ACTG launches phase 1 HIV cure study evaluating two promising therapies

The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced the launch of A5386, a phase 1 HIV cure study evaluating two promising therapies. A5386 will study whether N-803 (a clinical-stage biologic also called Anktiva?) can control HIV alone or together with combination broadly neutralizing antibodies (bNAbs) after participants stop their antiretroviral therapy (ART) and they are carefully monitored.

In pre-clinical and clinical research, N-803 (an IL-15 superagonist) has exhibited three activities that may help the immune system eliminate HIV reservoirs or control virus rebound. First, N-803 has been shown to reverse HIV latency (the process of no reproduction of HIV within long-lived cells in the immune system), allowing it to be detected by the immune system. Second, it activates NK cells and CD8+ T-cells, two elements of the immune system that specialize in killing virus-infected cells. Finally, it enables NK cells and CD8+ T-cells to move to lymphoid tissues where they will encounter and hopefully eliminate HIV-infected cells.

The actions of bNAbs (or antibodies that neutralize different variants of HIV) are well-matched to that of N-803. bNAbs neutralize HIV that is produced upon reactivation, preventing new infections; target (label) HIV-infected cells for destruction by NK cells; and may act to boost CD8+ T-cell responses. A5386 will utilize an array of virologic and immunologic tests to evaluate the degree to which each of these expected activities are induced in study participants. Ultimately, the study will test whether this approach results in immune control of HIV when ART is paused with careful monitoring.

HIV cure clinical trials remain a fundamental element of the ACTG's research agenda. A5386 is particularly exciting as it marries two of the approaches in the HIV cure research space with the most potential. We believe this study will provide important insights as we continue to pursue our ultimate goal of identifying a cure for HIV and making it available to the millions of people living with HIV around the world."

Judith Currier, M.D., M.Sc., ACTG Chair, University of California, Los Angeles

A5386 is a phase 1, open-label, randomized study evaluating the safety, tolerability, and efficacy of N-803 both with and without combination bNAbs. It will enroll 46 people living with HIV (23 in each study arm) whose virus has been suppressed by ART for approximately two years, including at least 30 percent cisgender women or transgender men. Participants will undergo leukapheresis (a medical procedure in which white blood cells, or leukocytes, are separated from the blood) to measure their HIV reservoirs and a subset will undergo optional lymph node fine needle aspirations to assess the effect of N-803 on lymphoid tissue. They will then be randomized to one of two arms: N-803 alone or N-803 with combination bNAbs. After receiving treatment, participants will stop taking ART and will be followed closely to monitor for signs that they need to restart ART. Most participants will be followed for approximately 100 weeks after receiving treatment.

"Pre-clinical studies have shown that this approach enables the immune system to control viral replication and suggest that N-803 and bNAbs will have a complementary effect on each other," said A5386 Protocol Vice-Chair Richard Brad Jones, Ph.D., Weill Cornell Medicine. "We hope A5386 will demonstrate whether this new approach can enable us to safely decrease the amount of participants' HIV."

A5386 is led by Timothy Wilkin, M.D., M.P.H. (Weill Cornell Medicine), Marina Caskey, M.D., (The Rockefeller University) and Dr. Jones. It is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and N-803 is provided by ImmunityBio, Inc. NIAID and collaborating NIH Institutes fund the ACTG.

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