've been an investor with PAR for some 9 years now....it's been quite a learning curve. To be quite honest with you, back in 2017 and before that I didn't even know what OA really was. I'm still learning (slow learner?).
Currently I await for the next set of (exciting!) milestones, if we get em'...well I'm gonna be bouncing off the walls even more...I tell Man from the West that once we hit oooh... I dunno, maybe $7 or so, I'm going to fly out to him business class (Maybe via Singapore or The Maldives) and share a beer. I tell Porsche Man that I need a day with him in the future (hmmmm Prob 2030?) so he can tell me what a good 'fit' for me will be, oh it's so fun to dream.
So while I wait patiently....let me post some science...more aimed for the new guys that dont know a lot about our drug and OA....please enjoy while we patiently wait....and wait.
INTRO
Historically, OA has been classified as a degenerative chronic disease that's focused on the wearing out of cartilage. But in the last 10 or so years the thinking has been greatly expanded and the boffins have worked out that wait a minute, this thing is a whole lot bigger than just cartilage wear and tear. It's all encompassing of the entire joint and surrounds. Tonight I will try and shine a little more light on this one and show you not only the mechanics but I'll relate it to what we have and how it works.
For those that are a bit over the science, I'll try and make it really easy to understand but importantly, you'll also get at least one Mozz paragraph of the direct translation into future dollars...let's go!
MECHANICS
OA starts early...it's start real small....it stems from micro fissures and micro cracks. These might be as a result of injury, it can result from poor diet or even genetic dispositions. Lack of exercise also isn't going to help and then add in higher mechanical loading due to additional kilos and then the state of OA progresses. Take a look at this fact:
One of the leading causes of OA development in younger people is:
"Having a job that requires sitting down for long periods of time (which can lead to osteoarthritis in the lower spine)".2
Move! If you have an office job, make sure you get up and walk around in between! Your cartilage needs it!
But don't for a sec think it's all focused on a single pathway. It's a really complex disease state that involves a lot of different tissues and biological processes. Over the years of reading I get a real sense that it can be observed overall at a higher bird's eye level, but it can be observed granuallry too. What I mean by that is certainly in the later stages, OA can be seen and felt symptomatically whether it be by pain, loss of function, a change in the way you naturally behave (ie limp, your gait, or how you compensate)...this can then lead to a vicious cycle, less exercise, more weight gain, more pain. less spring in your step, less deep sleep/rest and finally your enthusiasm and mental state/disposition...
But it can also be viewed granularly...I'm not talking the smallest of fissures in the articulated cartilage...I'm talking at the most basic level. Yep, the single cell. There are not only signalling concepts here, there are physical properties and ways in which the cells themselves behave differently when under the duress of OA, instigated and instigating inflammation.
Indeed the state of inflammation is quite the *clears throat* backbone of OA.
I spoke to a group of people involved in OA and OA research more than a year ago, it was a very exciting day for me as I had a mixed audience, some that knew the science really really well, and others that worked with it but had never had it explained in real, Mozz terms (err ...another way of saying BASIC!)...This is just one of the stories I told that I will now recount for you:
THE FIRE STATION
Imagine you are a firefighter, you've had your job for a year now and the big takeaway for you is drills. Over...and over...and over again!
In fact between you and me, you're a bit over it cos they do so much training ...when those alarms go off, it's not a question of having to THINK...it's a NATURAL reaction, in fact it is so drilled into you on how to react that you don't think of the steps, they come naturally! When the alarms go off, we don on our fire equipment, we make sure our helmet fits snug...we look for the big silver pole, we carefully grip and slide down it, we get into our designated spot in the fire truck and off we go.
Alarms go off, the body knows just what to do, how to react...it's a well learnt drill...
BUT...imagine one day those alarms are louder than normal...and in fact they just don't go off. This throws us...we forget our good and automatic training cos the alarms are louder and deafening and we just want to switch them off so we can get into our usual mode of what steps to take to fight fires...
Should we switch off the alarms TOTALLY? Oh no, that's not a good idea because if we do..we could forget something important.....we could totally forget about the FIRE itself!
So Unlike Tanezumab...we DO NOT WANT TO stop the alarms totally...we do not want to block out all pain sensation.
What we want is to DOWNREGULATE the alarms...quiet them down, dial them back...then we go into automatic 'fight the fire' mode once again...don on the fire protective clothes...slide down the pole, rush off and actually fight the fire, to address it properly.
This is inflammation...this is how iPPS works. It downregulates the inflammatory signals and alarms giving the body a real chance to then fight the real fire and to address and in some cases rectify the damage. You stop those alarms totally and you will have an immunosuppressant on your hands. You kill all cytokines and you will have even more problems than when we started.
The beauty of IPPS is the balance it allows the body to restore.
BUT THERE'S MORE...
Now the above would be a most excellent start...as I said, it's the backbone of the disease state. A simple example of how we got to the fire in the first place starts from the synovial membrane. It plays a key role in the beginnings of OA and in the later stages too.
Remember above, I mentioned that early OA starts small with the micro cracks...well that essentially splinters the cartilage, tiny fragments break off...it's like when there is less fluid, less nutrients, things dry out and they wear out quickly...you want the fibres to be hydrated, to be lush...to be fluidised. Remember this point, we'll come back to it.
So when things dry out and crack, you get bits of cartilage fragments...these tiny degraded particles and debris enter into the synovial fluid and that triggers irritation...that triggers inflammation.
While that's going on, you have OA manifesting in many other ways. One example is what I like to think of as the pool of nutrients supplying the cells...the science type dudes call this the ECM, extracellular matrix. I think of it as the fuel station on my long country drive...a chance for me to top up me water, go to the loo and maybe even grab a sweet treat bar of chockie goodness nutritious Apple.
Fuel Up!
The problems with OA is that it kinda raids the fuel shop and degrades the fuel quality ...once you start reducing the quality and indeed quantity of what that fuel depot stocks, you get angry customers....and that's when nasty letters are written. The biological equivalent of mucking up the fuel station is that cytokines are produced, think of these as the inflammatory proteins and signals...these are subsequently signalled and the balance is out of whack....soon you get those never ending and loud alarms and all the body can do is try and handle it as best as it can...the fire rages unabated causing further damage...you are now in a chronic inflammatory state...we call this OA.
Now all these 'letters of complaint' (cytokines), further release other proteins called metalloproteinases and inhibitors of type II collagen are produced but the worst thing is that we have cell death, not just any cells but the important chondrocytes. Now we really are incurring a faltering balance between the body being able to have a chance to repair and the ever rising destructive state.
This sad situation cumulates in further destruction of the joint, more damage of cartilage., more drying out of fibres...less nutrient supply to the vital components of the joint and less taking away of the waste ...a complete meltdown ensures the poor human (or mammal!) will no doubt pass through the Kellgren Lawrence grades of OA and finally, there is very little of the joint left and the only way out is replacement with an artificial one.
Along the way, there is plenty of pain...plenty of discomfort, loss of function less sleep and more anguish.
WHAT CAN A PATIENT DO?
Well if you get onto this early, there are a lot of options. You have mild triggers of this and you can be alerted and take corrective action.
One of the best ways (not advice, see your Health Care Professional) is to change your diet...less refined/processed foods...more natural...I'm not saying cut out all fats, oils and sugar...but follow the pyramid as best as you can3.
(Single left click above to enlarge).
Mild to moderate exercise is great, even though it's very counter institutive for most...when your knee hurts the last thing you think you should do is exercise it! I mean gentle mild to moderate non loading exercises...walking, swimming, cycling...moving....
The problem is, most ppl don't do the above, they don't have time, they don't have the incentive...they want a quick fix...a pill to get rid of the pain.
The problem is that there is no pill.
Well there are, NSAIDS, corticosteroid injections...and finally Opioids when things get really painful.
But all of those come at a cost...a dear cost, ie side effects.
ENTER THE KING
As I have mentioned, OA is all encompassing. Drug companies have found certain molecules and concoctions that can single-target certain aspects of OA. But we know OA is broad based, we know there are many components and addressing just one of them is only going to go so far. Tanezumab is the classic example where they went into the fire station whose alarms were blaring full pitch and simply disconnected them!!
This is not the solution, simply cutting the alarms totally isn't going to result in a long term viable positive fix!
What happened next? Well immediate and clinically meaningful pain relief resulted - yipee...wonderful, but the fire burnt the house to the ground, 2.8% of patients experienced RPOA - Rapid Progressive OA! It was enough for Big Brother (FDA) to stop them in their tracks and say NO to furthering their P3 trial. They were done,
This is where iPPS comes into play....
It addresses OA in so many unique and different ways that I couldn't begin to post them all and explain them all as there are so many!But a couple of main ways I can share in this post:
Remember the drying out of fibres I mentioned earlier? Well this is one of the key ways iPPS works to address this whole mess of OA. It naturally stimulates from within the production of what has to be my second favourite molecule, Higher Weighted HA (HWHA). This little baby is a star and it has such endearing properties.
The thing is that nothing stimulates it naturally...other companies have tried and do still try, to infuse it intra articularly, it is hit and miss....it causes infections sometimes, for some it does nothing. Anything injected intra articularly is going to be painful, sure local anaesthesia is available, but it's still painful...But IPPS stimulates it naturally from inside the cells and it is solely responsible for not only fluidising the fibres but iPPS stimulates meaningful amounts of HWHA in the synovial membrane which secretes it directly into the synovium itself and provides for the lovely mechanoelastic properties of the fluid to act as a shock absorber, literally cushioning the vibrations and the forces applied to the joints every time we move. It also assists to keep the subchondral cartilage slippery allowing it to glide without friction as we use our joints.
I'm sorry but HA is such a potent molecule that I need a Mozz Quiz at this point...
HOW MANY TIMES DOES HA HOLDS IT'S OWN WEIGHT IN WATER?
A) Look, I'm not a young bloke any more...I'd be happy if I could lift half my weight. So if this molecule is any good, I'd say twice it's own weight?
B) We all know it can never be answer A...I'd say 3 times its own weight?
C) 19 times?
You are all fairly good guessers if you tried C) , you are certainly close.... the answer is 1000 times.4
Ahh my beloved HA molecule, such impressive features it has, water retention just scratches the surface.
I'm talking assistance in collagen manufacture I'm talking about adding the lovely supreme viscoelasticity of the synovial fluid...the beautiful shock absorbency required to cushion shocks...
Right I know a few of you (you know who I'm talking about) may just read the Mozz Intro and the conclusion and move on....another bonus story if you managed to get this far...embedded right in the middle of this post...
MOZZ STORY TIME
I know a guy, and this guy's mate managed to get iPPS, let's call him x...we were chatting about x and how he is going on the program. X came across the HA concept and said to his pal, what the heck is all this bizzo about HA anyway?? So he explained it to x...how HA is potentially responsible for wound repair and fluidating the skin and fibres...as soon as he mentioned that, x piped up and said, before iPPS I used to have bags under my eyes...look at me now...
....the bags under me eyes are gone!
I used to not believe this stuff (L'Oréal) and think it's such marketing BS. No, I Mozz, was wrong, there are peer reviews proving it works, that's the topical version. See Ref 5 below if you want proof.
"Skin aging is also associated with loss of skin moisture. The key molecule involved in skin moisture is hyaluronan or hyaluronic acid (HA), a glycosaminoglycan (GAG) with a unique capacity to bind and retain water molecules.6HA belongs to the extracellular matrix (ECM) molecules". 5
I'm of course referring to the internal stimulation via iPPS but not so much the Lower Weighted blends that some of these cosmetic companies use...I'm talking about the real good oil...the higher weighted and the NATURALLY stimulated from within, blend. This is one of the most proficient mechanisms of action I believe that works in HFpEF...fluidating the heart wall muscles and bringing down one of the chief culprits, namely ADAMTS-4 (A Pro Inflammatory marker). But that's for another Mozz post in the future.
FURTHER DESTRUCTION
It doesn't however, end with the inflammation of the synovium, a new fact for tonight; with further extensive damage of the cartilage it allows the synovial fluid to actually enter into the subchondral bone marrow. This has the dire effect of bone marrow pseudocyst (Mozz Speak® - sacs of fluid) which "...lead to bone erosion and remodelling and the formation of osteophytes".1
Remember we had some good observations of IPPS's action on Osteophytes...Formation of these bone spurs is a sure sign of OA progression. In many patients they end up being another source of direct pain if they rub against nerves in this area.
The main paper on which this post is based on postulates that:
"... loading and disbalance may stimulate joint tissue cells to produce pro-inflammatory factors and proteases which ultimately promote OA development ".
I also have read that before, a lot of OA also manifests from malalignment, mostly naturally occurring. For example, did you know that one foot of yours is usually bigger than the other? In the same way much of the population have a slight tilt and malalignment of the bones which over time can be additive to stresses and various degrees of wear on the associated joint tissues and scaffolding structures surrounding the joints.
As I have also mentioned it's inflammation that's the key to this disease state, the paper coins it this way:
"Clinical findings showed that inflammation was present in OA well before the development of significant radiologic changes. Magnetic resonance imaging (MRI), as well as arthroscopy procedures suggested that even at the earliest stage before detectable cartilage degeneration has occurred, OA was already an inflammatory disease in progress".
Indeed inflammation plays a major role:
"Independent of any discussion whether the synovial or cartilage injury is the starting point of OA; inflammation is the first joint immune-reaction and the main cause of the OA chronic degeneration".
Synovitis is certainly an early stage culprit,
"In one histopathology report based on 70 synovial specimens obtained from arthroscopy, synovial inflammation was present in many patients with the minimal radiographic disease and, in 31% specimens, synovitis was staged as severe".
...and further...
"Although the synovial membrane is not the only tissue involved in OA-related inflammation, it seems to be a major site of initial inflammatory changes ".
STANDARD?
So what can be done to reduce inflammation then?
Well a search of common remedies point to the usual treatments, NSAIDS and Corticosteroids. Pathetic, you can't use these indefinitely, they are riddled with side effects. They may bring some pain down but the duration of effect isn't great and certainly drugs such as corticosteroids have the propensity of further destroying your cartilage!
What makes me so interested in iPPS is just how well it works and how safe it is.But now let's take a focused look at some additional granular evidence.
PAR'S OBSERVATIONS
Look, I've been following and researching giPPS for 5 straight years now...I've known the theory for some time...I've seen others reports on it, heck I even went to OARSI twice just to get a feel of the competition and ask others independent of us, are we real? Is the data I'm showing you, the expert in the field, correct?. Indeed PPS addresses inflammation but it took 008 to show it, and show it clearly. It took 008 to really document the DM connotations despite it never being powered for this! Imagine how amazing the MRI data is going to be in an upcoming P3. I mean to see these observations at scale will be something! Certainly the regulators should be very impressed. Par Investors, can you just imagine what that P3 read out would be like for us?
These next few tables and charts is the sure proof we have that the science works AND that others are surely going to learn. There will be some real latecomers, many won't invest till months from now, even years from now and they will tell their mates, "Hey Guys, Just bought me some of this Paradigm stock thingie...got it at a dip, it's so cheap just $3 a share"...(speculative example)...I dunno how many of you will be left in this stock at that future date but I will be one. I know what this thing is worth.
Ok here is a Table of all the really beaut structural observations we could hope for...I've blanked out the active....I'll reveal that soon:
Take a look at Placebo...a sad state of affairs by any way you dice it...they continued their inevitable progression of OA in most of those categories.
Overall Cartilage Thickness continues to dissipate.
You think the Overall cartilage thickness is sad....that's a great result compared to cartilage volume results.
What about the converse, are the BML's achieving at least some stability in the chorot?No...they are increasing in just 6 months!
Synovitis is at least trending the right way in the placebo group....
In fact the Placebo cohort demonstrated loss of cartilage thickness not just in a few chambers but in all medial regions at 6 months which was consistent with the natural progression of OA.Now let's see what iPPS did, did it slow down those four observations?
Right, ready for the big reveal? Most of you know this but I know there are a few new readers out there that haven't seen this or haven't focused on this....
Take a look not only how the Active performed but also the direction of the results!
Here are some image, we are literally witnessing on MRI's the Cartilage Thickness IMPROVEMENT. This has never been seen before, only our drug has shown this effect. This was not observed over two years, it occurred within just 6 months. How many know this? Not as many as you think but word will spread.
Let me tell you, there is nothing like seeing these images and the charts, take a look at the next two charts, NOT A SINGLE PLACEBO BET ACTIVE IN ANY CATEGORY on just n = 15 !!!
Mate, each and EVERY area above, Active (Blue) not only bet Placebo (Red) BUT Placebo continued to deteriorate AND active reversed!!
This in itself is pretty magnificent, now couple the above two charts with the following two facts:
1) n = 15
2) This observation was seen in only 6 months. Structural evidence like this would typically take place over much longer periods of time.
I know this, you know this...others need to know about this.
I ask you guys, please tell me what these results are going to be like when we eventually do a scaled up version of this study? Where n is in the hundreds...what will p be like? It'll take a starting of a P3 to really and finally get some decent numbers of outsiders to understand what is coming, how valuable iPPS is and what this data actually means.
Seriously, the fact that you have read to this point equates to YOU being already so much ahead of the curve...you do need patience...you do need some more time...but in my humble and speculative stance, this is going to be big, quite big...crazy big.
(Sidenote: Anyone that reads each and every post of mine will understand this: I went to Chadstone today, I went early, about 10:30am...the massive 12,000 car park was beginning to get busy, I walked past Lovisa, there were already more than ten ppl in there. This is the early clue I love...I'm seeing it with PAR...all over, everywhere. (Not advice). Lov listed 10 years ago at $2...today it is $33.20...16.6 X, ten years ...for what? Cosmetic Jewellery? With PAR I'm talking Joint failure..I'm talking acute pain..I'm talking Chronic Pain. Do the math).
FUTURE TRANSLATION
So how do I see our story unfolding from here?
I hope to one day write a manuscript of our story...it's already been quite a journey...let's see how the next few chapters unfold?
Look finally it's the data that's the catalyst for us. Yes I understand we released some really stellar data from the 008 study but that only really just came out (end of last year), it takes time to get it Peer Reviewed and to display and chat about it to others and potential partners, be it funding, distributional or otherwise. There is a lot of explaining to do, you can't just hand them over a big dossier of raw data.
If I were to step into the shoes of a BP or MP...it's these statements that I want to see:
• iPPS has the potential to change the OA treatment landscape as no approved OA drug has shown durable and meaningful improvements in pain and function at 12 months after a single course of treatment.
• iPPS could become an early intervention or first-line therapy in the OA treatment algorithm, with the potential to reduce reliance on other agents such as opioids, NSAIDs, and corticosteroids.
• This 12-month duration data provides substantial support to progress regulatory discussions with the TGA to obtain a provisional approval application for iPPS.
• Data demonstrating the ability of iPPS to reduce the use of other pain medications or OA therapies are expected to facilitate negotiations with pricing and reimbursement authorities globally.
• There are an estimated 500 million OA sufferers worldwide, with reports that up to 81% of OA sufferers are dissatisfied with current treatment options. iPPS, a non-opioid, subcutaneous injectable with 12-month durability has the potential for rapid uptake from launch as a treatment for knee OA.
• This new data demonstrating 12-month durability of iPPS forms an invaluable milestone to progress discussions with both regional and global pharmaceutical partnering companies.
It's things like both symptomatic and structural improvements, it's the pristine safety profile but it's the bonuses....the bonuses that we execute and it's patient convenience, it's durable AND it stops you from having to take those nasty painkillers. It improves your life and doesn't come at some other cost (like damage over the long term to your liver for instance). Not only that but there are more bonuses for the groups and companies that are thinking about partnering...
It works systemically (not one course of treatment PER individual joint, it addresses ALL joints at once)...as if that's not enough, it addresses inflammation, that opens a whole host of other, future indications.
I personally can't see how the Authorities could reject us outright, but you can't rely on my opinion...we need to see what they say, thankfully that shouldn't be too much longer ...but it's not impossible that there is more to'ing and fro'ing.
Once ...IF, we get a green light, we will know costs and we will know what's involved, it becomes a whole heap easier to continue convos and initiate new ones with any and all that are interested in forming some sort of alliance to help us out. Again, I reckon there will be a lot more interest when we are genuinely a Phase three company. We sorta are already, but the go ahead on the revised protocols for the P3 will seal this.
Yes it has been a long long wait to get to this point...but I genuinely believe things will move in the right direction once these next few milestones are adequately crossed.
CONCLUSION
OA is indeed a broad based disease and affects much of the population. It isn't a single targeting drug that's going to be the ultimate solution amongst a litany of failed drugs so far. We need a drug that is indeed multi acting. The FDA say it themselves. They really want a drug that doesn't just address symptomatic phenotypes, they want a drug that can make a difference structurally too. Give me all of that with an immaculate safety profile and I think we have something really quite special here, no matter what the current share price indicates.
My views expressed. No advice should be construed from this post.
've been an investor with PAR for some 9 years now....it's been quite a learning curve. To be quite honest with you, back in 2017 and before that I didn't even know what OA really was. I'm still learning (slow learner?).
(20min delay)