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FDA-approved

Investigational

Ibalizumab  Audio icon

Other Names: Hu5A8, TMB-355, TNX-355
Drug Class: Entry and Fusion Inhibitors
Chemical Name: Immunoglobulin G4, anti-(human CD4 (antigen)) (human-mouse monoclonal 5A8 γ4-chain), disulfide with human-mouse monoclonal 5A8 κ-chain, dimer
Company: TaiMed Biologics
Phase of Development: Phase IIb. Expanded access (use of a drug outside of a clinical trial) to ibalizumab may be available to patients who qualify for compassionate use treatment. (More details can be found on ClinicalTrials.gov [NCT02028819].)
(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and ClinicalTrials.gov3)
Patent Version Content

Pharmacology


Mechanism of Action: HIV-1 entry inhibitor. Ibalizumab, a humanized monoclonal antibody (mAb), binds to extracellular domain 2 of the CD4 receptor. The ibalizumab binding epitope is located at the interface between domains 1 and 2, opposite from the binding site for major histocompatibility complex class II molecules and gp120 attachment.4,5 Ibalizumab’s post-binding conformational effects prevent viral entry and fusion.6 

Half-life (T½): 3 to 3.5 days on average (estimated from a multiple-dose study of weekly ibalizumab 10 mg/kg in one study arm and biweekly ibalizumab 25 mg/kg in another study arm, given via intravenous [IV] infusion in HIV-infected adults).5

Resistance: Reduced ibalizumab susceptibility is associated with mutations that disrupt potential N-linked glycosolation sites (PNGS) in variable region 5 (V5) of HIV-1 envelope glycoproteins.4,7 Loss of glycan on the V5 N-terminus of gp120 is considered a major determinant of ibalizumab resistance. An in vitro study demonstrated that strategic placement of a glycan in the variable region of the ibalizumab L chain to create a modified antibody can restore ibalizumab’s activity against certain ibalizumab-resistant strains of HIV-1.8 

A Phase Ib study indicated that cross-resistance between enfuvirtide and ibalizumab does not occur.6


Dosing in Clinical Trials


Study Identifier: NCT000897009
Phase: IIa
Study Purpose: Safety and efficacy study of ibalizumab compared with placebo
Study Population: HIV-infected, treatment-experienced (triple-class-experienced)
Dosing: Ibalizumab 10 mg/kg administered via intravenous (IV) infusion weekly for 8 weeks, followed by either 10 mg/kg or 15 mg/kg every 2 weeks, versus placebo. All study participants also received an optimized background regimen.6,9,10
(See references cited above for information on study results.)

Study Identifiers: TMB-202; NCT0078414711
Phase: IIb
Study Purpose: Dose-response study of ibalizumab to determine optimal dose and regimen
Study Population: HIV-infected, treatment-experienced with documented resistance to at least one nucleoside reverse transcriptase inhibitor (NRTI), one non-nucleoside reverse transcriptase inhibitor (NNRTI), and one protease inhibitor (PI)
Dosing: Ibalizumab 800 mg administered via IV infusion every 2 weeks or 2000 mg every 4 weeks for 24 weeks. All participants also received an optimized background regimen.11,12
* Participants who demonstrated successful virologic response in Study TMB-202 could extend ibalizumab treatment beyond 24 weeks under a separate study protocol (NCT01056393).13
(See references cited above for information on study results.)

Ibalizumab has also been investigated as an agent for HIV prevention. A Phase I safety study of ibalizumab given via subcutaneous injection in HIV-uninfected, at-risk participants has been completed.14


Adverse Events


The most common treatment-emergent adverse events occurring in a Phase IIb trial were rash, diarrhea, headache, and nausea. Most events were mild to moderate. No drug-related deaths, serious adverse events, or discontinuations occurred. Laboratory and vital sign abnormalities were determined not to be clinically relevant.12


Drug Interactions


Ibalizumab drug interactions are currently unknown.


References


  1. United States National Library of Medicine. ChemIDplus Advanced. Available at: http://chem.sis.nlm.nih.gov/chemidplus/rn/680188-33-4. Last accessed on July 28, 2014.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Available at: http://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Last accessed on July 28, 2014.
  3. University of Colorado, Denver. Compassionate Use of Dolutegravir and Ibalizumab for the Treatment of HIV Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 3, 2014. NLM Identifier: NCT02028819. Available at: http://www.clinicaltrials.gov/ct2/show/NCT02028819. Last accessed on July 28, 2014. 
  4. Toma J, Weinheimer SP, Stawiski E, et al. Loss of Asparagine-Linked Glycosylation Sites in Variable Region 5 of Human Immunodeficiency Virus Type 1 Envelope is Associated with Resistance to CD4 Antibody Ibalizumab. J Virol. 2011 Apr;85(8):3872-80. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126132. Last accessed on July 28, 2014.
  5. Jacobson JM, Kuritzkes DR, Godofsky E, et al. 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. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2630626. Last accessed on July 28, 2014.
  6. Bruno CJ, Jacobson JM. Ibalizumab: an anti-CD4 monoclonal antibody for the treatment of HIV-1 infection. J Antimicrob Chemother. 2010 Sep;65(9):1839-41. Available at: http://jac.oxfordjournals.org/content/65/9/1839.long. Last accessed on July 28, 2014.
  7. Toma J, Weinheimer SP, Stawiski E, et al. Loss of Asparagine-Linked Glycosylation Sites in Variable Region Five of Human Immunodeficiency Virus Type 1 Envelope is Associated with Resistance to CD4 Antibody Ibalizumab. Poster presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Poster 586. Available at: http://retroconference.org/2011/PDFs/586.pdf. Last accessed on May 22, 2013.
  8. Song R, Oren DA, Franco D, Seaman MS, Ho DD. Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1-neutralizing activity. Nat Biotechnol. 2013 Nov;31(11):1047-52. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825789. Last accessed on July 28, 2014.
  9. Tanox. A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Three-Arm Study of the Anti-CD4 Monoclonal Antibody TNX-355 With Optimized Background Therapy in Treatment-Experienced Subjects Infected With HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 10, 2004. NLM Identifier: NCT00089700. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00089700. Last accessed on July 28, 2014.
  10. Norris D, Morales J, Gathe J, et al. Phase 2 efficacy and safety of the novel entry inhibitor, TNX-355, in combination with optimized background regimen (OBR). Abstract presented at: 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract TUPE0058. Available at: http://www.iasociety.org/Default.aspx?pageId=11&abstractId=2195524. Last accessed on July 28, 2014.
  11. TaiMed Biologics Inc. 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 (Amended to 24-Weeks). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 30, 2008. NLM Identifier: NCT00784147. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00784147. Last accessed on July 28, 2014.
  12. Khanlou H, Gathe J Jr, Schrader S, Towner W, Weinheimer S, Lewis S. Safety, Efficacy, and Pharmacokinetics of Ibalizumab in Treatment-Experienced HIV-1 Infected Patients: a Phase 2b Study. Abstract presented at: 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 17-20, 2011; Chicago, IL; Abstract H2-794b. Available at: http://www.abstractsonline.com/Plan/ViewAbstract.aspx?sKey=553b562f-106a-48ff-b263-3cf82d20946e&cKey=214ca279-ad2f-4c51-8226-6747ca35bbab&mKey=%7b0C918954-D607-46A7-8073-44F4B537A439%7d. Last accessed on July 28, 2014.
  13. Kaiser Permanente. Investigator-Sponsored Protocol - Continued Use of Ibalizumab. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 22, 2010. NLM Identifier: NCT01056393. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01056393. Last accessed on July 28, 2014.
  14. TaiMed Biologics Inc. A Phase 1, Randomized, Double-Blinded, Placebo-Controlled, Sequential Dose-Escalation Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Subcutaneously Administered Ibalizumab in HIV-Negative, At-Risk Volunteers. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on Feb 7, 2011. NLM Identifier: NCT01292174. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01292174. Last accessed on July 28, 2014.


Last Reviewed: July 28, 2014

Last Updated: July 30, 2014


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