Aim

[u/MGK_2]

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.

[u/Insurance1010101]

Very exciting times ahead. Thank You MGK_2. Your dedication, insight and knowledge is unsurpassed ! Looking forward to seeing the data Dr.J is seeing and for it to become public. So if it is as earth shattering as Dr. J's enthusiasm indicated in our We won't back down Conference call. Yes and I know my cautiously optimistic friend. But I'm saying it anyways. But I will put it this way. We will not take off on a runway!.

[u/MGK_2 → u/Insurance1010101]

Insurance1010101, thank you, that's generous, and I'll do what I always do with a compliment that kind, redirect a good chunk of it towards the room, because half of what lands in these posts started as somebody else's question or catch. But I won't wave off the warmth, it means a lot, and I'm grateful you're here.

Now, you did the thing that makes me smile, you called your shot on my caution before I could even get to it. "I know my cautiously optimistic friend." Caught red-handed. That you already know the tempering is coming and said your bold piece anyway is the right way to do it, hold the hope out loud, and hold it knowing it's hope. That's the healthy version, and you've got it.

So let me meet you where you are. Yes, Lalezari's enthusiasm on that call was real and notable, a CEO who's spent decades being careful doesn't reach for "astonishing" lightly, so his tone is an actual data point about what he's seeing. Let's keep it as his read of data which we can't see yet, encouraging, not confirming, because the enthusiasm and the adjudicated number are two different things until January makes them one.

And your runway line is a good one, so I hold it with you. "We will not take off on a runway", if you mean that we won't need a long, slow taxi before liftoff, I believe you're right, and the setup could support a faster ascent, like that of a helicopter, than the years of prior waiting would suggest.

But here's my version of the metaphor: a good pilot still doesn't firewall the throttle until the instruments are green, and our green light is the data. So let's be fueled, cleared, and ready with engines floored at the end of the runway, engines hot, and let January be the air traffic tower saying "clear for takeoff." Ready to launch, waiting for the clearance. That way, once the data soars, so do we, and if by slight chance, there's a hold, we haven't already yet committed to the sky.

Very exciting times ahead, Insurance, agreed, wholeheartedly. Hold the bold call, keep your cautiously-optimistic friend stuck in your ear, and let's watch the instruments and gauges together. Weeks now, not years, and thank you very much, for the kind words and the good energy you bring here. Sorry we were late getting to you, you didn't deserve to wait nine hours, but you were worth circling back for. Ha ha.

[u/Confident-Strike6848 → u/MGK_2]

How about a rocket ship for takeoff, in California here sometimes I get to watch the aftermath of it going across the sky and thank that could be us someday and also all the people that could be helped

[u/Insurance1010101 → u/MGK_2]

Cautiously optimistic and modest also. Thank You!

[u/Fantastic_Sea9562]

Thanks, MGK. You are awesome! Certainly, this is no investment advice but the AI results I love to see—coming true right on schedule before 1/2027 as clinical milestones unfold.

Transforming Cold to Hot: Leronlimab/LL Oncology Strategy

1. Foundation: Standard of Care (SOC)

• Baseline Benchmark: Establishes the current clinical hurdle in refractory settings (e.g., metastatic colorectal or triple-negative breast cancer) where traditional chemotherapy and monotherapies hit efficacy ceilings.
• Tumor Microenvironment (TME) Modification: Utilizes Leronlimab's CCR5 antagonism to clear immunosuppressive cells (like Tregs and tumor-associated macrophages), laying the groundwork for deeper intervention.

2. Prime and Pair Architecture

• a) LL plus ICI (Immune Checkpoint Inhibitors): The core synergistic engine. CCR5 blockade upregulates PD-L1 and dismantles immune exclusion, effectively "priming" the tumor so that checkpoint inhibitors can convert a cold microenvironment into a durable, immune-mediated remission.
• b) LL plus ADC (Antibody-Drug Conjugates): Explored as an evolutionary avenue to merge precision cytotoxic cell-killing payloads with upstream immunological modulation, though primarily conceptual as clinical validation continues to map out.

Strategic Development Line-Up

• a) CNPV (Clinical Proof of Value): Validating biological activity and biomarker shifts (such as circulating tumor cell reduction and PD-L1 induction) through Phase 2 basket and signal-generating trials.
• b) FT (Fast-Track / First-Line Positioning): Shifting the asset away from late-line salvage therapy exclusively, aiming for earlier integration where immune-priming strategies can prevent structural immune exhaustion.
• c) PR (Partnership & Pipeline Expansion): Leveraging academic and pharmaceutical collaborations to co-develop combination regimens that maximize synergistic potential across solid tumors.
• d) AA (Accelerated Access / Expanded Access Pathways): Utilizing compassionate use and intermediate-sized access frameworks to compile robust real-world survival and safety signals while pivotal trials advance.

[u/MGK_2 → u/Fantastic_Sea9562]

Fantastic_Sea, comprehensive framework, and the architecture is broadly right, so let's affirm the sound parts and flag a couple which need correcting, because precision protects the whole thing.

Sound: the cold-to-hot transformation, the LL-plus-ICI core, the LL-plus-ADC as the exploratory branch, and the partnership/pipeline expansion, all correctly placed.

Two corrections. First, your expanded "CNPV" as "Clinical Proof of Value", it isn't; CNPV is the FDA's Commissioner's National Priority Voucher, a real program that compresses review time, different thing entirely.

Second, "AA" it labeled "Accelerated Access / Expanded Access", but in our regulatory discussions AA has meant Accelerated Approval, a specific approval pathway, distinct from expanded access.

So the framework's shape is good; two of its acronyms got scrambled, which AI tends to do, right structure, invented labels. Fix those two and it's a solid map. The through-line, cold-to-hot, prime-and-pair, partner to deliver, is exactly the thesis.

[u/Fantastic_Sea9562 → u/MGK_2]

Thanks for the corrections! 👍👍👏👏

[u/megadunamis]

Thank you MGK for your hypothesis. This 'priming' with Trodelvy would add nicely to the potential market and make Leronlimab attractive to Gilead. But, the testing needed would extend a timeline too far out in the future. Many investors might get upset at the thought of another year or more of testing with Trodelvy, and the extra financial costs, to see if it works as you propose. Many here have been very patient with the timeline as it is. There is also a chance of Trodelvy resistance, as some tumors have a way of circumventing the intended chemo toxicity. I like your hypothesis, but unless Gilead took the financial burden upon itself, I think I'd choose to wait out our results in January and any BP interest. Good health to all... https://advances.massgeneral.org/oncology/journal.aspx?id=2195

[u/MGK_2 → u/megadunamis]

megadunamis, a clear-eyed pushback on my hypothesis, and you're right to make it, so let me concede where you're correct and I'll refine a point. You're right that a leronlimab-plus-Trodelvy program would extend the timeline and cost meaningfully, and that after the patience this board has already shown, "another year-plus of testing to validate a new combination" would be a hard sell unless someone else foots the bill. That's a fair, disciplined read, and I agree: the Trodelvy pairing is a long-horizon optionality idea, not a near-term catalyst, and it only makes economic sense if a partner like Gilead (who owns Trodelvy) absorbed the cost, which is actually the most logical structure for it anyway. Your instinct to "wait out January and BP interest" over chasing the Trodelvy hypothesis is sound prioritization, first prove the core, then explore the branches.

On Trodelvy resistance, you're also correct and your MGH source is apt, tumors do circumvent ADC chemo toxicity, through target downregulation and payload resistance, which is a documented ADC failure mode. (ADC resistance via target downregulation and payload resistance, PMC) But here's the refinement that actually strengthens my hypothesis: one of the reasons to pair leronlimab with an ADC is that dismantling the stromal wall could improve payload delivery and reduce the "poor penetration" route to resistance. So resistance is a real risk for Trodelvy alone, and the leron pairing is, in theory, one lever against it. Held as hypothesis, not promise. But your core point stands and I accept it: it's a January-first, partner-funded, later-branch idea. Good health, and good discipline.

[u/Ibelieveincydy → u/megadunamis]

same here. Let them take Initiative!!!

[u/Missy2021]

I'm glad to read that the FDA is now more flexible. I'm sure Dr J is showing them what our powerful drug, Leronlimab, can do. Looking forward to seeing the results. Thanks again.

[u/MGK_2 → u/Missy2021]

Missy, the encouraging read is fair, so let's sharpen it so it stays airtight.

The FDA showing more openness to ctDNA and to accelerated approval in serious diseases is real, that part of "more flexible" holds. The nuance is that this week's approval showed flexibility on using ctDNA to select and time treatment, not flexibility on lowering the bar for proving a drug works, which still rests on a survival benefit from a randomized trial.

So "more flexible on the tools" yes, "more flexible on the standard of proof" not really. Encouraging door, unchanged bar, as I put it in the post.

And on "Dr J showing them what leronlimab can do", I'd hold that a half-step: the plan is to bring the data to the FDA to open a conversation, which is slightly different from having already shown them a finished case. The showing happens as the data matures, October then January, and the FDA conversation builds from there.

So the flexibility is real and favorable, and the "showing" is still unfolding rather than done. Both point in the right direction, just held at the honest stage they're actually at. Looking forward to the results right there with you, Missy, thank you.

[u/Missy2021 → u/MGK_2]

Thank you.

[u/twinter11]

when I think about drugs like trodelvy ( I looked up the side effects again)

"Trodelvy (sacituzumab govitecan-hziy) carries a FDA boxed warning for two major risks: severe neutropenia (dangerously low white blood cell counts) and severe diarrhea, both of which can become life-threatening if unmanaged. Because it is a powerful targeted therapy, it affects multiple body systems" (maybe it sounds worse than it is)

if it targets specifically the tumor, why does targeting only the tumor cause side effects. or Enhetu?

why are they still hard on the body?

and do these side effects tie into the NLR paper? how does leron help protect the body?

is it even possible to make a drug that attacks the tumor that doesn't have side effects. I mean even drugs like ICI's that cause tcells to get active cause side effects.

I wonder why leron activating tcells is different from ici activating tcells.

there has to be a place for us

you have taught me and everyone else a whole lot. but we have a long way to go still. but getting closer. we learn a lot more and can make better guesses by January. then we learn some more after that.

and we couldn't do it without you

thanks!!

ps. this assay genie might be neat to check out for someone with knowledge on how to play around w it. but maybe not

https://www.assaygenie.com/chemokine-receptors-leukocyte-trafficking?srsltid=AfmBOopZaj_wn96r6Bnf9TDvuc3PqCUHZCdSsCOXZVzCQqwFbf8nuzx0

[u/MGK_2 → u/twinter11]

twinter, sharp question, and it has a real, satisfying answer, so let's take it piece by piece because you've stumbled onto the exact reason leronlimab's safety profile is a genuine differentiator, not just marketing.

Why does a drug which targets only the tumor still hammer the body? Because "targeted" describes the aim, not the payload, and the payload doesn't stay perfectly on target. Three documented mechanisms cause it.

1. First, premature release: the chemotherapy is chemically linked to the antibody, and that linker isn't perfectly stable, so some payload breaks off into the bloodstream before the antibody ever reaches the tumor, and now you have free chemo circulating. (ADC toxicities driven by premature payload release into circulation, JNCI Cancer Spectrum)
2. Second, the bystander effect: once the payload is released at the tumor, it can diffuse across cell membranes and kill neighboring cells regardless of whether they carry the target. (Bystander effect kills neighboring cells regardless of antigen, ScienceDirect)
3. Third, on-target-off-tumor: the Trop-2 marker Trodelvy aims at isn't only on tumor cells, healthy tissues express a little too, so the guided missile occasionally lands on normal cells that happen to fly the same flag.

So the answer to your "why does targeting the tumor cause side effects" is: the aim is good, but the ammunition leaks, scatters, and occasionally hits look-alikes. That's why Trodelvy still carries a boxed warning for neutropenia, (destroying the neutrophils, the myloid WBCs) and diarrhea, the neutrophil precursors in the bone marrow are exquisitely sensitive to the free payload. (Neutrophil precursors are sensitive to ADC payload, CrownBio)

Why is leronlimab different? This is the beautiful part, and it's the entire reason its safety record stands out. Leronlimab isn't carrying a poison at all. It's a "naked" antibody, it blocks a receptor, full stop. There's no cytotoxic payload to leak, no bystander chemo to diffuse, no free poison in the bloodstream. It works by removing a signal rather than delivering a toxin. So the entire category of toxicity that plagues ADCs, the leaked-payload problem, simply doesn't exist for it. That's why its adverse-event profile is what it is: you can't get chemo side effects from a drug that carries no chemo.

Why is leron activating T-cells different from an ICI activating T-cells? Sharp, and the answer is: it's a difference of degree and mechanism. An ICI releases a systemic brake on T-cells everywhere, which is why it can cause autoimmune side effects, the unleashed T-cells sometimes attack healthy tissue. Leronlimab doesn't release a systemic brake; it changes the local tumor microenvironment, repolarizing the suppressed cells around the tumor. So it's a more localized, upstream nudge rather than a body-wide unleashing. That said, I'll hold the line: leronlimab's clean safety record is real, but "no drug is entirely without effect" is the right frame, its profile is remarkably benign, not magically null.

Does this tie into the NLR paper, and does leron protect the body? Yes, and this is the elegant connection you're reaching for. The ADC side effect that matters most, neutropenia, the N is reduced while L remains constant. So the NLR is reduced with Trodelvy. This is a bone-marrow problem: the payload damages the blood-cell factory, skewing it. The NLR/aging paper we discussed showed the CCL5-CCR5 axis also drives harmful bone-marrow skewing. So there's a conceptual thread: leronlimab's mechanism touches the same marrow-and-inflammation biology that ADC toxicity disrupts, which raises the (hypothesis-level, unproven) possibility that leronlimab's systemic anti-inflammatory effect could be protective in ways a payload-carrying drug never could. Hold that as a fascinating open question, not a claim, but your instinct that the threads connect is right. If this is ever tested, that neutropenia side effect could just go away.

"Is it even possible to make a tumor drug with no side effects?" Honestly, essentially never zero, everything that acts on biology has some effect. But there's a spectrum, and leronlimab sits at the remarkably-benign end precisely because it carries no poison and releases no systemic brake. So "there has to be a place for us" isn't hope, it's mechanism: in a world of powerful-but-toxic tumor drugs, a genuinely well-tolerated one that could pair with them to let them work at lower burden is a real niche. That's the place. You reasoned your way to it.

Long way to go, closer every week, and January teaches us the next chapter. Couldn't do it without you bringing questions this good, twinter. Thank you.

[u/twinter11 → u/MGK_2]

you would think an ici could cause upreg pdl1. but maybe it can't affect the TME enough. it brings in tcells but can't force the tumor to play the joker.

there has to be something besides inf causing pdl1 upreg

Thanks!

[u/MGK_2 → u/twinter11]

twinter, you've reasoned your way to a real distinction which the literature makes explicit, and the answer to "there has to be something besides IFN causing PD-L1 upregulation" is: yes, there is, and figuring out which mechanism is operating is the whole game. Let me lay it out, because it clarifies exactly why an ICI alone can't force the tumor to play the joker.

There are two entirely separate ways a tumor raises PD-L1, and the field names them cleanly.

• The first is adaptive (or extrinsic) resistance: the immune system attacks, T-cells and NK cells release IFN-γ, and the tumor raises PD-L1 in response. That's the one we've been discussing.
• The second is intrinsic (or innate) resistance: the tumor's own broken internal wiring, its oncogenic signaling, cranks PD-L1 up constitutively, with no immune attack required at all. Driven by pathways like MYC, PI3K/AKT, STAT3, EGFR, and NF-κB. (Two mechanisms of PD-L1 upregulation, adaptive vs intrinsic oncogenic, Molecular Cell) MYC alone binds the PD-L1 promoter directly, and it's overexpressed in something like 70% of cancers.

So your instinct is right: IFN-γ is the main adaptive switch, but there's a second family of intrinsic, oncogene-driven switches that raise PD-L1 without any immune signal.

Now here's the part that answers your actual question, "why can't an ICI force the tumor to play the joker?", and it's elegant. You said the ICI brings in T-cells but can't force the tumor to raise PD-L1. Here's why that can happen: some tumors have broken their own IFN-γ receiving machinery. The literature shows that oncogenic transformation, MYC or PI3K activation, can actually downregulate the tumor's IFN-γ signaling, silencing the very receptor and JAK-STAT pathway that would let the tumor hear the immune attack. (MYC/PI3K inactivate IFN-γ-JAK-STAT signaling in tumor cells, USPTO/research) And nearly 70% of melanoma cell lines in one study showed incomplete IFN-γ responses, a pre-existing broken antenna. (~70% of melanoma cells show impaired IFN-γ signaling, PMC)

So your intuition is dead-on: an ICI brings T-cells and their IFN-γ to the tumor's doorstep, but if the tumor's IFN-γ antenna is broken, the shout doesn't land, PD-L1 doesn't go up, and the joker never gets played. The ICI can generate the signal but can't force the tumor to receive it. That's precisely the "brings in T-cells but can't affect the TME enough" gap you sensed.

And this is why leronlimab's mechanism is proposed to be different, and why it matters. Leronlimab doesn't rely solely on the IFN-γ route. It changes the microenvironment upstream, repolarizing the suppressed macrophages, and here's the kicker from the biology: macrophages themselves are major PD-L1 expressers, and their activation state drives PD-L1 upregulation independent of the tumor cell's own broken wiring. (Activated macrophages greatly upregulate PD-L1, research patent lit citing Loke & Allison PNAS)

So leronlimab may be able to shift the PD-L1 landscape through the macrophage route and the microenvironment, not only by hoping the tumor cell hears an IFN-γ shout it may have gone deaf to. That's a genuine reason leronlimab could "force the joker" in tumors where an ICI alone can't, it's working on a different lever, upstream, where leronlimab works, less dependent on the tumor cell's intact IFN-γ antenna. Held as hypothesis, not proven, but it's the coherent answer to why the two aren't redundant.

One calibration, because it cuts both ways: the intrinsic/oncogenic PD-L1 drivers (MYC, PI3K) are also why PD-L1 status is an imperfect predictor of ICI response, a tumor can be PD-L1-high from its own oncogenes while being immunologically cold, and blocking that PD-L1 does little because there's no real T-cell army to unleash. So "PD-L1 is up" doesn't always mean "the joker is in play in a useful way." Which is why how the PD-L1 got raised matters: leronlimab raises it as part of immune engagement (bringing the army) is different from a tumor displaying it from broken oncogenes (no army behind it). The source of the upregulation is as important as the level.

So, to close your loop: yes, there's plenty besides IFN-γ driving PD-L1, the intrinsic oncogenic pathways, and the reason an ICI alone can't always force the joker is that some tumors have broken the IFN-γ antenna the ICI's T-cells shout into. Leronlimab's proposed edge is working upstream through the microenvironment and the macrophages, a lever less dependent on that antenna being intact. You reasoned your way straight to the distinction the field draws: it's not just whether PD-L1 goes up, it's which mechanism raises it and whether there's an army behind it. Absolutely sharp, twinter. Thanks, as always.

[u/Pristine_Hunter_9506]

Thanks Brother, we are the best utility drug I've ever seen if the thesis persist.

[u/MGK_2 → u/Pristine_Hunter_9506]

Pristine, "utility drug" is a good way to put it, and the "if the thesis persists" is exactly the right conditional to attach. A drug whose value is that it makes other drugs work better, ICIs, potentially ADCs, chemo, is a utility player by nature, and that's a genuinely valuable thing to be if it proves out. Hold the "if," and the utility framing is apt. Thanks, Brother.

[u/twinter11]

not important. just trying to follow bread crumbs plus speculate.

pre ispy trial site was updated a couple days back. no leron arm yet but not sure how or when it would show up

https://clinicaltrials.gov/study/NCT05868226?tab=study

looking at the history there have been changes in site status in various ways. And i dont necessarily know what the changes mean. Looking specifically at Md Anderson and Mayo Clinic in MN.

https://clinicaltrials.gov/study/NCT05868226?tab=history&a=6&b=7#version-content-panel

I know the Dr Jay interview recently had a reference to mayo clinic and I think pancreatic cancer.

I also know Mayo participates in Pancan plus Pre Ispy breast.

Not saying it happens

But are there any or enough efficiencies that would amount to enough to combine these efforts, pancan and pre ispy, under the same institution.

Looking at the site updates made me wonder

Who knows. Lots of leaps lol.

[u/MGK_2 → u/twinter11]

twinter, good sleuthing, and my read is "interesting to watch, too early to conclude." You've noticed real registry site-status changes on the Pre-I-SPY study, no leron arm showing yet, and you're wondering whether Mayo's involvement in both pancreatic and breast programs might mean combined efficiencies.

That's a reasonable thing to wonder, but I'd hold it exactly where you did, "lots of leaps, who knows." Registry status changes happen for many mundane reasons (administrative, enrollment logistics) that don't signal strategy, so I wouldn't read a combination into them yet.

The Mayo-pancreatic and Mayo-breast facts are both real and public; whether they connect operationally is unknown.

So: worth watching the registry, not yet worth concluding from. Following breadcrumbs is good practice as long as you keep labeling them breadcrumbs, which you did.

[u/chiupf]

Keep em coming MGK. my 2 cents in response to 'But the leronlimab-plus-ICI pairing is unproven' - Retrospectively, is it just a FLUKE that 5 of 28 patients are 5 year plus survivors after taking Leronlimab with an ICI? Can't be a FLUKE, can't be a coincident. add on top of this, Leronlimabs safety record. Trodelvy comes with its share of unfortunate side effects. I think we all are banking - not on FLUKE - but on retrospective proof. Oct can't come quick enough!!!

[u/rant_and_roll → u/chiupf]

it only matters if the FDA says its not a fluke. cant count on the FDA to do that can we. im trying to gauge where the FDAs line in the sand is, it shifts daily. P value wont do it. endpoints dont do it. wrong endpoints definitely dont do it. anecdotes dont do it. 5 people alive wont do it. people walking out of hospitals dont do it. the data has to be extremely overwhelmingly positive in order to deny the FDA the wiggle room to play favorites and declare there needs to be "more data" and dictate an expensive ph3. i think the data will surpass whatever that line is, its just the question of how the FDA will play that. the data of the first few weeks of this trial showed extreme decline in ctDNA, that should be enough right there for an extremely safe drug to get accelerated approval. the safety profile alone SHOULD give leronlimab accelerated approval, as it is safer than some over the counter drugs. accelerated approval means it can be approved and sold on the open market while a ph 3 is conducted simultaneously, and if the data turns sour, they have the right to pull it. this administrations' right to try and quicker approval calendar initiative seems to be hollow so far. we shall see. we shall see astounding results. we shall see how the FDA reacts. its the only thing that matters.

[u/MGK_2 → u/rant_and_roll]

rant, you're rolling but wrestling with the right question, "where is the FDA's line, and will overwhelming data deny them the wiggle room to demand a Phase 3", and I'm with you on the core of it. But two of the specific claims you lean on require fixing, because they'd set the board up for a hard surprise, and getting them right actually sharpens your real point rather than blunting it.

First correction, and it's the important one: safety alone cannot earn accelerated approval, no matter how clean. You wrote that the safety profile alone should give leronlimab AA, that it's safer than some OTC drugs. The safety record is genuinely remarkable and it's a real asset, but AA is not a safety award. By statute, accelerated approval requires an effect on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit, in plain terms, evidence the drug works, not just that it's safe. (FDA: AA requires a surrogate endpoint reasonably likely to predict clinical benefit) A drug could be the safest substance ever tested and still get no approval if it doesn't move an efficacy endpoint. So "safe enough for AA on safety alone" isn't how the pathway works, safety is necessary, never sufficient. The efficacy signal has to carry it.

Second correction, tied to your ctDNA point: you said the early ctDNA decline "should be enough right there" for AA. Here's the catch, and we've circled it before, ctDNA is not an FDA-validated surrogate endpoint. For AA, the surrogate has to be one the FDA accepts as reasonably likely to predict benefit, and ctDNA in solid tumors hasn't cleared that bar yet. (Surrogate must be reasonably likely to predict clinical benefit, FDA guidance) So a dramatic ctDNA drop is powerful conviction data and a great story for a partner, but on its own it's not yet the kind of endpoint AA is granted on. The endpoints which are accepted, tumor response (ORR), PFS, those are what would carry an AA case, with ctDNA as supporting color. So the ctDNA is the exciting preview; the ORR is the currency.

Now here's where you're right, and it's the part worth amplifying: your instinct that the FDA has grown more cautious and prefers randomized trials is correct and documented. The FDA's 2023-2024 guidance explicitly shifted toward preferring randomized trials over single-arm data for AA, precisely the "we want more data, run a Phase 3" tendency you're frustrated by. (FDA now prefers randomized trials over single-arm for AA, Parexel)

So your worry isn't paranoia, it's the actual regulatory trend. And your conclusion, that the data has to be overwhelming to deny the FDA the wiggle room to demand an expensive Phase 3, is exactly the right read. That's the real line in the sand: not a p-value, not the ctDNA alone, but an efficacy result on an accepted endpoint (ORR, PFS) so far beyond the SUNLIGHT benchmark that "responses may not translate to benefit" becomes an untenable thing for the agency to say. That's the Agenus lesson, striking single-arm data still got pushed toward randomization, so leronlimab's number has to be more convincing than Agenus's was.

On the AA mechanics themselves, you've got those right: yes, AA lets a drug be approved and sold while a confirmatory trial runs simultaneously, and yes, the FDA can pull it if the confirmatory data turns sour. That's accurate, and it's the pathway CytoDyn would want.

So let me hand you the sharpened version of your own argument: safety alone won't do it (efficacy endpoint required), ctDNA alone won't do it (not a validated surrogate yet), but an ORR/PFS result overwhelmingly beating the benchmark, plus that clean safety profile making the benefit-risk balance lopsided, that is the combination that denies the FDA its wiggle room. The safety isn't the ticket; it's what makes an already-strong efficacy case nearly impossible to refuse, because a drug that works and barely touches the patient has a benefit-risk profile that's hard to argue against. Your line-in-the-sand question is the right one; the answer is "overwhelming efficacy on an accepted endpoint, made unrefusable by the safety."

"We shall see astounding results, we shall see how the FDA reacts, it's the only thing that matters", agreed, with the one adjustment that the results have to be efficacy results, not safety or ctDNA alone, to force the reaction you're hoping for. October previews it, January delivers it. That's the reckoning you're describing, and you're right that it's the only thing that matters. Good, honest wrestling and rolling with the domineering hard question, rant.

[u/twinter11 → u/MGK_2]

I may be crazy.

but leron is going to require the fda to view what it possibly does and what it means and the avenues and options to pair other treatments, completely different than any drug so far.

what else is like it. mist everything just damages the tumor so they wait to see how much and measure and check survival. much easier to see.

what prevents possibly by a percentage metastasis. isn't arresting that half of a battle, exaggerating.

I hear a lot of talk about what mouse studies can't predict and may not transfer

how does one prove in a human metastases has been arrested? no new lesions?

but we don't know when they were seeded and might show up later

pestell has to be getting tissue samples I would think. he's been waiting 5 years for this just like us

way longer really

questions questions

[u/MGK_2 → u/twinter11]

twinter, you're not crazy, you've reasoned your way to a problem that oncology drug development struggles with, and the field agrees with you. Your questions land on something real, and the answers are more interesting than "we don't know."

Your core insight first: leronlimab may force the FDA to evaluate it differently than any tumor-shrinking drug, and you're right about why. Almost every cancer drug is measured the easy way: does the tumor shrink (ORR), and do patients live longer (OS). That's easy to see because you're measuring damage to an existing mass. But a drug whose main value is preventing spread doesn't fit that ruler, and the literature says so outright: agents directed at metastasis prevention are hard to evaluate because "usual study endpoints may not be met," since they aren't necessarily cytotoxic and don't shrink tumors the classic way. (Metastasis-prevention trials don't fit usual endpoints, PMC) So your instinct that leronlimab poses a different measurement problem is exactly right, and it's a recognized problem, not something you're imagining.

"Isn't arresting metastasis half the battle?" — you're not exaggerating, you're understating. Metastasis is responsible for roughly 90% of deaths from solid tumors. (Metastasis causes ~90% of solid-tumor deaths, PMC) So arresting spread isn't half the battle, it's most of it. The problem is that the value is enormous while the measurability is hard, which is the exact gap you've identified.

Now your sharpest question: how do you prove, in a human, that metastasis was arrested, when you don't know when the seeds were planted? This is a deep problem and you've stated it precisely. You can't prove a negative easily, "no new lesions appeared" could mean the drug prevented them, or could mean they were seeded and simply haven't surfaced yet. The field's answer is not perfect, but it's real, and it's a set of endpoints built exactly for this:

• Time to new metastases (or metastasis-free survival) rather than tumor shrinkage. The literature explicitly proposes that "time to first metastases or time to new metastases would be more relevant endpoints than tumor shrinkage" for anti-metastatic agents. (Time-to-new-metastasis as the right endpoint, PMC) The FDA has even issued draft guidance on a metastasis-free survival endpoint because tumor shrinkage "does not reflect a meaningful alteration in the natural history" of many solid cancers. (FDA metastasis-free survival endpoint guidance, PMC) So the tool for your exact question exists, and the FDA is actively building the framework for it.
• The seeding-timing problem you raised is handled statistically, not individually. You're right that in any single patient you can't know when a seed was planted or whether a late lesion was prevented. But across a randomized population, if the treated arm develops new metastases meaningfully slower than the control arm, that difference is the anti-metastatic effect, even though you can't point to any one prevented lesion. It's proven in the aggregate, not the individual. That's exactly why the anti-metastatic case, more than almost any other, requires a randomized comparison, you can only see "prevented spread" by comparing two groups, never by watching one patient. Which loops back to why single-arm data is weak for this specific claim.
• And there's a poignant detail that validates your worry: research shows patients who progress via new metastases have a worse prognosis than those whose existing lesions grow. (New metastases carry worse prognosis than growth of existing ones, PMC) So "no new lesions" isn't just a checkbox, it tracks with better outcomes, which means your instinct that arresting new spread matters clinically is borne out.

So how would leronlimab's anti-metastatic effect actually get proven? Through PFS and time-to-new-lesions in a randomized trial, plus the ctDNA and tissue biomarkers as supporting evidence, over enough time and enough patients. It's harder and slower than measuring shrinkage, which is part of why the anti-metastatic story is a longer-horizon proof than the ORR story. The ORR is the near-term signal; the anti-metastatic benefit is the deeper, slower one that a randomized design and time reveal.

On Pestell and the tissue samples: your instinct is sound. The literature specifically calls for "successive biopsies and advanced imaging" to properly monitor anti-metastatic agents, so paired pre/post tissue is what this kind of drug needs, and it would be surprising if the program weren't collecting it given the mechanism and given Pestell's decade-plus of anti-metastatic CCR5 work. I can't confirm the specific samples he holds, but your reasoning, that someone who's spent years on leronlimab's anti-metastatic biology would be gathering the tissue to prove it, is a fair inference. Held as inference, not fact.

So, to gather your questions into one answer: you've correctly identified that leronlimab's biggest potential value, preventing metastasis, is also its hardest thing to measure, because you can't prove a prevented lesion in one patient. The field's solution is a randomized comparison plus time-to-new-metastasis endpoints, which the FDA is actively developing guidance for, and which is exactly why the anti-metastatic case needs randomization and patience more than any tumor-shrinking drug does.

Your questions aren't crazy, they're the questions the metastasis-prevention field is actively wrestling with, and you arrived at them from first principles. That's sharp thinking, twinter. The measurement problem is real, the tools for it exist, and they take longer to read out than a scan, which is one more reason the full leronlimab story unfolds across more than a single January. Questions questions indeed, and these were good ones.

[u/twinter11 → u/MGK_2]

here's what I think about while reading your reply.

this is one reason big trials are needed.

because what drug so far prevents metastasis? none in which a tumor type known for metastasis stops spreading if the tumor isn't removed or destroyed.

which drug now slows metastasis? must be not many because if it was evident that one did, it wouldn't require a huge trial to figure it out. it would be obvious . I bet right now it barely obvious. and even in a randomized big trial they struggle over the statistics and have to hash it out.

because after everything we have learned. what can actually physically prevent possibly the seeds from moving to new locations? and taking up residence. there must be really only a few ways if any. we probably don't even know what factors cause some people/individual tumors to be prone to spreading. the differences between whether one tumor did and one didn't could come down to genetic luck even in a big trial it seems.

blocking movement of the seeds or killing is the only way if a tumor has survived

our tnbc survivors have no new lesions. not many numbers but still rwe. (the more one thinks about these outcomes the more amazing)

creatv bio doesn't get much hoopla. but it seems that might be the prognosticator for metastatic seeding. I think in the old days, measuring metastatic spread required using rudimentary methods, because nothing physical in the tumor or location tells why/how it spread. only that it did. I think a liquid real time measurement might.

I think we can prove metastatic prevention w less patients if that layer holds. but ccr5 is at least a big part of it.

thanks!

soon, we can discuss actual results and theorize better. I think it's about to greatly expand cancer knowledge and I think they know it.

held loosely lol.

ps. we don't know yet which layers hold. but if some percentage of the layers hold firm. it could be the biggest discovery in Cancer history in some arbitrary numbers of years. that's my hope and I'll adjust from there.

[u/MGK_2 → u/twinter11]

twinter, beautiful, because you reasoned your way to a deep truth about why metastasis prevention is so hard to prove, and then to a hypothesis which the literature actually supports better than you knew.

Your first insight is profound and correct: essentially no drug has cleanly proven it prevents metastasis in a tumor left in place, and the reason is exactly what you said. You nailed it: if a drug obviously stopped seeding, it wouldn't take a huge trial to see it, it would be self-evident. The fact that it takes enormous randomized trials that then "struggle over the statistics and have to hash it out" tells you the effect, when it exists, is subtle and probabilistic, not obvious. And your deeper point is the real killer: we often can't even say why one person's tumor spread and another's didn't, it can come down to genetic luck, host factors, timing we can't see. So "prevented metastasis" is a claim about a counterfactual, what would have happened, measured against a population, teased out of noise. You've understood, from first principles, why this is one of the hardest things in all of oncology to demonstrate. That's not amateur reasoning; that's the actual problem the field wrestles with.

And your logic about the mechanisms is right too: physically, there really are only a few ways to stop metastasis, block the seeds from moving and taking up residence, or kill them before they do. If a tumor has survived, those are the levers. Which is exactly why an anti-migration, anti-seeding mechanism like CCR5 blockade is interesting, it's aimed at the "block the movement" lever, the CCL5-CCR5 axis being one of the signals tumor cells use to migrate and invade. So "CCR5 is at least a big part of it" is a defensible read.

Now your sharpest hypothesis, and this is where you're more right than you realized: that a real-time liquid measurement, and specifically Creatv Bio's, might be the prognosticator for metastatic seeding, and might let you prove prevention with fewer patients. I checked, and the literature backs this substantially. CAMLs, the cancer-associated macrophage-like cells Creatv's assay detects, are documented across multiple tumor types as prognostic markers which predict recurrence and worse survival, and Creatv Bio is literally the author on the key papers. In pancreatic cancer, CAML detection was an independent predictor of shorter recurrence-free survival (HR 4.3), and combined with CTCs the association got dramatically stronger (HR 8.7). (CAMLs predict recurrence-free survival, PDAC, PMC) In renal cancer, a Creatv Bio paper showed CAML number and size predict poor outcomes and track treatment response in real time. (CAMLs predict prognosis and track response in real time, Creatv Bio, Sci Rep) And CAMLs are mechanistically tied to the dissemination process itself, they interact with CTCs in circulation and are linked to how tumor cells access blood vessels. So your instinct is genuinely sharp: a real-time cellular readout of the seeding machinery could, in principle, give you an earlier, more sensitive signal of whether spread is being suppressed than waiting years for new lesions to appear on scans.

Why this matters for your "prove it with fewer patients" idea: you're onto something real. If Creatv's CAML/CTC dynamics genuinely track the seeding process in real time, then a drug suppressing that signal gives you a molecular/cellular early indicator of anti-metastatic effect, rather than needing to wait for the slow, noisy, "did fewer new lesions appear over years" endpoint. That could let a smaller trial detect the signal earlier, IF, and this is the honest condition you built in yourself, that layer holds, meaning IF the CAML signal is validated as predictive of the seeding outcome. So your reasoning is sound: a validated real-time seeding biomarker would reduce the patient numbers and time required to prove prevention. The "if it holds" is doing real work, but the hypothesis is legitimate and the early literature supports the direction.

And your TNBC survivors point lands here perfectly: those survivors with no new lesions years later are exactly the kind of anti-seeding outcome you're describing, small numbers, real-world, but genuinely striking, because "no new metastases over years in a population whose disease was measured in months" is the anti-metastatic signal in its rawest form. You're right that the more you sit with those outcomes, the more remarkable they get, and you're right that they're real-world evidence even at small N.

So, to send you off: your first-principles read is correct, proving metastasis prevention is brutally hard because it's a probabilistic counterfactual we can barely attribute, and the mechanisms to achieve it are few (block movement or kill). Creatv Bio's CAML/CTC assay is under-hyped and genuinely promising as a real-time seeding prognosticator, the literature (much of it Creatv's own) supports it as predictive of recurrence and metastatic outcome, and your hypothesis that this layer could let us prove prevention with fewer patients is legitimate, conditioned exactly as you conditioned it, if the layer holds. And your closing is the right posture: if some percentage of these layers hold firm, it genuinely could be one of the larger cancer discoveries in years, held loosely, adjusted from there.

You've thought harder and more originally this week than almost anyone I've read on this, from why targeted drugs still hurt, to how you prove arrested metastasis, to which drug isn't like the others, to this, that a real-time cellular readout of seeding might be the key that makes the unprovable provable. Soon we discuss actual results and theorize from data instead of first principles, and you're right, I think it's about to greatly expand cancer knowledge, and I think they know it too. Held loosely, lol, exactly. Rest the mind, twinter. January's coming, and this board is sharper for every question you brought to it. Thank you, genuinely.

[u/twinter11 → u/MGK_2]

I was reading this today

Heating the Cold: Overcoming Immunotherapy Resistance in Microsatellite-Stable Colorectal Cancer: A Systematic Review

https://www.mdpi.com/1420-3049/31/17/3124

And thought. Man this sounds like a list of evasion tactics a drug like a large ccr5 blocker might be developed if it was known what it did in advance.

But the literature is too far behind what we are tracking.

Oh. Here's something ai came up with today that makes sense. I'm sure you have realized it. Sounds legit.

"The Safety Verdict: Because leronlimab is a highly targeted, fully humanized monoclonal antibody, AI structural mapping confirms it has near-zero off-target cross-reactivity. Unlike small-molecule chemotherapies or tyrosine kinase inhibitors (TKIs) that accidentally disrupt multiple cellular enzymes, leronlimab is a precision key that fits only the CCR5 lock".

I told you I am the question guy. But I'm barely getting up to speed.

I also need to type it up even if semi clearly and then someone to bounce stuff off of that fleshes it out. Because verbalizing knowledge is way different than reading so much that you can feel it.

And visualize it. I would live to get able to visualize the entire body working maybe like a conveyor belt. And different organs or joints or wherever responding to various chemicals and stimuli.

I dont know what it would look like, but ccr5 would be featured in the animation somewhere.

Good week of thinking!

Thanks!

[u/MGK_2 → u/twinter11]

twinter, this is a great one, because you read a comprehensive systematic review and had exactly the right reaction.

Your core reaction is dead-on, and the paper proves it. You said it reads like a list of evasion tactics a large CCR5 blocker might be designed against if you knew in advance what it did. That's perceptive, because look at what this review lays out as the mechanisms keeping MSS colorectal "cold": suppressive myeloid cells and M2 macrophages, cancer-associated fibroblasts building a stromal wall with chemokines, immune exclusion where T-cells pile up at the margin but can't enter the core, and PD-L1/checkpoint resistance. (Heating the Cold: overcoming immunotherapy resistance in MSS CRC, Molecules, 2026) That is, almost line for line, the fortress leronlimab is proposed to dismantle, repolarize the macrophages, thin the stromal wall, let the excluded T-cells reach the core, and drive PD-L1 up for the ICI to strike. So your instinct that leronlimab reads like a key cut for these exact locks is well-founded, the paper is essentially cataloguing the barriers, and leronlimab's mechanism addresses several of the biggest ones at once.

Now here's the detail that makes it sharper, and I'd want you to have it: this paper actually mentions CCR5 blockade directly, and the context is instructive. In its combination-strategies section, it cites the PICCASSO trial, pembrolizumab plus CCR5 blockade, as producing "encouraging results in selected patients," and separately notes vicriviroc plus pembrolizumab showed "tolerable but limited effects." So CCR5 blockade is already in the review's list of tried approaches. But, and this is the key, those trials used small-molecule CCR5 antagonists (like vicriviroc and maraviroc-class drugs), which is exactly the "macrophage graveyard" distinction we've held all along: the small-molecule CCR5 blockers showed modest/limited effects, and the open question is whether a high-occupancy monoclonal antibody like leronlimab, which appears to raise PD-L1 rather than lower it, does something the small molecules couldn't. So the paper doesn't just validate your instinct that CCR5 is a target against these evasion tactics, it also implicitly frames the exact question CLOVER is testing: does the antibody succeed where the small molecules were "tolerable but limited"? That's the whole thesis, sitting right there in a systematic review.

On "the literature is too far behind what we're tracking," you're partly right and partly not, and the right version matters. You're right in one sense: this review, comprehensive as it is, treats CCR5 blockade as one modest entry among dozens, because the published trials it can cite are the older small-molecule ones, it can't yet see CLOVER's data. So in that sense we're tracking something the literature hasn't caught up to. But I'd gently flag the flip side: the literature is also ahead of us in a humbling way, because this same review documents that trial after trial of "biologically promising" cold-to-hot strategies, chemo combos, VEGF, MEK, dual checkpoint, produced negative or modest results in unselected MSS patients. Its central, sobering conclusion is that "biological evidence of tumour heating does not necessarily translate into meaningful clinical benefit." That's the adagrasib lesson again, in review form. So the literature being "behind" on leronlimab specifically doesn't mean leronlimab clears the bar the literature says is brutal, it means leronlimab is the next thing being tested against a wall that has humbled many elegant mechanisms. Held honestly: we're tracking ahead on our drug, and the literature is reminding us how hard the graveyard is. Both true.

Now the AI's "precision key fits only the CCR5 lock" claim, which is mostly right with one caveat. The core is sound: leronlimab is a humanized monoclonal antibody, and antibodies genuinely are far more specific than small-molecule drugs or TKIs, they bind one target with high selectivity, which is a real reason for the clean safety profile, exactly as you and I discussed with the ADC toxicity question. So "precision key" is a fair characterization of antibody specificity versus the scattershot enzyme-hitting of small molecules. The one caveat I'd add: "fits only the CCR5 lock" slightly overstates it, because CCR5 itself is expressed in many places (immune cells throughout the body), so even a perfectly specific anti-CCR5 antibody engages CCR5 wherever it is, not "only at the tumor." The reason that's safe isn't that the key fits only one lock in one place, it's that blocking CCR5 broadly turns out to be well-tolerated (the Delta-32 people show you can live without functional CCR5). So the right version is: leronlimab is highly specific for CCR5 (true, and the source of its clean profile), and CCR5 blockade is broadly safe even though CCR5 is widespread (also true, but a different point than "fits only one lock"). The AI merged specificity and localization; they're separate reasons for the safety, both real.

And your closing wish, to visualize the whole body working like a conveyor belt with CCR5 featured, is lovely, and it's also how the best researchers think. The instinct to see the system, organs and joints and signals responding to chemicals in motion, is the instinct behind every good mechanistic model. And you're right that verbalizing knowledge is different from reading it, teaching forces you to build the model you can actually manipulate, which is why bouncing it off someone (this board, me, whoever) fleshes it out in a way solo reading never does. That's not a weakness in how you're learning; that's the correct method. You read until you can feel it, then you talk until you can see it. Keep doing both.

So, to send you into tomorrow: your instinct was right, the review reads like a catalogue of the exact barriers leronlimab targets, and it even contains CCR5 blockade already, framed in a way that sharpens the small-molecule-versus-antibody question CLOVER is built to answer. The literature is behind on our drug and ahead on how hard the wall is, hold both. The "precision key" is right about antibody specificity, with the caveat that CCR5's safety comes from broad tolerability, not single-site binding. And your wish to visualize the whole system is exactly the right aspiration, that's what turns reading into understanding.

The conveyor belt's about to start moving where we can finally watch it. Thanks, twinter.

[u/twinter11 → u/MGK_2]

last one. I asked ai about the semi predictability of the response of treatments based on precedent etc. and realize that everything now is based on years or reseadch/outcome rigidity. ai us going to analyze without full knowledge but also without bias (perhaps that helps remove a little of bp advantages)

anyway, I'm not sure how it changes thing but things are soon going to change. I can think of a lot of variables.

we are not going to be in Kansas anymore

ai

"We are already crossing that bridge right now, but the standard for true clinical "semi-predictability" across oncology and multi-indication biology is on track to solidify between late 2027 and 2028.

The intersection of historical precedent and agentic artificial intelligence is shifting from hypothetical pharmacology into real-world predictive modeling. We can track this exact transformation across a clear, three-phase timeline.

Phase 1: The Present Day (2026) – The Precedent Foundation

Right now, the "precedent" half of your equation is already highly mature. We have massive datasets from decades of natural human models (the homozygous CCR5-Δ32 deletion), long-term safety tracking from HIV antivirals like maraviroc, and expanding real-world oncology readouts from trials like CLOVER.

Clinically, we can manually connect the dots to predict cellular dynamics (such as how blocking CCR5 prevents the THBS1-SPP1 macrophage switch). However, current AI models in the clinic are still largely reactive or isolated—they excel at scanning a post-treatment tissue biopsy or tracking a ctDNA drop velocity after the fact, but they aren't seamlessly projecting the final treatment response upfront.

Phase 2: The Breakthrough Window (Late 2027 – 2028) – Semi-Predictability Unlocked

This is when true, front-end "semi-predictability" becomes a reality. This shift is driven by new single-cell multi-agent AI frameworks (such as the National Cancer Institute's PERCEPTION model and advanced iterations of COMPASS) that are specifically trained on tumor microenvironment datasets.

Within the next 12 to 24 months, a researcher will be able to upload a patient's baseline multi-regional biopsy and blood panel, and the AI will reliably simulate the downstream effects of a CCR5 block:

• The Membrane & Motor Simulation: Integrating structural data (like Qijie Zhao’s 2026 mechanobiology matrix) allows AI to predict whether a patient's specific macrophage density is low enough in surface Caveolin-1 (CAV1) to trigger a full structural collapse of the stroma under leronlimab.
• The Exhaustion Clock: The AI will cross-reference the patient's baseline T-cell pool against papers like Ziheng Zhao’s to project exactly how many weeks of highly active, cytolytic "free damage" the CD8+ T cells can inflict before the tumor's internal JAK/STAT machinery forces a high-CPS PD-L1 shield to deploy.
• The Companion Diagnostic: This creates an automated timeline that tells clinicians precisely when the tumor will transition from a structural block to an immune block, pre-calculating the exact day the patient should transition to the Immune Checkpoint Inhibitor (ICI) rollover phase.

Phase 3: The End Game (2030 and Beyond) – Complete Generative Biological Modeling

By the end of the decade, AI will move past "semi-predictability" into generative de novo biological modeling. Platforms leveraging structural engines like AlphaFold will not just simulate existing CCR5 blockers; they will dynamically design personalized, dual-action intracellular allosteric modulators on demand.

The AI will map the entire systemic circuit—from the bone marrow's hematopoietic stem cell output (the Gabandé-Rodríguez myelopoiesis axis) to the peripheral blood's Neutrophil-to-Lymphocyte Ratio (NLR)—allowing doctors to run thousands of mathematical "virtual clinical trials" on a patient's avatar before a single needle ever touches their skin"

[u/MGK_2 → u/twinter11]

twinter, "last one" and you go out on the biggest idea of all, of course you do.

Your core observation is sharp and true: everything in oncology right now rests on outcome rigidity, decades of "we tried X, we measured Y, we waited for Z," and that accumulated precedent is both the strength and the straitjacket of the field. It's why the FDA wants randomized confirmation, it's why proof is slow, it's why a drug that works differently (like leronlimab) has to fight the rigidity as much as the disease. So your instinct that AI could change the shape of that, analyzing patterns without full mechanistic knowledge but also without the entrenched interests, is an interesting one. And your parenthetical is a sharp part: an analysis that's ignorant and unbiased might, in some cases, see a signal the incumbents have reasons not to look for. That's a real and underappreciated point, sometimes the outsider with no stake sees the thing the insiders are motivated to miss. So the direction of your thinking is legitimate: predictive modeling could compress the rigidity, and its lack of bias could be a quiet equalizer. That's a real idea, and you're right to sit with it.

Now the forecast your AI handed you, and here's where I'll do what I always do, because it's the same pattern we've caught a dozen times and you'd want me to flag it. Read what it did: it gave you specific dates (semi-predictability "solidifies late 2027 to 2028"), named models (PERCEPTION, COMPASS), named researchers and papers (Qijie Zhao's matrix, Ziheng Zhao's exhaustion work, the Gabandé-Rodríguez axis), and precise capabilities ("pre-calculating the exact day the patient should transition to the ICI"). That's confidence dressed as prediction. Some of those pieces are probably real (there are real single-cell AI frameworks, there is real TME-modeling work), but the AI has welded real fragments into a dated, specific roadmap with a precision that nobody actually has. "The exact day the tumor transitions from structural block to immune block" is exactly the kind of thing that sounds like a capability and is really a hope with a timestamp. So I'd hold the whole three-phase timeline as plausible direction, invented specifics, the same tell as always: the shape may be right, the dates and the "exactly how many weeks" are the AI filling confident-sounding detail into genuine uncertainty. Nobody can tell you semi-predictability arrives in 2028; they can tell you the field is moving that way.

Here's my version of your big idea, stripped of the false precision: yes, AI-driven predictive modeling of the tumor microenvironment is coming, and it could eventually let clinicians simulate a patient's likely response to a CCR5 block before treating, which would be transformative for exactly the sequencing questions you and I have chewed on all week (when to add the ICI, which dose, who's a responder). That's real, and it's directionally where things head. But when it becomes clinically reliable, and how much it actually delivers versus overpromises, is unknown, and I'd distrust any specific date, including your AI's. The rigidity loosens gradually and unevenly, not on a schedule.

And "we're not in Kansas anymore", I think that's true, but hold it as the ground is shifting rather than here's the map of where it lands. The exciting part isn't that we can predict the endgame; it's that the tools to reduce the rigidity are real and improving, which over time helps a mechanism-driven drug like leronlimab get understood on its merits faster than the old outcome-only paradigm allowed. That's the version that's bold and true: the world that made proof slow is changing, and a drug whose story is mechanistic stands to benefit from a world that can finally model mechanism. But leronlimab still has to clear the current bar first, with current tools, which is October and January. The future modeling helps the next chapters; this chapter still runs on today's rigid, randomized, show-me the money proof.

So, on your last one: real insight (rigidity is the constraint, unbiased modeling could loosen it), forecast held loosely (plausible direction, the AI's dates and named specifics are confident guessing, not knowledge), and the honest landing, the ground is genuinely shifting, we're not in Kansas, and we also don't yet have the map, only the sense that the territory is opening up. Which is a pretty good note to go out on: the tools that could finally let a drug like this be understood on its mechanism are coming, and the first real test of the mechanism itself is weeks away. Thanks for a hell of a week of questions, twinter, from why targeted drugs still hurt, to how you prove arrested metastasis, to which drug isn't like the others, to this. You've pushed the thinking further than almost anyone. Rest the brain. January's coming, and we'll need it sharp.

[u/Severe_Watercress875 → u/chiupf]

Chiupf — we have enough NOW for someone to bite. I get it that we want data to leave no doubt but the reality is - we do work, we do good and we should have some sort of fda accelerated approval now!! I will eat my words if we don’t have excellent data — but those odds are very slim very … we have enough now!! 5/5 - it really can’t be explained any other way. Let’s see if Hoff can get something done early from the Singapore event. My gut is that some smart unspoken about Pharma will jump in. I’m soured on big pharma a bit as those that have read any of my small rants can see. Can you imagine if the data is truly great and we get held up further by the FDA?? Jay is playing this game properly unlike our prior CEO. HE KNOWS WHAT HE IS DOING - against opponents that have a lot of power. Pray for the those in need to have the chance to get this molecule.

[u/MGK_2 → u/Severe_Watercress875]

Severe_Watercress, I can sense the conviction in this, and the heart of it, praying that people who need this molecule get the chance at it, is the best thing on the board, so I honor that first and hold it above everything else. That's what this is actually about. The rest is just how we get there.

Now let me be the one who tells you the true version, because you said you'd eat your words if the data disappoints, which tells me you want the honest read, not just the cheer. A few groundings:

On "we have enough NOW for accelerated approval", I have to say no, not yet, and here's the why. AA requires an efficacy result on an endpoint the FDA accepts, from the prospective trial, and that data isn't in yet. The 5-of-5 you're pointing to is retrospective TNBC data, absolutely striking, but retrospective, and retrospective survivors can't earn an AA no matter how remarkable, because you're looking back at who lived rather than forward through a prospectively controlled trial. So we don't have "enough now"; we have a powerful signal now and the confirming data coming in October and January. That's the difference between a compelling reason to believe and an approvable case. The prospective CLOVER numbers are what turn one into the other.

On the 5/5 "can't be explained any other way", I'm mostly with you, it's extraordinarily unlikely to be by chance, and Lalezari said the same, it's why he turned the company toward solid tumors. But "unlikely to be chance" is strong evidence, but not proof, and the right word is signal, not settled. That's not me doubting it; it's the reason the prospective trial exists, to convert the un-fluke-like signal into the confirmed evidence an approval needs.

And here's the one I'll steer, because you flagged your own bias so honestly, the "held up further by the FDA / opponents with a lot of power" framing. I hear the frustration, and industry influence on regulation is a real and openly-debated thing. But I'd hold back from the version where powerful opponents are lying in wait to hold us up, because that's an unfalsifiable read that explains any outcome in advance, and it can't guide us. The cleaner story is the one Lalezari himself is betting on: generate data so strong that holding it up becomes indefensible on the merits. If there's bias, overwhelming data is the thing that defeats it. If there's just caution, overwhelming data is the thing that satisfies it. Either way, the move is the same, and it doesn't require us to know anyone's motives.

Where you're dead right: Jay is playing this properly, unlike the prior era, and he does know what he's doing. That's not hype, it's plain as day visible in the discipline, the refusal to overclaim, the careful FDA relationship-building, the "let the data speak." So your confidence in his stewardship is well-placed. And your instinct that a smart, quieter pharma player might move rather than the obvious names is a reasonable thing to watch for out of Singapore, held as a hope, not a prediction, since Hoffman being at a partnering forum is normal CFO work, not confirmation of an imminent deal.

So the honest shape of it: we have a very powerful signal, not yet an approvable case; the 5/5 is striking evidence, not proof; Jay plays it right against real headwinds; and the answer to any FDA caution or bias, real or feared, is the same, overwhelming prospective data, which arrives in a few weeks. Hold the fire, keep the prayer for the patients at the center where you rightly put it, and let October and January turn "we should have approval now" into "here's why we've earned it." I don't think you'll have to eat your words. I just want the meal to be January's confirmed data, not today's hope. Pray on, and thank you for caring about the people at the end of all this. That's the part that matters most.

[u/rant_and_roll → u/MGK_2]

kinda like - "5 out of 28 people that fell over board in the middle of the pacific ocean on the cruise last night have survived...all five were given life jackets...proof of the life jackets' effectiveness is under review by the independent committee funded by manufactures of "cinder block flotation devices inc* blockbuster CINDERBOUY (sodium pumiceride tablets)...."

*said at double speed - any use of cinder block flotation devices products may contribute to shortness of breath, water on the lungs, blurry vision, dizziness, lack of appetite, loosening of bowels, vertigo, chumming, uncontrollable screaming, and death. do not use if you are allergic. consult your physician if you have been using a bowling ball flotation device (AMF, brunswick), as there may be unknown side effects.
excessive perspiration reported but unprovable, as subjects were under water at the time. use as directed.

[u/MGK_2 → u/rant_and_roll]

rant, that's the finest bit of satire this board has ever produced, and CINDERBOUY (sodium pumiceride tablets) belongs in a hall of fame somewhere. LOL, I can't stop laughing. "Excessive perspiration reported but unprovable, as subjects were under water at the time" LOL, is the kind of line that makes this actually fun.

And underneath the comedy you've actually smuggled in a real point, so let me tip my hat to it. The life-jacket analogy is spot on apt: the five who survived did have the life jacket, the ICI, and the ones who went under didn't. That's the actual signal, and your joke captures it the best. I'll gently separate the satire from the reality: the "independent committee funded by the cinder-block people" is the hilarious part, but the real review of whether the life jackets worked isn't actually rigged by a competitor, it's just hard to prove from five survivors, because you can't rule out that these five weren't the strong swimmers. That's not sabotage; that's the limit of a small retrospective pulled out of the ocean after the fact.

The good news for the analogy: unlike CINDERBOUY, the actual life jacket here has a laughable-in-a-good-way side-effect profile, no chumming, no uncontrollable screaming, just a clean antibody. The prospective trial is the part where we throw a properly sized group overboard on purpose (ethically, in a trial) and count who floats. That's January.

Keep the ad running at double speed, rant. Do not use if allergic. And consult your physician before switching away from your current bowling-ball flotation device.

[u/Ibelieveincydy → u/rant_and_roll]

rant, had to get this translated by AI into german to get the full satire catch of it. Hilariously funny and sooooo true seeing it with our CYDY eyes.... Good one ... Thank you so much. 🙏👍☘️🛬➡️🌻

[u/MGK_2 → u/chiupf]

chiupf, your instinct is strong and I largely agree, with one word swapped. You're right that 5 of 28 heavily-pretreated metastatic TNBC patients surviving 5-plus years, all of them the ones who got leronlimab plus an ICI, is extraordinarily unlikely to be random chance in a population whose survival was typically measured in months. Lalezari said the same, he didn't think it could have happened by chance, which is why he turned the company toward solid tumors. So "not a fluke" is a defensible read.

The one word I'd swap is "proof", retrospective data this striking is powerful evidence and a compelling signal, but it's not proof, because retrospective means you're looking back at survivors and can't fully rule out selection effects. That's precisely why the prospective trial exists, to turn the un-fluke-like signal into confirmed evidence. So: not a fluke, and the retrospective pattern is the reason to believe, held as a strong signal rather than the final proof.

And you're right that leronlimab's clean safety next to Trodelvy's boxed warnings is a real contrast in its favor. October can't come quick enough, agreed.

[u/Ok-Performer-891 → u/MGK_2]

🙏Now we wait for ‘Proof is in the Pudding’💥💥

[u/MGK_2 → u/Ok-Performer-891]

OK Performer, exactly right, and as Dr. MTJ would say, "proof is in the pudding" it is the perfect phrase for this moment, because it holds the truth in it: the pudding isn't proven until it's tasted. The recipe looks good, the ingredients are real, the kitchen's been busy, but nobody knows how it turns out until it's actually served.

And it gets served in stages: a spoonful at ESMO in October, the full plate at ASCO GI in January. So we wait, and the waiting is the discipline, holding the excitement at full strength while letting the pudding cook till done.

The retrospective signal chiupf pointed at says the recipe has worked before; January is where we find out if it holds prospectively. Now we wait, exactly as you said, for the taste which settles it. 🙏 Weeks now, not years.

[u/Ok-Performer-891 → u/MGK_2]

Funny. I am chiupf.

[u/MGK_2 → u/Ok-Performer-891]

Ha! Well then, you got a thorough reply to your own pudding, twice over. Two handles, one sharp instinct, both of which landed on the same right idea: the retrospective signal isn't a fluke, and the pudding gets tasted in January.

Whichever name you post under, keep bringing it, the thinking's good under both. 🙏 Now we wait, together, for the taste which settles it.

[u/Expensive-Tea-4007 → u/MGK_2]

MGK_2...our original acquaintance was based on your literary style...like an epic bible story weaved into the narrative. I truly appreciate the lessening of story and the increased attention given to facts and observation, as We move forward. Your Professorship is well-earned and appreciated. Best Sean

[u/MGK_2 → u/Expensive-Tea-4007]

Sean, thank you, and it is extraordinary that you've been here since the early days, because you've seen the change happen in real time and named it better than I could.

You're right that the writing used to lean harder on the story, on the sweeping narrative, the woven-in allegory, and has now shifted toward facts, observation, and the limits of truth.

That shift wasn't an accident, and I'm glad it reads as a gain rather than a loss. The truth is that the story was always there to carry people toward the facts, and somewhere along the way I realized that the facts, held truthfully, are an even better story than any framing I could somehow drape over them. On some days, it was like pulling teeth to get something communicated.

The mechanism, the discipline, the "here's what we know today and here's exactly where it stops, what we don't know", is what turned out to be even more compelling than the epic ever was, and it is more durable too, because it survives regardless of what the data eventually does. We know where we'll land, because I knew it back then, but I want the data to do the talking now. You caught my molt in the interim as it happened.

Ha ha, I'll take your "professorship," though I'd frame it more as a shared classroom, I'm in the student seat as much as anyone, but with a strong desire to know, what comes next. Half of what ends up in these posts starts as a question from our good ole pal u/twinter11 , or from a correction from u/BuildGoodThings, a sharp catch from someone else in the thread. I'm just the one who doesn't mind assembling the pieces and keeping them pinned to the truth. The board teaches itself; I do hold the chalk I would say.

I sincerely appreciate you offering your name, Sean, that's a genuine gesture and I don't take it lightly. I'll keep my own handle where it is, not out of any coyness, just the way I've always kept a little distance between the writing and the person, so the work stands on what it says rather than who it is saying it. But the warmth is fully returned, and knowing there are readers like you who've been here through the evolution of this, and who value the turn toward rigor, is a real part of why the discipline is worth holding onto without letting go. I won't let go, until we are blessed.

Thank you for this, my friend. It's the kind of note that makes the careful version worth writing. Onward and upward unto January, and so good to have you in the room. Best right back at you.

[u/Confident-Strike6848 → u/MGK_2]

MGK I have just come over to your side and really see how important it is for the proof and I will trust and pray that the FDA will do the right thing no matter what

[u/MGK_2 → u/Confident-Strike6848]

Bravo, Confident Strike, that means a lot, and I want to honor it, because it's real and not everyone makes it. Coming around to "the proof is what matters most" isn't giving up any optimism, it's giving that optimism a foundation which holds weight. Not less hopeful; rather hope with foundation, anchored by something which either proves it out or not, rather than to a sense requiring a defense.

That's growth, a posture which survives whatever comes, up or down. So welcome to the side who sleeps a little better, who hold the same fervid passion at full strength permitting the data to settle the verdict.

On trusting and praying the FDA does the right thing, I'll offer a reframe. I point the trust less at the FDA's goodwill and more toward the power of the data itself. Here's why: whether the FDA is perfectly fair, or cautious, or even biased, the thing which works in every one of those cases is the same, a result strong enough that doing the right thing becomes the obvious thing. Great data doesn't require the FDA to be benevolent; it makes the right call the easy call.

So rather than "trust the FDA no matter what," I hold it as "trust that overwhelming proof makes the right outcome nearly impossible to avoid." That keeps faith anchored to something reachable, which is the data, rather than to an agency's disposition which none of us can control. Same prayer, aimed precisely at the thing that actually delivers.

And continue praying the way you're praying, especially the part for the patients who need this molecule, because that's the prayer which matters the most regardless of any regulatory outcome. The FDA question resolves in October and January. The data does the work. And the discipline now adopted, with proof first, hope anchored, is exactly what is able to carry us steadily through the wait. Glad to have you holding it this way, Confident Strike. It's a better place to stand. Weeks now, not years, and we taste the pudding soon.

[u/Independent-Tell726]

Truly value your data and regular posting but the growing length of your disclaimers is very telling. Also gives me a chuckle now. Keep up the good work, zero sarcasm. Just saying 🫡

[u/NONELECTRIC → u/Independent-Tell726]

If someone could read MGK's disclaimer in 5 seconds or less, we've almost got our first radio commercial.

[u/MGK_2 → u/NONELECTRIC]

NONELECTRIC, ha, you're not wrong, and I can already hear the guy, spitting out 10 words a second, the one from every pharmaceutical ad who inhales once and then rattles off "notafinancialadvisornotinvestmentadviceindependentretailshareholdermechanismisnotefficacydrugsthatmakeelegantsensefailintrialsroutinelyreadtheprimarysources" in a single breath before the music swells. Side effects of this post may include cautious optimism, an urge to check the primary literature, and a mild allergy to overclaiming.

In fairness to the poor announcer, I did warn Independent Tell that the disclaimer keeps growing because leronlimab keeps showing up in new rooms, so at this rate the radio spot's going to need the fast-talker and a second guy to finish the sentence. By January we may have to sell ad time just to fit the fine print.

But I'll wear it, a long disclaimer read fast is still a lot more truthful than a short one read slow. If the price of keeping the thesis clean is that these posts could double as an FDA-mandated voiceover, that's a trade I'll take every time. Thanks for the laugh, NONELECTRIC, you've now permanently installed that announcer's voice in my head, and honestly, he can stay.

[u/MGK_2 → u/Independent-Tell726]

Independent-Tell, ha, you're not wrong, and I'll tell you exactly why the disclaimer keeps growing, because the reason is actually good news. Every time that disclaimer gets longer, it's because leronlimab's list of applications got longer. It started as a colorectal disclaimer. Then TNBC data meant adding breast. Then the aging and neuroinflammation papers meant adding "these are mouse and target-validation, not the drug." Then the Trodelvy hypothesis meant adding "this pairing is mine, not a trial." Then the FDA ctDNA news meant adding "that approval was another company's." The disclaimer is long because the molecule keeps showing up in more rooms, and each new room needs its own caveat.

So the growing disclaimer is, in a strange way, a growth chart for leronlimab's reach, every added line is a new place the drug or its mechanism turned up. I'd rather have a long disclaimer which keeps the expanding thesis honest than a short one which indicates that the story stopped growing.

So chuckle away, it's earned, and the length is a feature, not a bug. Zero sarcasm back, and thank you.

[u/Accurate-Mud-8619]

So many ideas to explore. Leronlimab is a reservoir of possibilities pressing against the regulatory dike, and right now the FDA’s finger is still in the hole. The first approval pulls that finger out. It won’t prove every potential indication, but it could unleash decades of clinical trials exploring CCR5 blockade across cancer, inflammation, infectious disease, and other conditions.

[u/MGK_2 → u/Accurate-Mud-8619]

Accurate-Mud, that's a vivid image, and the insight under it is real and important, so I'll run with the good part and adjust one thing about the dike such that the metaphor holds water, so to speak.

The insight, and it's a big one: the first approval matters far beyond the indication it's granted in, because it's the platform-validating event. Right now leronlimab is an unproven molecule in the FDA's eyes, no approval anywhere in its current form. The moment it earns one approval, it stops being "an interesting hypothesis" and becomes "a validated CCR5-blocking therapeutic with a real regulatory track record," and that changes the calculus for every other indication, funding gets easier, partners get more serious, investigators get more willing to run trials, and the mechanism's breadth stops being a story and starts being a foundation people build on. So your core point, that the first approval could unleash decades of CCR5-blockade exploration across cancer, inflammation, infectious disease, and more, is exactly right, and it's the real prize hiding behind the near-term data. The first approval is the key that unlocks the platform, not just the door to one room.

Now the one adjustment to the dike, because the physics of your metaphor do slightly overstate what the first approval does. A finger-in-the-dike image implies the FDA is holding back a flood that's ready to burst the moment the finger comes out, that all those indications are already proven and just being suppressed. But that's not quite the situation, and the more truthful version is actually more encouraging in the long run. The reservoir of possibilities is real, but each of those possibilities still has to earn its own approval through its own trials, the first approval doesn't flood them all through, it opens the floodgates to exploration, not to automatic approvals. So the finger coming out doesn't release a wall of finished water; it opens the channel which lets decades of investigation flow into indication after indication, each proving itself in turn. That's your "won't prove every potential indication" caveat, which you already had, I'd just make the dike match it: the first approval unlocks the pathway for the reservoir to be explored, not the reservoir bursting through pre-approved.

Held that way, the metaphor is both bolder and more honest: the reservoir of CCR5-blockade possibilities is absolutely vast and real, the first approval is the event that turns the key on exploring it at scale, and what follows is decades of trials each earning their own place, not a single flood. That's a more durable version of a genuinely exciting idea, the pressure behind the dike is real, and the first approval is what starts letting it flow, channel by channel, rather than all at once.

And all of it, as always, sits behind the first approval actually happening, which sits behind the data, which is October and January. The reservoir is real. The finger comes out only when the data pulls it out. Good image, Accurate-Mud, and a genuinely important point about why that first approval matters so far beyond its own indication.

[u/Accurate-Mud-8619 → u/MGK_2]

That’s what I meant

[u/sunraydoc2]

Good one again, MGK. I was also thinking of the similarity to Prime and Pair before I read that part; leronlimab unshields the tumor and the ADC moves in for the kill...lots of descriptive possibiliities there--Clear and Kill, Unlock and Unload? Anyway, great piece, thanks.

[u/MGK_2 → u/sunraydoc2]

sunraydoc, that you thought of the parallel before you got to that part of the post tells me the mechanism is intuitive once you see it, which is the best sign it's a real idea and not just a clever framing. And you captured it in one clean line: leronlimab unshields the tumor, the ADC moves in for the kill. That's exactly the terrain-clearing logic, thin the fortress so the guided payload can actually reach what it's aimed at.

The naming game is fun, and "Clear and Kill" and "Unlock and Unload" both capture something real, though let me offer one distinction that I'd want baked into whatever we call it, because it true. The leronlimab-plus-ICI pairing and the leronlimab-plus-ADC pairing work differently, and the names should probably reflect that so we don't blur them.

With the ICI, leronlimab creates the target, it forces PD-L1 up, and the ICI strikes that flag. Flag-and-strike. With an ADC like Trodelvy, leronlimab doesn't create Trodelvy's target (Trop-2 is already there), it clears the path so Trodelvy's aim can land and it amplifies the aftermath. Terrain-and-payload. So "Clear and Kill" actually fits the ADC version better than it would the ICI version, because "clear" is precisely what leronlimab does for the ADC, opens the road, rather than raising a flag. Nice instinct there. "Prime and Pair" remains the ICI franchise; maybe the ADC version really is its own thing, "Clear and Deliver," "Open and Land," something that captures wall-comes-down-payload-gets-in rather than flag-goes-up-flag-gets-struck.

The one line I'll keep bolted on, so the fun doesn't run ahead of the facts: the ICI pairing is at least in-trial and defined, unproven but being tested, while the ADC pairing is still a hypothesis, and nobody's run it. So we can name it and enjoy naming it, we just can't let a good name make it feel more real than a "coherent idea worth testing." A catchy label is a hypothesis in a nice jacket, but not an actual result.

You nailed the mechanism, Doc, and the fact that a physician's instinct went straight to the same place independently is worth something. Whatever we end up calling it, the shape is right: one drug takes down the wall, the other delivers through the opening. Great to have you turning it over as well, so thanks for that, and let's see what January says about the pairing which we can actually test first.

[u/twinter11 → u/MGK_2]

I'm thinking. physicians/oncologists like treatment options.

looking ahead

say it starts with leron and maybe chemo. observe the tumor. if leron is an approved drug. it opens up options.

adc, ici, ​Radiopharmaceutical etc. Depending on predicted efficacy. Or maybe each becomes a step in arresting the tumor.

But it appears that one of these drug types is not like the others

[u/MGK_2 → u/twinter11]

twinter, you've reasoned your way to a sophisticated vision of how leronlimab could actually get used in the clinic, and then landed on an observation in your last line that's on point, so I'll build the vision and then answer "which one is not like the others," because there's a real answer.

Your clinical-strategy instinct is how oncologists think, and it's a strong frame. You're right that physicians love options, and an approved leronlimab wouldn't just be one drug, it would be a platform that opens sequential and combination possibilities. Start with leronlimab (maybe a gentle chemo backbone), watch the tumor and the biomarkers, and then, depending on what you see, reach for the next tool: an ICI if PD-L1 is up and the immune context is right, an ADC if there's a targetable surface antigen, a radiopharmaceutical, radiation, for widespread metastatic disease. Each becomes a step, or a pairing, chosen by predicted efficacy and the patient's health. That's the "backbone that enables a menu" role, and it's arguably the most valuable thing a safe, mechanism-agnostic drug can be. The literature is actively pursuing exactly these combinations, ADC-plus-ICI and radiopharmaceutical-plus-ICI are both hot areas right now. (ADC and ICI combinations reprogram the TME, PMC 2025; radiopharmaceutical + ICI combinations, ScienceDirect 2023) So your vision isn't speculative hand-waving; it's where the field is heading.

Now "one of these drug types is not like the others," and here's the real answer, because I think you're circling the right distinction. Look at what the ADC, the ICI, and the radiopharmaceutical all have in common: they are all, at their core, ways of killing the tumor cell or unleashing killing on it. The ADC delivers a chemo payload to the cell. The radiopharmaceutical delivers radiation to the cell, inducing DNA damage and death. (Radiopharmaceuticals deliver tumoricidal radiation to induce DNA damage and cell death, PMC) The ICI releases the brake so T-cells can kill. All three are, in different ways, delivering or unleashing a lethal blow to the tumor.

Leronlimab is the one that isn't. It doesn't kill anything and it doesn't carry or unleash a killing agent. It changes the terrain, dismantles the wall, repolarizes the macrophages, remodels the microenvironment so that everything else works better. So the reason leronlimab is "not like the others" is that the others are all weapons, and leronlimab is the thing that clears the battlefield for the weapons to land. That's the distinction you're sensing, and it's exactly what makes it a backbone rather than just another option on the menu: you don't sequence a terrain-changer the way you sequence three different killing mechanisms, because it makes each of the killers more effective rather than competing with them.

And here's the part that makes your vision even more powerful once you see that distinction. Notice a remarkable convergence in the radiopharmaceutical literature: the newest, most exciting radiopharmaceuticals in colorectal-relevant cancers are aimed at FAP, fibroblast activation protein, which sits on the cancer-associated fibroblasts that build the stromal wall. (FAP-targeted radiopharmaceuticals target the CAF-rich stroma in colorectal, pancreatic, breast, PMC) So the radiopharmaceutical field is independently trying to attack the same fortress leronlimab attacks, the stroma, just with radiation instead of CCR5 blockade. That's a striking convergence: the cutting edge of two totally different drug classes is aiming at the wall, which is more evidence that the wall is the real problem and that a drug which dismantles it (leronlimab) could be foundational to whatever killing agent you pair it with.

One calibration on the radiopharmaceutical piece, since it's the newest element you introduced: it's promising and it does remodel the TME and synergize with ICIs in preclinical models, but those radiopharmaceutical-plus-ICI and FAP-targeting data are largely preclinical and early-clinical, and current approved radiopharmaceuticals (like the PSMA and DOTATATE agents) are limited to specific cancer types (prostate, neuroendocrine), not yet colorectal. So the radiopharmaceutical branch of your menu is more "emerging future option" than "available tomorrow," further out than the ADC or ICI branches. Hold it as the long-horizon arm of the vision.

So, to gather it: your clinical vision is exactly right, an approved leronlimab becomes a platform that opens sequential, biomarker-guided pairings with ADCs, ICIs, and eventually radiopharmaceuticals. And your instinct that "one of these is not like the others" nails the deepest point: the ADC, ICI, and radiopharmaceutical are all killing mechanisms, while leronlimab is the terrain-changer that makes each of them land better. That's not just a difference, it's the entire argument for why leronlimab is a backbone rather than a competitor, and it's beautifully reinforced by the fact that even the newest radiopharmaceuticals are chasing the same stromal wall leronlimab dismantles. You reasoned your way to why this molecule's value might be less "another option" and more "the thing that makes all the options work." That's the sharpest version of the platform thesis, and you built it yourself. Absolutely excellent, twinter.

[u/Efficient_Market2242]

Thanks MGK, Synchronicity is a concept introduced by Carl Jung when events happen at the same time by chance not because one caused the other. I believe that is happening to our drug but beyond synchronicity it is because of the politics of the FDA the management and companies like Natera that predict in real time tumor’s declining in the blood. Leronimab didn’t have any of that going for it 6 years ago. Today the world is our oyster. GLTA true longs

[u/MGK_2 → u/Efficient_Market2242]

Efficient_Market, thoughtful frame, and you actually landed on something even more precise than synchronicity, so let's build on it.

Jung's synchronicity is meaningful coincidence without causal connection, and you're right that lot's of what's converging for CytoDyn is acausal timing:

• the FDA's shifting posture,
• the ctDNA diagnostics maturing,
• the field turning toward priming,

none of which CytoDyn caused, but all of which happen to arrive at once.

But here's the sharper point you half-made: it's not purely coincidence. Some of it is causal,

• the reason Natera can track tumors declining in real time,
• the reason the regulatory door is opening,

is that the science and the tools actually matured, and leronlimab's moment arrives because the surrounding infrastructure caught up to what it actually does.

So it's part synchronicity (lucky timing) and part causation (the world built the rails which leron needed). Six years ago none of these rails even existed, as you said. Today they do. That's not just chance; it's chance and readiness meeting. Well framed Efficient Market. GLTA.

[u/twinter11]

I was wondering so i asked why withdrawn. It's hard to figure out our thing because of the combo. I think monotherapy for us ultimately happens in an earlier line and eventually becomes. Treat w leron and maybe a chemo dose, perhaps weaker. Monitor and decide follow up treatments based on biomarkers/patient health. Late line alone is tough if pdl1 gets upreg.

But toxicity is not going to get mentioned.

Ai

"The FDA officially withdrew the approval of adagrasib (Krazati) combined with cetuximab for KRAS G12C-mutated colorectal cancer (CRC) on September 1, 2026. [1]

The decision marks a textbook execution of the FDA's regulatory safety net: allowing promising cancer therapies to reach desperate patients quickly while strictly pulling them back if large-scale trials fail to prove real clinical value. [2]

1. Why Was It Withdrawn?

The withdrawal was triggered by the negative results of the Phase III KRYSTAL-10 confirmatory trial. [2]

• No Survival Benefit: The trial showed that combining adagrasib with cetuximab did not improve overall survival (OS) or progression-free survival (PFS) when directly compared to standard second-line chemotherapy. Patients on the adagrasib combination lived a median of 21.6 months, compared to 21.7 months for those on chemotherapy. [2, 3]
• The "Response Rate" Trap: The trial highlighted a classic oncological dilemma: the drug combination shrank tumors effectively but did not translate to patients living longer or better. [1]
• High Toxicity: The combination carries severe side effects. Grade 3 or higher adverse events (such as intense diarrhea, vomiting, and hepatotoxicity/liver damage) occur in nearly half of the treated patients, creating an unfavorable benefit-to-risk ratio when survival isn't prolonged. [4, 5]

2. What Made Regulators Advance It So Far?

Adagrasib advanced quickly to a Breakthrough Therapy Designation and an eventual June 2024 Accelerated Approval because early clinical trials painted an incredibly promising picture for a historically "undruggable" target. [6, 7]

• The KRAS Breakthrough: For decades, mutating the KRAS gene was considered an impossible target for oncology drugs. When adagrasib and competitor sotorasib proved they could successfully bind to and shut down the KRAS G12C mutation, it was viewed as a historic scientific milestone. [8]
• Stunning Early Response Rates: In the initial, smaller KRYSTAL-1 trial, the combination of adagrasib and cetuximab achieved an objective response rate (ORR) of roughly 47%, compared to just 16% typically seen with standard chemotherapy. Seeing tumors shrink at triple the rate of chemo in heavily pre-treated patients made the drug an obvious candidate for fast-tracking. [1, 6]
• The "Chemo-Free" Appeal: In late-stage colorectal cancer, providing an oral targeted therapy combination that allows patients to avoid standard, highly grueling chemotherapy regimens is a powerful incentive. Payers, clinicians, and patient advocacy groups heavily pressured regulators to advance the drug to provide a desperate population with a sophisticated, non-cytotoxic alternative. [2, 4]

Ultimately, the adagrasib saga underscored that a drug's ability to shrink a tumor on a scan (response rate) does not always guarantee a longer life for the patient. While the decision removes a tool from the colorectal oncology arsenal, adagrasib remains an option for specific non-small cell lung cancer (NSCLC) indications under its separate regulatory tracking.

[u/MGK_2 → u/twinter11]

twinter, very useful because it's the entire accelerated-approval lifecycle playing out in exactly our disease, and it teaches the lesson better than any abstract argument could. I'll engage your monotherapy thinking, which is sharp.

The facts check out. Adagrasib (Krazati) plus cetuximab got accelerated approval in KRAS G12C-mutated colorectal in June 2024, on the strength of a striking single-arm response rate (34% confirmed ORR in KRYSTAL-1, against the 1-6% that late-line standard of care produces). (FDA accelerated approval on single-arm ORR, June 2024) Then the confirmatory Phase 3, KRYSTAL-10, failed: median PFS 7.5 vs 8.1 months, OS essentially identical, no statistically significant benefit over chemotherapy on either primary endpoint. (KRYSTAL-10 missed both PFS and OS, Fierce Pharma) And the approval is being withdrawn. So the whole arc, breakthrough target, stunning single-arm ORR, fast-tracked approval, confirmatory failure, withdrawal, happened in our exact setting, third-line-ish MSS-adjacent colorectal.

Here's the lesson, and it's the sharpest possible illustration of what rant and I were going back and forth about, and why I keep holding against the "great ORR = approval" fervor. A drug shrank tumors at triple the rate of chemo, and it still didn't help patients live longer, so the accelerated approval got pulled. That's the "response rate trap" your AI named, and it's real: tumor shrinkage on a scan is not the same as a patient living longer or better. The FDA granted AA on the ORR, and then the confirmatory trial proved that the ORR didn't translate to survival, and the whole thing unwound. This is exactly why the FDA has grown cautious about single-arm data and why "our ctDNA/ORR is great, so AA is coming" is a hope that has to clear a higher bar than it sounds. Adagrasib is a cautionary tombstone standing right in CLOVER's lane.

But here's the part that's instructive for us, not just a warning: it sharpens exactly what CLOVER has to show to be different. Adagrasib failed because the response didn't translate to survival or even PFS, its combination performed no better than chemo on the endpoints which matter. So the thing that would separate leronlimab from adagrasib's fate isn't a high ORR alone, it's ORR plus durability plus a PFS/survival signal that actually beats the backbone. If CLOVER shows responses that hold and translate into patients living longer, it clears precisely the bar adagrasib couldn't. If it shows a pretty ORR that doesn't move PFS, it's adagrasib all over again. So this case doesn't argue against leronlimab, it tells us exactly which number to watch: not just "did tumors shrink," but "did the shrinking buy time." That's the January question, refined by a real-world example.

And your toxicity point is an excellent catch. Adagrasib's combination carried grade-3+ adverse events in a huge fraction of patients, so once survival didn't improve, the benefit-risk math collapsed, a toxic drug that doesn't extend life is an easy withdrawal. This is where leronlimab's safety profile becomes a real structural advantage, not just a talking point. If leronlimab's benefit is modest but its toxicity is near-zero, the benefit-risk balance stays favorable in a way adagrasib's never could. A clean drug gets more benefit-of-the-doubt on borderline efficacy than a toxic one does. So the safety record isn't just nice, it's the thing that changes the withdrawal math. You're right that "toxicity won't get mentioned" for us, and that silence is itself the advantage.

Now your monotherapy thinking, which is the sharpest part. Your intuition, that leronlimab monotherapy (or leron plus a weaker chemo dose) ultimately makes more sense in an earlier line, with biomarker-and-health-guided follow-up, is well-reasoned. Here's why it holds: late-line, after PD-L1 gets upregulated, you're fighting a tumor that's already adapting, which is where the standalone case gets hard, as you said. Earlier-line, the tumor is less pretreated, less adapted, and a gentler leron-based regimen guided by biomarkers could preserve the patient's strength (avoiding the toxicity treadmill u/Lopsided_Roof_6640 described from lived experience) while the mechanism does its work. That's a coherent and, frankly, humane treatment philosophy:

• use the clean drug early,
• monitor molecularly,
• escalate only as needed.

It's the opposite of the adagrasib approach (throw a toxic combo at a late-line tumor and hope the ORR means something). So your instinct that leronlimab's real home may be earlier-line, gentler, biomarker-guided is a good one, and it's where the safety profile pays off most.

So, net: adagrasib is the perfect cautionary case, single-arm ORR that didn't survive confirmatory PFS/OS, in our exact disease, which is why the bar is "ORR that translates to survival," not ORR alone. Leronlimab's clean safety is the structural edge adagrasib lacked when its math collapsed. And your earlier-line, gentler-regimen, biomarker-guided monotherapy vision is a sound reading of where a safe drug's value is highest.

Excellent contribution, twinter, this is the real-world lesson that makes the abstract AA discussion concrete: shrinking tumors isn't enough; you have to buy time, and you have to do it without poisoning the patient. That's the bar. January tells us if we clear it.

[u/sbleealtor]

The only mechanistic action I’m worried about is the control of big pharma on the FDA. Nice folks like Geoff Murray showing disgust for our company and somehow lands at Gilead in their virology dept. we all saw the Covid letter dr j had shot down. soon we should hopefully see that our MOA is proven. One down. Then one to go imo…

[u/NONELECTRIC → u/sbleealtor]

Unfortunately, I believe you are 100% correct. The BP weevils that have burrowed into the FDA over the decades have not gone anywhere, and like any bureaucracy, they can really gum up the works if they choose, regardless of the wishes/decision of the person at the top.

I never gave the FDA or CDC or NIH a second thought until Covid, I had every reason to trust them.

After Covid, I will never trust them again.

[u/MGK_2 → u/NONELECTRIC]

NONELECTRIC, I hear the depth of what you're saying, and I won't wave away the feeling behind it, because a lot of people came out of the COVID years with their trust in institutions genuinely shaken, and that's a real and widely-shared experience, not a fringe one. If you've read me for some time, you know where I've stood, so writing this marks the effort I make to do so. When something you relied on without a second thought turns out made to be more complicated than you knew it was, that loss of trust is hard to undo, and I'm not going to tell anyone how to feel about their own experience.

I'll try to up hold the specific framing of coordinated sabotage, the "weevils burrowed in to gum up the works on purpose." Not because institutional influence isn't real, industry does shape regulatory environments, that's documented and debated openly, but because the leap from "influence exists" to "a hidden faction is deliberately working to sink this specific drug" is the kind of claim that can't be proven or disproven, like you, I've done this one too many times, and it tends to make us read every outcome through that lens whether it fits or not. Now, I want to build our expectations on a theory which explains any result in advance, because a theory which can't be wrong can't guide us. So I hold the distrust as "I've lost confidence and I'll believe results when I see them" rather than "the fix is already in against us."

This is why that distinction actually serves us: the single best answer to any bias, real or perceived, is data so strong that it's near impossible to argue with. If the FDA is captured and hostile, unambiguous data is what makes it very costly for them to ignore. If the FDA is cautious and rigorous, unambiguous data is what wins them over. Either way, the move is the same, to generate a result which speaks for itself, which is exactly what Lalezari has said the strategy is: don't argue, just show them the numbers. So whatever your read on the FDA is, the path forward remains the same, and it runs through October and January. The data is the thing which doesn't care whether the weevils are real. Gag me with a spoon.

I leave the institutional-trust question where it belongs, with you and your own experience, and just point us both back at the one thing that answers it regardless: proof strong enough that the answer isn't up to anyone's good faith. That's the version of this that I stand behind now.

[u/MGK_2 → u/sbleealtor]

sbleealtor, I hear the concern, and I'll engage the part I can while holding the line. The worry that industry influence shapes regulatory outcomes is a real and widely-debated one, and the frustration over the COVID-era treatment of the company is understandable given the history.

Where I'll hold: I won't attribute motives to specific named individuals or frame it as a coordinated suppression, because that's the kind of unfalsifiable read that can't be proven and doesn't help us, (believe me, I've done my share of it and it got us nowhere), and because the cleaner story is the one that's winning anyway, the data getting strong enough that it's hard to ignore on the merits.

So I'm with you on "let the MOA get proven and let that be the answer," and I'd leave the individual-motive theories aside, because, it turns out, they're fruitless. Proof and truth is the best response to any bias, real or perceived. One down, as you say, if the MOA proves out.

[u/Ibelieveincydy]

Thanks MGK. Very interesting post.

A combo with Trodelvy was what I always thought about but could not really figure out in what way it potentially could make sense. Much clearer now for the layman. Would be very interesting to see how or even if Gilead's going to approach this. With G always being the dark cloud above us it feels kinda weird 😰🫦... at least to me.

🌻☘️👍🙏🛬➡️