TaiMed Biologics’ investigational monoclonal antibody ibalizumab led to significant reductions in viral load in patients with multidrug-resistant HIV when it was added to a failing drug regimen, according to results from a phase 3 trial.
According to a Healio report, researchers also said the drug, given intravenously once every 2 weeks, was safe and well-tolerated.
Dr Jacob Lalezari, medical director for Quest Clinical Research, based in San Francisco, said multidrug-resistant (MDR)-HIV infection is much less a problem today than it was 15 or 20 years ago, due to the “incredible success” of combination therapy. “This is really about the patients who got left behind,” Lalezari said during a press event at IDWeek 2016.
There are several ways in which patients can develop MDR-HIV infection, Lalezari said, including non-adherence to ART and methamphetamine use. Some patients, however, are “terminally unlucky” – those who are consistently assigned placebos in randomised clinical trials and then develop resistance to treatment, for example.
“This is not a rapidly expanding population, but rather a relatively small population who are in trouble,” he said.
Lalezari and colleagues conducted a single-arm study that included 40 treatment-experienced patients with MDR-HIV who were on a failing drug regimen. They monitored patients for 7 days during a control period and then intravenously administered a 2,000-mg loading dose of ibalizumab as monotherapy. They measured antiviral activity a week later, and patients were then started on an optimised background regimen (OBR) that included at least one sensitive agent. After day 14, patients continued to receive ibalizumab at 800 mg every 2 weeks for 24 weeks in combination with their OBR.
Patients in the study had lived with HIV infection, on average, for 21 years, and more than one in four were treated with at least 10 previous antiretroviral drugs. Half of the patients had resistance to all available drugs from at least three classes of ART.
According to Lalezari, the average CD4+ T-cell count was 160, half the patients had T-cell counts below 50, and one-third had T-cell counts below 10. “I think we can all agree that with T cells below 10, the clock is running down,” he said.
Results of the study demonstrated that 83% of patients achieved at least a 0.5 log10 decrease in HIV-1 RNA by day 14 – the study’s primary endpoint – compared with just one patient, or 3% of the total cohort, during the 7-day control period (P < .0001). Sixty percent of patients achieved a decrease in viral load of 1 log10 or greater (P < .0001). The average decrease in viral load after 7 days of therapy was 1.1 log10 (P < .0001) – and while this finding shows that ibalizumab is not potent enough to be used as a standalone agent, it is effective enough to be combined with other agents to improve outcomes in patients with MDR-HIV, Lalezari said.
There were no treatment-related serious adverse events or discontinuations by day 14, according to the researchers.
Resistance can develop against entry inhibitors like ibalizumab, but its resistance mutations do not overlap with other drugs in the same class, Lalezari said. “It’s a new tool to try to suppress virus in patients who are in need of rescue therapy,” he added. “The drug worked.”
Humanised monoclonal antibody therapy has also shown promise in other studies, both as monotherapy and in combination with ART. In a small phase 2b trial, 10 of 15 patients who replaced their daily oral ART regimens with a monoclonal antibody called PRO 140 had maintained viral suppression for up to 1.5 years.
In 2014, ibalizumab was granted orphan drug status, and it was given breakthrough therapy designation by the US Food and Drug Administration in 2015.
PRO 140 belongs to a new class of HIV/AIDS therapeutics — viral-entry inhibitors — that are intended to protect healthy cells from viral infection. PRO 140 is a fully humanized IgG4 monoclonal antibody directed against CCR5, a molecular portal that HIV uses to enter T-cells. PRO 140 blocks the predominant HIV (R5) subtype entry into T-cells by masking this required co-receptor, CCR5. Importantly PRO 140 does not appear to interfere with the normal function of CCR5 in mediating immune responses.
Jay Lalezari, Kush Dhody, Ula Kowalczyk, Kazem Kazempour, Nader Pourhassan, Paul J Maddon