RE:RE:RE:RE:Did I get this mostly right?There can be many reasons why this one person had neutropenia. For example, what was the treatment history of the person? Some chemos do a lot of damage to the bone marrow and that affects some people more than others. What other underlying health conditions does this person have? My wife has also has SLE and and we noticed well before she was diagnosed with cancer that her WBC was low in each blood test.
qwerty22 wrote:
SPCEO1 wrote: What if the one patient had a tumor that was not one that overexpressed sortilin? As the dosage level of TH-1902 increases the amount of Docetaxel in the patients body with nothing to attach to, could that account for the neutrpenia? Is it possible that a sortilin overexpressing patient might not have neutropenia when given the same dose?
As I said before I've never read this type of thing in the literature where safety changes depending on expression of the target molecule which suggests to me it's not a thing. It's something that popped up on this board without any evidence it's real. It sounds plausible if you think the majority of the drug interacts with the tumor in the presence of target but it doesn't. The majority of drug just circulates in the blood whether there is target or not, that seems to be more in line with what I've read in the literature. Also, should we even care? If we already know that we can pump 150% of the normal Docetaxel into humans safely and that 3-4x the normal amount of Docetaxel likely ends up in the sortilin overexpressing cancer cells, isn't that enough to get pumped up about? I know we cannot be certain that the sortilin receptor is dumping our Docetaxel chemo bomb into the cancerous cells the way we hope yet, but it seems we are heading in that direction. Since we have safety at the 150% level, that suggests that the sortilin is going somewhere other than randomly in the body causing trouble. So, while I will be happier if the phase 1a can go all the way to the highest dose without encoutering DLT's, I am already pretty happy with what we have proven to be safe.
I guess while we don't know what the therapeutic window looks like I'd prefer they had an open field to play in. As things stand the safety seems fine. As I was suggesting that patients neutropenia has to have an explanation. One of the obvious explanations is the drug is maybe degrading more readily in patients than in mice. That would be important to know. You wanted to know what we might infer from the small amount of data we were given. That's potentially one thing we might infer. Like I said I don't thing any of this is fatal to the program but lots of degrading drug isn't a particularly positive thing to add to the story. (there's probably other explanations too)
A lot of this is nerves until we get a heads up on any efficacy. Looking for where the bad news might come from in the absence of the good news. A bit more derisking, a bit less uncertainty, would be good.
qwerty22 wrote: One thing that's playing on my mind is WHY did that one patient get neutropenia, Obvious caveat n=1 is not a good basis for conclusions, there could be something in this patients history that explains this more than the drug. Having said that this doesn't look to me like a result that is in line with expectations. If you go back to the preclinical paper is has a section on the drug degradation in mice. It states that free Docetaxel exposure is 37x lower than PDC bound docetaxel. In laymen terms very little drug is breaking down in the blood. At double the docetaxel equivalent dose if the patients are behaving like mice then there should still be a tiny amount of free docetaxel in the blood, not enough to cause neutropenia. One thing absent from the update alongside efficacy was any insight into the Pk results. Is the drug looking as stable in humans as mice?
This is not necessarily wholely negative. Some ADCs trumpet their drugs degradation outside tumour cells because it potentially allows bystander killing, but it can't be ignored this also leads to toxicity. It could be that a mix of free docetaxel and PDC bound docetaxel produces a good drug profile/therapeutic window but it doesn't look like being in line with the mouse data.
(One thing to note is they've never published the rat toxicology data. My memory is they said the rats reached DLT at 3x docetaxel equivalent dose. It could be the human data is in line with the rat data but we've never seen that and we don't exactly know what the DLTs were in the rat. Certainly getting grade 4 neutropenia at 2x dose might make you think that DLTs are possible at 3x dose. Maybe that very clean mouse data which we've been relying on is not the best guide.)
Most of what SPCEO says looks good (noting some things project into the future). There are some of the more optimistic best case scenarios that have been possible in the absence of data that seem to go away with this update. (The normal situation of what is theoretically possible running face first into real world experience.)