Replies to post #151317 on Biotech Values

[DonShimoda]

Yes, KOL's like Dr Cortez are beginning to make the case that using ponatinib in a front-line setting may prevent mutations from developing in the first place. He mentions this possibility in an interview he gave at ASCO (starts around the 9:30 mark) https://accesscmldrugs.wordpress.com/2012/10/14/dr-jorge-cortes-explains-latest-on-existing-and-emerging-treatments/

[biomaven0]

Pona could actually prevent the T315i mutation from actually gaining traction?

In the case of CML, preclinical tests have proven remarkably good at predicting resistance with the current drugs. Pona is active in these tests against all single mutations. There are a couple of multiple mutations that could defeat it. So that's the primary argument for using it upfront - it's very unlikely indeed that multiple mutations could arise simultaneously. If you use a weaker agent first, then you raise the possibility of multiple mutations developing, particularly if the patient is not compliant. (Likely lack of compliance plays a significant part in the development of resistance).

Now mutations are not the entire story - there were a few patients in the trial who did not respond well even though they had no known mutations. Fortunately those are very rare - presumably there is some other pathway involved.

In the PACE trial, the single best predictor of response was dose intensity. Some of the sicker, older and more beat up patients had dose reductions. I had always wondered why their front-line trial was using the same dose that the third-line trial did, given that mutations present in the 3rd-line population have a significantly higher IC50 requiring a higher dose, and a lower dose would be somewhat more tolerable for front-line patients. The company seems to believe that the higher the dose the better the durability, and so they are going for best durability. (Same holds for AP26113- the current dosing is way higher than you would predict you would need for ALK+).

Peter