Gilead's HIV Functional Cure Candidate Vesatolimod Shows Significant Improvement Over Placebo in Phase Ib Trial

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The 2020 Conference on Retroviruses and Opportunistic Infections (CROI) is being held in Boston, USA. At the conference, Gilead Sciences presented results from a Phase Ib trial of vesatolimod (GS-9620), a Toll-like receptor 7 (TLR7) agonist, within its HIV cure research program. The data showed that, compared with placebo, TLR7 stimulation by vesatolimod was associated with delayed time to viral rebound, enhanced immune function, and reduced levels of intact HIV DNA. Gilead also presented additional preclinical studies evaluating the potential of vesatolimod-based combination regimens to achieve viral remission following discontinuation of antiretroviral therapy (ART).

Over the past 30 years, despite significant advances in HIV treatment, people living with HIV still face lifelong therapy and potential complications. Furthermore, even among those who achieve virologic suppression, latent HIV reservoirs persist, and their eradication is considered a key barrier to achieving an HIV cure. Vesatolimod is a potent, selective, oral TLR7 agonist that induces immune activation and, when used in combination regimens, has the potential to eradicate viral reservoirs and achieve a functional cure.

Steven Deeks, a professor of medicine at the University of California, San Francisco, and the principal investigator of the Phase Ib trial, stated, “This is the first study in humans to demonstrate that enhancing immune function with an immunotherapy can lead to a smaller viral reservoir and a longer time to viral rebound after interruption of antiretroviral therapy (ART). Although the efficacy was modest and far from meeting the definition of a cure, the data suggest that there is potential for genuine progress when this drug is combined with other approaches.”

Chemical Structure of Vesatolimod (Image source: medchemexpress.cn)

The following are the key summary data presented at the conference.

—Analysis of the Safety and Treatment Interruption Outcomes of Vesatolimod in HIV Controllers: This randomized, double-blind, placebo-controlled study evaluated 25 individuals with HIV who had demonstrated partial virologic suppression (HIV RNA viral load: 50–5,000 copies/mL) prior to initiating antiretroviral therapy (ART); this population is referred to as “HIV controllers.” In the study, patients received ten doses of the TLR7 agonist vesatolimod or placebo administered every two weeks while continuing ART, followed by treatment interruption. During the treatment interruption period, participants discontinued medication and were closely monitored for viral rebound and safety.

The study found that, compared with placebo, vesatolimod was associated with a longer duration of virologic suppression after treatment interruption. The median time to viral rebound (>50 copies/mL) was 4.1 weeks in the vesatolimod group versus 3.9 weeks in the placebo group (p=0.036). For rebound to >200 copies/mL, the median time was 5 weeks in the vesatolimod group and 4 weeks in the placebo group (p=0.024). Four patients in the vesatolimod group experienced no viral rebound (>50 copies/mL) for 6 weeks or longer.

——Combined Active and Passive Immunization in SHIV-Infected Rhesus Macaques: A Standalone Study Evaluating the Potential of a Combination Regimen Comprising an Investigational Therapeutic Vaccine, an Investigational Broadly Neutralizing Antibody (bNAb), and Vesatolimod as an HIV Cure Strategy to Activate and Eliminate the Latent HIV Reservoir. HIV bNAbs are a class of antiviral and immunotherapeutic agents originally derived from individuals with HIV who exhibit potent anti-HIV antibody responses, and are currently under development for targeted HIV therapy.

In this study, 49 rhesus macaques infected with simian/human immunodeficiency virus (SHIV) were administered tenofovir disoproxil fumarate/emtricitabine/dolutegravir (TDF/FTC/DTG) as antiretroviral therapy (ART). After 24 weeks, the animals were divided into four groups to determine the effects of active and passive immunity: one group received the Ad26/MVA therapeutic vaccine (n=12), one group received the broadly neutralizing antibody (bNAb) PGT121 (n=12), one group received both Ad26/MVA and PGT121 (n=10), and one group served as a sham control (n=15). All groups except the sham control received 10 doses of vesatolimod. At week 86, ART was discontinued, and viral rebound was monitored for 140 days.

The results showed that among the 10 animals treated with vesatolimod in combination with a therapeutic vaccine and the bNAb PGT121, 6 exhibited delayed viral rebound and post-rebound virologic control after ART interruption, whereas none of the sham-control animals did. These findings support further investigation of this multifaceted approach.

—PGT121 and vesatolimod for the treatment of chronic SHIV infection in rhesus macaques: This study evaluated the efficacy of a broadly neutralizing antibody (bNAb) in combination with vesatolimod in rhesus macaques chronically infected with SHIV, who had received once-daily suppressive antiretroviral therapy (ART; TDF/FTC/DTG) for 30 months starting one year after infection. Twenty-four SHIV-infected rhesus macaques were divided into three groups: one group received PGT121 and vesatolimod (n=8), another received the Fc-modified antibody GS-9721 and vesatolimod (n=9), and a third served as sham controls (n=7). ART was discontinued at week 42 after the initial antibody administration, which corresponded to 24 weeks after the last doses of antibody and vesatolimod, and viral rebound was monitored for 140 days.

The results showed that after cessation of ART, all animals in the sham control group exhibited rapid viral rebound, with a median time to rebound of 21 days, whereas combination therapy with vesatolimod and either PGT121 or GS-9721 prevented viral rebound in 41% of the animals. These findings suggest that combining broadly neutralizing antibodies (bNAbs) with TLR7 stimulation has potential therapeutic effects targeting the viral reservoir in rhesus macaques initiating ART during chronic infection.

Dr. Dan H. Barouch, Professor of Medicine at Harvard Medical School and Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, stated, “These data will provide insights into functional cure strategies for HIV and help focus research efforts aimed at transforming the care of people living with HIV.”

Reference Source: Treatment With Gilead’s Vesatolimod Is Evaluated for Safety and Virologic and Immunologic Response Versus Placebo in Phase 1B HIV Functional Cure Study