he synovium is a thin membrane that encases some of your joints (like the knee, yeah that's the one we are studying but iPPS plays a role in all joints and remember, iPPS delivery is NOT intraarticular...it affects all joints SIMULTANEOUSLY, another big plus point for you and me).
Tonight lets explore this most amazing membrane, it's critical function and importantly what is IPPS's role? How is our drug at all linked to this membrane and the disease state known as OA.
EARLY ONSET
It is only now being realised that the inflammation of the synovium plays a central role in OA:
"It is now recognized that synovitis is common in OA, both in early and late OA and this offers a potential target for treatment, both for symptom and potential structure modification". 1.5
Not only is it common in OA patients, there are theories that suggest that OA starts in the synovium... "Biopsies from the synovium of OA knees (taken at arthroscopy for knee pain or at joint replacement) have demonstrated several key changes in the synovium, which although more pronounced in advanced OA, are present from the earliest stages of the OA process".1.6
A LOOK INTO THE SYNOVIUM
So what does this membrane do? Well a couple of important things...it keeps the layer of synovial fluid within and surrounding the joint. This allows the joint to move smoothly and be hydrated at all times...but that's not all...it also allows the joint to take on compressional biomechanical force by acting as a liquid shock absorber.
It's easy to forget about all the twisting..the turning...the weight bearing forces that all act on joints such as the knee...the heavier we are...well the more forces are involved. These forces are at play every day for our entire lives. We have to look after our joints. We so want the beautiful viscosity of this fluid to be in top notch.
Ahh the viscosity of new unadulterated oil...our engines crave it...our joints crave it...we want that pure lowered friction gliding motions of when we were all young...to have that lovely HWHA rich synovial fluid again....
After years and years of life...well the fluid gets degraded. No longer are the cells only secreting a greater percentage of the lovely Higher (molecular) Weighted Hyaluronic Acid (HWHA) ...it starts to degrade and we get some of the lower weighed HA produced. Therein lies the problem and over time the cartilage starts to splinter, harden...and fibrosis is the end result. The synovial capsule ends up having more of the LWHA and this adds to the problems.
But there is much more to be learnt and much more to be experimented.
"However our knowledge of the immuno-histochemical architecture of the synovial membrane, particularly in normal subjects, is surprisingly limited".2
What's the structure and what is it's place in a joint? Well here is a pic 3:
A closer look at the parts of a joint and where the synovial membrane fits in.
The fluid in the synovium acts as a lubricant....and that is the intro for one of my favourite molecules, Hyaluronic Acid (HA). But it is the higher weighted version we want...the lower weighted version is what we get more and more as we age.
It is HA that acts..."as a cushion for synovial tissue and as a reservoir of lubricant for cartilage". 2
In fact early on, it has been suggested that it is low grade of inflammation that plays a major destructive role due to "...an overspill from the inflammatory edema in synovial tissue created by increased vascular permeability".
Mozz speak? Edema means swelling, the reference of vascular permeability means excessive blood flow into the synovium, literally bleeding through.To get more information on this I looked up one of the many papers by Dr Peter Ghosh. It's quite a read and it would be a task of several separate Mozz posts just to cover this one paper titled "Vascular mechanisms in osteoarthritis". So important this paper is, that I'm referring it to as my main reference for this post even though my title is really to cover the Synovium. (See the ref section below).
Ok so let's go to the Ghosh paper.
Paradigmers, friends, fellow investors. I often ask you...do we know what we own? The science here just keeps giving...
Gosh coins it like this: " We suggest that the progression of early cartilage fibrillation to symptomatic OA arises initially as a consequence of the release into synovial fluid of cartilage-derived antigens that activate joint lining macrophages and circulating leukocytes, thereby establishing a synovitis". 1
What then is the next step in the process?
"Pro-inflammatory mediators and pro-coagulant factors etc. not only perpetuate cartilage destruction but also promote a state of hypercoagulation, hypofibrinolysis, thrombosis and ischaemic bone necrosis at compromised sites such as in the subchondral vasculature".1
What does all that mean...it means destruction is abound!
Hypercoagulation - too much blood clotting.
Hypofibrinolysis - remember the word here is HYPO (not hyper). This can be thought of as the state of NOT being able to break down blood clots. Yes we need there to be a balance here, we need blood clotting in wound repair...but too little or too much is bad either way. Too little and you could get blockages of the arteries for instance...that can cause strokes at the extreme. Too little? Well that would result in excessive bleeding!
Thrombosis 4 is what occurs when the blood clots block the veins or arteries.
Necrosis - you don't want to really ever see this word...it means death of cells or even entire organs dying due to lack of blood supply.
Necrosis - you don't want to really ever see this word...it means death of cells or even entire organs due to lack of blood supply.
Professor Ghosh goes on to suggest that increase in lipid (fats) deposits and excessive coagulation are the hallmark signs that early OA is in progress. He goes further and purports that hypertension (higher blood pressure) also plays a role here.
"Venous stasis and hypertension associate with thrombosis, lipid emboli and bone necrosis of variable extent have been shown to be relatively early histological features of OA joints".1
CASCADE
Mate, the cascading nature of inflammation would take me weeks to cover, it's an entire massive darned complex process....want a taste?
Ok here is a pic 5:
Ask Dr Ravi Krishnan (Par's CSO), he knows this like the back of his hand. One day I promise I will get to know this better...high level still, but will know it better.
But guess what, that's only the half of it...there is a mechanical side too. Inflammation of the synovial plays a central role. Just take a look at the below diagram to get an idea of how and what goes on in these two areas of Mechanical destructive pathways and Immune mediated pathways6:
THE ROLE OF iPPS
I know what a few of you are thinking, Gee Mozz, the sci is good, I get that feeling...but what and when will this translate to my share price going up, not down?
Ok well bare with me for a bit longer and you will get a sense of where this is going...
While more is still being learnt on how iPPS plays a role in OA, a lot has been discovered recently. We get a sense of this in the data that has been published and is yet to come.
As we have seen the production of HWHA is one of the key ways iPPS works, PAR produced this chart below to give a sense that the production of HA should come from within...merely injecting it directly into the joint is kinda like taking a soup if vitamins and injecting it straight in...is it going to work? Is it going to be effective? Maybe a little, but it needs to be absorbed and at least partly naturally produced.
There is nothing like natural production.
You just can't beat it.
Here is a slide PAR produced last year...
Look at that long 12 month durational trail...finally it is this that the Big P partner wants....DURATION! They want to know that the drug they distribute and effectively pay us for LASTS...and lasts....yeah think of the energiser bunny, we don't want to have to replace the batteries every few weeks...we want the POWER to go for months....and months....I certainly don't want to have to poke myself, even if it is subcutaneously, more often than not.
HA AS A BIOMARKER
So we want the HWHA right?This also means that you detect LWHA in your synovium and OA is building.
Where am I getting that from? Well there is a peer review on it.7
They state it like this:
Results: Levels of ln serum HA were positively associated with all definitions of radiographic OA (P < 0.0001). Levels of ln serum HA were higher in Caucasians (P = 0.0094) and in men (P = 0.0038) and were moderately correlated with age (r = 0.35, P < 0.0001). The associations with radiographic OA, ethnicity, sex, and age remained statistically significant after adjustment (P < 0.0045). There were no interactions between ethnicity and the other covariates.
Conclusion: These cross-sectional data support a role for serum HA as a biomarker of radiographic OA. The variations in levels of serum HA attributable to ethnicity, sex, and age were not explained by radiographic OA, BMI, or comorbidities. The lack of strong confounding between serum HA and comorbidities further supports a role for serum HA as a potential biomarker.
BRINGING IT HOME
It's one thing to read the theory...always good to see the practical applications of this....I'll give you four applications of evidence and from varying sources.
BODY OF EVIDENCE - 1
Going back to the Ghosh Paper, Ghosh reported that the synovial cells such as the fibroblasts are charged with the secretions of HWHA...restore their activity and you will end up with a better synovial fluid content ...take a read at this quote:
"Moreover, the biosynthesis of high-MW hyaluronan by synovial fibroblasts, which is diminished in OA joints, was restored when these cells were incubated with NaPPS in vitro or after its intra-articular injection into joints of patients with OA". 8
BODY OF EVIDENCE - 2
Rats
So remember back to Peter Ghosh...he postulates that hypertension is also a leading cause in the onset of OA. Well we also know that iPPS is an anti-inflammatory. The relevance here is that iPPS plays a direct role but it also has an indirect pathway too, it reduces hypertensions via addressing the inflammation that may subsist in the kidneys, bring that down and you bring down blood pressure.
Mozz Speak it. For that, we need to cross over to another study that investigated specially, Pentosan's role on blood pressure, that is hypertension in rats. This was the conclusion, it's quite a read! Its Sci heavy but I'll do my best to Mozz speak it...
"This study suggests that inflammatory processes contribute to hypertensive renal microvascular dysfunction manifested as blunted pressure-mediated vasoconstriction and reduced microvascular reactivity to P2X1 receptor activation in this hypertensive model. The results of this study provide compelling evidence that anti-inflammatory intervention with PPS confers significant renal protection against the decline of renal autoregulation and this is associated with improved reactivity to P2X1 receptor stimulation in ANG II-infused hypertensive rats". 3
Confers significant renal protection I would suggest this is the key statement in the above statement.
Mozz Speak, what the above is saying is: : 1) Inflammation is bad...well chronic inflammation is bad...which means ongoing, never ending....acute inflammation however, is REQUIRED. Other drugs that have failed in assisting OA in the past have failed because they BLOCKED ALL INFLAMMATION. This is **so** not what we need.
Downregulation is key here....if you meet me in the street, sure, say 'Hi Mozz'...but then drop the word downregulate as you knowingly smile. You will make my week.
2) Dag nab it....the above is saying that blood pressure is a main culprit here, address that and you have something! I am working on a post (one of a few) that concentrates on fats...it's role in boosting the rates of OA....now again, I'm not saying remove that layer of cheese in your burger...I'm saying watch those lipids!...More on this in a future Mozz post! Those that have followed me for sometime will understand what iPPS can do for your blood pressure...new guys, read Body of evidence 3.
3) I mean c'mon guys, seriously, what out there gives you significant renal protection that's devoid of serious AE's? Aren't your kidneys the ultimate required filters? So bl**dy important that we don't have one..we have two...
Isn't it like a redundant feature..a bit like this:
Not one but two...sure we need two ...but its not impossible that we can function on one. Isn't it the same with kidneys? Interested in learning more here about iPPS and kidneys and how it is really relevant? I'll post it after this post below.
Getting back to that quote above, I know some of you like to see this graphically rather than words....
Look at the hammering down effect that PPS has on normalising TGF-B1 levels back to normal!
You simply bring down the hypertension and the flow on effect can be to increase blood supply....increase that and you are back in the business of feeding vital nutrients throughout the micro fibres of the bone and surrounding tissues.
You keep the synovial membrane healthy with an increase supply of blood and again nutrients go in, waste comes out, everyone is happy!
BODY OF EVIDENCE 3
Rats are a good start Mozz, can we go up the living animal pecking order tree?
What about humans...someone that's close to us in HC land?
"After 15 months pain starts to comeback a bit gets second course of treatment, in one month back to normal. Now after 11 months better than ever no pain at all even when walking up stairs no sinus pain and after having high blood pressure for 10 years its 120 over 80".
Pain relief we know about Function improvement lovely, but we know about this too...
But the thing that caught my eye was BP.
This was new...this was unseen previously...this was prolific....this to me as an INVESTOR is MULTIPLE LAYERS OF GROWTH AND FUTURE REVENUE.
Not saying next year...I AM saying in 5 years.
(Spec statement, no one knows when or if this play will come into fruition, DYOR)
Hamman's wife had blood pressure and was on blood pressure tablets all that time, ten years. She went in for iPPS under SAS for her knee...and she came out with not only benefits of the knee...but her blood pressure NORMALISED!
No more BP tablets for her.
@hamman an update if you can...please tell us how your wife is doing now, some 6 plus years after her first dose.....is she still off the blood pressure tablets...? Once you are on those, you are on those for LIFE! How's the pain levels? What is her feeling of the future prospects for PAR and iPPS?
BODY of EVIDENCE 4
Ok Mozz you've shown us some evidence in the rats...then we heard about some evidence from a fellow poster...how about some evidence relating directly to Synovial inflammation then?
This was released recently and as far as I know, was the first comprehensive documentation of iPPS's direct effect on an inflamed synovium. This is the evidence that is the exciting first step for us. I am a patient investor, I know that super duper evidence here doesn't mean we are all going to be partying on a yacht somewhere in the Mediterranean in a month's time.
Yeah nah..but if we crack $100 ...well all bets are on! Side note: You know that MRNA stock went from $62 USD to $430 USD plus with a year right?
In tabular form:
The beauty of this data is that it is in combination with a number of measures both structural as well as the wet biomarkers. All of this not over years but a mere 6 months. To get this improvement as an average is stunning.
In the December edition of the OARSI magazine Osteoarthritis and Cartilage,9 the editorial suggests that "Synovitis is now well recognised as part of the pathophysiology of posttraumatic osteoarthritis (PTOA). Chronic synovial inflammation that does not resolve is not only well documented in clinical imaging and histopathological studies of OA and PTOA but is now also associated with driving joint pain and the multifaceted disease processes in the joint".
It indeed p
lays a major role in OA and addressing it via other interventions to date has not been successful. We are at the tail end of our clinical trial program, get through that successfully and indeed we could finally have a safe and effective drug that not only addresses synovitis but tackles OA itself, head on.
DYOR
PS:
Mozz story. I went to Oarsi in 2023...
The day before they had a separate Clinical Trial Symposium. Around 11 competitors presented their individual solutions/drugs/trials. There were three of them that I counted that mentioned that they would've loved to have done a synovial fluid effusion as part of their studies and checked out the biomarkers but they did not.
We were the only ones that did this.
We are the only ones that weren't intraarticular.
In Oarsi 2024 it will be the first time that we will be presenting the full 12 month data set of our 008 program to our peers.
he synovium is a thin membrane that encases some of your joints (like the knee, yeah that's the one we are studying but iPPS plays a role in all joints and remember, iPPS delivery is NOT intraarticular...it affects all joints SIMULTANEOUSLY, another big plus point for you and me).
Hypercoagulation - too much blood clotting.
Hypofibrinolysis - remember the word here is HYPO (not hyper). This can be thought of as the state of NOT being able to break down blood clots. Yes we need there to be a balance here, we need blood clotting in wound repair...but too little or too much is bad either way. Too little and you could get blockages of the arteries for instance...that can cause strokes at the extreme. Too little? Well that would result in excessive bleeding!
Thrombosis 4 is what occurs when the blood clots block the veins or arteries.
Necrosis - you don't want to really ever see this word...it means death of cells or even entire organs dying due to lack of blood supply.
Necrosis - you don't want to really ever see this word...it means death of cells or even entire organs due to lack of blood supply.
The day before they had a separate Clinical Trial Symposium. Around 11 competitors presented their individual solutions/drugs/trials. There were three of them that I counted that mentioned that they would've loved to have done a synovial fluid effusion as part of their studies and checked out the biomarkers but they did not.
(20min delay)
