Spectrum Pharmaceutecals Inc (SPPI)

[antihama]

Poziotinib foot fetish.

Finally re-listened and took notes on Dr. Heymach's WCLC CC from last October. So now I can cross the following off my list.

Lots of good info in the CC; will re-listen in the days/weeks to come

Make that months to come. Really worth re-listening to. I paraphrased a lot of what Dr. Heymach said. Here's the part that has to do w the title of this post

This slide shows the difference between osimertinib and pozi. And we learned from drug screening is the key limitation for std drug is the area we call the terminal group labeled the Feet. So if you think of these molecules fitting into the pocket feet first and the hand is the part that has to reach out and covalently link to the C797 and you can see osi has big feet. The feet is exactly where the steric hindrance happens. So we realize we need a molecule that would be more flexible, it would have to deal w the twist to accommodate the pocket so it has to have some torsional flexibility as well as a smaller terminal group and pozi actually fits the bill for this.

Another slide he discusses why pozi is effective while other TKIs aren't which is due to the steric hindrance

Shows changes that happen w exon 20 ins. Helix shifts inward and the loop shifts downward and these 2 changes essentially squeeze that binding pocket. Left side shows how afatinib doesn’t bind well in that cleft. Our molecular models can calculate the Free energy and pozi can bind into this pocket dramatically more potentially with more favorable energetics then the next most potent drug which is afatinib.

He has a slide that notes Response Rates to traditional TKIs is < 20% (earlier in the CC he the Objective RRs to existing TKIs is 4 to 10% unless you include the mutation on the 763 molecule where other TKIs are effective (and notes because of that they've been excluding AA 763, at least for the 1st 11 pts). I bring this up because I was wondering in a post a week or 2 ago if a RR of 20% would make pozi successful. That's like a worst case scnario. As you know from the PR in April, the preliminary RRs on the 1st 11 pts was at 64%. Anyhows, I thought I'd share my relistening. It's really worth a re-listen.
https://www.nature.com/articles/s41591-018-0007-9