Leronlimab

Researchers have found a striking new way to potentially eliminate HIV soon after infection using a one-time combination of three therapies. In newborn nonhuman primates treated within three days of exposure, the regimen—standard antiretroviral drugs, broadly neutralizing antibodies, and the experimental antibody leronlimab—completely cleared the virus, even though none of the treatments could do so alone.More than 120,000 babies around the world acquire HIV each year. For millions of people living with the virus, controlling the infection means taking treatment for life, provided those medications are accessible and affordable. A new study led by Oregon Health & Science University points to a potentially very different approach. Researchers found that a combination of therapies administered to newborns within three days of birth could permanently eliminate the virus. The findings were published in Nature Microbiology. "The really exciting part is that it could go to clinical trials immediately to eliminate HIV infection in newborns," said co-lead author Jonah Sacha, Ph.D., professor and chief of pathobiology and immunology at OHSU's Oregon National Primate Research Center and Vaccine and Gene Therapy Institute. "The next step after that is to test if this can work in newly exposed adults." The work brought together numerous collaborators and involved nonhuman primates at both the Oregon and California national primate research centers. Three HIV Treatments Used Together For several weeks, the researchers administered three different therapies: neutralizing antibodies, standard antiretroviral therapy, and an experimental monoclonal antibody called leronlimab. All three approaches had been tested individually before, but none had succeeded in permanently clearing the virus. Sacha was initially skeptical that simply combining them would produce a better outcome. For years, Sacha has helped develop leronlimab, which is intended to prevent HIV from entering immune cells by blocking a surface protein known as CCR5. His longtime OHSU colleague and coauthor Nancy Haigwood, Ph.D., believed that pairing leronlimab with existing HIV therapies could prove more effective. The new results supported her idea. Haigwood, a former professor and ONPRC director, is a virologist and immunologist who has spent decades studying HIV antibodies. "We were astounded and overjoyed, actually," Haigwood said. "It's a remarkable result." A Potential Path Toward Human Trials Antiretroviral therapy is already approved for use in people. Broadly neutralizing antibodies and leronlimab, meanwhile, are each being evaluated separately in clinical trials. Before the newly identified three-part treatment could become widely available for newborns, it would first need to be tested in human clinical trials. The researchers expect those initial studies would most likely involve adults who were recently exposed to HIV. If successful, the strategy could eventually offer a new way to combat an HIV epidemic that still kills about 600,000 people worldwide every year. The scientists say there is reason for optimism because nonhuman primates and humans share important anatomical similarities. "There was no reason to think this would completely clear the virus," Sacha said. "It's one of those things where you test it and, holy cow, it works and you've discovered something new." Blocking HIV From Entering Immune Cells Researchers do not yet know exactly why the combined treatment worked so well. Sacha and Haigwood said the three therapies appear to become much more powerful when used together than when any one of them is used by itself. Leronlimab may play a particularly important role. The antibody blocks CCR5, a surface protein that HIV commonly uses as a route into immune cells. "For reasons we don't understand, HIV really wants to use CCR5 receptors to infect cells," Sacha said. "By blocking access, it's like you've kept fuel away from the fire." Haigwood describes the three treatments with another analogy: Turning off the faucet: Antiretroviral therapy doesn't eliminate HIV altogether, but it minimizes its ability to replicate. Mopping up: Neutralizing antibodies effectively corral HIV so there is less virus circulating in the body's blood supply. Sealing off: Leronlimab blocks what's left of the virus from infecting immune cells -- the equivalent of sealing off the room with a water-tight valve. The First Days of HIV Infection May Be Critical Haigwood believes the treatment combination may be particularly powerful when given very early after infection. "There's a lot more going on during the first week of infection than we previously thought," she said. "From this experiment, it looks like there's a dynamic interaction between the virus and antibodies that takes place as the virus begins to spread." The researchers now want to determine how long that early treatment window might remain open. In this study, the combined regimen was tested only within 72 hours of the initial infection. "We only tested out to three days," Sacha said. "Could it work a week after infection? Two weeks? How far can you go after infection, and still purge the virus?" Answering those questions could reveal whether the treatment remains effective when given later, potentially expanding the number of people who could benefit from the approach. Research Support The research was supported by the National Institutes of Health under Award Numbers R01HD080459 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); R01AI154559, R01AI166969, and R01AI129703 from the National Institute of Allergy and Infectious Diseases (NIAID); K01OD036063 from the Office of the Director (OD), NIH; P51OD011092 and U42OD010426 from the Office of Research Infrastructure Programs (ORIP), NIH, to the Oregon National Primate Research Center; and P51OD011107 from ORIP, NIH, to the California National Primate Research Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

CytoDyn's leronlimab may have struggled to secure approval as an HIV treatment, but research in infant primates has offered fresh hope for the CCR5-targeting antibody's ability to treat the virus. The latest findings, published August 10 in Nature Microbiology , come from a study of 55 infant macaques that received different combinations of three drugs—broadly neutralizing antibodies (bNabs), antiretroviral therapy and leronlimab. Among the eight monkeys that were treated with all three drugs in combination, the researchers noted that the virus failed to gain a foothold. These monkeys all remained HIV free for up to a year after stopping treatment. “The macaque immune system is very similar to the human immune system,” said Jonah Sacha, Ph.D., professor of pathobiology and immunology at Oregon Health & Science University’s Oregon National Primate Research Center, as well as the study's lead author. “The fact that you can use these human reagents and also that this so faithfully mirrors the human immune system—it really is the premier model of HIV cure that you can work in,” Sacha told Fierce. Sacha and his team are working to understand the biological mechanism for the responders to the triple treatment and want to take the step forward into human trials. But he cautioned that there remain some unanswered questions. “Will this work in adults or is it specific to infants? What is the window of opportunity? How late after acquiring the virus can you use this and it's still effective?” Sacha asked. “I don't think we are quite there yet, because the last piece we're missing is how soon after someone is exposed to HIV do you have to do this, or how long can you wait?” he added. “And that's really what you need to guide a clinical trial.” Nearly 41 million people globally are living with HIV. One aspect of the disease that makes it so hard to treat is the establishment of what is known as the viral reservoir. Sacha described this reservoir as the “defining feature of an infection,” which integrates into host cells. “When you take antiretroviral therapy, it makes the virus go to sleep,” he explained. “The virus is still there in your cells—it just can't replicate. As soon as those drugs go away, the virus wakes back up and starts replicating again.” This is why patients on approved antiretroviral therapies remain on these drugs for life, Sacha continued. For the study, researchers infected infant macaques orally with HIV virus and then began administering a treatment regimen 72 hours later. The eight macaques who were HIV-free after one year were dosed with two bNabs once, and antiretroviral therapy was then given subcutaneously daily for 27 weeks. Leronlimab was given weekly for three or six weeks, depending on if the dose was 10 mg/kg or 50 mg/kg, respectively. The bNabs were designed to “target the envelope of the HIV virus, physically preventing it from attaching to its target cells,” Sacha told Fierce. This therapy is still experimental and not yet approved, but is being tested separately in clinical trials. The researchers found that if macaques were treated with antiretroviral therapy, the viral reservoir still developed, and infection returned upon halting therapy. The same trend held true if the macaques were treated with bNabs or leronlimab alone. Leronlimab is designed to block the CCR5 receptor, an essential co-receptor for T-cell tropic viruses like HIV. CCR5’s importance was discovered after a mutation in its gene was found to protect individuals from being infected. GSK's ViiV Healthcare markets the CCR5 inhibitor Selzentry, which was originally launched by Pfizer. But leronlimab has struggled, with CytoDyn pulling an approval application for a specific HIV indication in 2022 due to issues with data from the CRO that had overseen a successful phase 2b/3 trial. CytoDyn has continued to keep the faith in leronlimab's potential, posting phase 2 data this year that suggested the drug can improve outcomes in patients with metastatic colorectal cancer, while kicking off a mid-stage study of the therapy in Alzheimer's disease.