VIRxSYS' RNA Immuno-Therapy Solution for HIV/AIDS
The current standard of treatment for HIV/AIDS is highly active antiretroviral drug therapy (HAART), consisting of a combination of several antiretroviral drugs. Although this combination has been successful in reducing viral load in HIV infected patient’s plasma and restoring some immune function, they do not represent a cure. There are also concerns regarding adverse effects associated with long-term usage of these antiretroviral drugs. Specifically, a variety of metabolic disorders including HIV-associated lipodystrophy, central adiposity, dyslipidaemia, hyperlipidaemia, hyperglycemia, and insulin resistance have been reported as resulting from combination therapies. These reactions, combined with complex and cumbersome dosing regimen, can have an adverse impact on patient’s adherence to their respective therapy. As a result, poor adherence has led to an increased rate of HIV resistance, resulting in viral strains that have reduced sensitivity to the drugs.
Cell and gene therapy for HIV infection have been proposed as alternatives to anti-retroviral drug regimens. A number of different genetic vectors and accompanying genetic antiviral payloads have been utilized to combat HIV, including RNA antisense, small interfering RNA, trans-dominant proteins, ribozymes or zinc finger nucleases, RNA decoys, and single chain antibodies to name a few.
For VIRxSYS’s investigational product, Lexgenleucel-T, VIRxSYS uses an autologous process by which CD4 T lymphocytes are removed from a patient and treated (genetically modified) with VRX496™, and then expanded to provide many multiples of the modified cells. Lexgenleucel-T is then cyopreserved in liquid nitrogen, which is subsequently thawed and re-infused into the patient. Our Phase I [1] and Phase II clinical trials to date have shown that this process is safe and tolerable for the trial participants. 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.)
The active ingredient of Lexgenleucel-T is a long RNA antisense sequence targeting the transcripts of the gene coding for the HIV envelope. This active ingredient is delivered by VRX496TM, an HIV-based lentiviral vector. VIRxSYS' Investigational New Drug (IND) application for VRX496 was the first for any biologic therapeutic product using an HIV-based lentiviral vector and it was approved by the FDA, making VRX496 First-in-Class, First in Humans.
Anti-HIV RNA immuno-therapies such as Lexgenleucel-T may provide several important advantages over current HIV combination therapies. This type of RNA antisense therapy was shown to be less toxic than current combination drug therapies because the RNA antisense with antiviral activity delivered by VRX496™ is expressed only in those transduced cells that subsequently become infected with HIV in vivo. Indeed, the production of the RNA antisense is dependent upon the expression of specific HIV proteins that are provided only by HIV following infection of the CD4+ T lymphocytes previously modified with VRX496™. In addition, the length of the RNA antisense, which is over 937 nucleotides long, makes it difficult for HIV to create resistant strains that are sufficiently fit to cause disease [2].
To date, preclinical and clinical studies have shown the HIV-based lentiviral vector VRX496™:
(i) efficiently delivered the RNA therapeutic payload into subjects' CD4+ T lymphocytes,
(ii) inhibited HIV replication, and ultimately
(iii) has demonstrated a safe and tolerable product profile as shown by the clinical trials for Lexgenleucel-T.
To our knowledge, VIRxSYS has the only RNA immuno-therapy product containing an HIV-based lentiviral vector, which has advanced to Phase II clinical trials in the United States.
Clinical Trials
VIRxSYS has conducted clinical trials to determine the safety, efficacy and dosing strategy for Lexgenleucel-T (VRX496™). The Company’s trials included (i) HIV-infected individuals who either were failing traditional drug therapies or who stopped taking antiretroviral drugs because of toxic side effects, and (ii) HIV-infected individuals who were well-controlled on antiretroviral drug cocktails (HAART), but who wanted to stop taking these medications. 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™ treated CD4 T cells (Lexgenleucel-T) was shown to be safe and tolerable, and the data provided evidence of an antiviral and immunological effect. This first-in-human first-in-class, five-patient study was conducted at the University of Pennsylvania.
According to some studies conducted by others, the viral load for HIV patients who have failed two or more HIV drug regimens, but remain on the failed regimen, increases by an average of 0.2 logs over a one-year period. However, subjects in this Lexgenleucel-T trial demonstrated no increase in viral load, and several subjects demonstrated a clinically significant decrease in viral load.
In late-stage patients who have failed two or more HIV drug regimens, CD4 T cell counts generally are at best expected to remain stable, and often decrease. In our trial we found that subjects generally demonstrated either stability or improvement in their CD4 T cell counts over this time period.
For the details of our Phase I clinical trial, see the scientific report in Proceedings of the National Academy of Sciences USA, 103: 17372-17377, 2006 [1].
Phase II – Dose finding study in patients failing one or more combination drug regimens
Following the Phase I trial, a Phase II trial was designed with the objectives of defining the optimal cell dose/dosing regimen and identifying which HIV-positive population was most likely to benefit from Lexgenleucel-T therapy. The study was conducted at five (5) clinical centers, including 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.
The study enrolled 43 treatment-experienced HIV patients, 32 of whom had stopped taking their prescribed antiretroviral therapy because of toxic side effects and 11 of whom remained on a failing (ineffective) HAART regimen. Each subject received either (i) 4 or 8 repeat infusions of Lexgenleucel-T (approximately 10 billion CD4 cells per infusion), or (ii) a single infusion of varying cell dose amounts (approximately 10 billion, 20 billion or 30 billion CD4 cells per infusion).
In this study, the dosing regimen that provided the best immunological benefit was the single infusion of approximately 10 billion CD4 cells. The data also provided initial evidence that the antiviral effect of Lexgenleucel-T is mediated via affecting the replication fitness of HIV. A therapy regimen of a single dose would have several advantages for the patient and the community such as being less costly and less time consuming to manufacture and infuse, and ultimately more convenient for patients.
Phase I/II – Study in fully suppressed (well-controlled) patients
HIV-infected individuals who are fully suppressed by HAART (well-controlled patients) represent a very large percentage of the HIV-infected population. A Phase I/II clinical trial in well-controlled patients (with no detectable viral load) was also conducted at the University of Pennsylvania. The study enrolled 18 subjects who received up to six doses of Lexgenleucel-T over a period of 16 weeks and one month later had their antiretroviral drugs withdrawn (Structured Treatment Interruption or STI). The goal of this trial was to determine if well-controlled patients could cease taking antiretroviral drugs after Lexgenleucel-T treatment [3].
The data from this trial are very encouraging. During the STI phase, subjects’ historical viral load set point was significantly decreased and CD4 cell counts were either stable or above pre-trial baseline. One subject in particular had no evidence of HIV in the circulation for 104 days following treatment interruption [3].
Phase II – Study in patients who have failed one or more combination drug regimens
Based on the encouraging data from the various trials for Lexgenleucel-T, VIRxSYS has collaborated with the AIDS Clinical Trials Group (ACTG) of the NIH to develop a trial that will evaluate a single dose of Lexgenleucel-T in a group of HIV positive patients who have failed multiple drug regimens. That trial would be conducted in collaboration with a corporate partner. The Company has undertaken a search for such a partner.
References:
[1] Levine et al. Gene transfer in humans using a conditionally replicating lentiviral vector. Proc Natl Acad Sci U S A. 103(46):17372-7, 2006 (http://www.pnas.org/content/103/46/17372.full.pdf+html)
[2] Lu et al. Antisense-mediated inhibition of human immunodeficiency virus (HIV) replication by use of an HIV type 1-based vector results in severely attenuated mutants incapable of developing resistance. J. Virol. 78(13):7079-88, 2004 (http://jvi.asm.org/cgi/reprint/78/13/7079.pdf)
[3] Tebas et al. Prolonged Control of Viremia After Transfer of Autologous CD4 T Cells Genetically Modified with a Lentiviral Vector Expressing Long Antisense to HIV env (VRX496). Abstract. 17th Conference on Retrovirses and Opportunistic Infection, February 2010.