Spectrum Pharmaceutecals Inc (SPPI)

[antihama]

Java, I'm getting ready to go on vacation tomorrow until early next week and pretty busy till I depart but I did do look a quick look at Dcaf’s post and skimmed through part of the reference “Discovery of a Highly Potent and Broadly Effective EGFR and HER2 Exon 20 Insertion Mutant Inhibitor”. I do appreciate Dcafs take on things (whatever they may be and/or agenda) but the bottom line is you have to expect that Dr Heymach and MDA's data is not disingenuous. They would never risk their reputation on less than reputable data. A couple of quick thoughts on the reference.

We used proliferation assays to assess the potencies of newly synthesized compounds against Ex20Ins mutants, using Ba/F3 cells transformed by three EGFR Ex20Ins and two HER2 Ex20Ins mutants. Oncogenic kinase transformed Ba/F3 assay is a commonly used model system to assess the potency and selectivity of kinase inhibitors.[14] We primarily focused on EGFR D770_N771insSVD (InsSVD) and EGFR V769_D770in-sASV (InsASV), which are the two most prevalent EGFR Ex20Ins mutants accounting for approximately 40% of EGFR Ex20Ins mutation, as well as HER2 A775_G776in-sYVMA (InsYVMA), the major HER2 Ex20Ins mutation.

One of the first things I noticed is the number of cell lines they used and that they used 3 EGFR Exon 20 lines and 2 Her2 Ba/F33 whereas in the MDA presentation, slide 6, they use 20 Ba/F33 EGFR Exon 20 cell lines. And if you look at the MDA outlier data points you could see one is not that potent and the other outlier is super-duper potent and if you take the average of those 20 cell lines you get a good representation of the data, much better than using 3 cell lines of the reference. Note the outliers in MDA slide 7 is even more extreme suggesting the point that the more cell lines (and data points) you use to get your average, the more reliable the data.

Also, it seems that the reference is being somewhat selective

We primarily focused on EGFR D770_N771insSVD (InsSVD) and EGFR V769_D770in-sASV (InsASV), which are the two most prevalent EGFR Ex20Ins mutants accounting for approximately 40% of EGFR Ex20Ins mutation

And this part of the reference is stating pozi is better!.

We then assessed the antiproliferative activities of 1a–c, 2a and 3 compared with known EGFR inhibitors in a patient-derived lung cancer cell line DFCI127, which harbors EGFR P772_H773insPNP (Figures 3 and Figure S3).[3] Like the results in Ba/F3 cells, all three carbamate analogs 1a–c achieved excellent antiproliferative activities against DFCI127 cells, but 2a and 3 were inactive. Especially, 1a and 1c showed superior antiproliferative activities relative to known EGFR inhibitors with exception of poziotinib which was consistently more potent than 1a–c. [EC50 = 11.5 nM (1a) and 22.3 nM (1c) vs. 44.0 nM (afatinib), 60.6 nM (dacomitinib) and 4.8 nM (poziotinib)] Moreover, treatment with 1a, the most potent analog, dose-dependently suppressed phosphorylation of EGFR and its downstream signaling effector, Erk. Consistently, afatinib was less effective and poziotinib was more effective at inhibiting EGFR signaling relative to 1a.

Also, none of these drugs will catch up to pozi anytime soon in clinical development.

So I really don’t have time to understand this further but it seems that they’re “molding” the data they are getting. I’m not sure if I’m reading this accurately but it seems they are saying that of the 3 Ba/F33 EGFR Exon 20 cell lines, 67% of that is geared to 40% of EGFR Exon 20 mutations. That seems pretty selective as opposed to using 20 cell lines used in the MDA data. So there’s that too.

So, even if you did not read this reference, you have to ask yourself, ’Would MDA compromise themselves and their prestige to put out misleading data’?. By extension, would they whole-heartedly pursue, pozi development, if they themselves didn’t believe in the data? And lastly, remember the proof of the pudding is in the eating (the clinical data MDA presented). You just can’t deny that. That is my lodestar.