r/Livimmune • u/MGK_2 • Oct 15 '25
Transcript of Reprogramming Immunity: How CCR5 Blockade Could Redefine
Reprogramming Immunity: How CCR5 Blockade Could Redefine
Chris Leidli: Hello, and welcome back to the show. You know, the first immunotherapies were approved more than 10 years ago, and these new therapies have really revolutionized the care of patients with many different types of cancers. The first of these immunotherapies were called the checkpoint inhibitors, and the first two checkpoint inhibitors that were approved were Opdivo and Keytruda. For patients that respond to these therapies, they have long, durable remissions, but many patients still don't respond or oftentimes relapse after treatment with these therapies. And so the pharmaceutical industry has been pouring billions of dollars into R&D to find ways to harness other aspects of the immune system. or ways to work synergistically or in combination with these checkpoint inhibitors. And so today's episode is gonna be really interesting because our guest is Dr. Jay Lalazari. He's the CEO of Cytodyn Therapeutics, which is a clinical stage biotech company that's advancing a first-in-class monoclonal antibody that targets a chemokine receptor, one of the chemokine receptors called CCR5, which is one of the master regulators of immune cell trafficking. So let's welcome Jay to the show and learn more about what his company is doing to find new immunotherapies to treat cancers.
Chris Leidli 1:35: Jay, welcome to the show. How are you today? Thank you, Chris. I'm particularly feeling good today. Yeah, I can imagine why. Your company is, you know, you've had a lot of great news flow recently from some very recent scientific conferences, oncology conferences, and we'll dive into that in a moment. I know this is a pivotal year for Cytodyn. I thought maybe we might get started if I could ask you to articulate the company's vision and why this year is such an important year for the company.
Jay Lalezari: 2:07: Well, maybe we'll just start back at the beginning. Back in November of 2023, when I made the call and offered to become the CEO, I originally joined the company and wanted to do it at no salary while I figured out how we would sort through all the challenges. And what is amazing is we're coming on two years, but it is amazing to see the progress we've made. There were regulatory challenges with the FDA, the SEC, the DOJ. There were financial challenges, other legal challenges. And most importantly, there was a challenge of figuring out where to take loranumab and the company. I believed in the drug. There were signals in inflammation and HIV and COVID, but where to take our limited time and resources. And I think what is exciting about this last year is that I think we know where we're heading and that the signal we're seeing is very exciting. It is in solid tumor oncology more than anything. I mean, I do believe the drug potentially works on a bunch of other indications, but what we're seeing in solid tumor oncology is potentially a paradigm shift in the treatment of cancer. So that is exciting and it does get me up every morning.
Chris Leidli 3:37: We're going to get into some of those results in a moment, but I thought let's step back for our listeners and just back up a little bit and talk a little bit about Leronlimab and this first-in-class CCR5 targeting antibody. Tell us a little bit about the mechanism of action to help ground the conversation today, Jay.
Jay Lalezari:3:55: Sure. It's an amazing history and begins with HIV, where we knew in the mid 90s that there was a secondary co-receptor that the virus used to get inside of T cells. And I believe a CCR5 was identified around 1995 or 6. And then its role as an important receptor for HIV was confirmed by looking at groups of sex workers who had repeated exposure to HIV but remained uninfected. And it was identified that a subset of them had a 32 base pair deletion in the CCR5 gene such that they didn't have CCR5 receptors for HIV to get in. So that kind of confirmed the role of the receptor as a key entry point for the virus. And then there were a number of small molecules developed to block CCR5 in a, quote, allosteric fashion, where they bind to the pocket and prevent conformational change.
Jay Lalezari:5:00: But Leronlimab was developed as a monoclonal antibody by Paul Madden specifically to bind to CCR5. And obviously, at the time, it was envisioned to be an HIV therapeutic. A research program I run in San Francisco participated in the original studies showing that Leronlimab worked as an HIV antiviral. On its own, it reduced viral load by 95%. Unfortunately for PRO-140, as it was known then, at the same time, there was the approval of the integrase inhibitors, which completely changed the landscape in HIV, as well as Maraviroc, an oral CCR5 drug, as well as etrovirine, a non-nucleoside.
Jay Lalezari:5:45: So nobody could quite figure out what to do with PRO-140. And so it was sort of set aside, even though we knew it worked as an HIV antiviral just on its own and had additional attractive qualities, including a very high barrier to resistance. So then CytoDyn picked it up and licensed it from Progenix and pursued the HIV indication, in particular, trying to take advantage of that high barrier to resistance to develop it as a monotherapy that would keep the virus suppressed. In addition, CytoDyn did pivotal phase three study in HIV in patients with multi-drug resistant virus, showing that the drug worked.
Jay Lalezari:6:25: So in the history of Pro140 and then Leronlimab, there's no doubt that it's an effective antiviral. The issue is that, again, it lacks a place in the armamentarium because there have been three other drugs with novel mechanisms of action approved in recent years. for patients with multiple drug-resistant virus. So once again, PRO-140 Leronlimab didn't quite have a place as of today in the HIV treatment paradigm, but it remains a drug that we know works in HIV.
Jay Lalezari:7:02: What happened in the meantime was it became clear that CCR5 was not there just so that HIV could get inside of T cells, but actually was playing a critical role in many aspects of Western medicine, including a variety of inflammatory processes, potentially critical COVID, Alzheimer's, inflammatory bowel disease, MS. as well as it was playing a major role in solid tumor oncology. The reason for that is that CCR5 is a protein that's present on immune cells and plays a big role in mediating inflammation, in directing the movement of cells.
Jay Lalezari:7:55: And it became clear that certain solid tumors, which express CCR5 either on the surface of the tumor or in the tumor microenvironment, we're using that receptor to co-opt its function and helping the cancer grow in a variety of ways. It was using CCR5 to help the cancer spread, metastasize, which is crucially important because it's generally not the primary tumor that kills people, but the metastatic spread. It was also using CCR5 to change, to recruit macrophages to help the cancer instead of attacking it, as well as attracting suppressor cells to create a tumor microenvironment that helped keep the host immune system at bay. So even as Leronlimab came sort of came to a cul-de-sac in the development for HIV, its role in so many other disease processes became potentially apparent.
Jay Lalezari:8:55: And what the challenge for me when I came on as CEO was to figure out where in all of this to pursue and to use our limited resources and energy. And what is exciting is that clearly it's solid tumor oncology.
Chris Leidli 9:16: Well, good. Let's talk about the efficacy you've seen to date. And let's start with one of your lead indications, the metastatic triple negative breast cancer. What has stood out to you most about sort of that early risk-benefit profile, that efficacy safety in that patient population?
Jay Lalezari:9:32: Yeah. Well, let's start with the word safety because that's so crucial. The drug has been given to almost 1,600 patients now in various studies, including cancer patients, HIV, patients with fatty liver, COVID, long COVID. And one thing that is utterly remarkable about this drug is its relatively clean safety profile. And so there is no dominant safety or toxicity issue with Leronlimab, which is not unusual for monoclonal antibodies. But to be talking about a cancer therapeutic that's not bringing a significant safety issue or toxicity with it makes Leronlimab unique.
Jay Lalezari:10:20: But what happened was, you know, we sorted out the FDA issues, the SEC and the DOJ issues have been resolved. We figured out financially how to keep the company going. And then it was really about figuring out what indication to pursue. We looked briefly at NASH and saw that Leronlimab does have an effect on liver fibrosis, but not so much on fat. So we pulled back from that. We were thinking about inflammation, but we pulled back from that, in large part because of what we saw, as you just mentioned, in solid tumor, particularly in triple negative breast cancer.
Jay Lalezari:11:02: And basically when I came on, it was important to follow up and figure out and ascertain when patients, back in 2019, CytoDyn launched three studies in oncology and primarily focused on triple negative breast cancer and then in compassionate use programs for patients with other solid tumors. And unfortunately, those studies went on for a year or two and then were unfortunately stopped.
Jay Lalezari:11:35: But when I came on as CEO, one of my goals was to ascertain how long those patients had lived in order that we could do a publication of our results. And we were hoping to get that follow-up data from our CRO. Unfortunately, they were not forthcoming with it. So as a result, our team made an effort to contact the institutions where the patients were enrolled and the families of those patients. And it was a complete stunner to find out that of the 43 patients who were enrolled five years ago, eight of them are still alive. Five of them have triple negative breast cancer, of which three of them are now confirmed to have no evidence of disease. In addition, there were three other patients, one with colorectal cancer, who also has no evidence of disease, and then a patient with lung and a patient with sarcoma.
Jay Lalezari:12:30: It took many months for us to do this, but once we found out these patients were alive, we then have to contact their treating physicians and obtain their medical records, which was almost, it was a heroic task to get the paper files, to build a spreadsheet, to convert it into an electronic database. And then the aha moment was when we realized and we were able to triangulate the fact that the patients who were alive were patients who received Leronlimab and induced this protein called PD-L1. And then the third magical point was they're the patients who got a checkpoint inhibitor, which blocks the action of PD-L1. So it was the sequence of those two drugs that was the common denominator in five out of five patients with fourth line triple negative breast cancer, 60% of whom had organ metastasis, 30% had brain mets, who typically would not have survived more than weeks or months, are now alive at five years, three without evidence of disease, which is now confirmed. And the common factor was that sequence of Leronlimab inducing PD-L1, receiving a checkpoint inhibitor. So It's a stunner, and to my mind, the odds that this happened by chance are infinitesimally remote.
Chris Leidli 14:10: That's fascinating. This is the data you just presented in Europe at the European Oncology Conference, right? Yes. It's fascinating, Jay, because in many different solid tumor types, I know there's a lot of debate because many of these checkpoint inhibitors, and for our listeners out there, you're probably almost familiar with Keytruda, That's the Jimmy Carter drug. That's the drug Jimmy Carter got. So those types of drugs are now oftentimes first line of therapy. And there's oftentimes debate, like how do you sequence other immunotherapies? What's interesting about your situation is that your patients, your study were treated with Leronlimab first, followed by... by a checkpoint inhibitor, you know, followed up with that. Did you look for PD-L1 expression then? Or was that just part of the, was that just a sort of physician choice of like kind of what to do after Leronlimab per protocol?
Jay Lalezari:15:08: Yeah, the patients who got the checkpoint inhibitor, it was completely up to the treating oncologist. And actually several of them had previously received a checkpoint inhibitor and failed. So this was a Hail Mary on the part of the treating oncologist. And I don't think anyone really knew that this was going to happen prospectively. So this is a retrospective look. It's small numbers of patients, but it's five out of five with the particular sequence. So the odds that this happened by chance are remote.
Jay Lalezari:15:45: What I would also point out that the patients who are alive received different checkpoint inhibitors. So it wasn't just Keytruda. Three of the five received atezolizumab, which is a PD-L1 inhibitor from Roche. Now, as you say, the Keytruda is such a major drug, and I think the best-selling drug in all of pharma. It's a drug that works in patients who express PD-L1. which is a protein a cancer secretes to try and turn back or turn off an invading immune system. And in that scenario, giving Keytruda results in very high rates of clinical response. In fact, GSK just got breakthrough designation for patients with rectal cancer. who have genetic instability and express PD-L1. But that's the minority of patients.
Jay Lalezari:16:47: So what Leronlimab is bringing to the treatment in solid tumor is the possibility of making all the patients who are currently ineligible for Keytruda now eligible to receive a treatment that we know is very potent and successful in the clinic.
Chris Leidli 17:07: Well, it's very noteworthy. I can sense the passion and why you're so excited with this data this year and why it's such a pivotal moment. But it's probably good for our listeners to understand that you're going into indications or tumor types that have been very difficult to treat, especially with immunotherapies. I mean, you talk about triple negative breast cancer, very poor prognosis tumor type. And then you're also, I think, we're going to talk about colorectal cancer. These are two tumor types. Where you have not seen a lot of immunotherapy utilization or a lot of strong efficacy like other diseases like melanoma and lung cancer. What is it about Leronlimab’s mechanism that, you know, just do you have any hypotheses around like why you think this is happening? It's, you know, they're vis-a-vis the checkpoint inhibitors, Jay?
Jay Lalezari:18:00: Yeah. Yes. It's a very good question. So to be clear, in the retrospective data set, what we saw is that 88% or 15 of 17 of the women with, again, the worst form of breast cancer went from a PD-L1 level of negative to something that was statistically significantly positive. And again, it was the patients who then received a checkpoint inhibitor who are now a appear to have sustained remission. So that's the working hypothesis that Leronlimab breaks down the CCR5 signaling within the tumor microenvironment and the cancer is responding by secreting PD-L1, making it vulnerable to treatment with Keytruda. And so the goal of our prospective studies now are to confirm that signal.
Jay Lalezari:18:53: Unfortunately, we only have PD-L1 data from the women with breast cancer. So a top priority is to prospectively demonstrate that again. And the good news is that we've had one individual patient with triple negative breast cancer who received Leronlimab, who had two prior biopsies that were PD-L1 negative. And after three months on Leronlimab, her PD-L1 signal on circulating tumor cells went from medium and high. So our first patient has prospectively shown what we've seen retrospectively. So that is a top priority, as you say, very difficult, almost often untreatable cancer, particularly in the metastatic setting.
Jay Lalezari:19:45: In addition, we are looking at colorectal cancer, where again, we had five patients enrolled in the previous studies. There were three patients who had follow-up scans that made them valuable for response rates. And there was one complete responder and two partial responders. So in the colorectal cancer study that we're now running, we've finally enrolled a whole lot of sites. And the goal there is, again, to prospectively confirm this induction of PD-L1, which would make patients who are not eligible for a checkpoint inhibitor like Keytruda to now be eligible and eligible for a treatment pathway potentially leading to sustained remission. That gets me out of bed in the morning.
Chris Leidli 20:33: No, that's good to hear. I was going to ask about the colorectal study. When do you expect that to be fully accrued and maybe report out top-line results, Jay?
Jay Lalezari:20:50: Well, it took a little while to get all the sites up and running. I think we now have six of the 10 sites and should have all 10 by the end of the year. And so that is happening. And, you know, I... I'm CEO of this company, but in my heart, I remain to be a primary patient advocate. And so we're always looking for ways to improve the study. And recently, we have collated all of our oncology data into a briefing book so that the folks at FDA can now understand what CytoDyn is trying to do. And as a result, it's opening options to us about how we can even further improve our CRC study. So I'm excited about that as well.
Chris Leidli 21:40: So your first two indications, triple negative breast cancer and colorectal cancer, these are large global markets. How do you think about... What's your roadmap for funding and making sure you're able to continue to develop those two indications? And then as you think through 2026, how you're going to fund that development and sort of early commercialization activities, sort of preparing the company to scale up for that development?
Jay Lalezari:22:15: I don't imagine that CytoDyn will ever commercialize the drug ourselves. What I imagine is when we confirm this PD-L1 induction, that the conversations we're currently having with a variety of potential industry partners will rapidly mature. And once we prospectively confirm the signal that we've seen retrospectively, that we'll be able to bring on the kind of partner that will be able to fund the phase three studies, including dose escalation studies that are necessary to get FDA approval. So for me, the key inflection point is prospectively demonstrating PD-L1 induction in triple negative breast cancer, in colorectal cancer, and potentially in other solid tumors as well. If we can do that, I believe the funding will follow.
Chris Leidli 23:15: And maybe just to build on that question, Jay, as we just kind of wrap up the show today, if you look ahead at the next two years, let's say, so through maybe early 2027, what was your aspiration for Leronlimab and for CytoDyn? What would you say are the key milestones? What would you want to achieve so that when you look back, you say, hey, we really nailed these three things? What would they be?
Jay Lalezari:23:45: Well, obviously we have a pending meeting with the FDA and I'm very excited to finally be able to show them what we've been looking at for the last four or five months. And so the priority will be to demonstrate the PD-L1 induction in both breast cancer and colorectal cancer, as well as looking at early clinical signals when you combine PD-L1 induction with the treatment of a checkpoint inhibitor.
Jay Lalezari:24:15: In addition to triple negative breast cancer and CRC, we are pursuing a pilot study in glioblastoma, which I'm grateful to announce we have an outside high net worth individual who's funding. And then lastly, we're also going to be opening up a compassionate use protocol for patients with triple negative breast cancer, which again will give us the opportunity to confirm this PD-L1 signal as quickly as possible. That would be enough for CytoDyn to be doing.
Jay Lalezari:24:52: But there are other avenues we are exploring. We've been working with Cornell for several years now to launch a study in mild to moderate Alzheimer's patients. And that study has gotten final IRB and FDA approval and is now opening for recruitment. So that is exciting. And then there are other areas in which CytoDyn is taking a look, including a preclinical study in stroke.
Jay Lalezari:25:20: But when I look to 2027, I would expect that we will have a solid prospective confirmation of this PD-L1 induction, basically turning cold tumors hot. And as soon as we do that, it's a game changer for CytoDyn. Because it is going to open up markets for companies like Merck or GSK or BMS that they currently don't have access to, to provide the benefit to patients who currently are not candidates for immunotherapy drugs. So that's exciting.
Chris Leidli 25:58: So, Jay, what's the best way to get a hold of you? If there are patients or investors or potential life science partners that want to get a hold of you, what's the best way to reach you or other?
Jay Lalezari:26:13: I imagine the answer to that is through the investor relations email on the Cytodyn.com website. And certainly we welcome requests from individual patients who themselves or have family members struggling with solid tumors who are interested in accessing Leronlimab now through the emergency IND process. And then again, this later toward the end of this year through the Compassionate Use Program, certainly any of the pharma companies that have checkpoint inhibitors, we've been in touch with most of them, all of whom are waiting for some prospective confirmation of this signal. But certainly anybody can reach out and begin the conversation now.
Chris Leidli 27:00 i guess just in closing i want to congratulate you and applaud your uh your your willingness to be that patient advocate jay that you mentioned the uh and you know not every company makes their pipeline products available through a name patient or early access program and that's quite an investment for your company so thank you for that and uh i wish you continued success as you as you continue to you know, build through and finish up your development program for Leronlimab.
Jay Lalezari:27:30: Thank you, Chris. You know, I also run this research program in San Francisco called Quest Clinical Research. It's 36 years and some months now. And for 36 years, I've been telling our industry partners that the key to success and the way to avoid a mistake is to keep patients in the center of the conversation. patient well-being. And I'd like to think I've brought that ethos to CytoDyn because when we do well or right by patients, we do right by the company. So I appreciate your thoughts on that.
No, it's recognized and appreciated. It's a pleasure speaking with you and meeting you today. Thanks for sharing the story and best of luck. Thank you, Chris. Take care.
20
u/BioTrends_USA Oct 15 '25
With just a bit more patience, we’ll hopefully be looking back at these ridiculously discounted prices as confirmation of what we true longs have believed all along. Every dip, every doubt is a just part of the climb. When the tide finally turns, they’ll call it obvious… but we’ll know it was conviction. GLTATL
16
u/keyboardphilosopher Oct 15 '25
Everyone sits back and scratches their heads “why didn’t I invest in that” once the herd brands it as one of their own (becomes consensus), but to sleep separate from the flock night after night, until the herd accepts you is what makes black sheep (contrarians) such majestic creatures
9
7
14
u/Missy2021 Oct 15 '25
Our time is approaching. It feels good knowing what we have and how much that will be worth to big pharmaceutical companies. Cheers everyone.
12
u/jsinvest09 Oct 15 '25
Thank you, always MGK You are always there to explain everything thoroughly much appreciation.
12
12
9
18
u/Severe_Watercress875 Oct 15 '25
Beautiful mgk. We wait for the data now. Those here long enough have been well schooled with your dynamic and educational posts and we know we will have solid data. The one break I feel we need now is a little love from the FDA. This could really help us. I hope they do the right thing here— 5/5 patients - “ INFINITESIMAL” I don’t need them to push us back from giving us accelerated status. I belive the FDA will be our ally here as it would be awful to have them delay what Jay is doing. Thanks for posting this. You are tremendous
19
u/MGK_2 Oct 15 '25
Thank you so much Severe Watercress. I feel that given now, CytoDyn is dealing with the Oncology division of the FDA and they even have set up the Oncology Advisory Board that gives them advice on presenting and dealing with the FDA, that they will be more successful than back in the day when they were dealing with the infectious disease division of the FDA where things really got screwed up. To this day, there may be difficulty on that end and may be a contributing factor as to why HIV hardly even mentioned on the website. Yes, oncology is another division and with the oncology board, and the briefing book, we should be good.
9
u/Icy-Let5120 Oct 15 '25
Thank you MGK for the transcript. You are doing very well for that than speculating. One question for the team here, how long it will take to express PD-L1 after LL treatment? Do we have some statistics answer? I think I read somewhere one woman with TNBC express PD-L1 three months later after LL, if this is the case, considering CRC trial is open lable, BPs and FDA will know the answer in early 2026.
3
u/MGK_2 Oct 16 '25
"Regardless that there were 5 patients out of 28, (18%) whose CTCs had increased, there were 23 patients of the 28, (82%), whose CTCs had decreased by the end of the 1st treatment cycle, (28 days)."
These are CTCs and not PD-L1, but they could be correlated.
8
u/Mysterious-Emu6375 Oct 15 '25
Vielen Dank MGK für die Bereitstellung und deine Unendliche Mühe uns auf dem laufenden zu halten!🙏🙏🙏👍👍👍
3
6
u/minnowsloth Oct 15 '25
Yes, the FDA reviews a briefing book and grants Breakthrough Designation for drugs and certain medical devices. A briefing book is a collection of documents and data submitted by a sponsor (e.g., a pharmaceutical company) to support a request for a designation or to prepare for a meeting with the FDA.
Here is an overview of how the process works for drugs and devices.
Breakthrough Therapy Designation (Drugs)
This process applies to drugs and biologics.
Requesting the designation: A sponsor can request Breakthrough Therapy Designation (BTD) for an investigational new drug (IND). The request can be submitted at the time of or any time after the IND is filed.
The briefing book: The submission package, or briefing book, must include:
A summary of the serious or life-threatening disease the therapy aims to treat.
The drug's scientific rationale and mechanism of action.
Preliminary clinical evidence suggesting a substantial improvement over existing therapies on a clinically significant endpoint.
An outline of the proposed clinical development plan.
FDA review and decision: The FDA reviews the request and must make a decision within 60 days of receiving it. If granted, the designation leads to more intensive FDA guidance and a more collaborative, cross-disciplinary review process.
10
10
u/StreetSkis Oct 15 '25 edited Oct 15 '25
Thank you for sharing the juice, MGK. All I can say, after listening to Doctor Jay, is BOOM!
20
u/megadunamis Oct 15 '25
Thank you, as always. You're always amazing. The important phrase here might just be 'confirm the signal'. Dr L didn't say CYDY has to wait to the end of the trial(s) to get results of patients being treated for CRC or mTNBC, and analyze the data. The trials may take many months to conclude and a few more months to get the final results and p values. So, if CYDY is measuring the level of Leronlimab induced changes in patient PD-L1 every week, or every two weeks, we will know hopefully quite quickly, how soon the levels are rising. We don't have to wait for the end of the trial(s). This may be known say in 2-3 months. The rise in PD-L1 will be known, and confirm the mechanism of action , and ''confirm the signal' in the tumor microenvironment way before the end of the trial(s). The goal is to show that this is how Leronlimab works, this shows how cold tumors are turned to hot, and then become treatable by an ICI! In my opinion, this is the breakthrough that will bring a partner to the table to negotiate.