Paxalisib is an inhibitor, so while it is targeting GBM .. it is only looking to slow down GBM. If they succeed and I hope they do, then it will be an advancement for early on-set GBM treatment.. but it isn't a cure. It does however have a place in the treatment of GBM, but it's at the early onset phase and serves to only prolong the life of the patient for a short period. So just like any other inhibitor in this space, it goes through phase 3 trials as it doesn't quite qualify for accelerated approval.
CAR-T therapy on the other hand is a paradigm shift in how cancer is being treated. It's objective is to destroy the cancer and ultimately offer GBM sufferers a cure. So if CLTX works, then some patients will have a partial response and their tumor will shrink... but others who undergo the treatment have a chance of complete response and potentially no relapse. No inhibitor is going to come close to that.
So the FDA has approved four of the five CAR-T therapies after a phase 2 trial, and one after a phase 1 trial. Simply because they are leaps and bounds ahead of anything that has come before it and they want to start treating patients as soon as possible, thus providing accelerated approval rather than require a phase 3 trial. So I don't believe CHM management are telling us anything we don't already know by saying they believe a phase 2 trial is expected to be an approval trial.. if they get even 10% complete responders in their phase 2 trial I'd say they would get accelerated approval given how unsuccessful standard of care is for GBM. I also believe this is a mult-step approach, with proving that CLTX is potent as a first step... but ultimately, CLTX is likely to be combined with another therapy to maximise its effect.. but that's for another discussion.
In terms of safety and manufacturing, these are two very good points and if we progress further down the development track we will have ample opportunity to discuss these in more detail. But for now, safety is paramount and that is the purpose of the phase 1 trial. CLTX has shown in pre-clinical studies that it can eradicate GBM cells with no relapse. That is simply unheard of.
So CLTX itself may be potent, but they are treating patients directly in the brain and surrounding areas. So anything being injected into your brain must be extremely safe and well tolerated, or you will end up with neurotoxicity (damaged brain and/or peripheral cells) / cytokine release syndrome (overactive immune response causing dangerous levels of inflammation and cell destruction). These are common side-effects of CAR-T therapy for blood based cancers, however it is tolerable to a certain degree given the patients dire circumstances. So it is almost an expectation that patients in the CLTX studies will have some degree of these side-effects, but there is hope that CLTX may have a slightly better safety profile.
Firstly with CLTX, it has been extensively used as a GBM staining agent and has been shown to be very safe. So the introduction of CLTX into the brain is not actually something 'new' and attaching it to a CAR-T theoretically should not cause significant neurotoxicity.... but of course the trial is there to examine this. What we do know is that the first four patients dosed with Chimeric's CLTX CAR-T did not experience any significant side-effects, as the City of Hope team were allowed to advance to the second cohort (which has double the initial cohort). The other key distinguishing feature of CLTX CAR T from the blood based approved CAR T's is that CLTX CAR T is injected to the source of the tumor as opposed to the blood stream. This is important because if you introduce a CAR-T into your blood stream that circulates through your entire body, then the chances of a cytokine storm (overactive immune response) increases. The hope here is that because it is isolated to the tumor, that the immune response is local and not going to result in a cytokine storm.
CDH17 is probably worth quickly noting as well as it's mechanism of action is somewhat unique and theoretically should be very safe. That is, while CDH17 is expressed in healthy tissue.. it is not on the surface of healthy tissue, rather it is packed tightly below healthy cells. CDH17 is only exposed when a tumor breaks through the healthy tissue and exposes the CDH17 present on the tumor cells and thus provides a target for the CAR-T. So there is hope that neurotoxicity can be minimal for this treatment as well.
On manufacturing, we are somewhat de-risked in that there are already five approved CAR T therapies... as such, there is a clear path to follow if CHM and/or a partner were to progress this far. And I don't only mean the ability to simply produce batch-to-batch consistency, the FDA will focus on things like critical quality attributes and how CHM are able to guarantee the product it manufactures is potent i.e. as good as the product they used in the trials? As such, there will be bio-markers that CHM must track from day dot and demonstrate through the trial and other studies how the identified biomarkers on the CAR-T correlate to potency. But from my view, this shouldn't really be a problem as the CAR-T is clearly defined and understood ... however I only wanted to point out that the process of manufacturing (being able to produce an identical product batch after batch) is only one hurdle they must clear.
I'd be more concerned if this company was run by management who may be technically strong, but lack the experience on how to get a CAR T through the FDA approval process. The CHM team are stacked with high caliber management and Board members who have been involved in four of the five FDA approval CAR T therapies and some of the largest pharma companies globally. These people were head hunted by Paul Hopper, so they weren't looking for a job. For a newly ASX listed company to attract such talent really caught my attention as they clearly saw something worth pursuing at CHM to leave their jobs. Dr Li Ren who is in charge of CHM technical operations was from Bristol-Myers Squibb and was in charge of the technology transfer from Juno who Bristol-Myers Squib acquired through the acquisition of Celgene for US$95bn in Nov19. These are some big hitters on the global stage.. and this talent is now at CHM. I've said this before, but I'll say it again.. CHM's management and Board look more like a multi-billion dollar biotech company rather than a newly listed ASX company sitting at a market cap of $0.1bn...
Goodluck all
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