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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


Clinical Trials


Study Identifier: NCT00089700
Sponsor: Tanox
Phase: IIa
Study Purpose: Safety and efficacy study that compared 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
Selected Study Results:

Study Identifiers: TMB-202; NCT00784147
Sponsor: TaiMed Biologics Inc.
Phase: IIb
Study Purpose: Dose-response study of ibalizumab that determined an optimal dose and regimen
Study Population: HIV-infected, treatment-experienced adults with documented resistance to at least one NRTI, one NNRTI, and one PI. Participants were either receiving a stable ART regimen for at least 8 weeks prior to screening or had treatment failure in the 8 weeks before screening and had 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 and chose to extend ibalizumab treatment beyond 24 weeks are continuing to receive open-label ibalizumab under a separate study protocol (NCT01056393).15
Selected Study Results:

Study Identifiers: TMB-301; NCT02475629
Sponsor: TaiMed Biologics Inc.
Phase: III
Study Purpose: Study evaluating the safety and effectiveness of ibalizumab
Study Population: Treatment-experienced adults infected with multidrug resistant HIV-1. Participants have HIV RNA >1,000 copies/mL, were 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 are monitored on their current failing ART regimen (or no therapy if the participant experienced therapy failure and discontinued treatment within 8 weeks prior to screening).
  • “Essential monotherapy period” (Days 7-13): Participants continue their current failing ART regimen (or no therapy) and receive a single loading dose of IV ibalizumab 2000 mg on Day 7.
  • “Maintenance period” (Day 14-Week 25): Participants receive an optimized background regimen starting on Day 14. Beginning on Day 21, participants receive IV ibalizumab 800 mg every 2 weeks through Week 23. End-of-study evaluations occur at Week 25.4,16

Selected Study Results
:


Study Identifiers: TMB-311; NCT02707861
Sponsor: TaiMed Biologics Inc.
Phase: III
Study Purpose: Study to provide ibalizumab access (open-label) to treatment-experienced individuals with multidrug resistant HIV-1
Study Population:
  • Cohort 1: Participants have successfully completed a prior ibalizumab trial.
  • Cohort 2: HIV-infected, treatment-experienced (but ibalizumab-naive) adults infected with multidrug resistant HIV-1. Participants have HIV RNA >1,000 copies/mL, were on ART for at least 6 months, and are currently receiving a failing ART regimen or have had past failure and are currently off ART. Participants should have viral sensitivity to at least one other ARV agent, other than ibalizumab.
Dosing:
  • Cohort 1: IV ibalizumab 800 mg once every 2 weeks or 2000 mg once every 4 weeks, each combined with an optimized background regimen. (Ibalizumab dosage will be based on the dosage the participant received in the prior successfully completed trial.) Ibalizumab will be given for 48 weeks or until the drug becomes commercially available.
  • Cohort 2: IV ibalizumab 800 mg once every 2 weeks, in combination with an optimized background regimen. Ibalizumab will be given for 48 weeks or until the drug becomes commercially available.17
* This study is currently recruiting participants.

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.18,19


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

In the Phase III TMB-301 study (NCT02475629), IV ibalizumab was reportedly “well tolerated” during the first week of treatment. Study results, however, are not yet available outside of the company’s news release.4,16


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 August 24, 2016.
  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 August 24, 2016.
  3. University of Colorado, Denver. Compassionate Use of 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 August 24, 2016.
  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 August 24, 2016.
  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 August 24, 2016.
  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 August 24, 2016.
  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 August 24, 2016.
  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 August 24, 2016.
  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 August 24, 2016.
  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 August 24, 2016.
  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 August 24, 2016.
  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 August 24, 2016.
  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 August 24, 2016.
  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 August 24, 2016.
  16. TaiMed Biologics Inc.: Press Release, dated May 25, 2016. TaiMed Biologics, Inc. Announces that 82.5% of Patients Achieved the Primary Endpoint in the Phase III Ibalizumab Trial. Available at: http://www.taimedbiologics.com/en/news-15.aspx. Last accessed on August 24, 2016.
  17. TaiMed Biologics Inc. A Phase 3, Multicenter, Expanded Access Study of Ibalizumab Plus an Optimized Background Regimen (OBR) in Treatment-Experienced Patients Infected With Multi-Drug Resistant (MDR) HIV-1. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 8, 2016. NLM Identifier: NCT02707861. Available at: https://clinicaltrials.gov/ct2/show/NCT02707861. Last accessed on August 24, 2016.
  18. 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 August 24, 2016.
  19. 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 August 24, 2016.


Last Reviewed: September 8, 2016

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