h tonight I give you a super special...a Mozz post on Biomarkers...

h tonight I give you a super special...

a Mozz post on Biomarkers but not just a deep science dive...nah we go practical.

Yes there will be a bit of sciency waffle but don't forget the bonus at the end...it's a paragraph I reckon you won't want to miss!



A little of this sciency stuff....


But we also want some of this investability analysis stuff...






Please as always, do now enjoy!




BIOMARKER - INTRO

Biomarkers are basically indicators or measurements. They can be quite insightful and can show us how a disease for instance, is progressing. They can give us clues as to whether a therapeutic intervention is having a positive or negative effect on these pathological processes and states.

Honing in a little more specifically on OA, we now know that OA is all encompassing. But it is a multifaceted disease comprising of inflammation, degradation but also lack of repair. Take a look at this definition:


"It is now apparent that OA is a disease of joint tissue degradation as well as inadequate joint tissue reparative response. The ability to measure both degradation and synthesis of a joint tissue component is therefore expected to provide a more accurate indication of the trajectory of disease in an individual than either type of indicator alone".²


Yes it is this trajectory that we are interested in. Joint Space Width and physical joint structures like cartilage morphology and presence of BMLS are all important but the biomarkers lend weight and they can be observed at a granular level often giving us inference much before the total failure of a joint!

Biomarkers equals important and valuable information?

Yeah I would think so!



THE 012 STUDY - A BIOMARKER BREAKDOWN

Recently we saw Clincial.gov website finally include our 012 (thanks again @strangelogic ) protocols and the program.

But guys, these biomarkers they are including, certainly aren't random. A heck of a lot of work has gone into which ones to include and why. Note: it is also stated that these aren't an exhaustive list.

Let's now take a closer look at these and what it means for us, why am I remaining just so enthused about our play though we go for months without much news at times!






The above biomarkers in our 012. I've colour coded them and numbered them which relate to the points below.


But guys, what are these, what's the relevance and what will the data be like?

Well of course I don't know how the data is going to pan out, yeah? But I do have some good darned clues that might assist with our confidence.

Let's tackle them now:







- COMP

This is one biomarker we have some exemplary evidence on, so far.
It was the 005 study where this biomarker shone brightly.

A quick flashback? Why not.

It was back in late August 2019 ³ that we got the COMP analysis, how about this statement:


"Among subjects with symptomatic knee OA, a single measurement of increased COMP predicted subsequent cartilage loss on MRI".



Ok a good marker to start with....results?
You bet...take a gander:



"Cartilage degradation measured by the detection of Cartilage Oligomeric Matrix Protein (COMP) in serum showed a mean percentage reduction of 11.9% from baseline at Day 1 to Day 53 in the iPPS treatment group..."


Yeah nice, we got a reduction, but what reduction did Placebo achieve?

They didn't.


What?

They didn't get a reduction!

You mean not at all??
Nope...

THEY WENT THE OTHER WAY!...

Here is the rest of that quote from above...(my red emphasis added)


"... in contrast to a mean percentage increase of 2.1% in placebo".


Let's see this graphically:





I like when our data does well, I like it better when the placebo cohort GOES THE OPPOSITE WAY.
It's a sure sign that the placebo cohort is continuing on the path of total internal destruction.

A gentle reminder ....the above was measured in just n = 112 (each cohort = 56).

Our brand new shiny 012 upcoming study?

n = 466


We are powered by a patient number factor of 4 compared to 005 numbers.





- ARGS

Now I have at least one major post in the past just covering ARGS. I will post this at the end of this post for those that haven't read it.

Aggrecan is a valuable molecule. What does it do? Its a load bearing molecule. Its gives the vital properties that we need to... well, hold ourselves up. If my body is struggling, it's Aggrecan that I want to strengthen, to fortify. OUR iPPS does this.

So ARGS is another cartilage breakdown biomarker:


"ARGS and COMP are both thought to reflect cartilage degradation, and ARGS is even used as a pharmacodynamic marker in the therapeutic development of OA drugs".⁴





- CRAC1

When I first read this biomarker in the 012 protocols a big smile spread across my face. My Mozz Green flags lit up in me (crazy) brain and I thought of one of the pre eminent scientists in the field. Dr Virginia Kraus. It was in one of her papers that she co-authored. The below extract from her paper:


" CRAC1 demonstrated the highest odds (OR 2.014, 95% CI [0.996, 4.296], p = 0.058) for predicting OA progression in the adjusted multivariable Model 3. This indicates that a 1 standard deviation increase in CRAC1(170-178) was associated with twice the likelihood of JSN progression".⁵


Let me just repeat that, a one std deviation increase in this biomarker, results in double the chance of your Joint space narrowing. Peoples, we do not want our joint space to narrow.





- PRO-C2


This biomarker is a relatively new one to me. It identifies the reverse, not so much prevalent cartilage destruction, but more on the other side, ie LACK of cartilage repair.


"This suggests that low cartilage repair capacity, assessed by markers such as PRO-C2 and PIIANP, is a risk factor for OA".⁶






- PIIBNP


A few quick definitions before we tackle this one.

HOMEOSTASIS = A state of balance required for our bodies to stay alive and function.
CATABOLISM = Is the breakdown of complex molecules. This results in the release of energy and simpler molecules.



ANABOLISM = As you would think, this is the opposite of catabolism. It's the building of more complex structures with some energy storage built in.

Right, let's tackle PIIBNP


"As singular molecular entities, fibrillar collagens are particularly well suited as indicators of tissue homeostasis and joint remodeling because biomarkers of both catabolism and anabolism exist for these collagen. For instance, such biomarkers are available for type II collagen (PIIANP, PIIBNP, CTXII) used in OA research".²


It's an interesting one as it's predominantly located in the extracellular matrix of the superficial and deep zones and chondrocytes in both normal and osteoarthritic articular cartilage. In the human cartilage explants model, levels of PIIBNP, but not PIIANP and C2M, were increased (2 to 7-fold) time-dependently in response to IGF-1.

Yeah it's gets a little technical, IGF-1 is an insulin like growth factor, its required for anabolic growth which promotes growth on bones and tissues. In other words, Mozz Speak, it's a good one to study to see how iPPS reacts and it's effect on PIIBNP. Find excess presence of this one in the serum (blood without clotting component) and you could be a candidate for OA.






- NTX-1

Another newbie to the Mozz list.

This little marker is used to measure Bone Resorption. Resorption is destruction of the bone into smaller bits, ie decreasing the mass of the bone. Now this in itself is a natural process and it promotes new bone to be produced, in other words, turning it over. The problem occurs when resorption is too much and you actually lose bone faster than it gets made! (This also reminds me of high inflammation, too many alarm bells going off, not enough addressing of the fire of inflammation and what it is telling us that something (eg. structures) are getting destroyed). This leads to a whole host of problems but bone fragility and increased risk of fractures/breakage prevails.

See pic below:⁹







NTX-1 is a bone resorption marker. It stands for N-terminal cross-linked fragment of type I collagen generated by cathepsin K during osteoclastic bone resorption.¹⁰





- HA

Hey, they left my fave till last...

HA is a key component and the production of the higher weighted blend that substitutes out the lower weighted is of particular interest.
We saw this vividly in PAR's pivotal canine study.


Oooh yeah, a quick reminder of the canine study?





Wait a minute Mozz, I got you here, it's a big flaw. Look at that chart, HA is coming DOWN? Isn't that a bad thing? Didn't you say HA is your fave molecule and you want MORE of it?


Maybe PAR has made a typo?


Nah, the problem is that when I say HA is one of my fave molecules., I mean the Higher Weighted Blend (HWHA).

We want LESS of the Lower Weighted (LWHA), and more of the Higher.

As we age, our cells in the synovial layer produce more of the LWHA. The lower is a poor substitute for the real good oil (HWHA). It's lower in viscoelasticity. It's lower in Biomechanical load assistance...it's lower in that lovely lubricating fluidity and water retention of the surrounds...and it's much lower in terms of what we want as living organisms AND investing individuals! (See I told you this would be practical). iPPS changes this and we produce more of the HWHA.

So when we see that HA is getting increased in the bloodstream just like that orange bar of the placebo group at Week 26 in the canines in the above chart, this is bad!
The active group had a great result as they went the opposite way and HA reduced (the lower weighted version).


I believe in this PAR canine study that this was the first time we saw Effect Sizes being published, indeed it was a nice change to see these measures, take a peek at this table:




Large effect sizes at Week 26?

Now remember, this in canines is the human equivalent of not one year, but 3 years.

No wonder these pets are getting such prolific responses from Catrophen and Pentosan Gold.

Wait till the humans catch on.

As a quick aside, A lot of these biomarkers work together, here is an example I came across while researching for this post:


"HA is the backbone by which aggrecan binds to in cartilage and contributes to the viscoelastic properties of synovial fluid".²


HA assists aggrecan as a combination. iPPS stimulates HWHA which in turns assists Aggrecan which in turn reduces ARGS.




CONCLUSION

Hey Mozz, seriously, I don't mind some of your optimistic flare but really, PIIBNP this and PRO-C2 that, does anyone in the investing fraternity really give an iota about any of these scientific jargon biomakers or biomarkers or whatever you call them?

Well...err...yeah

These are the indicators that scientifically we have something to show us that iPPS makes a positive change...

Pain coming down is of course the Primary.

Function improvement has to go in tow.

Safety trumps all.

Durability is delightful...

And exclusivity of manufacture and lack of any competition will drive home our investment.

But behind the scenes biomarkers will show the future partners just how much level'ed up we are going to be for them. We aint competing with no Nurofen....this isn't a Panadol arena we find ourselves in.


They haven't even as yet invented the stadium we are going to perform in one day...

There is no drug to date that can change the course of the OA disease. There is nothing that rescinds OSTEOPHYTES. But even bigger than that, there is no solution no pharmacological agent that reduces BMLS so quickly.


To achieve these structural events, to gain BACK cartilage in 6 months for any subset of the OA population has not been witnessed before.Those markers above...they are going to tell us NEXT YEAR just what a powerful drug YOU own.

So another point to add here...we aren't YEARS away...remember, normally a Phase three study comprises of a few THOUSAND patients, we have 466. Once we get going...well, we will speed through it.






ERR ...MOZZ DID YOU FORGET?

The bonus! Nah of course, how can I forget the Mozz Bonus ®....it's a big one and prob warrants it's own post.

But while excitedly (yeah I have no life right? I actually went out on the town last night, it was so much fun, my voice is a bit huskier today though) reading the 012 protocols I did a double take when I read this line:






See that red box above? That caused me eyes to pop.

Whuh?
What did I just read?



Who put that statement there?



PAR did.



Isn't that SLIGHTLY presumptuous?


No, it isn't.



FOR A POTENTIAL EARLY CONCLUSION???



Helllloooo did anyone read that??


Mate. That's a crazy big bonus.




There really is a chance that at interim we will get much lower p values on multiple endpoints. Stattically we have shown this already in 005 and 008...and even in a few ancillary trials and studies (think RRV for instance and Ghosh's work).

Do this on enough endpoints in 012 and there is a chance, I don't know what probability, but there is a CHANCE of early trial conclusion.


Get an "early conclusion" and it's some time maybe end of next year we really could go quite absolutely berzerko in terms of share price (not advice).

For PAR to actually put that in print on their protocols...well to me, that's a bread crumb on the way to that Gingerbread Nirvana House full of future share price goody delight.








Yum!




- Mozz






DYOR recommended, personal and speculative views often expressed.






REFERENCES

MAIN REFERENCE

1] https://clinicaltrials.gov/study/NCT06917404


OTHER REFERENCES

2] https://www.sciencedirect.com/science/article/pii/S1063458421008839
3] https://app.sharelinktechnologies.com/announcement/asx/1801a407c6bff2b2200d2ab1a15c7259
4] https://pmc.ncbi.nlm.nih.gov/articles/PMC10598037/5] https://pmc.ncbi.nlm.nih.gov/articles/PMC10726242/
6] https://journals.lww.com/co-rheumatology/fulltext/2022/01000/blood_and_urine_biomarkers_in_osteoarthritis___an.10.aspx
7] https://vbn.aau.dk/en/publications/a-novel-high-sensitivity-type-ii-collagen-blood-based-biomarker-p
8] https://d-nb.info/116393903X/34
9] https://pgblazer.com/factors-influencing-bone-remodelling/
10] https://www.sciencedirect.com/science/article/pii/S1063458421008839