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|Ibalizumab (TMB-355) Intravenous Infusion||
Ibalizumab (TMB-355) Intravenous Infusion
Ibalizumab (TMB-355) is the first humanized monoclonal antibody (mAb) developed for the treatment of HIV-1 infection by blocking viral entry. Unlike other antiretroviral agents, ibalizumab binds to the second extracellular domain of the CD4 receptor, away from Major Histocompatibility Complex II molecule (MHC II) binding sites, ultimately interfering with post-attachment steps required for entry of HIV-1 virus particles into host cells and preventing the viral transmission that occurs via cell-cell fusion. It prevents HIV from infecting CD4+ immune cells while preserving normal immunological function. Intravenous ibalizumab was launched in the US in 2018 under the trade name Trogarzo™.
Ibalizumab Intravenous Infusion Dosage Form Development
Ibalizumab caught the attention of the scientific community in 2003, when results from the phase-1, single-dose, intravenous (i.v.) infusion clinical trial showed a transient but clinically significant reduction in the patients’ viral load. Moreover, no evidence of adverse effects on CD4 T-cell function of the treated subjects were reported and ibalizumab was well tolerated unlike the majority of approved drugs for HIV. U.S. FDA granted ibalizumab fast track status in October 2003. The phase-2a clinical trial was successfully completed in 2006, with the results showing a clean safety profile and clear antiviral activity (10-fold reduction in viral load). The phase-2b clinical trial was also successfully completed in 2011, with the confirmation of a good safety profile and strong antiviral activity in HIV patients with multidrug resistance (MDR). U.S. FDA granted orphan drug designation of ibalizumab for HIV patients with multidrug resistance in 2014. Moreover, TaiMed received breakthrough therapy designation from the U.S. FDA for ibalizumab i.v. in 2015, which provides the privilege for a rolling biologics license application (BLA) submission. A pivotal phase-3, single-arm clinical trial with patient number of 40 was completed in 2016. The BLA was fully submitted in June 2017, and approved in March 2018.
Ibalizumab Intravenous Infusion Clinical Results
Phase 3 Trial
The Phase 3 trial was a single-arm, 24-week study of ibalizumab plus optimized background regimen (OBR) in 40 treatment-experienced patients infected with multi-drug resistant HIV-1. The primary objective of the study was to demonstrate the antiviral activity of ibalizumab seven days after the first dose of ibalizumab. Patients receiving their current failing antiretroviral therapy (ART), or no therapy, were monitored during a 7-day control period. Thereafter a loading dose of 2,000mg of i.v. ibalizumab was the only ART added to their regimen. The primary efficacy endpoint was the proportion of patients achieving a ≥ 0.5 log10 decrease in HIV-1 RNA seven days after initiating ibalizumab therapy, day 14 of the study. Ibalizumab was continued at doses of 800 mg i.v. every two weeks through 24 weeks on study treatment.
The primary endpointshowed the 82.5% of patients achieved more than ~3-fold reduction (0.5 log reduction) in vial load 7 days after loading dose. A significant decrease in viral load after receiving a loading dose of ibalizumab 2,000 mg intravenously in addition to their failing ART (or no therapy). At the completion of the 24-week study, the viral load decreases were maintained for a period of 23 weeks after starting the OBR. After 24 weeks of treatment, the mean reduction in viral load was 1.6 log10 (to 3% of baseline viral load) and a total of 48% of patients had a reduction in viral load of more than 2.0 log10 (to 1% of baseline viral load). At the end of the treatment period the proportion of study participants with undetectable viral load (HIV-1 <50 copies/mL) was 43% (mean viral load reduction of 3.1 log10, to 0.08% of baseline viral load) and 50% of patients had a viral load lower than 200 copies/mL.
A mean increase in CD4+ T cell of 48 cells/µL was observed. When subdivided by CD4+ cell count at baseline, patients with a lower CD4+ T cell count at baseline those with the lowest count (<50 CD4+ T cells/µL, 17 patients) had an increase of 9, those with 50-200 CD4+ T cells/µL (10 patients) had an increase of 75 cells/µL and those with >200 CD4+ T cells/µL (13 patients) had an increase of 78 cells/ µL. The safety results in this Phase 3 trial are consistent with previously observed in the Phase 2b study. Other than for one case of immune reconstitution inflammatory syndrome, an inflammatory response in HIV-infected patients that may be triggered after changing to more active antiretroviral therapy (ART), no serious adverse events (SAEs) were considered to be related to ibalizumab. Most treatment-emergent adverse events reported were mild to moderate in severity. No notable trends in laboratory abnormalities were observed. Additionally, no anti-ibalizumab antibodies were detected in any blood samples of patients.
Patients enrolled in the Phase III trial had high pre-existing levels of drug resistance and advanced clinical disease. Patients had a mean HIV-1 viral load of 100,287 copies/mL, with 18% having viral loads above 100,000 copies/mL. The median CD4 count was 73 cells/mm3 and nearly 30% had less than 10 CD4 cells/mm3. More than 85% of patients had more than one identified mutation conferring resistance to the Nucleoside Reverse Transcriptase Inhibitors (NRTI), Non Nucleoside Reverse Transcriptase Inhibitors (NNRTI) or Protease Inhibitors (PI) and more than 60% of patients had resistance to at least one Integrase Inhibitor (INI). Study patients were infected with HIV-1 resistant to more than 75% of all drugs in the NRTI, NNRTI and PI classes and to 1-2 drugs from the INI class, on average. Finally, just over 50% of patients had HIV-1 with resistance to all available drugs from at least three classes of ART.
Phase 2b Trial
In the phase-2b clinical trial with 113 HIV MDR patients, the safety and the efficacy profiles were observed and confirmed. In combination of OBR, both dose groups (2000 mg q4w and 800 mg q2w) of ibalizumab resulted in more than 10-fold reduction in viral load in 60% of overall patients with no drug-related serious adverse events. Undetectable viral load (<50 copies/mL) was observed in 36% of overall patients (ITT-MEF). Ibalizumab was well tolerated with the comment adverse events of rash and nausea which are manageable.
Phase 2a Trial
Ibalizumab i.v. infusion dosage form has demonstrated not only a clean safety profile but has also proven efficacious in HIV+ MDR patients. Compared to placebo, ibalizumab in combination with OBR resulted in statistically significant viral load reduction and clinically meaningful increases in CD4+ cell count in the phase-2a clinical trial with treatment-experienced HIV patients. Ibalizumab was well tolerated with no infusion-site reactions, no serious adverse events, and no laboratory abnormalities. In addition, good patient adherence to study visits and acceptance of intravenous administration were observed.
2003: Completion of a phase-1a clinical trial for i.v. infusion dosage form.
2003: Fast track status granted by U.S. FDA.
2003: Completion of a phase-1b clinical trial for i.v. infusion dosage form.
2006: Completion of a phase-2a clinical trial for i.v. infusion dosage form.
2011: Completion of a phase-2b clinical trial for i.v. infusion dosage form.
2014: Orphan drug designation granted for HIV MDR patients by U.S. FDA.
2015: Breakthrough therapy designation granted for i.v. infusion dosage form on HIV MDR patients by U.S. FDA.
2016: Initiation of rolling BLA submission for i.v. infusion dosage to U.S FDA.
2016: Completion of a phase-3 clinical trial for i.v. infusion dosage form.
2017: Completion of BLA submission and pre-approval inspection for i.v. infusion dosage form to U.S. FDA.
2018: U.S. market approval (Brand name: Trogarzo).