The Rationale for the use of Pentosan

THE RATIONALE FOR THE USE OF PENTOSAN - PART 1
t was all the way back in 1999 that Dr Peter Ghosh wrote a most amazing eye opening paper that appeared in the Journal Seminars in Arthritis and Rheumatism. To give you an idea of how comprehensive this paper is, there are no less than 390 references in it! Tonight's two part'er is a summary of this paper. It took me the better part of three weeks to read, summarise, type and edit my high level version of it.


PROLOGUE

I am no scientist. All I try to attempt to do is to garner a better sense of the underlying science. Why? Because the more I know HOW this molecule works, the more I am buoyed and convinced that it has some merit for the ultimate patient and of course for us, as ultimate investors! Ofcourse, just because I have some basic layman's idea of HOW it works doesn't mean it will be a success! Nah, for that I need more, for example, I need to talk to the patients. But talking to them, while it does involve some phone calls, the 'real talk' that I seek is face to face. I want to see their emotions in their eyes and their body language. I have been very fortunate enough to have done this over and over again over the last 5 years.

Does this mean I can rest now and just hold this PARinvestment passively for the next few years? Probably. But you know what, thefire is lit and it's burning strongly. All I am doing is catching up on themany great scientific reports and evidence of what our drug can do,



What can come about from a little spark?


I came across the 1999 paper by the well regardedPeter Ghosh some 2 or so years ago. It is only recently that I picked it up andfinally read it comprehensively.

It definitely is quite a read. Tonight I will attemptto Mozzify ® this amazing paper to break it down somewhat into a morereadable format. I will pull out some top line statements some of which arequite simply mind blowing. Watch out for some never before seen charts (atleast I have never come across them) along with some stellar data. It's hard tobelieve this is the uncovered evidence from way back in 1999.

The science tonight is thick and heavy but it is sodarned compelling....stick with it if you can, it's quite a read. That's not aself endorsement, that's an accolade to one of the true masters, Dr PeterGhosh.


Please now, enjoy!





THE FIRST STAT


In the very opening paragraph the reader is treatedwith this stat:


"Radiological assessment of OA indicates aprevalence in middle-aged individuals of approximately 80%, and this increasesmarkedly with aging, being almost universal by the seventh decade".


Almost universal after seventhdecade?

I can break this statement downfurther:

1. Radiological assessments certainly don't pick up all cases of OA, the actual stats are no doubt higher
2. 80% is massive and imagine, he states that this increases markedly with age, from middle age, to the point of it being almost universal by the time you make it to 70 years of age.

Hello Paradigmers - this is our market and not only isit massive...there is nothing out there that can yet do what we do to attempt to address it!



REMODELLING PATHOBIOLOGY

Dr Ghosh gives us a high level overview of the typicalprogression of the disease, starting with symptomatic appearance andimpairments of function. The next stage is the observation radiologically ofjoint space narrowing due to loss of cartilage and "...extensive remodellingof subchondral bone with osteophytes". (Bony protrusions).

In the later stage of the disease the patienttypically undergoes cartilage fibrillation coupled with loss of proteoglycansand "eburnation of bone at sites of high contact stress".

White andblack arrows depict the bony lumps/protrusions, known as Osteophytes.



Let's take these three conceptsand break them down a little.


A) Cartilage Fibrillation - thisis a process where the cartilage breaks down from resilient mesh to featherystrands.². Eventually, it breaks down so much that the underlying bonecan get exposed. Here is a picture to illustrate:

Figure0 - Yellow bone part exposed, we don't want this!!!


B) Proteoglycans are proteins that have long chains of sugar(glycosaminoglycans) attached to them. Their purpose is multi fold depending onwhere they are located but some general tasks include vertebratedevelopment, maintenance, and tissue repair.³


Thisis what a typical proteoglycan consists of.⁴


C) Eburnation refers to the picture (See Figure 0 above), think of this asthat lovely gliding smooth top surface eroding away and then the yellow part ofthe raw bone gets exposed.



Getting back to the pathology of the disease of OA, the next step ofdisintegration consists of denuded cartilage (completely eroded) and theimmature woven bone is exposed. Now the marrow spaces of the bone often becomeengorged with lipids and cholesterol as well as fibrin deposits. This impedesblood flow and finally results in death of the bone cells. Look, you don't haveto be a scholar in investiture and have a Mozz to explain to you tounderstand that if we have a drug that is going to slow down or even reversecell death, it's going to be a wanted drug.MORE DAMAGE?

Sure, what is left after bone cells dying? Oh it continues... Cartilagefragments play further havoc, they are released into the synovial fluid causingirritation and an inflammatory response results. Synovitis takes place and becomeschronic. Once established, alteration of the metabolism of the synoviocytesoccurs, Paradigmers, it is the synoviocyte cells that are the major source of hyaluronan in the synovial fluid.

Now the effect of this is lack of not only fluidity but the degradation of the elasto mechanical property of the fluid and surrounding cavity. This in turn causes further damage and loss offunction as you are losing the ability of fluidation, nourishment as well aslack of flexion. We are continuously losing the concentration of HA along withthe higher molecular weighted HA. (High to low). We are getting closer to endstage of the entire joint.
"Thisdilution of HY and reduction in its molecular weight due to abnormal synthesisby synoviocytes results in a decrease in the viscoelasticity of synovial fluidand thus it's ability to lubricate and protect articular cartilage".


As a result of the changes, Macrophages along with leukocytes that have enteredinto the synovial cavity also instigate cytokines and the inflammatory responsebecomes chronic.

Further destruction is then prevalent into the cartilage and extracellularmatrix and down regulation of collagen synthesis, we are in a hapless situationin this constant cycle of increasing destruction.
Indeed we need an agent to break this vicious cycle.



Whenit comes to inflammation, this is one cycle we must break.

"Failure of cartilage and bone in OA has the potential to both initiateand sustain disease progression by a variety of interrelated pathways. InFigure 1, an attempt has been made to represent these routes diagrammatically,and although this schema is an oversimplification of a complex and evolvingparadigm, it serves to highlight potential sites for pharmacologicalintervention in OA".

Nowyou are in a Mozz post, I don't just want to take the super document by Dr Ghosh andrehash it. You are all capable of reading it for yourselves. I wantto embellish. I want this to be a dynamic doc, incorporating Ghosh'sbrilliant ground work and super imposing some of PAR's latest work and ofcourse the work by others...Let's just do that now to the above Figure 1. I've added numeric labels to reference potential areas iPPS can play a role toaddress each "potential site for pharmacological intervention".



Thebelow are Mozz Notes ^© collated from various PAR and other studies.


1. Decrease HA size
Now here is a great place to start, we know that iPPS stimulates thehigher weighted version of HA (HWHA). In doing this, it effectively replacesthe lower weighted version that is being produced by synovial cells andgradually but surely degrading the contents of the synovial capsule. Remember,it's the lovely viscus prosperities of the HWHA molecule we want to cushionthose shocks, maintain integrity of the surrounding joints and allow for theflexibility of the joint while reducing the onset of OA.


2. Cartilage breakdown
When PAR announced the results of their 008 trial it was nothing short ofstunning. We got the pivotal chart that one of the single most prognosticbiomarkers is being addressed by the iPPS molecule. Guys, CTXII increasewas not only merely halted, it was REGRESSED. And what happened in the case of thePlacebo cohort? Take a look⁶:

.


Take a look at the p values above, that, in a trial where n was 56 ! Ourupcoming P3 will have an n of some 233 ! Can you imagine what the pvalues are going to be??

Take a look also at the effects of iPPS on cartilage. Paradigmers, it isone thing to address and reduce cartilage destruction. It is quiteanother to observe an INCREASE in overall cartilage thickness, take a read⁸:



Iknow there will be a few saying that these results seem good however, whatmakes these results remarkable is that we observed structural morphologies injust 6 months, that was never expected. These aren't subjective goodie happyfeelings of some pain relief. This is physical structures of the jointbioengineering, the actual tissues, fibres and surrounds CHANGING FOR THEBETTER. Nothing known to humankind has ever produced theseresults and specially in this acutely short duration of time.


3. Activation of Leukocytes
Lowering of inflammatory response, equates to lowering of Leukocytes(Think: White Blood cells), see also reference 5 for further evidence of this.


4. Procoagulant activities
Procoagulant activities infer the blood forming clots, clumpingtogether. Now we want a blood thinner but it needs to be balanced. No point in having too much of a blood thinner like Heparin. Pentosanprovides for a nice balance, thinning it moderately, enough to get thingsmoving again but not causing excessive unwanted bleeding that creates moreproblems.


5. Vascular occlusions
A vascular occlusion is in (pardon the pun) the same vein as point 4above. DVT is one particular area of concern here. Did you know thatPentosan is prescribed for DVT? In fact a study performed some years agofound that post surgery (where incidence of DVT can be higher), in the controlgroup some 51% of patients developed DVT, but when administered with PPS, thefigure fell to 15%.


6. Inflamed synovium
Ah, again we turn to the wondrous PARA 008 study. There is no betterevidence of the comparison of what happened in terms of synovial inflammationwhen you compare to placebo and the active cohorts side by side, Thischart still causes Mozz Goosebumps. It is the raw evidence I wasdelighted with. Again I say publicly, Well done Par:

Synovitiscontinued to increase with the placebo group, it was 4% worse in just 6months. The active group reversed this. Remember, it was anobservation at just the 56 day mark. Can you imagine what the longer termstudies would be like once they actually follow the course of patients over alonger term? The separation would be prolific. It's those p valuesI would suggest would be even more mind boggling.

7. Abnormal synoviocyte metabolism
It's the synoviocytes that are responsible for ejecting the HA into the synovial capsule. But it's a two way street, they are also responsible for absorption from the joint cavity too. You want these guys to be healthy, we want them to perform normally! Bringing down inflammation here is going to assist them a lot.


Skip forward by 24 years and these are the synovial inflammation addressing results ratified by Paradigm Bio late in 2023.


8. Proteolytic enzymes
A totally separate post would be needed just to cover this area of enzyme activity where OA is concerned. In a nut shell and certainly a feeble attempt to cover such a vast topic at a high level, MMP's play a significant role in the progression of OA. Ghosh makes mention of the following statement in reference to the action of PPS on these enzymes:

"...both NaPPS and CaPPS show positiveeffects on chondrocyte metabolism but also havebeen shown to inhibit or downregulate MMP andother enzymes implicated in cartilage destruction".


NSAIDS AND THE ANTI ARTHRITIC AGENTS

The Ghosh paper then goes on to discuss some of the pathways in which NSAIDS work and their relatively high incidence of potential gastrointestinal and/or renal side effects. He then also discusses the bioavailability of the different salts of Pentosan (Sodium and Calcium).

The next point in this amazing paper is the point that the following are all anti-arthritic agents:

• sodium hyaluronate
• glycosaminoglycan sulfate ester (GAGPS)
• chondroitin sulfate

However, Pentosan is not derived from animal or bacterial sources...and "...is nottherefore a potential source of contaminating prion proteins, proteins, or phospholipids".

Ghosh then describes some of the chemistry involved, he states that PPS competes...

"...effectively with endogenous sulfated glycosaminoglycans(GAGs), such as heparin (HEP), heparan sulfate,and dermatan sulfate (DS), for the protein andcellular sites normally occupied by these GAGs".


It is a very important point as molecules such as Heparin⁹ are used to treat blood clotting but it is also to be used with caution due to its anti clotting effect, In contrast PPS is also a blood thinner but a much milder one. It is a much better substitute and is of course as we know, much more effective from a pleiotropical (more than one effect) sense.

Importantly he contrasts it with any other GAGS (Glycosaminoglycans of which PPS is a member of) by stating:

"Because GAGs are ubiquitous and play a variety ofregulatory roles in biological systems, it is notsurprising that PPS exhibits diverse pharmacologicalactivities. Its smaller molecular domain andunique molecular structure also confers specificityof action not exhibited by the larger naturallyoccurring GAGs".

Now Ghosh launches into a new sub topic, titled:

The effects of Pentosan Polysulfate on chondrocytes and the metabolism of articular cartilage.

Again it is quite a read and there is no way I can do justice to it in just one post. This topic deserves its own post!
Anyway, I will try to articulate it at a high level.

Articular cartilage consists of chondrocytes which are embedded in a hydrated gel of Proteoglycans which is in turn all entrapped in a fibrous collagen network.

*whew*

So chondrocytes we know are the cells that are responsible for cartilage production.¹⁰

This collagen matrix is very key to the entire mechanism of cartilage and it serves to resist shearing stresses, it also limits the hydration of the PGs trapped within it. You don't want too much fluid otherwise everything turns to mush (Yeah that might be more of a Mozz type statement).

Now don't forget, I'm skipping over a fair bit of detail but there are some gems contained within this one paper, take a read of this one:

So key are which would chondrocytes, that Professor Ghosh states that "In normal cartilage, chondrocytes accommodatethe mechanical and chemical demands placed on them by synthesizing an ECM most suited towithstand these demands. This biosynthetic activity is in equilibrium with the catabolism of the matrixcomponents mediated by proteinases, whose production, activation, and inhibition are carefullyregulated by the chondrocyte."

In other (Mozz) words, the more you load up...the more things change to accommodate your activities. Its for this reason why it is so important to do some exercise, but preferably not overloading and not extreme bio mechanically stressing out the joints.

He then contrasts this with a case of OA:


In OA:



There is a net loss of PG's

There is a net loss of collagen in the cartilage Extra Cellular Matrix


The MMPs now play a central role and these degrade aggrecan


Prevalence of IL-1B stimulates breakdown of aggrecan



He then hints on one of the true values of Pentosan which I believe is hidden to most.

Let me explain.

Ghosh proclaims that when OA is present it's evident that we want to arrest the surge of MMPs. So we could target them by discovering and utilising a "specific inhibitor".The problem with that is that if you completely inhibit (block!) the production of ALL MMP's you will cause bigger problems down the line. He states that "consideration also must be given to theeffects such enzyme inhibitors might have on theanabolic aspects of chondrocyte metabolism". In other words we still need to accommodate the workings of the chondrocytes and not hinder this process.


This is the problem, but luckily in the next paragraph he gives us the solution:


"Inthis regard, both NaPPS and CaPPS show positiveeffects on chondrocyte metabolism but also havebeen shown to inhibit or downregulate MMP andother enzymes implicated in cartilage destruction".



I had to highlight that quote above because I think this is one of the most profound attributes NaPPS has for us. The fact that it is such a balancer....it down regulates (not blocks)...and it allows the underlying body, to do what it's got to do.

To me, PPS is the ultimate mediator....iPPS doesn't just come in and eradicate everything....no, it does JUST enough to revert, to rescind, to allow for the body to continue what it is best at, be it produce proteins, be it to still call in some macrophages but not too many, be it to allow the blood to circulate once again but not cause it to be too antithrombotic and not cause a mess....it is the ultimate balancer.


As an example Ghosh claims that NaPPS demonstrated positive effects on chondrocyte metabolism and was also shown to down regulate MMP and other enzymes implicated in cartilage destruction.


"..it was reported that NaPPS preservedcellular activity by increasing the incorporation ofPGs into the ECM when used at concentrationsbetween 10 and 200 pg/m".

And further ...

"In contrast to NaPPS, GAGPS, whencultured under the same conditions, failed to promotethe accumulation of PG-rich matrix aroundchondrocytes".





Here ends PART 1.

Stay tuned for Part 2. It's in part 2 we cover more evidence of what our drug is capable of. We see some charts that have never ever been published in any PAR HC thread before. We will also investigate a type of surgical procedure and what iPPS can do in this procedure.
It's also in Part 2 where we don't just talk theory, blackboard kinda stuff, we go practical. What are some real life evidence of the workings of our drug and how indeed does it makes patients' lives better, reversing the course of the disease.
Finally watch out for the conclusion where we get a mighty end statement from Dr Ghosh, a real guru of scientific research specifically investigating PPS and it's amazing effect on OA.