"Give me a lever and a place to stand, and I'll move the world." Archimedes, cicra 210 BC
Sure, beautiful quote Mozz, what's it to do with us and 008?Archimedes is well recognised as possibly one of the best scientists that lived, certainly in the classical era. He was postulating on how a simple sandstone block thrown into the sea would sink all the way to the bottom but an entire boat loaded with spices could happily float??? How was this possible...
One night he simply jumped into his bath a bit too aggressively and it was the 'Eureka' moment that rocked the world....the principle of Buoyancy. The displaced water was heavier than the floating body (ship) and thus the ship floats but the brick does not. After this they could use such principles and design hulls of ships to enhance the weight bearing capacity by displacing even more water because of the unique shape of the hull. In fact I remember back to my Year 12 maths where we covered imaginary numbers (i equals the square root of negative 1, and apparently this branch of maths assist in the design of these hulls!?! )...but yes I digress, back to the topic at hand...or at knee... (Yes I'm a dad...that was a dad joke)
Now you now how ships float, some are huge like the one that got stuck the other day jamming some 400 ships! Note mg = mass x gravity.
In case any of you are still wondering about the relevance of that quote, the way I see it...we have a small simple unnoticed drug that's been used in the vet industry for decades but hasn't made the shift into the human realm...we are about to leverage our teeny tiny barely bigger than a micro-cap company onto the biggest markets in the world and enter our P3....we should have a place to stand (Opening of IND)...and then we will simply move the entire world, literally. (Definitely my views)
TIMING IS EVERYTHING?
Would you believe that the time of the day matters when it comes to getting samples? Huh? I mean when you take a sample of the serum or synovial fluid....the actual time of the day can make a difference!
Mate, this is stranger than fiction....The time of the day matters:"This modification in Synovial Fluid levels of COMP was possibly due to an increase of activities after 12 pm." 11 In other words people tend to be more active later on in the day, after midday, it was found that levels of certain biomarkers like COMP can vary depending on the time of the day the sample was obtained. YES, I did call PAR and mention this little fact when I read it, yes they were aware of it...
THE FDA IS NOT RACIST
Why did the FDA want us to do a separate Western and an Asian study? All these set up of trials and studies, biomarkers and selections....trial design, is very critical and can really make or break a drug. Many companies have got it wrong, they have rushed into studies, their trial design was rudimentary or had holes in it....they certainly didn't spend the time getting feedback from the authorities to ensure the highest chance of success...."Some studies have concluded that serum COMP levels vary between sexes and among different ethnicities". 11 No doubt they (FDA) wanted to ensure that the differences weren't so great that the results produced from iPPS wouldn't only work for one classification or subgroup of patients.
MOZZ'S DILEMA
What are the facts so far....Let's pretend there are 40 of these such cytokines as an example that are relevant to OA....We know iPPS has a positive effect on reducing these little fellows.We also know that within the Synovial joint we find some of these many cytokines in higher concentrations compared to outside the joint (eg. in the serum) is vastly different to within the synovium...this is not some forlorn chamber that's passive...it's living...it's alive. It wasn't all that long ago that they thought OA was just some peripheral problem that involved only part of the joint...they now know it's all encompassing.
So I have thought about this following question over the last 2 months...I've thought about it in the shower...I've thought about it on the way to work....I've deliberated over coffee...I have pondered it over lunch...I've asked doctors both random and friends that I know.....heck I even asked a few PAR analysts and brokers...What is the question? What is the dilemma?
You'd have to say the below logic is true INDEPENDENT of any other factor/biology: It does not matter how many cytokines there are whether you be looking in the Serum OR the Synovial joint, iPPS will act roughly in the same fashion and the PERCENTAGE reduction of these could be more or less the same. True, the absolute volume will be much higher in the synovium.
My question is, does the fact that there is simply so much more activity within the synovium compared to the serum necessarily mean that we will get the same or greater level of bio marker reduction as a percentage? (Remember we got a 11.9% reduction in COMP in the serum). From all the research and answers and deliberation...there are two important points that I discovered:
1) It isn't really known...that's why we are doing the study in the first place....!
2) One of my friends who I have grown up with and is a GP said that it also depends on how much of this drug (iPPS) is getting into the synovium (compared to how much drug is present in the serum), I thought that was a really good point and I have read in one of the research papers on rats that iPPS ponds in the joint, this bodes very very well for us...we want this ponding...we want this magic to be present for some time.BUT finally.. here is my theory:
MY THEORY
Yes it doesn't necessarily matter so much as to the actual % drop of say COMP ...I think INDEPENDENTLY of anything it might be the same or fractionately more in terms of biomarker percentage drop that PAR may observe...to me it's somewhat like an earthquake...where are the most destructive waves?
Well at the epicentre...If there are more of these particles to act on (well they are bigger than particles, they are enzymes and proteins)..then you'd think there is more to do here on the part of iPPS thus we MAY see a slightly better reduction?? So I capitalised INDEPENDENTLY above because I'm not taking into consideration the extra action, let's call it proactive action of iPPS. It's a very important point that so much more is going on WITHIN the joint compared to somewhat more passive action in the serum...the serum to me just carries some of the debris of the said earthquake.....
Example? The binding nature of iPPS....there would be (my views but also the views of research) much more binding activity going on and we have evidence of this in animal models and limited human studies both in-vitro and invivo...I've read of this occurring in a number of ways, too many and too detailed to add to this post...but very briefly...iPPS links to protein chains...there is evidence that it stimulates other proteins to be created that are helpful in changing the nature of the destruction, it gets involved in the secretion of certain enzymes...other examples which we have covered is the mild anticoagulant nature and the positive effects it has on the cellular matrix production...there are many other ways it gets involved both directly and indirectly.
What I am trying to say is that there is so much more action within the synovium and if nothing else...we may get similar drops in percentages of the already observe biomarkers but what I personally suspect is that it will be something like a graphic equaliser from my days back in the 80's.
Huh?
Remember these babies? They still are around today but usually in digital format or an app!
I mean there are just so many more biomarkers present and available and being enacted (see heat map in Part 1) that the wonderful action of IPPS will be more broad based...yes it will be like dialling down a lot of the frequencies on a graphic equaliser....all at once...mate this is the power of what we own...this is the raw, behind the scenes biochemistry at work....and this is the reason our patients feel less pain and get back increased functional and flexion in week 4 and beyond in the majority of cases...some 90% feel at least some of the positive effects of iPPS.
"Joint injuries cause striking alterations in synovial fluid levels of compounds that may contribute to joint degeneration, including pro-inflammatory cytokines, and mediators such as tumor necrosis factor alpha (TNF-a), interleukin (IL)-1, nitric oxide, and matrix metalloproteinases (MMPs)." 12
Paradigmers, it is NOT just the fact that there is so much more action and presence in volumes and nature of cytokines and thus inflammatory response within the the joint...it is the proactive nature...the deliberate actions that iPPS is taking and this is one of the main reasons why I quietly suspect the read out both interim and final of 008 will be material.
Yes it is a small sample size, no it probably wouldn't be powered enough on its own BUT it is a lead...it is a case study....and it will, in just my humble opinion, be a negotiating tool with the giants...this is the little rubber slingshot that David-PAR the tiny upcoming Bio Pharma will have against (or perhaps with) Goliath when we get to the negotiating table...we have a magic like no other.
Small we are at the moment, I think with some good negotiations one day after 008 data, we will be sitting at the table with giants.
FURTHER EVIDENCE
Our friend and fellow poster Happell, wonderfully reminds us that he had the treatment and he hasn't been in pain for nearly 3 years. Indeed this is a very strong point. If iPPS worked as a temporary pain relief measure, you would need redosing and frequently. How frequently? Let's turn to some science again...iPPS levels peak after administration after a short time, "Peak levels of pentosan polysulfate were reached at 2 hours after administration (IM or SC method)." 13
What about levels of iPPS that directly show some therapeutic benefit? "Therapeutic levels are generally maintained for four days (Baici et al, 1981; Collier and Ghosh 1989)." 13 This is why you need to maintain the course of something in the order of 12 injections over the first 6 weeks, after that...the body takes over...this is why we see no pain coming back for quite some time and in some cases, longer than the rough duration of around 9 months like we see in Happell's case. Yes understood, our friend Hapell is a sample size of 1...but the extension and durability studies will set us straight and give us data on expected duration at a larger scale...We already suspect this will be excellent...I'm guessing around 40 to maybe 60% perhaps will need the booster on a yearly basis? Yes I know how some of you will think...isn't monthly good? We want recurring revenue...nah, don't worry...a drug that gives a durability threshold of 9 months or better 12 months will command a greater revenue and rebate...the insurers are going to love us and will pay for this huge benefit. It's going to in turn save them literally Billions over time. (My views).
This clearly indicates that iPPS is not simply just a band aid, it is allowing the body to gain control once more. Again we will see such data flow from the various studies over the next few years...this is a vital clue for us much in advance of the possible scientific backing and data to come.
I AM NOT ALONE
There is evidence that the course of OA starts early...starts small...I keep seeing and reading terms such as micro fissures and the merits of enacting iPPS early in the piece...certainly other posters here at HC such as Torpy have also indicated that iPPS particularly for athletes and sports related professionals may benefit by considering it early on and certainly immediately after injury or trauma as a pre-emptive strike.....we already know that some 50% of all people sustaining joint injuries will develop OA within 10 years of the initial injury....in light of such facts the following quote is highly relevant:
"Significant synovial inflammation in early OA, suggest a window of opportunity may exist in which disease-modifying interventions targeting inflammatory processes might be most efficacious for the prevention and treatment of OA." 14
If absolutely nothing else it is a fact that inflammation is higher within the joint compared to anywhere else in the case of a person that has OA....and even more so again in the case of an RA patient. This has been observed by the heat map comparison (comparing for example a patient without OA and with RA against people without any OA/RA.
It therefore possibly stands to reason that there is MORE TO DO within the joint for iPPS.BUT we are measuring % reduction finally...not absolute values...thus we need something else...BUT WE know that iPPS accumulates within the joint and in the tissues...iPPS DOES NOT accumulate in the blood...it doesn't stay there for an extended period of time....it does potentially linger or interact in the joint and in the tissues, there are studies that show this via blue (cobalt) staining to observe the path iPPS takes....and perhaps it may not stay that way in a liquid form...it may interact..proactively.
As an example, we have seen PPS acts by:
Promoting Fibrinolysis Reduces Joint Inflammation Stimulates hyaluronan fluid Stimulates proteoglycan synthesis in two ways....
1) By stimulating chondrocytes and 2) Down regulating MMP-13 Production (It's a cytokine).
Fellow Par People, the above IS DMOAD at work....008 will in my opinion demonstrate this via the biomarkers within the joint itself where the inflammatory action is at the pinnacle, the cascading and large waterfall of cytokines is at its greatest ....it may or may not result in better or the same reductions of already observed biomarkers such as COMP in our Phase 2...but it will most likely be:
1) Broad based...ie affecting a number of OA biomarkers 2) The action in scientific terms will be novel and multi disciplinary...it won't just be a simple reduction of Biomarker 1, 5 and 14 as an example...it will also be highly illustrative of just how our drug works on varying levels which is the trick to addressing a disease that affects more than just one area of the joint, it's all encompassing. 3) We will finally (my views) garner evidence at this level of trial that will show others the Disease Course modifying capabilities....it's going to be one heck of a fundamental and technical show.
Well this means that the results from 008 POTENTIALLY could be so much more comprehensive that what we observed as part of the P2b , specifically the action of reducing COMP and ADMATS-5. Yes we saw these two important bio markets reduce, I suspect that the reduction of many more bio markers will be observed within the synovium and this could make for some truly breaking news in the OA field.
Science has only just recently agreed that OA is a problem of the whole joint. Research paper after research paper mentions this 'crosstalk' between the various parts of the joint...from cell to cell...I have read things like the secretion of cells within the matrix...with the membranes...from the bones themselves...it's a whole community of cross talk...iPPS is not a band aid like applicator...it FORMS PART OF THIS COMMUNITY by interactions...we have already seen it as a binding agent...it is changing the dynamics of the underlying biology and the wonderful result is a decrease in inflammation, a thinning of the very important membrane to again allow for more nutrients to get into the joint once more and the facilitating of the body to heal itself...giving it a chance and changing the balance between evil and good as it were.
It is giving back years to the patients and improving for the very first time the actual quality of life of an OA sufferer... Yes the data that comes back at the two points, the interim and at the conclusion (early next year) will be insightful. It indeed makes sense for PAR to wait till this data is out in my view before they start talking seriously about deals or tie ups. They will just be so much more heavily armed with data simply not seen and simply not investigated before.
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Promoting Fibrinolysis
Reduces Joint Inflammation
Stimulates hyaluronan fluid
Stimulates proteoglycan synthesis in two ways....
517–521.
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