The Clearly Congruent Canine Compedium

onight Mozz has gone not to the dogs but WITH the dogs...yes its a cheerfully cunning canine curriculum!





On the 1st of June we got our final readout.

Sure Mozz, I get it, the dogs got some good efficacy, hip hip hooray...(or should that be knee knee hooray?). But c'mon man, this pales into insignificance, we really don't care so much about the canine cohort, the pooch parade the doggie division ...its human results we need, its human results we want.


Not quite true.


Tonight we will see what the data said to us and perhaps just how this data set may assist and how pivotal this program could actually be.
Please do now enjoy!






Twenty One client owned dogs were taken in a study of iPPS to investigate the efficacy of Pentosan in terms of naturally occurring OA. The dogs had either front or hind limb OA and were randomised in a 2:1 ratio into an active and placebo groupings.

Three key measures were to be investigated:


i) Joint function as measured by percentage body weight distribution (BWD%) in the affected limb as measured by the TPI%.

ii) Biomarkers of joint degeneration within the synovial fluid and in serum; and

iii) Structural changes determined by OA clinical scores as assessed by X-ray and MRI.


The dosing was the human equivalent of 3mg/kg weekly for 6 weeks.

After 8 weeks the results were as follows:


7 out of 9 dogs had clinically meaningful improvement in the affected limb.

A mean 5% is considered the clinically meaningful hurdle to cross in terms of improvement from baseline in TPI%.



_{Did we jump the minimal clinical meaningful hurdle?}


You bet! Dog on!

"A mean percentage change (improvement) from baseline in TPI% of 10.08% was observed for the affected hind limb (n=5) and 5.6% for the affected front limb (n=4)". ¹

TPI stands for total pressure index.

The other observation at this 8 weeks stage involved Aggrecan degradation (ARG) which is the human equivalent of ARGS. These levels were reduced in the synovial joint of 3 out of 4 dogs.

The other observable was that Hyaluronic acid (HA) from the degrading cartilage matrix was reduced in 4 out of 4 dogs into their synovium..HA has been coined as "nature’s moisturizer".²







Wait a sec....

Mozz, did you say that HA was reduced by iPPS?!I got you now Mozz...that's not a good thing...I remember you saying that iPPS STIMULATES the production of this vital shock absorber...this vital oil, in fact it was YOU who said that it assists the vital tissues to keep them hydrated! I got you now for sure Mozz:




_{Mozz is caught out, there is a gross inconsistency! The above statement is a very BAD observable!? Where are the Nay Sayers, they will have a field day with this.....won't they?}





Not quite.


Yes we do want HA production and we want this produced NATURALLY...we don't want external HA injections directly into the knee, others have tried it, its not great and can lead to infections at the site and other undesirable knock on effects. Yes we do want increased levels of HA into the tissues, and into the synovium...but here is the explanation for why observing that the levels of HA into the synovium FELL in our canine study and how is that a good thing??


As we get older the cells produce lower and lower molecular weighted HA...we want the Higher weighted stuff...think of it as varying grades of oil, we want the super oil, the oils we produce when we are younger. As we get older the cartilage matrix degrades and gets older and the result is a bit like an old grapefruit juice, not so sweet.


_{Fresh! We too will be all smiles when we have the Higher Weighted HA oil blend! More natural hydration - Less pain, more function...Where do I sign up? See Appendix A for more on HA.}


Guys, it is iPPS that stimulates the production of HA, be it directly or indirectly, re vitalising the matrix and ensuring that the blend of HA, the higher molecular good stuff is produced and THAT is diffused naturally into the synovium and surrounding tissues, keeping them hydrated and fresh. Its the higher weighted blend of this magically natural oil that stimulates the production of fibrocytes³.

What are these little beautifies (fibrocytes)? They are the cells responsible for producing vital collagen following things such as injury, during disease and that comes with aging. Collagen is the structural tissues predominantly present in the body's connective tissues. Yeah, kinda important, its also kinda prevalent, some 30% of your body's proteins are in fact, collagen! Collagen is the single most abundant protein in our body.⁴


Mozz, lots of words there, yeah time for a pic to give you the real feel for what higher weight HA does compared to the lower weight in terms of these fibrocytes...⁵




Mate, these are the charts that are coming across my table...

Look at those lines diverging...the HMWHA results in a stark increase of fibrocytes....this in turn increases collagen, this in turn helps the structured matrix of fibres...and this improves our Musculoskeletal system. Voila

When I am older...I want this. I'm not trying to necessarily prolong my life...What I am trying to ensure is that I have less aches and pains and I can continue walking, and enjoying life and visiting places relatively pain free and relatively function enhanced. If I can get this naturally and most importantly, safely....well you cant keep a good dog down.

As a final observation at the 8 week time point we saw the tell-tail (thought u'd like that one) cytokines of CTX-I and CTX-II which are collagen fragmentations....

6 out of 9 dogs had lower levels of CTX-I and 4 out of 9 had reduced levels of CTX-II.



THE OBSERVATIONS




On the 1st of June this year Paradigm released the announcement of the completion of the 26 week canine study in canines. A couple of high level statements caught my eye, namely:

iPPS was shown to stabilise disease progression at week 8 and week 26 in osteoarthritic dogs

This means that the disease progression did not continue unabated. There has been no drug that can do this to date, ever.


"iPPS favourably regulates serum levels of molecular biomarkers CTX-1, HA, and TIMP-1 at week 8 and week 26 in osteoarthritic dogs. The observed biomarker data changes support the proposed PPS mechanisms of action".


This statement alerts us to the fact that the drug continues to work from week 8 through to week 26. remember, this is three full years of human equivalence. The drug has long since cleared from the tissues...its having a profound knock on effect. Paradigm also stated that the observations back up the MOA, this gives the regulators an important and required insight into the MOA.



"The canine study provides consistent supporting evidence which mirror the improvements in clinical outcomes previously reported from the phase 2 PARA_OA_008 Day 168 results".



This statement forms a link between the 008 human study and the canine observations. We need to establish this link for a point I will get to later in this post.




OH BUT YOU CAN TEACH AN OLD DOG NEW TRICKS




.These charts below prove it... you really can not only teach an older dog new tricks, you will be able to make her/him run better, function better and be in a whole lot less pain, you will literally change her mind set and she will be less stressed and in a better position to learn these new tricks...

I saw this chart on the day of the announcement and I only had a proper second pass just the other day, it was then I was determined to post this...

So when I first was in receipt of the announcement, I saw this:

Figure 1 - What Mozz quickly glanced at, first pass...


What I saw was the two lovely blue columns of iPPS and the two orangey columns of placebo and I saw that iPPS trumps Placebo and I swiftly moved on....



BUT I'm probably slower than you folk.... This is what I saw and read the SECOND TIME ROUND:




Figure 2 What Mozz digested the second time round.


What's the difference? The difference is that not only iPPS trumped Placebo...but look at the , here is the operative word....TREND

Placebo is getting worse over time (See my green arrow above)...BUT active is getting BETTER (red arrow above)....To really spell it out to you....iPPS's effect even after a...

F U L L

T H R E E

Y E A R S

L A T E R

...it is trending away and is still improving... while the placebo group continues to deteriorate as a (mean) cohort)... the active group is diverging and separating at an increased pace over time. Don't forget, that iPPS has long since cleared from the tissues....that's the exciting part...iPPS has, and is, doing its work, its changing the progression, changing the course of the underlying disease.





Remarkable.




Now I have to preface the next statement with a disclaimer, while it is a true statement, it is a leading statement, it only applies to me, It in no way constitutes financial advice..it is merely for illustrative purposes.

The next chart made me buy more shares. Plain and b%oody simple.

Why? It shows what's happening with Cartilage Volume...this is key...its so key...nothing in the present world does this or has this effect and is coupled with a safe profile. Cartilage volume folks is just what its all about...I have drawn a little burgundy line to show the flip to make it extra obvious...but our iPPS flipped from week 8 to 26....



The above wasn't really supposed to happen in a mere 6 months...structural ramifications take a long time... remember, no other drug has this effect, no other drug reacts this quick in the OA space.




Finally like some crazed freak-of-nature racing horse (ok dogs then) trifecta, we get these three...


Again, each and every placebo cohort for all three indicators get WORSE over time...iPPS gets BETTER in 2 out of 3 of those markers. The other thing to highlight about the below is look at the Drug Effect size...all were Large effects for iPPS at week 26.






WORKING LIKE A DOG

A simple paragraph here, PAR team are working hard...thank you for giving us such detail...I know that it makes sense to hold back a lot for the peer review...I hear that these are in the making, they take time.


When the peer reviews hit the air waves out there in the dog-eat-dog world of ours, they have a chain of events at least to some extent:


Science guys will go nuts -------> They will tell their bosses -----> Their bosses work for Large Pharma -----> Large Pharma bosses will tell their Analysts to review and report ----->The will contact PAR...if they don't? They will miss out on the chance to partner up with what I like to say is a very good future investment (my personal thoughts only).


I don't actually say its a "very good investment" anymore to my close friends and pals,...I just tell them it could be one day be the worlds biggest selling drug, all time. (Oh no...how many more disclaimers do I need to state....not advice, may not work out, be aware of risks, everything has a risk).




RUN WITH THE BIG DOGS





Mozz, I get it, I'm happy for you and for PAR, I actually don't mind some of them charts what you are showing us......but seriously, why should we care about a cohort of larger mammals like dogs...we should be concentrating on HUMANS...these are the ones we are primarily going to be selling to, we aren't a vet company you know.


Ahh my dear reader. The Dog study is highly pivotal, more so than most can imagine, its highly meaningful and it forms a key piece in our journey to the stars (sorry Pool-Head-of_Operations)....yes indeed, to be a Top Dog...we need a study like this.


Why? How?

Because dear Paradimgers there are two important reasons...




In the title of this post one of my 'C' words was congruent. To be congruent with something means to be in harmony, this is my first point here.... Dog Pathology in terms of OA is very similar to our human OA. Some researchers back in 2019 went through no less than 230 peer reviewed research and amalgamate this into one single source of knowledge. It was found that indeed Dog and Human OA pathologies are closely aligned.


"It was found that both dogs and humans share the most common areas for the development of OA; the knee, hip, shoulder and elbows. The pain experienced by both dogs and humans with OA also has a common basis, leading the researchers to believe the neurophysiology of dogs and humans is also linked".


and further...


"By compiling this knowledge into one paper, the researchers hope this review will lead to future collaborative research of OA by human and animal health experts. This ‘one medicine’ approach could unlock new treatments to improve the welfare of both animals and humans". ⁶







The second reason is that it shows the equivalence of three full human years.

Yeah Mozz I get that, durational thing....but we are doing separate duration studies anyway, aren't you a bit like a dog with a bone here?

True, we do have duration studies covered but not over three years!.

The point I'm trying to make is that it will form the piêce de résistance for a surrogate.




IN MY OPINION





Look, I'm human, maybe hard to believe sometimes I know...but I have made mistakes in the past and haven't had the patience, the sheer fortitude just to ride bumps out...I've had plays that have gone up 200%...even 2000%...but I've quickly sold out leaving nothing or virtually nothing behind to capitalise on even further increases. In this regards I want....I need the patience of Warren....Lets look at a couple of quick quotes and ideas before we get to the last dogged paragraph!





I've seen this quote above a few times before and I'm sure most of you guys have too...for me, if I have a supreme product, I see that there is a better chance of not only increasing our share price and our proposition but doing so MARKEDLY...well it makes much more sense to hold into the future...Par know this too.

They are building and building week by week. In my opinion, don't be too tempted into the dark side of impatience...there, at least to me, without it being advice, seems to be way too many benefits for this one....the force is strong with this one....there are too many application albeit in the future...there are too many patients lining up already and the evidence is strong...go re-read some of the HC testimonials we have seen in the past...I will post one of the older ones as I know there are at least 20% of you that have never seen this. (You guys have a lot of reading to do!)...




^{What is the true value of our business, perhaps not a lot yet...but that day is coming...not just one market, not just one indication.}




THE STORY




You know I love my stories...it can be about the way our Pentosan molecule bonds with others...it can be a patient story...it can be a front line story...tonight another one, I'll keep all parties duly anonymous but I was chatting to a dear friend on the phone the other day, yes a PAR holder for quite some time. I don't often get to chat to this guy, maybe once every 6 months. He is a believer for sure and has helped me quite a lot over the years. I've had the good fortune to have met him on a number of occasions, he is both a gentleman and a dear friend.Salt of the earth...but on to the story.

We will call him Mr T. Mr T is well connected, plenty of friends and a good wallop of them have pets...of those pets, a great proportion of them happen to be dogs. Mr T has been conducting a very ad hoc high level survey in his mind and he passed on to me the fact that just about ALL of the dog owners that he knows, at some stage or currently, have been using Pentosan via their vets for their dog's OA. Amazing,. In fact one such recent owner hadn't been to the vet before for his own pooch and so Mr T said "When you go to the vet ask the vet if he will be prescribing Pentosan. "Sure" his friend commented.

He came back to Mr T the other day and said "Nope, sorry. No Pentosan, it was some other product...."

Mr T asked him what it was that was prescribed...




It was called Cartrophen.⁷






(New guys to us? Cartrophen is a vet product whose chief ingredient is....wait for it.... iPPS).





_{Now there's a banner, this one on Cartrophen's web site....Imagine the day when we can have that splash up on our web site when we are officially endorsed by the authorities? What an honour that would be.}




Paradigmers, the point of this story wasn't JUST to tie it in with tonight's pooch pageantry. It was to suggest that we are getting word from the front line, we are witnessing the queues, the masses trying and enjoying our future product....all before the great tidal wave of potential global sales.


In my opinion and without it being advice....this is going to be big one day.



EVERY DOG HAS IT'S DAY








Now you guys know I'm enthusiastic about this one...but its not my words, it's Paul's. He stated it like this:

"Additionally, the canine data demonstrated that iPPS reduced cartilage degradation at the 3-year human equivalent time-point (canine 26 weeks) and improved the disease biomarker profile by reducing CTX-1 and hyaluronic acid and increasing TIMP-1 compared to placebo. Paradigm will use these canine data in our ongoing discussions with the Regulators".


It's the very last line that provides the clue. PAR will discuss this with the authorities. The entire reason and rationale for this Mozz post is to allude to the fact that the canine study is pivotal, its important and where I'm going with this can all be summarised into just one word....


That word is 'surrogate'.


The results here, the conclusion is that this evidence will act as a surrogate, a proxy meaning that it is showing us what our iPPS does over a full three years. Potentially, we don't have to just wait for an actual three year human study.

Well what I really mean is that we could start our confirmatory trial and then apply for an AA based on a surrogate that has a reasonable chance of showing a passive drug effect and that it is addressing a disease that's a serious unmet disease (OA!) and we might be allowed to start selling while the confirmatory continues. This surrogate missive alone has vast potential for us. Humour me for just a sec...


If I was a company that had a world beating drug, something not seen or used in this capacity before, complete with DMOAD connotations and symptomatic relief all while being safe *deep breath*...I would at some future point also be tempted to file an AA. But I'm conservative, I don't want to file when it's way too early...I want to file when I am armed with a suitable and decent amount of hard core data. I don't really just want to just limp over the hurdle ...I want to be that dog in the first pic at the start of this post...I want to leap...I want to fly over the hurdle...to do this I don't just need one feeble bio marker. I want several strong ones...I want them from a number of representative groups (think BIPEDS)...AND I want so much surrounding evidence that the authorities can't but give me a red hot go.

That's what I want.

I want to pass with flying colours...I want to smash it out of the park....so far you cant even retrieve the ball.


Remember the pivotal word 'surrogate'? Well don't just listen to the ol' Mozz...one random PAR poster...listen to the FDA, here are their very own words⁸:






The canine study to many holders would seem its just another proof of iPPS working its magic, it might even come across has a little ho hum for the non astute investor. But for those of us in the know....

...this is a major pivotal step in the right direction, I class it as up there with the greater 008 program. I class it in the master stroke category.







DYOR of course











APPENDIX A

I love talking about Hyaluronic Acid, I'm due for a new post on it, professing the ways it works and what iPPS does for this incredible molecule....new to us? I will include a full post on HA after this post as a recap.

Not so new to us, here is another graphic⁹ I came across illustrating just some of the benefits of this HA molecule...






APPENDIX B


The Journal of Arthritis is the article that's referred to from the Cartrophen site and is the basis for their DMOAD banner. My red box added below. Take away for me?

SIGNIFICANT IMPROVEMENTS in clinical signs and ARTICULAR CARTLIAGE HEALING...

Guys, cartilage healing...imagine the shock on the faces of the FDA managers when PAR drops those words in the upcoming discussions later this year...




Full link to above paper:

http://www.cartrophen.com/wp-content/uploads/2016/07/Pentosan-polysulfate-as-a-disease-modifier-of-cartilage-degeneration-inexperimental-osteoarthritis_Journal-of-Arthrtitis.pdf




.

APPENDIX C

Post on HC - "An additional MOA - HA" Posted 5/11/22
See next Post





APPENDIX D

Loreal -HA "This cant be true"
Posted 19/2/23

See next Post after next






APPENDIX E

Specially for those new to us .... Testimonials from HC iPPS participants
"PAR - This is my proof"

Posted 18/7/2020

Worth a read!

See next Post after next after next post!






REFERENCES

1] https://app.sharelinktechnologies.com/announcement/asx/fa31694b6b5919adc469e18a683a3c83
2] https://www.frontiersin.org/articles/10.3389/fbioe.2022.913912/full
3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8718395/#:~:text=Fibrocytes%20are%20hematopoietic%2Dderived%20cells%20that%20directly%20contribute%20to%20fibrosis,during%20disease%2C%20and%20with%20aging
4] https://my.clevelandclinic.org/health/articles/23089-collagen
5] https://journals.plos.org/plosone/article/figures?id=10.1371/journal.pone.0026078
6] https://www.rvc.ac.uk/research/news/general/rvc-identifies-links-and-similarities-between-osteoarthritis-in-dogs-and-humans-in-landmark-nature-review
7] http://www.cartrophen.com/study/studies/
8] https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program
9] https://www.frontiersin.org/articles/10.3389/fbioe.2022.913912/full
10] https://davisfunds.com/wisdom/1_warren_buffett/
11] https://www.countryliving.com/life/kids-pets/g1824/quotes-about-dogs/