Half of participants taking the monoclonal antibody ibalizumab in a small phase 3 trial reached a viral load below 200 copies in 24 weeks despite multidrug-resistant HIV and high pretreatment loads . Half cut their viral load more than 100-fold, and 43% reached a load below 50 copies. Nine of 40 in this group with advanced HIV failed to complete 24 weeks of study.
Ibalizumab is a humanized monoclonal antibody that aims to block HIV entry to CD4 cells by binding to extracellular domain 2 of the CD4 receptor . This docking site lies away from the site for major histocompatibility complex (MHC) class II molecules, so ibalizumab should not upset immune responses governed by MHC II.
The single-arm phase 3 trial, TMB-301, enrolled 40 adults with resistance to at least one antiretroviral in 3 classes, at least 6 months of antiretroviral experience, and a viral load above 1000 copies on their current regimen . They needed an HIV strain susceptible to at least one antiretroviral other than ibalizumab. Participants had a life expectancy exceeding 6 months and could have no active AIDS disease in the past 3 months other than cutaneous Kaposi sarcoma or wasting.
For 7 days participants continued their failing regimen then added an intravenous 2000-mg loading dose of ibalizumab. Seven days later participants began receiving an optimized background regimen; 7 days after that they started an intravenous 800-mg dose of ibalizumab once every 2 weeks. The primary endpoint was proportion of participants with at least a 0.5-log10 viral load drop at day 14 (7 days after adding ibalizumab alone to the failing regimen). Secondary endpoints included proportions of people with a viral load below 50 or 400 copies after 24 weeks of ibalizumab plus the optimized background regimen.
Of the 40 trial participants, 85% were men and 45% nonwhite. Age averaged 51 years, viral load averaged 100,287 copies, median CD4 count stood at 73, and 43% had a CD4 count below 50. More than 85% of these people had HIV with more than 1 mutation conferring resistance to nucleosides, nonnucleosides, and protease inhibitors, and two thirds had resistance to integrase inhibitors. Just over half of participants had exhausted 3 antiretroviral classes. Seventeen people (43%) used another investigational antiretroviral, the fusion inhibitor fostemsavir , in their background regimen.
Thirty-three of 40 participants (83%) met the primary endpoint, trimming their viral load at least 0.5 log10 after 7 days of ibalizumab alone atop their failing combination (P < 0.0001). After 24 weeks of ibalizumab plus an optimized regimen, viral loads dropped by an average 1.6 log10 (about 40-fold). Nineteen people (48%) cut their viral load more than 100-fold, 20 (50%) reached a load below 200 copies, and 17 (43%) got their viral load under 50 copies.
One case of immune reconstitution inflammatory syndrome developed and led to discontinuation, but no serious adverse events were attributed to ibalizumab. Nine of 40 people (21%) dropped out of the study, including 4 people who died for reasons not related to study drugs, 3 people who withdrew, and 2 people who stopped returning for study visits. Anti-ibalizumab antibodies did not develop in anybody.
Study participants and other people with limited antiretroviral options may join an expanded-access study, TMB-311 . Enrollees must be adults with a viral load above 1000 copies either on a failing regimen or off therapy after failure. They must have HIV resistant to at least one drug in three antiretroviral classes. Ibalizumab developers are studying intramuscular dosing of this novel agent .
- Lewis S, Fessel J, Emu B, et al. Long-acting ibalizumab in patients with multi-drug resistant HIV-1: a 24-week study. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 449LB.
- AIDSinfo Drug Database. Ibalizumab. https://aidsinfo.nih.gov/drugs/511/ibalizumab/0/professional
- ClinicalTrials.gov. Ibalizumab plus optimized background regimen in patient with multi-drug resistant HIV. ClinicalTrials.gov identifier NCT02475629. https://clinicaltrials.gov/ct2/show/NCT02475629
- AIDSinfo Drug Database. Fostemsavir. https://aidsinfo.nih.gov/drugs/508/fostemsavir/0/patient
- ClinicalTrials.gov. Ibalizumab plus optimized background regimen in treatment-experienced patients with multi-drug resistant HIV-1. ClinicalTrials.gov identifier NCT02707861. https://clinicaltrials.gov/ct2/show/NCT02707861
- Lin HH, Lee SSJ, Wang NC, et al. Intramuscular ibalizumab: pharmacokinetics, safety, and efficacy vs IV administration. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 438.