RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:Very encouraging, but approval will take timeAbout the new protocol, my understanding is that they want to lower the free docetaxel generated in the bloodstream, and increase the amount of TH1902 internalized inside cells for a given cycle. This is just my guesswork around that. It was not clearly said in the presentation, even though some comments by Marsolais towards the end pointed in that direction.
So up to now in the clinic they saw that the higher the dose, the higher the toxicity, but not the higher the efficacy. That is probably due to a saturation effect of the sortilin receptors. There seems to be a limited capacity of the sortilin receptor to internalize a ligand over a limited period of time. So, giving 300 mg/square meter of TH1902 led to the quick saturation of the sortilin receptors and the capacity to internalize TH1902 over time was limited, and there was too much TH1902 to reach that capacity. So what was not internalized, ultimately led to free docetaxel that diffused in every cells causing toxicity.
So let's say that when you inject 300 mg/square meter of TH1902, because of the saturation of sortilin receptors quickly after injection and for a certain time afterward, only 20% of the dose is internalized (this 20% number is just for sake of demonstration of the idea, so not real). So, 20% of the dose is internalized, and 80% will be ultimately degraded down to free docetaxel and be able to diffuse everywhere in the body. I know they said in a recent PR that the ratio of free docetaxel/TH1902 in the bloodstream is 1/100, but I don't believe this data. Degradation of TH1902 is more complex than that, and diffusion of docetaxel into cells is very rapid since it's a very lipophiliv molecule. So Thera was unable to see the real picture of the situation only with blood testing. See it as a leaking reservoir, leaking in a much smaller one that is at the same time leaking in other big one where you cannot see. The 1% is the small reservoir continually leaking in a bigger one where it's impossible to see or in this case to test. So it's a dynamic process were sortilin internalization rate of TH1902 is in competition with free docetaxel rate of diffusion outside of the bloodstream. Be sure that the rate of free docetaxel diffusion outside te bloodstream is much higher, so the 1/100 ratio the gave is worth nothing.
OK, all that being said, the new protocol will try to circumvent the problem to some extent. They will split the dose in three equal parts. So in my example, instead of 300 mg/square meter, they will give three times 100 mg/square meter. So, if 20% of the injected 300 mg/square meter was internalized, it means 60 mg of TH1902 was internalized and 240 mg was left in the bloodstream to be degraded to free docetaxel. Now, if only 100 mg/square meter can be enough to saturate the the sortilin receptors, it would mean that a higher percentage of the 100 mg would be internalized and less left for degradation leading to toxicity. In theory if the internalization rate through saturation of receptors would be the same, it would mean that 60 mg out of 100 mg of TH1902 would also go inside the sortilin expressing cells, but it's ulikely. So let's say that only 40 mg of TH1902 would be internalized, it would nonetheless mean a 40% internalization rate. So after the three injections of 100 mg, it would lead to 120 mg of TH1902 being internalized, and 180 mg left in the bloodstream for degradation. So this way, if my guesswork is somewhat right, you would improve efficacy, and lower toxicity.
Again, this is just to illustrate the principle that I think is at play behind this new protocol. All the numbers about rate of TH1902 internalization are bogus, I invented them just the illustrate what I think is the logic behind that new protocol and I know they will now use simple weight for dose determination instead of body surface area. I kept the 300 mg/ square meter just to relate to the 300 mg/square meter dose we knew they were using, and I know they will do the first six patients at a dose similar to 200 mg/square meter, so lower than they used previously. If my logic is right, it means that even a higher percentage of TH1902 should be internalized at that dose. Another thing I was wondering about, but that they didn't speak about, is the rate of infusion. A slower rate of infusion could help to not saturate the sortilin receptors, and thus, allow more TH1902 to be internalized.