HIV/AIDS - A Global Problem
More than 25 million people have died of AIDS worldwide and an estimated 33 million people worldwide are currently living with HIV/AIDS (2008 UNAIDS/WHO Report). In the United States, more people than ever are living with HIV, at an estimated 1.1 million in 2009 (2009 CDC HIV/AIDS Surveillance Report). Changes in incidence along with rising AIDS mortality have caused global HIV prevalence to level off. However, the number of people living with HIV has continued to rise due to population growth and, more recently, the life-prolonging effects of antiretroviral therapy (2006 UNAIDS Report).
Limitations of Current Drug Therapies for HIV/AIDS
Highly-Active Antiretroviral Therapy (HAART), or triple cocktail drug therapy as it is also known, was once believed to have great promise in effectively combating the AIDS virus. Unfortunately, HAART has not proven to be a cure for AIDS because the virus is estimated to have the ability to remain latent for a period of 50 years or more (Siliciano et al. 2004).
Additionally, there are concerns regarding adverse effects associated with long-term use of HAART. Specifically, a variety of metabolic disorders including HIV-associated lipodystrophy, central adiposity, dyslipidaemia, hyperlipidaemia, hyperglycemia and insulin resistance have been reported as resulting from HAART (Vigouroux et al., 1999; Behrens et al., 2000; Powderly, 2002). These reactions, which occur in up to 30% of patients for each drug in a treatment regimen of three drugs, combined with complex and cumbersome dosing regimes, can have an adverse impact on patient adherence to drug regimens (Lucas et al., 1999; Max and Sherer, 2000). Considering the percentage of adverse events when taking three drugs together, it is evident that management of HIV infection with HAART is difficult for a large proportion of patients.
Lack of adherence to antiretroviral regimens leads to resistant HIV strains. In fact, HIV resistance to drug therapy is increasing and with research indicating that more than 20% of newly-transmitted HIV is resistant to any drugs available today (Rapid Report for the 2004 Resistance Workshop). It has become apparent that HAART therapy is not the solution for controlling the AIDS epidemic long-term, even in developed countries like the United States.
VIRxSYS' RNA Therapy Solution for HIV/AIDS
Because of the limitations of HAART, alternative therapies for HIV are needed. The Company's novel technology provides biological control of HIV infection by turning the HIV virus against itself using an HIV lentiviral vector, VRX496™. This HIV vector contains an very long antisense that inhibits HIV replication. Short antisense, such as ribozymes or RNAi, may be more likely to result in HIV strains that are resistant to the therapy. However, VRX496™ has a long antisense, which debilitates HIV's ability to resist the treatment -- a major problem with current drug treatments.
VRX496™ lies inactive in a patient’s white blood cells (specifically the CD4+cells), waiting for HIV to enter that cell. When HIV does enter, replication of HIV within that cell activates VRX496™, which then binds to and destroys the HIV.
Click here to see an animation of how VRX496™ works
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(Click above image to enlarge)
Preclinical and clinical studies to date have shown VRX496™ to (i) efficiently deliver therapeutic payloads, (ii) inhibit HIV replication, and (iii) be a safe and tolerable therapy. Such inhibition of HIV replication in HIV-infected patients could postpone HIV disease progression to AIDS. Currently, VIRxSYS has the only lentiviral vector which has advanced to Phase II clinical trials in the United States.
VRX496™, a CD4 T cell treatment against HIV, is the first application of VIRxSYS’s proprietary lentiviral vector platform. The backbone of VRX496™ is our proprietary lentiviral vector an efficient gene-delivery vehicle. VIRxSYS then equips the vector with a long antisense sequence against the HIV envelope protein to create VRX496™. VRX496™ is transduced (inserted) into a patient’s own CD4 T cells to block HIV replication. Researchers believe the VRX496™ modified CD4 T cell, more technically know as “Lexgenleucel-T”, can enable the immune response against HIV and protect or restore normal immune function against other infections.
VIRxSYS’s first therapy tested in clinical trials is VRX496™ (Lexgenleucel-T), an anti-HIV gene therapy (immunotherapy). The following graphic illustrates the steps involved in the ex-vivo cell processing of the patient's cells from a patient and manufacturing perspective. Click the image to enlarge.
VIRxSYS uses a state of the art, autologous process by which CD4 T cells are removed from a patient and treated (genetically modified) with VRX496™. These genetically modified cells are then expanded to provide many multiples of the modified cells, which are then reinfused into the patient. Our Phase I and Phase II VRX496™ clinical trials to date have shown that this process is safe and tolerable for the trial participants.
Current Clinical Trials
VIRxSYS is currently conducting clinical trials to determine the safety, efficacy, and target patient population for VRX496™ (Lexgenleucel-T). The Company is currently conducting trials in HIV-infected individuals who are failing traditional drug therapies. In addition, we also have clinical trials planned for patients whose viral load is well controlled by antiretroviral drugs. The combination of these patient populations represents a significant percentage of the HIV patient segments in the industrialized world.
Phase I – Safety study in HIV infected patients failing multiple drug regimens
In a Phase I clinical trial concluded in 2005, a single infusion of VRX496™ (Lexgenleucel-T) was shown to be safe and tolerable, and evidence indicated some antiviral effects. This five-patient study was conducted at the University of Pennsylvania. No adverse events due to the product, or dose limiting toxicities occurred during the trial. In addition, with the small initial dose used for Phase I, encouraging indications of efficacy were observed as described below,
In HIV patients who have failed two or more HIV drug regimens, data show that patients have an average increase in viral load of 0.2 logs over a one-year period of time. However, patients in this trial demonstrated no increase in viral load, and several demonstrated a clinically significant drop. For the scientific details of our Phase I clinical trial, see the scientific report in Proceedings of the National Academy of Sciences USA, 103: 17372-17377, 2006.
In late-stage patients who have failed two or more HIV drug regimens, CD4 T cell counts are at best expected to remain stable, and often decrease by a count of 70 or more over a one-year period. In our trial we found that patients in general demonstrated either stability or improvement in their CD4 T cell counts over this time period.
HIV causes a disease known as acquired immune deficiency syndrome (AIDS), which destroys the immune system of the person infected. In our Phase I patients, we noted evidence of improvement in patients' immune systems.
Phase II – Dose finding study in patients failing one or more drug regimens
In an ongoing Phase II clinical trial for VRX496™ (Lexgenleucel-T), the Company has dosed a total of 24 patients with multiple-doses, with half the patients receiving 4 doses of the therapy, and the other half receiving 8 doses. To date, this trial has demonstrated the safety and tolerability of multiple infusions. We continue to monitor these patients.
In addition, we have enrolled an additional 20 patients who each received a larger, single dose of the VRX496™ (Lexgenleucel-T) therapy. Treatment intervention with a single dose would has several advantages such as being less costly, less time consuming, and more convenient for patients.
The study is being conducted at the following clinical centers: Jacobi Medical Center in New York, New York; Circle Medical Center in Norwalk, Connecticut; Stanford University in Palo Alto, California; the University of Kentucky in Lexington, Kentucky and Mercy Medical Center in Miami, Florida.
Phase I/II – Study in fully suppressed (well-controlled) patients
This clinical trial in patients whose HIV is fully suppressed by HAART (well controlled patients) is being conducted at the University of Pennsylvania. The study enrolled 18 patients who were scheduled to receive up to six infusions of VRX496™, and thereafter undergo withdrawal of their antiretroviral drugs. The goal is to determine if these patients can go off antiretroviral drugs permanently. Patients targeted in this trial are of the type that represents a very large market share of the HIV-infected population. While the data from this trial is still not complete, the results are very encouraging.
For additional information about our clinical trial program, contact VIRxSYS at clinicaltrials@virxsys.com.