California-based biopharmaceutical company Gilead Sciences, Inc. (Nasdaq: GILD) has announced results from a Phase 1b clinical trial evaluating the safety and efficacy of toll-like receptor 7 (TLR7) agonist Vesatolimod for the treatment of human immunodeficiency virus (HIV) infection. The results of the clinical trial and those of additional preclinical studies evaluating the drug will be presented at the 2020 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, Massachusetts. According to the US Centers for Disease Control and Prevention (CDC), as of 2016, approximately 1.1 million people were HIV-positive, with a 9% decrease in the number of yearly diagnoses between 2010 and 2016. In 2018, an estimated 37.9 million people were diagnosed with the virus worldwide and 1.7 million new cases were reported.

Principal Investigator and Professor of Medicine at the University of California, San Francisco (UCSF) Steven Deeks stated, “This is the first study done in people that has shown with an immunotherapy that you can enhance immune function resulting in both a smaller viral reservoir and an increased time to viral rebound after treatment is interrupted. The effects are modest, and no one came close to any definition of a cure, but the data suggests real progress might be made when the drug is used in combination with other approaches.”

Senior Vice President, HIV and Emerging Viruses at Gilead Sciences Diana Brainard, MD, stated, “While HIV treatment has advanced dramatically over the past three decades, people living with HIV still face a lifetime of therapy and potential complications. Curing HIV remains the ultimate long-term goal for Gilead’s HIV research and development efforts. The breadth of our research presented at CROI 2020 furthers the collective scientific knowledge on potential pathways to achieve a ‘functional cure’, or long-term viral suppression in the absence of ART, for people living with HIV.”

The randomized, double-blind, placebo-controlled clinical trial, titled “Safety and Analytic Treatment Interruption Outcomes of Vesatolimod in HIV Controllers”, involved the treatment of 25 HIV-positive individuals with either Vesatolimod or a placebo twice weekly for 10 weeks, followed by a period of suspended treatment during which the participants were monitored for changes in virus levels and adverse events. Individuals selected to participate in the study were capable of partially controlling the virus without anti-retroviral therapy (known as “HIV controllers”), and had low titers of the virus in their bloodstream, with HIV RNA levels of 50 to 5,000 copies per milliliter. According to a publication in The Lancet, only a small proportion of HIV-infected individuals are capable of controlling the virus in this manner.

The clinical trial found that, after the cessation of therapy, individuals treated with Vesatolimod suppressed the virus for a longer period of time than those that received a placebo. Viral rebound (the return of HIV RNA levels to greater than 50 copies per milliliter) occurred after a median of 4.1 weeks for the group of patients treated with Vesatolimod and 3.9 weeks for those that received a placebo (p=0.036). Rebound of viral titers to greater than HIV RNA copies per milliliter occurred after a median of 5 weeks for the Vesatolimod group and 4 weeks for the placebo group (p=0.024). Among individuals treated with Vesatolimod, four did not experience a viral rebound of 50 HIV RNA copies per milliliter for at least six weeks. However, the press release noted that “Vesatolimod is an investigational agent and has not been approved anywhere globally; its safety and efficacy has not been established.”

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One of the preclinical studies, “Combined Active and Passive Immunization in SHIV-Infected Rhesus Monkeys”, assessed the efficacy of Vesatolimod, vaccination (Ad26/MVA vaccine), and anti-HIV broadly-neutralizing antibodies (bNAbs; PGT121) for treating infected rhesus monkeys. bNAbs are antibodies derived from HIV-infected individuals with a robust antibody-based immune response against the virus. The study involved the administration of Ad26/MVA, PGT121, and Vesatolimod to 49 rhesus monkeys infected with the Simian-Human Immunodeficiency Virus (SHIV). After 24 weeks of treatment with a cocktail of anti-retroviral drugs including tenofovir disoproxil fumarate, emtricitabine, and dolutegravir (TDF/FTC/DTG), the monkeys received one of four treatments (Ad26/MVA and Vesatolimod: n=12; PGT121 and Vesatolimod: n=12; Ad26/MVA, PGT121, and Vesatolimod: n=10; control: n=15) until week 86, when therapy was stopped. The monkeys were then assessed for viral rebound over the following 140 days. While 6 out of 10 monkeys in the Ad26/MVA, PGT121, and Vesatolimod treatment group experienced delayed viral rebound and controlled the virus after rebound, these were achieved by 0 out of 15 monkeys in the control group. According to the press release, “These results support further study of this multi-pronged approach.”

Another study, “PGT121 and Vesatolimod in Chronically Treated SHIV-Infected Rhesus Monkeys”, involved the treatment of 24 SHIV-infected rhesus monkeys with PGT121 and Vesatolimod (n=8), a modified version of PGT121 (known as GS-9721) and Vesatolimod (n=9), or a control (n=7) for 24 weeks and the TDF/FTC/DTG anti-retroviral drug cocktail for 42 weeks (for an additional 24 weeks after the cessation of treatment with Vesatolimod and PGT121 or GS-9721). Therapy was then discontinued and the monkeys were evaluated for recurrence of the virus over the following 140 days. While 7 out of 7 monkeys treated with a control experienced “rapid viral rebound” (median 21 days), according to the press release, “the combination of vesatolimod and either PGT121 or GS-9721 prevented viral rebound in 41 percent of subjects. These results suggest the potential therapeutic efficacy of combining bNAbs with TLR7 stimulation in targeting the viral reservoir in rhesus monkeys that initiated ART during the chronic infection phase.”

Dan H. Barouch, MD, PhD, co-author of the study and 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 help inform strategies aimed at a functional cure for HIV. These findings help focus research efforts in support of the goal to help transform care for people living with HIV.” The press release noted, “Vesatolimod, the bNAbs PGT121 and GS-9721, and the other experimental compounds noted are investigational and are not approved by the U.S. Food and Drug Administration or any other regulatory authority. Their safety and efficacy have not been established. There is no cure for HIV infection or AIDS.”

The toll-like receptor (TLR) family of proteins, which recognize molecular patterns associated with pathogens, are important for the early stages of immune responses. TLR7 recognizes single-stranded ribonucleic acid (RNA), such as that of HIV or the hepatitis C virus (HCV), and induces the expression of inflammatory cytokines important for the anti-viral immune response. Given the immune-activating properties of TLR7 agonists, these drugs have been investigated for the treatment of cancer delivered as a liposomal formulation or via nanoparticles.

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When left unchecked, infection by the human immunodeficiency virus leads to a progressive breakdown in the functionality of the immune system and can eventually result in the Acquired Immune Deficiency Syndrome (AIDS), a state of severe immune compromise that involves the occurrence of opportunistic infections or cancers. HIV targets an important subpopulation of white blood cells known as CD4+ T cells, which are important for orchestrating the anti-viral immune response, directly eliminating virally-infected cells, and protecting the body from re-infection. It is thought that HIV was introduced into the human population from a species of chimpanzee in Central Africa. Following the exposure of hunters to chimpanzee blood containing a chimpanzee version of the virus known as the simian immunodeficiency virus (SIV), the virus likely mutated into a human version (HIV) and has since spread throughout the globe. According to the US Centers for Disease Control and Prevention (CDC), while HIV-infected individuals could perish from the virus within a few years prior to the availability of anti-retroviral therapy, they can now live “nearly as long” as individuals not infected by the virus.











