two subtypes, interim clinical data revealed protective HAI titers of 1:40 or higher against each of the nine, unmatched strains of H1N1 in a significant percentage of immunized trial subjects. Additional phase I study results showed that this SynCon vaccine generated protective antibody levels comparable to a current FDA-approved seasonal influenza vaccine against a currently circulating influenza strain. This is the first demonstration of the DNA vaccine achieving a protective immune response rate comparable to a conventional seasonal vaccine.
Prior research has shown that Inovio's H1N1 influenza SynCon vaccine provided 100% protection of animals challenged with the 2009 swine origin H1N1 virus and, separately, the H1N1 virus that caused the 1918 Spanish flu that killed over 40 million people. Additional animal studies have also shown that the vaccination generated protective HAI titers against other important H1N1 strains.
Influenza - Universal Seasonal (65+ years)
Vaccines: Various Preventative
Antigen: HA
Phase I.
(funded by NIH Director's Office Transformative Research Award)
A study of an Inovio SynCon H1N1 vaccine in combination with a "conventional" H1N1 seasonal flu vaccine was launched in July, 2012. Trial data has showed that a single dose of the H1N1 universal SynCon flu vaccine in combination with a dose of a 2012 seasonal flu vaccine generated protective immune responses in 40% of elderly trial subjects compared with a 20% response rate in the elderly subjects who received the seasonal flu vaccine alone.
Malaria
Malaria is a deadly disease that still kills more than 500,000 children under age 5 every year. MVI accelerates the development of malaria vaccines by joining its scientific, managerial, and field expertise with companies, universities, and governments to develop malaria vaccines and continue to test and invest in those with the most promise.
Vaccines: Various Preventative
Antigens: Various
Clinical Phases: Various
Inovio intends to initiate a phase I/IIa clinical study in 2014.
(funded by MVI/PATH) Inovio is developing two synthetic multi-antigen DNA vaccines targeting the pre-erythrocytic stage of the malaria parasite Plasmodium falciparum to prevent the onset of malaria symptoms and further inhibit spread of the disease. INO-7105 targets four pre-erythrocytic, antigens, CSP, TRAP, LSA-1, and CelTOS, and one blood stage antigen, AMA-1. The second vaccine, INO-7103, targets pre-erythrocytic malaria antigens CSP and TRAP as well as one blood stage antigen, AMA-1. The vaccines will be delivered with Inovio's intramuscular CELLECTRA 5P delivery device.
Pre-clinical Study Results:
Pre-clinical studies demonstrated potent T-cell and antibody responses in animal subjects. This phase I/IIa study will test DNA vaccines INO-7105 and INO-7103 delivered using Inovio's CELLECTRA 5P electroporation technology in approximately 30 individuals as part of a challenge trial. Study subjects will be given four doses of one of the DNA vaccines prior to being exposed to the malaria parasite through the bites of multiple malaria infected mosquitoes. Successful results of this trial could prove these vaccines capable of inducing an immune response in humans that protects against malaria. This study is being completed in collaboration with PATH Malaria Vaccine Initiative and is being funded by the Gates Foundation.
In a study results published on August 15, 2013, Inovio researchers and collaborators designed a highly optimized DNA vaccine composed of four sporozoite and liver-stage malaria antigens using Inovio's SynCon technology. These antigens were chosen because of their important role in the control or elimination of malaria infection. Delivered using Inovio's CELLECTRA delivery system, this malaria vaccine generated robust and long-lasting T-cell responses in both mice and non-human primates. Moreover, these vaccine-produced T-cells exhibited the functional ability to kill and eliminate malaria-infected cells. Researchers also found vaccine-induced CD8+, or "killer T-cells," in the liver, which is essential for rapid elimination of liver-stage malaria parasites. The Inovio DNA/electroporation platform has demonstrated in prior preclinical and human studies the ability to induce potent immune responses to multiple antigens; in this study, robust and sustained antibody responses to all four malaria antigens were observed, a strong indication for a preventive response in humans.
Collaborator Vaccines & Studies
Leukemia CML & AML
AML, a cancer of the myeloid line of blood cells, is characterized by rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults; its incidence increases with age. Only about one-third of those between ages 18-60 who are diagnosed with AML can be cured. With conventional chemotherapy, 70% of the patients in the group under study will relapse within two years, and current therapy is devastating in older adults.
CML is a type of cancer that causes the body to produce large numbers of immature and mature white blood cells (myelocytes). Approximately 85% of patients with CML are in the chronic phase at the time of diagnosis. Ultimately, in the absence of curative treatment, the disease progresses to an accelerated phase where median survival is around three to five years. CML can occur at any age, but it more commonly affects middle-aged and older people.
Vaccines: WT1 Vaccine Therapeutic
Antigen: WT1
Phase II.
Owned/funded by U. of Southampton/ LLR and CRUK* (Inovio electroporation) Developed by the University of Southampton with funding from Leukemia and Lymphoma Research and Cancer Research UK, this DNA vaccine is encoded for Wilms' Tumor gene 1 (WT1), which is highly associated with leukemia. The vaccine is delivered using Inovio's ELGEN-1000 automated electroporation device.
Clinical Study Results:
Preliminary results of the phase II trial have shown robust vaccine-specific antibody and T-cell immune responses in all vaccinated trial subjects evaluated to date. In addition to favorable immunogenicity, the vaccine has proven to be safe overall and well tolerated by patients in the study. This open label, single dose level study is currently enrolling two patient arms (37 CML and 37 AML patients), and an additional 100-110 AML/CML patients as non-vaccinated controls, at multiple study centers in the UK.
Table II. Pre-clinical Studies & Vaccine Candidates Not Reflected on Inovio's Pipeline Diagram
Disease
Cytomegalovirus (CMV)
Cytomegalovirus (CMV) is a common virus that can infect almost anyone. Most people don't know they have CMV because it rarely causes symptoms. However, if you're pregnant or have a weakened immune system, CMV is cause for concern.
Once infected with CMV, your body retains the virus for life. However, CMV usually remains dormant if you're healthy. CMV spreads through body fluids, such as blood, saliva, urine, semen and breast milk. People with weak immune systems have a greater risk of becoming ill from CMV. If you're pregnant and develop an active infection, you can pass the virus to your baby.
There's no cure for CMV, but drugs can help treat newborns and people with weak immune systems.
Vaccine: Undisclosed Therapeutic
Antigens: Numerous - Undisclosed
Phase: Pre-clinical
Inovio researchers first investigated a novel panel of ten CMV immunogens comprised of mainly surface-associated proteins based on promising prior clinical and preclinical data that had been previously shown to be important for inducing cellular immune responses in CMV infection. To maximize the potential for broadly-reactive immunity, Inovio researchers created SynCon vaccines for each of the target proteins based on amino acid consensus sequences from multiple variant CMV clinical strains, and excluded those from potentially divergent, highly passaged lab-adapted strains. The researchers adopted the same strategy as was shown previously to enhance protective immune responses against divergent strains of influenza and HIV. The designed target sequences were further genetically optimized at the nucleic acid level.
Pre-clinical Study Results:
Researchers observed that vaccination with each CMV construct was highly T cell immunogenic in preclinical proof-of-concept mice studies, generating robust and broad T cell responses as extensively analyzed by the T cell ELISPOT assay. Each antigen produced responses against at least four and as many as 28 different regions of the antigen and, importantly, responses from both CD8+ and CD4+ T cells were observed. This increased diversity and magnitude of cellular responses may be critical for effectively mitigating CMV infection and disease in the transplantation setting.
These data demonstrate that Inovio's next-generation SynCon DNA vaccine technology is effective at inducing CD8+ T cell responses specific to CMV, in contrast to prior strategies that induced mainly CD4+-dominant responses. Additionally, a majority of epitopes identified for the gB, gH, and gL antigens also contained HLAs that have previously been reported to contribute to the suppression of viremia and amelioration of disease. In summary, the elicitation, identification, and characterization of extensive T cell responses driven by Inovio's CMV SynCon constructs will provide an important tool for guiding clinical development of a CMV vaccine. Further ongoing work will determine how many of the 10 antigens will be selected and taken further for clinical development as well as assess the induction of antibody responses to prevent CMV infection.
Hepatitis B
Hepatitis B is a disease characterized by inflammation of the liver. It is 50 to 100 times more infectious than HIV and is spread primarily by direct contact with human blood, semen, or bodily fluid from an infected individual. Hepatitis B contributes to an estimated 620,000 deaths worldwide each year.
Vaccine: Undisclosed Therapeutic
Antigen: Undisclosed
Phase: Pre-clinical
Pre-clinical Study Results:
In October 2011 Inovio entered into a product development collaboration agreement with its affiliate, VGX International Inc., to co-develop Inovio's SynCon therapeutic vaccines for hepatitis B and C infections. Preclinical trial data reported that the hepatitis B vaccine successfully generated strong T cell and antibody responses that led to the elimination of targeted liver cells in mice. These results indicate the DNA vaccine's potential to treat hepatitis B infection and prevent further development of the infection into liver cancer in humans.
Multiple Cancers
Vaccine: INO-1400 Therapeutic
Antigen: hTERT
Phase: Pre-clinical
PhI. Launch planned for 2014.
Human telomerase reverse transcriptase (hTERT) is an attractive DNA vaccine target in cancer immunotherapy. High levels of hTERT have been detected in more than 85% of all human cancers, while normal cells showed undetectable levels of telomerase expression.
Immunological analysis indicated that the hTERT is a widely applicable target recognized by T-cells and can be potentially used as a universal cancer vaccine.
Inovio has developed a highly optimized synthetic hTERT DNA vaccine with two mutations designed to target multiple cancers expressing the antigen hTERT, including non-small cell lung carcinoma, breast cancer, melanoma, and prostate cancer.
Pre-clinical Study Results:
The hTERT DNA vaccine has induced strong and broad hTERT-specific CD8+ T-cell immune responses in rodents and non-human primates in preclinical studies. When delivered with electroporation, Inovio's DNA cancer vaccine was able to break tolerance and elicit strong and broad hTERT-specific immune responses with the potential to eliminate tumor cells in monkeys, whose TERT is 96% similar to human TERT. Overall, Inovio's DNA hTERT vaccine showed immune responses that were more than 18-fold higher than the previous best- results of a peer's hTERT DNA vaccine delivered with electroporation. Because high levels of hTERT expression are found in 85% of human cancers, regardless of type, Inovio's cancer candidate holds the potential to perform as a "universal" cancer therapeutic based on early, but unprecedented, results from preclinical trials.
Ebola and Marburg Filoviruses
There is no approved vaccine or therapy available against these highly virulent pathogens that have killed up to 90% of the people they infected. Because these viruses could potentially be easily transmitted, result in high mortality rates and cause a major public health impact, various agencies are seeking solutions for public health preparedness. A DNA vaccine could offer faster design and manufacturing timelines than traditional vaccine approaches, but particularly important, Inovio's SynCon products offer the potentially preemptive advantage of enabling a design to provide broad protection encompassing multiple families of these so-called filoviruses.
Vaccine: Undisclosed Preventative Antigen: Undisclosed
Phase: Pre-clinical
Pre-clinical Study Results:
Using Inovio's proprietary SynCon design approach, Inovio researchers developed a polyvalent DNA vaccine consisting of three consensus plasmids to broadly target variant virus strains within three distinct families of Ebola and Marburg viruses. In the first part of this study, following two vaccinations using Inovio's proprietary CELLECTRA electroporation device, 100% of vaccinated guinea pigs were protected from death following a virus challenge. The researchers observed significant increases in neutralizing antibody titers and strong and broad levels of vaccine-induced T-cells, including "killer" T-cells, and subsequently conducted a test in mice using only one vaccination - this single dose also fully protected the animals from death following a virus challenge. In addition, unlike the non-vaccinated animals, vaccinated animals were protected from weight loss.
Peripheral Arterial Disease (PAD)
Finding an effective therapy for PAD and CLI is imperative because the current standard of care relies primarily on palliative drugs and amputation. PAD affects 8 - 12 million Americans and is associated with a 20 - 30% risk of cardiovascular death within five years. CLI is a more severe stage of PAD affecting over one million people in the US. Up to 20% of CLI patients will die within 12 months of diagnosis; the five-year mortality rate exceeds 70%. The disease is characterized by ischemic rest pain-severe pain in the legs and feet while a person is not moving-or non-healing sores on the feet or legs as well as gangrene. Major limb amputation occurs in up to 40 - 50% of CLI patients within 12 months of diagnosis.
Vaccine: Undisclosed synthetically optimized hypoxia-inducible factor-1 alpha (HIF-1a) gene Therapeutic
Antigen: n/a Phase: Pre-clinical
In this study, the gene sequence for HIF-1a was synthetically optimized to enhance expression of the growth factor. This DNA therapy was then delivered using Inovio's CELLECTRA constant current electroporation device, which has been shown to enhance the delivery of DNA plasmids by a 1000 fold using a millisecond pulse. A total of 39 mice were divided into 3 groups: (1) one group receiving HIF-1a DNA delivered with electroporation (EP) (n=13); (2) one group receiving HIF-1a DNA without EP (n=14) and (3) one group receiving a control empty plasmid (pVAX) delivered with EP (n=12). The left femoral artery in each mouse was tied up surgically to simulate an arterial blockage. The right legs were not treated and served as internal controls. The mice were then observed and scored for their limb function. Blood flow in their legs was measured by laser Doppler perfusion imaging.
Pre-clinical Study Results:
The results demonstrated that EP delivery of synthetically optimized HIF-1a plasmid DNA significantly improved blood flow in the left hind legs and reduced necrosis (premature cell death) in a mouse model of hind limb ischemia when compared to the results from the two control groups. The treatment also improved survival from severe limb damage and amputation, reduced tissue damage, and increased the number of new capillaries and formation of larger collateral vessels.
Chikungunya virus
CHIKV is an emerging mosquito-borne virus indigenous to tropical Africa and Asia. Acute illness is characterized by fever, arthralgia (pain in a joint), conjunctivitis (eye inflammation), rash, and sometimes arthritis. Relatively little is known about the antigenic targets for immunity and no licensed vaccines or therapeutics are currently available. Considering the potential for pandemic spread, understanding the development of immunity is paramount to the development of effective vaccines against CHIKV.
Vaccine: CHIKV Preventative
Antigens: E3+E2+E1
Phase: Pre-clinical
In this study, the research team isolated CHIKV from an acutely infected human patient and used this newly isolated virus to develop a virus neutralization assay and a challenge stock. The CHIKV challenge stock was used to establish a mouse infection model and study disease development. The candidate CHIKV vaccine developed by the researchers and tested in the mouse and macaque models is a SynCon(TM) synthetic DNA vaccine consisting of a single consensus envelope construct that expresses all three of the CHIKV envelope glycoproteins (E3+E2+E1). The vaccine is delivered by in vivo electroporation.
Pre-clinical Study Results:
The vaccine induced robust antibody and T-cell immune responses and provide 100% protection of mice against a challenge with this tropical infectious disease. Additionally, vaccine studies in rhesus macaques demonstrated generation of strong neutralizing antibody responses which mimicked those observed in CHIKV-infected human patients who subsequently recovered from this disease. These results demonstrate the ability of Inovio's DNA vaccine to provide protection and protective immune responses in two different preclinical models.
Animal Vaccine Studies
Foot and Mouth Disease (FMD)
Vaccines: Various Preventative
Antigens: FMD clades A, O, C, and Asia
Inovio recently announced that it had designed and tested in animals a set of multi-subtype synthetic vaccine candidates for FMD clades A, O, C, and Asia. Following administration of these synthetic vaccines using Inovio's proprietary vaccine delivery technology in swine and sheep, all the vaccines induced strong antibody and T cell immune responses. Inovio's patented SynCon vaccines cannot cause the targeted disease, providing a safe approach to potentially protect against FMD and reduce its serious impact on global food supply and commerce.
Perinatal mortality of piglets
Vaccine: LifeTide SW 5.0 growth hormone releasing hormone (GHRH) therapy
Regulatory Marketing Approval in New Zealand
LifeTide is a once-in-a-lifetime treatment for female pigs (sows) that has demonstrated significant decreases in perinatal mortality of piglets from treated sows compared to untreated sows. The treatment, which increases the number of weaned piglets and results in greater overall meat production, was previously approved in Australia. (VGX Animal Health Inc. - Inovio subsidiary)
Cancer in Dogs
Vaccine: VAH-5000D Therapeutic
Antigen: Tert
Phase: Pre-clinical
In mouse experiments, vaccinations with a highly optimized TERT DNA vaccine delivered by electroporation induced strong TERT-specific T cell immune responses. Furthermore, vaccination with the TERT vaccine delayed the growth of implanted tumors in mice and increased the survival rate of mice with tumors. (VGX Animal Health Inc. - Inovio subsidiary)
Table III. Intellectual Property Rights to Synthetic Vaccines for Specific Diseases - Not Yet Reported On
Clostridium difficile, or C. difficile
Cancer - new cancer therapeutic vaccines targeting Wilms' tumor gene or WT1.
Chemokine and cytokine molecular adjuvant technologies
RSV (respiratory syncytial virus)
MRSA (methicillin-resistant staphylococcus aureus)
http://seekingalpha.com/article/1652522-the-disruptive-potential-of-inovios-syncon-dna-vaccines
The purpose of this report is to highlight the disruptive potential of Inovio's (INO) SynCon DNA vaccines, and Inovio's increasing leadership role in revolutionizing vaccines.
The key takeaways from this article are:
Inovio's Synthetic Consensus (SynCon) vaccines have the potential to disrupt the vaccine industry - e.g. broadened immunological impact, speedier design, cheaper production costs, more stable and easier to transport than alternatives, superior safety profiles, higher efficacy profiles, leverages the power of the human immune system, etc. Inovio's electroporation provides a superior method of delivering and invoking a targeted human immune system response.
The safety and efficacy studies of DNA vaccines have now matured to the point that there is a clear implication that DNA-based vaccines are likely to play an increasingly important role in preventative and therapeutic solutions in the near future.
Inovio Pharmaceuticals Inc. is positioned to lead the 21st century vaccine industry based on its increasingly broad & maturing pipeline, formidable IP patent estate, significant non-dilutive funding of its research through government (GO) and non-government organizations (NGO), eminent management and advisory teams with years of vaccines & immunology experience.
Inovio's share price is currently in an oversold position in comparison with the recent 52 week high of $3.03 due to significant uptick in short-seller interest (10.12M shares as of July 31, expectedly much higher as of August 20), presenting an opportunity for investors to establish a position prior to 2014 Ph II. HPV Therapeutic Clinical Study Results, and future partnership announcements.
Inovio's increasingly broad & maturing pipeline, its expanding GO & NGO agreements, are tangible catalysts for significant stock appreciation in 2013 and beyond. This report provides a detailed view of the pre- and clinical vaccines & candidates to demonstrate that Inovio is the real deal…with vaccines to combat some of the toughest infectious diseases, viruses, cancers, etc.
I. Reflections on the 2013 McKinsey Global Institute Report: "Disruptive technologies: Advances that will transform life, business, and the global economy"
McKinsey & Company is a premier global management consulting firms that advises Fortune 500 firms & governments on business & technology strategy, enabling transformational change.
In the opening section of the report, McKinsey states "….we believe these technologies will have large and disruptive impact. More importantly, the results of our research show that business leaders and policy makers-and society at large-will confront change on many fronts: in the way businesses organize themselves, how jobs are defined, how we use technology to interact with the world (and with each other), and, in the case of next-generation genomics, how we understand and manipulate living things. There will be disruptions to established norms, and there will be broad societal challenges. Nevertheless, we see considerable reason for optimism. Many technologies on the horizon offer immense opportunities. We believe that leaders can seize the opportunities, if they start preparing now."
The McKinsey article also states: "The science of genomics is at the beginning of a new era of innovation. The rapidly declining cost of gene sequencing is making huge amounts of genetic data available, and the full power of information technology is being applied to vastly speed up the process of analyzing these data to discover how genes determine traits or mutate to cause disease. Armed with this information, scientists and companies are developing new techniques to directly write DNA and insert it into cells, building custom organisms and developing new drugs to treat cancer and other diseases. Over the coming decade, next-generation genomics technology could power rapid acceleration in the field of biology and further alter healthcare…."
The criteria McKinsey used for identifying disruptive technology were:
The technology is rapidly advancing or experiencing breakthroughs
The potential scope of impact is broad
Significant economic value could be affected
Economic impact is potentially disruptive
The McKinsey report defined Next-generation genomics as: "Next-generation genomics marries advances in the science of sequencing and modifying genetic material with the latest big data analytics capabilities…. The next step is synthetic biology-the ability to precisely customize organisms by "writing" DNA. These advances in the power and availability of genetic science could have profound impact on medicine, agriculture, and even the production of high-value substances such as biofuels-as well as speed up the process of drug discovery."
Inovio plays an important role in this transformational field by a.) Effectively harnessing the power & insights of genomic sequencing and b.) Combining patented & novel processes to create synthetic DNA (SynCon) vaccines that equip the human immune system with the means to prevent & fight life-threatening infectious diseases, cancers, autoimmune disorders. These vaccines are effectively delivered to the human immune system via electroporation.
II. Inovio's SynCon DNA Vaccines - Innovative & Disruptive
In the book "The Innovator's Dilemma", the author Christenson describes the following characteristics of disruptive innovations:
Disruptive technology is "simpler, cheaper, and lower performing"
Incumbent firms "most profitable customers generally can't use and don't want" disruptive technology
Disruptive technology is "first commercialized in emerging or insignificant markets"
Disruptive technology promises "lower margins, not higher profits"
Advantages: DNA immunization offers many advantages over the traditional forms of vaccination
It is able to induce the expression of antigens that resemble native viral epitopes more closely than standard vaccines do since live attenuated and killed vaccines are often altered in their protein structure and antigenicity.
Plasmid vectors can be constructed and produced quickly and the coding sequence can be manipulated in many ways. DNA vaccines encoding several antigens or proteins can be delivered to the host in a single dose, only requiring a microgram of plasmids to induce immune responses.
Rapid and large-scale production are available at costs considerably lower than traditional vaccines, and they are also very temperature stable making storage and transport much easier.
Another important advantage of genetic vaccines is their therapeutic potential for ongoing chronic viral infections. DNA vaccination may provide an important tool for stimulating an immune response in HBV, HCV and HIV patients. The continuous expression of the viral antigen caused by gene vaccination in an environment containing many APCs may promote successful therapeutic immune response which cannot be obtained by other traditional vaccines"
Inovio SynCon DNA Vaccines: the future of vaccines
Inovio has leveraged the valuable body of genomics, immunology, epidemiology, and bio-engineering research to dramatically improve on the effectiveness of its SynCon vaccines: (the following sections of this report are based on information available on Inovio's website: inovio.com)
Design and selection of appropriate antigen targets for a particular disease. These include targets associated with the induction of antibody or T-cell or both immune responses observed during natural infection.
SynCon vaccines use a DNA fragment with instructions that enable cells in the body to produce ONLY the targeted antigen relating to a pathogen or cancer. The fragment cannot replicate and is not able to cause the disease.
Rather than being constrained by the paradigm of matching a preventive or therapeutic vaccine to a single pathogen strain, [Inovio's] SynCon vaccines are based on genetic code for a specific antigen from multiple strains of the target pathogen.Thus, while the SynCon antigens may not be perfectly (100%) matched to the pathogenic strains, they are designed to protect against multiple existing strains as well as changing strains of a virus. Extensive preclinical data has validated their ability to protect against many strains of a disease; initial human data for [Inovio's] influenza vaccine has also provided evidence of this capability.
With respect to cancers, preclinical data has shown that these "unmatched" gene sequences aid the immune system's recognition of "self-made" cells that are cancerous. Whereas normally it might tolerate these cells made in the body, antigens produced by SynCon therapeutic vaccines are able to induce strong immune responses against the cancer cells.
SynCon vaccines can produce strong T-cell responses (both CD4+ and CD8+): T-cell immune responses are considered vital to fighting cancerous cells and chronic infections. While live virus vaccines are able to generate T-cells, this approach is not viable for many diseases, such as HIV. Other "conventional" vaccine technologies (such as recombinant proteins, virus-like particles, subunit vaccines, and peptides) can at best produce only weak T-cell responses. Experimental approaches such as viral vectors have achieved strong T-cell responses, but have limiting factors such as their inability to boost with repeated vaccination due to immune responses to the viral vector itself (which can be based on a virus, such as a cold virus, to which we have been previously exposed).
However, Inovio's SynCon vaccines have, in human studies for cervical dysplasia and HIV, generated best-in-class T-cell responses that exceed all these approaches. What is particularly exciting is that these responses include strong CD8+ T-cell responses which are able to kill targeted infected cells. In a recent human study, Inovio's vaccine for cervical dysplasia demonstrated for the first time that a DNA-based therapeutic vaccine can produce immune responses with a killing effect on target cells and potentially reverse disease progression to cervical cancer.
Inovio's synthetic DNA vaccines can be designed in weeks instead of months or years. They are manufactured by a fast and efficient fermentation process. They have a better stability profile and do not require maintenance of cold-chain requirements for storage and transport. These important advantages yield more timely vaccine development and can improve accessibility in nations with less developed infrastructure.
The novel SynCon genetic sequences, which do not exist in nature, are patentable.
The elegance of Inovio's SynCon vaccines is that [Inovio] is not creating an immunogen that would then be placed into the body to induce a desired immune response. Instead, [Inovio] creates a fragment of DNA to produce one or more targeted antigens and place that DNA into cells of the body (with the assistance of our proprietary electroporation systems) where it does nothing other than give instructions to the cells to produce the desired antigen. This approach results in the body creating an immunogen capable of inducing strong, multi-faceted immune responses similar to immune responses to actual pathogens. Human data to date has shown our approach has a positive safety profile."
III. Further Information
Company History:
Inovio Pharmaceuticals, founded in 1983, engages in DNA vaccine research through subsidiaries VGX Pharmaceuticals and VGX Animal Health. The company became incorporated in 2001, in Delaware, and is currently headquartered in Blue Bell, PA, USA. The three companies focus on the discovery and development of DNA vaccines for the treatment of cancer and infectious diseases. The CEO of Inovio, Dr. Joseph Kim, co-founded VGX Pharmaceuticals with DNA vaccine pioneer Professor David Wyner (University of Pennsylvania), in December 2000. In June 2009, his company merged with Inovio Pharma.
Cash Position & Runway:
As of June 30, 2013, cash and cash equivalents plus short-term investments were $23.6 million compared with $13.8 million as of December 31, 2012.
Based on management's projections and analysis, the Company believes that cash and cash equivalents are sufficient to meet its planned working capital requirements through the first quarter of 2015.
Corporate Development:
Inovio continues to advance discussions with large pharmaceutical companies with the goal of securing strategic partnerships to advance the development of SynCon vaccines.
Inovio and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) received a $3.5 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) to advance the development of Inovio's next generation DNA vaccine delivery device capable of simultaneously administering multiple synthetic vaccines via skin surface electroporation.
Inovio was recognized with Vaccine Industry Excellence (ViE) Awards for "Best Early Stage Biotech" and "Best Therapeutic Vaccine," for its HPV vaccine, VGX-3100, at the World Vaccine Congress. The ViE Awards recognize outstanding vaccine advancements and achievements of vaccine developers across the global industry as judged by a panel of global biotech industry stakeholders.
Due Diligence:
Prospective investors should research the potential risks and rewards associated with investing in Inovio, as well as any publicly held company. Inovio is a clinical-stage company, has been unprofitable thus far, and will likely require additional capital to further the research and development of vaccines. Investors may obtain access to the company's SEC reports at: http://ir.inovio.com/secfilings
IV. Inovio's Pipeline
Inovio has a growing and maturing pipeline of vaccines covering major infectious diseases, cancers, and autoimmune disorders:
Table I. Inovio's Pipeline: Clinical & Pre-clinical Test Results
Disease / Vaccine / Antigen / Clinical Study Results:
Cervical dysplasia HPV Type 16/18
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 510,000 women worldwide and results in 288,000 deaths annually.
Vaccine: VGX-3100 Therapeutic
Antigens: E6,E7
Phase II.
PhII results expected Mid-2014. (internally funded) 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.
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.
Clinical Study 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. 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.
Prostate Cancer
In 2010, more than 218,000 new cases were diagnosed and over 32,000 men died from prostate cancer in the U.S. alone.
Vaccine: INO-5150 Therapeutic
Antigens: PSA,PSMA
Phase: Pre-clinical
PhI. Study launch by Q4-2013. (internally funded) INO-5150 is Inovio's dual-antigen SynCon vaccine targeting prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA). INO-5150 was generated by the creation of PSA and PSMA synthetic consensus antigens based on human and primate antigen gene sequences. By creating synthetic consensus gene sequences for the antigens coded by the vaccine that slightly differ from native proteins, the intent of this vaccine design is to help break the body's tolerance of self-made prostate cancer cells.
Pre-clinical Study Results:
Inovio is advancing INO-5150 into human trials based on strong positive preclinical data, including a simian study in which vaccination with INO-5150 generated strong and robust T-cell immune responses, and a murine study in which treatment with INO-5150 induced potent antibody and T-cell responses. Inovio intends to initiate a phase I clinical study in 2013.
Hepatitis C Genotype 1a & 1b
Hepatitis C virus is a disease characterized by inflammation of the liver. HCV is spread primarily by direct contact with human blood; the major causes worldwide are the use of unscreened blood transfusions and re-use of inadequately sterilized needles and syringes. About 5% of infected persons may die from the consequences of long term infection that leads to liver cancer or cirrhosis. The disease has been notoriously difficult to treat, with a prevalence exceeding 170 million worldwide. An estimated 5 million people are living with chronic HCV in the U.S.
Vaccine: INO-8000 Therapeutic
Antigens: NS3/4A, NS4B, NS5A
Phase: Pre-clinical
Phase I/IIa clinical trial in HCV infected individuals (4Q 2013) (funded by VGX INTL Inc.) Inovio is developing a synthetic multi-antigen DNA vaccine covering hepatitis C virus (HCV) genotypes 1a and 1b and targeting the antigens NS3/4A, which includes HCV nonstructural proteins 3 (NS3) and 4A (NS4A), as well as NS4B and NS5A proteins. The vaccine will be delivered with Inovio's CELLECTRA delivery device.
Pre-clinical Study Results:
Supporting this product development advancement are positive preclinical results, which were published in Molecular Therapy. Following immunization, rhesus macaques mounted strong HCV-specific T cell immune responses strikingly similar to those reported in patients who have cleared the virus on their own. The responses included strong NS3-specific interferon-? (IFN-?) induction, robust CD4 and CD8 T cell proliferation, and induction of polyfunctional T cells. The study was funded in part by a $2.8 million PA CURE grant received by Inovio and its collaborators in 2010.
HIV Clade B
Nearly 30 million people have died from HIV-related causes and 34 million are living with HIV1. Although a highly active antiretroviral therapy regimen has dramatically transformed the treatment of the disease in developed countries, effective HIV vaccines are needed to stop the spread of disease and reduce the need for antiretroviral treatments, which can have harsh side effects and lose their efficacy over time.
Vaccine: PENNVAX-B Preventative & Therapeutic
Antigens: gag,pol,env
Phase I. completed
Inovio is focusing future development on the HIV PENN-VAX GP (HIV Clade B Ph I. study funded by HIV Vaccine Trials Network)
PENNVAX-B is a DNA vaccine that was designed for the prevention and treatment of the HIV subtype prevalent in North America and Europe. The vaccine consists of SynCon immunogens targeting HIV gag, pol, and env proteins from HIV subtype, or clade, B. It is delivered with Inovio's CELLECTRA electroporation device.
Clinical Study Results:
In March 2012, Inovio reported that in an open label, phase I clinical trial (HIV-001) of PENNVAX-B in 12 adult HIV-positive volunteers, the vaccine generated significant T-cell immune responses. These responses were predominately antigen-specific CD8+ T-cells, which are considered to be paramount in clearing chronic viral infections and an important performance measure. There were no significant adverse events. In this study, four doses of PENNVAX-B were delivered with the CELLECTRA electroporation device. The study was conducted at the University of Pennsylvania Medical Center.
In a prior phase I study (HVTN-080) of 48 healthy patients, PENNVAX-B demonstrated best-in-class immune responses. These results indicated the potency of Inovio's synthetic vaccine technology platform, raising the potential for the development of therapeutic vaccines against HIV.
Knowledge from the PENNVAX-B HIV program has been incorporated into the design of our multi-clade, globally oriented PENNVAX-GP vaccine, which is now our lead preventive and therapeutic vaccine that broadly targets global HIV strains. Inovio will not further develop PENNVAX-B.
HIV Clades A,C,D
Vaccine: PENNVAX-G Preventative & Therapeutic
Antigens: env,gag
Phase I. Completed enrollment.
(funded by USMHRP/NIAID) PENNVAX-G is a developmental vaccine for the prevention and treatment of HIV strains present in Africa and Asia. It is intended to induce broad antibody and T-cell immune responses. This multi-subtype vaccine is based on optimized synthetic immunogens targeting the env and gag antigens of HIV-1 global subtypes A, C, and D. It is delivered via Inovio's CELLECTRA electroporation device.
Clinical Study Results:
A phase I study is evaluating administration of Inovio's PENNVAX-G global HIV vaccine plus a viral vector vaccine, Modified Vaccinia Ankara-Chiang Mai Double Recombinant (MVA-CMDR), as a unique prime-boost preventive HIV vaccination strategy. Together, PENNVAX-G and MVA-CMDR target a mixture of antigens for HIV-1 subtypes A, B, C, D and E to potentially provide global coverage.
This study, designed to assess safety and immune responses, is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health (NIH), and is being conducted by the U.S. Military HIV Research Program (MHRP) through its clinical research network in the U.S. and East Africa.
Positive interim data was presented in September 2011. In the cohort of 11 healthy subjects enrolled in the U.S., administration of PENNVAX-G plus MVA-CBMR was associated with strong immune responses and safety. Early analysis of this initial data revealed a strong cell-mediated immune response, with CD4+ and CD8+ T-cells specific for both the gag and env antigens encoded by the prime and boost agents. The study was then expanded to three global MHRP sites, at which a total of 80 healthy, HIV-uninfected international participants have been enrolled.
HIV Clades A,C (B)
Vaccine: PENNVAX-GP Preventative & Therapeutic
Antigens: gag,pol,env
Phase: Pre-clinical
PhI. Study launch by Q4-2013 (funded by NIH/NIAID/HVTN)
PENNVAX-GP is a developmental vaccine to prevent and treat HIV strains primarily present in Africa, Asia, Europe, and North America. It is intended to induce broad antibody and T-cell immune responses. This multi-subtype vaccine is based on optimized synthetic immunogens targeting the env, gag and pol antigens of HIV-1 global subtypes A, C, and B. It is delivered using Inovio's CELLECTRA electroporation device. PENNVAX-GP is our lead preventive and therapeutic HIV DNA vaccine candidate.
Influenza - Universal Pandemic
Despite efforts to control the avian flu following outbreaks in 2004, the H5N1 influenza strain has spread from Asia. H5N1 was reported in wild birds in Europe in 2005, and in wild birds and poultry in both Africa and Asia in 2006. Nearly 600 human cases of H5N1 have been reported to the World Health Organization (WHO) from 15 countries with an alarmingly high mortality rate of about 60%. No occurrences of man-to-man transmission of H5N1 have been identified. The concern, however, is that through potential re-assortment with influenza subtypes that do transfer from man to man, highly pathogenic new strains may emerge.
Since the first-ever infection of a human with the new influenza subtype, H7N9, in early 2013, the very rapid spread of this subtype caused a total of 133 confirmed human infections in Asia, with 43 deaths. No occurrences of man-to-man transmission of H7N9 have been identified, however, experts remain fearful of the possibility of the virus mutating into a form easily transmissible between humans, with the potential to trigger a pandemic. In addition, laboratory tests showed that the H7N9 virus was resistant to treatment drugs in some patients.
Vaccine: VGX-3400X Preventative
Antigens: HA,NA,NP
Phase I. completed
(internally funded)
VGX-3400X is Inovio's proprietary, preventive DNA vaccine candidate to prevent infection by avian influenza (H5N1). In a completed phase I study this plasmid vaccine was initially delivered into muscle tissue using Inovio's CELLECTRA DNA Delivery System and followed by a booster vaccination in skin. In the future it would be exclusively delivered using intradermal electroporation to facilitate expression of the plasmid to produce the H5N1consensus antigen.
Clinical Study Results:
In this open-label phase I dose escalation study, a single intradermal electroporation boost of VGX-3400X generated hemagglutination inhibition (HAI) titers against six different, unmatched strains of H5N1; was associated with a four-fold or greater rise in HAI titers in 50% of boosted subjects; and generated antigen-specific antibody and cytotoxic T-lymphocyte responses against all three antigens that it was encoded to produce: HA, NA and NP.
The 17 patients boosted with the minimally invasive intradermal electroporation vaccination were given a second booster vaccination intradermally. 47% of immunized subjects generated an HAI titer of 1:40 or higher against at least one of the tested H5N1 viruses, and 71% had an HAI titer of 1:20 or higher against at least one H5N1 strain. This data indicates the potential of VGX-3400X to provide protection across influenza subtypes and strains.
More recently, positive results from a preclinical study of Inovio's influenza DNA vaccine against the newly emergent H7N9 flu showed protection against sickness and death in 100% of the vaccinated animals when they were challenged with a lethal dose of H7N9 virus. In addition to generating a strong immune response, the vaccine was designed, optimized, and manufactured within two weeks, proving Inovio's ability to not only rapidly create a DNA vaccine construct that can address a new global threat, but the ability of the SynCon vaccines to mount robust defenses against newly emerging viral threats with pandemic potential.
Influenza - Universal Seasonal (18 - 55 yrs.)
Influenza is one of the most communicable diseases, and is typically most severe in young children and the elderly. An influenza season usually strikes both hemispheres each year, resulting in three to five million cases of severe illness and up to 500,000 deaths annually.
The protective capability of currently available influenza vaccines is substantially limited: the vaccine can only protect against the influenza strains it contains; if the selected strains continue to mutate, the vaccine may not be effective. By encompassing multiple strains, Inovio's universal influenza vaccine strategy circumvents the traditional model and may potentially protect against changing strains within the targeted subtypes across many seasons.
Vaccine: H1 + H5 Preventative
Antigen: HA
Phase I. data reported
(funded by NIH Director's Office Transformative Research Award) Inovio is advancing the development of a synthetically created, prophylactic DNA vaccine against seasonal influenza based on multiple flu strains within different subtypes. Rather than specifically matching a single targeted influenza strain within a subtype, like today's conventional influenza vaccines, Inovio designs individual "constructs" based on a genetic consensus of multiple existing strains within each selected subtype. By combining multiple constructs, we created a vaccine to potentially protect against newly emergent strains and achieve "universality" within and across selected subtypes. Inovio has created subtype constructs for Type A H1N1, H2N2, H3N2 as well as Type B influenza, which are all strains that have caused seasonal influenza outbreaks.
Clinical Study Results:
Inovio has reported data from two phase I open label studies to evaluate safety, tolerability and immune responses generated by multiple combinations of Type A influenza subtypes.
In a phase I study assessing immune responses generated by a vaccine targeting two subtypes, interim clinical data revealed protective HAI titers of 1:40 or higher against each of the nine, unmatched strains of H1N1 in a significant percentage of immunized trial subjects. Additional phase I study results showed that this SynCon vaccine generated protective antibody levels comparable to a current FDA-approved seasonal influenza vaccine against a currently circulating influenza strain. This is the first demonstration of the DNA vaccine achieving a protective immune response rate comparable to a conventional seasonal vaccine.
Prior research has shown that Inovio's H1N1 influenza SynCon vaccine provided 100% protection of animals challenged with the 2009 swine origin H1N1 virus and, separately, the H1N1 virus that caused the 1918 Spanish flu that killed over 40 million people. Additional animal studies have also shown that the vaccination generated protective HAI titers against other important H1N1 strains.
Influenza - Universal Seasonal (65+ years)
Vaccines: Various Preventative
Antigen: HA
Phase I.
(funded by NIH Director's Office Transformative Research Award)
A study of an Inovio SynCon H1N1 vaccine in combination with a "conventional" H1N1 seasonal flu vaccine was launched in July, 2012. Trial data has showed that a single dose of the H1N1 universal SynCon flu vaccine in combination with a dose of a 2012 seasonal flu vaccine generated protective immune responses in 40% of elderly trial subjects compared with a 20% response rate in the elderly subjects who received the seasonal flu vaccine alone.
Malaria
Malaria is a deadly disease that still kills more than 500,000 children under age 5 every year. MVI accelerates the development of malaria vaccines by joining its scientific, managerial, and field expertise with companies, universities, and governments to develop malaria vaccines and continue to test and invest in those with the most promise.
Vaccines: Various Preventative
Antigens: Various
Clinical Phases: Various
Inovio intends to initiate a phase I/IIa clinical study in 2014.
(funded by MVI/PATH) Inovio is developing two synthetic multi-antigen DNA vaccines targeting the pre-erythrocytic stage of the malaria parasite Plasmodium falciparum to prevent the onset of malaria symptoms and further inhibit spread of the disease. INO-7105 targets four pre-erythrocytic, antigens, CSP, TRAP, LSA-1, and CelTOS, and one blood stage antigen, AMA-1. The second vaccine, INO-7103, targets pre-erythrocytic malaria antigens CSP and TRAP as well as one blood stage antigen, AMA-1. The vaccines will be delivered with Inovio's intramuscular CELLECTRA 5P delivery device.
Pre-clinical Study Results:
Pre-clinical studies demonstrated potent T-cell and antibody responses in animal subjects. This phase I/IIa study will test DNA vaccines INO-7105 and INO-7103 delivered using Inovio's CELLECTRA 5P electroporation technology in approximately 30 individuals as part of a challenge trial. Study subjects will be given four doses of one of the DNA vaccines prior to being exposed to the malaria parasite through the bites of multiple malaria infected mosquitoes. Successful results of this trial could prove these vaccines capable of inducing an immune response in humans that protects against malaria. This study is being completed in collaboration with PATH Malaria Vaccine Initiative and is being funded by the Gates Foundation.
In a study results published on August 15, 2013, Inovio researchers and collaborators designed a highly optimized DNA vaccine composed of four sporozoite and liver-stage malaria antigens using Inovio's SynCon technology. These antigens were chosen because of their important role in the control or elimination of malaria infection. Delivered using Inovio's CELLECTRA delivery system, this malaria vaccine generated robust and long-lasting T-cell responses in both mice and non-human primates. Moreover, these vaccine-produced T-cells exhibited the functional ability to kill and eliminate malaria-infected cells. Researchers also found vaccine-induced CD8+, or "killer T-cells," in the liver, which is essential for rapid elimination of liver-stage malaria parasites. The Inovio DNA/electroporation platform has demonstrated in prior preclinical and human studies the ability to induce potent immune responses to multiple antigens; in this study, robust and sustained antibody responses to all four malaria antigens were observed, a strong indication for a preventive response in humans.
Collaborator Vaccines & Studies
Leukemia CML & AML
AML, a cancer of the myeloid line of blood cells, is characterized by rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute leukemia affecting adults; its incidence increases with age. Only about one-third of those between ages 18-60 who are diagnosed with AML can be cured. With conventional chemotherapy, 70% of the patients in the group under study will relapse within two years, and current therapy is devastating in older adults.
CML is a type of cancer that causes the body to produce large numbers of immature and mature white blood cells (myelocytes). Approximately 85% of patients with CML are in the chronic phase at the time of diagnosis. Ultimately, in the absence of curative treatment, the disease progresses to an accelerated phase where median survival is around three to five years. CML can occur at any age, but it more commonly affects middle-aged and older people.
Vaccines: WT1 Vaccine Therapeutic
Antigen: WT1
Phase II.
Owned/funded by U. of Southampton/ LLR and CRUK* (Inovio electroporation) Developed by the University of Southampton with funding from Leukemia and Lymphoma Research and Cancer Research UK, this DNA vaccine is encoded for Wilms' Tumor gene 1 (WT1), which is highly associated with leukemia. The vaccine is delivered using Inovio's ELGEN-1000 automated electroporation device.
Clinical Study Results:
Preliminary results of the phase II trial have shown robust vaccine-specific antibody and T-cell immune responses in all vaccinated trial subjects evaluated to date. In addition to favorable immunogenicity, the vaccine has proven to be safe overall and well tolerated by patients in the study. This open label, single dose level study is currently enrolling two patient arms (37 CML and 37 AML patients), and an additional 100-110 AML/CML patients as non-vaccinated controls, at multiple study centers in the UK.
Table II. Pre-clinical Studies & Vaccine Candidates Not Reflected on Inovio's Pipeline Diagram
Disease
Cytomegalovirus (CMV)
Cytomegalovirus (CMV) is a common virus that can infect almost anyone. Most people don't know they have CMV because it rarely causes symptoms. However, if you're pregnant or have a weakened immune system, CMV is cause for concern.
Once infected with CMV, your body retains the virus for life. However, CMV usually remains dormant if you're healthy. CMV spreads through body fluids, such as blood, saliva, urine, semen and breast milk. People with weak immune systems have a greater risk of becoming ill from CMV. If you're pregnant and develop an active infection, you can pass the virus to your baby.
There's no cure for CMV, but drugs can help treat newborns and people with weak immune systems.
Vaccine: Undisclosed Therapeutic
Antigens: Numerous - Undisclosed
Phase: Pre-clinical
Inovio researchers first investigated a novel panel of ten CMV immunogens comprised of mainly surface-associated proteins based on promising prior clinical and preclinical data that had been previously shown to be important for inducing cellular immune responses in CMV infection. To maximize the potential for broadly-reactive immunity, Inovio researchers created SynCon vaccines for each of the target proteins based on amino acid consensus sequences from multiple variant CMV clinical strains, and excluded those from potentially divergent, highly passaged lab-adapted strains. The researchers adopted the same strategy as was shown previously to enhance protective immune responses against divergent strains of influenza and HIV. The designed target sequences were further genetically optimized at the nucleic acid level.
Pre-clinical Study Results:
Researchers observed that vaccination with each CMV construct was highly T cell immunogenic in preclinical proof-of-concept mice studies, generating robust and broad T cell responses as extensively analyzed by the T cell ELISPOT assay. Each antigen produced responses against at least four and as many as 28 different regions of the antigen and, importantly, responses from both CD8+ and CD4+ T cells were observed. This increased diversity and magnitude of cellular responses may be critical for effectively mitigating CMV infection and disease in the transplantation setting.
These data demonstrate that Inovio's next-generation SynCon DNA vaccine technology is effective at inducing CD8+ T cell responses specific to CMV, in contrast to prior strategies that induced mainly CD4+-dominant responses. Additionally, a majority of epitopes identified for the gB, gH, and gL antigens also contained HLAs that have previously been reported to contribute to the suppression of viremia and amelioration of disease. In summary, the elicitation, identification, and characterization of extensive T cell responses driven by Inovio's CMV SynCon constructs will provide an important tool for guiding clinical development of a CMV vaccine. Further ongoing work will determine how many of the 10 antigens will be selected and taken further for clinical development as well as assess the induction of antibody responses to prevent CMV infection.
Hepatitis B
Hepatitis B is a disease characterized by inflammation of the liver. It is 50 to 100 times more infectious than HIV and is spread primarily by direct contact with human blood, semen, or bodily fluid from an infected individual. Hepatitis B contributes to an estimated 620,000 deaths worldwide each year.
Vaccine: Undisclosed Therapeutic
Antigen: Undisclosed
Phase: Pre-clinical
Pre-clinical Study Results:
In October 2011 Inovio entered into a product development collaboration agreement with its affiliate, VGX International Inc., to co-develop Inovio's SynCon therapeutic vaccines for hepatitis B and C infections. Preclinical trial data reported that the hepatitis B vaccine successfully generated strong T cell and antibody responses that led to the elimination of targeted liver cells in mice. These results indicate the DNA vaccine's potential to treat hepatitis B infection and prevent further development of the infection into liver cancer in humans.
Multiple Cancers
Vaccine: INO-1400 Therapeutic
Antigen: hTERT
Phase: Pre-clinical
PhI. Launch planned for 2014.
Human telomerase reverse transcriptase (hTERT) is an attractive DNA vaccine target in cancer immunotherapy. High levels of hTERT have been detected in more than 85% of all human cancers, while normal cells showed undetectable levels of telomerase expression.
Immunological analysis indicated that the hTERT is a widely applicable target recognized by T-cells and can be potentially used as a universal cancer vaccine.
Inovio has developed a highly optimized synthetic hTERT DNA vaccine with two mutations designed to target multiple cancers expressing the antigen hTERT, including non-small cell lung carcinoma, breast cancer, melanoma, and prostate cancer.
Pre-clinical Study Results:
The hTERT DNA vaccine has induced strong and broad hTERT-specific CD8+ T-cell immune responses in rodents and non-human primates in preclinical studies. When delivered with electroporation, Inovio's DNA cancer vaccine was able to break tolerance and elicit strong and broad hTERT-specific immune responses with the potential to eliminate tumor cells in monkeys, whose TERT is 96% similar to human TERT. Overall, Inovio's DNA hTERT vaccine showed immune responses that were more than 18-fold higher than the previous best- results of a peer's hTERT DNA vaccine delivered with electroporation. Because high levels of hTERT expression are found in 85% of human cancers, regardless of type, Inovio's cancer candidate holds the potential to perform as a "universal" cancer therapeutic based on early, but unprecedented, results from preclinical trials.
Ebola and Marburg Filoviruses
There is no approved vaccine or therapy available against these highly virulent pathogens that have killed up to 90% of the people they infected. Because these viruses could potentially be easily transmitted, result in high mortality rates and cause a major public health impact, various agencies are seeking solutions for public health preparedness. A DNA vaccine could offer faster design and manufacturing timelines than traditional vaccine approaches, but particularly important, Inovio's SynCon products offer the potentially preemptive advantage of enabling a design to provide broad protection encompassing multiple families of these so-called filoviruses.
Vaccine: Undisclosed Preventative Antigen: Undisclosed
Phase: Pre-clinical
Pre-clinical Study Results:
Using Inovio's proprietary SynCon design approach, Inovio researchers developed a polyvalent DNA vaccine consisting of three consensus plasmids to broadly target variant virus strains within three distinct families of Ebola and Marburg viruses. In the first part of this study, following two vaccinations using Inovio's proprietary CELLECTRA electroporation device, 100% of vaccinated guinea pigs were protected from death following a virus challenge. The researchers observed significant increases in neutralizing antibody titers and strong and broad levels of vaccine-induced T-cells, including "killer" T-cells, and subsequently conducted a test in mice using only one vaccination - this single dose also fully protected the animals from death following a virus challenge. In addition, unlike the non-vaccinated animals, vaccinated animals were protected from weight loss.
Peripheral Arterial Disease (PAD)
Finding an effective therapy for PAD and CLI is imperative because the current standard of care relies primarily on palliative drugs and amputation. PAD affects 8 - 12 million Americans and is associated with a 20 - 30% risk of cardiovascular death within five years. CLI is a more severe stage of PAD affecting over one million people in the US. Up to 20% of CLI patients will die within 12 months of diagnosis; the five-year mortality rate exceeds 70%. The disease is characterized by ischemic rest pain-severe pain in the legs and feet while a person is not moving-or non-healing sores on the feet or legs as well as gangrene. Major limb amputation occurs in up to 40 - 50% of CLI patients within 12 months of diagnosis.
Vaccine: Undisclosed synthetically optimized hypoxia-inducible factor-1 alpha (HIF-1a) gene Therapeutic
Antigen: n/a Phase: Pre-clinical
In this study, the gene sequence for HIF-1a was synthetically optimized to enhance expression of the growth factor. This DNA therapy was then delivered using Inovio's CELLECTRA constant current electroporation device, which has been shown to enhance the delivery of DNA plasmids by a 1000 fold using a millisecond pulse. A total of 39 mice were divided into 3 groups: (1) one group receiving HIF-1a DNA delivered with electroporation (EP) (n=13); (2) one group receiving HIF-1a DNA without EP (n=14) and (3) one group receiving a control empty plasmid (pVAX) delivered with EP (n=12). The left femoral artery in each mouse was tied up surgically to simulate an arterial blockage. The right legs were not treated and served as internal controls. The mice were then observed and scored for their limb function. Blood flow in their legs was measured by laser Doppler perfusion imaging.
Pre-clinical Study Results:
The results demonstrated that EP delivery of synthetically optimized HIF-1a plasmid DNA significantly improved blood flow in the left hind legs and reduced necrosis (premature cell death) in a mouse model of hind limb ischemia when compared to the results from the two control groups. The treatment also improved survival from severe limb damage and amputation, reduced tissue damage, and increased the number of new capillaries and formation of larger collateral vessels.
Chikungunya virus
CHIKV is an emerging mosquito-borne virus indigenous to tropical Africa and Asia. Acute illness is characterized by fever, arthralgia (pain in a joint), conjunctivitis (eye inflammation), rash, and sometimes arthritis. Relatively little is known about the antigenic targets for immunity and no licensed vaccines or therapeutics are currently available. Considering the potential for pandemic spread, understanding the development of immunity is paramount to the development of effective vaccines against CHIKV.
Vaccine: CHIKV Preventative
Antigens: E3+E2+E1
Phase: Pre-clinical
In this study, the research team isolated CHIKV from an acutely infected human patient and used this newly isolated virus to develop a virus neutralization assay and a challenge stock. The CHIKV challenge stock was used to establish a mouse infection model and study disease development. The candidate CHIKV vaccine developed by the researchers and tested in the mouse and macaque models is a SynCon(TM) synthetic DNA vaccine consisting of a single consensus envelope construct that expresses all three of the CHIKV envelope glycoproteins (E3+E2+E1). The vaccine is delivered by in vivo electroporation.
Pre-clinical Study Results:
The vaccine induced robust antibody and T-cell immune responses and provide 100% protection of mice against a challenge with this tropical infectious disease. Additionally, vaccine studies in rhesus macaques demonstrated generation of strong neutralizing antibody responses which mimicked those observed in CHIKV-infected human patients who subsequently recovered from this disease. These results demonstrate the ability of Inovio's DNA vaccine to provide protection and protective immune responses in two different preclinical models.
Animal Vaccine Studies
Foot and Mouth Disease (FMD)
Vaccines: Various Preventative
Antigens: FMD clades A, O, C, and Asia
Inovio recently announced that it had designed and tested in animals a set of multi-subtype synthetic vaccine candidates for FMD clades A, O, C, and Asia. Following administration of these synthetic vaccines using Inovio's proprietary vaccine delivery technology in swine and sheep, all the vaccines induced strong antibody and T cell immune responses. Inovio's patented SynCon vaccines cannot cause the targeted disease, providing a safe approach to potentially protect against FMD and reduce its serious impact on global food supply and commerce.
Perinatal mortality of piglets
Vaccine: LifeTide SW 5.0 growth hormone releasing hormone (GHRH) therapy
Regulatory Marketing Approval in New Zealand
LifeTide is a once-in-a-lifetime treatment for female pigs (sows) that has demonstrated significant decreases in perinatal mortality of piglets from treated sows compared to untreated sows. The treatment, which increases the number of weaned piglets and results in greater overall meat production, was previously approved in Australia. (VGX Animal Health Inc. - Inovio subsidiary)
Cancer in Dogs
Vaccine: VAH-5000D Therapeutic
Antigen: Tert
Phase: Pre-clinical
In mouse experiments, vaccinations with a highly optimized TERT DNA vaccine delivered by electroporation induced strong TERT-specific T cell immune responses. Furthermore, vaccination with the TERT vaccine delayed the growth of implanted tumors in mice and increased the survival rate of mice with tumors. (VGX Animal Health Inc. - Inovio subsidiary)
Table III. Intellectual Property Rights to Synthetic Vaccines for Specific Diseases - Not Yet Reported On
Clostridium difficile, or C. difficile
Cancer - new cancer therapeutic vaccines targeting Wilms' tumor gene or WT1.
Chemokine and cytokine molecular adjuvant technologies
RSV (respiratory syncytial virus)
MRSA (methicillin-resistant staphylococcus aureus)
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