Why Leronlimab Isn’t Just Another Repurposed Drug: Q&A with Dr. Jay Lalezari

In a conversation with Pharmaceutical Executive, Dr. Jay Lalezari, CEO and CMO of CytoDyn, discusses his unusual path from front-line HIV clinician to leading a biotech company, and how CytoDyn’s lead drug, Leronlimab, has followed the science of the CCR5 receptor across an unexpected range of diseases.

Lalezari explains that Leronlimab was not designed to target HIV, Covid-19, and now oncology by plan, but because CCR5 itself keeps showing up across medicine.

He describes compelling early data in CCR5-positive MSS metastatic colorectal cancer, including declines in circulating tumor DNA, which he calls unprecedented and a potential proof of concept for a paradigm-shifting approach to solid tumor oncology. He was careful to note that this success is unique to Leronlimab’s specific mechanism of blocking CCR5 signaling, not a model that other repurposed HIV or inflammatory drugs could easily replicate.

Lalezari also reflects on the broader challenge of advancing a therapy through today’s regulatory and institutional environment, suggesting that scientific progress has become harder to execute than it once was, even as the underlying science grows more compelling.

Despite those structural obstacles, he expresses strong optimism about Leronlimab’s trajectory, pointing to upcoming data on dose response and tumor shrinkage ahead of the ASCO GI meeting.

A transcript of Lalezari’s conversation with Pharmaceutical Executive can be found below.

Pharmaceutical Executive: You spent decades as a front-line HIV clinician before becoming CytoDyn's CMO and CEO. Can you describe what it’s like to go from treating patients directly to running a company?
Dr. Jay Lalezari: Yeah, it's very strange. I am CytoDyn’s CEO and also their CMO until the company becomes big enough, we're all doing double duty. I came of age in the HIV era and ended up working on a lot of different viruses and worked with Leronlimab back in the early aughts to show that it was a pretty good antiviral, but I came to CytoDyn because I believed in this drug for HIV, and for Covid and I just thought there was more there, and I still run the research program.

The research program is doing a lot of work in cancer so even as I'm the CEO of CytoDyn trying to bring Leronlimab forward particularly for solid tumor oncology, I see cancer patients all the time, which is a help helpful reminder of the urgency with which we need to proceed on the CytoDyn front. So, I never forget that what we're treating here is patients, patients who are urgently in need of new therapies, and so no dawdling in terms of getting it done with cytidine.

PE: Leronlimab has moved from HIV, to Covid-19, to now oncology with CCR5-positive MSS metastatic colorectal cancer. How do you plan for a single treatment to work across such different disease areas?
Dr. Lalezari: Yeah, I didn't plan for anything. What is true is that CCR5 is showing up everywhere across the textbook of medicine. It's the door through which HIV gets inside the cell and the signal that brings inflammatory cells to the lungs in patients with Covid, and it turns out it's a key receptor that solid tumors have used to create a tumor microenvironment that allows the cancer to build blood vessels and thrive and specifically keep the host immune system out.

So, it's not that Leronlimab is chasing all these indications, but rather that Leronlimab is just trying to keep up with where CCR5 is showing up, and CCR5 goes way beyond even the things we talked about to a whole slew of inflammatory disorders, as well as the HIV infection, the plague bacillus uses it, as well as all over solid tumor oncology. So we're just chasing the CCR5 data in science.

PE: What does a positive reading for Leronlimab mean for how the industry thinks about repurposing old biologics into oncology?
Dr. Lalezari: I think we have very solid, compelling data, which I'll get into in a moment, showing that Leronlimab is doing something in MSS colorectal cancer that, frankly, nobody has seen before.

In terms of these readouts, we've been getting on circulating tumor DNA so that is an incredible development, and it's a proof of concept that suggests that CytoDyn has a potentially breakthrough paradigm-shifting drug on its hands, because if it's true in colon cancer, it's likely to be true on a number of other solid tumors. That said, this Leronlimab story is a one-off. It's not that there are other HIV or inflammatory drugs that can be repurposed and demonstrate the same kind of efficacy. This is unique to Leronlimab and the way it sort of competitively binds to the CCR5 receptor and subverts the cancer’s attempt again to create this protected microenvironment that keeps the host immune system out by blocking that signaling. Leronlimab just happens to disrupt the party and allow that host immune system in, and everything we see in breast cancer and colon cancer follows from that initial step, and it's not something that any other HIV drug or inflammatory drug or any other drug can be repurposed to exactly do the same thing.

PE: Now that the CCR5 blockade is moving into FDA-level trial design for metastatic colorectal cancer, what's turned out to be harder than the science suggested?
Dr. Lalezari: The science is great. The science is reading more and more like a poem, between the history of CCR5, how it was discovered and then confirmed in sex workers who weren't infectable with HIV, and then Dr. Pastel's work showing that cancer takes it, and then our discovery that these women with breast cancer who had received Leronlimab and then expressed PD-L1 and got a checkpoint inhibitor are alive today. Including the idea that fetuses use PD-L1 to protect itself from the maternal immune system, this whole story is coming together almost like a poem.

What’s harder than I anticipated is how hard it is to get anything done in our society. When Quest started, we were hand completing everything on paper and mailing it, but for some reason, it's much harder to get anything done now than it was 30 years ago. And really, the miracle is that anything ever gets done anymore. It' seems to me that post Covid, people have kind of all retracted. People lead with no instead of how can I help you. So that's a bit harder.

The science is staggeringly exciting, and I think Leronlimab success is now inexorable. We have this data that's public on the declines in DNA and we’re going to be releasing more around that, we also have comparator data, data suggesting a dose response, and then leading up to the ASCO GI meeting, sharing data on how patients actually did in terms of shrinking their tumors. So, I'm very optimistic, and I don't think even the dysfunctionality of our society can keep Leronlimab back anymore.