Innovation Pharmaceuticals Inc (IPIX)

[Orion Nebula]

Musings from the rabbit hole...

Last posted on this board at end of October when I went down the rabbit hole in response to some back and forth posts between TruthbyThought, Ardhee and myself. In the interim I have kept up with all the posts here but decided to stick to my probings of the science at the expense of a public mulling over of the slow decline in the PPS on the board. It was plain to me I had nothing to add to those discussions as all relevant points appeared analyzed thoroughly by others. Looks as if the decline is over and we can all hope for good times ahead. Go CTIX!

At the time of my last postings I was wrapped up in the beauty and complexity of what is involved with K and specifically the advantage of K vis a vis all the work done by Roche (nutlins) and the MDM2 and MDMX pathways. I was surprised to see today that Whoops remembered that old post so it inspired me to provide a little info on what I have been looking at since then.

As expected the rabbit hole led to Wonderland as there are amazing things being done in the battle against cancer. TruthbyThought, who has been conspicuously absent during the same period of my absence , surfaced for one cryptic post a couple weeks ago. He made an oblique reference to a drug of a competitor, which is easily identifiable and is a heat shock protein 90 inhibitor (Hsp 90). Heat shock proteins are increased in their expression by stress and by increases in temperature.

This is important to all here as K is also an Hsp 90 inhibitor and it is advantageous to know what the competition is doing. I probably have not identified all competitors of K on the Hsp 90 side of things but I have identified 15 drugs targeting this pathway. The trial of one of them was discontinued recently due to an inability to meet targeted endpoints. I have posted before that Hsp 90 is the pathway whereby mutant p53 is degraded - a mechanism of great importance as mutant p53 is the most common cause of the recurrence of cancer and eventual patient demise.

To back up for a moment - there are multiple pathways involved with K. At least two involve wild type p53 to repair cell damage or cause the cell to undergo either cell cycle arrest at the G protein receptor or apoptosis. Drug companies often target G protein receptor sites.

On this board there is always a lot of excitement surrounding whether p21 has been activated, which would indicate promising results along the p53 pathways, e.g., cell cycle arrest at G protein receptor 1. The CTIX poster presentations also note PUMA (p53 Upregulated Modulator of Apoptosis) as a pathway leading to apoptosis.

I have been poking around in the other pathway - the mutant p53 pathway involving Hsp90, which, in my view, is every bit as important as the cell cycle arrest and apoptotic pathways. I emphasize this importance for three reasons : 1) There are at least 15 drugs targeting the Hsp 90 pathway alone (Big Pharma and small biotech companies are all over this) and there are some amazing late human trial results even without any benefit of a positive effect on the wild type p53 pathway. These results are likely due to the already noted lethal nature and oncogenic potential of mutant p53 2) Dr. Menon, Leo and the poster presentations have emphasized both the wt p53 and mut p53/Hsp 90 pathways. 3) Hsp 90 is an attractive target because there are several oncologic clients of Hsp 90 (K has been shown to have potential with some of these oncologic clients such as mutant breast and pancreatic cancer cell lines). So this is an interesting part of Wonderland.

Kevetrin counts in both the Hsp 90/mutp53 and MDM2/p53 camps and, as far as I know, the targeting of both wt p53 and mut p53/Hsp 90 is unique to K. Hence, it remains my view this may prove to be the most important key to any competitive advantage of K as it winds its way through clinical trials.

Many publications make it clear that the Hsp 90 chaperone is the chief culprit when it comes to the stabilization of mutant p53. Consider this quote from a paper of a competing drug candidate:

"Mutant p53 (mutp53) cancers are surprisingly dependent on their hyperstable mutp53 protein for survival, identifying mutp53 as a potentially significant clinical target. However, exploration of effective small molecule therapies targeting mutp53 has barely begun. Mutp53 hyperstabilization, a hallmark of p53 mutation, is cancer cell-specific and due to massive upregulation of the Hsp90 chaperone machinery during malignant transformation.We recently showed that stable complex formation between Hsp90 and its mutp53 client inhibits E3 ligases MDM2 and CHIP, causing mutp53 stabilization."

The ASCO poster from June 2013 states that K "induced degradation of mutant p53 mediated by reactivation of MDM2 E3 ligase". This is a key mechanism as one can deduce from the quote of the competing drug candidate noted above. In other words, K, like the competing drug, is able to overcome mutant p53 stabilization and it does so by overcoming the inhibition of MDM2. The weakness of the other drug and its ilk is the lack of any effect on wt p53.

I think one reason we hear more about the MDM2/p53 pathway is the p21 marker was identified as a marker for the study. There are several reasons I suspect it is not as clear cut on the Hsp90 side of things: the Hsp 90/mutant p53 pathway is quite involved and I sense markers are not well understood as of yet; as if it is not enough for p53 to mutate there is also a propensity for Hsp 90 itself to mutate and become resistant to particular drugs; the tendency for Hsp 90 inhibition to activate other cancer survival mechanisms through Hsp 70 and Hsp 27 and possibly HSF-1 transcription factor, which is a key regulator of both Hsp 90 and Hsp 70 (all of these proteins are attractive cancer drug targets); and the fact that some of the drugs do not access the Hsp 90 of the mitochondria.

All this really leaves one in awe of how determined a foe cancer is and of the really amazing front line work being done to try to overcome cancer's incredible adaptability. As I encouraged the board some time ago - read Mukherjee's pulitzer prize winning book "The Emperor of all Maladies" and I think you will gain a new appreciation for what the Menons' of this world are up against.

I am trying to find out the ability of K to cope with these Hsp90 issues but I suspect a few more CTIX posters and presentations will be required before we know for sure. Many of these mechanisms are poorly understood as I have noted a full understanding of the pharmacokinetics of Hsp 90 seems to be lacking with many of the drugs targeting this pathway. It is complicated. About now in Wonderland the Red Queen has approached and -oops - is off with my head!

So for now that is about all I have discovered about the Hsp 90 side of things but I am still running into strange creatures in this part of Wonderland. There are a bunch of them here. I haven't even started to look at the angiogenesis pathway of K via alpha-tubulin. And there are creatures like HDAC6 , HDAC2, Akt, HAT etc. that I have only brushed up against a little bit.

So for now I am going back down the rabbit hole but I must confess I like the look of the terrain better than the last time I was up here. Things are looking up and I can't wait for the JPM conference and update. I will leave you with this:

One pill makes you larger
And one pill makes you small
And the ones Dr. Menon develops
Does wonderful things for all
Go ask Leo
Gov says he knows

And if you go
Chasing share price
You know you're going to fall
Just tell them a genius
Veterinarian
Has given you the call
Go ask Leo
He's feeling 10 feet tall

All the men on the IR Board
Get up and tell us where we'll go
And we just had a PR update
And the posters are in an uproar
Go ask Leo
Gov says he knows
When manipulation
And deception
Have fallen
We'll be millionaires
And the shorts will be buying backwards
And the red ink
Will no longer be here
Remember
What Kahuna said
Be in or dread
In or dread

Gov and BK-hope you don't mind. I did not say anything you haven't said yourselves. And I agree with both of you on those points.

If you are like me you will prefer this version...