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TNX-355
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Drug Class: Entry and Fusion Inhibitors
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Drug Description |
| TNX-355, also known as ibalizumab, is a nonimmunosuppressive, humanized IgG4, anti-CD4, domain 2 monoclonal antibody that prevents HIV entry into human cells.[1][2] TNX-355 is currently being developed by TaiMed Biologics, through licensing with Genetech, Inc.[3][4] |
HIV/AIDS-Related Uses |
| TNX-355 is being investigated in Phase II trials as part of combination therapy for the treatment of HIV-1 infection in treatment-experienced patients.[5][6] TNX-355 was granted fast-track status by the FDA in October 2003.[7] Additional Phase II, dose-finding studies had been initiated by Tanox Inc; however, the drug is now licensed to TaiMed Biologics through Genetic Inc, and no new studies have been initiated yet.[8][9] |
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Dosing Information |
Mode of Delivery |
| Intravenous infusion.[10] |
Dosage Form |
| In clinical trials, TNX-355 has been given intravenously once every other week, sometimes with a loading dose of once-weekly treatment. Doses evaluated include 6, 10, 15, and 25 mg/kg; the 10 and 15 mg/kg doses are being evaluated in an ongoing Phase II study.[11] |
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Pharmacology |
TNX-355 inhibits HIV entry into lymphocytes and binds to an epitope in domain 2 of the CD4 receptor on a cell's surface, preventing HIV entry into the cell. TNX-355 does not deplete CD4 cells. Unlike anti-CD4 antibodies that target domain 1 of CD4, TNX-355 does not appear to interfere with immunologic functions involving antigen presentation and is not immunosuppressive.[12]
In vitro laboratory studies of HIV-1 subtype B isolates from 82 triple-class-experienced patients evaluated TNX-355 susceptibility based on viral tropism. Of the 82 isolates, 49 were M-tropic, two were T-tropic, and 27 were dual- or mixed-tropic. All isolates were similarly susceptible to TNX-355, and degree of efficacy did not appear associated with tropism.[13]
A Phase Ia study evaluated single 0.3 to 25 mg/kg doses of TNX-355; these doses reduced viral load from baseline by 50% to 90%. This effect was transient, with most levels returning to baseline by Day 28. Significant viral load reductions were observed with the 10 and 25 mg/kg doses and were sustained for 2 to 3 weeks.[14]
In a Phase Ib study, 23% of patients had reduced viral loads by greater than 95%, and 64% had reduced loads by greater than 90%. However, these reductions were also transient, implying that monotherapy may cause quick development of resistance.[15]
An ongoing Phase II, multicenter, randomized, double-blind, placebo-controlled trial is evaluating TNX-355 efficacy and safety in 82 triple-class-experienced patients also on optimized background therapy. The trial is comparing HIV-infected patients who have failed or are failing highly active antiretroviral therapy (HAART) assigned to one of three arms: TNX-355 10 mg/kg once weekly for nine doses followed by 10 mg/kg every other week; TNX-355 15 mg/kg every other week; or placebo. The study is evaluating virologic failure rates and viral load reduction between the two doses and between each dose and placebo. Enrolled patients must have a viral load of 10,000 copies/ml or greater, a CD4 count greater than 50 cells/ml, and triple-class experience with HAART.[16] At the Week 24 interim analysis, viral load decreased by -nearly 10-fold in the 15 mg/kg arm, by 15-fold in the 10 mg/kg arm, and by nearly twofold in the placebo arm. Both treatment arm reductions were statistically greater than the placebo reduction.[17]
Susceptibility of enfuvirtide-resistant viral envelopes to TNX-355 was studied in vitro using G36D, V38A, and N43D substitutions. Envelopes exhibited 11- to 32-fold reduced susceptibility to enfuvirtide but less than twofold reduced susceptibility to TNX-355. No cross resistance to TNX-355 was observed.[18] |
Adverse Events/Toxicity |
| In Phase Ia and Ib safety studies, TNX-355 was well tolerated. No serious adverse effects were reported in the Phase Ia study. Depression recurrence, vasovagal reaction with new onset seizure, and acute renal failure with renal insufficiency were reported in three patients in a Phase Ib, 22-patient study.[19][20] |
Drug And Food Interactions |
| In vitro, TNX-355 demonstrates synergy in laboratory and in clinical HIV-1 strains with enfuvirtide, an FDA-approved entry inhibitor.[21] This synergy, along with the differing mechanisms of action and resistance between these two entry inhibitors, supports a strategy of coadministration.[22] |
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Clinical Trials |
| Click here to search ClinicalTrials.gov for trials that use TNX-355. |
Chemistry |
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CAS Number |
| 872357-57-8[23]680188-33-4[24] |
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Further Reading |
PMID/17668367 Dimitrov A. Ibalizumab, a CD4-specific mAb to inhibit HIV-1 infection. Curr Opin Investig Drugs. 2007 Aug;8(8):653-61.
Jacobson JM, Kuritzkes DR, Godofsky E, DeJesus E, Lewis S, Jackson J, Frazier K, Fagan EA, Shanahan WR. Phase 1b Study of the Anti-CD4 Monoclonal Antibody TNX-355 in HIV-1-infected Subjects: Safety and Antiretroviral Activity of Multiple Doses. Eleventh Conference on Retroviruses and Opportunistic Infections,San Francisco, CA, February 2004. Abstract 536.
TNX-355 With Optimized Background Therapy (OBT) in Treatment-Experienced Subjects With HIV-1. Available at: http://clinicaltrials.gov/ct/show/NCT00089700. Accessed 02/12/07.
PMID/16723592 Zhang XQ, Sorensen M, Fung M, Schooley RT. Synergistic in vitro antiretroviral activity of a humanized monoclonal anti-CD4 antibody (TNX-355) and enfuvirtide (T-20). Antimicrob Agents Chemother. 2006 Jun;50(6):2231-3.
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Manufacturer Information |
TNX-355
Tanox, Inc.
10555 Stella Link
Houston, TX 77025
(866) 312-5200
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References |
[1] Conf Retroviruses Opportunistic Infect - 11th, 2004. Abstract 536.
[2] Curr Opin Investig Drugs - 2007 Aug;8(8):653-61.
[3] TaiMed Biologics Inc - Genetech Partnership Information. Available at: http://seekingalpha.com/article/47462-genentech-partners-with-taiwan-company-on-aids-drug. Accessed 08/08/08.
[4] Houston Business Journal - AIDS drug survives Tanox: Genentech license launches new team at TaiMed Biologics [press release], April 11, 2008. Available at: http://houston.bizjournals.com/houston/stories/2008/04/14/story1.html?page=2. Accessed 08/08/08.
[5] Conf Retroviruses Opportunistic Infect - 11th, 2004. Abstract 536.
[6] ClinicalTrials.gov - TNX-355 with Optimized Background Therapy (OBT) in Treatment-Experienced Subjects with HIV-1. Available at: http://www.clinicaltrials.gov/ct/show/NCT00089700. Accessed 08/08/08.
[7] PRNewswire - FDA Grants Tanox's Anti-CD4 Drug Fast-Track Status for the Treatment of HIV-1 [press release], October 10, 2003. Available at: http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/10-09-2003/0002032826&EDATE=. Accessed 08/08/08.
[8] Curr Opin Investig Drugs - 2007 Aug;8(8):653-61.
[9] Houston Business Journal - AIDS drug survives Tanox: Genentech license launches new team at TaiMed Biologics [press release], April 11, 2008. Available at: http://houston.bizjournals.com/houston/stories/2008/04/14/story1.html?page=2. Accessed 08/08/08.
[10] Intl AIDS Conf - 16th, 2006. Abstract TUPE0058.
[11] ClinicalTrials.gov - TNX-355 with Optimized Background Therapy (OBT) in Treatment-Experienced Subjects with HIV-1. Available at: http://www.clinicaltrials.gov/ct/show/NCT00089700. Accessed 08/08/08.
[12] Conf Retroviruses Opportunistic Infect - 10th, 2003. Abstract 13.
[13] Conf Retroviruses Opportunistic Infect - 13th, 2006. Abstract 158LB.
[14] Conf Retroviruses Opportunistic Infect - 10th, 2003. Abstract 13.
[15] Conf Retroviruses Opportunistic Infect - 10th, 2003. Abstract 13.
[16] ClinicalTrials.gov - TNX-355 with Optimized Background Therapy (OBT) in Treatment-Experienced Subjects with HIV-1. Available at: http://www.clinicaltrials.gov/ct/show/NCT00089700. Accessed 08/08/08.
[17] International AIDS Conf - 16th, 2006. Abstract TUPE0058.
[18] International AIDS Conf - 16th, 2006. Abstract THPE0024.
[19] Conf Retroviruses Opportunistic Infect - 10th, 2003. Abstract 13.
[20] Conf Retroviruses Opportunistic Infect - 11th, 2004. Abstract 536.
[21] Intl AIDS Conf - 16th, 2006. Abstract THPE0024.
[22] Antimicrob Agents Chemother - 2006;50(6):2231-3
[23] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 08/08/08.
[24] USAN Proprietary Information - Available at: http://www.ama-assn.org/ama1/pub/upload/mm/365/ibalizumab.pdf. Accessed 08/08/08.
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Updated August 8, 2008
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