Member Info for Haywain

In general those who make the most noise have the least knowledge on a subject area - they don’t know that they don’t know- unconsciously incompetent -just mouthing off : conscious incompetence is a step forward towards conscious competence : masterful is unconscious competence - we have a spectrum here on LSE and that shouldn’t be a surprise I suppose. ultimately in my view the science wins the day here - if the science is good here then the money will follow: The real skill isn’t predicting the share price — it’s recognising when the science is telling you something important before everyone else does.

It’s usually just a protocol amendment to the existing IND just as they did to add paediatrics.

I can only go on what the protocol currently defines HFH which is >12 <18 - there could plausibly be a shift to include younger patients but that would require a protocol amendment - so we will see

Morscloud - there is a scientific unkown about paediatric administration - it relates to T-Cell fitness and expansion kinetics being faster (younger fitter immune system which quite often isn't as damaged as adult r/rAML patients) : this sometimes can lead to transient CRS due to faster expansion of CAR-T. Conversely because there is less antigen heterogeneity in children and because faster expansion means faster and deeper clearance of AML blasts -also children tend to recover faster than adults - HG-CT-1 should "work better" in children than in adults. Scientifically it will answer the question of whether the efficacy/safety profile is retained cross biology. If it is then it makes HG-CT-1 strategically very valuable in a treatment area where there are few available options.

I get the feeling that certain posters talk about DL2 as though Hemogenyx is still asking the same question it was asking before the first patient was dosed. It isn't. First in human is where the biggest unknowns sit: Will the CAR-T expand, will it cause unexpected toxicity, will it damage normal bone marrow & will it show any biological activity at all? DL1 has already answered a large part of that question. The initial cohort appears to have shown that HG-CT-1 can be administered safely- without dose limiting toxicity and without prolonged cytopenias that would have raised concerns about FLT3 as a target. If deep anti-Leukaemic activity was also observes (ie undetectable leukaemic blasts) then DL1 was not just a safety cohort in practical terms - It was proof that the construct can operate inside a therapeutic window. That makes DL2 a very different proposition from the original first in human leap. DL2 is not asking whether the whole idea is biologically plausible - it is asking whther the signal seen in DL1 can be replicated and potentially strengthened at the next dose level. That is materially lower risk question than the first ever patient treated because the program now has real human data: safety, tolerability, expansion kinetics, marrow behaviour, blast kinetics and early response markers. There is also an important learning component that I am not sure is understood: By following the DL1 patients, the team will have learned a great deal about which biomarkers matter that information should help to interpret and optimise DL2 and paediatric recruitment. It isn't blind repetition - its informed escalation.

Like one of those magic eye 3D level understanding ?

Thats a sensible post bdcarr123, though I believe HG-CT-1 is being trialed as a monotherapy rather than being a bridge to transplant i.e HSCT may not be necessary in this patient population

43% needed bone marrow transplant - it a chemo based control approach vs targeted immune eradication : in short

I think the point that most have missed is that when FDA approve paediatric extension in clinical trials they do so on the demonstrable risk/benefit with a particular focus on the risk in early stage trials. The risk here from a safety point of view is CRS, ICANs & Cytopenia and these risks are generally assessable early following treatment - within the first couple of weeks - the profile is well understood in AML patients ICAN's are driven by CRS and appear in peak T-Cell expansion - Cytopenias are observable early as well. Ask yourself how many other AML trials have been granted paediatric extension, then how many other trials have been granted it so early? The only way that HG-CT-1 was granted paediatric extension was that it was demonstrably safe in the first two adults - I would argue mechanistically safe (safe by design). That is the key point - absence of severe cytopenias in DL1 is not some side observation - its potentially the entire story. Most AML CAR-T programs fall apart precisely because they cannot separate AML eradication from destruction of normal bone marrow and cytopenias emerge early. If the FDA were comfortable enough to allow paediatric progression after two adult patients, then clearly they did not see an unambiguous signal with regard to marrow toxicity.

It’s amusing that you should say on the one hand hemogenyx is still “in the Petri dish” and point to studies that still are preclinical whose hope is to achieve exactly what HG-Ct-1 appears to be already achieving in the clinic- No Cytopenias. The irony is quite astounding.

Actually Jezza is correct - filled for paediatric extension 14th May 2025 - two weeks after the 2nd patient was dosed so hadn’t reached end of safety period - granted in June - standard IND ammendment timeframe 30days

Thanks for this kingpin - just reading how Hemo/ MDA have designed this trial - the summary tells you that MD Anderson is not just collecting safety data but a full clinical and mechanistic dataset—including response, survival, durability, CAR‑T persistence, trafficking, and predictors of activity. This means they already have detailed, patient-level biological insight into how HG‑CT‑1 behaves (not just whether it produces responses). For pharma, this is critical: they will be able to evaluate coherent PK/PD relationships, evidence of selectivity and whether responses are mechanistically explainable and therefore reproducible. In other words, MDA will be able to show not just that the therapy may work—but why it works: I do wonder if onlookers will come to the same conclusion as I have as this is ultimately what determines whether the signal is investable. Good to know that we are at least collecting the data that will inform that decision!

I don’t think that fully addresses the point. The key issue isn’t just efficiency of AML killing it’s how much total antigen the CAR‑T is engaging across the whole system. Prior AML CAR‑Ts have had a very large effective target pool due to shared antigen expression, which drives sustained activation and toxicity. A more selective construct reduces that pool which should reduce overall immune activation even if CRS isn’t eliminated - it is reduced and becomes manageable. Therefore greater therapeutic window (correct) reduced CRS (correct) - that sounds like something I would want to see in a CAR-T for AML no?

CRS precedes ICAN's - CRS is caused by overexcitation of the immune system and release of inflammatory cytokines like IL-6, IL-1 and IFN-g - It is directly related to the rate and extent of cellular killing (aligns to T-Cell maxima and expansion phase) and has been observed in most attempts of T-Cell therapies for AML. Do you think there would be more or less cellular killing in the example where the T-Cell is highly specific for its target and selective of tumour cells over normal healthy cells vs one with on target off tumour effects?

Sorry - deleted some of my message - updated

Paediatric inclusion is typically delayed until there is sufficient confidence in the adult risk–benefit profile; however, given the apparent comfort from both FDA and MDA, it is reasonable to expect paediatric cohorts could be started in parallel with adults in this case. HG-CT-1 is different by design where safety has been engineered into the ScFv binding domain. In addition most chemotherapeutic agents have a linear relationship with safety events (higher starting dose = greater probability of DLT's) which isnt the case for CAR-T in general because there is an expansion phase after the injection which see the T-cell maxima as many hundreds/thousand times higher than the starting dose. Therefore the T-cell maxima is directly proportional to the number and density of FLT3 (ie patient specific not starting dose specific).

Importantly prior CAR‑T approaches in AML have consistently shown on-target, off‑tumour effects—particularly prolonged cytopenias requiring bone marrow transplantation. HG‑CT‑1 appears to be addressing this limitation and is being developed as a standalone therapy - this is why there is a comfort level with exposing paediatric populations in this specific example.

Paediatric inclusion is typically delayed until there is sufficient confidence in the adult risk–benefit profile; however, given the apparent comfort from both FDA and MDA, it is reasonable to expect paediatric cohorts could be the ScFv binding domain. In addition most chemotherapeutic agents have a linear relationship with safety events (higher starting dose = greater probability of DLT's) which isnt the case for CAR-T in general because there is an expansion phase after the injection which see the T-cell maxima as many hundreds/thousand times higher than the starting dose. Therefore the T-cell maxima is directly proportional to the number and density of FLT3 (ie patient specific not starting dose specific).

Importantly prior CAR‑T approaches in AML have consistently shown on-target, off‑tumour effects—particularly prolonged cytopenias requiring bone marrow transplantation. HG‑CT‑1 appears to be addressing this limitation and is being developed as a standalone therapy - this is why there is a comfort level with exposing paediatric populations in this specific example.

Not at all - I have heard all of the bear arguments over the years and not been moved by any. The reason we talk about science is because the science will define whether HG-Ct-1 will be successful or not. The main clue from DL1 is no cytopenias : I will let others research the significance of that but if DL2 replicates which I think is probable for reasons I have mentioned before then the downside is capped (already priced at less than a preclinical company) and the ups side is huge. I don’t need charts to tell me that. We have also recently received funding from an institutional investor at £8 that will see us through DL2 and paediatric DL1 : that’s good enough for me.

I could be an arse-hole like Alde - but I chose not to be : I think that there are many applications for Avacta’s technology and if it improves safety with similar efficacy that is significant- I wouldn’t be so crass as to post on the Avacta board (unless pushed) and I wish them every success.

I’d probably stop at “SGC”… 😆

There’s a very big difference between lack of competition and difficulty of indication. AML is not some quiet playground — quite the opposite. It is one of the most biologically complex, treatment-resistant and historically high-failure settings in oncology, particularly for CAR-T. That hasn’t stopped plenty of companies trying, but most AML CAR-T programmes have failed early because of on-target/off-tumour activity wiping out normal haematopoiesis. In other words, the therapy kills the marrow along with the leukaemia, which is exactly why dose-limiting cytopenias have been such a recurring problem across the space.

So the more interesting question is not “is there competition?” but rather:

Have you actually seen that failure mode emerge here in DL1? Because if you haven’t — and especially if you are simultaneously seeing evidence of blast clearance and prolonged survival without follow-up therapy — then that is the point that should make people stop and think. By contrast ultra-rare indications such as salivary gland cancer are often attractive development pathways precisely because they involve lower competitive pressure, smaller trials and a lower bar for demonstrating early activity. That is completely rational strategically — I understand exactly why companies pursue those routes — but it is fundamentally a different objective. One approach is:“Let’s find a signal somewhere commercially accessible.” The other is:

“Can this therapy actually work under pressure in one of the hardest disease settings in oncology?” That is a completely different challenge. I’ve got nothing against Avacta — the platform may well prove valuable — but strategically, biologically and clinically these are not equivalent comparisons, and right now they are not operating in the same league. Additionally I don’t want to talk about these comparisons - so please stop posting about Avacta on the Hemo board - or I will highlight all of its floors.

I would tell you a bed time story too 1/4/1 - if I thought you had the mental faculty to understand it, but we are where we are.