The PhD - NO and the DMOAD magic of iPPS

The PhD - NO and the DMOAD magic of iPPS... PART 1




ecently I came across some more research involving our Magic Juice...It's a very involved and in depth report from Japan. Tonight I break this report down somewhat. I want to get you slowly into the science mood with our R&D just some 9 days away. This paper attracted me because of two reasons:

1) It is a pHD discourse that has the wordDMOADin it's title and of course pertains heavily to iPPS.


2) It was conducted by a contending Doctor from the university of Hokkaido. Why is this special? Because that's located in a city called Sapporo and I do like the beer that has the same title..(specially in the can, bottle is ok, but the cans are great!).


_{Cheers! Great beer, from the same place as the guy I'm basing this post off!}



In truth to really do justice to this PhD paper, I would need to break it into multiple parts, so comprehensive it is. But I while I do my best to Mozzify^®it (simplify it) I endeavour to limit this across just two parts. Those of you that are super keen to thoroughly investigate, do at least flick through the Japanese paper, duly linked in Reference 1 (see Part 2 for references). This will be a long post, so again, I implore you to get comfy, take your time to read this as there is a fair bit in it and I will try not to make it too heavy (yes primarily for your benefit, but more so for MINE!).

A sciency warning for sure, perhaps quite timely in light of our upcoming inaugural R&D Day. I understand this can get a little boring for some but if you can tough it out and endure it, I think you will enjoy it all the same. As with any research any of us provide, please do your own checking, I'm not a scientist, I don't often wear a white lab coat and those science glasses (though admittedly I do own some and I have mowed my lawn with those on in the past, only the backyard), I'm just interpreting the info as I see it and simplifying it as I come across it forourbenefit . In doing so there could be errors. Always best to...well you know, DYOR.



PROLOGUE

Paradigmers, I cannot sit still when it comes to PAR. I thirst for more....I know there are periods of time when nothing happens, nothing is visible, there are no announcements...there doesn't seem to be much happening...but you know what, LOTS is happening. We have much on the radar. The folks at PAR HQ are busy, very busy...they are not idle....to this day I'm impressed with the staff, as I said I was disappointed last year at the AGM I didn't make it to all of the staff...I could very easily have 30 min conversations with each and every one of them....to ask them of their story, to ask them how excited they are...to learn more about their role...

When I have a vested interest I am curious to know how it works. I have given the car analogy many times before....it is NOT enough for me to hear the footballers and the average citizens say that they feel better. I WANT THEHOW....I want theWHY. I really do not care how much science jargon they throw at me, I will take each word at a time and disseminate and extract the meaning . When I am an informed investor....I am in a different and much higher position. I can plan...I can derisk it in my mind and granted things can still go wrong (and get delayed *wince*)...but I'm at a different level of awareness.

PAR brethren, I strive to keep your momentum going. I want you to hold long term (not advice)...yes I understand it is boring...it is a long term play and perhaps a little longer than we initially expected...Don't give up....there can be both negative and positive surprises and OA, though it is a long slog, isn'tthe only thing we are tackling and in my express opinion, we should be able to garner revenue from MPS/TGA etc.beforethe P3 OA trial is done.

I really do believe that if you can just wait it out...and I'm not unfortunately talking months here...I am really talking years...at least four years. Five is better...however long you can keep them shares, will in my express views, be valuable. Not unlike APT...going form $7 to $100...not unlike MRNA..going from $26 (when it first came on Mozz's radar it was $26....to $156.93 USD at the time of me writing this.. and that was just 8 months ago! Yes I missed APT really...(does 55 shares current holding, count? That all that I have left *pout*). I made a little on MRNA...maybe a few sets of new tyres, certainly no new car!

PAR I will not miss...and neither should you. I'm not saying to go nuts and back up the truck, I am saying to get a meaningful exposure without being silly and WITH you still being able to sleep each and every night...what does that mean? I mean that if a disaster were to happen you could survive and you don't need to ever pass the hat around.



INTRODUCTION


The PhD presents a very good summation for OA and the associated workings of the disease. The emphasis is on dogs for this particular paper. There are a couple of good papers out there, this is one of them. Ok curious about the subject of this post? Yes we will get to what the random "NO" means...

In case there are any new guys to us..DMOAD stands for Disease Modifying Osteoarthritis Drug, and nope, there to date, is no such thing. For the first time I came across the prevalence percentage of OA in dogs...if you met me down the street and randomly asked me what % of dogs suffer OA I would've guessed 10%...The paper reports it as some 20% of dogs after just 1 year of age. It further gives us an insight on OA in horses suggesting the incidence is pegged at around 13.9%.

In Humans? Well we know some 3 million officially Aussies have it...Australia's' population is now 25 mil...getting out my trusty calc (I have bought one that can handle TENS of Billions specifically to cater for PAR's potential long term revenue (my views - oh hush legal dept)) that computes to be 3/25 = 12%. Hmm Mother nature is consistent isn't she?


_{None of these mere 8 digit calcs - 12 Digit required tool at Mozz HQ's...one day I will use this device to calculate our revenue...do not laugh, $100 a share IS possible!}




In the intro the PhD paper depicts OA as a "primary disease of joint cartilage" but the incidence of abnormal stresses on the joints also plays a significant part in the incidence. The Intro further goes on to succiecnelty state that the disease "not only affects articular cartilage but also involves the entire joint including the subchondral bone, ligaments, capsule, synovial membrane and menisci although a common feature in all OA and related disorders is loss of articular cartilage in association with bone features such as osteophyte and subchondral bone sclerosis". Yes as Paul Rennie just recently mentioned at the AGM and Evercore presentation, this is not a one symptom and not a one factor disease. There is much at play here and it required a multi faceted approach. A drug targeting a specific biomarker has not to date proven successful. We need a more broad based acting agent to go up against the carnage that OA inflicts.

Mozz, I get the Japanese Study part ...and the DMOAD aspect...but what's all this about "NO", was that a typo? Yes sorry for the confusion, I'll get to "NO" and what exactly this means soon and how I'm not necessarily losing the plot...


WORKINGS of iPPS


Ok so we know iPPS acts on multiple fronts in multiple ways...but one of the beaut things it brings to the table is the fact that it buys time for the articular cartilage to self-renew and repair itself. Current remedies only attempt to alleviate discomfort, merely and feebly attempting to tricking the body to quash some pain. The body is smart and automatically compensates by growing extra sensors to further detect pain and alert itself into action. No wonder the current of std simply works less and less effectively over time.

What is the point of putting a band aid over a bullet wound.....you ain't treating it..you aren't promoting healing. "However, these interventions do not alter the underlying pathophysiological process on the structural degradation of joint tissue". IPPS increases blood flow...it addresses pain via NGF...it allows for more nutrients...white blood cells...macrophages and a whole heap of other aids to be involved and delivered directly to where it is needed. It is here where more data..more analysis and research will be conducted and peer reviewed so we have an even better understanding of how these workings are at play.

So in Mozz words there are three levels we need to act on:

1) STYMIE further destruction
2) ALLOW for the body to heal itself
3) PROMOTE and ENCOURAGE the rejuvenation process with an 'active' but fundamentally natural drug.


A true DMOAD takes on all three...this is not just a band aid...this has the potential to stop AND possibly to reverse the disease. A separate trial to investigate this DMOAD property is inevitable...let me tell you here and now, that trial, if it shows officially even a small % of DMOAD ability, it will be another world for us.

My friend, Violin1? Pirate Day 2027 we actually might just hire out a cruiser, a fit and proper Pirate Ship indeed.



BALANCE

The paper then goes on to importantly state exactly how I have viewed the DMOAD properties of our Magic Juice...the allowing for the body's regeneration process to be encouraged to work ...this is articulated well in the following paragraph that is a citation from another source: "Cartilage tissue degeneration leading to OA occurs when the equilibrium between breakdown and repair of the joint tissues becomes unbalanced (Alcaraz et al., 2010)".²

Paradigmers...it is the equilibrium, this balance that is allowed to work as a direct consequence of the action of iPPS...It gives the body a chance to repair...to rebuild...there is nothing on the market like this....and whose mode of action is fundamentally safe (subject to P3, my views).The imbalance, as the article goes on to describe is the "cytokine cascades and the production of inflammatory mediators". It is iPPS that can handle the inflammation and is charged with the responsibility of reduction of the same in a safe fashion.


CYTOKINES

I always assumed cytokines are some sort of biological production ...kinda like a swarm of bees...released for some purpose.


_{Mate, something out of a sci-fi movie perhaps, can you believe this stuff is inside us?}



I didn't realise there are a few sub classifications, some of which include Interleukins, Lymphokines, Monokines, Interferons.⁴The challenge for PAR next year is to get through a good chunk of the phase 3......the challenge for me next year, it to come up with some meaningful interpretation of all of these cytokines and what it all means and Mozzify^® it. (Dumb-it-down). These all linked to the pathogenesis of OA.


RISK FACTORS

The paper then goes on to state the increased risk factors for OA:

1) Age
2) Joint trauma
3) Altered bio mechanics
4) Obesity

The paper states that after a period of degeneration, it becomes self-perpetuating. I have stated this fact much earlier on n a HC post, some 50% of sporting injuries lead to OA after 10 years. The Japanese paper states it in this way: "In some cases, the initial process may be a mild injury to a collateral ligament and these tend to recover fully, but the associated cartilage damage results in clinical disease of the joint years later."

It is the joint degenerating over time possibly due to the inflammatory process. This is just one way iPPS addresses and halts this destruction.


LET'S ADDRESS THIS PROPERLY

The so called current standard of care whether it be Opioids or NSAIDS or even Corticosteroids, merely focus on pain relief and the paper states "these interventions do not alter the underlying pathophysiological process on the structural degradation of joint tissue but merely control signs of pain and inflammation". Yes they control pain...yes they have some effect on inflammation but they result in problems.

My interpretation of the problems are:

1) The pain relief is limited (hardly 15%)
2) They have nasty side effects....one of them (eg corticosteroids) is the further destruction of Cartilage!
3) They can be addictive (eg Opioids).
4) They are band-aid treatments and do NOT address the underlying issues.

We want and have a solution that can assist in the altering of the underlying pathophysiological processes. The paper does refer to the study conducted by Dr Ghosh along with Sunaga et al.⁵ who was one of the research papers mentioned by Paul in the last NWR seminar in regards to a mouse model study...The paper then points to a study conducted to investigate the action of PPS on various cytokines and the conclusion was that the "protein expression was significantly abrogated by PPS" and further "The findings of this study demonstrated for the first time that PPS is a novel inhibitor of IL-1-induced iNOS, c-Jun, and HIF-1α mRNA up regulation and iNOS protein induction which may be beneficial for prevention and treatment OA."

One of the tell tale signs of OA is the presence of a gas known as Nitrous Oxide (NO). This is a gas produced by the enzymes that break the cartilage down. OK so the PhD paper then goes on to investigate the effects of PPS and evaluate its chondro inductive potential to restore and promote chondrogenesis of cBMSCs . WHO? Mozz you lost me. Mozz Speak? Simply, they wanted to investigate PPS's ability to to repair cartilage tissue and repair of OA related cartilage lesions. Yep. the whole DMOAD concept.

Now don't forget, to date, out there in the market...out there in the known world, there is nothing to date that has this property.



SO NO, IS GOOD?

HOLD ON MOZZ...NO ISGOOD! Well yes, NO in itself is good...but guess what? Too much NO, like a lot of things in life...is BAD...I mean real bad...How bad? Let me tell you.

Too much NO can lead to the following: ^5.5

• 
  
• It may cause headache in migraine.
• It may damage brain cells leading to neurodegenerative diseases like Parkinson disease, Alzheimer disease, Huntington disease and amyotrophiclateralsclerosis.

Ok great Mozz, gotta hand it to you...I understand that NO is a gas, we need some, but too much is bad...but what does it have to do with my PAR shares? Ah well Paradigmers, here is the connection: "Of particular interest, OA chondrocytes express inducible nitric oxide synthase (iNOS) which in turn produces high concentrations of NO, especially upon stimulation by pro inflammatory cytokines".

Yes you read that right, we have another bio marker in our midst. Quote time.....again from the paper: "Importantly, the elevation of NO production appears to be an important factor in the pathophysiology of OA iPPS the Inflammatory Buster."


The paper suggests that initially you might have a relatively small injury for example, but over time if not addressed this can lead to ongoing inflammation and this is where it becomes potentially serious and OA sets in, the joint degenerates due "continuing insult from the inflammatory process". In chorus with Paul, the paper states clearly "OA should therefore, not be thought of as a single disease, but rather as the clinical endpoint of numerous disorders leading to the eventual failure of one or more joints of the body". Paul and even Donna both deliberately highlighted this multifactorial nature of the disease and gave us clear examples of recent failures (GLP 1972) that attempted to address just one biomarker, one part of the disease and failed. Our war-game is so different, we fire a missile with multi war heads....we already have seen the evidence of just how well it works and the FDA and EMA will soon be witness to these workings for themselves. (My opinions).

STUDIES AND RESULTS

Ok so this PhD paper refers to the same researcher Paul mentioned in the AGM, namely Sunaga et al. from back in 2012 and of course Dr Ghosh's work. I enjoyed reading how this papers expresses the findings: "PPS has been shown to be involved in prevention of inflammatory intracellular responses...and preservation of cartilage integrity by supporting chondrocyte anabolic activities, including biosynthesis of aggrecan and suppression of catabolic MMPs". Why don't we Mozzify this a little. What they have found in the past is that PPS helps in the production of aggrecan. What is this? It's basically a hydrated gel structure⁷, vital in load bearing joints.



At the same time, a bit like the Yin and Yang in that it promotes the positive activity and ALSO suppresses the negative, it had a hand in the suppression of catabolic MMP's. MMP's are basically enzymes that are responsible in assisting wound repairs, quite important where there is cartilage destruction at play. Ok so the focus for the PhD paper was trying to determine if there is any merit of PPS as a DMOAD and the production of NO was a central phenotype that was looked into.


STUDY 1

In the first study this paper covered, the purpose of the experiment was to take three dogs and to "investigate the inhibitory effects of pentosan polysulfate (PPS) on IL-1β-induced iNOS, c-Jun and hypoxia inducible factor-alpha (HIF-α) isoforms upregulation in canine articular chondrocytes". *whew* a sciencey way of saying they wanted to research and investigate IF iPPS can prevent and at least reduce this NO production which we know too much of is a result of OA processes.

What was done? Chondrocytes were isolated and cultured from femoral head cartilages of three dogs. They then used varying levels of iPPS, namely 0, 1, 5, 15 and 40 μg/mL of PPS .Yes Paradigmers, effectively a kinda dosing regime that PAR will also go through perhaps with different amounts in the dosing study set to commence sometime next year.

Great Mozz...take me to the results. Sure...listen to this and I will quote from the paper itself as I just can't do justice and attempt to express it in Mozz words....: "The findings of this study demonstrated for the first time that PPS is a novel inhibitor of IL-1-induced iNOS, c-Jun, and HIF-1α mRNA upregulation and iNOS protein induction which may be beneficial for prevention and treatment OA."

"As consistently observed, a combination of rcIL-1β + rcTNF-α + LPS significantly induced iNOS protein expression but pre incubation of chondrocytes with PPS significantly abrogated iNOS protein induction hence proving the inhibitory effects of PPS on both iNOS mRNA and protein expression."

Paradigmers....fundamentally this stuff works...another biomarker like COMP...like ADAMTS -5 is being addressed.....there is scientific evidence out there....you just need to scratch a little under the surface.



This concludes part 1.

Part 2 in addition to considering just 6 ways in which iPPS works, we will further investigate more of the paper and rather than just reading more words, we will view a picture that really is worth 1000 words while observing the power and the underlying processes by which iPPS actually conducts it's magic.