NOTE TO MODS - Please note this post is very much on topic as it relates to PAR's manufacturer.
eah I kinda thought that that heading might just draw your attention...but this isn't one of those BAIT advertisement kinda posts where it's all much ado about nothing.
Now I've been posting for like 5 years on here...this here post that you are about to read and hopefully digest, will be possibly my most favourite ...ALL TIME!
It was a joy to experience, it was a thrill to write.
To give you a distinct clue regarding this post, here is the alternative heading I was thinking of going with:
"CharlieMozzie and the chocolate factory"
Well I did promise at the start of the year some surprises, here is a big one !
Please now sit back and enjoy!
Most of you know the original story of Charlie and the Chocolate factory, a book by one of my favourite authors, (at least as a kid) Roald Dahl.What a story teller he was, I want to be such a storyteller. Do we have a story to tell? What do you think? Hopefully this story of ours will get much better once the FDA gives us a green light?
MOZZ NOTE: If you have kids or grandkids, certainly suggest this book to them, it's a thrill to read as a youngster.
Briefly, it was a story of a simple boy that was not well off who has a dream to visit the infamous Chocolate factory. Like most kids, Charlie could only imagine what it might be like.... Going through the big front wrought iron gates...viewing the buildings...exploring the individual rooms, the machinery all over the place, the wonderful assortment of fine chocolate, talking to the staff and spending time in this magical place, a place that has the potential of one day being known to the entire world. Charlie was a humble boy...very modest upbringing, a good hearted kid.
The factory of Wonka was really the best in the world, super pridemanship, a long, long tradition of making the finest and best products in the whole world. Engineering like you have never seen it...they took sheer pride and indeed revelled in their workmanship...not over years...but over decades...
So the factory owner decided to run a comp to finally allow just 5 kids in....the rarest of chances to visit what is arguably the single best factory out there, it would be admission by lottery, seeding just 5 lucky tickets in random chocolate bars.
Charlie couldn't afford to buy a single bar of chocolate but luckily one day just before the comp ended, he stumbled across some cash in the snow while walking....he bought a bar from the money and donated the remaining money to his poor hard working mum... Slowly he peeled back the wrapper. Was that a bit of gold foil or was it just a reflection in his eye?
He had actually scored a ticket !
Tonight’s post is a somewhat similar story but it’s not Charlie I’m talking about...
......It’s Mozz.
General Disclaimer What you are about to read has nothing to do with Par. Par does not necessary promote, condone or sponsor in any way the endeavours that have transpired and are contained in this post.The below occurred purely as a consequence my own financial efforts. Anything mentioned in this post has no implied association with the Paradigm Company and none should be assumed.
Do not rely on any one party or poster. There is no advice contained in this post and none should be implied. The below is my own personal observations.Just because I experience certain events does not necessarily translate into an increased chance of success etc DYOR applies, as always.
General Disclaimer
So I had a golden ticket in my hand, I was on my way...It was a fair effort in terms of journey to get to this point, luggage that was accidentally taken in Frankfurt, the drama of all the forms I had to fill in ... the dismay that all my clothes and things I was carrying was gone!
Then finally the relief of making contact with the passengers that had accidentally taken my bag and left theirs on the baggage carousel and actually successfully getting in touch with them...and then the final relief of seeing them with my bag! This then translating to a much later night than I would've liked and then waking up a full two hours before I was supposed to get up (only 3 hours of sleep! (I usually need 7 hrs) cos I was just too darned excited)...in order to catch my next early morning flight!
Flying into the next city early morning, I was then on the clock, I had a good idea of where I needed to be, to be on time... then experiencing supposedly rare cancelled trains...not one but two...then finally getting on the third train and then almost freaking out in disbelief as the train stopped three full stations before I was to get off....and all announcements in German!! What was I going to do? Time was burning...
'We're on the road to nowhere' was playing in my head... would I really make it to my final destination, was there some evil force preventing me from going and making it? Oh and WHAT was my final destination (to be revealed really soon, see next section)?
I managed to Uber it from the stuck train to the central station in the city and finalllllly managed to get the next train on a different line heading down south...where was I off to?
The gorgeous German town of Wolfratshausen.
My host was so gracious and personally picked me up from the local station and whisked me away to ......wait for it....the factory…I was terribly excited!
But where was I off to? Could it really be what I'm inferring??? No way...what factory am I talking about...??
Surely not...
Yes you are correct… I was at the...
bene factory
OMG
I know there will be a few of you newer guys that don't know a lot about bene and their role. Let's do a quick cover off of that. I will go one better and replicate Scott's original post at the end of this one so you will have a better in depth background for those that are newish to our story. Bene, located south of Munich have been in production for some 7 decades. They do have a few products including one that's like paracetamol. They have the only registered Pentosan based product in the approved FDA Drug Master File. So much so that it was at the Pre IND meeting that PAR had with the FDA where the FDA simply told us, we can ONLY use the bene material in the ongoing clinical trials, no other Pentosan based product would be accepted.
The FDA are well aware of what other inconsistent varieties of the molecule are out there. (See also Chapter 5 below).
Bene have a number of totally in-house developed machinery and apparatus that is used to manufacture the final product, there have been many innovations over time that have led to the high standards and supreme consistency of the final product.
Paradigm are fortunate enough to have a 25 year exclusive supply contract with bene.
We'll get to the meeting in a sec.
Here are three pics for you:
Pic 1 View from above...look at how lovely and green it was...such beautiful townships dotted all over the country.
Pic 2 - View from the train on the way to the bene factory, very picturesque
Pic 3 - I fondly remember Scott's pic from 2019...I wondered if I ever would take the same one for myself. Yes that's the bene sign in the bottom right in that pic below.
The bene factory, hard to capture the full scale, pic taken with Mozz's own phone!
What a lovely meeting it was, we started off by going around the room with the introductions, actually they asked me if I wanted to intro myself first, I chuckled and said it’s going to take me a bit of time … I had whole swathes of info to tell them how I had come across the Pentosan molecule. I had the deepest love, appreciation and affection for all that happens to be Pentosan. They chuckled and suggested they should go first! When it was my turn I duly warned them, they would be talking to someone that doesn't hold a science degree!
They gave me a high level view of the molecule and we talked production and just why and how special that molecule is. I was kinda in heaven.
I started by asking them about the weight of the molecule, I knew it was circa 5400 Dalton but we talked about the ranges and their MD stated that I shouldn't get too hung up about the weight as there are a number of measures to finally define the end product.
I knew they were a little curious as to WHY I was asking something so specific about the weight?
That's when I launched into my stories...
Launched into what stories?
Launched onto my scientific rationale as to why I was curious and why I was asking such a specific question about the weight.
It all had to do with Dr Lilla Simonaro...
I explained to them all from memory (it's a story I just can't forget)...how could such a big molecule pass thru the BBB? It's usually not possible. She was asked this same question by the moderator of the 35th Annual Lysosomal Family conference...
I was terribly excited because I told them, if I didn't know the molecule well, I would be fairly impressed by even a 30% reduction of IL-8, the inflammatory marker in the brain, due to the wonderful effect of the Pentosan molecule... Then I stated that Dr Simonaro reported a virtually incredulous 90% drop in IL8 due to (I paused for a sec for effect) YOUR molecule! (Yes it was about this time that it dawned on me that I was talking to the people, the scientists that were actually manufacturing this amazing product! This was an amazing meeting for me, a story not unlike Charlie's, a story that I thought I may never experience and could only ever be a dream?!).
Dr Simonaro's work...
This was incredible. They could see the shocked expression on my face as I stated this observation, a full 90% reduction in a safe manner, no SAE's?
So I posed this question to bene, how was it possible? How could such a large molecule get through?
Guess what happened next?
They gave me a legit and plausible answer...
A possible rationale...
This was the perfect example of the meticulous nature of these guys. They knew the molecule so intimately. It's not just that they have managed to refine the molecule and perfect it's manufacture over and over and over again. They still study it...they still tinker with it...they still learn about it. After 7 decades. This is German perfection and quality.
They simply stated that the most probable reason the molecule could possibly get through was because the brain itself was in an inflamed state...when this happens, the surrounding membrane effectively could change properties and possibly allow a molecule like pentosan to breach.
From this point I went from being happily impressed, to being totally amazed.
They were obviously very proud of their achievements and what they had created over some seventy incredible years. I asked them quite a few questions, we did get down and dirty in terms of the science. Yeah the science did get heavy at times but was so awesome.Just to hear all their terms and how professional their answers were.
So what did I learn?
Well there were some direct insights and some indirect.
Some examples included a discussion of the difference between the calcium salt and the sodium salt, I had some basic idea but wanted to hear their thoughts, I asked them what the difference is? They essentially said that the calcium salt is more painful to the patient due to the inherent properties! I also got a clue that it was an initiative of Peter Ghosh to try this version as we all know the most predominant element of bone composition is also calcium. No wonder Dr Ghosh was such a definitive pioneer in the field of pentosan research.There was also some discussion of the hygroscopic nature (drawing moisture from the air) of the calcium salt thus making it less stable in comparison to the sodium version.
We chatted about how insanely incredibly complex the final molecule is . I actually told them I’ve heard a while back there are something like 40 different moieties (think of these as sub molecules) and more recently I heard it was more like 70? They all kinda smiled and wondered for a sec. who should answer that, finally the R&D Director/Scientist that was there took us through an approximation and started explaining the multiples… 4 x 16 to begin with, we were already at 64… then multiply that out by … yeah we are up there in numbers. It’s at that point I realised the gravity of what they were producing… they are measuring the final product by various chromatography and spectroscopy measurements and achieving batch to batch consistent results. This is no ordinary feat! It's extra spectacular when you realise how many subunits there are and what processes are involved to achieve it! How could anyone replicate this?
No other manufacturer has been able to attain this level of consistency. Remember dear reader, PPS has been off patent for a solid decade plus.
We covered a lot, from the wood chips right through to the moieties and even some of the high standards the factory must maintain due to standards imposed from the local, national and international authorities.
I also reiterated some of the science understanding I had, covering topics like the tri-molecular bond Pentosan forms with TIMPS and ADAMTS-5, not just greater than the Heparin bond but the fact that it increases by a factor of 100 fold if there are greater than 8 sugar chains involved, I said all of this from memory, there are some facts about PPS I just can't forget.
We chatted about some of the wonderful mechanisms of action and I even showed them before and after MRI's. They were most interested in hearing some of the stories I had accumulated over the years.
While only discussing it at a higher level, I alluded to their own peer review on what makes the bene molecule unique. We talked a little about this great read and a comparison to the mimetics.
I had prepared myself for a such a topic by reading the amazing Mimetic paper they published, only a few days before the trip, here is the abstract that came out half way through last year:
So if you had asked me before the visit, Mozz, what are you most looking forward to?Well of course I would've stated that it was the tour of the actual factory and meeting the staff.
Mid way through our discussions? I switched, I completely pivoted, I was having so much fun talking about iPPS with bene themselves, asking questions and telling them of my stories and experience with the PPS molecule. I wasn't just chatting about a molecule to someone that's merely interested...there I was chatting to the actual manufacturers of the very molecule! After some 5 years of research (casual research of course)...this was a field trip of a lifetime. Half way through the meeting, while I did have the tour on my mind, it wasn't any longer the priority. I was having wayyyy too much fun getting to know bene and just talking to them and listening to what they were saying. Each hour felt like a block of just 5 minutes...
We could've gone for hours and hours...well, we actually did, I would've thought getting a solid hour with the lovely bene company would be a huge success for me personally...I got 7 hours.
7 glorious hours.
They were so generous with their time!
I don't know how to translate that to you...some of you may strive to see a concert of their favourite singer/artist..some of you may strive to learn an instrument and attain the final grading...others still wait patiently to be able to retire and tour the world...well this was one of my highlights, but don't get me wrong, I had never really planned for this to happen ... I have fallen into this quite naturally. I started with really simple posts 5 years ago in HC just asking for your thoughts to see if I was somewhere on the right track with all this OA bizzo. Sure it's a fair amount of effort and research...often times I have to juggle priorities...but it has never been a job for me...it's been an absolute passion. Was this like attending a famous concert, I dunno, insert artists name here... ______ Elton John perhaps? Maybe The Weekend (I recently heard they have had some 3.47 Billion streams on Spotify). It's like then going back stage, sitting down with them in a quiet dressing room and chatting to them about the build up from the early days and what kept the artist going and how they come up with the music that is loved by the masses.
Backstage pass with a famous band?
I got more of a sense of where this is going one day...I hear the patient stories...but even that's a bit disconnected, I hear it from FRIENDS now...patients that I know well and have followed their stories for years. I see it in the reaction of peers to PAR... Sure we have hurdles to cross, we have legislation and authorities to deal with....but I know why PAR are confident... I'm aware of the risks...but I'm aware of what this product can do, what it will do for patients one day.
I keep searching for better investments....products that can excel, opportunities that haven't been tapped, while there are some really interesting plays out there, in my views and not being advice...this molecule and what it can do and more importantly what it IS doing to so so many people that are suffering terrible pain...terrible function loss...limping....and not enjoying their sleep...people that have psoriasis on their faces they want to cover....people that are on the fringe of heart failure....blood pressure sufferers (spec statements, all subject to trial evidence)...the list actually goes on and on. I do still hear a bit of noise coming from the share market screaming lower and lower....but I know what I'm investing in, I know there are great periods of disconnect, I also know not to have everything betting on one result and I'm conscious of this thing taking it's own sweet darned time. If I'm in a hurry, if I want a quick smart 100% return...this isn't the stock for me, I am not that sort of investor. I strive to be more like those instos...
It wasn't all one way, I showed them MRI's before and after, they were also really interested to hear about some of the patents we had, they were across most of them.
It also wasn't just a big one way optimistic fest. that day with bene, we also did talk to some more pragmatic topics like why is our share price low, what I was hoping to get out of OARSI, and what, high level, is the time frame typically like for PAR.
We finally got to the tour! For me it was nearly an after thought by that late stage in the day! In fact it was bene that reminded me! We exited the meeting room and went into another building, three levels of stairs and then checked out a number of rooms starting off with the control room. A very sophisticated operation with lots of monitors and racks of switches…
Then we visited another six or seven rooms, I think that was hardly like 20% of the factory... the machinery and complexity was amazing. It’s certainly not a case of just getting a large pot, a huge wooden spoon and a heater, yeah there is a lot involved! Pipes everywhere, massive cooking ovens, large stainless steel containers, pipes and wires going all over the place! I always had a naive thought that each room would be fairly simple, a pipe would come from the roof or the wall, go into a large stainless steel vat and then a couple of taps here and there and the pipe would continue into the next room/stage.
Nah it was 50 times more complex...The rooms were very clean and organised. I could sense that each of them had a real deep understanding of every process involved despite the sheer complexity of the machinery and the number of sensors and equipment.
I knew I wouldn't be allowed to take pics, but it is at this stage I wish I were an artist and could somehow recreate what I saw...it will always be blazoned in my memory.
In one room there was a whole stack of new lighting still in boxes neatly placed on the ground, they apologised for the mess...I couldn't see any mess, only everything planned and systematically laid out!
I was in awe...I was almost pinching myself thinking am I really here? I'm sure the bene folk must've wondered when is this guy's jaw going to stop dropping!
There was one big burnt orange coloured huge vat in one particular room that looked like an industrial sized pressure cooker...but at scale...it was taller than me and was bolted by like 45 huge bolts at the top, each as big as my entire hand. I was trying to get an idea of how much pressure force would be in that one piece of giant equipment.
In another room we saw their latest acquisition, a new oven...it was massive, it was shiny, (I could tell they were very proud). Cost? A million Euro for this one piece of equipment out of so many!
While we went from room to room I managed to ask a few questions, one was about scaling.Most of us understand there is a real chance of large sales eventually, growing patient demand and the real possibility of off labelling aggressive growth, so I asked how are you guys preparing for material scaling one day?
They said that currently they do one train...a second is easy enough to employ more staff and we can get to 2x. Then they showed me available space for a new building and said we can double again in the future if we have to, we know how to replicate the entire process and all the machinery.
There was so much colour I gained from bene, they certainly aren't passive. They are pushing the boundaries of research, they even have their own labs and spectrometers.
The final part of the tour concluded at the storage and delivery warehouse, it was large. How was the final product stored? Maybe in boxes? Well perhaps some of it might eventually find it's way into boxes but the finished product I saw was in powder form and it was stored in barrels! The large 159 litre oil kinda barrels!
This is an example (not actual photo) of what I saw but there were many rows and they were like three or four shelves high stacked to the roof!
I don't mean to be frivolous when I draw parallels with the story of Charlie and the amazing bene factory. They are so dedicated to the top quality of manufacturing of the wonderful PPS product. They have survived and thrived for not years, but decades, they are ultimately the top manufacturer for this molecule evidenced by the multiple audits they get from FDA/EMA, evidenced that their molecule has been off patent for YEARS...this bothers them not, they know that there is no other competitor that can come close to replicating what they do. They have such a proprietary grasp on the manufacturing. It will indeed be years before anyone can come close and have anything like the consistency, then those competitors would have to prove themselves with whatever version they end up with in clinical trials. I don't have to tell you how many years that could be!
I learnt so much that day. I learnt about the manufacturing prowess, I already knew a bit about it but it is quite the next thing to talk to the actual founder's son and their top scientists about it and then as if that's not enough, to see the equipment for myself. A dream come true, an experience I will never forget.
I often say, I love to read about how our molecule works, I love to read that in a journal, in a mag, in a newspaper cutting, on a brokers report. But to talk and see and look a patient in the eye, that's next level.
It's the very same with the drug....I love to see it, it's ultimate multi modal action and what it can do...but to talk and get the manufacturer's view on it and hear them speak with pride about how it is produced.....next level?
Absolutely.
I said to the founder's son half way through our wonderful meeting... "This really is a true marriage of great companies".
He smiled, and quite simply agreed.
A very sincere thank you to the staff and management of bene for entertaining me and hosting me. Your hospitality will never be forgotten and I very much look forward to spending time with you again in the future.. I sincerely and dearly cheer you on and wish you and PAR every success in this most exciting of stories.
Auf Wiedersehen !
(Farewell)
- Mozz
ps: Can't tell you how proud I was to be there, in a distinct way I felt I really did represent the small shareholder...some thanks must also go to you dear reader for your support and encouragement and valued feedback over the years!
eah I kinda thought that that heading might just draw your attention...but this isn't one of those BAIT advertisement kinda posts where it's all much ado about nothing.
General Disclaimer
(20min delay)
