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IDWeek 2016: Ibalizumab Monoclonal Antibody Looks Promising for HIV Patients Left Behind

Ibalizumab, an experimental antiretroviral agent that works differently than existing HIV drugs, demonstrated promising safety and antiviral activity in a small Phase 3 study of people with highly drug-resistant virus, according to a report at the IDWeek conference this week in New Orleans. If confirmed in larger studies, this could be good news for HIV patients who cannot be successfully treated using available therapies.

While most people with HIV do well on modern antiretroviral therapy (ART), a small proportion are unable to achieve and maintain undetectable viral load, usually due to extensive drug resistance. In some cases this is attributable to poor adherence, but other people developed extensive resistance due to using suboptimal drugs in incomplete regimens earlier in the epidemic. Because the number of patients in this category is small and dwindling, pharmaceutical companies generally do not devote much effort to so-called salvage or rescue therapy.

Ibalizumab (TMB-355), being developed TaiMed Biologics, is the first biologic drug for HIV. It is a monoclonal antibody that targets a human protein rather than attacking the virus directly. The antibody binds to the CD4 protein on the surface of T-cells. This does not prevent HIV from attaching to the cell surface, but rather blocks a conformational change that allows the virus to enter the cell.

Ibalizumab has been in development for more than a decade, previously under the auspices of Tanox (where it was known as TNX-355). Early studies showed that it has a unique resistance profile and works against HIV that is resistant to older antiretrovirals. It is not metabolized by the liver or kidneys and does not interact with other drugs.

After the antibody demonstrated modest efficacy in a previous Phase 2 study,the U.S. Food and Drug Administration (FDA) gave it orphan drug status and a breakthrough therapy designation.

At a late-breaker abstract session at IDWeek, Jay Lalezari from Quest Clinical Research in San Francisco presented results from a small Phase 3 trial evaluating the efficacy of ibalizumab for people who were unable to maintain viral suppression on their current antiretroviral regimen.

The study enrolled 40 heavily treatment-experienced participants; a quarter had used more than 10 previous antiretrovirals. They had documented resistance to at least 1 drug from 3 antiretroviral classes, but they needed to have at least 1 active drug available to use in an optimized background regimen; for about a third of patients this meant using another investigational agent such as the attachment inhibitor fostemsavir.

Most study participants (85%) were men, more than half were white, the median age was 51 years, and they'd had HIV for over 20 years on average. At baseline they had a viral load above 1000 copies/mL, with a median level of 100,000. The average CD4 T-cell count was just 160 cells/mm³ -- with a third having less than 10 cells/mm³ -- indicating that many were in "perilous" health, Lalezari said.

After a 6-day observation period, participants received a 2000 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 7 days.

The primary study endpoint was the proportion of people with at least a 0.5 log drop in viral load by day 14. At that point they switched to an optimized background regimen determined by resistance testing. They received a second lower-dose infusion of 800 mg ibalizumab on day 21 and then every other week until week 23.

Results

• At day 14 -- 7 days after the initial ibalizumab dose -- viral load decreased by an average of 1.1 log.
• During this monotherapy period 83% of patients had at least a 0.5 log drop, while 60% had a decrease of 1.0 log or more.
• In contrast, only 1 participant saw a significant viral load decline during the observation period before starting ibalizumab.
• Ibalizumab was generally safe and well-tolerated, with no treatment-related serious adverse events or early discontinuations.
• The most common adverse events were dizziness (10%), fatigue (5%), nausea or vomiting (5%), and rash (2.5%).

Ibalizumab is one of the first long-acting injectable therapies for HIV. Although its biweekly dosing is appealing, Lalezari predicted that it would fill a niche for difficult-to-treat patients, rather than playing a major role in first-line therapy.

"This is not the most potent drug we've seen, but it's pretty good, and in the setting of multidrug resistance it's very good -- maybe the best we have," Lalezari said.

While ibalizumab may not have a large market, Lalezari gave the FDA credit for advancing a new treatment for people who do not benefit from existing HIV therapies, and to the activist community for continuing to push it forward.

He estimated that less that 5% of people with HIV -- a number in the thousands -- are unable to achieve viral suppression on ART. Some individuals in this situation are already receiving ibalizumab through an expanded access program.

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

10/29/16

Sources

J Lalezari, WJ Fessel,S Schrader, et al. Primary Efficacy Endpoint and Safety Results of Ibalizumab (IBA) in a Phase 3 Study of Heavily Treatment-Experienced Patients with Multi-Drug Resistant (MDR) HIV-1 Infection. IDWeek. New Orleans, October 26-30, 2016. Abstract LB-6.

Infectious Diseases Society of America. New Drug Benefits Patients with Multi-Drug Resistant HIV First Monoclonal Antibody for HIV, Given Once Every Two Weeks. Press release. October 28, 2016.