VIRxSYS has concluded a 6-month Phase 1/2 clinical study under an IND of the vector VRX496 in HIV-positive subjects who have failed at least two HAART regimens. HAART typically consists of a triple "cocktail" of drugs. Although these cocktails have been successful in reducing viral loads and restoring immune function, they do not represent a cure. There are also concerns about adverse effects associated with long-term usage 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. These reactions, combined with often complex and cumbersome dosing regimens, can have an adverse effect on patient-subject adherence to therapy. Furthermore, poor adherence has led to increased rates of HIV resistance, resulting in viral strains that have reduced sensitivity to the drugs. Importantly, in the Phase 1/2 clinical trial conducted by VIRxSYS, there were no reported toxicities associated with the product.
Gene therapy for HIV-1 infection has been proposed as an alternative to antiretroviral drug regimens. A number of different genetic vectors with antiviral payloads have been utilized to combat HIV-1, including antisense RNA, transdominant proteins, ribozymes, RNA decoys, single chain antibodies, and RNAi (RNA-interference. Antisense RNA targeted to wt-HIV RNA offers a significant advantage over several other genetic antiviral approaches because it is not a protein and thus not immunogenic and because the size of the payload prevents virus escape mutants, such as occurs with the use of RNAi.
In this Phase 2 protocol, 6 subjects will be staggered for infusion by at least 2 weeks. The first group of 3 subjects will receive 4 infusions (4-dose cohort). If no dose limiting toxicities (DLT) are observed, the second group of 3 subjects, (i.e. subjects 4, 5 and 6) will continue with 8 infusions (8-dose cohort). Safety visits are scheduled 1 week after infusion and monthly for the first 6 months and at 9 months following the last infusion.
After safety has been evaluated, and in order to explore biological activity, additional subjects (6-10 evaluable subjects) will be entered into each cohort. Follow-up visits are scheduled 1 week after infusion and monthly for the first 6 months and at 9 months following the last infusion.
The effect of a single bolus will also be examined in a third cohort. The single bolus infusion will consist of the following cell doses: approximately 10 billion, 20 billion, and 30 billion, respectively. Subjects will be allotted to the respective cell dose groups according to the order in which they are enrolled. Three to 5 subjects will be allotted to the lower cell dose group and followed for safety for 4 weeks. After safety is evaluated, the next group (3 to 5 subjects) will be allotted to the next higher cell dose group and followed for safety for 4 weeks. If the intermediate cell dose group is determined to be safe, an additional 3 to 5 subjects will be allotted to the highest cell dose group. All subjects will be followed for safety at biweekly intervals for the first 4 weeks and thereafter at monthly intervals up to 6 months and then at 9 months.
The study has concluded it's 9-month active phase. Subjects are currently in a 15-year Long Term Follow-up Phase of the study.
In keeping with the recently released Guidance on Monitoring For Delayed Adverse Events, that states that for the first 5 years all subjects should undergo monitoring of vector sequences every 6 months, subjects will visit the clinic at a maximum of 6 months intervals for a blood test evaluating persistence of vector sequences.
Therefore for the first 5 years, subjects will have 6 months visits for safety assessment. For years 6 to 15, subjects will be contacted by phone or mail. At these contacts, subjects will be asked about their health status.
