OA Biomarkers, 008, and the PPS MoA

You will all have seen this video before. When I first watched it I thought “hey, that looks cool” but the science was all a bit granular and, yeah, over my head. Recently though, I tried to go back and wrap my head around it a little better. I’m now going to attempt to go through it in laymans terms because I’m not the only investor here who isn’t a scientist, but I just want to have as much understanding as possible on what we own.

The video attempts to show the compounding effects ofinflammation in the knee joint which lead to a vicious cycle culminating insubsequent degradation of the joint and lots of pain – i.e. the onset of thedisease we know as Osteoarthritis. It then goes on to describe the Mechanismof Action (HOW it works) of PPS in the knee joint, as it attempts to interrupt,or even break, the cycle of the disease and it’s progression.

The video references a bunch of little molecules, enzymesand cytokines with funny names. Many of these are the biomarkers whichour 008 study will try to show PPS’s effect on. I thought it might behelpful for people to familiarise themselves with the role these little guysplay, so that if we see them being downregulated in 008, we have anunderstanding of what positives this might indicate. This might be folly,and I might make mistakes (please correct at will), but I’ll do my best.

Break the cycle of the disease:

It all starts with inflammation. Whatever wear andtear over the years, or injury (mild or severe) takes place in your knee jointsthroughout your lifetime – it will be met with inflammation. That’s anatural and often helpful response, but in our joints, it can eventuallytrigger some unwanted cumulative effects which become an ever-worsening cycle. Some of this was already known and understood by science, but some was newbreakthrough information gathered in recent years - in part by PARs own RaviKrishnan. We’ll come back to that later.

So, when inflammation occurs, pro-inflammatory cells produce“Cytokines”. Here are a couple of cytokines which we can measure: IL-B1 and TNFa

Cytokines stimulate a range of effects in our joints,including INCREASING the number of other pro-inflammatory cells being releasedinto the joint by the lining of blood vessels. This is the start of thevicious cycle. It creates a compounding effect, leading directly tofurther causes of damage.

NFkB:

This cycle of inflammation, and it’s continuous accumulationin the joint, leads to the unwelcome activation of a little molecule calledNFkB. I don’t know how it happens, but basically when he’s wearing hisblack hat he is inactive:

…and then when he takes it off, he is active, and he isdangerous.

NFkB is kind of the villain of the piece because when activehe can make his way into your cells, stimulating even more inflammatorycytokines, and also into your bone cells (Osteocytes) where he causes some new havoc.

One of the things he does, is cause the osteocytes to produce and secrete NGF (Nerve Growth Factor). This brings thePAIN.

Now, we didn’t always know that osteocytes could produce NGF– but guess what, they can. And this goes a long way to showing why PPShas been able to produce durable pain relief in OA sufferers who are treatedwith it.

Ravi Krishnan and a few close pals proved this for the firsttime, and it was peer-reviewed in 2019 and published in PLoS One.

That’s right. No-one really knew that osteocytesdirectly released NGF before. They not only figured out “a hithertounknown role for osteocytes in the pain response” but also the root-cause ofthe “mechanism for the pain benefit in KOA patients taking PPS”. Pretty cool.

Now, a quick pause, becausewe’re already seeing some things that we’d probably very much like to seesuppressed or “downregulated” by PPS in our 008 study, right? Theinflammatory cytokines such as IL-1B and TNFa which, if unchecked, kick off andperpetuate an over-inflammation in the joint. What if we could bringthose down, so they don’t knock the little black hat off NFkB? Thatsounds like it would maybe interrupt the cycle which leads to severe pain,no? Surely we’d like to see a suppressed level of the active NFkB himselftoo? That way, he wouldn’t help produce more IL-1B abd TNFa, and maybe hewouldn’t get into the osteocytes, and make them release NGF giving people theagonising pain we associate so closely with OA.

I’ll definitely be looking out for reduction in the levelsof all those guys versus placebo in preliminary 008 results.

Cartilage damage:

Sadly, this rowdy little NFkB character isn’t finishedyet. As well as stimulating a pain response in your knee, his activationalso leads to enzymes which will begin to break down the cartilage protectingthe bone in your knee join. What a prick. One of these enzymes isADAMTS-5. We don’t want to see this guy. Here is some footage ofhim causing cartilage damage…

Jokes aside, these enzymes can make the surfaces of thejoint much more vulnerable to damage. Your osteoarthritis is reallystarting to heat up now. It’s starting to go after the very integrity ofyour knee joint. Without intervention, this just gets worse and worse andworse. Your cartilage is now degenerating, and producing what the videocalls “degradation products”. These are a sign that your cartilage isbreaking down.

A couple of these degradation products are COMP andCTX-II. These are regarded among the reliable indicators of diseaseprogression in OA. These are both biomarkers which will be tracked in008, and they are both biomarkers which PPS has a record of significantlydownregulating.

As these are literally products of knee joint degradation –are lower readings of these biomarkers already evidence of diseasemodification? Well, that’s pretty exciting to think about - and we lookforward to seeing more evidence of PPS’s MoA suppressing signs of these two in008 - but it hasn’t been totally proven yet that downregulating thesebiomarkers reliably predicts positive clinical outcomes for OA sufferers. Is it “reasonably likely” though? Because that could mean AcceleratedApproval if the FDA think so.

All of this degradation in the joint, however, ultimatelyleads to further pain, further loss of function, further degradation ofcartilage, and further progression of the disease.

Watch the rest of the video, to see where PPS comesin. PPS DOES inhibit the activation of NFkB, which in turn inhibits theproduction of further pro-inflammatory genes and cytokines, reducing thesupercharged damage to the joint (as shown by the reduction of “degradationproducts” such as COMP and CTX-II), and reducing pain by impacting theproduction of NGF. Barring a shock, this will ALL be shown again in our008 results.

Science, yo.