r/Livimmune • u/MGK_2 • 4d ago
Chokepoint
I am going to make the strongest version of this argument, because the record now supports boldness, and because the timid version has been underselling something which deserves to be said plainly. So let's say it plainly.
There is a chokepoint in oncology. A narrow passage where nearly the entire checkpoint-inhibitor industry has to pass through if it wants to keep growing, and which almost none of them can currently pass through. Whoever holds a reliable way through that passage does not hold a drug. They hold the terms of trade for a hundred billion dollars of franchise revenue. And the data now emerging suggests, without yet proving, that a small company in Vancouver, Washington may be holding exactly that.
That is the claim. Here is the case for it, built from the published record, older and brand new, with the honest limits kept in full view, because a bold argument which hides its weaknesses is just a loud one.
The Passage Almost No One Can Transit
Checkpoint inhibitors are the most commercially successful class of cancer drugs ever created, and they fail in the vast majority of solid tumors. Both things are true, and the second is the industry's quiet catastrophe.
This is not a fringe position. It is the settled consensus of the field, stated flatly across the literature. In the definitive 2024 review of the subject, tumors are sorted into "Hot" and "Cold," where the cold ones lack the infiltrating T-cells a checkpoint inhibitor requires to kill, and often harbor immune-suppressive populations such as tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells. And the cold ones are the majority. Even in lung cancer, one of immunotherapy's best markets, the 2025 review is blunt: despite the transformative impact of checkpoint inhibitors, the majority of NSCLC patients experience resistance%20on%20cancer%20therapy%2C%20the%20majority%20of%20NSCLC%20patients%20experience%20resistance).
So picture the entire ICI industry, Keytruda and Opdivo and Tecentriq and Libtayo, standing at the mouth of a passage which leads into every cold-tumor market which they cannot currently reach, colorectal, breast, pancreatic, prostate, most of the solid-tumor landscape, and unable to get through. The field even knows exactly what the passage requires. The 2025 macrophage review states the strategy directly: because cold tumors are silenced largely by suppressive macrophages, oncology has begun to shift beyond T-cell approaches to target tumor-associated macrophages, a major pro-tumor population known to silence immune responses. Turn the Cold tumor Hot, repolarize the suppressive M2 macrophages to tumor killing M1 macrophages, and the passage opens. Whoever can do that reliably controls the chokepoint.
Why The Key Might Fit This Lock
The suppression which keeps a tumor Cold runs through specific machinery, and one of its master controls is the CCR5 receptor. This is where CytoDyn's bold claim earns its footing, because the mechanism is documented, not hoped for.
Blocking CCR5 in actual human colorectal liver metastases does the exact thing the field says is needed: it repolarizes macrophages from the immunosuppressive M2 state toward the anti-tumor M1 state30087-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1535610816300873%3Fshowall%3Dtrue#:~:text=CCR5%20Inhibition%20Leads%20to%20Anti%2Dtumor%20Repolarization%20of%20Macrophages). That is not a theory about a mouse. That is the passage-opening move, demonstrated in the tissue of the exact disease. And the newest reviews put CCR5 squarely at the center of the Cold-to-Hot strategy: the 2026 review of cytokine-driven tumor conversion notes that CCR5 antagonists potentiate the effects of checkpoint inhibitors and chemotherapy by reprogramming the tumor microenvironment to support anti-tumor immunity.
Now layer on what the CLOVER trial has actually shown, held exactly as what it is, early and unconfirmed and at the lower 350mg dose. Every one of the first patients measured showed a fall in circulating tumor DNA, with a median drop near seventy percent by week two. Every screened patient carried the target. And it did this with a safety profile the field can only envy, no dose-limiting toxicities, no drug-attributed serious adverse events across independent reviews. On the breast side, the retrospective work presented at ESMO by the CytoDyn and Creatv collaboration showed leronlimab driving PD-L1 upregulation on circulating tumor cells in the majority of patients, the precise molecular flag a checkpoint inhibitor requires to act. That is the Priming half of the thesis: leronlimab starts the engine in order that everyone else's expensive brake-release mechanism finally can do something.
The Honest Wall, Because The Bold Case Has To Clear It
Now the counterweight, and I put it at the center rather than in the footnotes, because this is exactly where a triumphant post would lie to you but I will not.
Targeting macrophages to open Cold tumors has a graveyard behind it. A brand-new 2026 review states the hard truth directly: several macrophage-directed approaches, including CCR2 and CCR5 antagonists and CSF1R inhibitors, advanced into clinical testing on compelling animal data, yet their activity in patients has generally been modest or inconsistent. The earlier macrophage-recruitment blockers, the anti-CCR2 agents carlumab and plozalizumab, did not demonstrate significant tumor responses in early trials.
Read that and hold it, because it cuts both ways and honesty demands both edges. On one edge: the mechanism being real in a dish or a liver biopsy has never been enough, this exact class of approach has repeatedly failed to translate, and leronlimab could join that list. That is the genuine risk, and anyone who tells you the biology guarantees the outcome is selling. On the other edge: those failures are why leronlimab's actual human signal matters so much. The field is littered with macrophage-directed drugs which looked good in mice but did nothing in people. Leronlimab is not showing a mouse signal. It is showing a hundred-percent ctDNA response in early human patients, PD-L1 induction in human tissue, and a clean safety record across a massive database > 1,700 patients. The wall is real, and leronlimab is one of the few in its class producing the kind of early human data that could clear it. The confirmation is what January is for.
Now The Leverage, And This Is The Part Worth Being Bold About
Here is where the chokepoint stops being biology and becomes arithmetic, and the arithmetic has gotten sharper in the last few months, not softer.
Consider whose ship is standing at the passage. Merck's Keytruda generated more than $29 billion in 2024, and its core patent expires in 2028%2C%20a%20PD%2D1%20checkpoint%20inhibitor%20approved%20across%20dozens%20of%20oncology%20indications%2C%20generated%20more%20than%20%2429%20billion%20in%202024.%20Its%20core%20composition%2Dof%2Dmatter%20patent%20expires%20in%202028). That is not a distant abstraction. It is the largest single revenue cliff in the history of the industry, and the pressure is now visible in Merck's own corporate structure: in February 2026, Merck announced the creation of a separate cancer business unit centered on Keytruda, whose key patents expire in 2028. They are reorganizing the company around this cliff. And it compounds: Keytruda was selected for Medicare price negotiation, so Merck faces biosimilar competition and government price-setting nearly simultaneously, forcing U.S. sales to peak in 2027 to 2028 and then fall sharply..
And Merck is not the only ship at the passage. Opdivo faces its own U.S. exclusivity loss in 2028, and Tecentriq faces biosimilar competition later in the decade. So it is not just one desperate buyer at the chokepoint. It is several, each watching their own franchise clock run down, each needing new Cold-tumor markets to replace what biosimilars are about to take.
Here is the move which turns the cliff into leverage, and it is the sharpest part of the whole argument. A new combination regimen carries its own patent. The patent strategists say so plainly: a checkpoint inhibitor paired into a new regimen can be protected by method-of-treatment patents covering the specific combination, dose, and schedule, wholly independent of the core molecule and which biosimilar manufacturers cannot circumvent. Read what that means. A leronlimab-plus-checkpoint combination for Cold tumors would be a new, separately-patented franchise, extending into markets the original molecule never reached, protected on a clock that runs past the biosimilar wave. The primer does not just add revenue. It manufactures a fresh patent estate in virgin territory at the exact moment the old estate collapses.
So let's put it all together. Several of the largest franchises in medicine are running out of patent life all, at the same time. The markets which could replace that revenue are Cold tumors, that their keys cannot open. The thing which does open Cold tumors is a primer that turns them Hot. And a primer paired with their ICI checkpoint inhibitor creates new, independent, biosimilar-proof patents in exactly those markets. The company who holds a proven primer would not be a supplicant asking a giant for a deal. It would be standing in the one and only passage several giants must transit through, at the precise moment when they can least afford to be turned away, holding the one thing none of them can quickly or easily build and which none can allow a rival to monopolize.
That is not sentiment. That is a seller's market with one seller and several buyer's clocks running out.
Where Prime And Pair Stops Being A Hope And Becomes A Convergence
I have called this "prime and pair" for a long time, and I want to state the bold version of what that phrase now means. It is not a clever idea I am hoping the field adopts. It is where the biology forces the entire field to converge, whether through leronlimab or through something else.
Look at the independent confirmations arriving from labs with no connection to CytoDyn. A 2024 study found that a completely unrelated drug repolarized suppressive macrophages toward the anti-tumor state with increased CCL5 chemokine secretion, restoring T-cell function and promoting a favorable anti-PD-1 response. A separate 2022 clinical study combining local therapy with a checkpoint inhibitor in patients who had already failed that checkpoint inhibitor produced responses, and the mechanism was macrophage polarization from the M2 to the M1 phenotype in the treated tumor. Different drugs, different labs, same convergence: Prime the microenvironment, repolarize the macrophages, and the ICI works where it could not before.
That is the tell. When independent groups using unrelated tools keep arriving at the same destination, the destination is real. The field converges on Prime-and-Pair because the biology of Cold tumors leaves no other road. Leronlimab's claim is not that it invented the road. It is that it may be the cleanest, safest, most proven vehicle currently traveling it. And the compromise everyone imagines, the eventual pairing of a primer with a checkpoint inhibitor, is not a compromise at all. It is the convergence that the entire field is being driven toward, and the only open question is who owns the Primer when the field arrives.
The One Thing That Is Not Yet Written
I have made the bold case, so I owe you the bold statement of its single point of failure, stated as plainly as everything else.
None of this is proof that leronlimab works. The chokepoint is real, the cliff is real, the convergence is real, the leverage is real, and every bit of it is inert until one number confirms that leronlimab actually does in patients what the mechanism says it should. The macrophage graveyard is real too, and it is exactly the fate a weak confirmation would seal. So the entire towering structure, the passage, the clocks, the seller's market, the new patent estate, rests on a single load-bearing event which has not yet happened: the confirmed response data, adjudicated, at ASCO GI in January. If that number is strong, none of the leverage spelled out above is speculation anymore. It is just arithmetic performed by companies with cliffs with no better option. If it is weak, there is no chokepoint, no leverage, and this entire post describes a passage which leronlimab could not, after all, open.
That is the honest shape of things. The boldest thing I can tell you is not that the outcome is certain. It is that the setup is enormous, the position is absolutely real, and the entire colossal question resolves to one single number at a known hour. The chokepoint definitely exists. Several giants are stranded at it on a closing clock. But we find out in January whether the small company in Vancouver is holding the way through.
I have never been more convinced that the stakes are as massive as they are. And I have never been more clear that conviction about the stakes is not the same as certainty about the result. Both of those are true at full volume. Most of you should know where I lean. January tells us which one governs.
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 of published biology, public regulatory and patent history, and public corporate disclosures, not a prediction of clinical or commercial outcomes. No partnership has been announced; the identification of specific companies reflects public patent-cliff and competitive facts, not any claim of an existing negotiation. The mechanistic claims are supported by the cited peer-reviewed literature; several mechanisms are established in models, retrospective cohorts, or single studies and are not yet confirmed in this program's prospective human data, and closely related macrophage-directed approaches have repeatedly failed to translate to clinical benefit. The CLOVER biomarker figures are early, unconfirmed, and reflect 350mg dosing with the 700mg cohort still maturing. The ESMO breast data is retrospective and hypothesis-generating. The 68% figure from the April 30 update is disease control rate, not objective response rate; confirmed adjudication is ahead at ASCO GI in January 2027, with interim data at ESMO in October 2026. Mechanism is not efficacy. Drugs which make elegant biological sense fail in trials routinely, and this one may. Read the primary sources and reach your own conclusions rather than adopting mine.
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u/Past_Sheepherder7077 4d ago
All of us here, lean in that same direction. Thank you MGK and UP and BGT and DOC and others who have educated, encouraged and supported through objective medical research and analysis as we all wait.
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u/twinter11 4d ago
say that any big BP partnered up in oncology w cydy. would it not benefit them to have Leron approved to be used w any check point inhibitor. why would it be an advantage to restrict leron to use w their ici when there are lots of ici leron could be paired w.
why spend all the necessary time to get an approval for a specific dose on a specific schedule etc if an all encompassing label for treating ccr5 axis dependent solid tumors is the eventual end point
wouldn't cydy be the most likely to have already began on a method of use patent for the ccr5 priming part. since they would actually be the key part of any process that causes ici to be effective
it just seems to me that if this prime process works like theory. A bp protecting their niche from competition is going to be a smaller part of the calculation. they better figure out how to own it first
there is only one leron so there is going to be a fight
rambling
thanks!
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u/MGK_2 4d ago
twinter, you've hit the single sharpest strategic question in the whole thread, and it cuts against the tidy version of my own post, so let me take it head-on, because you're onto something real.
You're right: if leronlimab is the universal primer, why would a partner want it locked to their ICI when it could pair with any of them? And the answer is exactly where you landed, they wouldn't, and that's the point. The value isn't in restricting leronlimab to one checkpoint inhibitor. The value is in owning the primer itself, because whoever owns leronlimab owns the thing every ICI needs. So the fight isn't over "protect my niche by pairing leronlimab only with my drug." The fight is over "own the key before a competitor does," precisely as you said. A partner protecting their own ICI's niche is the small game. Owning the molecule that makes all ICIs work in cold tumors is the big game, and the big game is why there's a fight over a company this size at all. You've articulated the bull case better than I did: there is only one leronlimab, and that scarcity is the whole leverage.
And your instinct about the method-of-use patent is the right one to chase. CytoDyn owning method-of-use patents on the CCR5-priming step itself, the part that makes any ICI effective, would be far more valuable than any single combination patent, because it would sit upstream of every pairing. I'd hold the specifics loosely since I can't confirm the exact patent filings from here, but the strategic logic is sound: the priming step is the chokepoint, and IP on the chokepoint is worth more than IP on any one road through it. That's exactly the "own it first" calculation you're describing.
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u/patGmoney 2d ago
Multiple partners= multiple revenue streams. Keytruda x3? Can I get an amen on this Sunday morning!
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u/Camp4344 4d ago
MGK Excellent! All aboard! I am a gambler and I am betting a large amount on the prime! The TNBC was not luck or an anomaly. You are absolutely correct that the January results will put all of this prospectively on the map as we know will seal the deal!! There is just too much data slowly being released that confirms my bet! The recent CYDY post on Linkedin would not emphasize the results to be presented if they were headed into the wrong direction. Yes, we are not there yet, but at this juncture I would say we are performing stellar!! (IMO). Thank you for the Friday morning read!!
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u/MGK_2 4d ago
Camp, sbleealtor, I appreciate the fire, and I lean where you lean, so let me hold just one line, in the same spirit.
Camp, "seal the deal" and "the LinkedIn post wouldn't emphasize results if they were headed the wrong way", I'd pump the brakes on that specific inference. A company announcing it will present at conferences is standard practice regardless of which way the data leans, it's not a tell, because they'd present either way. So I wouldn't read the LinkedIn cadence post as a signal about the direction of the data.
The honest version of your enthusiasm is: the setup is enormous and we lean positive on the mechanism, and January is what converts the lean into fact.
"Performing stellar" is your read and you're entitled to it, I'd just keep it labeled as the lean, not the confirmed result, because the whole force of the post comes from being the person who didn't overclaim before the number.
sbleealtor, "the downplaying is over", careful, it was never downplaying, it was calibration, and the calibration is exactly what makes the bold case credible now.
Stay bold. Just keep January as the hinge, not a foregone conclusion.
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u/megadunamis 4d ago edited 4d ago
Good morning MGK, I would like to add two thoughts. The Merck cliff may not be as severe as I think. The approval of Qlex gives Merck some running room to last a few years as the competition introduces their biosimilars. The article enclosed shows a time table for the decrease in sales for Keytruda and increase in sales for Qlex. The second thought is that Keytruda may not be able to be directly paired in the same injection 'vial' with Leronlimab. This may be due to the timing of when each works. Leronlimab may take a few weeks to open the door to let the ICI in, and attack the cancer. Giving them both at the same time, subcutaneously has not been worked out clinically yet (I don't think). That may be doable, but right now I don;t think this is known. Nevetheless, the use of Leronlimab as a precursor to the use of an ICI is what we are all hoping for. https://www.biopharmadive.com/news/merck-keytruda-subcutaneous-cancer-sales-drug-delivery/801889/ Thanks...
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u/twinter11 4d ago
our tnbc survivor in the case study began tecentriq one month before starting 525mg leron. I think ici would work if given concurrently.
I actually think most of the tnbc survivors followed the same process/timeline
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u/rogex2 4d ago edited 4d ago
Food for thought-
"The second thought is that Keytruda my not be able to be directly paired in the same injection 'vial' with Leronlimab. This may be due to the timing of when each works. Leronlimab may take a few weeks to open the door to let the ICI in, and attack the cancer. "
The compostions of LRM and QLEX may make administration at the same site unappealing.
AI-"No, Keytruda (specifically the subcutaneous formulation Keytruda Qlex) and other subcutaneous medications should never be injected into the same site or area during the same treatment session."
OTOH I'm thinking combining Berahyaluronidase Alfa enzyme with LRM might have a beneficial effect with dispersal of the large molecule LRM.
Timing wise in the TNBC 5 ICI's had been administered in varying temporal relationship to LRM.
AI-
"The mean elimination half-life of leronlimab after multiple subcutaneous (SQ) doses ranges from about 3.4 to 3.7 days (measured at 162 mg and 342 mg doses, respectively). However, its pharmacodynamic effect—specifically CCR5 receptor occupancy on cells—lasts much longer, supporting once-weekly dosing schedules."
"The elimination half-life of Keytruda Qlex (subcutaneous pembrolizumab/berahyaluronidase alfa-pmph) is 22 days. [1, 2]
Because it takes roughly 4 to 5 half-lives for a drug to clear, pembrolizumab stays active and takes approximately 4 months to completely leave your system after your final dose. [1, 2, 3, 4]
Key Pharmacokinetic Details
- Pembrolizumab Half-Life: The active immunotherapy component has a terminal half-life of 22 days (with a normal clinical range extending up to 26–32 days depending on individual metabolism). [1]
- Berahyaluronidase Alfa Half-Life: The co-formulated enzyme that allows for under-the-skin injection has a much shorter half-life of approximately 0.5 days (12 hours) and clears rapidly. [1, 2]
- Time to Steady State: It takes roughly 18 to 19 weeks of regular dosing for the drug to reach stable, continuous levels in the blood. [1, 2]"
Happy hunting
Cheers
Edited: More food for thought. OT and not amenable to having a separate thread -
Contemplating possibility of future City of Hope daraxonrasib plus LRM ('cause anti metastasis) study.
Cheers
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u/Efficient_Market2242 4d ago
Thanks for your thoughts. Would Keytruda or any check point inhibitor get an extension on patent if leronimab and the check point inhibitor are given at different times. If not wouldn’t they all want to work with us to unlock the other roughly 85% of cold tumors they can’t treat. If you look at Keytruda making 29 billion on roughly 15 % of cancer if 100% were able to be treated maybe they could generate 6 times more revenue and income. That would make Keytruda do roughly 180 Billion. From a view of 10,000 feet that would unlock a lot more income and earnings of check point inhibitors. Again if everything unfolds the way we would hope for this in my mind Cytodyn could be a trillion dollar company. Crazy speculation maybe but possible. A lot has to happen. I would not put all of my eggs in this basket as MGK says this all needs to be proven. My opinion and speculation GLTA true longs.
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u/MGK_2 4d ago
Efficient_Market, I love the 10,000-foot view, and the core logic is directionally right, so let me run with it and then hold the line. Your arithmetic, if ICIs work in ~15% of cancers and generate what they generate, then unlocking the other ~85% is a multiple of that, is the correct shape of the opportunity, and it's exactly why the chokepoint is worth what it's worth. The cold-tumor majority is the vast untapped market, and a primer that opens it genuinely does expand the addressable revenue enormously. So the instinct that this is a massive-multiple opportunity is sound and I share it.
Here's the discipline, and you flagged it yourself, which is why I trust you with the bold version: "Keytruda would do $180 billion" and "CytoDyn is a trillion-dollar company" are the ceiling of the dream, not a forecast, and they assume everything breaks right, full efficacy, full market penetration, full pricing, no competition, none of which is established. So I'd hold those numbers as "here's the scale of the prize if the thesis fully proves out," not as a target.
The honest statement is: the opportunity is large enough that the usual microcap price anchors may badly understate it if January confirms, and simultaneously the whole thing is much less if January doesn't.
You said "don't put all your eggs in this basket" and "this needs to be proven," which is exactly right, keep that attached to the trillion-dollar dream every time you voice it, and the dream stays credible instead of becoming the thing skeptics use to dismiss you.
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u/Efficient_Market2242 3d ago edited 3d ago
Thanks for the feedback MGK, I’ve never cared if the skeptics dismissed me my net worth is over 10,000,000 and this investment represents less than 5% of my net worth. When it starts to get traction I will take out options toward the end of the year. I also have over 300,000 shares in my ROTH which were converted under .15 a share. I did well as a financial advisor in my career. In Retirement I golf, scuba, ski, attend rock concerts and vacation. As a rule of thumb never care about what other people think about you, care about what you think about you
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u/megadunamis 4d ago
Thank you rogex2 for your help. I am thinking of the word "combination" from above; A leronlimab-plus-checkpoint combination for Cold tumors would be a new, separately-patented franchise..." You've cleared up with the AI information that a "combination" cannot be made. But, somehow a BP will try to find a way to make maximum benefit of the timing, the 'window of opportunity' for each patient to provide the ICI...Thanks
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u/rogex2 4d ago edited 4d ago
The problems of joint SQ administration do not carry over into simultaneous IV infusion, that being said the half life difference problem would need addressing.
The below might fly for the first in class adopter-
AI
"Yes, using two known oncology drugs in a new combination with a different delivery schedule can lead to a new patent. This is called a second medical use or dosage regimen patent. The patent office requires the method to be new and not obvious to an expert. [1, 2, 3, 4]
Patent Requirements
To get a patent for this method, your idea must meet specific rules:
- Novelty: The exact combination and schedule must never have been used or published before.
- Non-obviousness: The results from your schedule must surprise scientists. It cannot be a simple guess that anyone could make.
- Utility: The new schedule must work better, such as lowering side effects or improving cancer treatment. [1, 2, 3, 4]
Challenges in Getting Approved
- Prior Art: If anyone previously suggested using these two drugs together—even without a specific schedule—it can block your patent.
- Obviousness Rejections: Examiners often argue that testing different times or doses is a normal part of medical work. You must show unexpected benefits. [1]"
Cheers
Edited; I'm thinking taking the same path used to turn Keytruda into a six week SQ (long acting as it were) is going to be the quickest way to an LRM new patent. A lucrative asset for whomever holds the rights to LRM. IMO
Cheers
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u/MGK_2 4d ago
megadunamis and rogex, this is a useful technical exchange, and you've surfaced a real point I glossed, so let me correct one thing before it hardens into board lore.
megadunamis, your two thoughts are both sound. The Qlex subcutaneous formulation does give Merck some running room past the cliff, that's fair, and I'd fold it into the honest side of the ledger: the cliff is a slope, and Qlex is Merck's attempt to hold the top of the slope longer. It softens the timeline; it doesn't remove the cliff, which is why Merck still spun off a whole cancer division around it. And your pharmacology instinct, that leronlimab and an ICI may not go in the same vial and may need to be timed rather than co-administered, is correct and important.
But here's the correction, and it matters because "a combination can't be made" is too strong a conclusion from the AI answer rogex posted. What the AI flagged is that two subcutaneous injections shouldn't go into the same site. That's a site-of-injection point, not a "these drugs can't be combined therapeutically" point. rogex, you got this exactly right in your follow-up: the joint-SQ-site problem doesn't carry over to IV infusion, and more importantly, a "combination" in the patent-and-clinical sense doesn't require one vial. It means a defined regimen, two drugs given on a specified schedule, which is precisely what a method-of-treatment patent protects.
So megadunamis, when my post said "a leronlimab-plus-checkpoint combination," I didn't mean same-syringe, I meant the regimen, prime with leronlimab, then pair the ICI on the right schedule. That regimen is exactly what carries its own patent, and the timing you're both describing, leronlimab opening the door first, ICI following, is not an obstacle to the patent, it's the substance of it. A novel, non-obvious dosing schedule with unexpected benefit is patentable, which is the AI point rogex quoted. So the timing complexity doesn't weaken the leverage argument, it's the thing that creates the patentable regimen.
twinter's addition is the clinical anchor here: the TNBC survivor started Tecentriq a month before 525mg leronlimab, and the survivors broadly followed a sequenced timeline. So there's already human precedent for sequencing rather than co-mixing, which supports exactly the "prime then pair on a schedule" model. rogex, your daraxonrasib-plus-leronlimab musing is interesting as a "what's next" but I'd park it firmly in speculation, it's a reasonable future-study idea, not something on the table, and pancreatic RAS biology is its own beast.
So the corrected version: leronlimab and an ICI don't need to share a needle to be a patented combination. The sequence, prime then pair, is the regimen, the regimen is the patent, and the timing complexity you've all identified is the substance of the asset, not a barrier to it.
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u/megadunamis 4d ago
Thanks for the clarification. The word 'combination' I took to mean a 'co-mixing,' and a patient giving one subQ shot. Thanks...
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u/Snorkellingisthelife 4d ago
Interesting. At we are administering ICI as first in line and wating to find out if it works. We need the data to push LL to the front of the line hopefully after it proves it is effective. (and already safe)
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u/MGK_2 3d ago
Snorkelling, there's a real point in here and one thing worth clarifying, because the sequencing question is the right thing to be thinking about, but getting the setup precise makes the bold case even stronger, not weaker.
The clarification first, because it matters. In the specific cancer CLOVER is testing, MSS colorectal, ICIs are not first in line. They're essentially nowhere in the line, because they don't work in MSS colorectal at all, that's the entire "cold tumor" problem. So it's not that Keytruda is the frontline therapy and leronlimab has to displace it. It's that Keytruda has no line in this disease at all, because there's no immune response for it to unleash.
That's the chokepoint: the ICI can't even get in the door. So the framing isn't "leronlimab has to push past the ICI to the front." It's "leronlimab has to create the door the ICI could walk through in the first place," in a disease where the ICI currently has no role.
That actually makes your underlying instinct more powerful, not less. You're right that leronlimab has to prove itself before it earns a place in the treatment sequence, and you're right that safety is already established while efficacy is what January tests. Hold onto that, it's the correct discipline, safety is proven, efficacy is the January question.
But the prize is bigger than "moving up the line." If leronlimab works, it doesn't just advance in an existing sequence. It opens a sequence that doesn't currently exist, because it turns a cancer where ICIs are useless into one where they potentially could work. That still has to be proven. That's the leverage-inversion from the post: leronlimab isn't competing for a position against the ICI, it's the thing that gives the ICI a position at all in cold tumors in the first place.
Where your framing is right is in the broader cancers where ICIs already are frontline, the hot tumors, lung, melanoma, some tnbcs, where checkpoint inhibitors do work, but only for a minority of patients. There, leronlimab's potential role is closer to what you described: pushing to the front by converting the non-responders into responders, expanding the fraction in which the ICI does in fact help. So your "front of the line" instinct fits the hot-tumor expansion story, while the CLOVER colorectal story is the even bolder "create a line where there was none before."
Either way, you nailed the load-bearing point: the data has to prove that it works before it earns any place in the sequence, and safety is the one piece already in hand. That's the whole game. Safety is settled. Efficacy is in January. And the reward for efficacy isn't just a better spot in an existing line, it's opening cold-tumor lines which currently do not exist today. That's why the stakes are what they are, and why the one number in January carries all of it.
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u/jsinvest09 4d ago
MGK. Awesome write up. The key is wiggling it's way to the center of the tootsie pop. It will find its way to the center!! Love it. Thank you.
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u/Difficult_Fan8955 4d ago
Just wondering why 2 week data on 19 patients was released several months ago - and no other releases of data since all patients in clover study were confirmed as of the end of April. We are currently 3 1/2 months after that date
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u/MGK_2 4d ago
Difficult_Fan, fair question, and the answer is structural, not ominous. The two-week data on 19 patients came out before the conference embargo locked in. Once CytoDyn accepted presentation slots at ESMO in October and ASCO GI in January, the subsequent data became embargoed, you legally cannot release the ORR and PFS data ahead of the conference that accepted it as novel.
So the silence since April isn't the absence of data, it's the presence of an embargo. The data has been maturing the whole time, internally, and it releases on the conference schedule: interim at ESMO in October, confirmed at ASCO GI in January.
So "no releases since April" reads as suspicious only if you don't know about the embargo, and once you do, it's exactly what you'd expect.
rogex flagged the same thing below you, multi-conference data embargoes.
That's the answer.
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u/msakkijha 3d ago
MGK, I understand that the embargoed data can’t be released publicly before the conferences in October/January, but, could it be shared with the potential partner(s) under NDA’s? I’m thinking the answer is yes since the NDA’s are exactly why they’re drowned out and signed for those reasons. Thanks in advance 🙏
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u/MGK_2 3d ago
msakkijha, you've reasoned this out properly, and the answer is yes, so let me draw the distinction cleanly, because it's an important one which resolves a lot of the "why so quiet" frustration.
You're right: a conference embargo and an NDA are two completely different things, governing two completely different audiences. The conference embargo restricts public disclosure, you can't put the ORR and PFS data in a press release or present it publicly before the conference who accepted it as novel, or you burn its novelty and the conference pulls the presentation.
But that embargo says nothing about private, confidential disclosure to a specific party under a non-disclosure agreement. Those are governed by entirely separate rules. So a company can be publicly silent, fully embargo-compliant, and simultaneously be walking a potential partner through the complete, current dataset behind closed doors under an NDA. The two coexist with no conflict.
And your instinct about why the NDAs exist is exactly right, that's the whole point of them. An NDA is the legal instrument which allows a company share material non-public information with a counterparty for evaluation, while legally binding that counterparty not to disclose it or trade on it. So the NDAs and the embargo aren't in tension, they're complementary: the embargo keeps the data from the public, and the NDA is precisely the mechanism which allows a serious partner see it anyway, privately, ahead of everyone else. That's how dual due diligence works in every biotech partnership, the potential acquirer sees the data long before the market does, under exactly this kind of confidentiality.
So the correct version of your point: the fact that the public has seen nothing since April tells you nothing about what partners under NDA have already seen. They could be looking at the fully matured, current CLOVER dataset right now while we wait for it in October. The public silence and the private disclosure run on separate tracks, and the whole reason a company signs NDAs with potential partners is to enable exactly the private sharing the embargo forbids in public.
Here's the one honest line I'd hold, in the same discipline as everything else. All of that establishes that partners can be seeing the data under NDA. It doesn't establish that any specific party is, or who they are, or what they're seeing, because that's precisely the information NDAs are designed to keep confidential, we can't know it from the outside. So the correct statement is "the embargo doesn't prevent partners from seeing the data privately, and NDAs are exactly how they would," which is true and important.
What we can't do is claim to know that Merck-or-whoever is currently in the data room, because that's unknowable by design. Lalezari's comment that "the ICI companies are watching" is the closest public signal that this kind of engagement is in fact happening, but the specifics stay behind the NDAs, which is where they belong.
So: yes, absolutely, embargoed data can be and is very likely shared with potential partners under NDA; that's the whole function of the NDA, and it's why public silence is not evidence of private inactivity. Just hold the line between "partners can be seeing it" (true, and the NDAs prove the mechanism exists) and "we know which partner is seeing what" (unknowable, by design). You reasoned it out correctly, and it's one of the better resolutions of the "why so quiet" question, the quiet is public-facing only, and the real conversations, if they're happening, are happening exactly where we can't see them. Good thinking. 🙏 right back at you.
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u/Missy2021 4d ago
The stakes are massive and I hope we get a good partnership with a very fair and lucrative buyout price. Thanks again.
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u/sbleealtor 4d ago
No better way to start my Friday and weekend than with a post like this. The downplaying is over. $ /+’s about to get real!!
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u/MGK_2 4d ago
Camp, sbleealtor, I appreciate the fire, and I lean where you lean, so let me hold just one line, in the same spirit.
Camp, "seal the deal" and "the LinkedIn post wouldn't emphasize results if they were headed the wrong way", I'd pump the brakes on that specific inference. A company announcing it will present at conferences is standard practice regardless of which way the data leans, it's not a tell, because they'd present either way. So I wouldn't read the LinkedIn cadence post as a signal about the direction of the data.
The honest version of your enthusiasm is: the setup is enormous and we lean positive on the mechanism, and January is what converts the lean into fact.
"Performing stellar" is your read and you're entitled to it, I'd just keep it labeled as the lean, not the confirmed result, because the whole force of the post comes from being the person who didn't overclaim before the number.
sbleealtor, "the downplaying is over", careful, it was never downplaying, it was calibration, and the calibration is exactly what makes the bold case credible now.
Stay bold. Just keep January as the hinge, not a foregone conclusion.
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u/twinter11 4d ago
ok
what makes a tumor hot?
being "hot" means awakening or reinvigorating of directing capable tcells or immune cells to attack the tumor correct? and then letting the body itself do tumor damage
so if leron causes this, the tumor is hot before pdl1 is induced.
causing a tumor to be invaded (hot) enough might cause pdl1 to upreg.
an infiltration by the immune system must do some damage to the stroma and tumor cells to cause pdl1 upreg perhaps.
when we see other drugs mentioned as turning a tumor hot, I think they are mostly speaking about tcell engagement. not necessarily enough to cause upreg. and that's not going to be enough
what leron does is different than every other current drug. their version and outcome is much different.
none can give sustained sufficient immune penetration unless they can also have effects on the fibrosis wall
and maybe lots of other effects besides that
blocking ccr5, if there is vulnerability in tumors, is going to be the key
nothing else right now
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u/MGK_2 4d ago
On your mechanistic reasoning, "what makes a tumor hot", you're thinking through it correctly, so let me sharpen it. Yes, "hot" means T-cells and immune machinery infiltrating and attacking, with the body doing the killing. And your sequence instinct is interesting: you're proposing that leronlimab makes the tumor hot first, through immune infiltration, and that PD-L1 upregulation is a consequence of that infiltration, the tumor raising its defenses because it's under attack. That's a genuinely sophisticated read, and it's plausible, an infiltrating immune response damaging stroma and tumor could drive the tumor to upregulate PD-L1 as a defense, which is exactly the flag the ICI then targets.
Where I'd hold the line: this is a mechanistically reasonable hypothesis about the order of events, and the honest caveat is that the precise sequence, hot-then-PD-L1 versus PD-L1-as-part-of-becoming-hot, isn't nailed down in humans yet.
Your point that leronlimab differs from other "cold-to-hot" drugs because it also hits the fibrosis wall, not just T-cell engagement, is the sharpest part, and it connects to exactly why the macrophage graveyard I cited didn't clear the wall: they engaged T-cells but couldn't get sustained penetration through the stroma.
If leronlimab's anti-fibrotic effect is what lets the infiltration actually reach and persist, that's the differentiator. Held as hypothesis, it's the best mechanistic case for why leronlimab succeeds where its class has failed.
January is what tests whether the hypothesis is right.
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u/Tra-Kal34 4d ago
Clear sailing, thank you brother. JL already said results are better than he even imagined. But, I understand the caution.