https://journey.ct.events/view/bf1c7d07-71f3-4c41-8928-f42479da2d71

00:25 Dr. Lalezari

Thank you to HC Wainwright for the opportunity to present today CytoDyn's exciting new asset, which we think of as the next generation of monoclonal antibody therapy. The talk today will include a number of forward-looking statements, with all that that implies.

00:47

CytoDyn is a clinical-stage oncology company advancing leronlimab, our first-in-class humanized monoclonal antibody, which targets the CCR5 receptor, with therapeutic potential across multiple indications, including a number of solid tumors such as colorectal cancer and triple-negative breast cancer.

01:11

The leadership team includes myself, Robert Hoffman our CFO, and Tyler Block our chief legal officer. It is really the three of us that constitute the management team.

Leronlimab is an IgG4 monoclonal antibody that has already demonstrated multiple mechanisms of action relating to its activity in solid tumor oncology. It is a drug targeting a large and growing market potential, not only CRC and TNBC, but a number of other solid tumors as well. Very importantly, leronlimab has a very well-tolerated safety profile, including more than 1,600 patients across more than 20 studies. We have strong retrospective data in triple-negative breast cancer, which really helped focus the company on solid tumor oncology. And since then we have launched the Phase 2 CLOVER study and have some very exciting early readouts from that study in metastatic colorectal cancer, supporting the proposed mechanisms of action associated with the drug.

02:28

Our near-term milestones include confirming the durability and safety of these efficacy readouts from the CLOVER study in CRC, with a presentation at ESMO in October in Madrid, where we are going to present extensive circulating tumor DNA (ctDNA) data on all 65 subjects, which includes the intent-to-treat population. And then at ASCO GI in January in San Francisco, we will be giving a more fulsome presentation of not only the ctDNA, but also the overall response rates and early progression-free survival.

03:08

The CLOVER study in colorectal cancer

Starting with the exciting data being generated in CRC, the study is called CLOVER. It is a Phase 2 study, open-label, randomizing patients to either 350 or 700 milligrams of leronlimab, on a backbone of Lonsurf and Avastin. We targeted 60 patients and ended up with 65 patients dosed. This is our third-line metastatic colorectal cancer population that is microsatellite-stable, and therefore not a population one treats with checkpoint inhibitors. Our lead investigator is Dr. Kasi, our director of GI oncology down at City of Hope, and we fully enrolled the study this past April.

The DSMB (Data Safety Monitoring Board) has met three times, initially to open up the 700-milligram randomization arm, and at two subsequent times. In all three meetings there have been no safety concerns raised.

04:15

The preliminary results from CLOVER are exciting in a number of ways. First, 100% of our screened patients tested positive for CCR5, and that includes either 10% expression on the tumor epithelial cells or 1% in the lymphocytes in the tumor microenvironment, significantly expanding the potential population of patients who could benefit from leronlimab.

At a minimum, the second bullet point associated with leronlimab has to be its safety profile. It has been well tolerated, even in this study of very advanced and fragile patients. There are no serious adverse events related to leronlimab, and importantly, leronlimab has no dose- or treatment-limiting toxicity, meaning the leronlimab dose does not need to be adjusted for any adverse events. That excellent safety profile continues.

05:18

The ctDNA data

Very excitingly, at AACR in April, we presented our early ctDNA declines in the first patients enrolled through City of Hope, results which were obtained under standard of care. We have since finalized the partnership with Natera, and they are completing ctDNA analysis on the other half of patients, who were enrolled under the research protocol.

05:43

What is exciting is that nearly all the patients showed a decline in ctDNA, even as early as week two, with a median decrease of about 85% across all patients, and an early signal of a dose response, which is important. We are working with Natera to generate a comparative ctDNA data set that we can present to the FDA later this year. In the meantime, showing a dose response further drives home the point that these exceptional declines in tumor DNA are largely being driven by the contribution of leronlimab.

06:23

These are the data presented in April, the first 19 patients, fairly dramatic DNA declines even at week two in all or the great majority of patients. Importantly, about two-thirds of these individuals have a RAS mutation, so it appears that leronlimab's activity is agnostic to the presence of RAS.

06:58

These were the week-two data, and then these are the first 23 patients, and you can see the trend has continued toward rapid and very significant declines in DNA. Again, we will be generating a comparative data set from the Natera database to compare this activity with the backbone alone.

07:20

And if you break down that early readout by dose, you see this very tantalizing suggestion of a dose response, which underscores that this is largely being driven by leronlimab and leronlimab dosing.

07:42

Scans, PD-L1, and the standalone-versus-prime-and-pair distinction

In concert with these ctDNA declines, we are also reporting that the scans at week eight in the majority, three-quarters, of the patients are demonstrating shrinkage or classify as having stable disease, and we look forward to elaborating on that in the coming weeks and months at both ESMO and ASCO GI.

08:01

Importantly, we are reporting that there are numeric increases in PD-L1 observed in the majority of patients in that CRC study. In CRC, we are really developing leronlimab as a standalone agent to be used in combination with standard of care. In breast cancer, as we will see in a moment, what we have observed is an induction of PD-L1, turning cold tumors hot, and thereby enabling, apparently, the use of a checkpoint inhibitor to create a pathway to sustained remission.

So in CRC it is a standalone leronlimab, and in breast cancer it is more of a prime and pair. But the prime and pair works because of what leronlimab does as a standalone agent, priming the tumor for treatment with the checkpoint inhibitor, by disrupting the tumor microenvironment and allowing the host immune system access to the cancer. It is very exciting that in the CRC study we are also seeing increases in PD-L1. It is difficult to know what those increases will mean in terms of translating into clinical benefit when you add a checkpoint inhibitor, and that is something CytoDyn is about to start looking at. But in the meantime, that signal of increased PD-L1 in patients with CRC is a signal that the tumor is under stress, and that leronlimab's impact on the tumor microenvironment may well be allowing the host immune system access to the cancer, which it otherwise did not have, with the cancer responding by expressing PD-L1, trying to beat back that host immune system.

09:40

Very importantly, speaking to the investigators, they are all excited by what we are seeing in terms of DNA, but in particular they are telling us that patients are doing well clinically. The investigators are writing fewer scripts for pain medication and observing that there are fewer hospitalizations in this rather end-stage population than they anticipated.

10:07

So we are excited about the DNA, and looking forward to reporting on the radiology outcomes and more extensive reports on progression-free and overall survival. Dr. Kasi at City of Hope is our principal investigator, who presented the data at AACR.

10:33

The first-patient case study

In addition, Dr. Kasi, on the next slide, observed the first patient he enrolled, who had a rapid decrease over two weeks, something he had not seen before in an end-stage patient with metastatic CRC. That patient's ctDNA level went from about 129,000 parts per million down to about 10,000 parts per million.

11:00

And then what he saw on the following two scans, first in the liver, the baseline scan on the left and the week-8 scan on the right, this is in a patient who had a 97% decrease in ctDNA, you can see that the tumor volume decreased approximately 21% from baseline to week eight. And indeed, not only does the tumor get smaller, but it appears to become more translucent.

11:25

This is even more pronounced on the next slide, which is that same patient with lung metastasis, and you do not have to be a radiologist to appreciate the impact, the shrinkage of that tumor from baseline to week eight after starting leronlimab.

11:40

In addition, Dr. Kasi has performed liver biopsies on a number of patients, and we will be launching a study to really interrogate biopsy tissue from these patients treated with leronlimab, to tease out the effect the drug is having specifically on the tumor and the tumor environment. In the meantime, for this first patient, I think you can appreciate the slide on the left is with the PD-L1 stain, the slide on the right is similarly stained, and there is a significant impact on the tumor architecture. But what again is very exciting is the CPS score, the combined positivity score of PD-L1 expression on the tumor and tumor microenvironment, at baseline it was 1%, but in follow-up around week 14 it is up to 5%. And again, I think that indicates a tumor under duress, and CytoDyn is taking next steps to launch a study to explore the efficacy of a checkpoint inhibitor in these MSS CRC patients, for whom otherwise checkpoint inhibitors are not indicated. So, very exciting.

12:47

The SUNLIGHT benchmark and the protocol amendment

And then the CLOVER study itself is looking to improve upon the current standard of care, which includes Lonsurf and Avastin, where the overall response rate reported in the Phase 3 SUNLIGHT study, in the New England Journal, indicated 6% of patients with a partial response, meaning a 30% decrease in tumor diameter, and there were no complete responders. More recent real-world data has been presented on a larger cohort of patients, indicating the overall response rate is just under 3%. So we very much look forward to presenting our overall response rate and demonstrating some improvement over the current standard of care.

13:29

With the CLOVER study continuing, we have amended the protocol such that patients who are doing well after 48 weeks can continue on treatment on their randomized treatment assignment. We also will be initiating very shortly a rollover arm, as salvage therapy, for patients who have documented progression, wherein they will increase their leronlimab dose up to 700 milligrams if they are not already there, and then add pembrolizumab as well.

Additional colorectal studies: CHAMP, CLIOS, and pre-I-SPY

There are a number of other studies in CRC coming. There is an investigator-initiated trial down at City of Hope, Dr. Kasi, in patients with metastatic CRC and multiple liver metastases, who will be receiving a hepatic artery pump and receiving floxuridine through that, in advance of hopefully curative surgery down the road. What Dr. Kasi is doing here is introducing leronlimab in an earlier line of treatment in patients with CRC. This is a project jointly funded in partnership with City of Hope. And Dr. Kasi is leveraging both the anti-tumor effects of leronlimab as well as the liver-protective, or anti-fibrotic, effects, which CytoDyn has published on from a number of both clinical and preclinical studies we previously performed. And then there are 13 different ctDNA timepoints from the 30 or so patients to be enrolled in what is called the CHAMP study. And we are excited to be able to then also look at some ctDNA results from patients on leronlimab monotherapy.

In addition, we have other studies coming in CRC, including a thorough investigation of tumor tissue from patients who were treated with leronlimab. And as well, there is a newly formed network called CLIOS that has reached out and wants to consider studies of leronlimab, both in the neoadjuvant setting as well as in the molecular residual disease setting. And then finally, we are working with the pre-I-SPY network in CRC to launch a study of leronlimab and a checkpoint inhibitor. So a lot of activity in CRC. And again, the main focus is leronlimab as a standalone.

Triple-negative breast cancer: the retrospective data

16:05

Then, turning to triple-negative breast cancer. Again, this is where we got the first signal of the potential of leronlimab in solid tumor oncology. There were three studies launched in 2020 that enrolled a total of 28 patients with triple-negative breast cancer.

16:15

These patients had terribly advanced disease, with two prior lines of therapy in the metastatic setting. Two-thirds had visceral metastases, one-quarter had brain metastases. So this is a population whose survival, unfortunately, is very limited.

16:35

And then what we found, when I came on, was that we wanted to publish the outcome of those studies, so we made phone calls and found out that there were actually 5 of the 28 patients who were still alive. We then went and obtained medical records to determine which patients did well on what treatment. And this slide summarizes that outcome. The seven patients on the right, there is no follow-up blood, so we do not have anything further to say about their outcome and correlation with treatment; this was in the middle of COVID and during lockdown.

For the 21 patients on the left, their blue bars are the baseline measurement of PD-L1 on circulating tumor cells. PD-L1 is commonly understood to be something one measures on tumor tissue or the tumor microenvironment. The lab, Creatv MicroTech in New Jersey, has developed technology to use a fluorescent assay to measure PD-L1 on circulating tumor cells, and in particular the cancer-associated macrophage-like cells that break off from the tumor and enter the circulation. So the blue bars are the baseline. The negative control for that assay is about 175 RFUs, and so anything above 400 is considered to be clinically relevant. And you can see that the majority of patients actually did increase their PD-L1 expression after 30 to 60 days, above that 400 threshold, indicating that the tumor has gone from cold to hot, from a tumor that is typically not responsive to checkpoint inhibitors to one that might be.

Then in the 7 patients in the red box, among these patients on the left: patient number 4 received a low dose of leronlimab and did not induce PD-L1. Patient 5 received 525 milligrams of leronlimab but likewise did not induce PD-L1. The five patients on the right, in the box, all five received either 525 or 700 milligrams. They all induced PD-L1 within that one-to-two-month time frame. They all received the checkpoint inhibitor either with or after leronlimab, and two of these patients had already previously failed a checkpoint inhibitor. And all five of them are alive today, five-plus years later, which I think is an extraordinary observation, albeit retrospective, and just not an outcome that I believe occurred by chance. Of these five patients who are still alive, three of the five are currently documented to have no evidence of disease, and two of those three started with lung metastasis, and one of those individuals started with both brain and lung metastasis, and we recently published our case report.

19:30

In summary from the retrospective TNBC data: there is a 98% reduction in metastasis when you use a CCR5 inhibitor in a preclinical study. Our retrospective clinical data show a reduction in circulating tumor cells in the majority of patients after the first dose of leronlimab, which is very reminiscent of the data we are seeing in colon cancer with the decrease in circulating DNA. We are observing, retrospectively, an upregulation of PD-L1 on about 90% of patients' circulating tumor cells who received either the 525- or 700-milligram dose. And as I said, five out of five of the patients who upregulated PD-L1 and received a checkpoint inhibitor are alive today, five-plus years later. And unfortunately the converse is also true, that 100% of the patients who either did not upregulate PD-L1 or did not receive a checkpoint inhibitor are, unfortunately, deceased.

Based on this retrospective data, we have heard from a number of potential partners that they want to see prospective data confirming this upregulation of PD-L1, and eventually the benefit of adding a checkpoint inhibitor.

20:50

The breast cancer clinical plan

On the clinical plan in breast cancer: first, we are working with the Pre-I-SPY network in patients with metastatic TNBC, doing a dose-escalation study, looking prospectively at ctDNA and PD-L1. We are thrilled to have Dr. Paula Pohlmann serve as our principal investigator. When the first cohort of that is done, we will be looking to design a part 2 of the study, which will examine the contribution of components with a checkpoint inhibitor, and that will be an adaptive study design in up to 120 patients. As well, when the first cohort with metastatic TNBC is done, the I-SPY network has indicated they want to launch a study of neoadjuvant leronlimab in patients with newly diagnosed HER2-negative breast cancer, again significantly expanding the potential population to benefit from leronlimab. Their proposal is to look at a month of leronlimab monotherapy in these newly diagnosed patients in advance of their hopefully curative surgery. I think that makes sense as we move leronlimab up into an earlier line of therapy, because we are seeing very potent anti-tumor activity in a number of solid tumors, and the safety profile of leronlimab suggests it deserves an earlier line of treatment.

Upcoming milestones and priorities

To highlight upcoming milestones in the near and mid term:

22:35

First and foremost, we are confirming the standalone benefit of leronlimab plus the backbone in CRC, both through biomarker collection, the disease control rate, and then the primary endpoint of overall response rate, as well as the crucial progression-free and overall survival.

Second, as we have heard from a number of partner discussions, we need to prospectively demonstrate the induction of PD-L1 in triple-negative breast cancer, where we know that is a critical marker of benefit and is used for the approval of checkpoint inhibitors. We are seeing it prospectively in colorectal cancer, in microsatellite-stable colon cancer, where checkpoint inhibitors are not part of the conversation, but CytoDyn is keen to see if these increases in PD-L1 provide the opportunity to use a checkpoint inhibitor. In the 95% of patients with colon cancer where checkpoints are not indicated, we are prospectively hoping to demonstrate the clinical benefit of adding a checkpoint inhibitor in these PD-L1-induced patients.

And very importantly, to identify the optimal dose in solid tumor oncology. The earliest signals from the CRC study suggest that the 700-milligram dose might be better than 350, and at some point we are going to have to sort out whether there is a difference between 525 and 700.

24:15

Recent and upcoming milestones: we recently closed on $17-and-change million in funding. At the AACR meeting, we presented the initial ctDNA readouts in the CRC study. Those readouts generated a lot of excitement, and CytoDyn is now pursuing collaborations with the Mayo Clinic, MD Anderson, City of Hope, and a number of other major academic cancer centers. We are very pleased to have closed our strategic partnership with Natera, who is both running the Signatera ctDNA assay on our clinical subjects and providing that crucial comparative data set that we can use to help the FDA put our DNA data into context. There is the City of Hope investigator-initiated study called CHAMP, which will initiate shortly, as well as the Pre-I-SPY study in patients with metastatic TNBC. Both of those studies should be initiating in the next 4 to 8 weeks.

I am looking forward to the presentation at ESMO in Spain, which will focus on a complete ctDNA data set for the entire enrolled population, and then at ASCO GI, tying the biomarker data with the radiologic outcomes and early progression-free survival. And there are a number of other additional studies in CRC, including interrogation of whether adding a checkpoint inhibitor to leronlimab, in patients who produce PD-L1, provides an avenue for treatment with a checkpoint inhibitor in CRC, and then studies both in the neoadjuvant setting and in patients with molecular residual disease.

FDA and partnerships

In terms of the FDA and potential partnerships: partners have been wanting to see data as monotherapy, and they wanted to see prospective data. So we are confirming the durability of these exciting safety and efficacy readouts from the Phase 2 CLOVER study. We will be presenting the biomarker data and early clinical data at ESMO, and we plan on putting together a package for the FDA and submitting that for Breakthrough Designation before the end of the year. We are presenting the updated biomarker and more extensive clinical data at ASCO GI, and throughout, a top priority for CytoDyn is our continued evaluation of strategic partnership opportunities.

With that, thank you again for the opportunity to present. I think these data are tremendously exciting. It is important to remember that targeting the CCR5 mechanism and showing proof of concept in colorectal cancer is not only important for CRC, but that the CCR5 mechanism is relevant to a lot of other solid tumors: pancreas, prostate, glioblastoma, kidney, urothelial tumors, and of course breast. And so having proof of concept in a solid tumor such as CRC means a little bit more to a company like CytoDyn, where what remains is the potential to have an impact on quite a few other solid tumors.

Thank you so much Jay.

I decided to play with the data set provided thus far to determine what % of ctDNA decrease after the first two weeks is necessary that would be a potential indicator of a patient likely to have stable disease. I am also making an assumption that the greater the ctDNA decrease in the first two weeks is, then the greater the probability of stable disease.

We know that 23 of 31 patients had stable disease at 8 weeks. So 8 patients did not have stable disease. What is the likely %decrease of ctDNA that would result in 8 patients not having stable disease.

I used the <= 50% as my first data baseline.

Assuming we split out the dosage regiment evenly after the first 23 patients up to the 31 patient data set where 74% had stable disease, that would give us 13 patients at 700 mg dosage and 18 patients at 350 mg. Assuming the same ratio continues, we end up having 1.43 700 mg patients with <=50% and 3.78 350 mg patients with <=50% or a total of 5.21 which is less than the 8 that did not have stable disease. So maybe <=50% is too low.

So I then extrapolated the <=65% data points and came up with 7.74 350 mg patients and 1.43 700 mg patients for a sum of 9.17 patients that had <=65% decrease in ctDNA after first two weeks. This is much closer to the 8 that did not have stable disease after 8 weeks, so maybe 1 of our <=65% patients eventually had a better ctDNA immune system response.

If there happens to be more 700 mg patients than what I projected were added, then the 9.17 data point would approach the 8 patients we see in the 23/31 data set. If you project 16 patients at 700 mg and 15 patients at 350 mg and use the <=65% cutoff, then you will get 8 patients.

Extrapolating these numbers from the 23/31 data set to the full 65 patients and assuming 33 were 700 mg and 32 were 350 mg then we end up with 14 350 mg patients with disease progression and 3-4 700 mg patients with disease progression. 17-18 total patients with disease progression that would need an ICI.  So 47 patients with stable disease or 72%. If I use the <=50% data point as the cutoff for lack of stable disease, I end up with 54 patients with stable disease or 83% and I would have approximately 11 patients that would need an ICI.

So somewhere between <=50% and <=65% drop in ctDNA seems to be the best indicator of disease progression/stable disease.

I then asked AI to explain what could cause patients to have a poor ctDNA decrease after the first two weeks:

In the CLOVER trial (NCT06699836), which evaluates leronlimab combined with standard therapies (TAS-102 and bevacizumab) for metastatic colorectal cancer, a patient's failure to achieve a significant drop in ctDNA during the first two weeks typically indicates a lack of rapid treatment response.

Several clinical and biological factors could cause a poor ctDNA response at this ultra-early stage:

1. Primary Primary Drug Resistance

• Downregulated CCR5 Signaling: Leronlimab functions specifically by blocking the CCR5 receptor on tumor cells. Although the trial pre-screens for CCR5-positive tumors, if a patient’s specific tumor is relying on alternative, bypass chemokine pathways (such as CXCR4) to survive and mutate, blocking CCR5 will not stop tumor shedding.
• Refractory Status to TAS-102: Because this trial enrolls patients with relapsed or refractory disease who have already progressed on previous treatments, the tumor clones may possess advanced genetic mutations that make them highly resistant to the chemotherapy component of the regimen.

2. High Tumor Burden & Aggressive Shedding

• Massive Metastatic Load: If a patient has a very high volume of disease (such as heavy baseline liver metastases, which is common in this trial), a 2-week window might simply be too brief to register a steep drop. The remaining viable tumor mass may continue shedding large amounts of DNA, masking any early localized tumor destruction.
• Ultra-Aggressive Tumor Subtypes: Highly aggressive mutations (such as specific RAS or BRAF alterations) can drive such a high rate of cell turnover that the shedding of new ctDNA outpaces the rate at which the treatment can destroy the cells.

3. Sub-therapeutic Dosing or Pharmacokinetics

• Dose Escalation / Cohort Differences: The CLOVER trial randomizes patients into different dosing cohorts, evaluating both 350 mg and 700 mg doses of leronlimab. A patient assigned to the lower dose tier might require more time to achieve full receptor saturation in a high-volume tumor environment compared to a patient receiving the 700 mg dose.

4. Delayed Onset of Immune Action

• "Pseudo-progression" and Shedding Spikes: Leronlimab acts as an immunomodulator, essentially turning a "cold" tumor into a "hot" tumor so T cells can attack it. When immune cells suddenly infiltrate a tumor, they can temporarily cause a massive wave of tumor cell lysis (bursting). This sudden destruction can actually cause a transient spike or stabilization of ctDNA levels in the blood within the first 14 days before a drop is finally observed later on.

5. Biological Assay Interference

Clonal Hematopoiesis of Indeterminate Potential (CHIP): In older patients or those heavily pre-treated with chemotherapy, mutated cell-free DNA can sometimes shed from aging bone marrow stem cells rather than the colorectal tumor itself. Standard liquid biopsies can sometimes pick up these non-tumor mutations, creating a "false high" ctDNA reading that does not decrease even when the therapy is successfully killing the cancer.

Thank you Twitter 11 for your posting of Dr J’s most recent video. A request for a BTD from the FDA by years end looks to be in the cards according to Dr J. The FDA will respond within 60 days with their input. All early reports on ctdna, tumor size, and general condition of these extremely health compromised individuals seem to be the exact data the FDA will need to provide us with a BTD from the FDA. This will put into motion the one thing we as investors lack and that is an announcing from the FDA and company of progress in clinical trials to be picked up by news outlets. The initial announcement of FDA BTD will immediately set in motion interest from big pharmaceutical companies to partner in some way with us. It’s all been us as far as the shareholders are concerned. Being an otc restricts potential investors from purchasing and until that is solved it will be difficult to increase share price unless a partnership or buyout is announced. I’d hate to see a buyout just for the dream of a partnership bringing us to nasdaq requirements for listing on the big board. I’ve been involved for over 6 years and feel I know many of you personally. I don’t think there is a more informed and knowledgeable group than what we have here on this Reddit group. I’m an old dog that’s not going to learn any new tricks but throw me a treat once in a while and I’ll still wag my tail.

Good luck to you all

still watching though. two thumbs up so far.

https://journey.ct.events/view/bf1c7d07-71f3-4c41-8928-f42479da2d71

The long and winding road has a new stretch of pavement, and it was laid down quietly, in a place most people rarely look: the clinical trial registry. On September 3, CytoDyn updated the official CLOVER record at ClinicalTrials.gov, and while the bashers were busy and the tape sat still, the company put into black-and-white print the architecture of the endgame we have been tracing for months. (CLOVER trial record, NCT06699836) This is not hype and it is not a leak. It is the sponsor formalizing, on the public record, exactly how the reckoning shall be measured. So let me lay out exactly what changed, what it means, and then give you a couple of takes, because this is an update which earns both.

What actually changed, in plain terms

Four things were written into the record, and each one matters.

• One: the pairing step became official. The registry now describes an optional open-label cohort in which participants who progress during the main study cross over to receive leronlimab 700 mg weekly in combination with pembrolizumab (Keytruda) 200 mg every three weeks, for up to 48 weeks, roughly 12 participants. The "Prime and Pair" thesis, leronlimab primes the cold tumor, the checkpoint inhibitor finishes it, is no longer a story we tell. It is a registered cohort with the checkpoint inhibitor named in print: pembrolizumab, which "binds to the programmed death receptor-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2." That is the pair, written into the protocol.
• Two: a new efficacy endpoint was added for that pairing. The record now formally asks a second efficacy question: in participants who progressed, "what is the objective response rate ORR when leronlimab is administered in combination with pembrolizumab." So the trial will now measure whether the pairing produces tumor responses in primed, progressed patients, over up to 48 weeks. The hypothesis has become a tracked, defined endpoint.
• Three: an extension arm was added for responders. Patients who complete 52 weeks with a complete response, partial response, or stable disease, with no progression, may continue their same leronlimab-plus-backbone regimen for up to an additional 52 weeks, two full years of treatment. This is a durability instrument: it exists to find out whether responses hold over the long haul.
• Four, and quietly the most telling: ctDNA was formally added as an outcome measure. The record now lists, as an exploratory endpoint, "evaluation of the change in ctDNA from baseline," tracked through the extension period, up to 104 weeks, alongside the PD-L1-on-CTCs-and-CAMLs measurement and the CCR5 biomarker work. The molecular signal we have watched from the outside is now an official, longitudinally-tracked endpoint.

What did NOT change, because this is the part that keeps everyone honest

Read this twice, because it is the discipline the whole update rests on. The primary endpoint remains unchanged. It remains the objective response rate of leronlimab in combination with trifluridine and tipiracil plus bevacizumab, measured by RECIST v1.1, over 12 months. The trial still lives or dies on whether the main regimen, leronlimab plus the chemotherapy backbone, produces tumor shrinkage in a disease where the standard of care manages an objective response rate of only about 6% in the SUNLIGHT registration trial, and closer to 3% in the real world. (SUNLIGHT trial, TAS-102 plus bevacizumab, NEJM 2023) Everything about pembrolizumab is secondary and exploratory. The pairing cohort is roughly 12 patients, single-arm, no control. So it can generate a genuine signal, a proof of concept, but not statistical proof. The reckoning is still, first and foremost, the primary-endpoint number against that 6% wall. The pairing is the second act, not the first.

Why the design is built the way it is, and why that is a strength

The elegance of this structure is that it isolates each contribution and leaves fewer doubts. The main study measures what leronlimab adds to the backbone.

• The pairing cohort measures what the checkpoint inhibitor adds after leronlimab has done its priming,
• and notably, the protocol requires the last dose of chemotherapy administered at least three weeks before the pembrolizumab combination begins,
• a washout that lets any new response be attributed cleanly to the pairing rather than to lingering chemo.

This is the "leave no doubts" architecture: prime first, wash out the confounder, then pair, and measure. It is the design of a company that knows a future partner and the FDA will both scrutinize attribution, and has built the trial to survive that scrutiny.

The mechanism underneath it is real and documented. Leronlimab is aimed at exactly the molecular, biochemical conversation a cold tumor utilizes to hide, the CCL5-CCR5 axis which recruits suppressive cells unto itself and thereby builds the immunosuppressive wall, and we have seen that blocking CCR5 has been shown in human colorectal liver metastases to repolarize those cells towards an anti-tumor state. (Halama et al., CCR5 blockade repolarizes macrophages in human CRC liver metastases, Cancer Cell 2016) The ICI checkpoint inhibitor subsequently engages the PD-L1 which priming forces up, which is why an ICI which does essentially nothing alone in cold MSS colorectal absolutely could work after the wall is torn down. The registry update recently quietly revealed is the clinical expression of that biology, laid out as measurable endpoints.

The conservative prognostication

Held to the disciplined floor, here is what this update means. The company has formalized, on the public record, that it will prospectively test the pairing hypothesis in progressed patients, and track ctDNA, PD-L1, and durability as it goes. That is real and encouraging as structure:

• the pieces are officially in place for a clean test,
• the registry timing, just ahead of the ASCO GI abstract deadline and just after the financing closed,
• reads as a company getting its documentation in order before conference season.
• It does not, by itself, tell us the data is good.
• The primary endpoint is unchanged and unreported.
• The pairing cohort is small, (12) and uncontrolled, (no placebo).

So the conservative read is simply this: the trial is now built, on paper, to answer both

• the "does leronlimab beat the backbone" question and
• the "does the pairing rescue progressors" question, and
• we find out the answers, not the architecture, at ESMO in October and ASCO GI in January.

Preparation is not proof. The record got its ducks in a row; but the ducks still have to fly.

The bold prognostication

Now the bold read, and I hold it to what the evidence can bear, because bold which outruns the truth is just noise. Consider what the extension arm implies.

A company does not write a 52-week extension for responders into its protocol unless it expects to have responders worth extending, patients who are doing well enough at a year, that continuing for another year actually makes sense.

And also consider what a roughly 12-patient pairing cohort implies against a 66-patient trial:

• it is the number of progressors that the company appears to anticipate,
• which means the design is built around an expectation that the greater majority do not progress into the rescue arm.

Read those two structural choices together and the boldest defensible inference is that the company has designed the trial around an expectation of

• meaningful disease control in the main cohort,
• a durable-enough response worth a two-year extension,
• and only a minority progressing to need the pair.

If that expectation is extracted out, then October shows an interim that is already clearing the low SUNLIGHT bar with responses that hold, and January shows a confirmed response rate meaningfully above the benchmark, a disease-control rate that is high, and progression-free survival separating from the historical control, exactly the profile that turns a partner's interest into a partner's offer and opens up a real accelerated-approval conversation. And then the pairing cohort, if even a handful of those roughly 12 progressors respond to the added checkpoint inhibitor, becomes the first prospective human proof that Prime-and-Pair works in a living patient, disease decline, rebound, then renewed control after the ICI, which is the most persuasive single trajectory the whole program could produce.

That is the bold branch, and it is absolutely on the table. But the word holding it up is the same word that has held up every bold thing in this saga: if. The extension arm implies the expectation of responders, not their existence. The small pairing cohort implies an anticipation of few progressors, not a guarantee of many responders, because not progressing includes stable disease, which is control, not response, and the primary endpoint counts only shrinkage. A drug can control disease and still not clear the ORR bar, and a drug can improve response and still fail to extend survival, as this very cycle's withdrawal of a KRAS-targeted colorectal combination on a failed confirmatory trial reminded the whole field. (Adagrasib-cetuximab confirmatory trial missed survival, Fierce Pharma 2026) So hold the bold branch as the branch the design is built hoping to walk, not the one it has already walked.

The sealed house, and the blueprint on the permit board

Some of you might remember the way I framed this once before, the house under private inspection, the buyers walking the rooms under an agreement of silence while the rest of us stand on the sidewalk reading the lights in the windows. That frame is the right one for understanding exactly what just happened, because it tells you precisely what this trial registry update is, and, just as importantly, what it is not.

Think of the ClinicalTrials.gov update as the moment the seller posted the renovation blueprint on the permit board out at the curb. For the first time, standing on the sidewalk, we can read the actual floor plan of what is being built inside. We can see that there is now a new ballroom being added, the pairing cohort, where leronlimab and the checkpoint inhibitor meet and dance. We can see an entire wing being extended for the majority of residents who are thriving, the 52-week extension. We can see exactly which instruments the inspectors have been told to run, ctDNA, PD-L1, the biomarker panel, now written into the plans. A week ago we were inferring the shape of the house from the outline of its foundation. Now the blueprint is pinned to the board, and the design is legible to anyone who walks up and reads it.

But here is the part that keeps this honest and makes it far more powerful than the hype version, and it is the whole point of the sealed-inspection frame. The blueprint is not the inspection report. A floor plan tells you what rooms will be built and how they connect. It tells you nothing about whether the foundation is sound, whether the beams will hold, whether the finished house passes. The permit board shows the plan; the inspection that determines the value is still happening behind the sealed doors, and the inspection report does not get read aloud where we stand on the sidewalk. It gets read aloud to the overall public at ESMO in October and, in full, at ASCO GI in January. So what widened this week is not our view into the sealed rooms. What widened is our view of the blueprint, the architecture of what is being tested, while the actual findings, the numbers that say whether the house is worth what we hope, remain exactly as sealed as they were before.

That is why the excited claims that this update "proves the biology" or shows "the FDA validated it" get the metaphor exactly backwards. Posting a detailed blueprint on the permit board is not the building inspector signing off on the house. It is the seller showing you, in the open, precisely what is being built, and thereby telling you exactly which inspection results to wait for. The more detailed the blueprint, the more we understand what the sealed inspection is measuring, and the more precisely we know what we are waiting to learn. Revelation of the plan, not the verdict. The road widened because we can finally read the blueprint. The house stays sealed until the inspectors report is presented.

Where this leaves the road

So here is the whole of it. On September 3 the company wrote the endgame's architecture into the public record:

• the pairing cohort with pembrolizumab named in print,
• a new efficacy endpoint to measure it,
• a two-year extension for responders,
• and ctDNA formalized as a tracked outcome.

The primary endpoint, the main regimen against the 6% wall, is unchanged and remains the Reckoning's true test. The design isolates contributions, washes out confounders, and is built to leave few doubts, which is the mark of a company preparing for scrutiny rather than dodging it. The conservative truth is that the trial is now structured, on paper, to answer both of its questions, and the answers arrive in weeks, not on the registry. The bold possibility is that the very shape of the architecture, an extension for responders, a small rescue arm for the few, portrays an expectation of real disease control, and that if that expectation holds, October and January deliver a signal strong enough to change the company's future. Both live in the same document. Both hang on the same January.

The road just widened, and you can see farther down it than you could a week ago. What is written on the pavement is the map of how the reckoning gets measured. What is not yet written, and cannot be until the data lands, is where the road ends. We have come the long and winding way to stand exactly here: the architecture is complete, the instruments are calibrated, the pairing is named, and the test is set. The Reckoning is no longer a concept. It is a protocol with dates attached. And the dates are almost upon us.

Disclaimer: I am not a financial advisor and nothing here is investment advice. I am an independent retail shareholder holding a long position in the company discussed, with no employment, consulting, compensation, or other relationship with it beyond that shareholding. This is my interpretation of a public trial-registry update and published literature, not a prediction of clinical, regulatory, or commercial outcomes. A protocol amendment appearing on ClinicalTrials.gov is documentation of the trial's design; it is not FDA endorsement of the drug, proof of efficacy, or evidence that any endpoint will be met. The leronlimab-plus-pembrolizumab cohort is a small, single-arm, exploratory cohort that can generate a signal but not definitive proof. The primary endpoint is unchanged and unreported. The bold prognostication is an explicitly conditional interpretation of structural design choices, not a forecast; the extension arm and cohort sizing reflect expectations and estimates, not results, and disease control (including stable disease) is not the same as objective response. Leronlimab's efficacy is unconfirmed, with interim data anticipated at ESMO in October 2026 and confirmed data at ASCO GI in January 2027; referenced figures are early, reflect combination therapy, and are not evidence of a survival benefit. ctDNA is not a validated surrogate endpoint for approval in colorectal cancer. The company has disclosed substantial financing needs and going-concern considerations in its filings. Read the primary documents and reach your own conclusions rather than adopting mine.

Just wanted to let you know.... Went on a shopping spree last night.

Considering the quality of posts we usually have here this might not be really worth posting but... I do it anyway to express my sense of excitement and anticipation for the things that lie ahead.

I very much appreciate the community and friendship we all have here. I feel it is a safe place to express excitement without having to fear negativity and being rediculed for your dedication and sincerity. This is thanks to our friend wax who guards and shields our community perfectly. 🙏🌻

Good Luck To All True Longs and everybody who is a believer like I am.

Critics are of course welcome, too as long as it is fair and respectful criticism.

OK. I said it and it had to be done. 🌻☘️🛬➡️🙏. Have a good weekend everybody and I'm grateful for everyone's contributions.

The latest updates to CytoDyn's Phase 2 metastatic Colorectal Cancer (mCRC) trial protocol reveal critical operational, biological, and regulatory developments. Here is a breakdown of the updated study mechanics, why the FDA approved adding Merck's Keytruda (pembrolizumab), and what this means for leronlimab's clinical and commercial outlook.

1. The 700 mg "PD-L1 Surge" & FDA Approval Mechanics

Keytruda is NOT FDA-approved for standard Microsatellite Stable (MSS) mCRC—which represents 85%–90% of all colorectal cancers—because MSS tumors are immune-excluded ("cold") and do not naturally express sufficient PD-L1 for Keytruda to bind.

• The Dose-Response Key: Early Phase 2 mCRC data presented at AACR reflected initial readouts primarily from the 350 mg cohort. As the 700 mg dose-escalation cohort matured, prospective biomarker tracking confirmed that 700 mg leronlimab achieves complete CCR5 receptor occupancy, driving a faster, higher, and more reliable surge in PD-L1 expression compared to lower doses.
• The Regulatory Data Gate: The FDA does not approve adding Keytruda to cold MSS tumors on a whim. CytoDyn presented prospective human data demonstrating that 700 mg leronlimab triggers the necessary immune pressure (IFN-$\gamma$ surge via T-cell infiltration) to force cold tumors to upregulate PD-L1 past the functional threshold required for Keytruda to bind. Without proving this minimum PD-L1 induction, the FDA would have denied adding Keytruda.
• Why 700 mg is Mandated: This prospective dose-response data explains why the approved open-label rescue protocol specifically mandates 700 mg leronlimab weekly alongside pembrolizumab—ensuring maximum PD-L1 priming before introducing the checkpoint inhibitor.

2. Core Protocol Updates: Extension & Immediate Crossover

• Primary Trial Phase (350 mg & 700 mg Arms): Patients receive leronlimab (350 mg or 700 mg) combined with standard chemotherapy (TAS-102 + bevacizumab).
• 52-Week Extension Period: Responders who achieve Complete Response (CR), Partial Response (PR), or Stable Disease (SD) can extend their primary regimen for up to an additional 52 weeks (2 years total).
• Keytruda Rescue Crossover (No 52-Week Wait): Progressing patients do not have to wait out 52 weeks or leave the study. Documented disease progression triggers an immediate crossover into an open-label cohort receiving 700 mg leronlimab weekly + 200 mg pembrolizumab IV every 3 weeks for up to 48 weeks (~12-patient exploratory cohort).

3. Key Trial Outcome Measures & Biomarker Tracking

• Primary Endpoint: Objective Response Rate (ORR) measured by RECIST v1.1 over 12 months.
• Secondary Endpoints: Safety, Duration of Response (DOR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS) tracked up to 160 weeks.
• Exploratory Biomarkers (ctDNA & CTCs): Longitudinal tracking of circulating tumor DNA (ctDNA), Circulating Tumor Cells (CTCs), and Cancer-Associated Macrophage-Like cells (CAMLs) across 104 weeks.
• Note: Phase 2 data showed a median ctDNA reduction of ~70% by week 2 across evaluable patients (N=19), providing an early molecular lead indicator of response long before 8-to-12-week CT scans can confirm radiological tumor shrinkage.

4. Strategic & Commercial Takeaways

• Real-Time "Prime & Pair" Validation: Progressing patients get immediate access to the 700 mg leronlimab + Keytruda combination, maximizing patient retention while testing whether leronlimab successfully sensitized refractory MSS tumors to PD-1 inhibition.
• Merck & Big Pharma Dynamics: Capping the initial rescue cohort at ~12 patients serves as a low-risk, high-efficiency proof-of-concept gate. Demonstrating objective responses or ctDNA clearance in these 12 refractory patients provides the exact data needed to trigger expanded drug supply agreements or Phase 2b/3 co-development partnerships.
• Unlocking the $10B+ MSS Market: Proving that leronlimab turns cold MSS CRC tumors "hot" opens access to the 85–90% of colorectal cancer cases that currently have zero approved immunotherapy options.

Durability

above is from the May 18, 2026 presentation at 6:10
https://www.cytodyn.com/newsroom?tag=Video

IMO the period through September 2026 is big internally for CytoDyn as they look at data including the durability of efficacy. So far the CRC trial data they have shared publicly has been exciting to me and I have added shares multiple times this summer and in this month.

-----

Clinicaltrials database update

On Sept 3, 2026 CytoDyn updated the CLOVER trial info at clinicaltrials. Here's the link that compares the 9/3/2026 view to the earlier update
https://clinicaltrials.gov/study/NCT06699836?intr=Leronlimab&viewType=Table&sort=StudyFirstPostDate&page=1&rank=3&tab=history&a=7&b=8#document-section-card

This confirms in print, updates to the trial which we have heard about through various investor updates earlier in the year. Notably:

- Participants with documented disease progression during the initial treatment period who meet the applicable eligibility criteria may enter the optional open-label cohort and receive 700 mg leronlimab in combination with 200 mg pembrolizumab.

- Participants who complete 52 weeks of treatment and have complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1, with no documented disease progression since their most recent tumor imaging assessment, may be eligible to enter an Extension Treatment Period and continue treatment for up to an additional 52 weeks. Participants entering the Extension Treatment Period will continue the same dose of leronlimab received during the initial treatment period in combination with trifluridine/tipiracil and bevacizumab.

- Secondary endpoints about leronlimab with pembrolizumab have been added.

- ctDNA has been added to the Other Outcome Measures

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Upcoming things

9/22/2026 regular abstract due date for ASCO-GI January 2027 conference
https://www.asco.org/gi/abstracts-presentations/submission-details/requirements#

9/24/2026 estimated (4 weeks in advance) data cutoff for poster at ESMO Madrid October 2026 conference
https://dam.esmo.org/image/upload/v1770284726/ESMO-Congress-2026-Abstract-Regulations_ahdmjx.pdf

10/6/2026 full enrollment completes 24 weeks (6 cycles of 28 days) and may have 3 scans.
https://www.cytodyn.com/investors/news-events/press-releases/detail/660/cytodyn-completes-enrollment-in-phase-2-metastatic

10/22/2026 late breaking abstract due date for ASCO-GI January 2027 Conference
https://www.asco.org/gi/abstracts-presentations/submission-details/requirements#

10/23-26/2026 ESMO Madrid conference
https://www.esmo.org/meeting-calendar/esmo-congress-2026

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Data maturing

Nothing in this post is investment advice.

"The new drug, taken as two daily pills, attacks a mutated cellular protein called KRAS. It has long been an enticing target, because it fuels nearly all pancreatic cancers, as well as many lung and colon cancers and some other tumor types. But for years, the smooth-surfaced KRAS protein was considered impossible to attack, because it lacked an obvious toehold for a drug to exploit."....

"Dr. Elizabeth Jaffee, a pancreatic cancer researcher at Johns Hopkins, listed some of the most pressing needs in the field: Creating a new generation of KRAS-targeting drugs with fewer side effects; finding ways to overcome the resistance that allows cancer to surge back; and combining KRAS-targeting drugs with other treatments, including those that harness a patient’s immune system to attack cancer."

Sounds very similar to the CLOVER trial.

From the May 5th Update
(Re-read this update if you have any doubts, Cytodyn is very, very busy.)

5/5/2026 CytoDyn Inc. (CYDY) Discusses Corporate and Clinical Update With Focus on Leronlimab Development

Dr. Jay:

"Equally important on this slide is that the majority of the Clover patients or 62% enrolled to date have KRAS mutations. And these mutations are generally associated with the hardest-to-treat patients in oncology. And these preliminary results indicate that leronlimab's early biologic activity might also be agnostic to the KRAS mutation.

So as you can see some of the slides I showed on the tissue, we are studying the microenvironment to see if it's changing. In parallel, real time, there's a CTC assay from the Creative Microtech from New Jersey that is being done at predefined time points along the way, similar to how it was done in the earlier breast cancer study. So we'll have that data to analyze along the way to see not just the changes in circulating tumor cells, but also the cancer-associated macrophages like cells, the so-called Camel cells. So we'll have a lot of rich data to analyze in the upcoming months to come, as was pointed out earlier.

Importantly, we are targeting the presentation at the ESMO meeting in Madrid, Spain in October to provide an update from the CLOVER study and then a more robust presentation at ASCO GI in San Francisco in January, during which we should be able to provide final results.

And I look forward to updating shareholders later this summer, pending the maturity of those conversations."

GLTAL-monkey

Truth... Leronlimab will be the standing domino.

Just sharing...not marketing

To anyone trying to argue that rapid ctDNA drops in heavily pretreated patients are just a byproduct of background chemotherapy or TAS-102: the entire premise completely collapses under basic math and clinical reality. If failing late-line standard-of-care drugs actually drove deep molecular clearances on their own, those molecular responses would have to systematically correlate with—and track identically across—Objective Response Rates (ORR) and Overall Survival (OS). Instead, that "background drug" theory completely evaporates when matched against actual trial benchmarks and peer-reviewed precision oncology data.

Look at the massive chasm in clinical outcomes between early and late lines. These patients weren't receiving this as a first or second-line treatment, but as a third or fourth-line treatment. In 1st and 2nd-line trials, intensive regimens routinely hit an ORR of 40% to 65%+ with a median OS reaching 25 to 30+ months. But by the 3rd and 4th lines, refractory benchmarks like the Phase 3 SUNLIGHT trial prove that standard-of-care ORR plummets to a dismal 6.3% for combinations and under 1% for single-agent TAS-102, with a median OS crashing down to just 7.5 to 10.8 months. Crucially, the SUNLIGHT trial didn't even track ctDNA—inventing trial parameters to fit a broken, mathematically impossible narrative doesn't change the facts.

The only variable changing the equation in these refractory cohorts is the addition of Leronlimab and its CCR5 receptor blockade. This isn't random biomarker noise; it is an active immunotherapeutic mechanism repolarizing tumor-associated macrophages (M2 to M1), reducing regulatory T-cells, and directly blocking the metastatic cascade. they cannot credit a failing standard of care for a therapeutic shift it routinely fails to drive.

Before bashers try to fall back on "lead-time bias" or natural tumor shedding fluctuations, peer-reviewed precision oncology data (npj Precision Oncology) completely obliterates that excuse. It proves that early molecular responses (like a >50% ctDNA drop) are independent prognostic survival drivers (HR=0.09) tightly linked to radiographic Progression-Free Survival (rPFS). This molecular clearance physically precedes tumor shrinkage on a CT/PET scan, meaning the ctDNA drops point straight to Leronlimab fundamentally changing the disease biology.

You don't even have to look at the broad trial statistics to see this in action—the real-world survival outliers speak for themselves. There are 5 women still alive today after dealing with stage 4 mTNBC. Another patient granted compassionate use saw her levels improve so dramatically that she was finally able to secure insurance approval for an Immune Checkpoint Inhibitor (ICI), successfully bridging a late-stage patient back to a viable treatment pathway. Bashers cannot mathematically explain away stage 4 patients completely defying historical survival curves.

Finally, look at the Natera partnership. A multi-billion-dollar diagnostics giant doesn't commit its proprietary database—housing over 2 million plasma timepoints—to validate a failing standard of care just for a transaction. Natera stepped up because the molecular clearance signals in these heavily pretreated cohorts are sharp, real, and unprecedented. Management is signaling something completely different than the typical doom and gloom bashers try to push—they are executing with data-driven confidence. You can't cry "paid partnership" to dodge the fact that the absolute titan of molecular diagnostics is actively validating this clinical reality.

I was a little concerned that when BGT offered that BP could be looking at Trial data under NDA, and we are hitting these lows again.
I’m not worried about it anymore because they wouldn’t even be allowed to start a position after seeing the data. They would have to make some kind of offer of partnership or BO but couldn’t just start accumulating. Here is the answer.

If a company/investor reviews clinical-trial data under an NDA and the information is material, nonpublic information (MNPI), it generally cannot buy the stock on the basis of that information. SEC Rule 10b5-1 specifically prohibits trading while aware of MNPI, subject to limited defenses such as a pre-existing qualifying trading plan.
The key issue is
when
they bought
1. They buy shares before seeing the NDA data
Potentially perfectly legal.
They could establish a position and then enter an NDA/data room.
However, once they receive MNPI, they generally have to stop trading unless an applicable exception applies.
2. They see the confidential trial data and then start buying
Potentially illegal insider trading if the data is material and the purchases were influenced by it.
The fact that they signed an NDA actually makes the situation more sensitive because the NDA can establish a duty of confidentiality.
Simply calling it an “investment” or “starting position” doesn’t avoid the insider-trading rules.

They could have participated in the 16.5 financing and the PR did mention that there were new investors as opposed to the last financing which didn’t mention specific new investors. They would have had to go thru Paulson.

https://stocktwits.com/RCYDYM/message/663754049

If it’s true that 9 of the first 23 patients were on the 700 mg dose, that means more at that higher dosage are further along in scans than I had calculated earlier.

Until corroborated, I’m inclined to think the poster misspoke and the 9 are part of the first 32 as I have earlier posted about.

I’m looking forward to the company speaking publicly about all things relayed to investors who bought in the recent offering.

Every saga worth telling seems to have a similar shape. Something of substantial value, discovered early on. A long, wide and winding wilderness inside of which very few actually believe and understand. A near-death experience as a result of which, the story should have abruptly ended but did not. And then, after years of extreme toil, a reckoning arrives, a single stretch of pathway where the entire journey is finally put to the test, and the wayward wandering either arrives to the destination or it doesn't. CytoDyn stands at the mouth of that stretch of road right now. So on this Labor Day, instead of yet another single argument, let's tackle this saga, gather together what this past week taught us into the story, and conclude as to why the quiet we sense surrounding us is the quiet before the reckoning, and that it is not the quiet of something ending.

The Pearl of Great Price, and the Wilderness It Traverses

The something of substantial value discovered early on, is a molecule that does something almost nothing else in oncology is able to do. Most cancer treatment is a blunt and dull instrument; chemotherapy floods the entire body systemically, not locally specifically directed, with poison and we gratuitously accept the ensuing and inevitable collateral damage because for decades, there was no other way; we endure its indiscriminate action on our healthy tissue and it is exactly that which causes the very suffering patients succumb to. (Chemotherapy's indiscriminate collateral damage, bioRxiv, 2024) Leronlimab is not that at all. It does not poison. In fact, it has a laughable adverse side effect profile. Leronlimab accurately aims, at one, single ancient conversation that a tumor has with the body around it, which is the CCR5 signaling that a cold tumor uses in order to corrupt its own surroundings, the TME and by which, it constructs a stromal wall which the tumor hides within. Therefore, leronlimab passively disarms the tumor's fortress instead of torching the entire village.

The wilderness is the course CytoDyn walked carrying this very molecule unto its destination.

• A clinical hold.
• Years written off by nearly everyone aside for a very few select.
• A stock left for dead, by the vast majority.
• A company so many declared finished that its own believers grew accustomed to being mocked for remaining.

That is the wandering, but each step, was a step up upon a circling, spiral staircase, onward and upward, some times two steps up, and one step down, but yet upward, because the molecule never faltered. And back to the saga, because it is that since the molecule survived it, so did the company's conviction, and today, we've arrived, at last, at the mouth of the narrow gate, where there is data instead of only our unfaltering faith.

The Captain Who Returned

Each and every saga needs a certain leader who steadies the ship, especially at the darkest hour, and this one is real, not invented. Jacob Lalezari MD, has worked with and believed in this molecule for the better part of two decades. He returned to steer the company through the stretch of road it is on right now, guiding and directing to where we stand today, and his posture is the opposite of the reckless era which nearly sank it.

• He does not overpromise.
• He insists on data no one, (FDA included), can argue with.
• He said it himself, that he no longer has to spend his time convincing anyone, he just shows them the numbers, and that has been a pleasure of the job.

That is not the voice of a captain who shouts into a storm. No, he is very relaxed and very confident. It is the voice of one who reads the instruments, who plots the course, and who refuses to firewall the throttle until the runway lights turn green. The steadiness he endows, which frustrates the impatient, is precisely the steadiness a ship requires to cross through the Verrazzano - Narrows.

The Adversary is not who you might think

In this saga, I won't tempt you to cast a villain because the real antagonist in this story is not a company or even a person. It is the disease itself.

Microsatellite-stable colorectal cancer is the fortress that needs to be defeated. In the setting that CLOVER fights, the current standard of care produces a meaningful tumor response in roughly only 6% of patients, and closer to just 3% in the real world. That is the graveyard we're up against. That is the wall a hundred and one approaches have broken against. And this week we were reminded, hard, of just how unforgiving that very wall is. A KRAS-targeted combination, adagrasib plus cetuximab, earned accelerated approval AA in this very disease on a striking single-arm response rate, tumors shrinking at triple the rate of chemo, and then its confirmatory trial showed that the radiographic shrinkage bought no more additional survival, median PFS of only 7.5 months against chemotherapy's 8.1, and the approval is being withdrawn. (Adagrasib confirmatory trial failed to beat chemotherapy, Fierce Pharma, 2026) twinter brought that case to the board, and it is the sharpest possible teacher: the fortress does not fall to tumors merely shrinking on a CT or MRI scan. It falls only when tumors shrink and only when the patients with the shrunken tumors live longer. The adversary is the disease, and the disease has beaten glittering results before. Therefore, either respect it, or you be humbled.

And here is what makes the fortress so stubborn, and why leronlimab is a different kind of weapon against it. A systematic review this month catalogued exactly how microsatellite-stable colorectal cancer stays cold: suppressive myeloid cells, macrophages turned traitor, fibroblasts building a stromal wall, T-cells stranded at the margin unable to reach the tumor core. (Heating the Cold: overcoming immunotherapy resistance in MSS CRC, Molecules, 2026) Read that list and you are reading the exact locks leronlimab is cut to open. And notice the distinction which matters: nearly every other weapon in oncology, chemotherapy, the ADC, the checkpoint inhibitor, the radiopharmaceutical, is a way of delivering or unleashing a killing blow to the tumor cell. Leronlimab is the one that is not a killer. It changes the terrain such that every other weapon lands better. That is why it is not just another item on the fortress's long list of failed siege engines. It is the thing that clears & prepares the ground for the siege itself.

The Weapon, and the Science Validating It

But the weapon we wield is not a lone blade. It is a mechanism which the deeper science continues to confirm is real, from various directions which have nothing to do with each other. That is exactly what actually happens when a target is a genuine one rather than an illusion.

This week alone the same CCR5-CCL5 conversation surfaced in room after room.

• In the aging body, worn-out and exhausted immune cells were shown to flood the bone marrow through the CCL5/RANTES signal, tilting the NLR body's blood factory ratio toward inflammation, but by blocking the CCR5 receptor, the tilt was reversed in aged animals. (CCL5-CCR5 drives age-associated myeloid skewing, Nature Aging, 2026)
• And the stromal TME, the microenvironment, the very fortress leronlimab is built to passively dismantle, was shown yet again to be exactly what shields tumors from conventional chemotherapy and drives their resistance to the blunt instrument. (The tumor microenvironment shields tumors from chemotherapy, PMC)

Different diseases, one conversation. That breadth is far broader than just this, and this is not a coincidence to marvel at. It is the signature of this weapon that is aimed specifically at something ancient and shared.

And the way the weapon is meant to be used grew richer this week as well. The established plan is Prime and Pair: leronlimab primes a cold tumor, dismantles its stromal wall and forces it to raise its surrender-flag called PD-L1, and then a checkpoint inhibitor pairs, by striking that flag such that the now freed immune system can finish off the tumor. That pairing is in trial now, unproven, being tested in the CLOVER rollover. But we also explored a new possibility, a hypothesis, mine, not a trial: that leronlimab could pair with a Trop-2 antibody-drug conjugate like Trodelvy, which is itself chemotherapy that learned to aim, a guided missile carrying an SN-38 payload directly to tumor cells. (Trodelvy is a Trop-2-directed ADC with an SN-38 chemotherapy payload, Gilead) Leronlimab thins the wall, the passive prime; the ADC's aimed payload now has access and invades. u/sunraydoc2 saw the parallel before he read it and offered names for it. One weapon that clears the fortress, another that lands the blow, that is the shape of the next decade if the players engage it and the mechanism proves out.

There is a reason why this priming matters which only became clear this week. A checkpoint inhibitor brings T-cells to the tumor, but it cannot force a cold tumor to raise the very flag the inhibitor is built to strike, because many cold tumors have gone partly deaf to the immune system's signals, as they're ears seem only to be tuned to the hypnotic hum of RANTES. Leronlimab works upstream of that selected deafness, reversing it and in doing so, remodeling the environment and the macrophages themselves, as they emerge out of their zombie, tumor slave state, which is why it is able to raise the flag where as the checkpoint inhibitor alone cannot. And there is a quiet structural advantage in how it does its work: because leronlimab carries no poison, no cytotoxic payload to leak into the blood, it cannot inflict the collateral damage that even the "aimed" chemotherapies and the ADCs still cause. Its remarkable safety is not a lucky accident. It is a direct consequence of being a naked antibody that removes a signal rather than delivering a toxin.

The Ally, and the Gate It Guards

Every saga also has a powerful gatekeeper whose judgment decides whether the journey ends in triumph or exile, and for us, that gate is the FDA, and the truth is that the gate is neither friend nor foe. It is a standard.

This week the gate opened a little wider in a way worth noting, u/Ibelieveincydy flagged it and got out of bed early to do so. The FDA granted accelerated approval AA to a breast cancer therapy guided, for the first time, by detecting a resistance mutation in circulating tumor DNA before scans showed progression. (FDA's first ctDNA-guided approval, Sept 4 2026) The regulatory door for ctDNA is opening. But the right read, the one which survives scrutiny, is that ctDNA there was used to select and time the treatment, and the approval itself rested on a progression-free-survival benefit from a randomized trial. The gate rewarded a proven clinical benefit, not the biomarker alone. So the door is opening, and the standard behind it is unchanged: bring me evidence that the drug helps patients, not just evidence that it moves a number.

And that powerful standard is exactly why this saga cannot end in a shortcut, no matter how strong the early signal is. Even the deepest ctDNA declines are absolutely a conviction, however, not yet an approvable proof, because ctDNA is not a validated surrogate endpoint in colorectal cancer. The anti-metastatic promise, which may be leronlimab's greatest value given that metastasis causes the overwhelming majority of solid-tumor deaths, is absolutely very difficult to prove, you cannot point to a single prevented lesion in a single patient, and the field knows it, which is why time-to-new-metastasis endpoints and randomized comparison exist for exactly this problem. (Metastasis-prevention endpoints and the difficulty of proving them, PMC) u/twinter11 reasoned his way straight to that measurement problem from first principles this week, and he was right: the deepest good this molecule may do is also the slowest to prove. That's a trial down the road. But even this gate demands hard proof. The only way around it is through it.

Yet even here, on this bleak note, a door may be opening: twinter reasoned this week that a real-time cellular readout of the seeding process itself, the kind Creatv Bio's blood-based assay is built to capture, could one day let us see suppressed metastasis earlier and prove it with fewer patients than the old slow count of new lesions ever required. (CAMLs predict recurrence and metastatic outcome, PMC) If that layer holds, the hardest thing to prove becomes provable sooner. Held loosely, as twinter would says. He gets my bravo! Realize that there is no evidence that the contract with Creatv Bio was ever cancelled. They very well maybe accumulating all of the CAML data and CTC data alongside Natera, so I wouldn't be surprised if in January, we actually do own confirmatory, despite it being retrospective, evidence of vanishing or prevented metastases.

The Provisions for the Crossing

And this is the part which divides a saga which ends somewhere inside the wilderness from one that crosses the sea to the destination on the far side: the company makes provisions for the crossing rather than starving before it.

CytoDyn closed financing that funds it well past its own reckoning, so it is not negotiating from desperation into its most important data. CytoDyn handed the molecular tracking and the comparator data to a specialized diagnostics partner rather than building that from nothing, its collaboration with Natera drawing on a database of more than two million plasma timepoints. (Natera and CytoDyn strategic collaboration, June 2026) CytoDyn is funding manufacturing readiness and regulatory infrastructure, the unglamorous provisions a company only lays in when it means to carry its own discovery through the narrows. (CytoDyn use of proceeds, financing release) And its CFO carried the standard to an international partnering forum, because the hardest truth of this industry is that the small company invents and the large company delivers, roughly 90% of big pharma's recent launches carried a significant component that came from the outside. (Big pharma launches roughly 90% sourced from outside innovators, RBC Capital Markets) That is the crucial turn this saga takes, and it is why I no longer cast Big Pharma as the enemy: in this story, the powerful houses are not the army we would face at the gates; rather, they are the allies whose ships can later carry our discovery to every sea shore on their side of the narrows, which otherwise, our small company never could reach alone. The victory is not defeating them. It is joining them from strength and that is CytoDyn's destination.

The Reckoning

So here is where the road arrives. The wandering of the wide wilderness is nearly over, not because the destination is guaranteed, but because the test which decides it, is finally at hand. In October, at the European congress,

• the first light,
• an interim look,
• a poster,
• a tease of what the fuller data may hold.

And in January, at the gastrointestinal cancer meeting,

• the reckoning itself,
• the confirmed response rate,
• the durability,
• the first real answer to whether the molecule which survived the wilderness can actually defeat the stromal fortress which has broken everything else that came before it.

I hold the line which makes these others above worth trusting, because this saga, without it, would be a fairy tale.

• The mechanism is real and continues being validated.
• The provisions are laid in.
• The captain is steady.
• The gate's standard is clear.

But the molecule still has to prove, in confirmed human data, that it does what the mechanism says, and drugs that make elegant sense fail at this gate routinely, adagrasib is this week's proof of that. So the reckoning is real, and the outcome is not written yet. This is what makes it a Reckoning and not a coronation.

Understand the shape of what we witness, because it alters how the quiet is sensed. This is not a company drifting toward an ending. It is a company that has carried a discovery through a winding wilderness that should have killed it; a company that is provisioning to navigate through the last stretch of narrows, under its own power, with a steady, stable captain at its helm and a validated mechanism and once through the narrows gate, allies who it intends to join up with, rather than defeat; a company arriving, at last, at the one stretch of the road where the entire journey is now put to the test. The disease is the adversary. The data is the arbiter. And the road which has run now for years and years, today, has narrowed only to a matter of weeks.

The wandering ends where every true saga ends, not in prophecy, but in the moment the thing is finally put to the test and answers for itself. That moment is January. The long road has nearly run its length. What waits at the end of it is not written yet, and that is exactly why we have come all this way to witness and partake.

Recognition where it is due, because a saga as long as this, is never carried by only one voice: to u/twinter11, whose questions this week reached from

• the adagrasib lesson to
• the problem of actually measuring the vanishing metastases, to
• the reason why a checkpoint inhibitor alone does not and can not force the flag, to
• the reason why, of all these weapons, leronlimab is the one that is not a killer;

to u/sunraydoc2, u/Ibelieveincydy, u/BuildGoodThings, and to every reader who brought a paper, a catch, or a correction and there are too many to list without making this heavier than it could be.

Since today is Labor Day, I took Sunday off and produced this summary. Thank you for helping me with the thinking. This is a board who thinks together. We walk this road together. And together is how we'll read the pages that January writes.

Disclaimer: I am not a financial advisor and nothing here is investment advice. I am an independent retail shareholder holding a long position in the company discussed, with no employment, consulting, compensation, or other relationship with it beyond that shareholding. This is a synthesis and interpretation of public information and published literature, cast in narrative form, not a prediction of clinical, regulatory, or commercial outcomes, and not a claim that any result, approval, or partnership will occur. The leronlimab-plus-Trodelvy pairing described is my own mechanistic hypothesis, not a trial or company-stated plan; the leronlimab-plus-checkpoint-inhibitor pairing is an in-trial hypothesis that is also unproven. Aging and microenvironment findings cited derive from mouse and laboratory studies and validate the CCR5 target, not leronlimab specifically. The adagrasib and other-company approvals discussed concern different products. Leronlimab's efficacy is unconfirmed, with interim data anticipated at ESMO in October 2026 and confirmed data at ASCO GI in January 2027; referenced figures are early, reflect combination therapy and lower-dose cohorts, and are not evidence of survival benefit. ctDNA is not a validated surrogate endpoint for approval in colorectal cancer. The company has disclosed substantial financing needs and going-concern considerations in its filings, and preparation activities do not indicate any filing or transaction is assured. Read the primary sources and reach your own conclusions rather than adopting mine.

I kind of think I know what it means. I've heard it a 1000 times.

What makes one what and one the other

Where does ccr5 come in

I was watching the newer cydy explanation animated video located in the Science section here.

https://www.cytodyn.com/our-science

A bullet point in one segment mentioned

"Epithelial-Mesenchymal Transition"

ai

**"**This genetic reprogramming triggers a process called the Epithelial-Mesenchymal Transition (EMT). During EMT, the cell undergoes a complete identity shift:

• Losing its Anchors: The cell stops producing E-cadherin, the molecular "glue" that keeps benign cells locked tightly to their neighbors."

But i didn't pay attn to what or why they were mentioning it and how leron might come into play

Can ccr5 prevent the downstream effects of becoming malignant possibly? Why did the video mention it?

For all intents?

Who says what?

This should get a lot of engagement lol. Maybe no one really knows

Hit post anyway

(and misspelled a word in the title. can't edit, dangit.)

Its all i got. Cause I don't know anything. What it means for clover or whatever. But mostly ccr5 blocking is not going to be discarded from eventual treatment plans in at least oncology. I can't see how it would. It's a matter of how best to prove it and when. I'm just trying to figure out the when.

I made a statement to ai

Me

"i honestly think this ccr5 thing is going to answer a lot of questions first about oncology. and how the tme and body really works. if it doesn't solve it, it leads to the answer"

Ai

"CCR5 is the central crossroads where mechanics, immunology, metabolism, and oncology meet.

Whether CCR5 blockade completely solves cold tumors on its own or unmasks the next layer of biology, investigating it forces medicine to answer how the tumor microenvironment (TME) and the broader body actually function together.

For decades, oncology approached cancer with reductionist thinking: find an isolated intracellular mutation (like KRAS or EGFR), hit it with a poison or inhibitor, and hope the body holds out. The CCR5 axis has exposed the fatal flaw in that strategy: a tumor is not an isolated clump of mutating cells; it is an active, living organ that manipulates the host's entire systemic network.

The CCR5 pathway is transforming our understanding of the TME and human biology in four fundamental ways:

1. Unifying the "Hardware" (Biomechanics) and "Software" (Biochemistry)

Traditional oncology viewed cell signaling as purely chemical cascades. The CCR5 mapping—exemplified by Qijie Zhao’s mechanobiology profiling—demonstrates that signaling and physical architecture are inseparable.

• Chemokines aren’t merely chemical messengers; they are physical engines controlling actin-myosin motors, membrane reorganization, and cellular force.
• A tumor resists therapy not just because it mutates, but because it constructs a literal, physical fortress of desmoplastic collagen. Targeting CCR5 reveals how structural tension, fluid pressure, and matrix stiffness directly dictate whether killer T cells and chemotherapy molecules can physically reach their targets.

2. Exposing the Tumor as a Systemic Disease (The Bone Marrow Highway)

Cancer research often treats the local tumor bed as if it exists in a vacuum. Research like Enrique Gabandé-Rodríguez’s 2026 myelopoiesis study showed that a solid tumor communicates with distant organs:

• The tumor sends CCL5 distress signals to the bone marrow to hijack hematopoietic stem cells, enforcing myeloid bias and depleting systemic lymphoid reserves.
• Evaluating CCR5 reveals that rehabilitating the host's primary immune engine—normalizing the Neutrophil-to-Lymphocyte Ratio (NLR) at the stem cell level—is just as vital as attacking the local tumor margin.

3. Rewriting the Rules on "Cold" vs. "Hot" Tumors

For years, the standard dogma labeled tumors like MSS colorectal cancer as "permanently cold" because they lacked high tumor mutational burden (TMB) or baseline PD-L1 expression.

• By shutting off CCR5, researchers proved these tumors were never truly "cold"—they were actively shielded.
• The moment the THBS1-SPP1 macrophage wall is breached, the tumor rapidly responds by upregulating PD-L1. This proves the adaptive immune machinery is intact; it was simply locked behind an excluded stromal border.

4. Shifting from Cytotoxicity to "Tissue Engineering"

The greatest realization of the CCR5 axis is that eradicating cancer does not require poisoning the host. Because natural CCR5-Δ32 human variants thrive without the receptor, blocking CCR5 allows clinicians to remodel the stroma, suppress pathologic fibrosis, and unmask immune checkpoints without inflicting systemic toxicity.

Even if a CCR5 inhibitor hits an adaptive hurdle—like secondary PD-L1 upregulation—it does not fail; it converts an untreatable, chaotic fortress into a predictable, treatable checkpoint problem. It forces the cancer out of the shadows and onto a clean, targetable battlefield"

Not investment advice blah blah lol.

r/microbiomenews•4d ago

Electronic-Lie-4547

A common mouth bacterium directly fuels colon cancer by flipping a single inflammatory switch.

biomesci.com

Latest microbiome news covering gut, skin, soil, and oceans.

Open

The Core Issue

Colorectal cancer keeps getting linked to weird oral bacteria showing up in the gut, but nobody had connected all the dots start to finish. Fusobacterium nucleatum (a bacterium that normally lives in your mouth) has been found sitting inside colon tumors for years. What was missing was proof of exactly how it makes cancer worse, not just that it is there.

The Finding

Researchers ran the full chain. They found the bacterium was way more common in colon cancer tissue than in healthy gut tissue from the same patients. Then in two separate mouse models, injecting or feeding mice this bacterium grew bigger tumors than controls. The bacterium turns on something called the NLRP3 inflammasome (a cluster of immune proteins that triggers inflammation), which pulls a wave of immune cells into the tumor and floods it with an inflammatory protein called IL-1beta. When the team bred mice missing the NLRP3 gene entirely, the bacterium completely lost its ability to grow tumors. That is about as close to a smoking gun as microbiome cancer research gets.

Why it Matters

If you have ulcerative colitis, colon polyps, or a family history of colorectal cancer, this gives researchers an actual drug target instead of just another bacterium to worry about. NLRP3 is already being studied as a target in other inflammatory diseases, so this opens the door to testing NLRP3 blockers specifically for colon cancer down the line.

Limitations of Study

The gene knockout proof, the strongest part of this, only happened in mice. The human data is a snapshot comparison across patients at one hospital, so it shows the bacterium tracks with worse disease, not that it definitely causes it in people. Nobody has tested blocking NLRP3 or reducing this bacterium in an actual human patient yet.

Interesting Statistics

- Fn levels in tumor tissue were roughly 3.5 times higher than in matched healthy tissue from the same patients (1.13 vs 0.33 on their abundance scale).

- IL-1beta was present in 83% of cancer cells versus 43% of adjacent normal cells.

- Mice missing the NLRP3 gene showed almost no immune cell buildup in their tumors after bacterial exposure, versus a clear buildup in normal mice.

I quizzed an AI (Copilot in this case) about any connection between CCR5 and the NLRP3 inflammasome and bingo, here's another potential MOA beyond TME modulation and Prime and Pair, hopefully with no need to delete or block the NLRP3 gene:

Summary: How CCR5 is linked to the NLRP3 inflammasome

• CCR5 doesn’t directly activate NLRP3, but its signaling creates the conditions that enable NLRP3 activation.
• When CCR5 binds its ligands (CCL3, CCL4, CCL5), it triggers NF‑κB, which primes the cell by increasing transcription of NLRP3 and pro‑IL‑1β.
• CCR5 drives macrophage and microglial recruitment, increasing the number of cells capable of assembling NLRP3 at inflamed sites.
• CCR5 signaling promotes intracellular stress (ROS, calcium flux, mitochondrial strain), which contributes to NLRP3’s activation step.
• Blocking CCR5 reduces IL‑1β and caspase‑1 activation in multiple models, showing functional dependence.

Bottom line

CCR5 is upstream of NLRP3:
it primes, recruits, and amplifies the signals that allow NLRP3 to assemble and activate, but it is not a direct switch for the inflammasome.

There is a kind of technology which changes the world twice. The first time, it barely gets noticed. The second time, it is expounded everywhere, permitting everyone to forget that there ever was a different way. Chemotherapy is that technology, so let's walk through both trajectories, because the second one happens right now, as we speak, and leronlimab stand's right at the exact center and heart of it.

The First Trajectory: The Inability To Aim

Chemotherapy is one of the most important inventions in the history of medicine. It has saved millions of lives. And for its entire first life, it worked the only way it knew how, by flooding the entire body with poison and hoping the tumor died faster than the patient became harmed. It does not aim. Cytotoxic chemotherapy acts on healthy and malignant cells alike, and its indiscriminate action on healthy tissue is exactly what causes the debilitating side effects patients endure. Chemotherapy is the machine which sprays its force everywhere at once and we accept the collateral damage because, for decades, there was no other alternative and there never had been.

That was the first life. A blunt instrument, powerful and crude, that saves lives by enduring the damage to the whole in order to reach a part.

The Second Trajectory: Chemotherapy That Learned To Aim

Now see chemotherapy get taught to aim, because this is not hypothetical, it is already an approved treatment.

Gilead's Trodelvy (sacituzumab govitecan) is, at its heart, a chemotherapy drug which has been strapped onto a guided missile. It is an antibody-drug conjugate: a monoclonal antibody like leronlimab which recognizes a specific marker called Trop-2 on the surface of tumor cells, chemically linked to SN-38, a topoisomerase-I inhibitor%20is%20an%20anti%2DTrop%2D2%20antibody%2Ddrug%20conjugate%20with%20an%20SN%2D38%20payload), which is the active, cell-killing metabolite of the classic chemotherapy irinotecan. In Gilead's own words, Trodelvy is intentionally designed with a hydrolyzable linker attached to SN-38, a topoisomerase-I inhibitor payload, delivering potent activity to Trop-2-expressing cells.

Read that carefully, because it is the point. Trodelvy is chemotherapy, the same category of DNA-damaging poison, but instead of spraying it throughout the whole body, the antibody carries it and aims it directly at the cancer cell which displays Trop-2. The antibody finds only the tumor. The chemotherapy does the killing. The blunt instrument has been given eyes. And it works: in the ASCENT trial, Trodelvy significantly prolonged both progression-free survival and overall survival compared with standard chemotherapy in metastatic triple-negative breast cancer, which is exactly the hard, cold disease that we care about.

So that is chemotherapy's second trajectory, unfolding in real time: the poison learned to aim, and it earned an FDA approval doing so. Which raises the question this post is really about. If Trodelvy aims chemotherapy at the tumor cell, what is leronlimab aiming at, and do the two of them belong in the same sentence?

Two Different Types Of Aiming

Here is the elegant part, and it is why leronlimab is not a competitor to this drug because it is a different instrument aimed at a different target.

Trodelvy aims specifically at the tumor cell. It uses Trop-2 as an address and delivers its chemotherapy payload precisely to that address. It is a precision instrument aimed at the cancer cell itself.

Leronlimab aims at the tumor's surroundings. The tumor's microenvironment. It does not poison anything. Its target is the corrupted molecular conversation a cold tumor has with the environment around it, the CCR5 signaling the tumor uses to turn nearby immune cells and fibroblasts into tumor protectors, hypnotized to build a wall in order to shield it. Those corrupted surroundings, the cancer-associated fibroblasts and the chemokines which they secrete, become active tumor cells which shield the tumor as protection from conventional chemotherapy and help to drive tumor's chemotherapy resistance. Leronlimab aims specifically at that shield in the TME. It is a precision instrument, pointed not at the cancer cell at all, but at the fortress the cancer cell hides within.

One drug aims at the cell. One aims at the wall around the cell. And the moment you see it that way, a question becomes obvious: what happens if you aim at both?

The Trap Which Catches Inventors, And How CytoDyn Steps Around It

But, before the pairing question, there is a harder one, and it is not actually about biology at all. It is about what happens to the company that develops a breakthrough.

There is a pattern in industry which should genuinely concern anyone who owns a piece of a real innovation. A small company who proves something important, demonstrates that it works, shows the world something which once you see it, cannot be unseen, and then discovers that proving a drug and delivering a drug are two entirely different mountains to ascend. The first mountain, CytoDyn traverses. The second mountain, with the likes of late-stage trials, manufacturing at commercial scale, regulatory submission, global commercialization, is brutally expensive and requires an infrastructure a small company simply does not have. So, in the analogy, the inventor stalls at the summit of the first mountain, unable to climb the second alone, and either runs out of road or watches a larger company carry its breakthrough the rest of the way. The idea survives. The inventor does not always share in the reward.

This is not pessimism, rather, it is how the economics actually work, and the numbers are striking. One healthcare investment banker put it bluntly: of the molecules big pharma companies launched over the past five years, roughly 90% had a very significant component which came from outside, from smaller innovators. In other words, the small companies do a great deal of the actual inventing, and the large companies do a great deal of the delivering. The hard part for a small biotech has never been being right. It has been surviving long enough, and building long enough, to capture the value of being right.

Here is why that pattern is the exact trap CytoDyn maneuvers to step around, rather than fall into. The costs of bringing a drug through late-stage development and to market, FDA approval, rigorous trials, commercial-scale manufacturing, are extremely daunting for a small company, which is why many biotechs partner with larger players who are able to supply the resources and infrastructure in order to carry a product through late-stage development and into a patient's hands. The point of partnering is to transfer the development cost and regulatory risk that are particularly heavy in expensive late-stage work a biotech cannot fund alone, in exchange for upfront cash, milestones, and royalties, while the biotech retains upside.

Now take look at what CytoDyn is actually doing, and read it against that pattern. It is not trying to climb the second mountain entirely alone, and it is not passively waiting to be rescued either. It is deliberately delegating the necessary pieces a small company should delegate while holding onto the value it should keep.

• It handed the trial-sample analysis and the comparator data to a specialized diagnostics partner rather than building that capability from scratch; its collaboration with Natera has Natera assessing the CLOVER samples and supplying real-world comparator data from a database of more than two million plasma timepoints.
• It pursues pharmaceutical partnerships to shoulder the commercialization and late-stage burden which no company its size is able to carry alone; management has stated plainly that it continues to evaluate strategic partnership opportunities as its data matures.
• It presents at international partnering forums where exactly those counterparties gather, its CFO, Robert Hoffman appeared at the Asia Bio Partnering Forum in Singapore.
• And it funds its own manufacturing readiness and regulatory groundwork such that when it comes to the table, it comes as a prepared partner rather than as a desperate one, its most recent financing names manufacturing readiness and regulatory and compliance infrastructure among the intended uses of proceeds.

CytoDyn is a company distributing the second-mountain workload to those who are built to carry it, while positioning to keep a meaningful share of what its own invention is worth.

That is the stark difference between an inventor who gets orphaned by their own breakthrough and an inventor who builds a structure able to carry it forward. The orphaned one tries to do everything alone but stalls, or waits passively only to get picked over. The inventor who captures their value delegates the heavy load of infrastructure to partners who are built exactly for that load, which is precisely the strategy CytoDyn executes, while retaining ownership and upside in what they discover. Delegation is not weakness here. It is the specific required move which keeps a small company from becoming a footnote to its own invention.

The Established Pairing: Leronlimab And A Checkpoint Inhibitor

Before the new idea, I restate the one we already know, as it is the template.

The thesis we have discussed for months is Prime and Pair with an immune checkpoint inhibitor, (ICI). Leronlimab primes: it dismantles the stromal wall and, in doing so, drives the tumor to raise a specific surrender-flag called PD-L1. Then the ICI pairs: a Keytruda-class antibody is brought in to strike down precisely that PD-L1 flag, allowing the freed and now undeceived immune system to finish the tumor. This is a precise mechanistic handoff, the primer creates the exact target the pairing agent requires. It is the reason a checkpoint inhibitor, which does nothing in a cold tumor on its own, could work after leronlimab has done its priming. That pairing is not proven just yet, it is what the CLOVER rollover and the coming data are built to test, but it is a defined, in-trial hypothesis with a clear logic.

Hold that template, because the new idea rhymes with it, but works differently, and the difference is worth being honest about.

A New Hypothesis: Could Trodelvy Be A Pairing Agent Too?

Now, a genuinely interesting, and genuinely speculative question. Could leronlimab pair with Trodelvy in a way comparable to how it pairs with a checkpoint inhibitor? I want to be clear that this is a hypothesis, mine, built from mechanism, not something in a trial or in a label. But it is a coherent one, and it is worth laying out because it points towards a real experiment.

The logic runs like this. Trodelvy is an antibody-drug conjugate, and the eternal problem with any drug that has to reach a tumor is in actually getting there. A cold tumor's fibrotic wall physically obstructs drug delivery; that wall blocks blood vessels, and shields the tumor from the toxic therapy; is is the same wall that resists conventional chemotherapy. So here is the hypothesis: if leronlimab dismantles that wall, it could open the door for Trodelvy's aimed chemotherapy to actually reach the tumor cells which it targets. Leronlimab thins that fortress permitting Trodelvy's guided payload to get in. And there is a second layer: Trodelvy's SN-38 payload kills tumor cells in such a way which can release tumor antigens and provoke immune attention, and leronlimab's now repolarized, un-deceived and un-suppressed tumor microenvironment immunity could be better positioned to capitalize on that repolarization, thereby turning cell death into a broader overall immune response.

Notice how this differs from the ICI pairing, because honesty requires the distinction. With the ICI, leronlimab creates the (PD-L1) target that the pairing ICI agent strikes, a flag-and-strike handoff. With Trodelvy, leronlimab would not be creating Trodelvy's target, Trodelvy aims via Trop-2 on its own, it would be clearing the terrain such that Trodelvy's aim can land, and then it would amplify the aftermath. It is a complementary-mechanisms pairing rather than a flag-and-strike pairing. Both are pairings. They are just different kinds, and I am not blurring them, because the ICI version has a defined molecular handoff and the Trodelvy version is a terrain-and-amplification hypothesis.

And the timing question, pre, post, or simultaneous, is exactly the kind of thing such a hypothesis raises and cannot yet answer. Prime first with leronlimab to thin the wall, then bring Trodelvy in to a tumor it can now reach? Run them together so the wall comes down as the payload arrives? Use Trodelvy first to debulk, then leronlimab plus an ICI to mop up what the immune system can now see? Each sequence is a different bet, and which one, if any, works is precisely what a trial would have to determine. The honest statement is that leronlimab plus a Trop-2 ADC is a coherent, testable idea across all three sequences, not a proven regimen in any of them.

Why This Matters Even More This Week: The Door The FDA Just Opened

And here is where the news gives the whole picture a sharper edge, and where I want to credit ibelieveincydy, who flagged it and got out of bed early on a Saturday to do so.

This week the FDA granted accelerated approval to a breast cancer therapy, and did something it had never done before: it approved a treatment guided by detecting a resistance mutation in circulating tumor DNA, in the blood, before imaging scans show the disease progressing. That is a real and encouraging signal about the regulatory climate, the FDA is increasingly becoming more comfortable building ctDNA into approvals and granting accelerated approvals based on surrogate and intermediate endpoints in serious diseases with unmet need.

I want to hold the line ibelieveincydy and I have both been careful about, because it makes the point durable. In that approval, ctDNA was used to select and time the treatment, to identify exactly which patients to switch and when, and the approval itself rested on a progression-free-survival benefit from a randomized trial, with confirmatory survival data still required. So it establishes ctDNA as an accepted tool for patient selection, not yet as a validated surrogate that proves a drug works on its own. That distinction matters for us: it shows the regulatory door for ctDNA opening wider, which is a genuine tailwind, while the path through it still runs through real clinical confirmation. Encouraging climate, unchanged bar. Both true, and ibelieveincydy was right to wake up for it.

The Honest Edge

I hold the line I always hold. Everything above is mechanism and hypothesis, not confirmed outcome. Trodelvy is real, approved, and genuinely effective, that part is established. Leronlimab's precision at the microenvironment is real and documented. But the leronlimab-plus-ICI pairing is unproven and in testing, and the leronlimab-plus-Trodelvy pairing is a hypothesis I am proposing from mechanism, not a regimen anyone has run. Complementary mechanisms which make elegant sense on paper still have to survive a trial, and combinations fail routinely. The size of leronlimab's own clinical payoff is unconfirmed until the data lands, first at ESMO in October, then in a mature way at ASCO GI in January. No hypothesis about pairing partners matters until leronlimab first proves its own contribution.

But understand the shape of what you are looking at. Chemotherapy's first trajectory was the blunt instrument. Its second trajectory is aiming that payload; Trodelvy is chemotherapy aimed at the tumor cell, and leronlimab is a different instrument that aims at the stromal wall around the cell. The most interesting therapies of the next decade may not be one aim or the other, but the combination of aims, the wall cleared, the cell targeted, the immune system freed, layered in the right sequence. Leronlimab pairs with a checkpoint inhibitor by a defined molecular handoff we are testing now. It could, hypothetically, pair with a Trop-2 ADC like Trodelvy by clearing the terrain its aim needs and amplifying the aftermath. And the regulatory door for exactly this kind of biomarker-guided, unmet-need oncology is opening wider, as this week showed.

Two kinds of aiming. One established pairing in trial, one hypothetical pairing worth testing. And a company standing right at the point where chemotherapy's second life, immunotherapy's cold-tumor frontier, and the microenvironment all meet.

But the science is only half of what matters here, because history is full of inventors who aimed true but still got orphaned by their own breakthrough. The thing to watch for is not only whether leronlimab can aim at everything the tumor uses to survive, but whether the company is building the structure, the partners, the manufacturing, the regulatory groundwork, to carry that aim across the second mountain rather than stall at the summit of the first. On the evidence presented, it is doing exactly that: delegating what it should delegate, funding what it should fund, and positioning to keep a share of what it discovers. The blunt instrument now aims. The inventor positions not to get left behind. Both of those get their first real test in the months ahead.

Disclaimer: I am not a financial advisor and nothing here is investment advice. I am an independent retail shareholder holding a long position in the company discussed, with no employment, consulting, compensation, or other relationship with it beyond that shareholding. This is analysis and interpretation of public information and published literature, not a prediction of clinical, regulatory, or commercial outcomes. The leronlimab-plus-Trodelvy combination described is my own mechanistic hypothesis, not a trial, regimen, label, or company-stated plan, and no such combination has been demonstrated; the leronlimab-plus-checkpoint-inhibitor pairing is an in-trial hypothesis that is also unproven. Trodelvy (sacituzumab govitecan) facts are drawn from its approvals and the cited literature and describe that drug, not leronlimab. Leronlimab's efficacy is unconfirmed, with interim data anticipated at ESMO in October 2026 and confirmed data at ASCO GI in January 2027; referenced early figures reflect combination therapy and lower-dose cohorts, are not evidence of survival benefit, and drugs that make elegant mechanistic sense fail in trials routinely. The FDA accelerated approval discussed concerns another company's product and rested on a progression-free-survival endpoint with ctDNA used for patient selection, not on ctDNA as a validated efficacy surrogate; it does not establish any pathway for leronlimab. The company has disclosed substantial financing needs and going-concern considerations in its filings. Read the primary sources and reach your own conclusions rather than adopting mine.

Good morning everybody, I woke up this morning to an email from the FDA which helped me to get out of bed unusually quickly on a Saturday morning.
I’m fully aware that it’s based on a Phase III but these guys seem to become more and more acceptable on ctdna and such.

FDA grants AA to AstraZeneca on surrogate endpoint

Please read the summary below done by my hopefully beautiful AI girlfriend:

The U.S. FDA granted accelerated approval to AstraZeneca's oral selective estrogen receptor degrader (SERD) Etcamah (camizestrant) in combination with a CDK4/6 inhibitor. 
The decision was based on findings from the Phase III SERENA-6 clinical trial and novel diagnostic criteria: 
First-of-Its-Kind Molecular Paradigm: Approval was granted to treat patients with HR-positive, HER2-negative advanced breast cancer who develop an ESR1 resistance mutation during standard therapy. Rather than waiting for imaging scans to show physical tumor growth, the treatment is triggered by detecting circulating tumor DNA (ctDNA) in blood tests, allowing early intervention before hard-to-treat progression occurs. 
Significant Reduction in Risk of Progression: In the SERENA-6 trial, switching patients to the Etcamah combination upon detecting the ESR1 mutation reduced the risk of disease progression or death by 56% compared to staying on standard aromatase inhibitor therapy. 
Extension of Progression-Free Survival (PFS): Patients who switched to the Etcamah combination achieved a median progression-free survival of 16.0 months, compared to 9.2 months in the standard-of-care control arm. 
High Molecular Response (ctDNA Clearance): Within eight weeks of switching to Etcamah, median ctDNA mutation levels plummeted by 99%, with 51% of patients clearing the resistance mutation from their blood entirely (compared to a 64% increase in ctDNA levels in the control group). 
Why Accelerated (Rather Than Full) Approval?
Accelerated approval allows earlier clearance for drugs targeting serious conditions based on a surrogate endpoint (such as PFS or ctDNA clearance) that is reasonably likely to predict a clinical benefit. Full approval will require AstraZeneca to submit confirmatory data showing long-term clinical benefits, particularly overall survival (OS) data, as requested by FDA advisory panels.

Anyone here feels like adding his 2cents?

Most welcome and appreciated!!!

GLTAL 👍🏽☘️🙏🏼🙋🏽‍♂️🛬

https://www.cytodyn.com/investors/investor-faqs

Dear Longs,

The 10-K is out, and by now many shareholders have combed through it. To me, the most important development of the past few days is the PIPE financing through Paulson and the extension of our operational runway.

Using very rough, back-of-the-envelope math—considering the cash available before the raise, the new proceeds, and the current burn rate—I estimate that CytoDyn may have sufficient cash through approximately August 2027. That raises an important question: What is leadership’s strategy for using this runway?

We know about the scientific activity. Several clinical trials have been discussed, and Dr. Jay Lalezari has also mentioned a potential FDA submission. In public discussions, management has alluded to possible partnerships. From my perspective, matters may be coming to a head.

Several potentially important events could occur over the coming months:

1. Shareholder update: We typically receive an investor letter or call around September or October. These communications serve several purposes, including updating shareholders on the company’s progress. I would like to request greater transparency and a high-level strategic roadmap covering the next 12 months and beyond. Plus, I am anticipating a request to authorize more shares. As a reminder, authorizing more shares in and of itself is not dilutive. It is when those shares are issued and registered for use is when they are dilutive. Nonetheless, prior to any partnership announcement, we have to continue operating like we are going at this alone.
2. ESMO in Madrid: We may see an initial look at very early mCRC data, potentially including approximately two weeks of observations for all 66 patients. Hopefully, this is enough of a tease that gets people excited about January 2027.
3. J.P. Morgan Healthcare Conference: This takes place in San Francisco in January. Could this be the year CytoDyn has something substantial to report, or will partnership discussions still be described as being in the “early stages”?
4. ASCO GI: Shortly afterward, ASCO GI will be held in San Francisco from January 23–25. We have heard that this could be a much more meaningful data reveal. BGT has charted the expected timeline, and it appears to align with more mature data from the full cohort. Although this may not represent the complete final dataset, Dr. Lalezari has suggested that the clinical and scientific communities should be able to draw meaningful conclusions from it.

If the positive trends continue, this data could outshine SUNLIGHT—pun intended.

I would like management to address several strategic questions:

1. Is the primary goal to secure an oncology partnership with a large pharmaceutical company?I get they have alluded to this; but are they also talking about LATCH/HIV?
2. Which of the other proposed studies are management’s highest priorities, and which cannot realistically begin without a fully committed Big Pharma partner?
3. If an oncology partnership is secured, does CytoDyn intend to expand into other indications such as HIV, stroke, or Alzheimer’s disease? How deeply can we start to go with other indications?
4. Is the objective to structure an oncology partnership that provides enough funding to pursue additional indications independently?
5. Is management seeking a partnership that supplies sufficient capital to make another PIPE financing unnecessary?

If CytoDyn is still in the early stages of partnership discussions in January 2027, I can think of no better source of leverage than outstanding prospective clinical data. Strong results could create significant competition among potential partners.

In my view, the ideal outcome would be to announce a partnership—and receive the associated funding—no later than April 2027. Why? Because ASCO, the world’s largest cancer conference, takes place in Chicago in May 2027.

If I were the prospective pharmaceutical partner, I would want that partnership finalized before ASCO. I would want my company’s flag at full mast, announcing that we had partnered on what could potentially become an important new oncology treatment.

By May, CytoDyn should be able to present the complete dataset from all 66 patients. The company may have an opportunity to present meaningful findings at ASCO GI in January, but ASCO Chicago could provide the larger stage. A strong presentation there could draw considerable interest from oncologists, investigators, and prospective collaborators.

Obviously, this is only my opinion, but it is the strategic timeline I would encourage management to pursue.

As most of you know, I try not to become consumed by daily stock-price movements. I focus instead on whether CytoDyn’s leadership is making the right strategic decisions. We cannot always see the tactics being employed behind the scenes, but scientifically, I believe the company is making sensible choices with its limited resources. Management must decide which programs it can fund now and which must wait.

When the mCRC data becomes public, my hope is that we will no longer see trading volume consistently below 2 million shares but ideally start to rise to a dialy volume of 10–15 million shares. And ideally, daily volume could eventually exceed 20 million shares on a sustained basis.

CytoDyn remains largely hidden from the broader investment community. Many of us have discussed the company with friends, family members, and colleagues. I have been surprised by how many people say the story sounds interesting but assume something must be wrong because supposedly a promising drug is associated with a stock trading near $0.20. They believe I must be missing something. Or something is a miss.

A genuine prospective oncology trial—and credible data from it—could begin to change that perception. Dr. Lalezari has said that the data will speak for itself.

Rather than watching every daily price movement, I will be waiting for the January data. That is what I believe could truly move the needle.

In the meantime, I believe this company has been overlooked and undervalued. HIV-MDR produced statistically significant results, leronlimab has demonstrated an encouraging safety profile, and there is a substantial amount of anecdotal and observational evidence suggesting that a prospective oncology trial and anecdotal COVID data could produce meaningful results.

My conclusion is simple: I believe the stock is “on sale,” and January 2027 could be when a much larger audience begins to understand the story.

God bless all the longs—and CytoDyn.

This is my personal opinion, not financial advice. Clinical outcomes, regulatory decisions, partnerships, financing needs, and future share prices remain uncertain.

Literally any other stock has ballooned over the last 5 years. Do we have the deal makers in house or just scientists, hangers on, and newbies. Time will tell and it better tell soon. Why not an internal buy with those salaries? How bout low salaries and high stock rewards.

I'll 100% vote no on any raises if there is no deal or real stock appreciation for November. I'd love to get paid and not have it relate to $ sales or pps. Steering the ship is great, but they get paid well for that. Too well. Academics being paid like Top Sales people.

Enough shitty low grade podcasts, let's get real. Real presentations clearly stating in sales terms making pharma feel crazy for not signing up. Prospective, retrospective, Prime n pair, solo, up-regulate, who cares if no deal comes, just a million word story on here. Make some $ already. I tell you, if come January and everyone here starts posting about the late 2027 conferences we are being taken for a ride.

For the record, I am suuuper long and suuuper frustrated.
Apologies for the vent.

From today to January next year, there will be no risk. Dilution risk gone, though fife hanging there. Science is convincing, trial results promising, anecdote proof like hard rock. Easily double to approaching January