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 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 whether the dose was 10 mg/kg or 50 mg/kg, respectively.
The bNabs were designed to “target the envelope of the HIV, 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 even when 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.