Inovio Product Pipeline: PENNVAX™family of Human Immunodeficiency Virus (HIV) vaccines
Product & Indication
Inovio is developing its PENNVAX™ family of SynCon® DNA-based preventive and therapeutic vaccines for HIV. The objective of these vaccines is to generate strong T-cell responses to limit the transmission ability of the virus and generate strong antibody responses to prevent the viruses’ ability to infect.
Inovio is presently testing its PENNVAX™-B DNA vaccine against HIV clade B, the prevalent HIV strain in North America and Western Europe, in combination with electroporation delivery and various cytokine and chemokine adjuvants.
The HIV Vaccine Trials Network (HVTN) is conducting a phase I clinical trial of PENNVAX™-B in a prophylactic setting involving 48 healthy adult volunteers. The study is expected to complete in 3Q 2011. In an interim analysis, T-cell immune responses observed in this study were better than those observed from other recombinant HIV vaccine approaches previously tested by the HVTN, including those of viral vectors (such as adenovirus and MVA) and protein/peptide vaccines.
Separately, the University of Pennsylvania is conducting a clinical trial of PENNVAX™-B in a therapeutic setting involving adult HIV-infected patients. The study is expected to complete in 4Q 2011.
Inovio has also developed SynCon® DNA vaccine constructs for HIV envelope clades A, C, and D for the developing regions of Africa and Asia (PENNVAX™-G, PENNVAX™-GP), which also have the potential to provide both therapeutic and prophylactic benefits.
The National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health (NIH), is sponsoring a phase I clinical study of a unique prime-boost preventive HIV vaccination strategy aimed at global coverage. The prime is Inovio’s PENNVAX™-G and the boost is a virus vector vaccine, Modified Vaccinia Ankara-Chiang Mai Double Recombinant (MVA-CMDR). Together the vaccines are designed to deliver a diverse mixture of antigens for HIV-1 subtypes A, B, C, D and E. The study, being conducted by the U.S. Military HIV Research Program (MHRP) through its clinical research network in the US, East Africa and Thailand, will enroll 92 total participants and is designed to assess safety and immune responses.
In 2008, the (NIAID awarded Inovio a $25+ million contract to develop a preventive HIV DNA vaccine candidate (PENNVAX™-GP) and electroporation delivery devices. The program provides for funding through 2015, including a base period and follow-on option years.
Market Potential
Since scientists identified the human immunodeficiency virus (HIV) as the cause of acquired immunodeficiency syndrome (AIDS) in the early 1980s, it has spread relentlessly, causing one of the most devastating pandemics ever recorded in human history. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), more than 30 million people have died from HIV-related causes and roughly 33.3 million are living with HIV.
According to UNAIDS, the annual rate of new HIV infections declined from an estimated 3.1 million in 1999 to roughly 2.6 million in 2009. This apparent decline is to some extent explained by improvements in disease surveillance and data collection. But it also arises from natural trends in the course of the pandemic and, in all likelihood, expanded HIV education and prevention programs.
However, AIDS remains the fourth leading cause of death in low-income countries, according to the World Health Organization. Every day more than 7,100 people worldwide become newly infected with HIV, and the most vulnerable people in the world continue to bear the heaviest burden of this disease. Sub-Saharan Africa, home to about 67% of people infected with HIV, accounted for nearly three-quarters of all AIDS-related deaths in 2008. If the epidemic is stabilizing somewhat in this region, it seems at the same time to be emerging with a new ferocity in other parts of the planet, including China, Indonesia, pockets of Eastern Europe and Central Asia as well as in high-income countries like Germany, Britain and Australia.
Stage of Development
In June 2010, the peer-reviewed journal Molecular Therapy published a paper entitled "Comparative Analysis of Immune Responses Induced by Vaccination With SIV Antigens by Recombinant Ad5 Vector or Plasmid DNA in Rhesus Macaques." The paper, co-authored by researchers from Merck, University of Pennsylvania School of Medicine, and Inovio Pharmaceuticals, described that in a head-to-head comparison with an adenovirus serotype 5 (Ad5) vaccine considered to be the most immunogenic among viral vectors, Inovio's optimized SynCon® DNA vaccine delivered using its proprietary electroporation technology demonstrated numerous advantages in both magnitude and breadth of immune responses produced in non-human primates. Compared to Ad5, the SynCon® DNA vaccine resulted in:
- Significantly stronger antigen-specific cellular immune responses, in particular CD8+ T cells. T-cells are considered instrumental in clearing cancerous or infected cells from the body. Such responses are therefore imperative to achieving sufficient potency in new vaccines against cancers and chronic infectious diseases such as HIV and hepatitis C virus. Importantly, Ad5 immunizations failed to boost immune responses following the first immunization, whereas immune responses from DNA vaccination were continually boosted even after four immunizations.
- Increased breadth of T-cell-based immune responses. CD4+ and CD8+ T-cell immune responses produced with DNA vaccination were broader and produced multiple immune molecules called cytokines (IFN, IL-2, TNF-a, and CD107a). Broad immune responses are considered an important potential marker for vaccine efficacy.
- Immune responses were long-lasting and maintained at high levels.
Study One
Phase: I, treating healthy subjects at risk of HIV.
Conducted by HIV Vaccines Trials Network (HVTN).
Purpose: To determine the safety, tolerability, and immune response to the DNA HIV vaccine, PENNVAX™-B, alone, in combination with IL-12, or with two different doses of IL-15.
Study Type: Interventional
Study Design: Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study
Study Start Date: October 2007
Status: Completed, awaiting final data
Sponsors and Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)and HIV Vaccine Trials Network
For more information: www.clinicaltrials.gov Identifier: NCT00528489
Preliminary data from the trial included safety data from all trial participants (48) and immunogenicity data from 38 out of 40 samples from vaccine recipients post-second-dose and from 31 out of 40 samples from vaccine recipients post-third-dose. The data indicate that antigen-specific T-cell responses were generated by the vaccine in a majority of subjects. Either CD4+ or CD8+ or both T-cell responses were observed against at least one of the vaccine antigens in 61% (23 out of 38) of evaluated subjects after two vaccinations. After three vaccinations, 84% (26 out of 31) of evaluated subjects had positive T-cell responses.
For more details of the phase I interim results, see the news release.
Study Two
Phase: 1b, treating patients with HIV.
Purpose: To evaluate the safety and immunological effects of PENNVAX™-B with or without co-administration of constructs containing DNA encoding for the expression of either IL-12 or IL-15.
Study Type: Interventional
Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety Study
Study Start Date: September 2008
Status: Recruiting, final data expected Q4 2011
Sponsors and Collaborators: University of Pennsylvania, Drexel University
For more information: www.clinicaltrials.gov Identifier: NCT00775424
Study Three: PENNVAX™-G + MVA Boost, Preventive
Phase: I, treating healthy subjects at risk of HIV.
Conducted by HIV Vaccines Trials Network (HVTN).
Purpose: To determine the safety and immune response to the DNA HIV vaccine, PENNVAX™-G (env & gag) administered by intramuscular Biojector 2000 or CELLECTRA® intramuscular electroporation device followed by MVA-CMDR (HIV-1 CM235 ENV/CM240 gag/pol) boost
Study Type: Interventional
Study Design:
Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Study Start Date: October 2010
Status: Enrolling; Potential interim data expected by year end, 2011.
Sponsors and Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Conducted by the U.S. Military HIV Research Program (MHRP)
For more information: www.clinicaltrials.gov Identifier: NCT01260727
Commercialization
PENNVAX™ DNA vaccines: Licensed from the University of Pennsylvania (Penn).
Delivery technology: owned by Inovio.
License agreement: Inovio has worldwide commercialization rights for vaccine and delivery technology. Financial terms of the license agreement with Penn for the DNA vaccine undisclosed, but deal terms include milestone payments and royalties.
Technical
DNA Vaccine Design for HIV-1 Infection
In the case of PENNVAX™-B, Inovio has created SynCon® constructs for the gag, pol, and env antigens. These three proteins contain information needed to make the structural proteins of HIV and as such have been the targets of many of the vaccines in development for HIV. In designing SynCon® antigens for the three target proteins, Inovio and its collaborators at the University of Pennsylvania considered sequences from hundreds of reported sequences for clade B envelope antigens from HIV infected people to develop a clade B consensus env. Because gag and pol are less divergent compared to env, for the SynCon® gag and pol antigens the researchers considered sequences from hundreds of reported gag and pol proteins across the different HIV sub-types (A, B, C, D, E, AE) from HIV infected people. Thus, the gag and pol components have the potential to provide broader – more “universal” – immune responses against multiple sub-types of HIV, while the envelope immunogens (the antigen with the greatest diversity) are designed to provide broad responses within each sub-type of HIV, i.e. A, B, C, D, or E/AE. These components have also been incorporated into Inovio’s global HIV vaccine programs – PENNVAX™-G and PENNVAX™-GP.
- HIV clade B: North America and Western Europe (PENNVAX™-B)
- HIV clades A, C, and D: developing regions of Africa and Asia (PENNVAX™-G, PENNVAX™-GP)
- Inovio strategy for world HIV vaccine
- SynCon® DNA vaccine constructs for HIV envelope clades A, B, C, and D
- SynCon® DNA vaccine constructs for gag and pol proteins
Inovio HIV Vaccine Trial Strategies
Conduct Clinical Testing with Clinical Partners
- Prophylactic Clade B Vaccine: Collaborations w/ HIV Vaccine Trials (PENNVAX™-B) Network (HVTN)
- PENNVAX™-B + Cytokine (IL-12 and IL-15) Genes (HVTN-070 Study) - Phase I initiated
- PENNVAX™-B + CELLECTRA® EP (HVTN-080 Study)
- Prophylactic Clades A, C, and D Vaccines:
- PENNVAX™-GP + CELLECTRA® EP
- Therapeutic Clade B Vaccine:
- PENNVAX™-B + CELLECTRA® EP
SynCon® DNA Vaccines for HIV: Increased T Cell Immune Responses in Monkey Models
- HIV or SIV vaccines administered at 1 mg/construct + CELLECTRA® EP
- 10-30x improvement in immunogenicity compared to that observed via other vaccine methods*
- "Best" Cytotoxic T Lymphocyte (CTL) responses in Monkey Models for HIV
*Hirao LA, Wu L, Khan AS, Satishchandran A, Draghia-Akli R, Weiner DB. Vaccine. 2008 Jan 17;26(3):440-8. Epub 2007 Nov 8. Intradermal/subcutaneous immunization by electroporation improves plasmid vaccine delivery and potency in pigs and rhesus macaques.
Cristillo AD, Weiss D, Hudacik L, Restrepo S, Galmin L, Suschak J, Draghia-Akli R, Markham P, Pal R. Biochem Biophys Res Commun. 2008 Feb 1;366(1):29-35. Epub 2007 Nov 26. Persistent antibody and T cell responses induced by HIV-1 DNA vaccine delivered by electroporation.