The miracles of iPPS on MPS and a super bonus.

“The FDA is committed to fostering innovation in drug development, especially for rare diseases. Patients who are suffering with rare diseases frequently have few or no treatments available to treat their condition and new approvals can often mean hope for an enhanced quality of life and in some cases, survival."

Janet Woodcock MD (Director of Centre of Research for Drug Evaluation and research - FDA) - Feb 2020.



id you know as I type this post, we are already up to some week 28 for patient one in the latest PAR MPS I Trial?

At the same time we are close to starting the latest trial in Brazil for MPS VI. Combining these two results will allow us to go forward into the last pivotal trial in MPS. It's quite possible once we get results back from the two MPS trials (but before the final pivotal trial) we may strike a deal with a distribution partner which most likely will be a company that also has an ERT solution, somewhat not unlike Biomarin for example.

(Mozz note: Why do I keep using Biomarin as a partnering potential in the MPS area? Because of our own Dr Michael Imperiale. Who is he? Well he is our Global Chief Safety Officer and is also the clinical head of the MPS program. Relevance to Biomarin? He was the Senior Director of Global Medical Affairs at BioMarin !).

Yes we are kinda in limbo land right at this present minute. We are indeed beyond the IND submission but we haven't quite been granted the car keys yet...When can we hit the road?

So we know MPS I and VI have been classified as Orphan Drugs pertaining to us from the FDA, but tonight I concentrate on the miraculous type evidence that has been uncovered via some Rat research, evidence of what our drug can do...


Are you new to us?

This research is going to blow you away.



BACKGROUND FOR THIS POST

I like to read and research anything connected with PAR...iPPS and the indications we are covering. Get me in a conversation with someone new and I could talk for hours on what we have, why it's good and what it can do. In a usual year I'd churn through about 20 investment books...the last 2 years I reckon I've read 3. Just about all my spare time goes into PAR research.

A while ago I came across a rat study specifically on MPS and at that time I had a number of things going on so could only get to the abstract. The abstract is designed to give the reader a very high level overview of what the study was about and what it achieved.

My original intention was to go over this article again and post at a very high level what the merits were perhaps in a fancy bullet style post. This is now impossible for me to do and I flat out refuse....

Why? What's wrong?

What is the back story?


_{MOZZ, editors and supporting journalist on strike? Refusing to write up the Rat study?}



Nah, not on strike, I refuse to publish this post covering only high level material on the topic...let me explain.


It was only last weekend that I found the time to go beyond the abstract and actually read over the details to see if I could perhaps find anything else in the detail to add to my proposed high level post... I thought I should read the detail (devil in the detail?) so as to embellish the original high level bullet point type post that I had in mind....

I kid you not I was parked in my car waiting for my son to finish a class (I had a good 1.5 hrs of waiting time) and I have never said that many expletives under my breath while reading through the detail of this same scientific study, even @poolboy and @oxxa23 would've been quietly impressed. The parents waiting in other cars would have blushed if they were lip readers...


The expletives weren't because I was angry or dismayed or disappointed, it was out of sheer shock.


I discovered such compelling and jaw dropping evidence that I cannot do justice to this post at a high level summary, tonight we dig deep into the details. It's one of those posts where you will need a nice glass of red or a hot cup of tea, girls (or guys!) fix yourself a sweet white or perhaps a Manhattan?...maybe if you are in the UK you could load this up on your laptop at the pub? (heck, show the bar man or that young waitress with the friendly smile, he/she might become your new best friend and a shareholder overnight)? I know@edski1 has promised me a night out on the town one day when we make it! We will go bar hopping and then straight to hospital ...no no not because we got blind and damaged ourselves (*) ...because we want to ask the Rheumatologists over there in the hospital if they have heard of what iPPS is and if they know what is about to hit them sometime in 2024/2025 or so.


* = (Not advice, anything other than moderate consumption of alcohol is dangerous and bad for your health, if you are under 18 and reading this (21 in the USA) then duly skip the above paragraph). Wait a sec, if you are under 18 and are reading this and own PAR shares then I salute you, according to what I'm researching you are already way ahead of the curve....(my views)..make sure you keep at least some of these shares, they will be quite precious after a number of years...crystalise some along the way if you need to, but hold some forever (not advice). If you really think you have done well after some point in the future, just promise me you will keep a handful forever...if it works out, then buy me a beer in the future with a small fraction of the proceeds just from the tiny amount of shares you actually did manage to keep and store. Not advice).



Less humour...more research...right let's get to it:


LAYOUT OF THIS POST

Again, too much for just one post, I'll break it up into two parts:

Part 1 - We'll cover a brief background and intro, what the study entailed (apologies, rat humour there), and some initial observations from the study.

Part 2 - We'll get stuck into the jaw dropping stuff...be on the watch for some quotes that will stun you.I was going to say that this part will be 'littered' with quotes...

PS: Watch out for a bonus miracle of my own...right at the very end....ah, no cheating/skipping forward till the end ...you'll need the background info contained in parts 1 and 2 first.




MPS - BACKGROUND

Classified as a Lysosomal storage disease, there are 11 sub classifications. Unfortunately there are many adverse symptoms of the disease, everything from enlarged features such as head, cheeks, tongue, lips to misaligned teeth. Enlarged vocal cord, sleep apnea, enlarged spleen and liver, short stature, hearing loss and the list goes on.²

Most patients experience some joint pain which can be severe in some instances, currently there is no cure for this. Even Enzyme Replacement Therapy (ERT) only alleviates inflammation to some extent. Here's where iPPS can play a dual role (boosting the inflammatory reduction as well as addressing joint pain) and is currently being observed at a clinical trial level. The disease (strains I and VI) have already been officially classified as an Orphan disease from both the FDA and EMA agencies for our treatment purposes.

Orphan indications warrant special treatment from an FDA/EMA perspective with examples of benefits including reduced fees along with an expedited and preferential review status. An extended time of exclusivity are also granted in these markets as well. Indeed as we originally learnt from a certain Mr X in the initial interview conducted last year, the FDA pay a particular interest in companies submitting potential drugs in the Rare Disease space.



CURRENT TREATMENTS

The current standard of care treatment is ERT. It gives some relief in terms of alleviating some of the symptoms but its "effect on cartilage and bone are modest" ¹. In some patients there have been antibody responses to the newly injected enzymes.The researchers for this study found that GAG stimulated inflammation played an important role and was previously unrecognised as a feature in the skeletal pathology in MPS. The scene was set for Pentosan...

I remember Gan_Gans posted a video comparison between MPS mice/rats and the same treated with PPS...Here is the link to that post:

RAT UNTREATED AND TREATED VIDEO



THE STUDY

Rats that had MPS Type VI were divided up into two groups, a control group and a group that were treated with PPS. The good thing about this study is that it was conducted over some 9 months.The other interesting thing is that the researchers started treating rats early, I'm talking prenatal as well as at 1 and 6 months after birth.


FINDINGS?

Before we tackle the findings that pertain to Pentosan, the researched also conducted studies using anti TNF antibody therapy (think of this as a pseudo competitor treatment). While this showed some encouraging results and some benefits over ERT alone, it was hypothesised that it would be difficult to implement this along with ERT as there were "potential immunosuppressive side effects". Again it bodes well for us...you want to be better than the competition AND you want to provide something novel, something unique, something only OUR drug can give while having the great merit of being SAFE!

Partnering up material? You bet! If you are from Biomarin or one of the other ERT providers and are reading this...please get in touch (after reading this post in its entirety of course).

Read this post for more on ERT and the current providers: ERT and Providers

Ok let's take the findings for Pentosan one by one....

We are soon to visit Bio Marker city. Our 008 Synovial study could possibly be one of the most amazing studies conducted to discover just how this iPPS act and what are the flags that are being set to really study and learn about how iPPS acts and what it can do to such markers of the body when it comes to OA and pain.

The Rat study was also illustrative in this field. Let me give you three quotes pertaining to this observation, my emphasis added in orange.

"...elevated levels of several serum inflammatory markers in the MPS VI rats were reduced to near normal levels in the PPS-treated animals".


"Reduced TNF-alpha levels also were observed on the livers, spleens and hearts by immunohistochemistry".

And finally, how about this one:

"Advanced glycan endproducts ...are another class of inflammatory markers that were found for the first time to be elevated in untreated MPS VI rat serum, and also were significantly reduced in the PPS-treated animals".



As we observed in the human Phase 2 B trial, biomarkers such as ADMATS-5 were reduced. This is a biomarker that is prevalent when OA exists. The same finding was observed in the rat study, "The expression of TNF-alpha, p38, and Cox-2, each of which are elevated in MPS VI rats were reduced to normal levels in the PPS-treated animals".

Right...let's tackle a miracle...




Paradimers..what is a trachea?

Simple...it's commonly known as the windpipe, think of it as a tube about 4 inches long (in humans) and less than an inch in diameter in most people.³ Lets see this as a diagram:







Great, so what's a trachea typically made of?

Mozz Quiz? Now? C'mon it's been months....humour me.



WHAT IS THE TRACHEA MADE OF?

A) I dunno, a sponge type material?

B) Iron (Well you have heard of an iron lung right?)

C) Plastic piping like what's under my sink


Ok all wrong of course...but the answer might just be an "Ah Haaaaa" moment...


Cartilage.

...see where I am going with this?But before you think this Mozz guy is off his tree...will it surprise any of you that correctly knew it was made of cartilage that there is a difference between the cartilage of the joint and the cartilage of the trachea?

Let's take the next jump to make it even more obvious to join the dots...

The rat study also examined the integrity of the trachea. This is important in an MPS patient as typically they have thinner walls and are less open...(also results in deeper voices). Paradigmers, read this quote from the researchers:


"Untreated MPS VI rat tracheas are generally collapsed by 9 months. In contrast, tracheas from the PPS-treated MPS VI rats were more open and the cartilage walls were thicker."

If that's not enough, read on:


"Together, these results indicated that PPS treatment was reducing inflammation and increasing both articular and hyaline cartilage integrity in the MPS VI animals".


When I read about how our drug increases cartilage integrity I quickly scan my room to see if there is anything of value left to sell (Spec statement, not advice, not prudent to invest too much in one stock). There is nothing out there that does this. It may not be observable in all patients, but for even some percentage of patients, it will be revolutionary.


A drug that can improve cartilage integrity and do so safely is a miracle in my books.Oh and remember how I stated that there are two different types of cartilage? The study had this to say about it: "Articular cartilage and tracheas represent two distinct types of cartilage, and the positive changes we observed in both tissues indicate the broad importance of GAG-mediated inflammation on cartilage pathology in the MPS disease".

The report also went on to say that the "positive effects of PPS observed in the tracheas were similar to those previously obtained using anti-TNF-alpha antibody therapy". But this is where we must do further research and analysis. Whereby such TNF treatments may show a similar efficacy as PPS (think also the efficacy displayed by such drugs as Tanezumab), the disadvantages outweigh the advantages. Other research has been done to show that the incidence of cancer is more prevalent along with immunosuppression and increased infections.⁴

Not only PPS displays a similar efficacy as such drugs as Tanezumab, PPS is so much safer! It's a key point. Afterall, agencies like the FDA are all about safety, it's their number one focus.



That concludes Part 1....In Part 2 we cover quite a bit more amazing evidence...and we may discover another miracle or two....oh, and remember to watch out for the Mozz Bonus Miracle...right at the end.