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Investigational

Ibalizumab  Audio icon

Other Names: Hu5A8, TMB-355, TNX-355
Drug Class: Entry Inhibitor
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 III. 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].)
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(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 and ClinicalTrials.gov3,4)
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.5,6 Ibalizumab’s post-binding conformational effects prevent viral entry and fusion.7

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).6

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.5,8 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-1.9

A Phase Ib study indicated that cross-resistance between enfuvirtide and ibalizumab does not occur.7


Dosing in Clinical Trials


Study Identifier: NCT0008970010
Phase: IIa
Study Purpose: Safety and efficacy study comparing ibalizumab to placebo.
Study Population: HIV-infected, treatment-experienced (triple-class-experienced) adults. Participants were on ART for at least 6 months and had evidence of present or past treatment failure (within 8 weeks prior to screening) of their ART regimen.
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, for a total of 48 weeks, versus placebo. All study participants also received an optimized background regimen.7,10-12
(See references cited above for information on study results.)

Study Identifiers: TMB-202; NCT0078414713
Phase: IIb
Study Purpose: Dose-response study of ibalizumab to determine optimal dose and regimen
Study Population: HIV-infected, treatment-experienced adults with documented resistance to at least one nucleoside reverse transcriptase inhibitor (NRTI), one non-nucleoside reverse transcriptase inhibitor (NNRTI), and one protease inhibitor (PI). Participants were either receiving a stable ART regimen for at least 8 weeks prior to screening or had failed therapy in the 8 weeks before screening and discontinued treatment.
Dosing: Ibalizumab 800 mg administered via IV infusion every 2 weeks for 24 weeks or 2000 mg every 4 weeks for 24 weeks. All participants also received an optimized background regimen.13,14
* Participants who demonstrated successful virologic response in Study TMB-202 could extend ibalizumab treatment beyond 24 weeks under a separate study protocol (NCT01056393).15
(See references cited above for information on study results.)

Study Identifiers: TMB-301; NCT024756294
Phase: III
Study Purpose: Study to evaluate the safety and effectiveness of ibalizumab.
Study Population: HIV-infected, treatment-experienced adults infected with multi-drug resistant HIV-1. Participants must have been on ART for at least 6 months and have evidence of present failure or past failure (within 8 weeks of screening) of their ART regimen.
Dosing: 24-week, open-label, single-arm study:
  • “Control period” (Days 0-6): Participants will be monitored on their current failing ART regimen (or no therapy if the participant failed therapy and discontinued treatment within 8 weeks prior to screening).
  • “Essential monotherapy period” (Days 7-13): Participants will continue their current failing ART regimen (or no therapy) and will receive a single loading dose of IV ibalizumab 2000 mg on Day 7.
  • “Maintenance period” (Day 14-Week 25): Participants will receive an optimized background regimen starting on Day 14. Beginning on Day 21, participants will receive IV ibalizumab 800 mg every 2 weeks through Week 23. End-of-study evaluations will occur at Week 25.4


A completed Phase I study (NCT01292174) investigated a subcutaneous (SC) formulation of ibalizumab for potential use as an HIV treatment or prophylactic agent. This study examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of three escalating doses of once weekly ibalizumab administered via SC injection over 4 weeks in HIV-uninfected, at-risk participants.16,17


Adverse Events


The most common treatment-emergent adverse events occurring in a Phase IIb trial (NCT00784147) 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.14


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 September 7, 2015.
  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 September 7, 2015.
  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 September 7, 2015.
  4. TaiMed Biologics Inc. A Phase 3, Single Arm, 24-Week, Multicenter Study of Ibalizumab Plus an Optimized Background Regimen (OBR) in Treatment-Experienced Patients Infected With Multi-Drug Resistant HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 11, 2015. NLM Identifier: NCT02475629. Available at: https://www.clinicaltrials.gov/ct2/show/NCT02475629. Last accessed on September 7, 2015.
  5. 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 September 7, 2015.
  6. 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 September 7, 2015.
  7. 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 September 7, 2015.
  8. 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.
  9. 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 September 7, 2015.
  10. 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 September 7, 2015.
  11. 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://library.iasociety.org/AbstractView.aspx?confID=2006&abstractId=12593. Last accessed on September 7, 2015.
  12. Norris D, Morales J, Godofsky E, Garcia F, Hardwicke R, Lewis S. TNX-355, in combination with optimized background regimen (OBR), achieves statistically significant viral load reduction and CD4 cell count increase when compared with OBR alone in phase 2 study at 48 Weeks. Abstract presented at: 16th International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract THLB0218. Available at: http://library.iasociety.org/AbstractView.aspx?confID=2006&abstractId=51042. Last accessed on September 7, 2015.
  13. 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 September 7, 2015.
  14. 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 September 7, 2015.
  15. 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 September 7, 2015.
  16. 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 September 7, 2015.
  17. Ernst J, Keefer M, Lalezari J, et al. Subcutaneous Ibalizumab in At-Risk Healthy Subjects. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); September 5-9, 2014; Washington, DC. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2014. Available at: http://www.natap.org/2014/ICAAC/ICAAC_21.htm. Last accessed on September 7, 2015.
     


Last Reviewed: September 7, 2015

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