More about Roche - Roche is an interesting competitor because they have invested so much into p53 which yielded the Nutlins , which in turn, provided much of the insight into the science needed to continue the efforts to reactivate p53 in a more efficacious manner. Now Roche seems to be placing it's bet on Aileron, a company that is touting "stapled peptides" as the way to reactivate p53. Roche has provided millions and perhaps could reach $1 billion with Aileron and Lilly, Glaxo Smith Kline and Novartis are also participating via venture funds.
When you look at the Aileron PRs they claim a superior approach because the stapled peptides allow them to modulate both MDM2 and MDMX which are the "big two" protein regulators of p53. MDM2 is regarded as the primary inhibitory pathway because it acts on p53 in more ways than MDMX. MDM2 inhibits through 2 mechanisms (inhibition and degradation) while MDMX inhibits p53 but does not degrade it.
Kevetrin does not directly modulate MDMX so this would appear to give the stapled peptide approach an advantage over K, which only modulates MDM2. To quote: " The inability of MDM2 inhibitors to target MDMX-p53 interaction or induce MDMX degradation prevents full activation of P53, imparting resistance to MDM2 inhibitors." It also is important to note that MDM2 and MDMX interact with each other and those interactions allow MDM2 to in turn degrade MDMX. But if Kevetrin has downregulated MDM2 that is not going to happen.
So score a point for Roche/Aileron.
But before we dismay too much there are two important points to consider: First, Kevetrin is in human trials while Roche/Aileron is claiming they will start a human trial in 2014. The transition from preclinical to human trials is tricky and who knows if they can pull it off with a candidate that is both efficacious and non-toxic.
The second point is a huge advantage for Kevetrin as it does something which the Aileron drug candidate does not. Kevetrin affects both wild type and mutated p53. The Roche/Aileron drug affects only wild type P53. This is quite significant as mutant p53 may promote tumor progression and resistance to therapy. Consider these quotes:
"p53 mutants that promote tumor progression and resistance to therapy become the most common prognostic indicator for both cancer recurrence and death."
or this:
"Introduction of wild type P53 by gene therapy can correct loss of function in tumor suppression, but cannot diminish the oncogenic effects of mutant p53 on tumors. "
So the fact that K is in human trials and addresses the type of P53 mutants that harbor "the most common prognostic indicator for both cancer recurrence and death" garners Kevetrin a couple of points. And there is this too - the following quote hints that Kevetrin may still have some effect on MDMX because CTIX data indicates K activates Bax.
"Thus, the combination of MDM2 inhibitors with chemotherapeutic agents such as doxorubicin, which induces MDMX degradation, or with a BH3 mimetic ABT-737, WHICH ACTIVATES Bax AND OVERCOMES MDMX-MEDIATED SUPPRESSION OF p53 FUNCTION, MIGHT HAVE THERAPEUTIC VALUE.
If that bolded section is indicative that Bax activated by Kevetrin would provide an indirect means to degrade MDMX then any advantage of the stapled peptide approach of Roche/ Aileron disappears. And that might occur without the combo therapy described in the quote but by the use of K by itself if the Bax expression CTIX has noted is significant enough to do the job. But this is speculative on my part as there is no direct quote from CTIX regarding any effect on MDMX.
To me it is obvious which approach holds more promise and that is where I have put my money. It would seem even a less robust activation of P53 partially inhibited by the lack of downregulation of MDMX is better than no defense against an oncogenic mutated P53 which will only buy some time before resistance and recurrence. So CTIX is the most advanced candidate and, in my opinion, has an important advantage that outweighs the MDMX issue.
For what it is worth. My degree in biology is 40 years old - a time I refer to as the "pre-genetic era" LOL. Still, I like this stuff and my conclusion favoring K is what I take from delving into the science of the two different approaches. But you can draw your own conclusions.
