GAITHERSBURG, Md., Feb. 14 /PRNewswire/ -- VIRxSYS Corporation, a private biotechnology company focused on the development of novel genetic medicines and vaccines for the treatment and management of serious diseases such as HIV/AIDS and cancer, announced today that it will initiate Phase I clinical trials for the genetic treatment of HIV/AIDS. The trials will involve the first-ever use of a lentiviral vector in humans, called VRX496, whereby HIV is genetically turned against itself in a clinical setting. The therapeutic goal is to show in human trials what has been demonstrated in the laboratory and in small animals. In the laboratory, the VIRxSYS vector repeatedly showed extremely high delivery efficiency to CD4 T cells (immune cells), significant inhibition of HIV replication and ability to thwart wild-type HIV's (wt-HIV) tendency to create resistance to the treatment via mutation. In small animals, safety and non-toxicity of the VIRxSYS vector were also demonstrated.

The Phase I clinical trials are expected to begin in the next 90 days at the University of Pennsylvania's School of Medicine and will involve HIV infected patients, who have failed two consecutive combination anti-retroviral drug therapy regimens. The treatment involves the removal of T cells from patients infected with HIV, treating these immune cells with the HIV lentiviral vector and then reintroducing them back into the patient. The trials are being led by University of Pennsylvania's Drs. Rob Roy MacGregor, principal investigator, and Carl H. June, co-investigator, both leaders in the fields of T cell transplantation and infectious diseases.

Dr. Boro Dropulic, Founder and Chief Scientific Officer of VIRxSYS, commented, "VIRxSYS has met the extensive requirements of the RAC committee of the NIH, the BRMAC committee of the FDA, and the FDA regarding appropriate pre-clinical safety testing of its VRX496 vector. Receiving clearance to initiate Phase I clinical trials for this new and promising class of vectors is as important a milestone for the company as it is for the field. Lentiviral vectors hold significant promise for the treatment of many disease states because they efficiently deliver payload genes into targeted human cells. The goal for HIV/AIDS is to permanently decrease viral loads to levels that are not conducive to disease and protect CD4 T cells from being killed by HIV so that they can fight and control the infection. We are optimistic that our approach will significantly improve the quality of life for individuals suffering from HIV/AIDS."

VIRxSYS' HIV lentiviral vector technology is a radically different approach to HIV treatment. Instead of developing newer classes of HIV replication blockers, VIRxSYS has developed a gutted version of HIV, called VRX496, by taking out the components that foster its replication and cause disease and inserting instead an anti-HIV 'antisense' payload that destroys the genetic material of HIV. This vector is then added to the CD4 T cells of an HIV-infected patient to enable that patient's T cells to inhibit HIV replication and resist their destruction by HIV. VRX496 resides in these CD4 T cells in a dormant state until the infectious wt-HIV invades the cell. Upon infection and then subsequent activation of that cell, wt-HIV attempts to reproduce itself. This in turn triggers VRX496 replication that ultimately destroys the wt-HIV genetic material and prevents its replication.

The goal of the VIRxSYS treatment approach is to reverse and potentially cure individuals with HIV/AIDS by creating an "army" of VRX496-enabled CD4 T cells in the patient's body that permanently suppresses HIV infection and restores the body's immune system.

In pre-clinical trials, VIRxSYS consistently achieved greater than 90% T cell delivery with VRX496 and also repeatedly demonstrated a greater than 99% reduction in HIV viral replication in human immune cells. The introduction of sufficient numbers of the VRX496 enabled CD4 T cells into HIV infected individuals may permanently postpone AIDS disease progression and restore the patient's immune system.

Combination anti-retroviral drug therapy, currently commonly used for the treatment of HIV infected patients, is not a cure; rather, this treatment suppresses HIV replication as long as the patient adheres to the drug dosing requirements. Dr. Dropulic further explained, "Many patients have been forced to discontinue combination anti-retroviral drug therapy because strict and continual adherence to these drug regimens, essential for control of HIV replication, produces toxic side effects. In other patients, HIV has become resistant to these drugs, rendering them useless. VIRxSYS' lentiviral vectors have shown no toxic side effects in pre-clinical animal studies. Also, preclinical studies have shown that HIV cannot mutate around the long anti-HIV antisense payload contained within VRX496 and yet be sufficiently fit to replicate at levels that would be necessary to sustain disease."

"VIRxSYS has made significant progress in this important new field of medicine," commented, Bob Ackmann, Interim Chief Executive Officer and Chief Financial Officer of VIRxSYS. "The Company believes that successful Phase I human clinical trials for this vector class will lead to new therapies for AIDS as well as an extension of the VIRxSYS technology platform to potentially create a vaccine for the disease."

About VIRxSYS

VIRxSYS Corporation is a private biotechnology company founded in 1998, which focuses on the development of a novel HIV lentiviral vector platform technology for the treatment of serious diseases such as HIV/AIDS and cancer. The Company's highly patented, proprietary technology platform and product application strategy is based on research originally conducted at and exclusively licensed from The Johns Hopkins University (JHU) in Baltimore, Maryland by VIRxSYS' Founder and Chief Scientific Officer, Dr. Boro Dropulic. VIRxSYS has taken proof-of-concept studies performed at JHU to Phase I clinical trials in just under four years. Signature Capital, the Company's lead investor, is a unique venture capital company co-founded and co-managed by Bill Sick and Bill Turner that specializes in identifying companies with innovative approaches. Additional information is available at VIRxSYS' Web site at http://www.virxsys.com , and at Signature Capital's Web site at http://www.sigcap.com .

BOSTON, Feb. 14 /PRNewswire/ -- TMC114, a next-generation protease inhibitor, has demonstrated significant antiviral activity in multiple PI-experienced HIV patients currently failing PI therapy. In the 50 patient study, the median reduction in plasma viral load was -1.35 log10 copies/ml HIV-1 RNA after 14 days treatment with TMC114 boosted with low-dose ritonavir (TMC114/r); the maximum reduction was -2.49 log10. TMC114 is being developed by Tibotec, a Belgian pharmaceutical research and development company.

The results, the first efficacy data reported for TMC114, were presented this week at the 10th Conference on Retroviruses and Opportunistic Infections by Dr Keikawus Arasteh of Vivantes Auguste-Viktoria-Klinikum, Berlin.

Antiretroviral resistance now accounts for a large proportion of HIV treatment failures and is a major concern for people living with HIV/AIDS. Cross-resistance among the currently approved PIs can render many of them ineffective.

"From the data collected so far, TMC114 seems to continue to be active in the presence of many of the strains of PI-resistant virus; these results are very encouraging," said Dr Arasteh.

The study, TMC114-C207, was a Phase IIa open label, randomized trial in 50 multiple PI-experienced HIV patients currently failing on a PI regimen. The median number of PI-resistance associated mutations at baseline was 6; all primary PI-resistance associated mutations were found among study participants. The median number of PIs previously used was 3; all patients had received at least 2 PIs and 2 NRTIs.

Patients in the study were randomised into three treatment arms (A, B, C) and one control arm, D. In arms A-C failing PIs were replaced by TMC114/r (A: 300/100 mg bid; B: 600/100 mg bid; C: 900/100 mg qd), all other antiretrovirals remained unchanged; in arm D patients continued on their failing regimen. The median change in plasma HIV-1 RNA from baseline to endpoint in arms A, B, C and D was - 1.24, - 1.50, - 1.13 and +0.02 copies/ml respectively.

Patients received TMC114/r for 14 days after which it was discontinued. None of the subjects experienced any rebound in viral load and there was no phenotypic evidence of the development of resistance to TMC114 during the two week trial. The most commonly reported AEs were GI and CNS disorders; no consistent TMC114/r related changes in blood chemistry or hematology were seen. There was one case of reversible hepatotoxicity in the TMC114/r group. TMC114 was generally well-tolerated during this study.

"These early clinical results of TMC114 in highly treatment-experienced patients are very positive," commented Wim Parys MD, Vice President of Clinical Development at Tibotec. "TMC114 was selected for clinical development on the basis of its novel in vitro antiviral profile and potency against PI-resistant HIV. These data, showing that TMC114 is active against PI-resistant virus, confirm previous results indicating that it is a next- generation PI that could potentially contribute to more effective HIV management in the future."

Further studies to evaluate long-term safety and efficacy and to define the optimal dose will be initiated later this year.

Additional TMC114 Data Presented at 10th CROI

Poster 549: TMC114, A Next Generation Protease Inhibitor: Pharmacokinetics and Safety Following Oral Administration of Multiple Doses With and Without Low Doses of Ritonavir in Healthy Volunteers.

About Tibotec

Tibotec is a pharmaceutical research and development company with headquarters in Belgium and operating subsidiaries in the United States and Ireland. The company is a subsidiary of Johnson and Johnson.

Tibotec is dedicated to the discovery and development of novel, new drugs for HIV/AIDS and other infectious diseases with the ultimate aim of enhancing and extending peoples' lives. The Company is focusing on the development of HIV/AIDS compounds that are active against both wild-type and drug resistant strains of HIV.

Tibotec has two novel antiretroviral compounds in Phase II clinical development; TMC125, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and TMC114, a protease inhibitor (PI).

BOSTON, MA--(INTERNET WIRE)--Feb 14, 2003 -- Results of the 2NN study show no statistical difference between VIRAMUNE® (nevirapine, Boehringer Ingelheim) and efavirenz (Sustiva®, Bristol Myers Squibb Company) in anti-HIV efficacy with respect to viral suppression and immune restoration at 48 weeks. 2NN is the first large-scale, prospective randomized trial directly comparing non-nucleoside reverse transcriptase inhibitor- (NNRTI) containing regimens in patients initiating anti-HIV therapy. Results from this study, which enrolled 1,216 patients in 17 countries, were presented today at the 10th Conference on Retroviruses and Opportunistic Infections. NNRTIs are commonly used in combination therapy to treat patients with HIV-1 infection.

"The results of this large, randomized, prospective, multi-center trial clearly demonstrate the comparable efficacy of VIRAMUNE and efavirenz in HIV treatment," said lead 2NN investigator Professor Joep Lange of the International Antiviral Therapy Evaluation Center (IATEC). "2NN was specifically designed to allow a scientifically rigorous prospective comparison of VIRAMUNE- and efavirenz-based regimens, unlike previous retrospective cohort studies."

In the intent to treat (ITT) analysis, a viral load of less than 50 copies was reached by 70 percent of the patients in the VIRAMUNE once-daily* arm, 65.4 percent in the VIRAMUNE twice-daily arm, 70 percent in the efavirenz arm and 62.7 percent in the VIRAMUNE + efavirenz arm. The treatment arms had comparable increases in CD4 cells over 48 weeks, which were 170 cells/mm(3) in the VIRAMUNE once-daily arm, 160 cells/mm(3) in both the VIRAMUNE twice-daily arm and the efavirenz arm, and 150 cells/mm(3) in the VIRAMUNE + efavirenz arm in the ITT population. All treatment arms also included the two nucleoside analogue drugs stavudine and lamivudine.

There was no statistical difference in the rates of grade 3-4 serious clinical adverse events or rates of treatment discontinuations in the single NNRTI arms. The most common adverse events experienced in the VIRAMUNE arms were rash and hepatic events. The most common adverse events experienced in the efavirenz arms were rash and central nervous system/psychiatric events. The VIRAMUNE once-daily arm had a significantly higher incidence of grade 3 or 4 liver associated laboratory abnormalities compared to the efavirenz arm.

Results of the 2NN lipid sub-study were also presented. In patients who remained on their allocated treatment (n=833), a VIRAMUNE-containing regimen resulted in higher levels of HDL-c ("good" cholesterol). In this sub-study, the VIRAMUNE once-daily and twice-daily regimens were analyzed together. The percentage of HDL-c increase was 37 percent in the VIRAMUNE regimens compared to 24 percent in the efavirenz regimen. Additionally, treatment with VIRAMUNE resulted in a significant decrease in the ratio of total cholesterol to HDL-c, an important cardiovascular risk factor. Patients in the VIRAMUNE regimens experienced an 8 percent decrease in ratio, compared to a 1 percent increase in the efavirenz regimen.

"We're pleased to see that the results of 2NN have demonstrated comparable efficacy between VIRAMUNE and efavirenz, and that VIRAMUNE has demonstrated lipid benefits similar to what has been seen in past studies," said Sheldon Berkle, Executive Vice President Marketing and Sales, Prescription Medicines, Boehringer Ingelheim Pharmaceuticals, Inc. "The importance of these results is further realized considering that the price of VIRAMUNE is nearly $2.75 less per day than efavirenz at U.S. average wholesale price. Any time a drug with comparable efficacy can be offered at a lower price, we believe it can only be positive for the community."

The U.S. average wholesale price (AWP) of a one-month supply of VIRAMUNE is $366.94 at $12.23 per day. The U.S. AWP of a one-month supply of efavirenz is $449.64 at $14.99 per day.

A composite end-point comprised of virologic failure, drug discontinuation, HIV disease progression/AIDS or death was also presented. The percentage of patients who reached the primary end-point was 43.7 percent in the VIRAMUNE twice-daily arm, 43.6 percent in the VIRAMUNE once-daily arm, 37.7 percent in the efavirenz arm and 53.1 percent in the VIRAMUNE + efavirenz arm. The arm that combines both VIRAMUNE + efavirenz was statistically inferior to the efavirenz arm due to decreased tolerability, resulting in more drug discontinuations. There was no statistically significant difference among the other arms.

Study Design

2NN was conducted by the International Antiviral Therapy Evaluation Center (IATEC). The trial enrolled 1,216 patients from 65 centers in 17 countries. Treatment-naive patients received the nucleoside analogues d4T (stavudine) and 3TC (lamivudine), and were randomized to one of four NNRTI treatment arms: VIRAMUNE once-daily, VIRAMUNE twice-daily, efavirenz, and VIRAMUNE + efavirenz. Study participants were required to have a minimum viral load of 5,000 copies/ml at study entry; there were no entry restrictions as to baseline CD4+ cell count. Analyses include efficacy, safety, plasma lipid profile, lipodystrophy profile, quality of life, and plasma pharmacokinetics.

VIRAMUNE

VIRAMUNE is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on one principal clinical trial that demonstrated prolonged suppression of HIV-RNA and two smaller supportive studies.

The most clinically important adverse events associated with VIRAMUNE are rash (9%) and hepatic events. Other commonly reported events include fever, nausea and headache. Cases of hypersensitivity reactions have been observed. Severe and life-threatening skin reactions and hepatotoxicity, including fatal cases of each, have occurred in patients treated with VIRAMUNE. Some events have occurred after short-term exposure. The first 12-16 weeks of therapy with VIRAMUNE are a critical period during which it is essential that patients be intensively monitored. VIRAMUNE should be discontinued and not restarted following severe hepatic, skin or hypersensitivity reactions.

The dose of VIRAMUNE for adults is one 200 mg tablet daily for the first 14 days (this lead-in period should be used because it has been found to lessen the frequency of rash), followed by one 200 mg tablet twice daily. Resistant virus emerges rapidly and uniformly when VIRAMUNE is administered alone. For the treatment of HIV-1 infection, VIRAMUNE should always be administered in combination with other antiretroviral agents.

VIRAMUNE is a product of original research done at Boehringer Ingelheim Pharmaceuticals, Inc. For more information, visit www.VIRAMUNE.com. For more information on Boehringer Ingelheim, please see www.boehringer-ingelheim.com/hiv.

* VIRAMUNE is not indicated for once-daily dosing in the United States.

References and Notes

Sustiva® (efavirenz) is a registered trademark of Bristol-Myers Squibb Company.

Abstract #176 Results of the 2NN Study: A randomized comparative trial of 1st line antiretroviral therapy (ART) with regimens containing either nevirapine (NVP) alone, efavirenz (EFV) alone or both drugs combined, together with stavudine and lamivudine. (2NN Study).

Abstract #752: Lipid changes in a randomized comparative trial of 1st line antiretroviral therapy (ART) with regimens containing either nevirapine (NVP) alone, efavirenz (EFV) alone or both drugs combined, together with stavudine and lamivudine (2NN Study).