AHFS Class:

• HIV Entry and Fusion Inhibitors 8:18.08.04

Generic Name(s):

• Ibalizumab

• Ibalizumab-uiyk

Ibalizumab-uiyk, a humanized immunoglobulin G (IgG) monoclonal antibody, is a human immunodeficiency virus (HIV) entry inhibitor.1 The drug is a CD4-directed post-attachment HIV type 1 (HIV-1) inhibitor.1

Treatment of HIV Infection in Antiretroviral-experienced Adults

Ibalizumab-uiyk is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current antiretroviral regimen.1 Ibalizumab has been designated an orphan drug by FDA for this indication.4

Clinical Experience

Efficacy of ibalizumab-uiyk was evaluated in a single-arm, multicenter clinical trial (TMB-301; NCT02475629) that included 40 heavily treatment-experienced HIV-infected adults 18 years of age or older with multidrug-resistant HIV-1 infection.1,10 All patients were required to have a viral load exceeding 1000 copies/mL and documented genotypic or phenotypic resistance to at least 1 antiretroviral from each of 3 antiretroviral drug classes for study inclusion.1,10 Additionally, patients were required to have been treated with antiretrovirals for at least 6 months with failing or recently failed therapy (i.e., within the last 8 weeks).1,10

The study was conducted in 3 phases: the control period to establish baseline HIV viral load, a functional monotherapy period to establish virologic activity of ibalizumab, and a maintenance period to establish safety and the durability of virologic response to a regimen of ibalizumab in conjunction with an optimized background regimen.1,10 During days 0-6 (control period), patients were either monitored on their current failing antiretroviral regimen or received no antiretroviral therapy if the failed treatment had been discontinued within the 8 weeks prior to screening to establish a baseline viral load.1,10 During days 7-13 (functional monotherapy period), all patients received a 2-g IV loading dose of ibalizumab-uiyk on day 7 and those receiving a failing antiretroviral regimen at study entry continued that regimen in addition to receiving the ibalizumab-uiyk loading dose.1,10 During day 14 to week 25 (maintenance period), viral load was assessed and the background antiretroviral regimen optimized to include at least 1 antiretroviral with in vitro activity against the patient's HIV strain, both done on day 14.1,10 Beginning on day 21, a maintenance dosage of ibalizumab-uiyk (800 mg IV once every 2 weeks) was initiated and continued through week 25.1,10 The primary efficacy end point was the proportion of patients achieving a 0.5 log₁₀ or greater decrease in viral load from baseline (end of control period) to day 14 (end of the functional monotherapy period ).1,10

The enrolled population was 85% male and 55% white; the median age was 53 years, baseline median viral load was 35,350 copies/mL, baseline median CD4+ T-cell count was 73 cells/mm³, and 53% of patients had been treated with ≥10 previous antiretroviral drugs.1 At the end of the functional monotherapy period, 83% of patients achieved a 0.5 log₁₀ or greater decrease in viral load compared with 3% of patients at the end of the control period.1,10 At week 25, 55% of patients had a ≥1 log₁₀ redution in viral load, 48% had a ≥2 log₁₀ reduction in viral load,43% of patients had a viral load of <50 copies/mL and 50% had a viral load of <200 copies/mL.1,10 From baseline to week 25, median CD4+ T-cell counts increased by a median of 17 cells/mm³.1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

In the 2023 HHS adult HIV treatment guideline, ibalizumab is listed among other drugs with novel mechanisms of action, which can be included as part of a fully active antiretrovial regimen for treatment of HIV infection with virologic failure, including following failure of a second-line regimen and beyond.200

General

Patient Monitoring

• Observe patients for infusion-associated adverse reactions for 1 hour after completion of the loading dose as an IV infusion or IV push.1
• For patients without reactions after the first dose, observe for 15 minutes after completion of subsequent maintenance doses (administered either as an IV infusion or IV push).1

Other General Considerations

• Ibalizumab-uiyk should be prepared and administered by a trained medical professional.1
• Dosage modifications of ibalizumab are not required when administered with any other antiretrovirals or any other treatments.1

Administration

Ibalizumab-uiyk is administered as a single loading dose followed by maintenance doses every 2 weeks.1 Doses may be administered either as a diluted IV infusion or undiluted IV push.1

Ibalizumab-uiyk should be administered (as an IV infusion or IV push) into the cephalic vein of the right or left arm.1 If the cephalic vein is not accessible, another appropriate vein may be used.1

Store unopened single-dose vials containing ibalizumab-uiyk injection concentrate at 2-8°C, protect from light, and do not freeze.1 injection concentrate should appear as a colorless to slightly yellow and clear to slightly opalescent solution; do not use if it appears cloudy or discolored or contains particles.1

IV Infusion

Prior to IV infusion, ibalizumab-uiyk concentrate must be diluted.1

After the IV infusion is complete, flush the IV administration set with 30 mL of 0.9% sodium chloride injection.1

Dilution

To prepare the solution for IV infusion, ibalizumab-uiyk injection concentrate must be diluted in 0.9% sodium chloride injection; other diluents must not be used.1

Dilute appropriate number of vials to prepare the desired dose of the drug.1

To prepare the 2000-mg loading dose for IV infusion, 10 single-dose vials of the injection concentrate are required; withdraw 1.33 mL from each of the vials (total volume of 13.3 mL) and add to an IV infusion bag containing 250 mL of 0.9% sodium chloride injection.1

To prepare an 800-mg maintenance dose for IV infusion, 4 single-dose vials of the injection concentrate are required; withdraw 1.33 mL from each of the vials (total volume of 5.32 mL) and add to an IV infusion bag containing 250 mL of 0.9% sodium chloride injection.1

A small residual amount of injection concentrate may remain in each vial; discard this unused portion.1

Administer the diluted solution immediately or store under refrigeration (2-8°C) for up to 24 hours or at room temperature (20-25°C) for up to 4 hours.1 If the diluted solution is refrigerated, allow it to stand at room temperature for at least 30 minutes (but less than 4 hours) prior to administration.1

Rate of Administration

After the drug is diluted, administer the loading dose by IV infusion over at least 30 minutes and maintenance doses by IV infusion over at least 15 minutes.1

IV Push

Maintenance doses of ibalizumab-uiyk can be given undiluted.1

To prepare the 2000-mg loading dose for administration as an IV push, 10 single-dose vials of the concentrate are required; allow vials to stand at room temperature for approximately 5 minutes and withdraw 1.33 mL from each of the vials (total volume of 13.3 mL) into a single syringe.1 Administer the undiluted solution immediately.1

To prepare an 800-mg maintenance dose of ibalizumab-uiyk, 4 single-dose vials of the injection concentrate are required; allow the vials to stand at room temperature for approximately 5 minutes and withdraw 1.33 mL from each of the vials (total volume of 5.32 mL) into a single syringe.1 Administer the undiluted solution immediately.1

After the IV injection is complete, flush with 2-5 mL of 0.9% sodium chloride injection.1

Discard partially used or empty vials and any unused portion of undiluted solution.1

Rate of Administration

Administer the undiluted solution via IV push over at least a 90-second period (for the loading dose) or over at least a 30-second period (for maintenance doses).1

Dosage

Adult Dosage

Treatment of HIV Infection in Antiretroviral-experienced Adults

For the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-experienced adults, a single IV loading dose of 2000 mg should be administered, followed by a maintenance dosage of 800 mg IV once every 2 weeks.1

If a maintenance dose is missed by 3 or more days beyond the scheduled administration day, a 2000 mg IV loading dose should be administered as soon as possible.1 Thereafter, resume the maintenance dosage of 800 mg IV once every 14 days.1

Special Populations

Hepatic Impairment

The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1

Renal Impairment

The manufacturer makes no specific dosage recommendations for patients with renal impairment.1

Geriatric Use

The manufacturer makes no specific dosage recommendations for geriatric patients.1

Contraindications

• Prior hypersensitivity reaction to ibalizumab or any components of the product.1

Warnings/Precautions

Hypersensitivity Reactions

Hypersensitivity reactions including infusion-related reactions and anaphylactic reactions have been reported during post-approval use of ibalizumab-uiyk.1 Symptoms may include dyspnea, angioedema, wheezing, chest pain, chest tightness, cough, hot flush, nausea, and vomiting.1 If such symptoms occur, immediately discontinue ibalizumab-uiyk and initiate appropriate treatment.1

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome has been reported in at least one HIV-infected patient receiving ibalizumab-uiyk in conjunction with other antiretrovirals.1

During initial treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections.1 Such response may necessitate further evaluation and treatment.1

Immunogenicity

There is a potential for immunogenicity with ibalizumab-uiyk therapy.1

In studies evaluating the safety and efficacy of ibalizumab-uiyk (TMB-301 [phase 3 clinical trial] and TMB-202 [phase 2b clinical trial]), all enrolled patients were tested throughout the studies for the presence of antibodies against the drug.1 Only one sample from one patient tested positive for anti-ibalizumab antibodies;1 no adverse reaction or reduced efficacy was attributed to the low titer of anti-ibalizumab antibodies reported in this patient.1

Embryo-Fetal Toxicity

Based on animal data, ibalizumab-uiyk may cause reversible immunosuppression (CD4+ T cell and B cell lymphocytopenia) in infants born to mothers exposed to ibalizumab-uiyk during pregnancy.1 Consult experts for immune phenotyping of the peripheral blood to provide guidance regarding monitoring and management of exposed infants.1

Safety of administering live or live-attenuated vaccines in exposed infants is unknown.1

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to antiretroviral medicines during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263.1

There are no available data on ibalizumab use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1

According to the 2023 HHS perinatal HIV treatment guideline, data are insufficient to make recommendations or characterize the risk of congenital anomalies with ibalizumab use during pregnancy.202

Monoclonal antibodies, such as ibalizumab-, are transported across the placenta as pregnancy progresses.1 Based on animal data, ibalizumab use during pregnancy may cause reversible immunosuppression (CD4+ T cell and B cell lymphocytopenia) in infants exposed to ibalizumab-uiyk in utero.1 In a reproductive study in monkeys, reversible decreases in CD4+ T cells and B cells and increases in CD8+ T cells were observed within the first 4 weeks after birth in infants born to pregnant monkeys receiving ibalizumab-uiyk intravenously.1 Lymphocyte counts returned to near normal levels by 3 months of age.1 One infant monkey died from a systemic viral infection that may be related to ibalizumab-induced immunosuppression.1 No malformations or premature births were observed.1 If pregnancy occurs during ibalizumab treatment, refer to a specialist to provide guidance regarding monitoring and management (such as need for antibiotic or immunoprophylaxis) of exposed infants.1

The safety of administering live or live-attenuated vaccines in exposed infants is unknown.1

Lactation

The Centers for Disease Control and Prevention (CDC) recommends that HIV-1 infected mothers not breastfeed their infants to avoid the risk of postnatal transmission of HIV-1.1

It is not known whether ibalizumab-uiyk is distributed into human milk, affects the breast-fed child, or affects milk production.1 Human IgG is distributed into milk in humans.1 However, data indicate that antibodies in breast milk do not enter the neonatal or infant circulatory system in substantial amounts.1

Pediatric Use

Safety and efficacy of ibalizumab-uiyk have not been established in pediatric patients.1 The pharmacokinetics of the drug have not been evaluated in pediatric patients.1

Geriatric Use

Ibalizumab-uiyk has not been studied in geriatric patients.1 The pharmacokinetics of the drug have not been evaluated in geriatric patients.1

Hepatic Impairment

The pharmacokinetics of ibalizumab-uiyk have not been evaluated in patients with hepatic impairment.1

Renal Impairment

The pharmacokinetics of ibalizumab-uiyk have not been evaluated in patients with renal impairment.1 The manufacturer states that renal impairment is not expected to have an effect on the pharmacokinetics of the drug.1

Weight

Population pharmacokinetic analysis suggests that ibalizumab-uiyk concentrations decrease as body weight increases; however, the manufacturer states that this is not expected to affect virologic outcome and dosage adjustments are not necessary.1

Common Adverse Effects

The most common adverse reactions (≥5%) include diarrhea, dizziness, nausea, and rash.1

Specific drug interaction studies have not been conducted to date with ibalizumab-uiyk.1 Based on the drug's mechanism of action and target-mediated drug disposition, the manufacturer states that drug interactions with ibalizumab-uiyk are not expected.1

Antiretroviral Agents

There is some in vitro evidence of synergistic antiretroviral effects between ibalizumab-uiyk and enfuvirtide against laboratory and clinical strains of human immunodeficiency virus type 1 (HIV-1).3

There is no in vitro evidence of antagonistic anti-HIV effects between ibalizumab-uiyk and abacavir, atazanavir, didanosine, emtricitabine, efavirenz, enfuvirtide, maraviroc, tenofovir, or zidovudine.1

Description

Ibalizumab-uiyk, a recombinant humanized immunoglobulin G isotype 4 (IgG₄) monoclonal antibody, is a human immunodeficiency virus (HIV) entry inhibitor.1,2,5 The drug is a CD4-directed post-attachment HIV type 1 (HIV-1) inhibitor that blocks HIV-1 from infecting CD4⁺ T cells by binding to domain 2 of CD4 and interfering with post-attachment steps required for entry of the virus particles into host cells.1,2,5 This prevents the viral transmission that occurs via cell-cell fusion.1,2,5 Ibalizumab-uiyk does not interfere with the domain 1 binding site that is required for CD4 binding of major histocompatibility complex (MHC) class II molecules.1,2,5,8 Due to the specific binding of ibalizumab-uiyk to domain 2 of CD4, the drug blocks viral entry into the cell without altering immune functions mediated by CD4 and without causing immunosuppression.1,2,5,8,9 In addition, ibalizumab-uiyk does not interfere with gp120 attachment to CD4.1,2,8,9

In the phase 3 clinical trial evaluating efficacy and safety of ibalizumab-uiyk in heavily treatment-experienced HIV-infected adults with multidrug-resistant HIV-1 infection (TMB-301), the median maximum percent inhibition (MPI) of ibalizumab-uiyk for HIV-1 isolates from 38 patients was 97% at baseline;1 in 10 patients who experienced treatment failure with the drug, the median MPI was 55% at the time of treatment failure.1 Decreased susceptibility to ibalizumab-uiyk (i.e., decreased MPI) has been observed in some patients receiving ibalizumab-uiyk and may be associated with genotypic changes in the HIV-1 envelope coding sequence that result in the loss of potential N-linked glycosylation sites (PNGS) in the V5 loop of gp120.1,6,7 The clinical importance of decreased susceptibility to ibalizumab-uiyk has not been established.1 Known CD4 polymorphisms were analyzed to determine if any naturally occurring amino acid substitutions in the CD4 molecule potentially could affect the antiretroviral activity of ibalizumab-uiyk and results indicate that known CD4 polymorphisms appear unlikely to affect ibalizumab-uiyk binding to CD4.1

There has been no evidence to date of cross-resistance between ibalizumab-uiyk and other antiretrovirals, including HIV entry and fusion inhibitors (e.g., CCR-5 co-receptor antagonists, gp41 fusion inhibitors), HIV integrase strand transfer inhibitors (INSTIs), HIV nucleoside reverse transcriptase inhibitors (NRTIs), HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs), and HIV protease inhibitors (PIs), in phenotypic and genotypic testing.1,7,8 Ibalizumab-uiyk has been active in vitro against HIV-1 resistant to all other antiretrovirals currently commercially available in the US, including CCR5-tropic, CCRX4-tropic, and dual-tropic HIV-1.1 Phenotypic changes associated with ibalizumab-uiyk resistance do not alter susceptibility to other commercially available antiretrovirals and do not result in selection of CD4-independent viral isolates.1

Ibalizumab-uiyk exhibits nonlinear pharmacokinetics.1 Following a single dose given by IV infusion over 30-90 minutes, AUC increases in a more than dose-proportional manner.1 As ibalizumab-uiyk dosage increased from 0.3 to 25 mg/kg, clearance of the drug decreased from 9.54 to 0.36 mL/hour per kg and elimination half-life increased from 2.7 to 64 hours.1 When the recommended dosage of IV ibalizumab-uiyk (a single 2-g loading dose followed by a maintenance dosage of 800 mg once every 2 weeks) is administered, steady-state concentrations of the drug are achieved after the first 800-mg maintenance dose.1 The initial loading dose as an IV push administration over 90 seconds is predicted to achieve similar peak plasma concentrations and AUC relative to administration by IV infusion over 30 minutes.1

Advice to Patients

• Advise patients of the critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1,200 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1,200
• Advise patients of the importance of using in conjunction with other antiretrovirals.1
• Advise patients of the risk of hypersensitivity reactions including anaphylaxis and the need to seek immediate medical attention if signs or symptoms of hypersensitivity occur or are suspected.1
• Advise patients to not take ibalizumab-uiyk if they have had a previous hypersensitivity to the drug.1
• Advise patients that they may receive ibalizumab-uiyk by IV infusion or IV push and to consult their healthcare provider regarding the most appropriate route of administration.1
• Advise patients that immune reconstitution inflammatory syndrome has been reported in a patient receiving ibalizumab-uiyk; inform patients of the importance of immediately informing clinicians of any symptoms of infection.1
• Advise patients of the importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, and any concomitant illnesses.1
• Inform women of the importance of informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise women with HIV not to breast-feed.1
• Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. Theratechnologies. Trogarzo^® (ibalizumab-uiyk) injection for intravenous infusion prescribing information. Montreal, Quebec Canada; 2023 Dec.

2. Freeman M, Seaman M, Rits-Volloch et al. Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody. Structure . 2010; 18:1632-41.

3. Zhang X, Sorensen M, Fung M et al. Synergistic in vitro antiretroviral activity of humanized monoclonal anti-CD4 antibody (TNX-355) and enfuvirtide (T-20). Antimicrob Agents Ch . 2006; 50:2231-3.

4. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website. Accessed 2018 Jul 19. [Web]

5. Iacob SA, Iacob DG et al. Ibalizumab targeting CD4 receptors, an emerging molecule in HIV therapy. Microbiol . 2017; 8

6. Pace C, Fordyce M, Franco D et al. Anti-CD4 monoclonal antibody ibalizumab exhibits breadth and potency against HIV-1, with natural resistance mediated by the loss of a V5 glycan in envelope. Acquir Immune Defic Syndr . 2013; 62

7. Toma J, Weinheimer S, 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; 85:3872-80.

8. Bruno C, Jacobson J et al. Ibalizumab: an anti-CD4 monoclonal antibody for the treatment of HIV-1 infection. J Antimicrob Chemother . 2010; 65:1839-41.

9. Song R, Franco D, Kao C et al. Epitope mapping of ibalizumab, a Humanized anti-CD4 monoclonal antibody with anti-HIV-1 activity in infected patients. J Virol . 2010; 84:6935-42.

10. Emu B, Fessel J, Schrader S et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N Engl J Med . 2018; 379:645-654. [PubMed 30110589]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (March 23, 2023). Updates may be available at HIV.gov website (http://clinicalinfo.hiv.gov/en/guidelines).

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2023).Updates may be available at HIV.gov website (http://clinicalinfo.hiv.gov/en/guidelines).

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (January 31, 2023). Updates may be available at HIV.gov website (http://clinicalinfo.hiv.gov/en/guidelines).