TNX-355 is a type of medicine called an entry inhibitor. Entry inhibitors work by blocking HIV from entering human cells.
HIV/AIDS-Related Uses
TNX-355 is an investigational medicine that is not yet approved by the FDA for use outside of clinical trials. It is being studied for the treatment of HIV infection. This medicine does not cure or prevent HIV infection or AIDS and does not reduce the risk of passing the virus to other people.
Dosage Form/Administration
TNX-355 comes in a liquid form that is given by intravenous infusion into a vein. Many different dosages based on body weight are being studied in clinical trials.
Contraindications
Individuals should tell a doctor about any medical problems before taking this medicine.
Possible Side Effects
Along with its desired effects, TNX-355 may cause some unwanted effects. These side effects are not yet known. So far, TNX-355 has been well tolerated in limited human studies.
Drug and Food Interactions
A doctor should be notified of any other medications being taken, including prescription, nonprescription (over-the-counter), or herbal medications.
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use TNX-355.
Manufacturer Information
TNX-355
Tanox, Inc.
10555 Stella Link
Houston, TX 77025
Phone: 866-312-5200
Fax: 713-578-5002
Last Updated: June 24, 2009
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]
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 05/05/09.
[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 05/05/09.
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. [1] [2] TNX-355 was granted fast-track status by the FDA in October 2003. [3] 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. [4] [5]
References
[1] Conf Retroviruses Opportunistic Infect 11th, 2004. Abstract 536.
[2] 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 05/05/09.
[3] 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 05/05/09.
[4] Curr Opin Investig Drugs 2007 Aug;8(8):653-61.
[5] 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 05/05/09.
Dosing Information
Mode of Delivery
Intravenous infusion. [1]
Dosage Form
In one clinical trial, 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. [2] In another study TNX-355 is also being administered intravenously but at a dosage of 800 mg every 2 weeks or at 2000 mg every 4 weeks. [3]
References
[1] Intl AIDS Conf 16th, 2006. Abstract TUPE0058.
[2] 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 05/05/09.
[3] ClinicalTrials.gov A Phase 2b, Randomized, Double-Blinded, 48-Week, Multicenter, Dose-Response Study of Ibalizumab Plus an Optimized Background Regimen in Treatment-Experienced Patients Infected With HIV-1. Available at: http://clinicaltrials.gov/ct2/show/NCT00784147. Accessed 06/04/09.
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. [1]
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. [2]
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. [3]
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. [4]
A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of TNX-355 was conducted with 22 HIV-1-infected patients. Treatment with TNX-355 demonstrated significant reductions in HIV-1 RNA levels in 20 of 22 patients. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Emerging resistance to TNX-355 was shown. TNX-355 did not have immunogenic activity, and no serious drug-related adverse effects occurred. TNX-355 administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. [5]
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. [6] 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. [7]
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. [8]
References
[1] Conf Retroviruses Opportunistic Infect 10th, 2003. Abstract 13.
[2] Conf Retroviruses Opportunistic Infect 13th, 2006. Abstract 158LB.
[3] Conf Retroviruses Opportunistic Infect 10th, 2003. Abstract 13.
[4] Conf Retroviruses Opportunistic Infect 10th, 2003. Abstract 13.
[5] Pubmed.gov Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Available at: http://www.ncbi.nlm.nih.gov/sites/entrez. Accessed 05/05/09.
[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] 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 05/05/09.
[8] International AIDS Conf 16th, 2006. Abstract THPE0024.
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. [1] [2]
References
[1] Conf Retroviruses Opportunistic Infect 10th, 2003. Abstract 13.
[2] Conf Retroviruses Opportunistic Infect 11th, 2004. Abstract 536.
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. [1] This synergy, along with the differing mechanisms of action and resistance between these two entry inhibitors, supports a strategy of coadministration. [2]
References
[1] Intl AIDS Conf 16th, 2006. Abstract THPE0024.
[2] Antimicrob Agents Chemother 2006;50(6):2231-3
Clinical Trials
Click here to search ClinicalTrials.gov for trials that use TNX-355.
Chemistry
CAS Number
680188-33-4 [1] 872357-57-8 [2]
References
[1] USAN Proprietary Information Available at: http://www.ama-assn.org/ama1/pub/upload/mm/365/ibalizumab.pdf. Accessed 05/05/09.
[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 05/05/09.
Further Reading
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 05/05/09.
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.
Jacobson JM, Kuritzkes DR, Godofsky E, DeJesus E, Larson JA, Weinheimer SP, Lewis ST. Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1-infected adults. Antimicrob Agents Chemother. 2009 Feb;53(2):450-7. Epub 2008 Nov 17.
A Phase 2b, Randomized, Double-Blinded, 48-Week, Multicenter, Dose-Response Study of Ibalizumab Plus an Optimized Background Regimen in Treatment-Experienced Patients Infected With HIV-1. Available at: http://clinicaltrials.gov/ct2/show/NCT00784147. Accessed 06/04/09.
Manufacturer Information
TNX-355
Tanox, Inc.
10555 Stella Link
Houston, TX 77025
Phone: 866-312-5200
Fax: 713-578-5002
Last Updated: June 24, 2009