On March 6, 2018, the FDA approved TROGARZO (ibalizumab-uiyk) injection, for intravenous use for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced adults with multidrug resistant (MDR) HIV-1 infection failing their current antiretroviral regimen. TROGARZO, 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
TROGARZO is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications. Patients should receive a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks.
A total of 292 patients with HIV-1 infection have been exposed to TROGARZO IV infusion. The most common adverse reactions to TROGARZO were diarrhea, dizziness, nausea and rash. Severe side effects included rash and changes in the immune system (immune reconstitution syndrome).
The safety and efficacy of TROGARZO were evaluated in a clinical trial of 40 heavily treatment-experienced patients with MDR HIV-1 who continued to have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs. Many of the participants had previously been treated with ten or more antiretroviral drugs. The majority of participants experienced a significant decrease in their HIV-RNA levels one week after TROGARZO was added to their failing antiretroviral regimens. After 24 weeks of TROGARZO plus other antiretroviral drugs, 43 percent of the trial’s participants achieved HIV RNA suppression.
The clinical trial focused on the small patient population with limited treatment options and demonstrated the benefit of TROGARZO in achieving reduction of HIV RNA. The seriousness of the disease, the need to individualize other drugs in the treatment regimen, and safety data from other trials were considered in evaluating the TROGARZO development program.
Clinical Trial Results
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 (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 (i.e., in the last 8 weeks) therapy.
The trial was composed of three discrete periods:
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 McNemar’s 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.
TROGARZO is administered intravenously once every 14 days by a trained medical professional and used in combination with other antiretroviral medications. Patients should receive a single loading dose of 2,000 mg followed by a maintenance dose of 800 mg every 2 weeks.
A total of 292 patients with HIV-1 infection have been exposed to TROGARZO IV infusion. The most common adverse reactions to TROGARZO were diarrhea, dizziness, nausea and rash. Severe side effects included rash and changes in the immune system (immune reconstitution syndrome).
The safety and efficacy of TROGARZO were evaluated in a clinical trial of 40 heavily treatment-experienced patients with MDR HIV-1 who continued to have high levels of virus (HIV-RNA) in their blood despite being on antiretroviral drugs. Many of the participants had previously been treated with ten or more antiretroviral drugs. The majority of participants experienced a significant decrease in their HIV-RNA levels one week after TROGARZO was added to their failing antiretroviral regimens. After 24 weeks of TROGARZO plus other antiretroviral drugs, 43 percent of the trial’s participants achieved HIV RNA suppression.
The clinical trial focused on the small patient population with limited treatment options and demonstrated the benefit of TROGARZO in achieving reduction of HIV RNA. The seriousness of the disease, the need to individualize other drugs in the treatment regimen, and safety data from other trials were considered in evaluating the TROGARZO development program.
Clinical Trial Results
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 (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 (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 subject’s 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 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
| Proportion of Subjects Achieving a ≥ 0.5 log10 Decrease in Viral Load N=40 | 95% CI* | |
| End of Control Period | 3% | (0.06%, 13%) |
| End of Functional Monotherapy Period | 83% | (67%, 93%) |
p < 0.0001 based on McNemar’s 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
| TROGARZO (N=40) | |
| HIV RNA < 50 copies/mL at Week 25 | 43% |
| HIV RNA ≥ 50 copies/mL at Week 25* | 45% |
| HIV RNA < 200 copies/mL at Week 25 | 50% |
| HIV RNA ≥ 200 copies/mL at Week 25** | 38% |
| No virologic data at Week 25 | |
| Discontinued due to AE or death | 13% |
**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*
| Subjects achieving < 50 HIV-1 RNA copies/mL (%) | Subjects achieving < 200 HIV-1 RNA copies/mL (%) | |
| CD4 Cell Counts
< 50 (n=17)
50-200 (n=10) > 200 (n=13) | 18 60 62 | 24 70 69 |
| Viral Load
≤100,000 (n=33)
> 100,000 (n=7) | 49 14 | 58 14 |
| Resistance
With INSTI Resistance (n=27)
Without INSTI Resistance (n=13) | 41 46 | 44 62 |
| OSS
0 (n=5)
1 (n=12) 2 (n=18) 3 (n=3) 4 (n=2) | 20 42 50 33 50 | 20 50 61 33 50 |
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.
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Division of Antiviral Products
Food and Drug Administration
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