TROGARZO Solution for injection Ref.[10292] Active ingredients: Ibalizumab

A clear trend was identified between exposure and response rate for the Phase 2b trial (TMB-202) which studied two different intravenous doses given at two different dosing intervals (every 4 weeks vs. every 2 weeks). The recommended intravenous dosing regimen consisting of a 2,000 mg loading dose followed by a maintenance dose of 800 mg every 2 weeks was selected on the basis of these results.

Ibalizumab-uiyk administered as a single agent exhibits nonlinear pharmacokinetics. Following single-dose administrations of ibalizumab-uiyk as 0.5 to 1.5-hour infusions, the area under the concentration-time curve increased in a greater than dose-proportional manner, clearance decreased from 9.54 to 0.36 mL/h/kg and elimination half-life increased from 2.7 to 64 hours as the dose increased from 0.3 to 25 mg/kg. The volume of distribution of ibalizumab-uiyk was approximately that of serum volume, at 4.8 L.

Following the recommended dose regimen (a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks), ibalizumab-uiyk concentrations reached steady-state levels after the first 800 mg maintenance dose with mean concentrations over 30 mcg/mL throughout the dosing interval.

Specific Populations

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 result suggests that ibalizumab-uiyk concentration decreases as body weight increases; however, the effect is unlikely to impact virologic outcome and does not warrant a dose adjustment.

Pediatric/Geriatric Patients

Ibalizumab-uiyk pharmacokinetics have not been evaluated in pediatric or geriatric patients [see Use in Specific Populations (8.4, 8.5)].

Renal/Hepatic Impairment

No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of ibalizumab-uiyk. Renal impairment is not anticipated to impact the pharmacokinetics of ibalizumab-uiyk.

Drug Interaction studies

No drug interaction studies have been conducted with ibalizumab-uiyk. Based on ibalizumab-uiyk’s mechanism of action and target-mediated drug disposition, drug-drug interactions are not expected.

Mechanism of Action

Ibalizumab-uiyk, a recombinant humanized monoclonal antibody, blocks 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.

Ibalizumab-uiyk Does Not Impact CD4 Function

The binding specificity of ibalizumab-uiyk to domain 2 of CD4 allows ibalizumab-uiyk to block viral entry into host cells without causing immunosuppression. Epitope mapping studies indicate that ibalizumab-uiyk binds to a conformational epitope located primarily in domain 2 of the extracellular portion of the CD4 receptor. This epitope is positioned on the surface of CD4 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. Additionally, ibalizumab-uiyk does not interfere with gp120 attachment to CD4.

Antiviral Activity

Ibalizumab-uiyk inhibits the replication of CCR5- and CXCR4-tropic laboratory strains and primary isolates of HIV-1 in phytohemagglutinin stimulated peripheral blood lymphocytes. The median EC₅₀ value (50% effective concentration) for ibalizumab-uiyk against HIV-1 group M isolates (subtypes A, B, C, D, E, or O) was 8 ng/mL (n=15, range of 0.4 to 600 ng/mL) in cell culture, with lower susceptibility observed in macrophage-tropic HIV-1 strains (BaL, JR-CSF, YU2, and ADA-M). In a single-cycle infection assay, ibalizumab-uiyk inhibited 17 clinical isolates of subtype B with a median EC₅₀ value of 12 ng/mL (range of 8.8 to 16.9 ng/mL; mean 12 ± 3 ng/mL) and a median maximum percentage inhibition (MPI) of 97% (range of 89 to 99%; mean 97 ± 3%). Three CCR5-tropic clinical isolates from subtypes B, C, and D, were inhibited with EC₅₀ values ranging from 59-66 ng/mL and 3 CXCR4-tropic clinical isolates from subtypes B, C, and D, with EC₅₀ values ranging from 44-59 ng/mL.

Antiviral Activity in Combination with Other Antiviral Agents

No antagonism was observed when PBMCs or MAGI-CCR5 cells infected with the subtype B Ba-L or ADA variants of HIV-1 were incubated with ibalizumab-uiyk in combination with the CCR5 co-receptor antagonist maraviroc or when PBMCs infected with the subtype B HT/92/599 variant of HIV-1 were incubated with ibalizumab-uiyk in combination with the gp41 fusion inhibitor enfuvirtide; a nonnucleoside reverse transcriptase inhibitor (efavirenz); nucleoside analog reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, tenofovir, or zidovudine); or a protease inhibitor (atazanavir).

Antiviral Activity in Antiretroviral-Resistant Virus

Subjects enrolled in TMB-301 were heavily treatment-experienced subjects infected with multidrug resistant HIV-1. Ibalizumab-uiyk inhibited 38 baseline isolates at a median EC₅₀ value of 31 ng/mL (range of 13 to 212 ng/mL; mean 39 ± 35 ng/mL) with a median MPI of 97% (range of 41-100%; mean 91 ± 14%). For 10 subjects in TMB-301 who failed treatment, at the time of failure the median ibalizumab-uiyk EC₅₀ value was 566 ng/mL (range of 148 to >54,900 ng/mL; mean 11,768 ± 21,650 ng/mL) representing an EC₅₀ value shift of >18-fold. For the HIV-1 derived from the same subjects, the median MPI was 55% (range of 43-72%; mean 56 ± 8%) representing a 42 percentage point reduction.

Decreased Susceptibility

Decreased susceptibility to ibalizumab-uiyk, as defined by a decrease in MPI, has been observed in some subjects experiencing virologic failure and may be associated with genotypic changes in the HIV-1 envelope coding sequence that results in the loss of potential N-linked glycosylation sites (PNGS) in the V5 loop of gp120. The clinical significance of decreased susceptibility to ibalizumab-uiyk has not been established.

Cross-Resistance

Phenotypic and genotypic test results revealed no evidence of cross-resistance between ibalizumab-uiyk and any of the approved classes of anti-retroviral drugs (CCR5 co-receptor antagonists, gp41 fusion inhibitors, integrase strand transfer inhibitors [INSTIs], non-nucleos(t)ide reverse transcriptase inhibitors [NNRTIs], nucleos(t)ide reverse transcriptase inhibitors [NRTIs], or protease inhibitors [PIs]). Ibalizumab-uiyk is active against HIV-1 resistant to all approved antiretroviral agents and exhibits antiretroviral activity against R5-tropic, X4-tropic, and dual-tropic HIV-1.

Decreased susceptibility to ibalizumab-uiyk following multiple dose administrations of ibalizumab-uiyk has been observed in some subjects. Cell culture studies performed with HIV-1 variants with reduced susceptibility to ibalizumab-uiyk indicate that phenotypic changes associated with resistance to ibalizumab-uiyk do not alter susceptibility to other approved agents and do not result in the selection of CD4-independent viral isolates.

CD4 Polymorphisms and Ibalizumab-uiyk Activity

CD4 polymorphisms reported in public databases were analyzed to determine if any naturally occurring amino acid substitutions in the CD4 molecule from different human populations would potentially impact the antiviral activity of ibalizumab-uiyk. None of the known CD4 polymorphisms are likely to have an impact on ibalizumab-uiyk binding to CD4.

Carcinogenesis, mutagenesis, and reproductive toxicology studies with ibalizumab-uiyk have not been conducted.

Trial TMB-301

Trial TMB-301 was 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 one antiretroviral medication from each of three classes of antiretroviral medications as measured by resistance testing. Subjects must have been treated with antiretrovirals for at least 6 months and be failing or had recently failed (i.e., in the last 8 weeks) therapy.

The trial was composed of three discrete periods:

• Control period (Day 0 to Day 6): Subjects were either monitored on their current failing therapy or received no therapy if they had failed and discontinued treatment within the 8 weeks preceding screening. This was an observational period to establish baseline HIV viral load.
• Functional monotherapy period (Day 7 to Day 13): All subjects received a 2,000 mg loading dose of TROGARZO on Day 7. Subjects on a failing ART regimen continued to receive their failing regimen in addition to the loading dose of TROGARZO. This period was to establish the virologic activity of TROGARZO.
• Maintenance period (Day 14 to Week 25): On Day 14 of the treatment period, viral load was assessed for the primary endpoint, and thereafter the background regimen was optimized to include at least one drug to which the subjects virus was susceptible. The use of an investigational drug(s) as a component of the optimized background regimen was allowed. Beginning at Day 21, an 800 mg maintenance dose of TROGARZO was administered every two weeks through Week 25. This period was to establish the safety and durability of virologic suppression of TROGARZO when used in combination with an optimized background regimen.

The majority of subjects in Trial TMB-301 were male (85%), white (55%) and between 23 and 65 years of age (mean [SD] age: 50.5 [11.0] years). At Baseline, median viral load and CD4⁺ T cell counts were 35,350 copies/mL and 73 cells/mm³, respectively. The subjects were heavily treatment-experienced: 53% of participants had been treated with 10 or more antiretroviral drugs prior to trial enrollment; 98% percent had been treated with NRTIs, 98% with PIs, 80% with NNRTIs, 78% with INSTIs, 30% with gp41 fusion inhibitors, and 20% with CCR5 co-receptor antagonists.

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 “Functional monotherapy period” as compared to the proportion of subjects achieving a ≥0.5 log₁₀ decrease from the beginning to the end of the “Control period”, as defined above. The results of the primary endpoint analysis are shown in Table 4 below.

Table 4. Proportion of Subjects Achieving a ≥0.5 log₁₀ Decrease in Viral Load at the End of the Control and Functional Monotherapy Periods:

* exact 95% confidence interval

p<0.0001 based on McNemars test comparing the proportion of subjects achieving ≥0.5 log₁₀ decrease in viral load at the end of the control and functional monotherapy periods.

At Week 25, viral load <50 and <200 HIV-1 RNA copies/mL was achieved in 43% and 50% of subjects, respectively. Fifty-five percent of subjects had a ≥1 log₁₀ reduction in viral load, and 48% of subjects had a ≥2 log₁₀ reduction in viral load at Week 25. An increase in the mean and median number of CD4⁺ T-cells (44 cells/mm³ and 17 cells/mm³, respectively) was observed from Baseline to Week 25. Week 25 outcomes are shown in Table 5 and Table 6.

Table 5. Trial TMB 301 Virologic Outcomes (Snapshot Algorithm) at Week 25:

* included subjects who had ≥50 copies/mL in the Week 25 window, subjects who discontinued study drug due to lack of efficacy, and subjects who discontinued study drug for reasons other than an AE, death and at the time of discontinuation had a viral value ≥50 copies/mL
^† included subjects who had ≥200 copies/mL in the Week 25 window, subjects who discontinued study drug due to lack of efficacy, and subjects who discontinued study drug for reasons other than an AE, death and at the time of discontinuation had a viral value ≥200 copies/mL

Table 6. Virologic Response at Week 25 by Baseline CD4 Cell count, Viral Load, Integrase Inhibitor Resistance and OSS*:

* OSS – Overall Susceptibility Score. The OSS indicates the number of fully active drugs in a subject’s OBR based on both current and available historical resistance test results. Demonstrating drug susceptibility by both genotypic and phenotypic testing was required, when testing by both methods was technically feasible. As an example, an OSS of 2 would indicate that the HIV-1 isolate tested was fully susceptible to two drugs in the OBR.