orry about the acronym fest there in the subject of this here post...we'll duly get to those in a sec...
Sometime in Quarter One 2023, we will be privy to more incredible data.
Mozz, please tell me why we should get even remotely excited? We got 008 - 56 day already, isn't 6 month just going to reconfirm what we already saw back at the very end of Sept 2022? It's just a re-hash...right?
What's new? Why is it going to be any different this time round?
Further separation between the cohorts
Possibly more evidence on the Bio Chemical markers, but the big one...
Juicy new data - STRUCTURAL biomarkers
As I was telling a mate earlier this week...YOUR pain might be 3/10...for me that same pain could be a 5? Maybe a 7....its a little subjective at times...but structural? How many millimetres is my BMEL before...how many is it AFTER the iPPS magic? You cant fake that.
What's my Joint Space Width before and after? Grade of BMEL? Volume? You get the point, its more objective. There will be more new eyes on us...to get structural change safely is one thing, to do so in just 6 months?
Ok where was I, is there anything more?
.4. WOMAC Pain and Function and PGIC, again refer to point 1) Further separation, I'm expecting the placebo cohort at 6 month to drop off more heavily compared to the active arms.
.5. Canine - Mozz, we have already had the news here, the doggies are doing alright. Yeah - Nah...we will have full data, this is the equivalence to a full 3 years of human study. Lets just see how the longer durational aspect is looking?
All well and wonderful Mr Mozz...but are we at all a chance of any sorta DMOAD connotations here? Well we will get to the DM aspect eventually...
Firstly...lets turn to a fairly technical peer review done back in 2011.
Paul Rennie has referred to these researchers a couple of times in various presentations before...it's worth a look despite the complexity...tonight, I present to you Sunaga et al. (See main reference in the Reference section below)
InhibitoryEffects of Pentosan Polysulfate Sodium on MAP-Kinase Pathway and NF-κBNuclear Translocation in Canine Chondrocytes In Vitro
Don't fall asleep...I will make this relevant....hang in there.
CATABOLIC - The breaking down of complex molecules
MACROPHAGE - A type of white blood cell tat surrounds and kills microorganisms, removes dead cells and stimulates the action of other immune cells.
MMP - Short for Matrix metalloproteinase *whew* glad they shortened it to MMP. There are a number of these such types of Proteinases. Think of these guys as mediators on inflammation. the metal in the name comes from the fact that they are dependant on Zinc to thrive. Again a lot of the body's processes are all about regulation, we need some of these guys to assist in the regulation of inflammation and other such related processes like assisting remodelling of tissues for example. It's for this reason we cant simply just block out all these guys, we need to regulate, in fact we need to down regulate, this is part of iPPS's magical component. It's also not single targeting and single acting. See Appendix B.
EXTRA CELLULAR MATRIX - Ok this one is not only fairly complex but it is multilevel. yeah I need an entire paragraph, maybe a couple. Bare with me, it will be worth it.
So cells tap into a pool of nutrients and proteins and a heap of other goodies called the extra cellular matrix (ECM for short)....here is a simplified picture, let's call it Figure 1.
Figure 1 - The easier to understand graphic baby'ing for us to understand what is an ECM.3
We use simple graphics like in the above pic to help us simplify and understand, but in actually, figure 2 below depicts the same thing above but shows us how it really looks...well actually they use a stain to highlight various parts otherwise it would just look like one monochrome (single coloured) soup! The above graphic helps us understand what we are observing below in Fig 2, otherwise it could be downtown New York on a busy night, maybe an impending storm over Alice Springs or it could be part of my brain light up when I see our share price finally go up!
Figure 2 - In the above image nuclei are stained in blue and the ECM is stained in green. Note how the ECM forms a network that surrounds the cells.3
Ok so how is the MMP linked to the ECM ?
Good question...I always assumed that the ECM is always a good thing and it just feeds the cell. Nah its a lot more complex of course. In fact some degradation of the ECM is required that assists in cell repair and morphogenesis. This is a fancy term for a cell to change its shape. It can be elicited by either mechanical force and/or chemical changes. There are a whole heap of things here including cell signalling which plays a massive role for us. Huh, what's cell signalling?
Yeah its the action of iPPS..it has a LOT to do with signalling and the very best example I can give you is through the down regulation of NGF.
New guys to us? See the new guy paragraph just below.
NEW GUYS READ THIS
Actually don't worry about the just the new guys, I learnt something new from this myself....
----------------------------NGF -------------------------------------------------------------------------- Talk about a post within a post, first time I'm doing this, let's go!
Note before we start, bold emphasis in below quotes is added by me for emphasis.
oo much pain is bad! Who wants to be in chronic pain, ie pain all the time....but the answer is not as simple as you think: just BLOCK the pain!!!!???
I think Inflammation is exciting, the subset of NGF and iPPS's action on the same is a number of levels underneath inflammation and is a total mind blowing experience, I'm just scratching the surface...
Hey! What about a Mozz stat.® before we continue, to really HAMMER home our raw FUTURE potential...
Chronic pain affects more patients than cancer, cardiovascular disease and diabetes combined. D
Totally block NGF? (Full form = Nerve Growth Factor). NGF can be thought of as a protein, well it actually makes NGF Beta which is the protein....but if one were to block it totally when it is produced, yes you will reduce the pain...but no, it may not be the end of your troubles!
Enter the drug, Tanezumab. They thought they had the answer, but what actually ended up happening apart from reducing pain is that there was a certain percentage of patients that developed rapid joint failure.... You simply can't block all pain, all NGF. Some NGF is not only ok, it is vital!
Two studies A, namely 'Anti-NGF antibody muMab 911 both prevents and reverses pain behaviour and subchondral osteoclast numbers in a rat model of osteoarthritis pain' and another study, 'Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritis' were conducted and they found that while NGF blockers were effective in reducing pain, they did however, also promote more rapid cartilage degeneration, synovitis, and possibly subchondral bone changes, particularly when treatment started in the earlier stages of disease!
The exact exact opposite of iPPS! iPPS has shown more merits when started EARLY in the piece. How does iPPS act differently from blocking the NGF totally? Simple, it doesnt...it only downregulates it enough so that some NGF is still produced and that's what the body needs...some basic amount so that the body can act and repair as required.
Here is more of a clue:
"...the role of NGF signalling in these tissues has not been fully elucidated, and it is possible that NGF signalling within the joint may also be protective in some way. In addition, anti-NGF treatment in adult rodents has been shown to reduce the function of the sympathetic nervous system. The role of sympathetic nerves in the pathogenesis of OA remains unknown, but studies have demonstrated that there are sympathetic nerves associated with neovascularization in the area of the osteochondral junction as well as in osteophytes in OA".
Paradigmers, new to us and older holders....what I'm saying to you is that we actually need some NGF ! Part of the sheer magic of iPPS is that it doesn't fully block NGF (and other cytokines such as IL6 for example).
But why rely on other's papers ...Paradigm also said it themselves via their own peer reviewed paper:
"The answers to the scientific questions are Yes, the bone cells do produce high levels of the pain mediator NGF and Yes, the drug pentosan polysulfate can reduce the production of NGF by those bone cells. The mechanism of action of reducing the production of NGF by PPS is novel. The reduction of the production of NGF by PPS is not by blocking the NGF (like NGF antibodies) by rather at the mRNA level to reduce the production of NGF by the bone cells thereby reducing the joint pain. This research now clearly elucidates the mechanism by which PPS reduces pain from osteoarthritis".C
Ok Mozz, lets get back to the point and the main post - ECM and MMP with a little DM thrown in......so MMP's plays a vital role here because when the ECM is normal, all is good, its when it becomes dysregulated, we get problems, This dysfunction of the Extra Cellular Matrix is the cause of many diseases and YES, arthritis is one of them, take a read of this one:
"It is precisely regulated under normal physiological conditions, but when dysregulated it becomes a cause of many diseases such as arthritis, nephritis, cancer, encephalomyelitis, chronic ulcers, fibrosis, etc. Uncontrolled ECM remodelling of the myocardium and vasculature are features of cardiovascular disorders such as atherosclerosis, stenosis, left ventricular hypertrophy, heart failure, and aneurysm".4
Now you have some good background on MMP...we can continue, remember, if this is a bit boring and technical, just remember, MMP is a biomarker, too much of it ain't good, we want to see it at normal levels. We want to see it reduced when it is typically elevated in an inflammatory state.
A LOGICAL PATHWAY
So how did I come about this particular paper? Where does the Mozz Money line stem from in this post (see later)?
Ah well it all started with one of my new Doc heroes (The old one was Dr D Felson, of course he is still on my list to one day meet!)...yep, I'm talking about Dr Virginia Kraus, not only a KOL and Global leader in the field of OA like Dr Felson, but you know what...both of these Docs are consultants for PAR!
Mate.
Please remind me to thank PAR for taking on the best in the business, it no doubt comes at a cost but this is one area we want pure quality! Trial design, experts in the field, top of game material and as one more additional kicker; they are both in the FDA's ear!
(Mozz Note: The other day I was trying to explain to a friend what it would mean for Mozz to one day meet Felson and Kraus, I told her...it would be like you meeting Elton John and the head of Rufus Du Sol (Good Aussie group) Tyrone Lindqvist... These two are the top of their game and you know what, they are both closely associated with the FDA...how?
Top performers? Different categories of music...different categories of magic!
Dr Felson used to work on the advisory committee for the FDA - now a consultant to PAR amongst many roles.
Dr Kraus is jointly charged with leading the biomarker consortium reporting back to the FDA - yes, another consultant to PAR.
I await patiently till we hear directly from these leaders in the OA space. Their insights and report on our iPPS will be quite a read one day.
Dr Virginia and a few others published this article in 2019 5:
In that peer reviewed publication she mentions 6 biomarkers that are highly correlated with macrophage markers, namely:
MMP-3
TIMP-1
VEGF
ICAM
VCAM
MCP
These markers above rang out to me as we have heard at least the first three before...
From there my eyes lit up when I saw their conclusion in the publication:
"A subset of six SF biomarkers was related to synovial inflammation in OA, as well as radiographic and symptom severity. These six OA-related SF biomarkers were specifically linked to indicators of activated macrophages and neutrophils. These results attest to an inflammatory OA endotype that may serve as the basis for therapeutic targeting of a subset of individuals at high risk for knee OA progression".
It was a simple task to cross reference the mentioning of MMP with Sunaga's research 6...
MMP-13 also gets a mention in another paper which had this to say about their pivotal and destructive role in OA:
"MMP-13 is the enzyme responsible for the degeneration of the cartilage ECM and the degenerative process of OA pathogenesis".
While the following line isn't my money line...it's not a bad read from the main reference (See Ref Section):
"Suppressive effects of PPS to OA progression in cruciate deficiency dogs after surgical stabilisation of stifle joints. In humans, it was reported that PPS oral administration significantly reduced pain score and cartilage metabolism marker, C2C in sera from OA patients".
One more for you, again, gets a bit technical. It has to do with myocardial expression of the extra cellular matrix, but again, this statement focuses on the magic of Pentosan. We know we have various cytokines that get activated during the inflammatory process. ADAMTS 4 is one PAR have demonstrated themselves (See Appendix A below).
What percentage would you guess iPPS assists to reduce ADAMTS 4?
Something notable right?
3.5% reduction?
11%?
How about slightly north of that.
36% ???
Let me not spoil it for you, you have a read:
"We discovered that myocardial mRNA and protein levels of ADAMTS1 and -4, and mRNA levels of versican, aggrecan, and ADAMTS8 increased after AB, and TNF-α and IL-1β synergistically increased mRNA of versican and ADAMTS4 in NCM and NFB and secretion of ADAMTS4 from NCM. Furthermore, PPS-treatment improved systolic function, demonstrated by an improved fractional shortening (vehicle 48±3% versus PPS 60±1%, p<0.01) after AB. Following PPS-treatment, we observed an ∼80% reduction in myocardial ADAMTS4 mRNA (p = 0.03), and ∼50% reduction in the extracellular amount of the p150 versican fragments (p = 0.05), suggesting reduced versicanase activity". 7
Yeah kinda off the chart at 80% reduction.
How many know of the power of iPPS, I mean really?
The above has real positive connotations for iPPS as a heart failure therapeutic agent. Don't forget, Half of ALL Heart Failures are HFpEF, for this group of patients numbers, there is NO solution, nothing that works. Only one possible drug, iPPS (subject to human clinical trials), we have seen this working in our pre clinical model already!
I don't often have too many of these Mozz Money Lines...I think I've had like three in three years...but here is one for you tonight....From the main study (see References below) - I give you this one simple line.
. "From the results of previous in vitro and in vivo studies, PPS would be qualified as DMOADs". [8, 12, 21, 22].
See Appendix C for the reason why I've included those little footnotes in the above Money Line.
I know there will be at least eight of you (my guess completely) that have LITTLE to NO idea of what DMOAD is and why we, as investors, should at all care.
Let me put it this way:
We get DMOAD on our label and it will mean this:
1) WE will TRIPLE our over night revenue potential (dollars, you want specific dollars?) How about this then, not advice....
31,000,000 USA OA patients x 10% cos I'm conservative x $2500 USD per annum x 22.5% revenue
Versus
31,000,000 USA OA Patients x 10% x $6000 USD x 22.5% Revenue royalty per annum plus at least 2 Boosters per annum for the average patient.
@ceviche I reckon you are one of the best DCF guys, bring that future revenue back in today's dollars for me.
2) We will overnight become not 2nd in line..we will become FIRST in line...
3) Docs will start using us as a prophylactic treatment, adding Millions of dollars of revenue to our already significant future potential (my views) . 4) Off label anyone, I'm not even tackling that in this post.
PAR is acutely aware of this ...they know the end goal is to get a DMOAD on the label...we have heard this from Paul during his long interview with Scott Williams...you do that and not only will you overnight TRIPLE the revenue potential...you will NOT only make a VAST difference to millions that are suffering in pain and tackle the last of the major disease....but, you will become first in class...first in line and be a very valuable company to boot. Its at this point the better Docs that suspect you have a torn meniscus, a torn ACL, a small fracture in surrounding joint tissue will highly recommend a course of iPPS as a preventative prophylactic disease warding off treatment.
Paul said as much back in 2021:
"The flip around is to put these biomarkers as the primary endpoint here, so that we have got data to support discussions with the agencies over disease modification and to also help with promotion and marketability of the product once it is registered"
"...if you go into a physician's office and say we've got data to show you get symptomatic relief and pain, improvement in function but we also got disease modification data ... the doctor will be scrambling to write a script for hundreds of patients who are currently not being well looked after".
We know what is coming...we have seen the evidence...for others to have gotten this clue some TEN YEARS prior really indicates just how much under the radar we are and how early we still are early to the game.
This disparate share price lag will definitely rectify one day. While in no way could and should this be construed as advice...I'm patiently waiting for some exciting data to come imminently as further objective proof ...but it's really the long term that drives me to research just what are we all really holding...
- Mozz
DYOR is a good idea.
APPENDIX A
Oh what about another glimpse at DMOAD?
How about this study showing the salts of PPS to inhibit ADAMTS-4:
"Clinically, CaPPS and the corresponding sodium salt, NaPPS have been shown to significantly improve the symptoms and functional index of joints in a double blind placebo controlled clinical trials with OA patients. Although the observed improvement in joint symptoms may not reflect any beneficial of CaPPS on joint articular cartilage in the short time frame used in these clinical trials, the present observations of the ability of this agent to inhibit ADAMTS4 and increasing TIMP-3 production lend further support to the assignment of this agent to the class of disease modifying drugs for OA".8
APPENDIX B
Did you know there is actually an MMP Blocker that's been approved by the FDA. It's called doxycycline. There are side effects associated with this one. It's generally used to specific treat inflammatory conditions like inflammatory acne and a second in line treatment for sinus infections. There are a number of precautions when using this drug. 9
APPENDIX C
Yeah the Mozz Money line for this post indicated that we already have some fairly good evidence that iPPS is DMOAD.... but look at the references used by the researchers themselves, they know how effective iPPS is:
[8] Ghosh, P. 1999. The pathobiology of osteoarthritis and the rationale for the use of pentosan polysulfate for its treatment. Semin. Arthritis Rheum. 28: 211–267. [Medline] [CrossRef]
[12] Kumagai, K., Shirabe, S., Miyaka, N., Murata, M., Yamaguchi, A., Kataoka, Y. and Niwa, M. 2010. Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis—an open clinical trial—. BMC Clin. Pharmacol. 10: 7. [Medline] [CrossRef]
[21] Takizawa, M., Yatabe, T., Okada, A., Chijiiwa, M., Mochizuki, S., Ghosh, P. and Okada, Y. 2008. Calcium pentosan polysulfate directly inhibits enzymatic activity of ADAMTS4 (aggrecanase-1) in osteoarthritic chondrocytes. FEBS Lett. 582: 2945–2949. [Medline] [CrossRef]
[22] Troeberg, L., Fushimi, K., Khokha, R., Emonard, H., Ghosh, P. and Nagase, H. 2008. Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. FASEB J. 22: 3515–3524. [Medline] [CrossRef]
As a further hint, look at ARGS as an example of what we found in our own 008 Top line data:
orry about the acronym fest there in the subject of this here post...we'll duly get to those in a sec...
oo much pain is bad! Who wants to be in chronic pain, ie pain all the time....but the answer is not as simple as you think: just BLOCK the pain!!!!???
(20min delay)