In March 2018, the FDA approved ibalizumab-uiyk (Trogarzo, Theratechnologies), an injectable CD4-directed post-attachment HIV-1 inhibitor, indicated 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. With its approval, ibalizumab-uiyk became the first monoclonal antibody to treat HIV. It is also the first HIV therapy with a new mechanism of action to be approved in 10 years.
Here are several key therapeutic areas with ibalizumab-uiyk that every pharmacist should know.
Ibalizumab-uiyk, in combination with other antiretroviral(s), is indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen.
Limitation of Use3
The safety and effectiveness of ibalizumab-uiyk in pediatric patients have not been established. Additionally, due to the potential for HIV-1 transmission, mothers should not to breastfeed if they are receiving ibalizumab-uiyk.
Mechanism of Action3
Ibalizumab-uiyk is a CD4-directed post-attachment HIV-1 inhibitor. It works by blocking HIV-1 from infecting CD4+ T cells by binding to domain 2 of CD4 and interfering with post-attachment steps required for the entry of HIV-1 virus particles into host cells and preventing the viral transmission that occurs via cell-cell fusion.
Notably, the medication binds opposite to the site in domain 1 that is required for CD4 binding of the MHC class II molecules and therefore does not interfere with CD4-mediated immune functions.
Formulation and Storage3
Ibalizumab-uiyk is supplied as a single-dose, colorless to slightly yellow solution, 2 mL vial containing 150 mg/mL of medication. Each vial delivers approximately 1.33 mL containing 200 mg of ibalizumab-uiyk. It is commercially available in a carton containing two single-dose vials.
Ibalizumab-uiyk vials should be stored refrigeration at 2 to 8ºC (36-46 ºF), protected from light, and should not be frozen.
Ibalizumab-uiyk is administered intravenously as a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks after dilution in 250 mL of 0.9% Sodium Chloride Injection, USP. The loading dose of 2000 mg will require 10 vials of ibalizumab-uiyk while the maintenance dose of 800 mg will require 4 vials.
Diluted ibalizumab-uiyk solution should be administered by a trained medical professional. Dose modifications are not required when administered with any other antiretroviral or any other treatments.
All patients should be observed for 1 hour after completion of ibalizumab-uiyk administration for at least the first infusion. If the patient does not experience an infusion-associated adverse reaction, the post-infusion observation time can be reduced to 15 minutes thereafter.
If a maintenance dose is missed by 3 days or longer beyond the scheduled dosing day, a loading dose should be administered as early as possible. Resume maintenance dosing every 14 days thereafter.
The efficacy of ibalizumab-uiyk was assessed in a single arm, multicenter clinical trial conducted in 40 heavily treatment-experienced HIV-infected subjects with multidrug resistant HIV-1. Subjects were required to have a viral load greater than 1,000 copies/mL and documented resistance to at least 1 antiretroviral medication from each of 3 classes of antiretroviral medications (NRTI, NNRTI, and PI) as measured by resistance testing. Subjects must have been treated with antiretrovirals for at least 6 months and be failing or had recently failed therapy.
The majority of subjects in the trial were male (85%), white (55%) and between 23 and 65 years of age. More than half had been treated with 10 or more antiretroviral drugs prior to enrollment. The primary efficacy endpoint was the proportion of subjects achieving a ≥ 0.5 log10 decrease in viral load from the beginning to the end of the monotherapy period (day 7 to day 13) as compared to the proportion of subjects achieving a ≥ 0.5 log10 decrease from the beginning to the end of a preliminary observational period (day 0 to day 6).
Data results showed the majority of participants experienced a significant decrease in their HIV-RNA levels one week after ibalizumab-uiyk was added to their failing antiretroviral regimens as compared to the observation period (83% vs 3%; p<0.001).
After 24 weeks of ibalizumab-uiyk plus other antiretroviral drugs, 43% of the trial’s participants achieved HIV RNA suppression defined as <50 HIV-RNA copies/mL.
Separately, a population pharmacokinetic analysis was performed to explore the potential effects of selected covariates (age, body weight, sex, baseline CD4+ cell count) on ibalizumab-uiyk pharmacokinetics. The results suggest that ibalizumab-uiyk concentration decreases as body weight increases; however, the effect is thought to unlikely to impact virologic outcome and therefore does not warrant a dose adjustment.
Phenotypic and genotypic test results revealed no evidence of cross-resistance between ibalizumab-uiyk and any of the approved classes of anti-retroviral drugs.
The most common adverse reactions of ibalizumab-uiyk reported in clinical trials include diarrhea, dizziness, nausea, and rash.
No drug interaction studies have been conducted with ibalizumab-uiyk; however, based on its mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected.
In clinical studies, ibalizumab-uiyk was shown to be highly effective in decreasing HIV-RNA levels one week after it was added to failing antiretroviral regimens; however, after 24 weeks of ibalizumab-uiyk plus other antiretroviral drugs, only 43% of patients achieved HIV RNA suppression. Still, ibalizumab-uiyk may prove to be beneficial in patients with multidrug-resistant HIV, many of which lack any treatment options at all. Notably, ibalizumab-uiyk is not indicated to be used as monotherapy or for antiretroviral-naive people living with HIV. Future studies will be beneficial to assess the long-term safety and efficacy of ibalizumab-uiyk.
- HIV/AIDS. Centers for Disease Control and Prevention. https://www.cdc.gov/hiv/default.html. Accessed March 16, 2018
- Blank C. FDA approves breakthrough drug for HIV patients with dwindling options. Modern Medicine. March 13, 2018. formularyjournal.modernmedicine.com/formulary-journal/news/fda-approves-breakthrough-drug-hiv-patients-dwindling-options. Accessed March 23, 2018.
- Trogarzo [prescribing Information]. Montreal, Canada: Theratechnologies, Inc.; 2018. accessdata.fda.gov/drugsatfda_docs/label/2017/208437lbl.pdf. Accessed March 16, 2018.
Timothy O'Shea, MS, PharmD
Timothy O'Shea, MS, PharmD, is a Clinical Pharmacist working at a regional health insurance plan on the east coast. Additionally he works per diem at a nationwide retail pharmacy chain. He graduated from MCPHS University - Boston in 2015 and subsequently completed a PGY-1 Managed Care Pharmacy Residency. He completed his M.S. in Health Services Administration, with a focus on Health Economics and Outcomes, in 2018. His professional interests include pharmacy legislation and managed care pharmacy. He can be followed on Twitter at @toshea125.