In Part 1 we covered the basics. What is a cytokine, why is it important and how does it work?
Part 2 will cover the relevance to us and just what is this sneak peek window all about?
THE STUDY
Paradigmers, in the middle of 2017 there was a study conducted and the thing I like about this one is that it was peer reviewed.3 A little background before we get to the crux....Nitric Oxide, NO for short, is a gas that is produced when chondrocytes are in an Osteoarthritic environment. This is not new info, I have posted on it in the past.
However, what I did specifically link in those posts is that it is the increased production of NO that is partly responsible for the upregulation of interleukin 1-beta-converting enzyme (ICE) and IL-18 synthesis while decreasing the level of the ICE inhibitor PI-9.
So in Mozz terms, this NO gas not only is at least partly responsible for an increase in IL1-B but it DECREASES the IL1-B inhibitor. The best example I can liken this to is the fact that you have two types of cholesterol, the good and the bad....what you DONT want is More of the bad and at the very same time Less of the good. .. the same applies to the IL1-B in reverse....you want it to be less and you want the inhibitor of it to be more.
As another example, when I have money invested in the sharemarket, I want two things...I want unlimited upside....(ie I want to be invested in stocks that can go up with no ceiling) but I ALSO want insurance...I want limited downside. Can this be achieved? Welcome to the world of derivatives, but that's a story for another day and probably another forum if the moderators have a say.
Tell you what, if we hit that $30 plus a share...I will retire, I'll do the 2 year Financial advisor course and then we can meet one on one and we can post/chat at will...Actually I'm hoping you will do so well too from PAR that we don't need to discuss anything else whatsoever! (My spec opinions only).
So as a reminder, it is the IL-1B that has been linked as a proficient biomarker in the pathogenesis of OA and inflammation.
Furthermore from the study, there is also evidence indicating that NO plays a regulatory role in the activation of metalloproteinases in articular chondrocytes. What are metalloproteinases, they are used to break down certain matrix and non matrix proteins, you need a balance of these, too much = not good, too little = not good.
Ok so now you have the background, you have OA, you have inflammation, you get a biomarker called IL1-B as just one example of the biomarkers that are increased when inflammation, OA, is present. Now let's investigate what the study found.
We maybe can get a sneak peek into upcoming 008 results...via a study that was performed not all that long ago on some dogs...
Very simply, the study declared:
The inhibition of iNOS by it's natural inhibitors and selective agents has been shown to modulate the disease by reducing synovial inflammation and tissue damage.
Let me simplify it even more....
YOU got OA? You got Inflammation? You in pain? Stop/reduce iNOS.
How do I do that?
Take a course of iPPS (My opinions)
GRAPHICALLY...
Many students get a trifle bored of all the scientific terminology...they can't relate it to everyday activities...a graph...a picture means so much to them...
Let's take a look at the effect that was observed with PPS in terms of four mRNA expressions. Oops that was a bit technical, think of it as a resulting process from genes that can lead to some sort of change.I've drawn the red lines to show you a rough trajectory/gradient downwards as the concentration of PPS was increased:
The expression of c-Jun and HIF-1α mRNA were significantly inhibited (P < 0.05) at almost all PPS concentrations compared to the Control. However, HIF-2α mRNA remained relatively upregulated at 1, 5 and 15 μg/mL of PPS and was only significantly inhibited at 40 μg/mL compared to the Control.
Mozz speak?
Remember the belle curve? Too much PPS starts to become counter productive, or at least not as efficacious, hence why the FDA and PAR have agreed to dosing studies to start off proceedings once IND is opened. Makes sense, you want the perfect average quantity to be administered to get max bang for your buck...well for your dosing buck/amount.
Let's spend a few minutes on exploring some of those indicators above.
iNOS - we know about this, this is the effector of IL-1B via production of NO as discussed earlier in this post. C-JUN - Rightio, think of this as another type of protein (Another one!) that utilises gene coding which then in turn forms signals to regulate the expressions. Yeah it's mind boggling the complexities.4
If you want a head spin, read reference 4 below to attempt to get a better sense of this C-Jun thing. I got lost after a couple of paragraphs, think I would need a full two days with someone like Dr Ravi (our CSO) to understand it all.
But my point in going into this is that if you have too much of this (C-Jun for example), it can lead to other conditions. Some examples include Whooping Cough and other such pulmonary inflammatory conditions. There is some link with Alzheimer's potentially too. I'm not kidding when I say that there could be a relational link between iPPS one day and these other indications. Maybe 10 years from now, sure but you will still have some core holding left right? (not advice).
If you think I'm stretching it a bit too far, remember what other indications we are looking at right this minute...ARDS....Viral Arthralgia conditions....and potentially Long Covid...finally one of the main symptoms of Long Covid are low level rises in inflammatory mediators and immune cells...Here is a quote from a study not conducted in some foreign far away country, it was done in Sydney:
(LC = Long Covid, MC = Matched Controls)
"The elevated cytokines in LC and MC included a seven-to-eight-fold rise in Type I interferons, a 2-to-3-fold increase in Type III interferons and a 3.5-fold rise in interleukin-8 (or CXCL8). These remained high up to eight months."5.
Paradigmers, these increases are in cytokines. Type III interferons are antiviral cytokines in innate Immune responses.6
The next one from the above bar charts above are HIF-1a and HIF-2a, How about a Mozz story.
HIF-1a stands for Hypoxia-inducible factor 1-alpha. This little bugger is so important in growth of humans but it has also been associated heavily in some cancers and has been labelled as a "master transcriptional regulator of cellular and development response to hypoxia".7 So profound this discovery was that in 2019 it won a Nobel prize in Physiology for the scientists that discovered it.
Paradigmers , YOUR very own molecule has some positive effect against this cytokine. Proof? Check out that bar charts above. Now that's what I call story of discovery and our own story in the making.
Ok all very good Mozz, nice Bar charts trending down, that's what we like to see....but why not go one more....why not zoom in and not just tabulate figures in a bar chart...but let's go check out the innards of a cell itself! To do this we need a few things....let's draw up a shopping list.
Let's do this...
High powered electron Microscope
Dye
Those C-Jun things as well as a pinch of NFkB, some PPS and some Dog Bones (Sorry), Articular Chondrocytes
A big mixing spoon
Ok so 4) wasn't really required...
The scale we are dealing with in the below images are 20 millionths of a meter...yeah that's sorta small.We don't want just a situation where PPS localises with NFkB and c-Jun....we want a situation where they COLOCALISE.
What's the difference? Localise is to just gather in an area...colocolaise is to mix together typically within the same cell.
Now the term NFkB should ring a bell, yes that's Dr Ravi's graphic that showed us a secondary pathway. Here is a reminder, see the big black arrow.
SO we have already heard this theory before at the R&D Day...now we can SEE IT with the help of that shopping list above....A little background first to help explain what you will see.
DAPI = Is a fluorescent stain, this shows up when it mixes with certain aspects of DNA.
NFkB - This is, wait for it, another protein complex but it actually is very instrumental in the body, it controls transcription of DNA, cytokine production and cell survival.
TRITC - PPS - this is basically just PPS mixed with a dye so it can be easily seen under a microscope.
So the merged slide above occurs when colocalization occurs. It's showing us at ultra microscopic level how PPS is integrating with NFkB.
The above pic depicts the same merging of PPS and c-JUN...yes this is just part of the magic way our drug works at a cell level.
Wonderful.
SORRY MOZZ - REMIND ME - WHY DO I CARE?
Sure, why bother about cytokines...
The canine study clearly demonstrated that PPS works with NFkB to address cytokines along the pathway. Not only that but it restricts and decreases such destructive cytokines as MMP-13 which has been shown to be responsible for the promotion of cartilage degradation.
Ah this is important, not just to me...it should be important to you too....It's these cytokines that are under investigation, specially in an inflammatory sense. If we show in a trial setting that iPPS has some sort of effect on reducing them....from halting the cascading nature in the case of an OA patient like in trial 008, it will be a game changer. It will be a tipping point. It will finally lead to a DMOAD status and you get that on a label and my friends, we will have a driving impact on future sales and world wide acceptance (spec thoughts)...it will also be instrumental in getting some pre sales through before the big read out from our main trial, yes Provisional TGA application. We may only get a year or so up front sales but it will be instrumental in demand forecasting and showing us all the real potential of what we have and what is to come.
Paradigmers, there is not just one level of excitement for me here.....we aren't just addressing pain ...we aren't just giving back function. That in itself is excellent as we do it safely...but there are two more other stages:
1) The potential HALTING of this cartilage and scaffolding tissue matrix destruction...slowing it down....and 2) The ability to give the body a break so in at least SOME patients there will be an ability to repair...the balancing force between repair and regunvernation will outweigh the force of destruction and degradation. It is this DMOAD action I believe is at play with at least some % of patients, Hapell and a few others being some examples.
Thus the potential for us is three fold:
A) Repeat cohort that needs top ups annually or thereabouts
B) Patients that are one hit wonders, they just need one course of iPPS and they are done, their own bodies can take over and somewhat like Happell and a few others, well no boosters required!
C) Preemptive strike type customers that have an injury, can detect something slightly changing over time but are still early enough to get a preventative course and manage to stave off OA.
Any one of the above revenue groups in my view would be lucrative...numbers from each group would certainly be compelling over time as word spreads. My views.
SUMMARY
This canine study showed for the first time that our own PPS is a novel inhibitor of IL-1B induced iNOS. Perhaps it sounds like another language but this entails that this is one of the ways we address inflammation. I've often talked about not really having to know what's under the car bonnet, how does a gear work, what are the components of an engine and how does it all come together to make a car...well...GO!
To me its illustrative of what's to come, it gives me an insight that this isn't just randomly working, there is a mechanism of action, there are pathways and it's not just one way we address OA and inflammation, but that there are indeed several ways. That's the best bit and I think that's part of the charm, part of the the magic and yes, part of the efficacy.
(20min delay)