PAR and the ADP - Part 2

n Part 1 of PAR and the ADP, I investigated what WOMAC is and compared it with ADP. We also explored the Day 112 shift.

In Part 2 tonight, I present a little more information about ADP and then we will move on to a few other Protocol amendments.

As per usual, remember that I'm no scientist and these are my personal thoughts. There is no financial advice contained in any of these posts, you really need to weigh up for yourselves if this is a possible play for you.


THE ADP STUDY

Back in 2010 a study¹ was done on some 157 patients to investigate pain recall in patients, specifically pertaining to a chronic condition and even more specific to us, chronic OA pain. The study stated that in the past there were some observations that patient's recall of pain particularly at the end of the day may influence what the patient experienced earlier in the day.

The study conducted a VAS (Visual Analogue Scale) score question some 7 times during the patient's day. The patient would not be able to 'see' their prior scores so had to rely on what they felt at the time.

The study added to the prior research by contributing three new thrusts of findings, namely:

1. Previous studies had reported on pain recall but none had specifically focused on OA
2. This study focused on pain recall over only one day, most prior studies had examined pain over periods of 1 week or longer
3. This study examined whether associations between recalled and real-time pain ratings differed between weekends and weekdays, as well as according to patient characteristics including age, gender, race, study enrollment site, and pain catastrophizing (ie, the tendency to focus on and magnify pain sensations, and to feel helpless in the face of pain).

RESULTS

Well before we get to the results of this ADP study, prior studies had mixed results when examining the accuracy of patient's recall over a 1 week period or longer.


Interestingly this study found that patient recall was validated over the day.

"In this sample, we did not find evidence to support an end or recency effect, where participants’ current painlevel biased their recalled pain".
...and further..


"...the last pain rating did not seem to have an overly influential effect on participants’ recalled average of pain ratings during the day".


In summary the researchers commented:


"In summary, these results support the accuracy of single-day recalls of average pain level, particularly among patients with OA".



TRANSLATION FOR US

That's really nice Mozz, I'm very happy for you and the researchers, but how does it help us?

Well this is one of the reasons that not only PAR are adopting this pain measure but it has made it to not only a secondary but in fact it has become a PRIMARY endpoint. The entire focus of the trial is about this pain measure.

It therefore becomes vitally important that there is the ability for patients to be able to accurately record their pain, specially when it is OA pain we are talking about, specially when it is CHRONIC OA pain we are talking about.



^{Patient's recording and recall of pain - vital for PAR's P3 trial.}


Why is tis so important?

Because if iPPS works, we want this also to be accurately captured and observable via the patients' recording it. If there is a higher correlation between what the patients are recording in terms of perceived pain and actual pain, this will bode very well for us when the final results of iPPS kicks in. It will become very apparent and very observable on those charts.



PROTOCOL BACKGROUND

Ok time to move on from ADP, let's explore some of these protocol amendments. But just before we do, I want to impress upon you guys how much work has gone into even getting to this stage.

It's easy for us to say it has taken so long and PAR has over promised. But I don't see it that way. I would normally agree that it has taken this long IF WE WERE STILL BACK AT 002 Stage 2.

We are not.



We are *so* not.

We are 012.

Mozz,mate and buddy, putting an extra digit before the '2' and making it 012 does not make a compelling trial.

True, but here we are and review what we have now.

PAR took the supreme results of 008 and have proposed an update and the FDA came back WITHOUT a single word from the almighty FDA...no questions asked. No minor change....not even a typological correction!!

We are through, we have a P3 in progress. You say what you like about how long it has taken,...but there is no company in the world that has a drug that is handling (prospectively) symptomatically and structurally a possible solution n OA. But of course the informed holders in amongst us will understand that this story is just so much more than OA


It's all Pain


It's inflammation.


That's way bigger than just OA (and MPS).



But let me continue....

Protocol, background...

.
But just before we get to the protocol changes, a little background.


We know OA is a complex disease involving many structures and it certainly isn't a one size fits all. We can have cases where there is material Joint Space loss and yet there is little to no pain. We can have cases where there appears to be less BMELs and yet there is pain. On top of all of that there are confounding factors where you might be able to address it symptomatically but structurally there is no effect from a given approach or therapy or even the other way around...



"Despite the limitations as a measure for DMOAD efficacy, delay in JSN has been reported for a small number of potential DMOADs to date. However the lack of associated symptomatic benefit in these studies has prevented any of these agents from being successfully registered".²



For those that are new to us, JSN stands for Joint Space Narrowing, occurs when cartilage get depleted and the space between the bones reduces. In the worst case, it becomes bone on bone. The above quote highlights the fact of just how acutely wanted a drug like ours is. So much so that in our major Phase 3 there is no comparator.

Was this because the FDA were in a good mood?

No.

It was because there IS NO Competitor. Certainly not in the non intra articular category!

Hellloooo, don't you realise we have no other ACTIVE? It's just us and Placebo.
IF we get our P3 done, there actually is NO viable competitor. The market is huge.


To observe iPPS reducing the symptomatic effects of OA along with structural observations all within just 6 to 12 months coupled with top shelf safety profile, it is quite frankly, miraculous.


Rightio, let's tackle some other changes we read about in terms of the accepted Protocol amendments.



THE REVISED PROTOCOL

Ok so we know Day 56 has shifted out to Day 112, we aren't perturbed by this as we still have WOMAC recordings taking place.

While it isn't a change, PAR are incorporating both the meaningful (>30%) and substantial improvement (>50%) measures for both Pain and Function.

Finally, the Primary is all about pain. Now pain is important for a number of reasons and I have at least one other future post on pain that I will one day write up, though I've covered it in the past a few times. The long and the short of it is that not only is it the primary cause of suffering in OA but it has a lot of knock on effects such as the causation to accept Painkillers, and we know the nasty side effects of those to the point of some of them being addictive and even lethal.


Not only that but OA Pain can act as a surrogate.


"Worsening of TF cartilage defects and TF osteophytes on MRI, and increased pain severity could be seen as surrogate outcomes for long-term OA incidence". ³


This has major ramifications for us but we will cover that off also in a future post. (This post is going to get long even without such side topics).

Again, not strictly a change, but the inclusion of Rescue Medication will be very insightful in our P3 adding real evidence to the lowered reliance on the poor std of current care, ie NSAIDS, Corticosteroids and Opioids.


Now the big one for me is the new addition of MRI's. The big point here is that in our original 002 MRI's were included, but these were included as "Other Observables". ⁴


_{MRI's - a valuable addition to our P3.}


They were not listed as Secondaries before this point in time.. Paradigmers, they are now.

This upgrade may seem subtle but let me assure you it is in this author's view that it is so totally NOT.

To upgrade such measures is very deliberate and I believe it is as a result of the meetings that PAR had with the FDA earlier this year as a direct consequence of the results from 008.

The repercussions of this are far reaching in that as Secondaries, if they show what we saw in 008 and at Statistical Significance, then it is these such observations and findings that will make it onto the all important final label. Do that, and the prescribing Docs and their respective Associations (Think AMA) will understand that there are indeed sightings and undertones of DM. If that happens we will not only become front line but we will potentially become a profolaytic type medicine along with an interventional drug.


The consequences of this would indeed be higher coverage from payers and indeed a deeper market penetration.

A new one to the protocol list was also the addition of Work Productivity and activity (WPAI scores), again this also a secondary endpoint and will have scope for the Insurers. Cases of Workcover and the like could reduce as a result of iPPS prescriptions and the insurers would be delighted to cover iPPS in this case.

There is one more observation I want to cover from these revised protocols but that is actually so special that I need to incorporate it into a separate Part three all to itself. Apologies to make you wait but I do personally think it will be worth the wait! It blew my mind when I thought about it and I want to dedicate some decent research time an effort to do it justice.




ADDITIONAL POINTS

In Dungiven's post, he mentioned about the NRS Screening. I'm not across what exactly will be covered in the inclusion and exclusions however, we should possibly get a sense of this when 012 gets listed on the clincial.gov website possibly early next year sometime?

I do want to make a comment that it appears to me that PAR are learning as they conduct such studies. There was a marked improvement from SAS batch to batch. We also saw a big jump from 005 to 008. Considering the numbers we had in the 008 program, the results were remarkable and indeed PAR have a good grasp on how to better handle the Placebo effect, Placebo effect in pain trials are always a hard one to rein in,

To possibly answer Dungiven's thinking in this area, I would like to venture that throughout the various papers I've had the good fortune to come across, there is a real case to get IPPS early.

The best personal example I remember was the study with the Donkeys and the micro fissures in the cartilage and how they rescinded in the iPPS cohort. I won't forget that and the MPS Rats and how their snouts and trachea experience positive morphology in their juvenile and infant cartilage due to IPPS's actions.

So profound was the iPPS Donkey study that I am including an extract here for your perusal, the original post was from 9/9/23. I will publish it in full at the end of this Post.

-----------------------------------------------------------


I wasn't going to go into the images but they are too compelling....*clears throat*...ok let's do this:

Fig 1 below depicts the NON PPS group, see that big white line/crevice going all the way down to the bottom? See that number 3 I've circled in red? Well this aint good. This means the cartilage has fractured and it's gone all the way down to section 3. What the heck is section 3? The subchondral bone. The donkeys in question aren't in a good place. (That's not my opinion, thats a bl**dy fact)


Figure 1 - Control donkeys - no PPS



Please, let's go to a more cheerful place Mozz...sure, let's take a lil' look at the PPS donkeys, yeah the ones that after a few months have a bit of a skip in their stride (enthusiastic leading statement).



Figure 2 - PPS donkeys


I don't think I can express the above observation (Fig 2 above) any clearly or better than the researchers themselves, here is their interpretation of the Happy Place that the PPS donkeys found themselves in:

This is one of the clearest evidence we have at the micro level of what exactly our pentosan is capable of. I simply cannot express to you what the above means. Pentosan is literally proliferating, or at least assisting, in the growth of new cartilage !!!

----------------------------------------------------------------------------------






My point here is that iPPS's effect can potentially be magnified if you are treated early in the course of the disease. I believe this is the somewhat case in 005 -v- 008 and certainly within 005 as Dungiven alludes to by mentioning the NRS stratum.

To make it more poignant,

005 inclusion criteria was slanted to accept more patients with BMELS.

008 was less reliant on this phoneotype inclusion.

When a patient has BMELS, their OA is generally more progressed. It's the same with pain though it's not universal or absolute.

So yes, PAR has certainly learnt from these prior studies and duly built this into the patient cohorts to ensure a greater chance of success.




Watch indeed, this space!




-Mozz






PS: Watch out for Part 3....it has a novel Mozz Bonus ^®, a concept I was slow in picking up, and it was a dear friend from Perth that pointed it out to me.










REFERENCES

1] https://pubmed.ncbi.nlm.nih.gov/20096640/
2] https://pmc.ncbi.nlm.nih.gov/articles/PMC3260466/
3] https://www.sciencedirect.com/science/article/pii/S1063458423000201#:~:text=Worsening%20of%20TF%20cartilage%20defects%20and%20TF%20osteophytes%20on%20MRI,for%20long%2Dterm%20OA%20incidence.
4] https://clinicaltrials.gov/study/NCT04814719?term=PARA_OA_002&rank=1
5] https://app.sharelinktechnologies.com/announcement/asx/1b1cd12ad6777e76774be9d9954acd9f