A most comprehensive exploratory study...

esults, well at least top line, from our wonderful 008 study should be out in about 2 months from now. No doubt a pivotal study. Its quite possible that it is this study that will lead to a raft of future exciting actions for us.

Tonight, in preparation for our top line, lets explore what this study is about and just why I rate it up there with all the fine work PAR have put together thus far.

No no not just another boring recital of our study rehashed...watch out for a teaser on the synovium and iPPS's actipon and more details on a certain heat map, not sure where you are located but I could do with a Heat Map, its just so cold in Melbourne right now.

Please now enjoy.




AIM

What is the ultimate aim of the 008 study?

"This study is designed to measure synovial fluid biomarkers indicative of the inflammation and cartilage degradation present in symptomatic knee OA, and to determine quantitative changes in individual biomarkers resulting from treatment with PPS". ¹


Yes all good Mozz, I know WHAT they aim to do...but WHY? What will it result in if the results are good?


"The results from this study will enhance understanding of the PPS mechanism of action and will provide information on the effect of PPS on joint inflammation and on the processes responsible for OA disease progression".


Just take a re-read of that statement....it will enhance the understanding of the MOA of PPS AND will give us insight on the effect of PPS on not only joint inflammation but on the processes involved in the actual disease progression. These are the two primary endpoints of this study.


But dear reader, the secondary endpoints are comprehensive as well:

• Evaluate effect of PPS on change in pain
• Evaluate effect of PPS on change in function
• Evaluate effect of PPS on change of stiffness
• Evaluate effect of PPS on quality of life
• Evaluate effect of PPS on serum biomarkers associated with inflammation
• Evaluate effect of PPS on urine biomarkers
• Evaluate effect of PPS on consumption of rescue medication
• Observe number of days of rescue medication used from Day 1 to Day 365
• Evaluate safety and tolerability of PPS Observe any Treatment Emergent AE's
• Evaluate the effect of PPS 6 months after treatment
• Evaluate PPS on serum biomarkers associated with OA disease progression

Gosh, that's a lot of evaluation. The on goings of the synovium form a key part of the progression of OA. We'll touch on this a little later in this post.



SERUM -V- SYNOVIUM

Before we take a more detailed look at what this study involves, we need some background to get a better sense of the key role of the synovium.

As a quick top level definition, think of the synovium as a thin membrane encapsulating the joint. Don't forget its not just the knee joint that has a synovium. The vast majority of joints have a synovium/synovial fluid, a few that don't include where the ribs meet the sternum and the fused bones of the skull.²


_{An example of the synovium.}³


I will come back to the synovium in much greater detail, there is much to cover in this key membrane and cavity. The action of iPPS here is remarkable.

A teaser if I may: iPPS helps to keep this membrane thin....it can actually assist to thin it out, this in turn helps these precious cells in the lining to allow more fluid to pass through to the joint cavity. In actual fact, the cells of this membrane are the ones responsible for secreting the vital lubricating fluid into this joint space.

Look after your synovium membrane, if you don't and let inflammation go unabated you will cause bleeding into the joint and further damage.⁴ The solution?

Ah ha, I'm just so happy you asked that - treat it EARLY...yes this is our cue...Prophylactic? Yeah I'm thinking that too... But this a teaser, more on this to come in another future Mozz ^® post.


Back to the Serum and Synovium...

At a higher level it is important to establish a link between the two, the serum and the synovium.



Mozz Speak ©:

Serum is just a fancy word for Blood. Technically it is bloods without the clotting material. They use a fast spinner, (80's guys, remember a ride at the show called a Gravitron, it'd spin you around and you could actually experience a little zero gravity and start crawling up the walls, [yeah nah - HR wouldn't allow it these days I reckon]) to separate the plasma part within the bloods.










We know that in the case of OA there are common traceable biomarkers that subsist in both areas. We also know that the concentration of some of these key biomarkers are many times more prevalent within the synovium. Here are a few examples:

COMP
Varies based on the KL scores of between 2 and 5 times for Medium to Severe KL grades⁵:





MMP-3


"We found consistent secretion of MMP-3 in all synovial fibroblast cultures with enormously increased levels upon cytokine stimulation. The considerable high amounts of secreted MMP-3 point to the inflamed synovium as a major source of this protease, presumably responsible for the elevated MMP-3 levels observed in OA synovial fluid".



"The results provide strong evidence for a significant impact of synovial-derived MMPs on cartilage destruction in OA. In this context, fibroblasts present in the synovial fluid appeared to play an outstanding role". ⁵

..in terms of RA, its more pronounced, again we will see this soon in the Heat Map section. Cytokines are much higher in RA patients compared to OA, take a look at this quote:


"Concentrations of MMPs in synovial fluid of patients with RA are several hundred‐fold higher than in serum".


Remember, inflammation of the synovium results in a higher chance of OA, how much?

"Synovitis confers a 9-fold greater risk of individuals presenting with painful knee OA". ⁶



THE MAP THAT IS HOT

Also possibly more commonly known as a Heat Map...⁷

This one blew me out of the water when I saw it many months ago for the first time...


Jeepers Mozz, what the heck is this Golden Red tapestry below? Is it a carpet?

Not quite...this map can be broken down into 4 distinct parts that some of you have seen before. If you haven't, the four parts are

Normal person's serum
OA Serum
OA Synovium Fluid
RA Serum
and finally RA Synovium Fluid


Mate...look at the number of cytokines on the right most side. The red indicates just how prevalent these little cytokines are, specially in RA SF...@Happell, jeepers mate, no wonder you got a lot of pain relief, please update us, please tell us how long it has been since you had pain...for the new guys to us, let us know what pain you were in pre iPPS, what you couldn't do, what happened during and after your course of iPPS and where you stand now? What are you able to do now that you just couldn't BEFORE iPPS?

Speaking of Biomarkers we are studying, here is a table I put together with a sample of them and my thoughts:



_{Left single click to enlarge the above}




THE STUDY

008 is broken into three separate groups:

PPS twice weekly: 2.0 mg/kg IBW PPS twice weekly for 6 weeks

PPS once weekly: 2.0 mg/kg IBW PPS once weekly + placebo (0.9% saline) once weekly for 6 weeks

Placebo: placebo (0.9% saline) twice weekly for 6 weeks



Hey! Did you realise that as if all those observables and endpoints isn't enough...008 also breaks down for us for the first time, a dosing of twice weekly of 2.0 mg -v- 2.0 mg just once a week!?

Don't get the meaning of that? Let me make it a bit clearer. Commercially, this is REDUCING the Cost Of Goods Potentially. Ie if the second group ONLY drops the efficacy by say 30%....we are dropping the drug dosing by a full 50%...commercially even better for the owners of the company...err that's you and me remember.

Ummm... you do own shares don't you? (Yes Ebs, that was a special message just for you).



I LOVE BONUSES

Guys, 008 in humans is going to be pretty insightful (my view), but what about a study of what's going on in a synovium within a joint over a much longer period of time... oh I dunno, like about three years?

Mozz mate and bud, we cant just sit around and wait for three years and put everything on hold can we?



Nope...we don't have to, we can rapidly accelerate the observations of three years right down to 20 weeks...how?

From one of our best friends....a dog, well a few of them...



_{Hey you! Yes you puppy-face, we need you...}


Well a group of them, the pathophysiology is similar enough to be able to record all the observations of 008....biochemically and structurally.

"The joints primarily affected by OA in humans such as the knee, hip and shoulder closely resemble the pathological changes observed in canine stifle (knee), hip and shoulder joints". (PAR announcement 21st Jan 2011).


But you know what, I'm Mozz...I don't just want to give you one bonus...I want you to have another..


Why study the synovium? Why should you or I care?
WHO cares whether we have a lot going on in the joint, isn't this story all about OA and reducing pain and increasing function?

Oh no no no no...this story, yeah this stock we have bought into...it is just so much more than pain and function....how about a heading, not from me this time....from a peer review, Now this is what I call a bonus:


"Early osteoarthritis: synovial inflammation precedes structural change". ⁸


What does this mean for us MOZZ?

The current American College of Rheumatology's categorisation for OA stated that it "... requires the presence of radiographic changes of bony enlargement or osteophyte formation" to classify a patient with OA.⁹

How about this quote:

"It is now clear that inflammation is present in OA joints well before the development of significant radiographic change".



.."The combination of sensitive imaging modalities as well as direct arthroscopic visualization has suggested that, even at its earliest stages, before visible cartilage degeneration has occurred, OA is already an inflammatory disease".



"In one study, serial arthroscopies performed on knees with symptomatic but preradiographic OA revealed a clear association between the presence of synovitis and the future development of medial cartilage loss [Ayral et al. 2005]. Studies using magnetic resonance imaging (MRI) with or without contrast enhancement have similarly suggested an association between the presence of synovitis and OA progression [Krasnokutsky et al. 2011; Felson et al. 2003; Roemer et al. 2011]. "



Guys....Synovial inflammation is a precursor to structural OA change....WE are conducting THE study to look at biomarkers within this space.Prognostic potential surrogate endpoints?


Lets wait and see.





THE LATEST

Well we just heard an update from Dr Donna Skerett, what did she say?

We got some clues here....yes we are getting some good top line data at day 56...but its prob the 6 month read out that will be even more telling. Yes we suspect (my views) that 008 will tell us that there is an effect of iPPS on the on goings within the synovium, we may (hopefully) get some feedback on some of the biomarkers...this could also give us a clue on DMOAD...but perhaps even more telling will be how the active arm stacks up against placebo over 6 months and certainly over 12...we have some waiting to do...but this will be where one of the most pivotal studies starts to shine.

How many days till end of September? Its like counting down the days till Christmas...or your Birthday (perhaps as a kid, as an adult I'm not sure I want these years to be passing so fast as they are currently doing).




_{Bahh c'mon already, when will 008 results be out Christmas be here? I'm a PAR long long term holder but I've been so patient!}




CONCLUSION


Most certainly this one study is the most comprehensive of all. Yes the N is low...but if the data is off the charts (my speculation) the P value will be hopefully low and we will be able to dissect these incredible results. Yeah we may actually have to wait for a few months after FULL read out...that's prob a good year away from now...but the prelude, the entrée, that is, top line, may indeed be quite exemplarily.


A Most comprehensive exploratory study that may just be the start of all things good?






DYOR is required.


- Mozz








REFERENCES

1] http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=381039&isReview=true
2] https://www.webmd.com/arthritis/synovial-joint-fluid-analysis
3] https://youmemindbody.com/disease-illness/The-Synovium-Synovitis-Inflammation-and-Joint-Pain
4] https://www.hog.org/handbook/article/4/18/what-is-synovitis
5] https://www.sciencedirect.com/science/article/pii/S1063458404000299
6] )https://academic.oup.com/rheumatology/article/42/1/83/1779749
7] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638313/
8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638313/