Ibalizumab, a Novel Monoclonal Antibody for the Management of Multidrug-Resistant HIV-1 Infection

Limited antiretrovirals are currently available for the management of multidrug-resistant (MDR) HIV-1 infection. Ibalizumab, a recombinant humanized monoclonal antibody, represents the first novel agent for HIV-1 management in over a decade and is the first monoclonal antibody for the treatment of MDR HIV-1 infection in combination with other forms of antiretroviral therapy in heavily treatment-experienced adults who are failing their current antiretroviral regimen.

ABSTRACT

Limited antiretrovirals are currently available for the management of multidrug-resistant (MDR) HIV-1 infection. Ibalizumab, a recombinant humanized monoclonal antibody, represents the first novel agent for HIV-1 management in over a decade and is the first monoclonal antibody for the treatment of MDR HIV-1 infection in combination with other forms of antiretroviral therapy in heavily treatment-experienced adults who are failing their current antiretroviral regimen. Ibalizumab demonstrates a novel mechanism of action as a CD4-directed postattachment inhibitor and has a favorable pharmacokinetic profile that allows for a dosing interval of every 14 days after an initial loading dose. Clinical studies have demonstrated reasonably substantial antiretroviral activity with ibalizumab among a complex patient population with advanced HIV-1 infection who are receiving an optimized background regimen, where limited therapeutic options exist. Ibalizumab was well tolerated in clinical trials, and the most common adverse effects included diarrhea, nausea, dizziness, fatigue, pyrexia, and rash. Resistance to ibalizumab has also been observed via reduced expression or loss of the potential N-linked glycosylation sites in the V5 loop of the envelope glycoprotein 120. The mechanism of action, pharmacokinetic parameters, efficacy, and safety of ibalizumab present an advance in the management of MDR HIV-1 infection. Future studies and postmarketing experience will further determine longer-term clinical efficacy, safety, and resistance data for ibalizumab.

INTRODUCTION

Human immunodeficiency virus (HIV) and AIDS pose considerable public health concerns for countries worldwide, including the United States (https://www.cdc.gov/hiv/basics/statistics.html). To date, HIV has infected more than 70 million people and led to approximately 35 million deaths (http://www.who.int/gho/hiv/en/). The advent of antiretroviral therapy (ART) has significantly improved the prognoses of patients infected with HIV. Despite the existing benefits of current ART, there are growing concerns regarding resistance to available therapies (1). Approximately 25,000 patients living with HIV in the United States are considered to harbor multidrug-resistant (MDR) strains, including an estimated 12,000 patients in vital need of new treatment options due to previously failed regimens(2). Thus, patients living with MDR HIV, defined as phenotypic or genotypic resistance to at least one drug in three classes of antiretroviral agents, would benefit from the development of new agents with unique mechanisms of action and modes of delivery (3).

Numerous monoclonal antibodies (MAbs) have been developed and are currently being investigated for the treatment of multiple disease states, including malignancies, autoimmune disorders, and infectious diseases (4). Treatment with a MAb offers several advantages for HIV therapy, such as a unique mechanism of action, ability to restore CD4 T cell counts, minimal mechanisms for acquired resistance, and low potential for toxicities compared to alternative antiretroviral agents. Ibalizumab-uiyk (Trogarzo [TaiMed Biologics], referred to here as ibalizumab) is the first intravenous (i.v.) MAb developed for the treatment of HIV-1 infection and the first novel agent for HIV-1 management in over 10 years (1, 5). Ibalizumab was approved by the U.S. Food and Drug Administration (FDA) in March 2018 for the treatment of MDR HIV-1 infection in combination with other ARTs in heavily treatment-experienced adults who are failing their current antiretroviral regimen (5). This review highlights the pharmacologic characteristics of ibalizumab, the clinical trials for use in the management of patients with HIV-1 infection, and the resistance mechanisms to this novel agent. Literature searches of PubMed, EMBASE, and Google Scholar were performed to identify peer-reviewed publications as of 6 March 2019 using the search terms ibalizumab, ibalizumab-uiyk, TMB-355, and TNX-355. When data were not yet available as a published article, abstracts and posters were obtained and utilized to review pertinent data.

Pharmacology and mechanism of action.

The trimeric envelope glycoprotein of HIV consists of glycoprotein 120 (gp120) and gp41 domains (6). The gp120 domain consists of 5 variable loops (V1 to V5). The V1, V2, and V3 loops are located in close proximity to each other and stabilize the apex of the trimer. The V3 loop is located beneath the V1 and V2 loops and functions as a major coreceptor binding site. The V4 and V5 loops are located exteriorly and project outward from the gp120 domain. The mechanism of viral entry begins with the interaction of HIV envelope gp120 with CD4 T cell extracellular domain 1 (7).

Ibalizumab, a recombinant humanized immunoglobulin (Ig) G4 MAb derived from mouse MAb 5A8, inhibits HIV entry into the CD4 T cell via a novel mechanism (Fig. 1) (1, 3, 8). Ibalizumab binds to the CD4 T cell extracellular domain 2 at amino acid sites L96, P121, P122, and Q163 (7). This agent also binds to amino acid sites E77 and S79 on domain 1. These amino acid residues are located on the interface between domains 1 and 2 of human CD4, on a surface opposite of the site where gp120 and the major histocompatibility complex II (MHC-II) molecule bind on domain 1. Traditionally, when the HIV envelope gp120 binds to CD4 T cell extracellular domain 1, a conformational shift occurs that causes the V1 and V2 loops to expose the V3 loop, which converts the trimer from the closed state to an open state (6). The binding mechanism of ibalizumab induces steric hindrance, which prevents these conformational changes within the complex of the CD4 T cell and the HIV envelope gp120 (1, 3). This subsequently inhibits the interaction of gp120 with the CXCR4 and CCR5 coreceptors via the V3 loop, as well as the rearrangement of the gp41 domain, which prevents viral fusion and entry into the CD4 T cell (1, 9). This novel mechanism of action makes ibalizumab effective against CXCR4- and CCR5-tropic strains and led to its classification as a parenteral CD4-directed postattachment inhibitor (3).

FIG 1.

Ibalizumab mechanism of action as a CD4-directed postattachment inhibitor.

Pharmacokinetics.

Human pharmacokinetic data for ibalizumab are derived from several clinical trials (3, 8, 10) and are summarized in Table 1 . In a single-dose phase Ia study, 30 patients with HIV-1 infection were enrolled into five sequential dosing cohorts consisting of six patients in each cohort (10). Single doses in this study ranged from 0.3 mg/kg for the first enrolled cohort up to 25 mg/kg for the final cohort. At lower doses, peak serum concentrations (C_max) were achieved within 1 h of administration; however, the time to maximum concentration (T_max) was prolonged in patients receiving higher doses (10 mg/kg and 25 mg/kg). The C_max and area under the concentration time curve (AUC) increased disproportionally to dose, with the elimination half-life (t_1/2) also increasing with dose, suggesting saturable elimination.

TABLE 1.

Summary of pharmacokinetic data for ibalizumab^a

Study	Dosing regimen (n)	Mean (SD)
		Tmax (h)	Cmax (μg/ml)	AUC (μg ⋅ h/liter)	t1/2 (h)	V (ml/kg)
Kuritzkes et al. (10)	0.3 mg/kg, single dose (6)	0.8 (0.3)	5.4 (0.8)	29.3 (5.9)	3.4 (2.5)	44.6 (8.1)
	1.0 mg/kg, single dose (6)	0.8 (0.3)	21.0 (3.4)	277.9 (129.4)	8.1 (2.0)	43.7 (6.9)
	3.0 mg/kg, single dose (6)	0.8 (0.3)	122.9 (12.3)	2,938.6 (63.1)	14.1 (2.1)	25.5 (7.3)
	10.0 mg/kg, single dose (6)	2.2 (2.6)	328.0 (38.8)	20,644.2 (376.1)	28.7 (6.6)	29.5 (5.6)
	25.0 mg/kg, single dose (6)	4.6 (4.5)	750.2 (233.1)	73,024.8 (1,886.3)	57.2 (20.5)	42.7 (10.8)
Jacobson et al. (8)	10.0 mg/kg, weekly for 10 doses (9)	NA	402 (117)	86,496 (36,720)	79.2 (21.6)	44 (21)
	25.0 mg/kg, every 2 wk for 5 doses (3)	NA	564 (267)	118,584 (106,392)	74.4 (43.2)	50 (20)
Emu et al. (3)	2,000 mg, followed by 800 mg every 2 wk (40)	NA	567 (235)b	NA	NA	NA

^aSources include references 3, 8, and 10. NA, not applicable. n, number of patients.

^bCollected immediately after administration of the ibalizumab 2,000-mg loading dose.

In a subsequent multiple-dose phase Ib clinical trial, 19 patients were randomized to receive 10 mg/kg of ibalizumab i.v. once weekly for 10 doses (arm A; n = 9) or 10 mg/kg on day 1, followed by five maintenance doses of 6 mg/kg i.v. every 14 days starting 1 week after the first dose (arm B; n = 10) (8). A nonrandomized third group was evaluated after enrollment of the first two arms to study higher doses of the drug, and these individuals received 25 mg/kg of ibalizumab i.v. every 14 days for a total of five doses (arm C; n = 3). Pharmacokinetic parameters were only estimated from arms A and C (Table 1). Compared to data from equivalent dosing ranges in the previous study (10), the t_1/2 and C_max values were similar; however, the AUC values were greater than the values observed in the phase Ia study, which may be attributable to drug accumulation with multiple doses. The volume of distribution of ibalizumab is similar to the serum volume (4.8 liters), which suggests that this agent does not significantly distribute to the extravascular space (5, 8, 10).

In the phase III study, a loading dose of 2,000 mg, followed by 800 mg every 14 days, was utilized (3). The C_max values were similar to values observed in the phase I studies. After the initiation of the 800-mg maintenance dose every 14 days, the mean ibalizumab concentration was at least 30 μg/ml throughout the dosing interval, demonstrating a time above the EC₈₅ (i.e., the concentrations required for at least 85% receptor occupancy) of 100%. The estimated t_1/2 of ibalizumab with maintenance dosing is 72 to 84 h (8, 10, 11). This half-life is significantly shorter than that of an IgG molecule under normal physiological circumstances, which is typically 2 to 3 weeks (8). Similar to other anti-CD4 MAbs, this difference in elimination half-life is due to alternative clearance mechanisms where the ibalizumab-CD4 T cell receptor complex undergoes either internalization or shedding, which results in more rapid antibody degradation (12, 13).

No specific studies have been performed to assess the effect of hepatic or renal dysfunction, including effects from renal replacement therapy, on the pharmacokinetics of ibalizumab (5). However, renal and hepatic dysfunction are not expected to alter pharmacokinetic parameters. Furthermore, no specific drug interaction studies have been performed, but interactions are not anticipated, due to the novel mechanism of action of ibalizumab (5).

Pharmacodynamics.

The extent and duration of activity of ibalizumab against HIV-1 is correlated with CD4 T cell receptor coating during the dosing interval (8, 10). Serum ibalizumab concentrations exceeding 5 μg/ml are associated with complete receptor coating, whereas concentrations below 0.5 μg/ml result in receptor uncoating (8). In the aforementioned phase Ia study, complete CD4 T cell receptor coating lasted 8 to 20 days and 15 to 34 days following single ibalizumab doses of 10 and 25 mg/kg, respectively (10). In the phase III trial utilizing an ibalizumab loading dose of 2,000 mg, followed by maintenance doses of 800 mg every 14 days, 97 and 81% of patients exhibited at least 85% CD4 T cell receptor occupancy at day 21 and week 25, respectively (3). Furthermore, curve fitting analyses demonstrated that this receptor occupancy level was supported by ibalizumab serum concentrations above 0.13 μg/ml (14).

Ibalizumab demonstrated similar maximal percentage of inhibition (MPI) regardless of baseline resistance to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), enfuvirtide, or maraviroc (15). The mean MPI values for ibalizumab were 98, 91, 89, and 81%, and the mean concentrations required to achieve 50% of the MPI (IC_halfmax) fold changes were 0.9, 1.0, 1.1, and 1.3 for isolates susceptible to NNRTIs, INSTIs, PIs, and NRTIs, respectively. Comparatively, mean MPI values were 91, 92, 91, and 94%, and mean IC_halfmax fold changes were 1.2, 1.1, 1.3, and 1.2 for isolates resistant to all NNRTIs, INSTIs, PIs, and NRTIs, respectively. Isolates with reduced susceptibility to enfuvirtide, an entry inhibitor that binds to the gp41 subunit of the viral envelope glycoprotein, demonstrated mean ibalizumab MPI values of 84 to 99% and IC_halfmax fold changes of 0.7 to 1.4. Two isolates with reduced susceptibility to maraviroc had mean MPI values of 94 and 100% from ibalizumab. The antiretroviral activity of ibalizumab has also been studied against Tier-2 Env-pseudotyped viruses to represent HIV-1 envelope diversity (16). Ibalizumab achieved 50% infection inhibition in 92% of these HIV-1 strains and 80% inhibition in 65% of these strains.

An important consideration with the use of ibalizumab is its effect on other human CD4 T cell functions. Human MHC-II and HIV envelope gp120 bind to the same surface on CD4 T cell extracellular domain 1 (7). The main function of MHC-II molecules is to present processed antigens to CD4 T cells (17). This process is critical for the initiation of the antigen-specific immune response. Previously studied anti-CD4 MAbs bound to domain 1 were found to be immunosuppressive due to interference with the immune response mediated by MHC-II (8). As for ibalizumab, this agent binds to the interface between CD4 T cell extracellular domains 1 and 2 on a surface opposite to where MHC-II binds to domain 1 (7). Due to this spatial separation, ibalizumab does not appear to interfere with MHC-II-mediated immunity (3).

In addition, antibodies of the IgG subclass consist of a fragment antigen-binding (Fab) domain and a fragment crystallizable (Fc) domain (18, 19), These domains interact with complement component 1q (C1q) and Fc gamma receptors (FcγRs), which may lead to antibody-dependent cellular cytotoxicity and phagocytosis. In comparison to other MAbs, ibalizumab was developed with an IgG4 structure (1, 8). The IgG4 isotope specifically has low affinity for C1q and FcγRs of natural killer cells (1, 18, 19). Thus, ibalizumab largely avoids C1q- and Fc-mediated lysis of CD4-bearing cells.

Safety, efficacy, and clinical trial experience.

(i) Phase I. The safety and efficacy of ibalizumab were evaluated in the previously described single- and multiple-dose phase I clinical trials (8, 10). In the single-dose phase Ia study, the effects of ibalizumab were dose dependent, with peak median reductions in plasma HIV-1 RNA levels minimally affected by 0.3- and 1.0-mg/kg doses, whereas 10- and 25-mg/kg doses resulted in reductions of −1.33 and −1.11 log₁₀ copies/ml, respectively(10). Dose-proportional increases in CD4 T cell counts were also observed. Twenty (66.7%) subjects experienced at least one adverse event after receiving ibalizumab. No serious adverse events or discontinuations of ibalizumab related to adverse events were documented.

In the multiple-dose phase Ib clinical trial, the largest mean reductions in plasma HIV-1 RNA levels occurred at week 1 in arms A and C (−0.95 ± 0.33 log₁₀ copies/ml and −0.96 ± 0.61 log₁₀ copies/ml, respectively) and at week 2 in arm B (−0.83 ± 0.43 log₁₀ copies/ml) (8). Viral loads returned to baseline values in all treatment arms by the end of the infusion period. However, it should be noted that 6 patients were failing their current ART regimen, and the remaining 15 were not taking antiretroviral medications. Therefore, ibalizumab was likely the only active antiretroviral drug for all patients. Reduced susceptibility to ibalizumab was demonstrated in a majority of posttreatment isolates relative to baseline. All patients experienced increases in baseline CD4 T cell counts, with the largest increases occurring within the first 14 days. Subsequently, CD4 T cell counts declined and stabilized toward baseline values at the end of the treatment period. There were no statistically significant differences between arms with respect to changes in CD4 T cell counts. The most frequent treatment-emergent adverse events included headache (6/22 patients; 27%), nausea (3/22 patients; 14%), and productive cough (3/22 patients; 14%). No infusion-related or infusion site reactions occurred. Four serious adverse events occurred (the nature of which are not described), but none were attributed to ibalizumab.

(ii) Phase II. The safety and efficacy of ibalizumab was evaluated in two phase II clinical trials (TNX-355.03 [NCT00089700] and TMB-202 [NCT00784147]), both of which remain as unpublished data (20, 21). TNX-355.03 was a phase IIa randomized, double-blind, placebo-controlled study that evaluated two dosing regimens of ibalizumab plus an optimized background regimen (OBR) versus placebo plus OBR (20). This study randomized 82 triple-class experienced patients, defined as patients who received antiretroviral drugs from at least three drug classes, with baseline plasma HIV-1 RNA values of ≥10,000 copies/ml and CD4 T cell values of ≥50 cell/mm³ to receive ibalizumab at 10 mg/kg i.v. once weekly for nine doses, followed by 10 mg/kg i.v. every 14 days plus OBR (loading regimen), ibalizumab at 15 mg/kg i.v. every 14 days plus OBR, or placebo plus OBR. Both ibalizumab-containing regimens achieved statistically significant reductions in plasma HIV-1 RNA values from baseline at 24 and 48 weeks, with the most significant reduction in plasma HIV-1 RNA values occurring with the loading regimen at 48 weeks (−1.16 log₁₀ copies/ml; P < 0.001). The mean absolute CD4 T cell count increased from 299 cells/mm³ at baseline to 347 cells/mm³ at 48 weeks for the loading regimen (P = 0.031) and from 223 cells/mm³ at baseline to 274 cells/mm³ at 48 weeks for the 15 mg/kg i.v. every 14 days regimen (P = 0.016). Safety data were not reported.

TMB-202 was a phase IIb multicenter, randomized, double-blind, dose-response study that randomized 113 HIV-1-infected individuals to receive either ibalizumab 800 mg i.v. every 14 days plus OBR (n = 59) or ibalizumab at 2,000 mg i.v. every 4 weeks plus OBR (n = 54) (21). Enrolled patients were required to have plasma HIV-1 RNA values of at least 1,000 copies/ml and have documented decreased susceptibility to at least one NRTI, NNRTI, or PI at baseline. The primary outcome was the proportion of patients achieving undetectable viral loads, defined as plasma HIV-1 RNA values of <50 copies/ml, at week 24. Of the 113 patients, 101 (89%) were male and 79 (70%) were Caucasian. Patients had a mean age of 48 years, a mean weight of 81 kg, and a median period of 17 years of HIV-1 infection at baseline. Mean baseline plasma HIV-1 RNA values and CD4 T cell counts were 124,859.8 (4.6 log₁₀) copies/ml and 109 cells/mm³, respectively. At 24 weeks, undetectable viral loads were achieved in 26 (44%) patients receiving ibalizumab at 800 mg i.v. every 14 days and 15 (28%) patients receiving ibalizumab at 2,000 mg i.v. every 4 weeks (P = 0.160). The mean reductions in viral load from baseline, the percentage of patients achieving a 1.0 log₁₀ reduction in viral load, and the mean increases in CD4 T cell counts were similar between both arms at week 24.

Fifteen serious adverse events occurred, none of which were determined by investigators to be related to ibalizumab. The most frequent treatment-emergent adverse events included rash (14/113 patients; 12%), diarrhea (9/113 patients; 8%), headache (8/113 patients; 7%), upper respiratory tract infection (8/113 patients; 7%), nausea (8/113 patients; 7%), and fatigue (7/113 patients; 6%). One subject developed anti-ibalizumab antibodies, but low titers were observed, and drug efficacy was not affected. The pharmacokinetic analysis performed in this phase IIb study indicated that ibalizumab doses of 2,000 mg achieved more rapid maximal drug exposure, and doses of 800 mg every 14 days resulted in a more stable drug exposure over a 24-week period. Therefore, a loading dose of ibalizumab at 2,000 mg, followed by 800 mg every 14 days, was selected to be studied in the phase III clinical trial (3).

(iii) Phase III. The clinical trial that led to FDA approval of ibalizumab was a phase III, single-group, open-label study that enrolled 40 patients from 30 centers throughout the United States and Taiwan (TMB-301, NCT02475629) (3). Eligible patients were required to have received ART for at least 6 months prior to screening, baseline plasma HIV-1 RNA values of >1,000 copies/ml during receipt of ART for at least 8 weeks prior to screening, and documented phenotypic or genotypic resistance to at least one drug in at least three classes of antiretroviral agents. The study was conducted across three time periods. During the control period (days 0 through 6), patients were monitored while they received their current ART regimen. During the functional monotherapy period (days 7 through 13), patients received a 2000-mg i.v. loading dose of ibalizumab (on day 7) and continued their prior ART regimen. During the maintenance period (day 14 to week 25), patients were initiated on an OBR (on day 14) and received i.v. doses of ibalizumab at 800 mg every 14 days starting on day 21. The OBRs were selected on the basis of the patients’ treatment history and resistance testing, and they were required to include at least one fully active antiretroviral agent. The primary endpoint was the proportion of patients with a reduction in plasma HIV-1 RNA values of at least 0.5 log₁₀ copies/ml from baseline (day 7) through day 14. Secondary endpoints included the number of patients with plasma HIV-1 RNA levels <50 and <200 copies/ml and the mean change from baseline CD4 count at week 25.

Of the 40 enrolled patients, 34 (85%) were male, 22 (55%) were Caucasian, and the median age was 53 years old (3). Baseline mean viral loads and median CD4 T cell counts were 4.5 ± 0.8 log₁₀ copies/ml and 73 (range, 0 to 676) cells/mm³, respectively. Rates of documented resistance to all drugs in at least one, two, three, or four classes of antiretroviral agents were 85, 73, 50, and 33%, respectively. Five (13%) patients had documented resistance to all approved antiretrovirals, and 17 (43%) patients required addition of fostemsavir, an investigational antiretroviral agent, in order to construct at OBR with at least one fully susceptible agent.

Results for the primary efficacy endpoint and secondary endpoints are displayed in Table 2 (3). Overall, the primary efficacy endpoint was met in 33 patients (83%; 95% confidence interval = 67 to 95) during the functional monotherapy phase compared to 1 patient (3%) during the control period (P < 0.001), with 60% of patients (n = 24) achieving at least a 1.0-log₁₀ reduction. At the end of the maintenance period, plasma HIV-1 RNA values of <50 and <200 copies/ml occurred in 17 (43%) and 20 (50%) patients, respectively. The mean reduction in viral load from baseline was 1.6 log₁₀ copies/ml, and the mean increase in CD4 T cell count was 62 cells/mm³. This increase was numerically lower in patients with baseline values of <50 cells/mm³ compared to those with counts of >50 cells/mm³, but the difference was not statistically significant (P = 0.44). At the end of the maintenance period, 7 (18%) patients had virologic failure, which was defined as two consecutive measurements after day 14 that showed a <0.5-log₁₀ reduction in plasma HIV-1 RNA copies/ml. In addition, three (8%) patients had viral rebound, which was defined as an increase of at least 1.0 log₁₀ copies/ml in plasma HIV-1 RNA from the nadir value. Of the 10 (25%) patients with virologic failure or viral rebound, 9 demonstrated reduced susceptibility to ibalizumab compared to baseline, which was related to the loss of potential N-linked glycosylation sites (PNGS) in the V5 loop of HIV-1 envelope gp120 in 8 of the 9 (89%) patients.

TABLE 2.

Virologic response to ibalizumab among 40 patients evaluated in TMB-301^a

Virologic response	Control period (days 0–6)	End of functional monotherapy period (day 14)	P	End of maintenance period (wk 25)
Decrease in viral load of at least 0.5 log10 copies/ml, n (%)	1 (3)	33 (83)	<0.001b	25 (63)
Decrease in viral load of at least 1.0 log10 copies/ml, n (%)	0 (0)	24 (60)	NA	22 (55)
Change in viral load, mean log10 copies/ml ± SD	0.0 ± 0.2	–1.1 ± 0.6	<0.001	–1.6 ± 1.5
HIV-1 RNA level of <50 copies/ml, n (%)	NA	NA	NA	17 (43)
HIV-1 RNA level of <200 copies/ml, n (%)	NA	NA	NA	20 (50)

^aSource: Emu et al. (3). n, number of patients; NA, not applicable.

^bPrimary efficacy endpoint.

Overall, ibalizumab was generally well tolerated with at least one adverse event occurring in 32 (80%) patients (3). The majority of the adverse events (87%) were mild to moderate in severity and are summarized in Table 3. A total of 22 serious adverse events occurred in 9 (23%) patients, including pyrexia (n = 3), Kaposi sarcoma (n = 2), lymphoma (n = 2), and asthenia (n = 2), as well as septic shock, urinary tract infection, altered mental status, hepatic mass, rectal hemorrhage, hepatic failure, diplopia, pulmonary hypertension, immune reconstitution inflammatory syndrome (IRIS), progressive multifocal leukoencephalopathy, anal squamous cell carcinoma, rectal cancer, and cytomegalovirus viremia (n = 1 for each). Of the serious adverse events, only one (IRIS) was considered to be related to ibalizumab therapy, and this resulted in drug discontinuation. This led to a labeled warning and precaution of IRIS for ibalizumab. There were no reports of hepatotoxicity, cancer, or infusion site reactions related to ibalizumab treatment, and none of the patients developed anti-ibalizumab antibodies during the study period.

TABLE 3.

Summary of nonsevere adverse events reported in the phase III clinical trial (TMB-301)^a

Nonsevere adverse event	n (%)
Diarrhea	8 (20)
Nausea	5 (13)
Fatigue	5 (13)
Pyrexia	5 (13)
Rash	5 (13)
Dizziness	5 (13)
Vomiting	4 (10)
Lymphadenopathy	4 (10)
Nasopharyngitis	4 (10)
Decreased appetite	3 (8)
Excoriation	3 (8)
Headache	3 (8)
Upper respiratory tract infection	3 (8)

^aSource: Emu et al. (3). n, number of adverse events.

The TMB-311 study (NCT02707861) was a phase III clinical trial allowing for continued administration of ibalizumab at 800 mg i.v. every 14 days to patients who have previously completed TMB-301 (https://clinicaltrials.gov/ct2/show/NCT02707861) (22). Of the 31 patients who completed TMB-301, 27 enrolled in TMB-311 to be assessed for safety and efficacy for a combined duration of 48 weeks. Of the 24 patients who completed 48 weeks on ibalizumab in TMB-311, 16 (59%) and 17 (63%) maintained plasma HIV-1 RNA levels of <50 and <200 copies/ml, respectively. Of note, all 15 patients with plasma HIV-1 RNA levels <50 copies/ml at the end of TMB-301 maintained suppressed viremia after 48 weeks of therapy. There were no unanticipated or new safety concerns that developed among these patients. This trial also recruited qualifying ibalizumab-naive patients with MDR HIV-1 infection with limited treatment options.

Resistance.

The therapeutic effect of ibalizumab is potentiated by steric hindrance with HIV-1 gp120 after binding to extracellular domain 2 on the CD4 T cell receptor (3, 7). This effect may be overcome by resistance mechanisms which minimize this interaction (16, 23, 24). The V5 loop is present as an external portion of gp120 (6). Reduced expression or loss of V5 PNGS and the specific positions of PNGS appear to be the primary mechanisms of resistance to ibalizumab (16, 23). In the phase III study, loss of PNGS was the primary genetic change associated with reduced susceptibility to ibalizumab, however, a reduced MPI from baseline was not predictive of virologic failure or rebound (3).

The activity of ibalizumab was also assessed over a 9-week period using pseudoviruses (23). The MPI values decreased from 89 to 99% to 33 to 83% in a number of samples during this time period. Susceptibility differences were noted in regard to the quantity of V5 PNGS, with the absence of PNGS having the strongest degree of resistance. In addition, this study determined that removal of specific locations of PNGS further affected susceptibility, with site 1 being absent most frequently in resistant variants. These findings were supported by Pace et al., who also determined that the location and number of V5 PNGS were the primary causes of decreased MPI values and increased resistance (16). Viruses with absent V5 N-terminal PNGS had significantly lower MPI values compared to V5 PNGS absent from other locations. Further reductions in MPI values occurred when this resistance mechanism was coupled with longer V2 loops, which suggests the V2 loop alteration may aid with viral binding despite the presence of CD4 T cell-bound ibalizumab.

Resistance has been observed to occur rapidly within 1 to 2 weeks in patients receiving ibalizumab as monotherapy (11). Decreased virologic response and concern for resistance has also been noted with one missed infusion in at least one case in the setting of 2,000-mg dosing every 4 weeks (21, 24). Furthermore, increased infective potential has been observed in vitro in the presence of ibalizumab resistance, which presents particular concern (23). There are no resistance testing methods that are commercially available currently for patients with suspected resistance to ibalizumab.

Cross resistance has not been reported between ibalizumab and other antiretroviral medications, including enfuvirtide and maraviroc (1). One study demonstrated that ibalizumab susceptibilities were not decreased in the presence of enfuvirtide-associated mutations (8). In fact, ibalizumab has previously exhibited synergistic antiretroviral activity against HIV-1 when coadministered with enfuvirtide in vitro (25).

No data currently exist for the use of ibalizumab in patients with HIV-2 infection. In addition, no studies specifically assessed the efficacy of ibalizumab in HIV-1 type N or O infection or in the different subtypes of HIV-1 type M infection. There is known genetic variability across the numerous subtypes of HIV-1 infection, with some clades demonstrating a higher propensity for select mutations (26, 27). Differences in the variable loops have been observed among the different subtypes, and alterations can occur as HIV-1 progresses from acute to chronic infection (28, 29). In theory, this could raise concern regarding the efficacy of ibalizumab based on virus subtype and disease progression. In addition, it has been demonstrated that chimpanzee CD4 T cell receptors are highly polymorphic (30). This diversity interferes with interactions between the receptor and the simian immunodeficiency virus envelope, which protects against viral entry. It is unclear whether these CD4 T cell receptor polymorphisms could affect ibalizumab efficacy in humans.

Specific patient populations.

(i) Obesity. An analysis was performed to determine the effect of body weight on the pharmacokinetics of ibalizumab (5). This analysis demonstrated that serum concentrations decreased as body weight increased, especially in patients weighing 85 kg or more. However, there was no significant difference observed in ibalizumab trough concentrations. Overall, body weight is unlikely to impact virologic outcomes, and overweight or obese patients do not warrant a dose adjustment.

(ii) Pregnancy and lactation. Adequate human data are lacking regarding the pregnancy risk involved with the utilization of ibalizumab (5). Animal reproductive studies with ibalizumab have also not been conducted. However, there is a potential for ibalizumab to be passed from mother to fetus, since it is known that other MAbs cross the placenta throughout the progression of pregnancy. Breastfeeding is not recommended if a woman is receiving ibalizumab since it is currently unknown whether ibalizumab passes through breast milk.

(iii) Pediatric and geriatric. The safety and efficacy of ibalizumab in pediatric and geriatric patients have not yet been evaluated (5).

Dosage, preparation, and administration.

Ibalizumab is FDA-approved as an IV infusion (5). It is available in single-dose vials containing a sterile colorless to slightly yellow and clear to slightly opalescent solution. The intact vials should be protected from light, refrigerated (2 to 8°C), and never frozen (−50 to −15°C). The single-dose vial delivers 200 mg of ibalizumab per 1.33 ml. Ibalizumab should be administered as a 2,000-mg loading dose, followed by maintenance doses of 800 mg every 14 days. When administered with other medications, including antiretrovirals, ibalizumab does not require a dose adjustment.

The appropriate dose of ibalizumab should be diluted in a 250-ml bag of 0.9% sodium chloride and infused immediately after dilution (5). If it is not infused immediately, the solution can be stored at room temperature (20 to 25°C) for up to 4 h or refrigerated for up to 24 h. Upon removal from refrigeration, the solution should be kept at room temperature for at least 30 min prior to infusion. Ibalizumab should never be administered as an i.v. push or bolus. The loading dose should be infused over at least 30 min, and patients should be monitored for 1 h following administration. If no infusion-related adverse effects occur, maintenance dose infusions can be administered over at least 15 min, and the patient monitoring time can be reduced to 15 min following administration. After administration, the i.v. line should be flushed with 30 ml of 0.9% sodium chloride. If an ibalizumab maintenance dose is missed by 3 days or more after the originally scheduled dosing day, the patient should receive another loading dose immediately. Maintenance dosing can then be continued every 14 days thereafter.

Practical considerations and future directions.

While the available clinical trial data provide important evidence to support the role of ibalizumab in the management of MDR HIV-1 infection, several key considerations remain regarding its use. TMB-301 was limited by its small sample size, the variability of baseline resistance profiles and OBRs among the trial participants, and the absence of a control group to evaluate longer-term virologic response (3). Many participants had extremely limited treatment options, as would be expected among likely ibalizumab recipients in clinical practice. However, nearly half of the trial participants received an experimental agent as part of their OBR, complicating the applicability of the results. Only 50% of patients achieved viral loads of <200 copies/ml by the end of the 25-week study period. Furthermore, virologic failure or rebound occurred in 25% of patients, highlighting the need for additional long-term efficacy and resistance data for ibalizumab. It is difficult to interpret these results fully without more information about the patients who experienced virologic failure, including their baseline resistance profiles and adherence to OBR throughout the trial. Another concern is the lack of commercially available genotypic or phenotypic resistance testing methods to assess ibalizumab resistance at baseline or when suspected. Nonetheless, it is fair to say that ibalizumab remains a salvage option in a challenging MDR HIV-1 patient population in combination with an OBR, and clinical success may not be guaranteed. Fortunately, from a safety perspective, ibalizumab was well tolerated with little evidence of significant treatment-associated adverse effects. Most reported adverse events were likely associated with the participants’ advanced HIV/AIDS.

As with many MAbs for high unmet medical needs, these agents are often associated with high costs and challenging circumstances for patient access. The average wholesale price for ibalizumab is estimated to be $1,024.06 for a 200 mg per 1.33-ml single dose vial, with an estimated wholesale annual acquisition cost of approximately $118,000 prior to considering the cost of the patient’s current OBR, as well as the staffing or facility costs associated with the provision of an infusion (2). Coverage by insurance plans is patient specific, and yet this is a small target population that will likely be approved for coverage with the limited alternative antiretroviral agents available. Patient support options are also currently available from the manufacturer. This potential cost burden should be considered when weighing the benefits and risks of ibalizumab use where limited treatment options may remain.

Ibalizumab may be administered in multiple settings, including outpatient clinics, infusion clinics, or the patient’s home. Various medical and social factors, including hospitalization, poor visit adherence, unstable housing, incarceration, and transportation barriers, may impact optimal use of this MAb. Guidance is provided for missed doses; however, in light of the current efficacy data, strict adherence to the recommended dosing schedule is wise but may not always be feasible in certain patient scenarios.

While ibalizumab has demonstrated advantageous properties and pharmacokinetic parameters, there are still areas for improvement that may potentially overcome some of the concerns and limitations to use. First, as with all antiretrovirals, resistance to ibalizumab has emerged despite its relatively limited time in clinical use, and currently there are no commercial tests for resistance testing available. An alteration to the structure of ibalizumab could expand its potential and reduce the development of resistance. The addition of a N-linked glycan to the light chain would help reduce the loss of PNGS in the V5 region of gp120 and restore activity in HIV-1 isolates that were resistant to the parent ibalizumab (19, 31). Second, the maintenance dose of ibalizumab is currently administered every 14 days (5). An extended half-life and a less frequent dosing interval could make this a more appealing option and increase patient compliance. Selected mutations in the heavy-chain region of ibalizumab could result in reduced degradation and allow the antibody-CD4 receptor complex to be reestablished on the cell surface resulting in a longer half-life (32).

Third, the potency of ibalizumab may be improved by combining this agent with other antiretroviral molecules to develop antibody-drug conjugates. Ibalizumab has previously been linked to the antibody recognizing the conserved m36 epitope of gp120 and has shown early potential (33). This area of therapeutics has already emerged in the treatment of certain types of cancer as well (34). Lastly, while ibalizumab is currently only approved for i.v. administration, a phase I/II placebo-controlled trial evaluated an intramuscular (i.m.) dosage form and demonstrated pharmacokinetics comparable to those for i.v. administration, with no observed injection site reactions or adverse effects related to the drug (11). The manufacturer plans to apply for a label extension from the i.v. to i.m. dosage form of ibalizumab with the same dosing regimen (http://www.taimedbiologics.com/pipeline/34). Subcutaneous (s.c.) administration has also been evaluated at a dose of 480 mg s.c. weekly for 4 weeks, which was well tolerated and achieved complete CD4 T cell receptor occupancy for at least 14 days after the final dose was administered (35). It is important to note the potentially large volume (approximately 5.3 ml to achieve an 800-mg maintenance dose) required for administration via either the i.m. or the s.c. route. Expansion of delivery options and extension of the half-life might also make ibalizumab an appealing agent to study for HIV prevention in preexposure prophylaxis, postexposure prophylaxis, and/or prevention of mother-to-child transmission. However, its current requirement for i.v. infusion makes these roles potentially less practical.

There is an urgent need for additional antiretroviral agents to construct active regimens in patients with MDR HIV-1. Since 2015, over 10 new agents have been approved by the FDA, and many of these exist as fixed-dose combination tablets (https://aidsinfo.nih.gov/understanding-hiv-aids/infographics/25/fda-approval-of-hiv-medicines). Bictegravir and doravirine are two of these newer agents that exhibit higher barriers to genetic resistance than their predecessors within the INSTI and NNRTI class, respectively (36). However, clinical studies were conducted in treatment-naive patients or in those without preexisting resistance; thus, their utility in patients with MDR HIV-1 infections is unknown. Additional ART options are in development that may also have a role in the management of treatment-experienced patients with MDR HIV-1 infection, including fostemsavir, which was used in 43% of patients in TMB-301 to construct an OBR with at least one fully active antiretroviral agent (3, 37). These future antiretroviral agents may play a competing role to build an optimized ART regimen for this complex and vulnerable patient population.

Ibalizumab (Trogarzo), a novel CD4-directed postattachment inhibitor, represents the first MAb that is FDA-approved for the management of MDR HIV-1 infection in patients who are failing their current ART regimen. In clinical studies, ibalizumab was well tolerated and demonstrated reasonably substantial antiretroviral activity among patients with advanced HIV-1 infection taking an OBR where limited treatment options are available. Although more data remain to be revealed by postmarketing experience and future studies, this agent is a welcome addition to the armamentarium for management of MDR HIV-1 infection where novel treatment options are needed.