Member Info for Haywain

As BBB1 said - I believe they have found a safe therapeutic window through the use of bivalent antibody binding design - both arms of the ScFv need to bind FLT3 to produce cell killing effects. There isn't a high enough FLT3 antigen density on normal haematopoetic stem/progenitor cells to enable bivalent binding and therefore these cells are spared - this creates an FLT3 density dependent logic gate FLT3 +ve leukaemic blasts are selectively killed. The great thing is that the same design was used for CDX which means that confirmation of result in DL2 not only validates HG-CT-01 - it cross validates CDX so I should imaging that both modalities will be in the scope as an "anti-FLT3 oncology platform" in any ongoing pharma discussions .

Davie B - I think what you have to appreciate is that all former attempts of using CAR-T as a treatment for AML have led to off tumour effects which have necessitated bone marrow transplant. Hemogenyx have created a construct that didn't lead to those effects in DL1. I believe that the reason for that is clever design of the ScFv binding component - this is what it was designed to do. I couldn't make head nor tail of FDA's decision to include paediatric patients so early in the DL1 - That to my knowledge hasn't happened before. The reason it did happen here (I can only assume) is because saftey is hard encoded into the CAR-T design it appears to leave normal healthy tissue alone and only target the AML blasts - Which leads to the "encouraging signs of efficacy" whilst inherently safe through design. If that is true then if differentiates HG-CT-01 from all that have come before : its a first. Now the question is will it replicate in DL2 - if yes then beyond doubt that signal will be recognized and confirm that HG-CT-01 is the first effective CAR-T in AML treatment. So DL2 = confirmatory : that is a very strong position to be in at this stage.

No safety issues is more important than people think - that in itself is a first for CAR-T in AML : all other attempts have lead to major safety issues - you have to ask yourself why that is ? It is also the main reason why CAR-T has largely failed in this indication. I know the answer which is why I have always been so positive about hemogenyx and why the neighsayer arguments morph and twist but ultimately are shown to be false. It doesn’t matter to them : they think it’s fine to reappear as a new user name and change the line of attack. I havnt changed my user name and I have been saying the same thing from the start- my working hypothesis remains valid.

You’re projecting how you think a company should behave- not how regulated clinical trials actually behave. In reality programmes run under serious institutional oversight tend to communicate less not more. If HEMO were drip‑feeding survival claims as you suggest it would hurt credibility with regulators and partners not enhance it. You do seem to have an awful lot of time on your hands- I would suggest your time is better spent worrying about why the company that shall not be named put out promotional RNS’s every five minutes - they work hard to keep their investor base - you should be helping them over on the other forum rather than posting endless tripe here.

I can’t believe you have the gaul to say that - from a risk‑reward standpoint, Hemogenyx is far more asymmetric at this point in time.

That doesn’t make Avacta wrong. It makes Avacta priced, and Hemogenyx mispriced.

I’m not dismissing Avacta.
 i’m also not arguing Avacta vs Hemogenyx - you brought that argument here. What I am arguing is that: Removing a fundamental biological impossibility ( a CAR-T for AML that doesn’t induce cytopenia) creates a different class of value than improving how well we exploit a known one (Avactas delivery system).

Both can make people a lot of money.
 they just sit on different parts of the risk spectrum. Good luck to anyone backing Avacta – genuinely.
 but disagreement here isn’t ignorance or emotional attachment.
 it’s simply recognising that not all “paradigm shifts” look the same and for that reason their regulatory burden of proof sit at different levels.

“With respect” Aldebaran, there are a few points I agree with you on. But when you drew the comparison of Avacta having the holy grail - you reached for the golden jewel encrusted challis at the front of the table and missed the humble cup at the back. I agree that safety is very important and that a drug that is able to treat cancer with reduced safety impact is important. But they are iterative - “bit better” - safer and boring. Contrast that to an immunotherapy that I predict will change the treatment landscape of AML and that might be a curative monotherapy without the need for bone marrow transplant and I think even you can agree we are talking about different leagues of potential therapeutic benefit. As I have said before - I have no problem with Avacta. I do however have a problem with respect to you, empty vessels sound the loudest and all that. Gentle reminder - keep Avacta off this board please

I can keep it simple - the difference is iterative with better safety profile (hopefully) vs potentially curative for the first time - that sums up the difference.

splitting signals across receptors is an iteration, not a replacement - and specifically not how our car-t was designed - instead hemo decided that co-stimulatory domains of the hg-ct-01 car (3rd gen) car-t should be sufficient with respect to durability and t-cell exhaustion - stop the bull****.

please write something sensible rather than this general handwavy pseudoscience bull**** "modern medicine is improving" - great but we have something in the hand - real clinical data in a disease area that has confounded science for decades.

Ok - I take the bait. This is muddling up classic immunology- Natural killer cells are part of the innate immune system and are inherently short lived. They typically present from days up to a couple of weeks with very little capacity to expand to form memory. That means the effect they have is transitory unless you keep re-dosing or artificially support them. Contrast that to CAR-T cells which are derived from the adaptive immune system - they are specifically designed by biology to expand massively invivo and then persist as memory cells for months /years after antigen exposure. That persistence is precisely why CAR-T therapies can produce deep and durable remissions from a single infusion. They do no simply wane - they proliferate, establish immunological memory and continue to surveil and eliminate malignant cells over time. From early CAR-T cell studies in patients memory t-cells have been detected up to ten + years post initial dose. The comparison to NK is ill informed.

Erm - yes : anti-BCMA invivo car-T bought by AZ for 1billion from Esobiotech for multiple myeloma - despite what 1/4/1 and others might say about evolving tech - turns out in this example it’s unsafe.

Correct - I am claiming that it has the potential to be curative : if it irradicates the FLT3 +ve leukaemic stem cells and progenitors while sparing normal haematopoetic stem cells - a cure is exactly what it could be and time will tell.

Personally, I’d much rather Hemogenyx focus on quietly delivering real progress — which is exactly what they appear to be doing - rather than resorting to the kind of over-promotional noise you see else where where expectations are constantly inflated - to fill the coffers- but meaningful results rarely follow. Substance over hype, every time

Fantastic

Can we give it a rest with the Allogeneic vs autologous - Its a total red herring. The point Archbishop is making is that we are not quite there with allogeneic CAR-T (because it is non-self ie donor cells nobody has been able to crack the graft vs host response yet) - HG-CT-1 is an autologous CAR-T ie GVHD is not an issue - in fact in-vivo CAR-T may displace attempts of allogeneic CAR-T anyway (off the shelf and no GVH issues): What we are talking about is different modalities to achieve the same/similar effect - Its a red herring from someone who doesn't understand what the hell he is talking about.

I have no doubt we will hear about the trial progress in due course- period of quietness most probably crossing t’s and dotting the i’s - the tech transfer forms the basis of all that is to come and therefore it needs to be robust and unquestionable - ie all aligned that analytical comparability is spot on, all batch data reviewed all deviations closed out, it’s quite a lot of work but necessary work to ensure a robust foundation for the CMC - we want to focus on patient outcomes when the trial restarts rather than worrying about the reliability of manufacturing.

I see the mouse man is still spouting his verbal diarrhoea - bless. It will all come out in the wash : onwards and upwards.

Trying to work out who is more stupid - one4one for writing this steaming heap of crap or the two people who liked the post ? I mean the standard of trolling has really gone down hill.

Nominally all stages must be completed but there is a great degree of variance and complexity across clinical trials - they are not all designed the same way. For instance where you have a rare disease in oncology that impacts paediatrics - typically every regulatory form of expedition is applied. They may move early to phase 2/3, they may gain breakthrough designation in phase1 and phase 2/3 could be single arm design (no need to buy comparator drug) and relatively short 10's of patients rather than hundreds/thousands - there is also an expedited review process applied once BLA submission is reached so the clinical development pathway can be squeezed from multiple years down to a couple of years.