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.
There has been extensive coverage of the results of Sanofi’s HIV vaccine trial (31.2% fewer HIV infections in the group receiving the vaccination, versus a placebo group). It was also reported that there was no meaningful difference in the viral load set points between the groups following HIV infection. Much of the positive press surrounding these results appears to be mostly fueled by the highly pessimistic expectations from this trial. In the absence of published scientific data on the quality of the immune response following vaccination, it is extremely difficult to judge the value of the vaccination regimen. Regardless, the trial results are significant because they demonstrate that an effective vaccine may be possible and also that a viral vector-based vaccine can achieve some level of protection against HIV infection in a prophylactic (prevention) setting. The sponsors of the trial should be commended for continuing to push forward this vaccine initiative to generate all possible scientific information which could be helpful for future studies. We are encouraged by the progress we are making with our HIV vaccine candidate VRX1023. While the vaccine tested in the Sanofi/Thailand trials is based on a canarypox virus (derived from the canary bird), our vaccine candidate is based on the human HIV virus – we believe this may provide an advantage in the vaccine’s ability to provide protection against HIV itself and potentially a long term reduction on viral load. Last year we presented encouraging mouse data on VRX1023 and we are preparing data for publication on non-human primates (monkeys). The quest for a prophylactic or therapeutic vaccine is ongoing and we are encouraged by all positive news.
VIRxSYS is collaborating with many research institutions to investigate ways that the company’s SMaRTTM (spliceosome-mediated RNA trans-splicing) technology can potentially be used in therapeutic applications for a variety of diseases. Results of a recent study, conducted with researchers from King’s College London in Britain and Duke University in the United States, have been published in Human Molecular Genetics (2009, Vol. 18, No. 17, p. 3266-73) in a paper entitled “Correction of tau mis-splicing caused by FTDP-17 MAPT mutations by spliceosome-mediated RNA trans-splicing.”
The study, which was led by Jean-Marc Gallo, PhD, of King’s College London, used SMaRTTM technology to correct aberrant RNA splicing caused by a genetic mutation of the microtubule-associated protein tau (MAPT) gene. Mutations in this gene are associated with neurodegenerative disorders including Alzheimer’s disease, Pick’s disease, and frontotemporal dementia. In this study, the researchers focused on correcting the mutations specifically associated with a rare type of frontotemporal dementia called “frontotemporal dementia with parkinsonism linked to chromosome 17” (FTDP-17). The laboratory experiments conducted by Dr. Gallo and colleagues successfully demonstrated that RNA reprogramming using VIRxSYS’s SMaRT technology can correct the aberrant RNA splicing that occurs with FTDP-17 mutations.
Based on these results, the investigators believe that RNA trans-splicing—which involves joining the RNA from two different genes to create a hybrid messenger RNA—could provide the basis for developing therapeutic strategies to correct neurological and other diseases that occur as a result of RNA splicing aberrations.
VIRxSYS now has more than 40 publications in top tier journals showing the effectiveness of SMaRTTM in a broad variety of applications. We expect to begin testing this technology in human trials in the second half of 2010.
Our work with induced pluripotent stem cells (iPSC) was featured on FOXNews this July, broadening public awareness of the availability of alternative, viable options to embryonic stem cells.
Like embryonic stem cells, iPSC have the ability to become any type of cell in the human body. The potential for clinical use of these cells includes treatments for diseases such as Parkinson’s, type 1 diabetes, heart disease and cancer. However, it has been shown that iPSC can be effectively derived from adult skin cells – avoiding the controversy associated with using cells from human embryos.
Further, iPSC generated from patients with genetic diseases can be corrected for the genetic defect and then used to replace the damaged tissue or regenerate new tissue for damaged organs. This is an application we are currently researching, using our lentiviral vector and RNA technologies to modify defective genes; the stem cells then replicate, with the resulting cells carrying and passing on the modified gene material.
This is an exciting time for our research, and the list of potential diseases is really significant.
Two Chinese studies caused a stir in the media, when results published in Nature and Cell Stem Cell showed that stem cells created from mouse skin cells – induced pluripotent stem cells, or iPSCs – had the ability to regenerate in much the same way as embryonic stem cells, resulting in both cases in the birth of baby mice.
iPSCs can potentially circumvent the use of ethically controversial human embryonic stem cells and provide many opportunities for therapeutic applications. Of course, much research is yet to be done before this approach can be brought to the clinic.
VIRxSYS is currently working to develop safer methods for creating induced pluripotent stem cells using the company’s proprietary spliceosome-mediated RNA trans-splicing (SMaRT™) and lentiviral gene delivery platform technologies; our research was recently funded by a grant [link to press release on VIR website] from the Maryland Stem Cell Research Commission.