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TNX-355 in combination with Optimized Background Regimen (OBR) Exhibits Greater Antiviral Activity than OBR Alone in HIV-Treatment Experienced Patients
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Reported by Jules Levin
ICAAC, Dec 17, 2005, Wash DC
D. NORRIS 1, J. MORALES 2, J. GATHE 3, E. GODOFSKY 4, F. GARCIA 5, R. HARDWICKE 6, J. JACKSON 7, S. LEWIS7, L. PARADISO 7;
1Comprehensive Res. Inst., Tampa, FL, 2Clinical Res. Puerto Rico, Inc., San Juan, PR, 3Therapeutic Concepts, Inc., Houston, TX, 4Bach & Godofsky, Bradenton, FL, 5Valley AIDS Council, Harlingen, TX, 6UTHSC, Houston, TX, 7Tanox, Houston, TX.
Background: TNX-355 is a novel humanized monoclonal antibody that binds to domain 2 of the CD4+ receptor, blocking entry of HIV-1 into target cells. A 24-week (wk) interim assessment of the ongoing 48-wk randomized, double-blind, placebo-controlled Phase 2 study was conducted.
Methods: Triple-class experienced HIV-1 infected patients were randomized to receive TNX-355 intravenously: 15 mg/kg Q 2 wks; 10mg/kg Q wk for 8 wks followed by 10mg/kg Q 2 wks; or placebo. In addition, all patients were treated with OBR. Upon experiencing virologic failure (< 0.5 log10 drop from baseline [BL] after week 16), participants receive open-label TNX-355 in combination with new OBR. The primary endpoint was the mean change in HIV-RNA (VL) from BL at wk 24. A modified intent-to-treat (mITT) population (received ≥ 1 infusion), was analyzed.
Results: 82 patients (87% male, 46% white) enrolled: mean age 46 years
Summary of Efficacy Data at Wk 24:
1NC=LOCF, the mean of last two values imputed for wk 24
2NC=F, missing value imputed to no change from BL
p-values=active treatment arm compared to placebo
Conclusions: TNX-355 in combination with OBR versus OBR alone produced greater antiviral activity in triple-class experienced patients with limited therapy options. These data support continued development of TNX-355 as a potential new agent for treatment of HIV infection.
In Vitro Antiretroviral Activity of the Humanized Anti-CD4 Monoclonal Antibody, TNX-355, against CCR5, CXCR4, and Dual-Tropic Isolates and Synergy with Enfuvirtide
E. GODOFSKY1, X. ZHANG 2, M. SORENSEN 3, M. FUNG 4, T. DUENSING 4, S. T. LEWIS 4, R. T. SCHOOLEY 2;
1Bach and Godofsky, Bradenton, FL, 2Univ. of California, San Diego, CA, 3Dartmouth Med. Sch., Hanover, NH, 4Tanox, Inc., Houston, TX.
Background: TNX-355 is a humanized monoclonal antibody that binds to domain 2 of CD4 and prevents entry of HIV-1 into target cells. The current investigation examined (1) in vitro susceptibility of HIV patient isolates expressing various chemokine co-receptor tropism to TNX-355 and (2) synergy between TNX-355 and another entry inhibitor, enfuvirtide.
Methods: Tropism: HIV-1 RNA isolated from samples obtained from 17 patients in a clinical trial was amplified by RT-PCR and used to construct pseudotyped viruses. These viruses were tested for susceptibility to TNX-355 using the PhenoSense™ Entry assay (ViroLogic, Inc. South San Francisco, CA). Envelopes representing viruses from 4 patients were sub-cloned and each sub-clone also tested for susceptibility to TNX-355. Synergy: 7 different strains of HIV-1 were tested using an 18-hour single-exposure and a 4-day continuous exposure in vitro neutralization assay. HIV replication was quantified by measurement of HIV-1 p24 Ag by ELISA. The results were presented as 50% inhibitory concentrations (IC50). Synergy between TNX-355 and T20 was calculated using the Chou dose-effect equation. By convention, a Cooperativity Index (CI) <0.9 indicates synergy, 0.91.1 indicates antagonism.
Results: 13 isolated viruses exhibited tropism for CCR5 expressing cells, 1 exhibited tropism for CXCR4 expressing cells, and 3 exhibited tropism for both. Susceptibility to TNX-355 was similar for all viruses, regardless of their tropism (IC50 values of 0.04 - 0.12 µg/mL). Results were confirmed with sub-cloned viruses, which exhibited a broader range of IC50 values (0.06 - 0.44 µg/mL) that was also independent of co-receptor tropism. Combination studies revealed significant TNX-355 and T20 synergy; CI’s were 0.27±0.13 and 0.12±0.11 for single and continuous exposure, respectively.
Conclusions: Chemokine co-receptor entry inhibitors may be limited by HIV tropism specificity. This study demonstrates that TNX-355 is a potent entry inhibitor that is active against CCR5-, CXCR4-, and dual/mixed-tropic HIV-1. In addition, strong synergistic antiretroviral activity was demonstrated between TNX-355 and enfuvirtide in vitro. Synergy demonstrated in this study suggests that combination treatment with dual entry inhibitors may represent an attractive approach to treatment of HIV infected individuals.
Press Release from Tanox
Data Indicates Tanox HIV Drug Candidate Active In Vitro Against CCR5 and CXCR4 Viruses and Synergistic with Entry Inhibitor
PRNewswire-FirstCall
TNX-355 Data Presented at 2005 ICAAC
Dec. 17, 2005, 12:40PM
WASHINGTON, Dec. 17 /PRNewswire-FirstCall/ -- Tanox, Inc. (Nasdaq: TNOX) today presented data on its lead HIV drug candidate, TNX-355, at the American Society for Microbiology's Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). The presentation highlighted the compound's unique ability to inhibit entry of HIV-1 into healthy CD4-positive cells regardless of the virus' co-receptor tropism.
TNX-355 is a humanized viral-entry inhibitor monoclonal antibody that coats CD4-positive cells - the primary target of HIV infection. By blocking viral entry into the CD4 cell in this manner, TNX-355 creates a unique new hurdle for HIV, different from entry inhibitors that target viral proteins or chemokine co-receptors. Study results show that TNX-355 is equally active in vitro against virus strains that exhibit tropism for CCR5 as well as CXCR4 - making TNX-355 the most advanced entry inhibitor in development with this crucial property of tropism independence.
"TNX-355 shows significant antiviral activity and could be a powerful new advancement in the treatment of HIV," said Dr. Stanley Lewis, Tanox medical director. "These new data confirm that unlike other viral-entry inhibitors that target cellular proteins, TNX-355 is equally effective against viruses regardless of tropism. This is extremely important, as a significant proportion of treatment-experienced patients harbor mixed virus or dual-tropic virus."
As the company announced in October 2005, Week 24 results of the Phase 2 clinical trial demonstrated that, when compared with an optimized background regimen (OBR) alone, TNX-355 in combination with OBR reduces viral loads in HIV-infected patients, without suppressing their immune systems or causing significant side effects.
Tanox's ICAAC abstract also reported results of testing TNX-355 with another entry inhibitor, enfuvirtide. Synergy between the two agents was demonstrated by conventional in vitro techniques. These data support the use of TNX-355 and enfuvirtide together in the clinical setting. Because HIV must be treated with combination therapy, negative drug-drug interactions are a major concern for clinicians treating the disease. These results suggest that co-administration of TNX-355 and enfuvirtide may enhance the activity of both agents.
About TNX-355
TNX-355 is a humanized monoclonal antibody that binds to CD4 receptors on the surface of CD4-positive cells, preventing the entry of HIV particles into lymphocytes. Phase 1 studies demonstrated that TNX-355 is active against multiple strains of HIV and does not deplete CD4-positive cells. The 48-week Phase 2 study, which met its Week 24 primary endpoint, is a double-blind trial to compare the safety and efficacy of two dosages of TNX-355, each combined with an optimized background regimen, to OBR therapy alone among HIV-1 treatment-experienced patients. The drug was fast tracked by the Food and Drug Administration in 2003. The fast-track designation expedites approval of therapies for life-threatening diseases and allows for rolling new drug application (NDA) submissions.
About Tanox, Inc.
Tanox is a biotechnology company specializing in the discovery and development of monoclonal antibodies. The company develops innovative biotherapeutics for the treatment of immune-mediated diseases, inflammation, infectious disease and cancer. Tanox's lead investigational therapy, TNX-355, is viral-entry inhibitor antibody to treat HIV/AIDS. TNX-355 has shown significant antiretroviral activity in Phase 2 clinical testing. Tanox's first-approved drug, Xolair(R) (omalizumab), is the first antibody approved to treat moderate-to-severe confirmed, allergic asthma. Xolair was developed in collaboration with Genentech, Inc. and Novartis Pharma AG and is currently approved for marketing in the United States, Canada and major European countries. Tanox is based in Houston and has a manufacturing facility in San Diego. Additional corporate information is available at http://www.tanox.com.
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