008 - My Theory, page-2

008 - MY THEORY - PART 2

In part 1 we had a basic introduction to biomarkers and cytokines, this sets us up to explore more about the relevance of 008 and what it is exactly trying to determine. Why indeed have a separate trial/study?


THE SPIRIT OF 008

Well we can ascertain the idea behind 008 from the R&D Day, from what Paul and others at PAR have said already...and the important study itself as defined in the ANZCTR site.The crux is that it is a study to observe the effects of iPPS in the synovium, specifically looking at a prescribed set of biomarkers along with the usual endpoints such as Pain and Function.

The spirit of 008 is multi factored according to how I see it:

1) It sets up a link between what's taking place WITHIN the joint as opposed to perhaps more secondary evidence as to what's happening in the serum (read: blood stream).This link is vital as it will illustrate scientifically the bridge between the two areas and provide insight as to how iPPS acts within the joint.

2) Associating what's happening in the joint can lead to a broader label or at least provide initial evidence to document that there is a case here for further exploration. This cannot be done as part of 002/003.

3) 008 will provide evidence as to the possible DMOAD effects...if successful, we will have a situation where we don't just get:

Reduction in.5 pain

Increase in function

Durability

But in some cases we hope to see that it is slowing....halting or even in some cases reversing the course of the disease for the very first time. This is the diamond embed in the gold vein.



A BIT MORE ON THE BIOMARKERS

Biomarkers indeed give us clues as to what's happening in the body. There was a study that found that in a sample population that had Knee OA: "Patients with the inflammatory ‘IL-1β PBL signature’ had higher pain scores, decreased function, and higher risk of radiographic progression." ⁹ In other words, there are definite links, a definite correlation between these biomarkers and the underlying OA.

Paradigmers, you now get what biomarkers are and we can couple it with what 008 is trying to do...let's take this up a fraction by another example involving the activity that is going on in an OA sufferers joint. Take a look at the following supergraph...it's a string plot, what it aims to do is show the interrelationships between some of these cytokines and the interplay in terms of OA ^9.5 :






_{String Plot chart of selected biomarkers.}



In the above depiction you can notice the circles (biomarkers) that are more heavily involved in the pathophysiology of OA...MMP3 is a critical one so is TIMP1...What I want to pester (a bit like those persistent Mozzies you get at the beach sometimes of an evening) is the question, ARE THESE KEY BIO MARKERS BEING studied in 008?


The answer is a resounding YES. This is the science part that will make the cross over into the business part...ie the share price one day in the future (my views). Now we start to understand the biology in terms of OA is so much greater in the synovium...This is the next question, HOW much is it greater in the synovium compared to the serum, let's investigate.

So we now know that MMP3 seems to play a somewhat central role within the joint of an OA sufferer...but is the prevalence significant? How does it compare with the serum...is it detectable in any kinda meaningful numbers?

Hmmm ...make sure you are sitting for this next one...remember back in PART 1 we did a (fun) Mozz Quiz and I told you about how COMP has a somewhat (21 odd times) increase in the synovial fluid as compared to the serum in an OA patient?

What then is the prevalence of this MMP3 biomarker ...ie how many more times is it typically present in the synovium compared to the serum. If at this point your guess is more than 21 times then well done, you are right and you get a Mozz Gold star sticker...But did you guess that it could be anywhere near a 100 fold increase? If you did...you are still underestimating the potential....

Seven Hundred and Thirty Eight times.

Let me write that in figures for mainly the benefit of my pal Oxxa who loves his numbers, 738 times!


Mate.What does this even mean? This means that the activity of biochemistry as I started this very post off with a quote from Dr D Felson within the synovium compared to the serum is like comparing a candle to a volcano.

It's incredible.

Paradigmers, this is the violence that is taking place within the joint when it comes to OA destruction. It's off the charts. The pain is real...the solution is coming.

In case you forgot, go check that string plot, didn't MMP3 play a central role? It's another clue for us....we know the prevalence is up there...I want to see by how much this MMP3 falls by...now MMP3 isn't specifically mentioned as one of the observable biomarkers in the 008 ANZCTR study) though there is a definite caveat in the ANZCTR site that says that there may be other biomarkers that get observed....another is TIMP, which not only has a greater central role (see string plot diagram above) but it is specifically mentioned as one of the to-be observed biomarkers in the 008 trial.





WHAT I WANT TO SEE

Paradigmers, we have at least some research that delves into some important biomarkers like MMP3, these are important because

1) They feature so heavily in the patient of OA as well as RA
2) There is a lot of unique actions occurring within the joint (as opposed to the serum)
3) We know there is an interaction of iPPS in this process...to address it directly and to cause others to address it....and to assist...


SO Mozz, what do you want to see....that's an easy one...I want the observed biomarkers as stated in the ANZCTR site to be an interplay between other such studies...I initially kinda hoped that the percentage reduction would be somewhat greater than 11.9%...I no longer think that that is the be all and end all...its more a broader fall in more biomarkers that would appease me...the good news is that there is already some evidence of DMOAD out there...and we will further touch on this point in Part 3.



In Part 3 we will also cover a remarkable fact of timing. It's in part 3 where I make this personal...I will give you my own thoughts on 008....