The miracles of iPPS on MPS and a super bonus., page-2

The miracles of iPPS on MPS and a super bonus. - PART 2

In PART 1 we read about biomarker evidence being reduced to near normal levels and soon 008 will add to to these inner workings (my views)....we read about a miracle of the structural integrity of cartilage being enhanced by PPS and covered the trachea and the amazing positive influence PPS can have on it ...In Part 2 we will discover more miracle material....Make sure you are sitting down for this stuff.

Please enjoy.



Functionality along with pain was a primary end point in our Phase 2B and will also feature in our upcoming (my fingers are crossed) phase III. This study also noted some amazing observations in terms of functionality, let's explore:

"Failure load and stiffness of the untreated MPS IV vertebrae also were significantly lower than those of normal vertebra, and these were slightly improved following treatment".In terms of practical functionality, the treated group of rats was compared with the untreated group on a rotarod.

What pre-tell is a rotarod?


WHAT OR WHO IS A ROTAROD?

Doesn't it sound like one of those hotted up Hot Rod cars?

Less this...



_{(Mouse model Hot-a-rod???)}


More this...


_{Mouse/rat rot-a-rod.}


A rotarod is the new equivalent to those old manual mouse round treadmill type devices...its the ultimate test if you are a mouse or a rat in terms of functionality.
The following 2 minute video describes this instrument used to compare a control group with a MPS cohort of mice.



^{...a 2 minute video explaining what a rotarod is and hows its used.}


Ok so what was the observation involving this rotaroad contraption? I think a quote from the study itself summaries it concisely:"In each of the treatment groups there was a significant improvement in the rotarod performance compared to the MPS VI rats." and further "This occurred at all speeds." Above 30 rpm the MPS VI rats could not remain on the rotating bar. This is just one of the exemplary fundamental improvement PPS delivers.


BEHAVIOURAL YES, BUT PHYSICAL?

Ok Mozz, so we know it can help in these subtle behaviour changes such as grooming and being able to hold on to this rotating drum like the thing you have just explained, but mate, Miracle is a strong word?Paradigmers, the researches here held a comprehensive study, they employed:

A) MicroCT
B) Radiographic images
C) Photographic evidence

...Before and After.....here is what they noticed....

The PPS treated MPS VI rats compared to the untreated MPS Vi rats had "significantly longer skulls and snouts".

"The skulls were also thinner following the PPS treatment".

Eye secretions that are typical in MPS rats were improved in the treated group.Here is another physical attribute, the treated group also displayed "more erect and stiffer ears".

There are no Mozz awards for Excellence here if you know what snouts and ears are made of...yes....you guessed it,


cartilage.


This is the evidence you and I have in advance. Through such scientific research papers we already know what improvements we can expect...we have read time and time again about the influence on the matrix of collagen, think tensile strength scaffolding that is the cartilage. You want more hard core evidence of this...here is more scientific evidence conducted from a study by our own Dr Ghosh.

The influence of PPS on Mesenchymal precursor cells (MPC for short) was performed,..In summary the results were:

1) A massive 38% reduction of IL-4

2) By day 5 there was an incredible 130% stimulation of Proteoglycan synthesis (The P value was a convincing P < 0.0001) !

3) Significant collagen type II deposition


In concluding Dr Gosh and the researchers plainly stated "This is the first study to demonstrate that PPS promotes MPC proliferation and chondrogenesis, offering new strategies for cartilage regeneration and repair in osteoarthritic joints".⁵
Let's continue with the Rat research observations:



IS THERE A DENTIST IN THE HOUSE?

Usually malocclusions result in mammals with MPS and this is due to "...the shift in the relationship of the maxillary and mandibular molars". Its this misalignment that prevents the natural grinding of the incisor teeth. The result of this is extra growth of the incisors and the formation of curved teeth. The result of that is trauma in the soft palate, infection and abscesses. So what role did PPS play here?

The PPS treated rats amazingly resulted in:


Greater degree of alignment between mandibular and maxillary molar


Correction of the malocclusions


Tooth mineral densities also were "significantly improved".



Not only that but "Similar skull and dentition changes were observed in all of the treated animals, indpendantly of when they were started on treatment or the duration".

Bahhhh Mozz...you are blowing my mind with malocclusion this and Maxillary that.Ok how about a pic!



Someone get me a whiteboard, an X-ray and a crayon...







Ok What the heck is this?
That top pic is a normal rat
The middle one is a rat with MPS...notice the abnormal layering of the teeth, the arrows point it out.
The bottom pic is where you and I come in....that's our PPS's effect on the MPS rat....check out the normalisation. What you are observing is PPS at work.


Ok Fine Mozz...what about the 'mineral densities' ? How can you show me that?






Tooth mineral densities were observed from microCT analysis.The first column is normal rat's teeth, white column is the Untreated MPS Rats, Grey were Rats treated with PPS a one month onwards and the final Black column were Rats treated with PPS since prenatal.

This is hard core evidence.



Next Miracle/observation?

"The nasal opening widths, which were moderately reduced in the treated rats, were normalized in the treated rats, along with a ~10% increase in nasal length".

It's one thing for PPS to alleviate pain, it's quite another thing when the word 'normalisation' appears all over the place...it truly suggests a positive momentum shift...a disease modifying aspect if you will. I often get asked, how do you filter out what the highest potential stocks are, what should I invest in. My mates at work very well know I love stocks and follow them diligently. The simple answer is a DMOAD stock. (In no way advice). Simply buy a stock that performs a miracle...Moderna was one I caught early ($29 USD...I even posted it here...what is it now? $185...yeah so what Mozz, how many decades was that over... err..14 months). That's nothing in my humble views...send me back this very post in 3 years time...I think PAR will be somewhat north of $2.27. (Only my personal opinions)


We know that the miracle of iPPS isn't concentrated to one aspect, there are a number of areas it can act simultaneously. PAR are undertaking this via the 010 trial, namely investigation of iPPS on the hip. In the same way the research on the MPS rats also affected other parts of the musculoskeletal system, namely the vertebrae. Let's check the findings:

It was observed in the MPS rats compared to normal rats,

1) Femurs in the untreated rats were approx 78% of normal
2) Trabecular Bone score (think of this as a rating or measure for bone texture or miroacrhtecural composition⁵ was around 83% of a normal rat bone reading
3) Trabecular spacing was some 125% of normal.

Paradigmers, let me quote the results of the action of your PPS:"Each of these parameters was improved in the responder group"...and further, "Trabecular thickness and tissue mineral density also were moderately reduced in the untreated MPS VI rat femurs, and improved in the responder group".

Increase in tissue mineral densities kinda does it for me. We are one of the first to understand the ramifications of this in a commercial sense. We just need time to get through the trials and then get approved...from there word of mouth, in my views, will take over. We are early. The share price is low...and though it's still a ways off....this is the time to strike. (Not advice).

This rat study uncovered a lot of incredible observations, one of which was grooming. It was found that the rats has a much smoother coat indicative of improved ability of grooming.


Next Miracle?


OXIDATIVE STRESS

Oxidative stress is a situation caused by an imbalance between the production and the accumulation of reactive oxygen species (ROS).⁶ ROS basically means an unstable molecule that contains oxygen but it can easily react with other molecules within a cell.⁷ This is bad news as it can cause damage to DNA and RNA, the basic building blocks. So important is this concept that it plays a role in the treatment of cancer, ie addressing this ROS phenomena in cells and tissues.

Let's get back to the Rats now that you have this background...here's a quote from the study:"We also report that AGEs, another class of inflammation markers that trigger oxidative stress and other damage, are elevated in the serum of MPS VI rats, and were significantly reduced by treatment".To really cement home the effect of PPS the researchers went on to state "Overall, these findings are in accordance with the known anti-inflammatory properties of PPS, and show that it is effective even in animals with GAG storage, which is known to stimulate the inflammatory response".

Paradigmers, what they are in essence saying is that PPS addresses inflammation as we have seen time and time again, but the excellent ramifications of this isn't just merely found in some % of pain relief....there are many potential benefits for the typical MPS patient. Patients in which so many dreadful and unwanted symptoms occur. Truly the the clinical supervisor in our MPS trials is going to be potentially saying a lot of similar Mozz expletives when the data starts flowing back.. My spec views.



THE ARTICULAR OVERLAP

At a high level PPS has been mooted for MPS and OA, the obvious commonality is joint pain. This study also explored this process, again best summarised by them:

"TNF-alpha, COX-2 and p38 also are components of the TLR4 signaling pathway that are normally elevated in articular chondrocytes from MPS VI animals, and each were reduced to normal in the treated rats".

They also found a similar reduction in ADAMTS-5, "Moreover, ADAMTS-5/aggrecanase-2 was decreased to normal, consistent with the elevated serum TIMP expression". This was consistent with what PAR's own Dr Krishnan and team published in 2019:





Read that underlined section again if you feel uneasy about the future....(my opinions). OUR DRUG HAS SHOWN TO PROTECT THE CARTILAGE FROM PROGRESSIVE DEGRADATION.

Yes I get goosebumps when I read that. Yes it amazes me when I see Gan_Gan's videos of the rats that have MPS, that are so lethargic, lacking the energy to hop up and see what's on the other side of the cardboard wall despite their immense and natural curiosity. We then compare it to the rats that were in the SAME situation (that had MPS) but got the PPS treatment...and we see that they are supremely active and vibrant.


THE BACKBONE OF THE RAT RESEARCH

How about we now move to the spine, how's this for a quote?

"In addition, PPS modestly restored the disc height index (disc height divided by adjacent vertebral length), disc height, torisonal NZ length and NZ apparent modulus in the spines of MPS IV rats".

NZ stands for: "The neutral zone is a region of intervertebral motion around the neutral posture where little resistance is offered by the passive spinal column". ⁸

The report goes on to state "These changes are suggestive of improved spinal instability, which is a critical problem in MPS patients that lead to spinal stenosis and cord compression".

Mate, I'm no scientist, I've never pretended to be one...but the science here is overwhelming. I do not know of a drug that can have any percentage modification of a spine or vertebrae or cartilage and that can do it safely. If YOU know of something that can do this you need to post it in this here thread.



There are entire paragraphs of evidence, I'll summarise them as there is so much material:

• Improvements observed in vertebral failure loads
• Improvement in vertebral stiffness
• Improvements were observed in torsional biomechanics which was suggestive of improved collagen integrity

The above amazing observations all tell a story of just how the PPS treated rats and mice were able to have such improved mobility and again be able to stand on their hind legs and peer out over the cardboard thresholds, to be able to perform so much better on the Rotarods and yes, have improved overall health and abilities.



THE STARLING REVELATION OF MOTILITY

First a definition, Motility according to the Collins English dictionary is the ability to move spontaneously and independently.⁹ Again, I can not state it better than the researchers themselves: "One of the most striking and significant clinical observations in all of the treated rats was the effect on motility".

The most interesting part of this is that the researchers concluded that the micro effects observed through the research (eg the Micro CT data, the observations of small improvements in disc space etc did NOT strongly correlate with these modest improvements. The researches postulated that there was ONE SINGLE factor that the PPS treatment gave these little mice and rats the ability for significant motility.....and that factor was...










It was hypothesized that the relief of pain provided by PPS was the main contributing factor for these animals to regain their strength and ability to be able to perform at more normalised levels.Paradigmers, we don't have to take a leap of faith from animals to humans, we already have some pretty compelling evidence of what PPS does for us...

SLEEP AT NIGHT
WALK UP STAIRS
PAIN AT REST
PAIN WHILE STANDING
PAIN WHILE WALKING

These are the categories where we have seen incredible improvement...when you get rid of pain or at least reduce it heavily, one's entire temperament changes for the better.You add the reduction of pain to improvements in bone morphology and small improvements in spine mechanics and you get a powerful result. This, at the most fundamental level is the beauty of YOUR drug...multi actionary indeed.


THE HEAD OF THE CLASS

Again a quote from the researchers sums it up best:"Another striking observation in the treated MPS VI rats was the effect of PPS on the skulls". Paradigmers, the researchers found that the skulls and snouts were longer which were quantified by radiographs and micro CT analysis. The snouts also were more normalised ie thinner than the untreated brethren.

The research team also suggested that due to the vascular effects of PPS this could also decrease the rate of subchondral bone necrosis and sclerosis. Again this is what we hope to observe through the 008 study, the ability to bring down the biomarkers and show at such a level that we are slowing and indeed halting the disease in some cases.



HEY PAR, DON'T SELL OUT TOO CHEAPLY

I have this fairly nasty habit of actually reading a lot of the terms and conditions especially when there is more money on the line...you get the odd customer that does this and it often brings a slightly surprised look on part of the salesperson that a customer will actually be bothered reading through the conditions. Admittedly I don't always read it line by line, sometimes I skim...and if it's not material (a few dollars involved) then I wont bother.




_{Terms and conditions, who reads all this?}

So what's the point of this, how does it relate to PAR selling out to cheaply?? Read on:

So I always was under the impression that a tie up with an ERT provider was perfect...they supply the enzymes replacement stuff, we give the patient joint pain relief and all is good....Yeah but there is more to it...and how did I find out about it? Through this very same rat research...and it wasn't in the abstract...it was in the detail... painstakingly going through every single line on that research report...this is what I found:

The Rat guys...sorry, the Rat Researchers, stated that in their previous studies they have found that while "ERT was effective at reducing systemic inflammation, it had little or no effect on the cartilage and bone disease in MPS VI rats, and limited effects on motility". PAR...take note of this...we are not just potentially providing some pain relief, we are making a material contribution here...the hypothesis is that combining PPS will be a powerful adjunct and we deserve a fair cut of the revenue pie.




^{Hmmm wait PAR, don't be too quick off the mark to make a deal no matter how cute that smile is....know what we have first...then we shake hands.}




CONCLUSION

Absolute miracles here...not just one, a number of them. PPS indeed improves not just the all important mobility but it lends itself to improvements in vital "organ system pathologies' on top of the reduced inflammation and pain. We all know just how lucrative inflammation and the pain markets are.But guess what...Like a few Mozz type bonuses that I have managed to scatter in various prior posts over the last couple of years I have another one for you tonight....It's the real miracle.....of this post.

Ready?




Ummm...Paradigmers?

ALL of the above evidence in Parts 1 and 2....all of the above findings...in the rat models...what PPS did, what was incredibly observed....the wonderful unique effects noted...




THAT my friends was based on the Pill format of PPS...



(Pssssst: new guys? Didn't understand the meaning of that last miracle/bonus? iPPS has a much greater (my estimates is a factor of 4 in some areas) uptake (called bio-availability) than the pill format, can you just imagine what result set those treated rats might have experienced IF they got the Subcutaneous version? Just imagine the great data and results we are going to start getting later this year and next... I'm talking about the science and the data....yeah the share price will eventually catch up when the world's patients talk to each other and the mass population hear about what exactly iPPS is.

I wasn't the only one that caught on to this fact though, the researchers themselves stated it (which I read after I wrote that above paragraph), here are their words:

"It is important to note that our study evaluated oral PPS treatment for MPS, whereas in the OA literature the drug is generally administered subcutaneously. It is reasonable to speculate that the effects of subcutaneous PPS administration on the skeletal disease in MPS may be better than oral administration due to greater drug bioavailability".





This is the miracle of iPPS.










(My views, subject to clinical trials, DYOR is important, do not invest all of your available capital in any one investment vehicle no matter how good it seems, for no one knows the future)





REFERENCES


Main reference 1] https://pubmed.ncbi.nlm.nih.gov/23365668/
2] https://rarediseases.info.nih.gov/diseases/10335/mucopolysaccharidosis-type-i
3] https://med.stanford.edu/ctsurgery/clinical-care/thoracic-surgery-services/diseases-of-the-trachea-and-airway.html
4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779683/
5] https://www.chatswooddensitometry.com.au/trabecular-bone-score-tbs.html
6] https://www.hindawi.com/journals/omcl/2017/8416763/
7] https://www.cancer.gov/publications/dictionaries/cancer-terms/def/reactive-oxygen-species
8] https://journals.lww.com/jspinaldisorders/Abstract/1992/12000/The_Stabilizing_System_of_the_Spine__Part_II_.2.aspx#:~:text=The%20neutral%20zone%20is%20a,by%20the%20passive%20spinal%20column.
9] https://www.collinsdictionary.com/dictionary/english/motile
10] https://arthritis-research.biomedcentral.com/articles/10.1186/ar2935