MPS - A tablet -v- subQ - The results before the test.

PART 1 MPS - A TABLET -V- SUBQ - THE RESULTS BEFORE THE TEST




aradigmers. Tonight a special report. I tackle a study that was conducted with MPS I and dogs and some amazing results. So revolutionary this stuff is that I will break it up into two amazing parts, it's going to be a bit of a thriller marathon tonight so please ensure you are comfy, grab a glass of your favourite beverage/snack, even if it is a tea or a biccie...make sure you are sitting down, there are some eye openers in this one!



PROLOGUE

This is the second study that was performed on larger animals, the first one was performed on rats. The beauty of this study is that it not only compares placebo to PPS but it compares PPS to PPS...Huh? I mean comparing PPS in tablet form to injectable! It was a great read and reference 1 in the reference section contains the full paper.

All references can be found at the end of Part 2.

It get a little sciency in parts but bare with me, plough on, I will try and simplify as much as I can.



INTRODUCTION

The experts at FiftyOne Capital commented in one of their previous reports that us getting back SAS results during a Phase 2 trial was somewhat like getting the answers to a test beforehand. Paradigmers, I want more. It certainly isn't for a lack of faith, I value our company and feel they are doing a good...no, great job. They are under pressure, they have a LOT on their plate and it isn't (yet) a cast of hundreds at PAR HQ, they are well experienced and have the right people for the job and are being steered by the right board and the right CEO...

I want to further my research, not by a cursory little amount...I want depth and I want other studies to confirm and to challenge me...I want to weed out any negatives and I want to read the positives for myself...I want to talk to the patients...I want to understand what the science is and I don't want it to come from just one other source, It needs to be from wide and varied sources.

Tonight I take you through another amazing study with findings that add real weight to what we have, we can sure use some of this hard core evidence as our shares continue to sink just recently, it doesn't bother me, it's a time to top up and though they are little spoonfuls, none the less, I'm topping up. When this thing takes off there is no hope for me to be able to add to my positions...it will be unaffordable. My views.

PLOS One is a scientific series of journals and studies that are world recognised. In one such study¹ an investigation of PPS in the two types of formats, Pill format and Injectable as a Subcutaneous injectable (SubQ for short) were trialed. New guys, do you know we recently published our own PLOS one paper? Here is the link, worth a look if you haven't already -----> PARADIGM'S OWN PLOS PAPER




^{PLOS One - peer reviewed scientific journal, we have made it into the hall of fame type publications.}



This is a Mozz summarised high level of the MPS canine report, do enjoy!



MPS - A BRIEF RECAP

So what is MPS? Mucopolysaccharidosis, it is a disease and it basically means a lack of enzyme that is required by the cells to remove waste. Affecting some 3.5 births in 100,000 it's a terrible Orphan disease and one that PAR has had some good success with utilising iPPS. There are around 11 recognise strains. The good news for us is that while we are approaching the beginning of the very exciting Phase 3 trial in MPS VI, we are also very soon to be beginning a separate Phase 2 on MPS I.

Adding to my excitement is that fact that iPPS has efficacy on GAG accumulations which we will see later in this post and ALL strains of MPS display this symptom. This means, as was previously postulated by PAR themselves, all strains of MPS may garner some benefit with iPPS. The other thing I learnt in this study is that MPS occurs naturally in some dogs, the condition is also rare and is genetically transmitted in their case too. There are some really sad pics of these animals suffering which I have avoided posting here. Truly this is one heck of a condition for us to tackle early on in our story, leave aside the huge potential for revenue, we are about to bring a LOT of good into the world.


THE STUDY

Back in 2016 a group of scientists and researchers took groups of affected MPS I dogs and treated some with daily oral and some with biweekly subcutaneous PPS (iPPS, also referred to as subQ). The human equivalent doses for 17 months and 12 months respectively were used.Safety parameters were observed at the 6 month mark and at the conclusion of the study. After treatment the GAG levels and cytokine levels were determined.Assessments of the aorta and liver were also performed along with other tests and observations.


BACKGROUND - A BRIEF RUN DOWN ON GAGS

What is a GAG? Short for glycosaminoglycans, think of it like a long sugar molecule. It's a vital part of the body's functioning, used in many areas in many ways. From signalling, regulation of the body's growth, cell adhesion, to wound repair, the list goes on. BUT from what I understand, most GAGS need modification in order to be effective. I mean they need to be broken down into smaller parts for them to function in the right way. Each cell has a part called a Lysosome, this is an area of the cell that is responsible for breaking down these GAGS and also removing waste. In the MPS patient, they either lack the enzyme required or are deficient in these enzymes and this function does not take place. This can lead to cell deformities and cell death.


The problem with GAGs is that this accumulation occurs when there is no enzyme present to break them down. (Hence Enzyme replacement therapy attempts to add good enzymes to restore this functioning). The build up of these GAGS is potent and can be highly destructive and disruptive to the body's functions resulting in many terrible symptoms. Corneal clouding, retardation of the brain (There are a higher proportion of lysosomal storage units within cells of the eye and the brain for example), joint deformities and subsequent pain are just some of the many symptoms.

Need more evidence of the destructive nature of missing this enzyme? Here is a quote from the study.


"GAG accumulation in all MPS types has a direct effect on connective tissue formation and function, resulting in an array of skeletal, skin and other connective tissue abnormalities, as well as lesions in other organs such as the central nervous system".¹


Let me break that informative quote up:

1. All MPS types are affected by GAG accumulation
2. Connective tissue formation is affected
3. Skeletal abnormalities are affected
4. Lesions are abnormal changes to a given organ/tissue

A very severe and serious disease, no doubt the FDA were quick to label our iPPS solution as a treatment with Orphan status and did you know despite the FDA and EMA having 90 days to get back to us, they were back to us in 60 days for the PRE IND? I have no doubt they will work closely with us to attempt a speedily and definite resolution to the final trial (my opinions).

So just how do we fit in exactly in terms of the MPS condition? Well ERT has some good benefits but it doesn't help at all with pain of the joints. Why do pain of the joints manifest so much in these patients? Good question. The reason is because these GAG molecules also act as lubricants on the joints, no lubricant and you are in trouble...imagine the damage you will do to a car's engine without oil. It's as simple as that. Moving parts...moving joints need lubrication.

Quick fact, GAGS are so complex and so versatile that there is s separate study named after them, Glycobiology. ²


RESULTS

First let's counter the negatives that were discovered from the study....

• No drug related increase in liver enzymes were found in this study
• No Coagulation factors were found
• No Adverse Effects were found

Now for the good positive stuff:

• Significantly reduced levels of IL-8 and TNF- Alpha were found in urine after the iPPS treatment GAG reduction was also observed in the urine and tissues.
• Increases in the luminal openings along with reductions in the intimal media thickening in the carotids and aortas of PPS Treated animals.
• Reduction of storage vacuoles.
• Improved elastin integrity

Again, each of these amazing benefits are separate Mozz posts in themselves but I want to pick up just one as an example of exactly what you are reading and exactly what does this mean? That last one...Elastin integrity. ³ Think of this like a scaffold or membrane, they can be found in such areas of the body like smooth muscle cells in airways and the blood vessels, they form the essential elastic fibre which can be found everywhere from the pulmonary vessels or continuous sheets that separate smooth muscle layers. It is all connected, there is reference to multiple disease such as COPD where iPPS has also shown to have a role in repair and down regulating inflammation. In fact COPD is one of the indications mentioned way back in our prospectus back in 2015.

Further along in the studies I came across this quote:

"Hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapies (ERT) are available for MPS patients, but neither treatment completely ameliorates GAG accumulation or the progression of disease."


Let me again break this one up, ERT as I mentioned, has some positive effects for sure, our iPPS is being measured primarily as a remedy for reduction of PAIN and in terms of MPS specifically it is more likely to be a measure of improvement on the patient's life along with joint pain...but Paradigmers, look at the potential OTHER benefit which is not being fully achieved currently by ERT...namely, as you can see in that last quote above, GAG levels are not completely made better...iPPS will assist in reducing these levels. How much reduction? Well the next trial will shed more light, but the data to date suggests around 65%..that's more than significant and more than enough to be commercial.

The average investor out there is simply clueless as far as what our drug is...what it does....how it does it, how safe it is...and of course, what the future benefit and potential is.
In my own opinion there are very very view that know these workings and you know what, I reckon some of those instos are slowly catching on.



NEED MORE?

Sure...here is another passage for you to digest.

"Residual GAG accumulation is particularly prominent in tissues such as the heart, brain, and the musculoskeletal system, which are less accessible to exogenously delivered enzymes."

I suspect, and it is only my opinions, that we will see some efficacy in such areas as the heart, we already know that there can be positive effects on the musculoskeletal system with some evidence to date on cartilage, There are two aspects here;


1) Stopping further cartilage destruction

2) Rebuilding or stimulating cartilage growth.

Both aspects needs to be studied further. Both are compelling. Don't forget our main focus (specially in reference to OA) so far has been pain and pain reduction.



A COMPARISON OF DELIVERABLES

So, the beauty of this study is that:

1) it was performed on large animals rather than just rats or mice,
2) It did a full comparison between PPS and iPPS.


What were the findings? Again, let me quote:

"The effects of subQ administration (once weekly) were greater than for daily oral treatment in the MPS VI rat model, particularly in vascular tissues such as the cartilage and bone."


Paradigmers, this study was comprehensive, they measured all sorts of parameters and tissues.Examples?

1) Cytokine Determinations
2) Total GAG determinations
3) Mass Spectrometry GAG Analysis
4) Histopatholgy
5) Cervical Spine Analysis
6) Immunoblot Analysis

I'm not trying to bore you (and I!) with an anatomical and biological discourse and thesis...I AM trying to illustrate how comprehensively this study was and HOW it can help us by shedding a LITTLE extra light on this, well what do you call it, Magic Juice.

Ok Mozz, show me the money....



RESULTS IN DETAIL

Right...so we have three groups of MPS dogs...


GROUP 1 - Placebo , they were given no medication.

GROUP 2 - PPS but in tablet form.

GROUP 3 - iPPS, the magic juice!




Results? Let's go to figure A :




FIGURE A


Ok this one needs a little explaining, In the first pic (descending Aorta) you can see those purple rings, No AF, they aren't smoke rings after a great night out at Pool_Director's party...What we want to see here is that the outer walls are as thin as possible and the inner tube (white space) is as large as possible. For me (Mozz speak), it's a 5 lane freeway with no cars on it, what's the quickest way to get home? When there is no traffic or there is a fair bit of traffic but it is all flow and all go as there are plenty of lanes to choose from!



Mozz on his way home....sorry I meant →


(That's not actually my model of Volvo but this isn't the post to discuss that!)



Back to work, and back to Figure A...
The black bars on the bar graph is group 1, the white bars are Group 2, and the grey bars are the Magic Juice MPS Dogs....The lower these Bio Markers fall, the better the efficacy....There are two sets of graphs as they took samples from two areas in the dog's bodies...A) was Serum, B) was CSF (Cerbrospinal fluid).

This is what we suspected and these are the facts to prove it, there is a vast difference between tablet form and injectable...Yes PAR have shown us this in humans but I thought it was great to see PPS -v- iPPS albeit in animals.I guess it's not even a comparison in humans, we know that the tablet version doesn't do much for OA and MPS as well.

What were some of the other results in the Dog study in terms of MPS results?As evidenced by figure A above, this and the prior Rat study showed for the first time the potential of iPPS to influence the Central Nervous System manifestations. Ok another quote time which was an 'Ah ha' moment for Mozz. These guys noticed using mass spectrometry (think of this like a specialised 'magnifying glass' that breaks down compounds into individual molecules and is also used to calculate the exact molecular weight of compounds/molecules which is what is used to test that what we have is the iPPS molecule manufactured by Bene), that a particular bio marker called Di-6S was reduced due to the action of iPPS...but the quote that caught MY eye was:

"The greatest response was seen with Di-6S, a primary GAG fragment that also accumulates in MPS VI."

Paradignmers, our VERY FIRST Phase 3 on any of the MPS strains is of course MPS VI.What I'm saying is that this Dog study is an eye opener, it contains a lot of interesting clues for the deep and thorough investor, that's you and me. It is a precursor to the hard evidence Im guessing we will discover more about in our Phase 3.

Mate, this is already a lot of good evidence, but you want more? Plenty more to come!



In PART 2 we discover more amazing proof about what you and I own...and just how is this a possible glimpse into our future...and some confirmation of some facts and research that the study at the time (2016) speculated on and is now becoming a reality with the wonderful work PAR is doing...