Blog Stories

We just got back from presenting data at the 13th American Society of Gene and Cell Therapy (ASGCT) Annual Meeting. It was a great opportunity to connect with the scientific community and share our work vaccine and treatments through RNA therapies. We presented eight abstracts representing results of the company’s clinical trials for Lexgenleucel-T (VRX496™), an autologous cell and gene therapy product for the treatment of HIV/AIDS; preclinical trials of the company’s prophylactic HIV vaccine VRX1023, now called VRX1273; and work utilizing the company’s spliceosome mediated RNA trans-splicing (SMaRT™) platform technology. VIRxSYS has over 40 publications in top tier journals showing the effectiveness of SMaRT™ in a broad variety of applications. Highlights of the presentations include data from VIRxSYS’s Phase 2 study of Lexgenleucel-T, which continue to show no evidence of long-term safety issues after the cumulative infusion of over 4 x 10¹² vector copies in a total of 2 x 10¹² modified CD4 T cells. To date, data from the Lexgenleucel-T clinical trial program comprises of the largest safety database of subjects enrolled in a clinical trial using a lentiviral vector. In accordance with FDA guidelines, all subjects will continue to be monitored for safety for up to 15 years. Additional data from the Lexgenleucel-T Phase 2 study demonstrate that the therapeutic efficacy of Lexgenleucel-T treatment is not affected by the development of anti-vector antibodies, nor is the development of these antibodies associated with clinically detectable adverse events, a common concern in gene therapy trials. Although our research has not, as of yet, been proven with human trials, our monkey study data is so compelling that it gives us great encouragement and optimism for its potential as an effective HIV Vaccine.

Today is HIV Vaccine Awareness Day, and we at VIRxSYS would like to recognize the thousands of volunteers, community leaders, health professionals, and scientists that work to develop a safe and effective preventive HIV vaccine. Existing HIV drugs are limited to merely treating symptoms and are facing serious obstacles to availability, even in wealthy nations. VIRxSYS is honored to be a part of the movement toward a solution to global HIV prevention and treatment with our research on vaccine therapies. A wealth of data from our research is being presented at the 13^th American Society of Gene and Cell Therapy (ASGCT) Annual Meeting this week, illustrating the potential of RNA therapies in developing a HIV vaccine as well as answers to other medical issues. HIV Vaccine Awareness Day calls attention to the need for an effective method of HIV prevention—VIRxSYS is committed to this goal and is optimistic that our research will contribute to a victory in the fight against global HIV/AIDS.

In a new paper published in the February issue of Vaccine, my VIRxSYS colleagues discuss the benefits of lentiviral vector-based vaccine candidates for HIV and provide additional details on our HIV-based lentiviral vector vaccine candidate for HIV, VRX1023, now called VRX1273.

As the paper, “An HIV-based lentiviral vector as HIV vaccine candidate: Immunogenic characterization,” points out, in contrast to vectors used in many previous HIV vaccine trials, lentiviral vectors have been shown to be less sensitive to anti-vector neutralizing activity, while displaying desirable characteristics, such as transduction of non-dividing cells (including antigen-presenting cells) and long-term transgene expression. At VIRxSYS, we have seen these benefits in our preclinical studies of VRX1023. As described in the new paper, this lentiviral vector-based HIV vaccine candidate induced significant mucosal and systemic cellular and humoral responses against HIV after sub-cutaneous injection in mice. We have also successfully used this candidate with a DNA prime (e.g. a prime-boost vaccine strategy) in mice, where it elicited as high as 21% HIV Gag-specific CD8 responses as measured by intracellular cytokine staining. Moreover, anti-vector immunity has not been an obstacle to repeated lentiviral vector-based vaccine administrations, as shown by improved anti-vector immune responses compared with repeat vaccine administrations compared to one-time administration. In addition, in head to head comparisons with adenoviral (Ad5) vectors expressing the same vaccine payload in mice, VRX1023 elicited higher and more persistent cellular and antibody responses to HIV than its adenoviral counterpart.

Adding to the preclinical data on VRX1023, in February we presented data from our non-human primate studies at the Conference on Retroviruses and Opportunistic Infections, showing that VRX1023, used as a prophylactic vaccine, is capable of achieving significant control of viral load and improving immune response following a large challenge with a highly pathogenic simian immunodeficiency virus (SIV), a virus found in non-human primates and similar to HIV. VIRxSYS is currently preparing for a Pre-IND Meeting followed by an Investigational New Drug Application for the therapeutic use of this HIV vaccine candidate in HIV infected patients.

VRX1023, our HIV-1-based lentiviral vector vaccine candidate for HIV, is the topic of a new paper authored by three of my VIRxSYS colleagues and published in the January issue of Vaccine. VRX1023 has been engineered to deliver HIV-1 Gag, Pol and Rev antigens.

In the new paper, “Heterologous HIV-based lentiviral/adenoviral vectors immunizations result in enhanced HIV-specific immunity,” our scientists report on the vaccination of mice with VRX1023 and an adenovirus serotype 5-based vector, using a “prime-boost” approach (an immunization strategy in which one vaccination is given, followed by a second vaccination at another time).

Compared to homologous prime-boost regimens (i.e. using only one type of vaccine, such as only the adenoviral-based candidate), the heterologous immunization regimen using both the lentiviral and adenoviral vector candidates dramatically improved immunogenicity, increasing the number of CD4+ and CD8+ immune cells that were specific to HIV. In addition, this combined approach did not induce high levels of anti- vector-neutralizing antibodies, whereas a high level of anti-vector neutralization was observed in mice who received homologous prime-boost regimens using the adenoviral vaccine.

Our data on the VRX1023 lentiviral vaccine in macaque monkeys in a prophylactic setting was presented at the Conference on Retroviral Opportunistic Infections (CROI) in San Francisco this February.

It’s been a busy day for us at CROI: We are pleased to announce that researchers from the University of Pennsylvania School of Medicine presented a poster today detailing the results from an ongoing Phase I/II open-label clinical trial of our VRX496™ (Lexgenleucel-T) RNA therapy for the treatment of HIV/AIDS.

This Phase I/II, NIH funded clinical trial evaluated whether multiple infusions (6 infusions or 3 infusions) of VRX496™ will allow patients with undetectable viral loads on antiretroviral treatment (HAART) to stop taking HAART (treatment interruption) and still control their viral load.

Interim results of the study showed that seven of eight evaluable subjects experienced a decrease in viral load set point (HIV RNA value specific for each infected individual in absence of anti-retroviral drug control) – and one subject experienced prolonged, complete control of HIV viremia for more than 14 weeks in the absence of HAART.

Current therapies for HIV-infected patients require daily drug regimens and have well documented side effects. It is anticipated that VRX496™ will require only a minimal number of infusions. To date VRX496™ has been infused in 65 patients, which represent an accumulative safety time period of 211 therapy years. VRX496™ also is different from previous gene therapies because it uses a lentiviral vector derived from HIV-1 itself. Unlike other viral vectors, lentiviral vectors appear to sustain expression of the delivered genes of interest for a longer period of time and do not appear to elicit an inflammatory immune response.

We’ve just presented the data from our prophylactic HIV vaccine (VRX1023) study in Rhesus Macaque monkeys at CROI, and are proud to report that it was well received.

Franck Lemiale, Ph.D., my colleague and Director of Immunobiology at VIRxSYS, presented the findings. We are extremely encouraged by the results, which demonstrated that this vaccine candidate achieved a 95% reduction of viral load in Rhesus monkeys which received lentiviral vaccination, as compared to non-vaccinated control animals, as well as a strong and durable immune response and major CD4+ T cell preservation.

Our candidate differs from other HIV vaccine candidates in that it employs an engineered HIV-based lentiviral (LV) vector to deliver the vaccinating antigens. In a mouse study recently published in Vaccine, our lentiviral vector has demonstrated benefits over adenovirus serotype 5 (Ad5)-based vectors (the current industry standard, utilized in the Merck STEP Study, for example) in terms of:

• Anti-vector immunity – Unlike Ad5, LV are not sensitive to anti-LV neutralization by the immune system. This allows the vaccine to be successfully re-administered.
• Anti-HIV immunogenicity – LV either outperformed or induced similar magnitude of T-cell responses compared to two Ad5 vectors, and LV-induced responses persisted for a much longer period than the responses triggered by Ad5, which achieved only short term immunogenicity.

We are currently developing the vaccine for use in the therapeutic setting, but also intend to discuss developing the product for prophylactic use with regulatory agencies, based on the risk/benefits for this population. A successful therapeutic vaccine could significantly delay or even prevent progression to AIDS. Such a therapy could also significantly reduce or eliminate the need for HIV patients to take costly and dangerous medications, and may also reduce the risk of HIV transmission.

This is an exciting milestone for us, and we currently are pursuing an Investigational New Drug (IND) submission to the U.S. Food and Drug Administration (FDA). We hope to begin testing this vaccine candidate in human clinical trials in 2011.

A recent issue of Time featured an article of Dr. David Ho regarding his newest scientific endeavors against HIV and AIDS and his team’s attempts to develop a new generation of antibodies that would block HIV entry into CD4 T cells. The referred antibody, ibalizumab or TNX355, has already been tested in the clinic with decent results (Jacobson et al. Antimicrobial Agents and Chemotherapy. 53(2):450-457, 2009). The authors did find, however, that HIV could mutate and by-pass the blockade of the CD4 receptor. This therapeutic approach is not what we would consider a traditional “vaccine” since it would require a constant re-infusion of the antibody to exercise its therapeutic effects. The data in the literature seem to indicate this product will never be a stand alone therapy as a more formal vaccine would be, but could be another interesting biological against HIV when combined with other anti-HIV products for HIV infected subjects who are already resistant to several classes of anti-HIV drugs. Only future clinical trials beyond Phase 1 will tell.

Biotechnology company Sangamo confirmed the inadvertent disclosure of results from a Phase I STI (structured treatment interruption) HIV trial being conducted at the University of Pennsylvania, using what is known as Zinc Finger Nuclease (ZFN) to shut down gene expression. ZFN is not an RNA but a protein-based technology – it is distinct from the RNA antisense used in our Lexgenleucel-T (VRX496™) anti-HIV therapy.

The patients in the Sangamo trial had zero viral loads when on conventional antiretroviral therapies. Following re-administration of the patients’ own T-cells, which had been modified ex-vivo via an adenoviral vector containing the ZFN, the antiretroviral therapy (ARV) was stopped and viral load recrudescence monitored. According to this presentation, one patient had no viral load detectable for four weeks, or two weeks past the usually observed viral load rebound after ARV cessation. If this information is confirmed, it represents an interesting—but limited—extension of the usually observed time frame before the viral load rebound. However, it is difficult to draw any conclusions from anecdotal information obtained from a single subject in a clinical trial.

We will be presenting the results of our own Phase II STI clinical trial with VRX496, conducted at and by the University of Pennsylvania, in February, 2010 at the Conference on Retroviral Opportunistic Infections (CROI) in San Francisco.

The momentum continues in the cell and gene therapy field with the completion of Dendreon’s FDA drug application for Provenge, an experimental prostate cancer vaccine which, if approved, would be the first gene/cell therapy product to make it to market. While Provenge has yet to undergo actual FDA review and there is no guarantee that it will be approved, this is a significant step. Coming on the heels of the positive results published earlier this month for the HIV-derived lentiviral gene therapy treatment for ALD, this news adds to the growing excitement over the potential for gene therapy.

We are thrilled to be part of the surge toward making the prospect of gene therapy a reality. Our own anti-HIV gene therapy treatment, VRX496, continues to be proven safe and clinical results look encouraging. The results of our Phase II trial will be presented in February, 2010 at the Conference on Retroviral Opportunistic Infections (CROI) in San Francisco.

Today’s news about an HIV-derived lentiviral gene therapy treatment arresting progression of the rare but fatal brain disease ALD in two children is the latest in a string of good news—and adds much-deserved and continuing credibility to the concept of gene therapy.

Released in the November 6th issue of Science, the results are from a Phase I trial in which patients were infused with their own peripheral blood mononuclear cells—much like in a bone marrow transplant—that were transduced via lentiviral vector with an active copy of the ABCD1 gene, which is defective in patients with ALD. While the boys have not been cured of the disease, its progression has been effectively halted for more than two years—a significant accomplishment and similar to what is observed in cell transplantation. The limitation of cell transplantation is the availability of matched donors.

This success is further proof of what we at VIRxSYS have already known and have been testing in human trials since 2003: that lentiviral vectors are one of the safest, most effective and efficient systems for delivering genetic and therapeutic payloads into targeted cells. VRX496™ (Lexgenleucel-T), our lead candidate in development for treatment of HIV/AIDS, was the first use of the lentiviral vector platform to advance to Phase II clinical trials in the US.

In a Phase I clinical trial concluded in 2005, a single infusion of VRX496 was shown to be safe and tolerable, and evidence indicated antiviral effects with no adverse events or dose limiting toxicities. In ongoing clinical trials, VRX496 is continuing to show itself to be safe, with continuing indications of efficacy for people with HIV. To date, VRX496 has been administered to 65 patients, representing an accumulative time period of 200 patient-years of safety. We hope to be ready to release results of the VRX496 Phase II trials in early 2010.