Ann: CLTX CAR T PRESENTS POSITIVE INITIAL PHASE 1 CLINICAL DATA, page-67

I took it to mean that how CLTX binds to GBM now has an 'increasing importance' to the field in general, with the underlying message that because CLTX has shown positive in-human clinical data, the need to figure out how CLTX binds to GBM now has an 'increasing importance' because it will lead to more lives saved. At the end of the day, this is the end goal is it not? To save lives...

So if CLTX showed data that was not great, then how CLTX binds to GBM (or in this case, it didn't bind well at all) is not important at all and is not worth mentioning. It's not worthy of follow up or further investigation... but if I were to apply the same line of thinking, well this must be a good thing because there is no 'increasing importance'... it's just not important, and thus not mentioned.

But because CHM did generate strong initial in-human data, suddenly its a negative?

I pose this question, who determines if its an issue or not? Let me tell you, its the FDA.

So when the FDA don't even consider it an issue if the mechanism of action is not certain i.e. specifically for cell therapy, they recognise that the cells being studied can be highly complex and their mechanism of action uncertain.. yet they still have a framework to allow these treatments to be FDA approved, in spite of some questions outstanding around how exactly the cells work.

In short, to overcome the uncertainty in complex cell therapies mechanism of action.. the FDA recommends ways to get around it, and one of them is an assay matrix, which is simply a number of cross-checking assays that support your proposed mechanism of action.

Why this is important, is that once you move to submitting a BLA (FDA approval) after your approval trial is complete, they will need to ensure you understand your product well enough so that you can guarantee the drug you create is consistent batch to batch, in terms of potency and quality. How you measure this is through potency assays, which you can measure things in the make-up in your drug (e.g. active ingredient), as well as the effect your drug has on the patient e.g. proliferation of T cells. So these potency assays will need to show that there is a correlation between the amount of active ingredient in your drug, and the clinical benefit in the patients as well as the correlation to proliferation of T cells.

So the 'matrix' has to hold up, and demonstrated in vivo (in a living organism/ typically human) and thus gives the FDA the confidence that you are able to measure how potent/effective your drug is post approval i.e. each patient paying for this drug, is getting what they paid for, and you know how to determine if a certain batch is high or low quality.

FDA guidance on cell therapy






Remember the team that has been assembled at CHM.. they've been through this all before.. being involved in 4 out of the 5 FDA approved CAR T therapies .. they know all this and much much more, and I can assure you this is something they are working on as we speak and will have between now and the BLA lodgement to figure it out. The FDA doesn't expect us to have figured it out yet.. but a poster here does, and it's a big concern. FDA or anonymous poster on HC?

Here is another easier to read FDA presentation on this topic, for those who want to learn a bit more.

FDA bioassay presentation




Note how the FDA expects that product characterisation is built from pre-clinical through to phase 3 and then optimized at BLA submission time. We are at phase 1, and we still have questions outstanding... we still have plenty of time to figure it out. And the FDA recommends that the development of the potency assays are done throughout the trial, and do not need to be finalised at phase 1.. we are all still learning, and the FDA recognises this... that is why it is a non issue right now, and even if we don't figure it out completely by BLA submission time (if we are lucky enough to get this this stage), then the FDA has a mechanism to overcome this (see documents above) using matrix assays etc.


Goodluck all