uite recently our CMO, Dr Donna Skerrett presented at a Virtual Healthcare seminar. In that presentation she included a slide of the major human studies involving Pentosan. Tonight I want to focus on a particular study I haven't covered in depth before. A special shout out to our own
@poolboy as his question and call out made me go back and dig this one up.
INTRO Dr Peter Ghosh was quite the researcher. His seminal work on OA and Pentosan founded such a solid concrete foundation for Paradigm.
He and his team conducted a study with n=114. At high level we get this:
But what you and I don't see are a couple of things:
1) The Introduction and insights that Ghosh et al. gives us in terms of the the problems of OA and the feeble 'solutions' in terms of analgesics available to patients, but also...
2) The granular result set.
Please as always, now enjoy.
THE GHOSH STUDY - PART 1 BACKGROUND In the Ghosh et al paper
1 the researchers beautifully and succinctly coin the disease of OA as a "multifactorial disorder in which aging, genetic, hormonal, and mechanical factors are all important contributors to disease onset and progression".
They go on to state that it is the convergence of these etiological factors that manifest in joint injury impairing function, causing stiffness and resulting in pain. (Mozz Note: all three of those aspects {Pain, Function and Stiffness} are firmly embedded as endpoints in our upcoming P3).
Ghosh and team then state that these clinical symptoms are accompanied by physical insults, namely:
Joint Space Narrowing (JSN) Subchondral bone sclerosis Osteophytes A quick Mozz recap:
JSN - we don't want this cavity to narrow, it narrows and eventually you get bone on bone crunching and pain. Keep them apart, keep that area cartilaginous.
Bone Sclerosis - This is thickening but also hardening of the bone and is typical in late stage OA.
But isn't thicker and harder bone great for us? No...it results in pain...loss of function...grating feelings...harder lumps (see next definition)
Osteophytes , see last definition! Harder lumps and protrusions, if they hit a nerve and it's going to be painful.
We don't want these protrusions (see arrows)...these are called Osteophytes. Ok definitions out of the way...let's keep going.
The next step in this slow train wreck of OA is fragments that seep into the synovial cavity. Now these molecular fragments bind to T-receptor cells and it is this that causes an inflammatory reaction. This in turn causes a step up in synovitis and in fact Ghosh refers to this as a "Secondary synovitis".
Once this sets in, the of OA progression chain is complete....
Ghosh then goes on to mention the common forms of pain relief...take a read of what he says about them
"In addition to analgesics, the agents most frequently used to treat OA are the steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs). However, these drugs mainly relieve the symptoms of OA and exhibit negligible beneficial effects on the underlying pathology and/or disease progression. In fact, some reports suggest that some NSAIDs might exacerbate the failure of cartilage and bone in arthritic joints by inhibiting cellular repair mechanisms and connective tissue homeostasis". Let me just highlight that last bit...
"some NSAIDs might exacerbate the failure of cartilage and bone in arthritic joints by inhibiting cellular repair mechanisms and connective tissue homeostasis" .
It kinda reminds me a Simpsons Cartoon scene, where safety goggles are supposed to be the be all and end all of safety equipment...but when hit with a tidal wave of concentrated Sulphuric acid....well, "The Goggles do nothing". (see Appendix A below). In the same way, the NSAIDS, the very thing that should give decent pain relief and even some feeble hope that the destruction is at least addressed, actually just potentially makes it worse, depriving the patient of any sense of hope.
But that's not all, there are suggestions of long term use of NSAIDS being associated with Severe Adverse effects in the elderly population (the ones that have a higher propensity to need them as they have OA)....Newer NSAIDS may have a reduced propensity for gastrointestinal AE's but according to Ghosh, "...controlled studies have found an increased risk for thrombosis and myocardial infarction associated with their use in susceptible patients with OA ".
You guys know how many NSAIDS get consumed per year right? Yes of course it will take time for iPPS to replace most of the NSAIDS, word of mouth will spread super fast...but realistically, for us to gain major traction, major momentum, it will be at least a few years. Happy of the few of us that actually can retain a decent parcel of shares well into the period of materially increased revenue! Remember,
Humira took a full 19 years to reach their Peak sales. I think our trajectory
could be better...(I was going to say "Will be better" but Man from West said I should use "Could").
A DM DEFINITION The researchers then state that for a true DM a reduction in the rate of cartilage loss in the affected joint would need to be observed. But that's not all. We need the other side of the coin too.."However, this structural change in cartilage would need to correlate with improved symptoms".
And this is where Pentosan potentially trumps...we have seen both.
In a key statement, Ghosh et al. comments: "Time to total joint replacement has been suggested as an alternative efficacy end point and a possible index of positive clinical outcome of DMOAD treatment".
Take a read of the requirement Ghosh puts forward in reference to a DMOAD candidate:
"...clinical studies to support the classification of NaPPS as a DMOAD are lacking. Based on recommendations from the Group for the Respect of Excellence and Ethics in Science, Liege, Belgium, to assess NaPPS as a clinically efficacious DMOAD requires a placebo-controlled, double-blind clinical trial of sufficient duration to allow changes in JSN to be reliably determined and correlated with improved symptoms". But Paradigmers, we now have this in 008. Increases in cartilage volume results in a reversal of JSN. We are literally getting the "changes" that this consortia from the above quote suggests.
Most of you will remember this from the release of results of our Synovial study, here it is for the new ones to us.
In the natural course of OA, it has been found that on average, it is expected that a person with moderate to severe OA will lose -40 Um (which is 0.04 mm) of cartilage thickness in the central medial femur each and every year .
3 Guys, please someone tell me what PAR observed in their Phase 2B study?
"Participants who received iPPS had an average improvement of cartilage thickness in the central medial femur of the knee of 60 µm (0.06 mm) at 6 months. This is compared to placebo who lost an average -20 µm (-0.02 mm) of cartilage thickness". To make it bleedingly obvious, the Placebo cohort consistently continued at this average rate of destruction (-40 μm per year is -20 μm for 6 months).
That's exactly what Placebo cohort encountered and experienced. iPPS was not only ZERO loss...they
GAINED 60 μm .
This is what we own.
Owners of something special? Yeah - there is no drug ever that has shown to do this safety and in SUCH A SHORT DURATION OF ONLY 6 MONTHS.
Indeed this evidence in my mind supports a Blockbuster opportunity.
Paragimers this is why our 008 program was so pivotal. It showed both sides; symptomatic relief, but also an arresting of structural progression. It was shown within 6 to 12 months. That is extremely quick in light of how long OA manifests itself (over a decade plus in most cases).
It becomes the ultimate surrogate for us. This is what excites me. There is at least a chance of a much quicker pathway for us.
THE SCIENCE BIT Dealing with Dr Ghosh, you are going to deal with the science. But here is the beauty if it, you can learn so much. And guess what, this isn't abstract science happening in some other galaxy or in some random lab....this is science happening inside YOU and ME!
A number of times in the past I've talked about the car analogy. My eldest son loves cars. He value adds by getting all these parts from all over the world to embellish his car. He wants to know how the car works...why it works...he has a passion. He has value added so much and has spent relatively less...I encourage him to do a side business in it, there are a number of rev heads that would love to get those looks for less price.
How does this work? Why does this work? What has this to do with iPPS?
A lot.
I, for one, also want to know how the heck this thing works. What is under the bonnet?
Tonight, I found out more than what I knew.
What did I know?
I know that ol' Pentosan assists cartilage producing cells. I remember our own Dr Ravi Krishnan chatting to us in an R & D sessions (PAR, can we bring these back after we get funded in the future? Where he talked about the NF-kB...I knew the long chains of HA that we want and need get broken down over the years as we age.
Ghosh summed it up all in one paragraph for me in this paper.
Here is what he said:
Mate, I know that's sciency..but let's just break it down a touch...
Definitions first:
Chondrocytes, remember, are the blessed little cells we have that are responsible for cartilage formulation.
4 Fibroblasts are the little cells that help in the formation of connective tissues.
5 Remember, Catabolic processes break down complex molecules, anabolic builds up small to larger molecules.
Right, let's get into the Learnings!
1) Human Biology is innately complex.
2) So Hyaluronidase are enzymes , these break down those longer chains of HA. So that's bad in a way because we want the longer chains , it's those longer chains that have the magical properties of lubrication and elastoviscosities, also the biomechanical and fluidising properties we need.
BUT at the same time, you cannot remove all traces of it. You actually need some of these Hyaluronidase too. The perfect example is that it facilitates white blood cells to move more easily through connective tissues!
7 Bacteria themselves can produce it to break down and penetrate connective tissue barriers! This is another reason why such research papers discuss the concept of homeostasis, a concept of balance. We need a drug that will encourage production of higher weighted HA but it should NOT be at the cost of removing hyaluronidase totally. This is not how an efficacious drug is going to be successful
8 .
Bacteria! This also reminds me a long time ago I did a post on IL-6, it was titled,
The Good....the Bad...and the Ugly . What I meant by that post is that despite IL-6 being classified as Bad...you CANNOT eradicate it totally. We need some of it as some is good...it's a little like Cholesterol, there is good and bad. Wiping out cholesterol totally from our bodies will, well,,... err ...wipe US out! The same holds true for NGF. Paradigmers, what I'm saying to you is....it's more about DOWNREGULATION...NOT eradication. I suspect this is the essence of bene's molecule.
.
In Part 2 we will cover some practical stuff...but let me leave you with this one bit of science for now...I found it to be quite a read, one of many "quite a reads" in this amazing paper by P Ghosh:
"...the biosynthesis of high-MW hyaluronan by synovial fibroblasts, which is diminished in OA joints, was restored when these cells were incubated with NaPPS in vitro or after its intra-articular injection into joints of patients with OA". We know in the case of OA the wonderful and important HWHA is reduced, it's
"diminished" ...what does our Pentosan do?
It
restores these levels.
That's what I want.
See you in Part 2
POST EDIT RAMBLE I started this post late, of course I should've known it was a
Ghosh paper I was reading, ie there was always going to be extra material I wouldn't have ever seen before that was totally amazing, totally thrilling! Anyway, this means I have run out of time to do the full edit for both Parts 1 and 2. So I will post only Part 1 tonight and Part 2 should be done by either tomorrow night or Monday night depending on how much time I get.
Cheers
Mozz
APPENDIX A VIDEO REFERENCES FOR PART 1 1]
https://www.sciencedirect.com/science/article/pii/S0011393X05001311?via%3Dihub OTHER REFERENCES 2]
https://www.webmd.com/osteoarthritis/osteoarthritis-subchondral-sclerosis 3]
https://app.sharelinktechnologies.com/announcement/asx/058732021c8928f27d89da8502ca692a 4] https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/chondrocyte#:~:text=Chondrocytes%20are%20the%20cells%20responsible,critical%20role%20in%20fracture%20repair
5] https://www.genome.gov/genetics-glossary/Fibroblast#:~:text=A%20fibroblast%20is%20a%20type,the%20structural%20framework%20of%20tissues
6] https://byjus.com/biology/differences-between-catabolism-and-anabolism/#:~:text=Catabolism%20breaks%20down%20big%20complex,Anabolic%20processes%20require%20energy
7] https://link.springer.com/rwe/10.1007/3-540-29662-X_1273#:~:text=Hyaluronidase%20is%20produced%20by%20some,an%20initial%20site%20of%20infection
8] https://my.clevelandclinic.org/health/articles/homeostasis
(20min delay)