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For people with drug resistant HIV, monoclonal antibody shows promise as “rescue” therapy

, by Liz Highleyman

Most people living with HIV are successfully able to suppress their viral loads to undetectable levels with modern combination antiretroviral therapy. But a small proportion of people, who have extensive drug resistance, are unable to maintain undetectable viral loads on currently available HIV treatments. A recent study, of a monoclonal antibody therapy, showed promise for a small group of people with highly drug-resistant HIV.

Jay Lalezari, MD

Jay Lalezari, MD

At the IDWeek 2016 conference this month in New Orleans, Jay Lalezari, MD, from Quest Clinical Research in San Francisco presented results from a Phase 3 trial evaluating ibalizumab, the first biologic therapy for HIV treatment (abstract LB-6).

Ibalizumab (also known as TMB-355 and previously as TNX-355) is a monoclonal antibody that targets a human protein—the CD4 protein on the surface of T-cells—rather than attacking HIV directly. The antibody binds to CD4 and prevents the virus from entering susceptible cells.

Ibalizumab has been in development for more than a decade. Earlier studies showed that it has a unique resistance profile, works against HIV that has developed resistant to older antiretrovirals, and does not interact with other drugs.

Dr. Lalezari estimated that less than 5% of people living with HIV are unable to maintain an undetectable viral load due to extensive drug resistance. Although this group may be small percentage-wise, he estimates that the total number of people is in the thousands. Because this group is small and dwindling, pharmaceutical companies generally do not devote much effort to so-called “salvage” or “rescue” therapy.

“By and large, the great majority of our HIV patients are doing fine—this is about the patients who are left behind,” Dr. Lalezari said. “This group is not large in number, but they are extremely vulnerable.”

For this reason, after the antibody demonstrated good safety and modest efficacy in a previous Phase 2 study, the U.S. Food and Drug Administration gave it orphan drug status and a “breakthrough therapy” designation.

The Phase 3 study presented at IDWeek enrolled 40 heavily treatment-experienced participants with documented resistance to at least one drug from three antiretroviral classes. However, they had to have at least one other active drug—in many cases this was another experimental therapy—to use in an optimized background regimen with ibalizumab.

Most study participants were men and the median age was 51 years. On average, participants had been living with HIV for over 20 years. They were unable to maintain viral suppression on their current ART regimen and had a viral load above 1,000 copies/mL, with a median level of 100,000 copies/mL. The average CD4 count was just 160 cells/mm3, with a third having less than 10 cells/mm3, indicating they were in perilous health.

After a six-day observation period, all participants in this open label study received a 2,000 mg “loading dose” of ibalizumab as an intravenous infusion while remaining on their failing regimen —that is, the antibody was essentially used as monotherapy for seven days. They then started on an optimized background regimen containing at least one other active drug, as determined by resistance testing. They received a second 800 mg infusion of ibalizumab on day 21 and then every other week until week 23.

At day 14—seven days after the initial ibalizumab dose—viral load decreased by an average of 1.1 log. Four out of five participants (83%) had at least a 0.5 log drop in HIV RNA, while 60% had a decrease of 1.0 log or more.

Ibalizumab was generally safe and well tolerated, with no treatment-related serious adverse events or early discontinuations. The most commonly reported adverse events were dizziness (10%), fatigue (5%), nausea or vomiting (5%), and rash (2.5%).

Dr. Lalezari said that while this is not the most potent drug we’ve seen, “it’s pretty good, and in the setting of multidrug resistance it’s very good—maybe the best we have.”

Ibalizumab is one of the first long-acting injectable therapies for HIV (researchers are working on others including cabotegravir). While ibalizumab’s biweekly dosing schedule is appealing, intravenous infusions must be done by a medical provider and can be expensive. Dr. Lalezari predicted that ibalizumab would fill a niche for difficult-to-treat patients, rather than playing a major role in first-line HIV treatment.

Liz Highleyman is a freelance medical writer and editor of HIVandHepatitis.com.

 

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