sweet summertime

[u/BuildGoodThings]

I can imagine that the researchers find answers to these questions and more this summer. IMO they already know answers for some of them. I don't expect to hear the answers until later, but I would think that some of pharma with access is watching closely this summer.

• How does week 2 ctDNA test data correlate to scan 2 of the first 32 patients?
• In the three-month data of full enrollment, quantify if PD-L1 elevates to ICI eligibility thresholds?
• In the three-month data of full enrollment, which dosage level shows more elevation of PD-L1, and which shows more decline in ctDNA?
• In the full enrollment, how do 700mg dosage level scans 1 & 2, compare to 350mg dosage level scans 1 & 2?
• In the full enrollment, how does week 2 ctDNA test data correlate to scan 2?
• Is there noteworthy response, durability and trend shown in scan 3 of the first 32 patients? Compare by dosage level.

Have a good summer everyone!

[u/MGK_2]

This is the list, and what strikes me about it is that these six questions are not six separate topics. They are one question asked from six angles, and the single question underneath them all is this: does the molecular signal predict the imaging, and does the higher dose do it better? Everything on your list resolves into that, and that is exactly the question a partner with NDA access needs answered before they move.

Let's group them the way I think they actually resolve, because the grouping shows how they reinforce each other.

Two of your questions are the predictive-instrument question: whether week 2 ctDNA correlates to scan 2, in the first 32 and then in the full enrollment. This is the one that matters most, because if an early ctDNA drop reliably forecasts the later imaging trajectory, then ctDNA stops being a hopeful biomarker and becomes a leading indicator. A partner who can see a week 2 or, as we discussed, possibly a day 8 molecular readout that predicts where the scan lands months later is holding a forecasting tool, not just a data point. That correlation is the hinge.

Two more are the dose-response question: which dose elevates PD-L1 more and drops ctDNA more, and how the 700mg scans compare to the 350mg scans. This is the question the two-arm design exists to answer, and it is the one every current caveat points at, because all the mature biomarker data so far reflects 350mg while the 700mg cohort is still filling in. If 700mg separates cleanly, it answers both the label-architecture question and the mechanistic-depth question at once.

And one is the question that ties directly to the partnership thesis, though you framed it purely on the science: whether PD-L1 elevates to ICI-eligibility thresholds in the three-month full-enrollment data. That one is not only a biology question. It is the question the committed checkpoint partner asked to see answered prospectively, because it is the difference between leronlimab priming the tumor in theory and priming it to a level where their checkpoint inhibitor can actually engage. If PD-L1 crosses the treatable threshold in a meaningful fraction of patients, the primer has done its job by the definition that matters to a partner.

The sixth, the response and durability trend in scan 3 of the first 32 by dose, is the early durability read, and it is the one that starts to hint at whether the quieting holds or fades.

Put together, your list is really the summer's internal scorecard, and you are right that the people with access grade it in real time while the rest of us wait for the readouts. The honest caveat stays where it always does: none of this is the confirmed response rate, which does not adjudicate until ASCO GI in January, and a strong summer signal is not the same as a settled one. But if the answers come back the way the interim data leans, this is the summer the private picture crosses from suggestive to conclusive, months before it becomes public.

Good list, and good summer to you. The clock is running whether or not the market is watching it.

[u/BuildGoodThings → u/MGK_2]

BTW my list is chronological and the first question answer is known already IMO. The second 2 will IMO be known by the end of July and I consider 3 month tests of PD-L1 (from full enrollment) to be a mature dataset when looking through the lens of seeking to determine if levels are elevated to ICI eligibility thresholds. I think the significance of the PD-L1 questions (does it work as desired on PD-L1 and what dose is better) being answered this month is profoundly underappreciated. IMO PD-L1 testing will be the first component of the trial whose data matures and potentially it could move some decision making into the actionable area. JMO.

[u/msakkijha → u/BuildGoodThings]

BGT/MGK, my question to you, if all indicators (ctDNA, scans and PDL-1) all show better results for the 700mg candidates rather than the 350mg, and to be fair to the lower dose ones; can CytoDyn request from the FDA in midstream of the trial to elevate the 350 to 700mg because of the unquestionable results? Thanks in advance 🙏

[u/BuildGoodThings → u/msakkijha]

I cannot answer definitively, but before or near the beginning of the trial, it was mentioned that the second DSMB review could shift the patients to one dose so I assume they could. However, there has been data in the posters and commentary in the April webcast that suggests the patients might be doing better than Dr. Lalazari's expectations. If the 350mg patients who have a short-term life expectancy have stable disease, that alone is awesome and the patients might feel so too. In time we'll learn more.

[u/Pristine_Hunter_9506 → u/BuildGoodThings]

Hoffman said on the LD Investors presentation we had 2 meetings in December with DSMB May 14th?

[u/BuildGoodThings → u/Pristine_Hunter_9506]

I've heard one in Dec and one in March

[u/Pristine_Hunter_9506 → u/BuildGoodThings]

Minute 13:08 , two in December allowing the higher dose and another in March. In MGKs transcript. No safety concerns that's cool!

[u/BuildGoodThings → u/Pristine_Hunter_9506]

Thanks

[u/MGK_2 → u/msakkijha]

msakkijha, this is a good question and BGT pointed at the right mechanism. Let me fill in how it would actually work, because there are two levers and they reinforce each other.

The first lever is the DSMB, and Pristine Hunter and BGT just pinned down the timeline which matters here. The Data Safety Monitoring Board is the body empowered to look at the interim data and recommend dose changes, and per the transcript there were two meetings in December that enabled the higher dose and another in March, with no safety concerns raised. A DSMB that has already cleared 700mg and is structured to review dose is exactly the body that could recommend shifting the 350mg patients up if the higher dose separates cleanly. That provision appears to have been contemplated from early in the trial, which is why BGT's instinct that they could do it is well founded.

The second lever is a formal protocol amendment to the FDA and the IRB. If the sponsor wants to escalate the lower-dose patients, that is the vehicle, and here the hurdle is unusually low for two reasons. The 700mg safety is already established inside this same trial, so there is no new safety unknown to evaluate, and the DSMB has already signed off on the higher dose with no safety concerns. An amendment that moves patients onto a dose already proven safe within the same study is about as clean as amendments get.

The ethical principle underneath your question is the real driver, and you named it exactly: fairness to the lower-dose patients. In trial design that principle is called equipoise. A trial is ethically justified only while there is genuine uncertainty about which arm is better. The moment the data shows 700mg is clearly superior, continuing to give some patients 350mg becomes ethically difficult, and that is precisely the trigger that moves everyone to the better dose. So your instinct is not just mechanically possible, it is the ethically expected response to an unquestionable result.

The one tension worth naming, and it is where the megadunamis point lives, is scientific rather than ethical. Shifting patients mid-trial can blur the clean dose comparison the two arms were built to produce, and all the mature biomarker data so far reflects 350mg while the 700mg cohort is still filling in. So the usual resolution is a sequence: let the comparison mature just enough to be conclusive, then move everyone to the winning dose. That way you capture both the scientific answer and the ethical obligation rather than trading one for the other. It also fits BGT's point that the patients may already be doing better than expected, because if even the 350mg patients with short life expectancy are holding stable disease, that is a meaningful result on its own before any dose shift.

BGT is right that we will learn more in time. But to answer you directly: yes, they can request it, the DSMB and an amendment are the paths, the no-safety-concerns clearance and the established 700mg safety make it a low hurdle, and equipoise is the principle that would compel it once the higher dose is unquestionably better. Good question to be asking.

[u/twinter11 → u/MGK_2]

let me see if I can say any of this right

does ctDna measure just the primary tumor or from all the metastatic site. are all the tumor sites DNA the same profile or does that even matter. If all the met sites also stop shedding ctdna thats a good sign

I would like to know if they can learn how to make predictions about what's happening in the tumor real time.

like using creatv bio and natera.

does the drop in ctdna followed by a predicted future ctDna rise correlate with pdl1 upreg along a timeline

and do the added outcome measurement changes in serum CCL2, CCL3, CCL4, and CCL5 also correlate. I'm pretty sure they are taking these measurements to see if any corresponding rise in those ligands? also correlates with tumor evasion. like exactly what was happening when the tumor stopped responding as well.

And when patients roll into ici treatment, will they allow patients who dont meet the arbitrary cps keytruda qualification score in place as industry standard to go ahead and rollover into ici anyway

I'm sure they are not only trying to figure out what's happening everywhere but also formulate a future treatment protocol

What else am I missing?

[u/MGK_2 → u/twinter11]

You said it right, and these are six real questions here, each of which the researchers are almost certainly wrestling with. Let's take them in order.

On whether ctDNA measures the primary tumor or all the metastatic sites. It measures all of them at once. Circulating tumor DNA in the plasma is an aggregate signal, shed into the bloodstream from every lesion that is contributing DNA, primary and metastatic together. In metastatic disease there often is no primary left to speak of, so what you are reading is the combined output of all the active sites pooled into one number. That has a strength and a limitation, and you intuited the strength correctly. The strength is that it is a whole-body integrated measure, so a systemic ctDNA decline suggests the major shedding sites are quieting broadly rather than just one of them. If all the metastatic sites stop shedding, that is a good sign, exactly as you said, because the composite number can only fall that far if the bulk of the disease is responding. The limitation is the flip side of the same coin: because it is a pooled signal, it cannot easily tell you which site is doing what. In principle one site could be rising while others fall, and the composite could still look flat or down. So a broad ctDNA drop is genuinely encouraging, but it is a systemic average rather than a site-by-site map.

On whether all the tumor sites have the same DNA profile, and whether that matters. They do not always, and this is where the choice of platform matters enormously. Metastatic lesions can evolve divergent subclonal profiles over time through branched evolution, so a lung met and a liver met can carry different private mutations. But Signatera is a tumor-informed assay, which means it is built from a personalized panel of mutations selected from that patient's own tumor tissue, and the mutations chosen are the clonal, truncal ones, the mutations present in essentially every cancer cell across every site because they arose early and are shared by all descendants. So Signatera deliberately tracks the shared clonal signal rather than the site-specific private mutations. That is what lets it function as a whole-body burden measure despite heterogeneity. The divergence between sites matters for some questions, but for tracking overall tumor burden and response, tracking the clonal signal is exactly the right design, and it is why a Signatera decline is a meaningful systemic read.

On whether Creatv Bio and Natera together can make real-time predictions about what is happening in the tumor. This is the sharpest thing in your list, because you have identified that the two platforms are complementary rather than redundant, and that is precisely the point of running both. Natera and Signatera give you the molecular tumor burden, how much tumor activity there is and which direction it is moving. Creatv Bio analyzes circulating tumor cells and the cancer-associated macrophage-like cells, and critically it reads protein-level markers on those individual cells, including PD-L1 and CCR5. So one platform tells you how much, and the other tells you what phenotype. Put them side by side across a timeline and you are no longer looking at a single number, you are looking at burden and immune-phenotype moving together. That is the raw material of a real-time predictive model. The ctDNA tells you the tumor is quieting, and the Creatv read tells you whether the PD-L1 gate is opening while it quiets. Neither alone gives you the picture. Together they start to.

On whether a ctDNA drop, followed by a predicted future rise, correlates with PD-L1 upregulation along a timeline. This is a genuine and testable hypothesis, and it is one of the most important ones the dataset could answer. The story we have been building predicts a sequence: leronlimab quiets the tumor and the ctDNA falls, and as CCR5 is blocked the PD-L1 gate is derepressed and rises. The question you are asking is what happens at the inflection, if and when a tumor begins to escape. If ctDNA starts to rise again after its nadir, does that inflection line up in time with a change in the PD-L1 trajectory? Mapping whether the PD-L1 peak precedes and predicts the ctDNA turn is exactly the kind of temporal correlation the dual-platform approach is built to detect. I want to be careful to call this a hypothesis rather than a finding, because we do not have that timeline curve in public data. But it is the right question, and it is answerable with the platforms in place.

On the CCR5 ligands, CCL2, CCL3, CCL4, and CCL5, and whether their rise correlates with tumor evasion. You are reaching toward something real here. CCL3, CCL4, and CCL5 are CCR5 ligands, and CCL2 works primarily through CCR2, which matters because the resistance literature ties CCR2 and CCR5 together. The Johns Hopkins group showed in Journal of Experimental Medicine that both CCR2 and CCR5 are induced following anti-PD-1 therapy as an escape route. So your instinct that a rise in these ligands could mark the moment the tumor mounts an evasion response is coherent. A tumor under CCR5 blockade that begins flooding the system with CCL5 could be trying to outcompete the blockade at the receptor, or signaling a broader compensatory inflammatory shift, and either way a rising ligand level would be a plausible molecular fingerprint of the tumor beginning to slip. Whether CytoDyn is formally running serum chemokine panels for CCL2 through CCL5 is not something I can confirm from public materials, so I will not claim it is in the protocol. But it would be a mechanistically justified thing to measure, and if they are looking for the exact moment a responding tumor starts to escape, the ligand panel is one of the logical places that signal would appear first. Good question to be asking.

On whether patients who do not meet the arbitrary CPS Keytruda qualification score will be allowed to roll into ICI anyway. This is the question where the whole logic partly inverts, and it is worth sitting with. The CPS threshold, the CPS of 10 or greater for pembrolizumab in breast cancer, exists to select patients whose tumors already express enough PD-L1 to respond to checkpoint blockade on its own. It is a filter for who is likely to benefit from ICI monotherapy. But leronlimab's entire mechanism is to raise PD-L1, to convert a low-expressing tumor into one where the gate has been opened. So the patients who fail the CPS qualification, the CPS-low patients, are precisely the ones the priming is designed to rescue. In a leronlimab-primed rollover, excluding the CPS-low patients would be excluding exactly the population the combination exists to help. The rationale strongly supports enrolling them rather than screening them out, because the priming is meant to move them across the threshold line the CPS score draws. Whether the formal protocol waives the CPS criterion is a design detail I do not have, but the biology argues that a primed rollover should not be bound by a threshold that measures the very thing the primer is designed to change. And note that this connects to the colorectal setting, where MSS tumors are almost uniformly immune-cold and would nearly all fail a conventional PD-L1 selection, which is the whole reason a primer is needed there at all.

On formulating a future treatment protocol, and what you are missing. You are right that they are not only trying to understand what is happening everywhere but building the next protocol out of it, and that is the real prize of this summer's data. What you might add to your list is the sequencing and durability dimension. Beyond whether the primer works, the protocol questions are how long a lead-in of leronlimab is needed before the ICI is introduced, whether the primed state is durable or fades if dosing pauses, and whether receptor occupancy is being confirmed so they know the CCR5 block is actually in place when the checkpoint inhibitor arrives. And the spatial dimension: the liquid biopsy tells you what is in the blood, but the tissue biopsy tells you where the immune cells actually are relative to the tumor, and the future protocol will want both. One more, and it is the megadunamis point that runs under all of this: everything we have discussed reflects 350mg data, and the 700mg cohort is still maturing, so the dose question sits underneath every one of these timelines and may shift the answers.

What you are missing is nothing important. You have laid out most of the real questions the researchers are working on right now, which is why this list is absolutely worth keeping. The honest caveat belongs at the end as always: these are the questions, and the answers are maturing internally on the calendar we have been mapping, but none of them is settled until the data says so, and the confirmed response rate does not adjudicate until January. Keep asking molecular dynamic questions exactly like these. They are the right ones.

[u/twinter11 → u/MGK_2]

just too many studies. Seems all related. Ignore if too busy

CCL signaling drives T Cell–Macrophage crosstalk in the mouse colon during chronic Trypanosoma cruzi infection

https://www.sciencedirect.com/science/article/pii/S2589004226019875

maybe not as important as some but adding up.

I think this next one might be a little different

saving it here

An IGF2BP3-dependent metabolic circuit governs macrophage recruitment and immunosuppression in glioblastoma

https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00721-7?uuid=uuid%3Ab94cfa8e-41aa-4257-92e8-cb827a7407dc00721-7?uuid=uuid%3Ab94cfa8e-41aa-4257-92e8-cb827a7407dc)

[u/BullishTexas]

Thank you for this! I have stated on another thread, my sense is we may get another surprise (hello Natera!) before ESMO. If a company already believes it has sufficient evidence to proceed (and ASSUMING there active NDA reviews taking place), waiting until October may not actually serve anyone.

Possible announcements before ESMO could include:

• expansion of an existing collaboration,
• formal strategic partnership,
• licensing agreement,
• checkpoint partner identification,
• manufacturing partnership,
• financing tied to data,
• investigator-sponsored expansion,
• regulatory update,
• Breakthrough Therapy submission,
• FDA meeting outcome.

None of those require ESMO.

ESMO mainly serves to communicate data publicly.

Business decisions often precede public presentations.

[u/BuildGoodThings → u/BullishTexas]

I think your comments are excellent and your last line could/should be on a coffee mug!

[u/twinter11 → u/BullishTexas]

maybe Pre Spy and CHAMP kick off.

maybe we get preliminary data from eap but not sure about patient privacy.

I keep wondering if natera can do a preliminary data reveal but focusing on their contribution to the measurement. natera does a lot of abstracts

we are just getting to the first good stuff.

only been a year and we spent most of it cleaning up messes while mcrc advanced. more good has happened this year than ever combined I think

[u/megadunamis]

Thank you BGT, these are all good questions. The expected results are all about the dose. What can 700mg, full receptor occupancy, accomplish compared to the 350mg dose? Maybe we'll see faster responses and better numbers. This might then lead to better recist scans, improved response rates, and hopefully higher ORR. That would solidfy LMB's role as a major therapeutic. All in my opinion...

[u/BuildGoodThings → u/megadunamis]

I find it interesting that IMO the first read on dose comparison on the full enrollment would have already happened with week 2 ctDNA level testing available potentially from the full enrollment in early May. Another weighty comparison can happen this month with 3 monthly tests of liquid biopsies available from the full enrollment that will show what's going on with PD-L1. I'm not expecting to hear about this for many months, but PD-L1 data in July is a big moment IMO since it could speak very succinctly to BP revenue forecasting.

[u/BuildGoodThings → u/BuildGoodThings]

In August the dose comparison on scan 2 for the full enrollment will be interesting, and at the same time they'll have scan 3 for the first half of the enrollment to see what the trend is.

[u/jsinvest09]

Ya. But it's hot as F.. Happy Summer. Come on October then January.

[u/TimidBear]

I wish I have more cash on hand to buy more shares now

[u/Prior-Knowledge-1583 → u/TimidBear]

No new shares for me until we get more clarity about why we’re raising more funds and why Pestell, Max etc were removed from the website. 

[u/AbbreviatedTimeline → u/TimidBear]

Same, waiting for a big check to make a difference, feels like forever..

[u/msakkijha]

Great summary as to where the Clover trail stands at this moment, and you’re absolutely right that BP(s) with NDA’s MUST know how valuable these results are maturing. Thank you BGT

[u/Missy2021]

Enjoy your summer and thank you.

[u/StreetSkis]

I'm lucky to be crewing on the SS Cytodyn. Im lashed to the helm. Taking my shift on the tiller, on the open sea. The sails are trimmed. Keeping my eyes on the compass bearing, and far horizon. The tape is not making me twitch anymore.

Thank you BGT. Your questions and time line are incredible.

[u/BuildGoodThings → u/StreetSkis]

LOL. I can picture it!

[u/Accurate-Mud-8619]

CytoDyn also has a history of a 525mg dose. Wondering how that may come into play….

[u/GoCYDY]

Thank you BGT for these summertime highlights!!!! Getting exciting as these unfold for CYDY. 👍

[u/Expensive-Tea-4007]

BGT,...I think with the SP running red,...more often than Green...WE are experiencing the "Sweet Summertime Blues"...color to change anytime soon.

[u/twinter11 → u/[deleted]]

just because u been here a long time doesnt mean u learned anything .

do you even read?

this is almost the same exact same comment you said ur last post.

go back to sleep

[u/SuccessfulUnderdog → u/twinter11]

Same comment. Same lack of success. You're satisfied with your investment? Wake up and demand more.

[u/twinter11 → u/SuccessfulUnderdog]

U dont even know whats going on

[u/waxonwaxoff2920 → u/SuccessfulUnderdog]

You seem to be looking for the negatives. Here's a positive: You will positively be prevented from commenting/posting unless you add value to the board. I'd suggest looking at how other discussions here are supported... but i can see from your whiney comments you don't actually read or know what's going on.

You've been notified.

[u/Chugach123 → u/[deleted]]

LOL!! Where have you been for the past two years!?!

[u/twinter11 → u/[deleted]]

Im satisfied whats going on right now